formulation and evaluation of controlled release matrices of...

Formulation and Evaluation of Controlled

Release Matrices of Selected Propionic Acid

Derivatives

A Thesis Submitted

To

Gomal University, D.I. Khan

In partial fulfillment of the requirements for the degree of

DOCTOR OF PHILOSOPHY

(Pharmaceutics)

By

Abdul Wahab

B. Pharm.

Department of Pharmaceutics, Faculty of Pharmacy

Gomal University, D.I. Khan, KPK, Pakistan

(2006-2010)

In the name of Allah, the Most Merciful, the Most

Beneficent

“He who creates everything from nothing and

creates all things with the knowledge of what will

happen to them”

DECLARATION

I hereby declare that this Ph.D thesis entitled “Formulation and Evaluation of

Controlled Release Matrices of Selected Propionic Acid Derivatives” is my own

original piece of work and it has not been published anywhere else previously.

Abdul Wahab

Faculty of Pharmacy,

Gomal University,

D.I. Khan, Pakistan

CERTIFICATE OF APPROVAL FROM

SUPERVISOR

The thesis entitled “Formulation and Evaluation of Controlled Release Matrices

of Selected Propionic Acid Derivatives” prepared by Mr. Abdul Wahab under

my guidance in partial fulfillment of the requirements for the degree of Doctor of

Philosophy (Pharmaceutics) is hereby approved for the award of Degree of Doctor

of Philosophy in Pharmaceutics.

.

Prof. Dr. Gul Majid Khan

Research Supervisor

CERTIFICATE OF APPROVAL

This thesis entitled “Formulation and Evaluation of Controlled Release

Matrices of Selected Propionic Acid Derivatives” submitted by Abdul Wahab is

hereby approved & recommended as partial fulfillment for the award of Degree of

Doctor of Philosophy in Pharmaceutics.

1- ______________________


Research Supervisor

2- ______________________

Internal Examiner

3- ______________________

External Examiner

4- ______________________


Dean Faculty of Pharmacy

Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pkaistan

To

MY PARENTS

Whose foresight, love, zeal to educate and moral support have brought me

to the position where I am today

CONTENTS

Acknowledgement i

Objectives ii

Hypothesis ii

Specific aims ii

Abstract iv

List of Abbreviations vi

List of Figures viii

List of Tables xiv CHAPTER 1

INTRODUCTION Part-1

INTRODUCTION 1

1.1 Drug Delivery 1

1.2 Drug Delivery systems 2

1.2.1 Traditional or conventional or immediate release drug delivery systems 2

1.2.2 Modified release drug delivery systems 2

1.2.2.1 Controlled release drug delivery Systems 2

1.2.2.1.1 Reservoir or membrane controlled systems 5

1.2.2.1.2 Osmotic pump systems 6

1.2.2.1.3 Ion-exchange resins systems 7

1.2.2.1.4 Matrix tablets systems 8

1.2.2.1.5 Oral controlled drug delivery 12

1.2.2.1.6 Concepts in oral controlled release 15

1.3 Preparation of Matrix tablets 16

1.3.1 Direct compression method 17

1.3.2 Wet granulation method 18

1.4 Release mechanism of drug from matrix tablets or systems 19

1.4.1 Diffusion 20

1.4.2 Swelling 23

1.4.3 Erosion 23

1.5 Factors affecting release of drug from matrix tablets or systems 24

1.5.1 Formulation variables 24

1.5.1.1 Particle size of drug 25

1.5.1.2 Effect of drug-polymer ratio 25

1.5.1.3 Type of polymer 26

1.5.1.4 Particle size of polymer 26

1.5.1.5 Effect of fillers 27

1.5.1.6 Impact of ion-exchange resins 27

1.5.1.7 Surfactants 27

1.5.2 Process variables 28

1.5.2.1 Compression force 28

1.5.2.2 Tablets size 28

1.5.2.3 Tablets shape 28

1.6 Polymers used in the formulation of matrix tablets 29

1.6.1 Polymer 29

1.6.1.1 Polymer Ethocel® 30

1.7 Excipients 32

1.7.1 Lactose 33

1.7.2 Magnesium stearate 34

1.7.3 Methocel® 34

1.7.4 Starch 35

1.7.5 Carboxymethylcellulose (CMC) 35

1.8 Solid dispersions 36

1.8.1 Carrier used in solid dispersions 37

1.8.2 Preparation of solid dispersions 38 INTRODUCTION

Part-2 1.9 Nanoparticles 38

1.9.1 Application of nanoparticles 40

1.9.2 Polymers used in nanoparticle preparation 41

1.9.2.1 Poly (glycerol adipate) PGA 42

1.9.3 Nanoparticle preparation methods 43

1.9.3.1 Solvent Evaporation method 43

1.9.3.2 Interfacial Polymer Deposition Method (IPD) 44

1.9.3.3 Spray Drying Method 45

1.9.3.4 Salting out Method 45

1.9.3.5 Supercritical fluid expansion method 45

1.9.3.6 Complex Coacervation Method 46

1.9. 4 Drug Release Mechanisms 46

1.9.5 Methods of determination of drug release 46

1.10 Model drugs 46

1.10.1 Ketoprofen 46

1.10.1.1 General description and properties 47

1.10.1.2 History and synthesis 48

1.10.1.3 Clinical and pharmacological aspects of Ketoprofen 51

1.10.1.4 Anti-inflammatory effects 52

1.10.1.5 Antipyretic and analgesic effect 52

1.10.1.6 Mechanism of action 52

1.10.1.7 Therapeutic uses 54

1.10.1.8 Contraindications 54

1.10.1.9 Adverse reactions of ketoprofen 54

1.10.1.10 Ketoprofen interaction with other drugs 55

1.10.1.11 Pharmacokinetic of ketoprofen 55

1.10.1.12 Pharmaceutics of ketoprofen 56

1.10.1.13 Dose of ketoprofen for different disease conditions 57

1.10.2.1 General properties and description of ibuprofen 58

1.10.2.2 History and synthesis of ibuprofen 59

1.10.2.3 Mechanism of action 59

1.10.2.4 Therapuetic uses of ibuprofen 60

1.10.2.5 Pharmacokinetic of Ibuprofen 61

1.10.2.6 Contraindications 61

1.10.2.7 Adverse reactions of ibuprofen 62

1.10.2.8 Interaction of ibuprofen 62 CHAPTER 2

REVIEW OF LITERATURE

REVIEW OF LITERATURE 63

2.1 MODIFIED RELEASE FORMULATION 63

2.1.1 Polymers for modified release formulations 63

2.1.2 Development of modified release formulation 65

2.1.3 Formulation development via direct compression method 67

2.1.4 Drug release mechanism and kinetics 68

2.1.5 Ibuprofen and Ketoprofen modified release formulations 69 CHAPTER 3

MATERIALS AND METHODS Part-1

MATERIALS AND METHODS 76

3.1 MATERIALS 76

3.1.1 Chemical and reagent 76

3.1.2 Instruments and equipments 76

3.1.3 Animals 77

3.2 METHODS 77

3.2.1 Pre-formulation Studies 77

3.2.1.1 Drugs identity conformation 77

3.2.1.2 Percentage purity determination of model drugs 78

3.2.1.3 Particles size analysis 78

3.2.1.4 Selection of suitable wave length of model drugs 78

3.2.1.5 Powder‟s flow properties 79

3.2.1.6 Angle of Repose 79

3.2.1.7 Compressibility index and Hausner Ratio 80

3.2.1.8 Differential scanning calorimetry (DSC) studies 81

3.2.1.9 Fourier transform Infrared (FT-IR) studies 81

3.2.1.10 Preparation of Phosphate Buffer solutions (pH 7.4) 81

3.2.1.11 Construction of standard curves 82

3.2.1.12 Calculation of concentration of Ibuprofen and Ketoprofen 82

3.2.1.13 Solubility study 82

3.2.1.14 Preparation of solid dispersions 83

3.2.1.15 Preparation of physical mixtures 83

3.2.1.16 Evaluation of solid dispersions and physical mixtures 84

3.2.1.16.1 Determination of drug content 84

3.2.1.16.2 Differential scanning calorimetry (DSC) studies 85

3.2.1.16.3 Fourier transform Infrared (FT-IR) studies 85

3.2.1.16.4 X-ray powder diffractometory studies 85

3.2.1.16.5 Scanning electron microscope (SEM) analysis 85

3.2.1.16.6 Solubility measurement 86

3.2.1.16.7 In –vitro dissolution studies 86

3.2.2 Formulation studies 86

3.2.2.1 Formulation of matrix tablets containing Ibuprofen and ketoprofen by

direct compression method

86

3.2.2.2 Physical evaluation of matrix tablets 88

3.2.2.2.1 Weight variation test 88

3.2.2.2.2 Thickness and diameter 89

3.2.2.2.3 Crushing strength or Hardness test 89

3.2.2.2.4 Friability test 89

3.2.2.2.5 Content Uniformity Assay 89

3.2.2.3 In vitro dissolution studies 90

3.2.2.4 Drug Release kinetics 91

3.2.2.4.1 Zero-order kinetics 91

3.2.2.4.2 First-order kinetics equation 92

3.2.2.4.3 Hixon Crowel‟s Equation (Erosion model) 92

3.2.2.4.4 Higuchi‟s Squre of Time Equation (Diffusion model) 93

3.2.2.4.5 Power law equation or Korsmeyer- Peppas equation for mechanism of

drug release

93

3.2.2.5 Testing dissolution equivalency 94

3.2.2.6 Accelerated stability and reproducibility studies 95

3.2.2.7 Preparation of matrix tablets containing solid dispersions of model

drugs

96

3.2.2.8 In-vivo evaluation 96

3.2.2.8.1 Study Protocol and Design 96

3.2.2.8.2 Animals used for in-vivo studies 97

3.2.2.8.3 Food, animal housing and maintenance for rabbits 97

3.2.2.8.4 Tablets administration to rabbits 97

3.2.2.8.5 Blood sample‟s withdrawal or collection from rabbits 97

3.2.2.9 Extraction of drugs from plasma 98

3.2.2.9.1 Extraction procedure for Ibuprofen and Ketoprofen from plasma 98

3.2.2.10 HPLC analysis of drugs in rabbit plasma 99

3.2.2.10.1 Analysis of plasma Ibuprofen concentration 99

3.2.2.10.2 Analysis of plasma Ketoprofen concentration 100

3.2.2.11 Pharmacokinetic analysis 100

3.2.2.11.1 In-vitro and In-vivo correlation 101

3.2.2.12 Statistical analysis 101 CHAPTER 4

RESULTS AND DISCUSSION Part-1

RESULTS AND DISCUSSION 102

4.1 Drugs identity conformation studies 102

4.2 Particle size analysis 104

4.3 Selection of suitable wavelength for model drugs (Ibuprofen and

Ketoprofen)

105

4.4 Powder‟s flow properties 106

4.5 Differential scanning calorietry (DSC) studies 110

4.6 Fourier transform infrared (FT-IR) studies 112

4.7 Construction of standard curves 114

4.8 Solubility study 116

4.9 Preparation of solid dispersions 117

4.9.1 Solubility study of solid dispersion 118

4.9.2 Differential scanning calorimetry (DSC) studies 118

4.9.3 Fourier transform Infrared (FT-IR) studies 120

4.9.4 X-ray diffractometry studies 122

4.9.5 Scanning electron microscope analysis 124

4.9.6 In –vitro dissolution studies 126

4.10 Physicochemical Assessment of Matrix Tablets 128

4.11 In-vitro dissolution study of directly compressed matrix tablets 133

4.11.1 Effect of Ethocel® viscosity grade (Molecular weight) on drug release 133

4.11.2 Effect of drug-to- polymer (D: P) ratio on release rate 135

4.11.3 Ethocel® standard premium vs. Ethocel® standard FP premium 138

4.11.4 Influence of co-excipietns on drug release rate 140

4.12 In-vitro release study of the matrix tablets containing solid dispersions 149

4.13 Analysis of drugs release kinetics 150

4.14 Selection of the optimized test tablets 168

4.15 Reproducibility and accelerated stability study 168

4.16 In-vivo evaluation 174

4.17 In-vitro and in-vivo correlation 186 CHAPTER 5

MATERIALS AND METHODS Part-2

MATERIALS AND METHODS 189

5.1 MATERIALS 189

5.1.1 Chemical and reagent 189

5.1.2 Instrumentation and equipments 189

5.2 METHODS 190

5.2.1. Nanoparticles formulation 190

5.2.1.1 Differential scanning calorimetry (DSC) studies 190

5.2.1.2 Fourier transform Infrared (FT-IR) studies 190

5.2.1.3 Preparation of Stock Solution 190

5.2.1.4 Preparation of Empty Nanoparticles 190

5.2.1.5 Preparation of drug-loaded particles 190

5.2.1.6 Separation of free drug from nanoparticles 191

5.2.1.7 Freeze-drying study 191

5.2.1.8 Drug Release study 192

5.2.1.9 HPLC analysis of the nanoparticles 192

5.2.1.10 Preparation of standard solutions and construction of calibration curves 193

5.2.1.11 Determination of drug loading 195 CHAPTER 6

RESULTS AND DISCUSSION Part-2

NANOPARTICLES RESULTS AND DISCUSSION 196

6.1 Drug-polymer interaction studies 196

6.1.1 Differential scanning calorimetry (DSC) 196

6.1.2 Fourier transforms infrared spectroscopy (FT-IR) 198

6.2 Preparation of empty and drug loaded nanoparticles 201

6.2.1 Physical evaluation of nanoparticles 202

6.3 Drug loading 205

6.4 In-vitro drug release study 206

OVER ALL CONCLUSION 209

REFERENCES 211

LIST OF PUBLICATIONS 249

ACKNOWLEDGEMENTS

For most I am humbly obliged to ALLAH ALMIGHTY, who helps me always in every step of

my life. Salam & respect for the HOLY PROPHET MUHAMMAD (SAW), who is the real

code of the ethics.

I do wish to express my real feelings, appreciations and thanks to my supervisor and mentor,

Prof Dr. Gul Majid Khan for his continuous academic, moral and emotional support and for his

valuable advices, nice attitude and encouragement throughout my research work. Special thanks

to him for giving me the opportunity to work in his research group and for giving me the

guidance to grow into an independent researcher. He has transferred me his courage and

determination through valuable discussion and friendly dealings, which I will try to maintain.

It is a delightful moment for me to put into words all my gratitude to Dr. Paraskevi Kallinteri,

who supervised me for “Nanoparticles part of my research work” at University of KENT, UK.

I highly acknowledge the Higher Education Commission of Pakistan for granting me PhD

Fellowship and financial assistance for my research work and for my visit to UK.

I am obliged to Dr. Nadeem Irfan Bukhari, Asstt. Professor, University College of Pharmacy,

Punjab University Lahore for extending his kind co-operation in calculation of

Pharmacokinetics Parameters, Prof Dr. Nisar-ur-Rehman, Comsats Abbotabad, and Mr.

Mubasher Ali Hussain Abid & Muhammad Amir of WELSHIRE Pharmaceutical, Laboratory,

Lahore for their assistance regarding HPLC analysis of plasma samples.

I am indebted to my teachers viz. Prof Dr. Muhammad Farid Khan (Former-Vice Chancellor),

Mr. Satar Bakhash Awan, Mr. Nusrat Ullah, Mr. Anayat Ullah Bhatti, Mr. Fayaz Ahmad and

Mr. Fazal Rehman for their valuable suggestions and continuous encouragement.

My warmest thanks go to all of my friends and research fellows at the Faculty of Pharmacy,

especially to Muhammad Akhlaq, Nauman Rahim, Abid Hussain, Hroon Khan, Saif Ullah

Mehsud, Tahir Saleem Faiz, Kamran Ahamad Khan, Asium-ur-Rehman, Kafayt Ullah Shah,

Sheik Abul Rahsid, Hashmat Ullah, Asif Nawaz, Nasim Ullah, Mukhtyar, Fakhar Uddin, and

Alm Zaib for all of their cheer-ups and many unforgettable moments with them.

My deepest thanks are also for the lab and office staff viz. Ihsan Ullah Khan (Engr), Mirzali

Wazir, Mushtaq Ahamad, Asif, etc.

Words can‟t express my heartfelt appreciation to my ever loving and affectionate Daddy (Dr.

Saleem Mar Jan), Mummy, my wife, brothers (Abul Rahim Khan Mehsud and Rahim Uddin

Khan Mehsud), father-in-law (Mr. Muhammad Alam Khan Mehsood, Additional Registrar,

Gomal University), mother-in-law, cousins (Mirdil Khan, Najeeb and Falak Naz Mehsud), Dr.

Shafiullah Khan, Samiullah Khan, Sajid Anwar and all other family members for their life time

support, everlasting love, encouragement and prayers, without which I would not have achieved

my goal and to stand where I am today.

Abdul Wahab

CR Matrices of Propionic Acid Derivatives By: A.Wahab

Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page ii

OBJECTIVES, HYPOTHESIS AND SPECIFIC AIMS

Objectives

The objectives of this research work were:

To develop and evaluate controlled release matrix tablets of two commonly used

non-steroidal anti-inflammatory drugs, Ibuprofen and Ketoprofen, using

hydrophobic matrix system.

To develop solid dispersions of the model drugs (Ibuprofen and Ketoprofen).

To develop nanoparticle of Ibuprofen, Ibuprofen sodium salt and Ketoprofen.

Hypothesis

Ethylcellulose Ether Derivatives Polymers (Ethocel® standard premium and

Ethocel® standard FP premium) may produce 24 hours controlled release matrix

tablets of Ibuprofen and Ketoprofen.

Glucosamine HCl may be used for the preparation of solid dispersions to enhance

the dissolution rate and solubility of sparingly soluble drugs, Ibuprofen and

Ketoprofen.

Novel polymer poly (glycerol adipate) and its acylated derivatives may be used to

develop nanoparticles of Ibuprofen, Ibuprofen sodium salt and Ketoprofen.

Specific Aims

To perform pre-formulation studies of the model drugs (Ibuprofen and

Ketoprofen).

To prepare controlled-release matrix tablets of Ibuprofen and Ketoprofen.

To study the effect of the following variables on the release rate and release

mechanisms of the respective drugs from the test tablets.

Ethylcellulose Ether Derivatives Polymer of different viscosity grades

(Ethocel® standard premium and Ethocel

® standard FP premium).

Different Drug-to-Polymer


Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page iii

Partial replacement of primary filler (lactose) with co-excipients such as

hydroxypropylmethylcellulose (HPMC), corboxymethylcellulose (CMC)

and starch.

To determine the quality of newly developed formulations by using different

pharmacopeial and non-pharmacopeial tests.

To compare the in-vitro release profiles of the optimized test tablets of the model

drugs.

To conduct the stability studies of the selected/optimized test tablets of Ibuprofen

and Ketoprofen in ambient and accelerated conditions.

To compare the in-vitro dissolution profiles of the optimized test tablets with the

available marketed brands.

To evaluate the in-vivo pharmacokinetic parameters of the optimized test tablets

of model drugs (Ibuprofen and Ketoprofen) and compare with reference SR

tablets available in market.

To develop in-vitro and in-vivo correlation between test formulations and their

reference formulations.

To develop solid dispersions of the respective drugs.

To develop nanoparticles of Ibuprofen, Ibuprofen sodium salt and Ketoprofen.


Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page iv

ABSTRACT

Ibuprofen and Ketoprofen are propionic acid derivatives and belong to the non-steroidal

anti-inflammatory group of drugs. These are also used as analgesics, antipyretics and as

adjuncts in steroid therapy, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis,

acute musculoskeletal injury and for systematic relief of dysmenorrhea.

Due to their short half-life, dosage frequency, patient non-compliance and side effects

such as gastrointestinal disturbance, peptic ulceration and gastrointestinal bleeding, they

are considered to be good candidates for formulation into controlled release dosage

forms.

Optimization of a drug substance through the determination and/or definition of some

physical and chemical properties are mandatory in the development of stable, effective,

safe and reproducible dosage form. Therefore, during our pre-formulation work, our

efforts encompassed the detailed study of parameters such as optical rotation, melting

point, percentage purity, particle size, size distribution, solubility at different

temperatures and pH, IR spectra for conformation, λ max determination, micromeritics

properties determination of model drugs, polymers and excipients used in this research

work and interaction conformation studies of drugs with polymers and co-excipients,

using DSC and FT-IR. During this studies attention was also focused on some

contributing approaches to improve the dissolution rates of Ibuprofen and Ketoprofen,

which are sparingly soluble drugs. For this purpose solid dispersions of Ibuprofen and

Ketoprofen were prepared by solvent evaporation technique, using Glucosamine HCl as

dispersion carrier. The drug-carrier interactions were investigated through SEM, DSC,

FT-IR and X-ray diffraction analysis. The influence of proportional amount of the

carrier on the dissolution rate of Ibuprofen and Ketoprofen were also investigated. The

results obtained did not show any chemical decomposition or well defined interaction

between drugs and carrier, indicating a good compatibility among them. The solid

dispersions with Glucosamine HCl demonstrated a marked increase in the dissolution

rate and solubility of Ibuprofen and Ketoprofen. The enhancement in the dissolution

rate and solubility of Ibuprofen and Ketoprofen could be attributed to several factors

such as improved wettability, local solubilization, conversion from crystalline form to

amorphous form and drugs particle size reduction.

In Part-1 of my research work conducted at Drug Delivery Research Centre, Faculty of

Pharmacy, Gomal University, D. I. Khan, Pakistan, directly compressed controlled

release matrix tablets, using granular Ethocel® standard premium and Ethocel

® standard

FP premium were designed, prepared and evaluated in-vitro, in the first instance,

followed by in vivo evaluation of the best products. Physicochemical assessment of the

formulated tablets was performed, using different physicochemical, dimensional and

quality control tests such as weight variation, thickness and diameter, hardness test,

friability test, content uniformity, disintegration and dissolution testing. Results for all

these tests were found within acceptable range and tablets meet the pharmacotechnical

requirments. The effect of different viscosity grades of Ethocel® on the tablets


Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page v

characteristics, drug release rates, release patterns and release kinetics were

investigated. Ethocel® with lower viscosity grades showed good compressibility,

resulting in harder tablets. Particle size and amount of polymer used were found to be

the determining factors in controlling the release rates of Ibuprofen and Ketoprofen

from the tablets. The mechanism of drug release from the tablets seemed to be

changeable from formulation to formulation, depending on the amount of Ethocel® and/

particle size of the polymer used.

Our research also focused on the effect of partial replacement of primary excipient

(lactose) by various co-excipients such as hydroxypropylmethylcellulose (HPMC),

starch and corboxymethylcellulose (CMC) on the release rate and mechanism of drugs

release from the matrix tablets. All of the co-excipients used enhanced the release rates

to different extent.

In-vitro studies revealed that tablet formulations containing polymer Ehocel® standard 7

FP premium, at D: P ratio 10: 3 were the best amongst the formulations for both drugs

(Ibuprofen and Ketoprofen) because they provided better release patterns with optimum

amount of the drugs released in 24 hours; and due to their prolonged release rates with

either zero or near to zero-order release kinetics.

The optimized Ibuprofen and Ketoprofen matrix tablets formulations were further used

for in-vitro and in-vivo bioavailability-bioequivalence and stabilities studies as

compared to the comparative studies with SR Ibuprofen and Ketoprofen available in

market and stability studies. Stability studies were performed for the optimized

formulation for one year in ambient and accelerated condition and the tablets were re-

evaluated physicochemicaly at different interval of time. The results obtained showed

maximum stability for one year.

The comparative in-vitro dissolution studies showed prolonged release rate of test

formulations as 87.66% and 95.4% of Ibuprofen and Ketoprofen were release after 24

hours, respectively, while all of the drugs were released from the market SR

formulations well before 24 hours.

In-vivo studies of the optimized tablets were conducted; using HPLC based modified

methods for analysis of Ibuprofen and Ketoprofen in rabbit‟s plasma. Measured plasma

concentrations of the drugs were used in calculation of pharmacokinetic parameters

including Tmax, Cmax, AUC0-t, MRT0-t, t1/2, Vd, Vdss, Kel and Cltotal for the CR test

tablets and reference SR tables of Ibuprofen and Ketoprofen, using PK WinNolin

software. Significantly prolonged Tmax, t1/2 and MRT0-t of the test CR matrix tablets of

model drugs indicate smooth and extended absorption phase of the drugs under

investigation. As compared to reference SR tablet formulations the test CR tablets

showed better and linear in-vitro and in-vivo correlation.

In Part 2nd

of my research work conducted at the at University of KENT, UK,

Nanoparticles were also developed of the model drugs (Ibuprofen, Ibuprofen sodium

salt and Ketoprofen), which were evaluated for their capability prolonging the drug


Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page vi

realse, using a novel functionalized biodegradable polymers PGA (poly glycerol

adipate) and its acylated derivatives, such as 40% C-18 PGA and 100% C-18 PGA by

interfacial deposition method. Before development of nanoparticles, different

techniques such as DSC and FT-IR were used for determination of drug-polymer

interactions. After development of nanoparticles different physicochemical

characteristics were determined, such as zeta potential, particle size, polydispersity

index and in-vitro drug release study was conducted for 17 days. These polymers are

able to self-assemble into well-defined particles of relatively small size and high

homogeneity with an ability to entrap Ibuprofen, Ibuprofen sodium salt and Ketoprofen

with high efficiency.


Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page vii

LIST OF ABREVIATIONS

CR Controlled release

IR Immediate release

SR Sustained release

ER Extended release

API Active pharmaceutical ingredient

IBF Ibuprofen

KTP Ketoprofen

SDs Solid Dispersions

DC Direct compression

IDP Interfacial deposition

MR Modified release

NSAIDs Non-steroidal anti-inflammatory drugs

USP United states pharmacopeia

BP British pharmacopeia

RH Relative humidity

GLP Good laboratory practice

IVIVC In-vitro and in-vivo correlation

HPMC Hydroxypropylmethylcellulose

CMC Corboxymethylcellulose

HCL Hydrochloric acid

HPLC High performance liquid chromatography

MDT Mean dissolution time

MEC Minimum effective concentration


Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page viii

ICH International Commission on Harmonization

MTC Minimum effective concentration

PKa Ionization constant

UV Ultra violet

AUC Area under curve

Cltotal Total clearance

Cmax Maximum plasma concentration

Tmax Time to maximum plasma concentration

MRT Mean residence time

Kel Elimination rate constant

t1/2 Half-life

Vd Volume of distribution

H Hour

G Gram

µg Microgram

µL Microliter

Kg Kilogram

L Liter

Mg Milligram

Ml Milliliter

µm Micrometer


Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page ix

LIST OF FIGURES

Figure # Title Page #

Figure 1.1. Schematic representation of reservoir controlled system, matrix

system and osmotic system

5

Figure 1.2. Schematic presentation of drug release from reservoir or

membrane controlled drug delivery system.

6

Figure 1.3. Osmotic pump system 7

Figure 1.4. Schematic presentation of Ion-exchange resigns system 8

Figure 1.5. Schematic presentation of non-erodible matrix tablets 11

Figure 1.6. Schematic presentation of erodible matrix tablets 11

Figure 1.7. Plasma drug concentration profile Immediate Release (IR) and

Controlled Release (CR) Formulations, MEC= Minimum

Effective Concentration and MSC= Maximum Safe Concentration

13

Figure 1.8. Schematic presentation of the powder compression process using

a single punch press.

17

Figure 1.9. Presentation of release mechanisms of drug from matrix tablets 20

Figure 1.10. Idealized schematic presentation of leaching-based released

mechanism

22

Figure 1.11. Structure of ethylcellulose 31

Figure 1.12. Structure of lactose 33

Figure 1.13. Structure of Methocele (HPMC) 34

Figure 1.14. Structure of CMC 36

Figure 1.15. (A) Matrix type nanoparticles where the drug molecules are

homogenously dispersed in the matrix, (B) Core shape

nanoparticles, (C) Matrix type nanoparticles in which drug

molecules(crystals) are Imbedded in a polymer matrix.

40

Figure 1.16. Structure of PGA and acylated PGA. 43

Figure 1.17. Schematic presentation of IDP (Interfacial Polymer Deposition

method)

45

Figure 1.18. Structure of ketoprofen 47

Figure 1.19. Ketoprofen Enantiomers 48

Figure 1.20. Ketoprofen synthesized by starting from (3-carboxyl-phenyl)-2-

propionitrile

49

Figure 1.21. Ketoprofen synthesized by starting from 2-(4-amenophenyl)-

propionic acid

50

Figure 1.22. Ketoprofen synthesized by starting from (3-benzoylphenyl)-

acetonitrile

51

Figure 1.23. Prostaglandin (PGs) formation pathaway 53

Figure 1.24. Ketoprofen metabolism pathway 56

Figure 1.25. Structure of Ibuprofen 58

Figure 1.26. Ibuprofen enantionmer 59

Figure 1.27. Synthesis of ibuprofen by Boot process and Hoechst process 60


Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page x

Figure 3.1. Schematic representation of angle of repose 79

Figure 3.2. Pharma-test dissolution apparatus 91

Figure 3.3. Marginal ear vein of rabbit 98

Figure 4.1. FT-IR spectra of (a) BP Standard (b) Pure Ibuprofen sample 103

Figure 4.2. FT-IR spectra of (a) BP Standard (b) Pure Ketoprofen sample 103

Figure 4.3. Particle size distribution of Ibuprofen 104

Figure 4.4. Particle size distribution of Ketoprofen 105

Figure 4.5 UV/Visible spectra of Ibuprofen with different wave lengths in

phosphate buffer solution pH 7.4

105

Figure 4.6. UV/Visible spectra of Ketoprofen with different wave lengths in


106

Figure 4.7. DSC thermogram of pure Ibuprofen (a) and physical mixtures of

Ibuprofen with polymer ethylcellulosel, magnesium stearate,

lactose, using co-excipients; HPMC (b); starch (c); and CMC (d).

110

Figure 4.8. DSC thermogram of pure Ketoprofen (a) and physical mixtures of

Ketoprofen with polymer ethylcellulosel, magnesium stearate,


111

Figure 4.9. FT-IR spectra of of pure Ibuprofen (a) and physical mixtures of

Ibuprofen with polymer ethylcellulosel, magnesium stearate,


112

Figure 4.10. FT-IR spectra of pure Ketoprofen (a) and physical mixtures of

Ketoprofen with polymer ethylcellulosel, magnesium stearate,


113

Figure 4.11. Standard curve for Ibuprofen in phosphate buffer 7.4 114

Figure 4.12. Standard curve for Ketoprofen in phosphate buffer 7.4 115

Figure 4.13. DSC Thermograms of (a) Glucosamine; (b) Pure ibuprofen; (c)

Physical mixture; and (d) Solid dispersions of ibuprofen with

glucosamine.

119

Figure 4.14. DSC Thermograms of (a) Glucosamine; (b) Pure ketoprofen; (c)

Physical mixture; and (d) Solid dispersions of ketoprofen with

glucosamine.

119

Figure 4.15. FT-IR spectra of (a) Glucosamine; (b) Pure ibuprofen; (c)

Physical mixture; and (d) Solid dispersions of ibuprofen with

glucosamine

121

Figure 4.16. FT-IR spectra of (a) Glucosamine; (b) Pure ketoprofen; (c)

Physical mixture; and (d) Solid dispersions of ketoprofen with

glucosamine.

121

Figure 4.17. X-ray diffractograms of (a) Pure Ibuprofen; (b) Physical mixture;

and (c) Solid dispersions of Ibuprofen and glucosamine

122

Figure 4.18 X-ray diffractograms of (a) Pure ketoprofen; (b) Physical mixture;

and (c) Solid dispersions of ketoprofen and glucosamine.

122

Figure 4.19. Scanning electron photomicrographs of (a) Carrier (Glucosamine

HCL); (b) Pure Ibuprofen; (c) Physical mixture of Ibuprofen-

124


Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page xi

Glucosamine HCL; (d) Solid dispersion of Ibuprofen-

Glucosamine HCL.

Figure 4.20. Scanning electron photomicrographs of (a) Carrier (Glucosamine

HCL); (b) Pure Ketoprofen; (c) Physical mixture of Ketoprofen-

Glucosamine HCL; (d) Solid dispersion of Ketoprofen-

Glucosamine HCL.

125

Figure 4.21. In-vitro dissolution profiles of pure Ibuprofen and physical

mixture with different drug-carrier (Glucosamine HCL) ratio.

126

Figure 4.22. In-vitro dissolution profiles of pure Ibuprofen and solid

dispersions with different drug-carrier (Glucosamine HCL) ratio

127

Figure 4.23. In-vitro dissolution profiles of pure Ketoprofen and physical

mixture with different drug-carrier (Glucosamine HCL) ratio.

128

Figure 4.24. In-vitro dissolution profiles of pure Ketoprofen and solid

dispersion with different drug-carrier (Glucosamine HCL) ratio.

128

Figure 4.25. Release profile of Ibuprofen from Ethocel®

matrices with

different viscosity grades and D: P ratio of 10:3.

134

Figure 4.26. Release profile of Ketoprofen from Ethocel®

matrices with

different viscosity grades and D: P ratio of 10:3.

134

Figure 4.27. Release profiles of Ibuprofen from Ethocel® standard 7 premium

and Ethocel® standard 7 FP premium matrices with different D: P

ratios.

135

Figure 4.28. Release profile of Ibuprofen from Ethocel® standard 10 premium

and Ethocel® standard 10 FP premium matrices with different D:P

ratios.

136

Figure 4.29. Release profiles of Ibuprofen from Ethocel®

standard 100

premium and Ethocel®

standard 100 FP premium matrices with

different D: P ratios.

136

Figure 4.30. Release profiles of Ketoprofen from Ethocel® standard 7 premium

and Ethocel® standard 7 FP premium matrices with different D: P

ratios.

137

Figure 4.31 Release profiles of Ketoprofen from Ethocel®

standard 10



different D:P ratios.

137

Figure 4.32. Release profiles of Ketoprofen from Ethocel®

standard 100



different D: P ratios.

138

Figure 4.33. Release profiles of Ibuprofen from Ethocel® standard 7, 10 and

100 premium and Ethocel® standard 7, 10 and 100 FP premium

matrices with D: P ratio 10:3.

139

Figure 4.34. Release profiles of Ketoprofen from Ethocel® standard 7, 10 and

100 premium and Ethocel® standard 7, 10 and 100 FP premium

matrices with D: P ratio 10:3.

140

Figure 4.35. Influence of partial replacement (30%) of lactose with various co- 143


Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page xii

excipients (HPMC K100M, CMC and Starch) on release profiles

of Ibuprofen from tablets containing Ethocel® standard 7 premium

with D: P ratio, 10:3.

Figure 4.36. Influence of partial replacement (30%) of lactose with various co-


of Ibuprofen from tablets containing Ethocel®

standard 7 FP

premium with D: P ratio, 10:3.

143




standard 10


144




standard 10 FP


144




standard 100


145



of Ibuprofen from tablets containing Ethocel® standard 100 FP


145

Figure 4.41. Figure 4.41 Influence of partial replacement (30%) of lactose with

various co-excipients (HPMC K100M, CMC and Starch) on

release profiles of Ketoprofen from tablets containing Ethocel®

standard 7 premium with D: P ratio, 10:3.

146



of Ketoprofen from tablets containing Ethocel®

standard 7 FP


146




standard 10


147



of Ketoprofen from tablets containing Ethocel® standard 10 FP


147


excipients (HPMC K100M, CMC and Starch) on release profile


standard 100


148


Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page xiii

Figure 4.46. Figure 4.46 Influence of partial replacement (30%) of lactose with

various co-excipients (HPMC K100M, CMC and Starch) on

release profile of Ketoprofen from tablets containing Ethocel®

standard 100 FP premium with D: P ratio, 10:3.

148

Figure 4.47. Comparative dissolution release profile of Ibuprofen and

Ibuprofen solid desperisons from matrix tablets containing

Ethocel® standard 7 FP premium polymer.

149

Figure 4.48. Comparative dissolution release profile of Ketoprofen and

Ketoprofen solid desperisons from matrix tablets containing

Ethocel® standard 7 FP premium polymer.

150

Figure 4.49. Drug-release profiles for Ibuprofen from test and reference tablets

up to 24 hours.

173

Figure 4.50. Drug-release profiles for Ketoprofen from test and reference

tablets up to 24 hours.

173

Figure 4.51. A representative chromatogram of standard solution consisting of

5µg/mL of Ibuprofen

175

Figure 4.52. A representative chromatogram of Ibuprofen extracted from a

sample of rabbit plasma spiked with 10µg/mL of Ibuprofen

176

Figure 4.53. A representative chromatogram of Ibuprofen extracted from a

sample of rabbit plasma with drawn 4 hours after administration

of Ibuprofen Test tablet.

177

Figure 4.54. A representative chromatogram of standard solution consisting of

5µg/mL of Ketoprofen

178

Figure 4.55. A representative chromatogram of Ketoprofen extracted from a

sample of rabbit plasma spiked with 10µg/mL of Ketoprofen

179

Figure 4.56. A representative chromatogram of Ketoprofen extracted from a

sample of rabbit plasma with drawn 4 hours after administration

of Ketoprofen Test tablet

180

Figure 4.57. Standard curve for Ibuprofen in plasma. 181

Figure 4.58. Standard curve for Ketoprofen in plasma. 181

Figure 4.59. Mean plasma concentration of Ibuprofen from test tablets and

reference tablets (n=12).

182

Figure 4.60. Mean plasma concentration of Ketoprofen from test tablets and


183

Figure 4.61. Percent of drug absorbed (Fa, Y-axis) plotted against percent of

drug released (Fr, X-axis) at times 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10,

12, 18 and 24 hours to show the In-vitro and In-vivo correlation of

Ibuprofen Test tablets

187




Ketoprfofen Test tablets

187

Figure 4.63. Percent of drug absorbed (Fa, Y-axis) plotted against percent of 188


Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page xiv



Ibuprofen Reference tablets




Ketoprofen Reference tablets

188

Figure 5.1 Size Exclusion Chromatography column packed with Sepharose

4B-CL. Column length ~24 cm, diameter 16 mm

191

Figure 5.2 Viva spine Concentrator tubes 192

Figure 5.3 Standard curve for Ibuprofen 193

Figure 5.4 Standard curve for Ketoprofen 194

Figure 5.5 Standard curve for Ibuprofen sodium salt 194

Figure 6.1 DSC thermograms of (a) PGA polymer, (b) Ibuprofen-polymer

(PGA), (C) pure Ibuprofen.

196

Figure 6.2 DSC thermograms of (PGA polymer), (b) Ketoprofen-polymer

(PGA) mixture, (c) pure Ketoprofen.

197

Figure 6.3 DSC thermograms of (a) Ibuprofen sodium salt-Polymer (100%

PGA C-18) mixture, (b) Ibuprofen sodium salt-Polymer

(40%PGA C-18) mixture, (c) Ibuprofen sodium salt-Polymer

(PGA C-18) mixture, (d) Ibuprofen sodium salt pure.

198

Figure 6.4 FT-IR spectra of (a) PGA polymer, (b) Ibuprofen-polymer (PGA)

mixture, (c) pure Ibuprofen.

199

Figure 6.5 FT-IR spectra of (PGA polymer), (b) ketoprofen-polymer( PGA)

mixture, (c) pure Ketoprofen

200

Figure 6.6 FT-IR spectra of (a) Ibuprofen sodium salt-Polymer (PGA C-18)

mixture, (b) Ibuprofen sodium salt-Polymer (40%PGA C-18)

mixture, (c) Ibuprofen sodium salt-Polymer (100%PGA C-18)

mixture, (d) pure Ibuprofen sodium salt.

201

Figure. 6.7 Average drug contents on each plolymer 206

Figure. 6.8 The release behavior of various formulations (the results are the

mean and standard deviation of three determinations).

207

Figure. 6.9 The release behavior of various formulations (the results are the

mean and standard deviation of three determinations).

208


Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page xv

LIST OF TABLES

Table # Title Page # Table 1.1. Advantages and disadvantages of direct compression method 18 Table 1.2. Advantages and disadvantages of wet granulation method 19 Table 1.3 Application of matrix for drug delivery systems 25 Table 1.4. Polymer used in the matrix tablets 30 Table 1.5. General properties of Ethocel

® Standard polymers 31

Table 1.6 Different grades of Ethocel® and their physical properties 32

Table 1.7. Ketoprofen dosage forms, route and strength 57 Table 1.8. Dose of ibuprofen 62 Table 3.1. Angle of repose and flow properties according to B.P 2007 80 Table 3.2. Compressibility Index and Hausner Ratio limits according to B.P

2007. 81

Table 3.3. Composition of solid dispersions and physical mixtures Ibuprofen 84 Table 3.4. Composition of solid dispersions and physical mixtures of

Ketoprofen 84

Table 3.5. Different matrix tablets composition of Ibuprofen 87 Table 3.6. Different matrix tablets composition of Ketoprofen 88 Table 3.7. Interpretation of release exponent “n” in power law for release

mechanism of different geometries 94

Table 3.8. Dosing Schedule design of test tablets and reference tablets for

pharmacokinetics study 96

Table 4.1. Results of identity conformation tests 102 Table 4.2. Percentage purity of Ibuprofen and Ketoprofen 103 Table 4.3. Micromeritics or flow properties of pure Ibuprofen and

formulation blends 108

Table 4.4. Micromeritics or flow properties of pure Ketoprofen and

formulation blends 109

Table 4.5 Absorbance and concentration of Ibuprofen for different dilutions 114 Table 4.6. Absorbance and concentration of Ketoprofen for different

dilutions 115

Table 4.7. Solubility of Ibuprofen in different solvents at different

temperatures 116

Table 4.8. Solubility of Ketoprofen in different solvents at different

temperatures 117

Table 4.9. Solubility data of different Ibuprofen and Ketoprofen

formulations 118

Table 4.10. Physicochemical characteristics of Ibuprofen controlled release

matrices 131


Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page xvi

Table 4.11. Physicochemical characteristics of Ketoprofen controlled release

matrices 132

Table 4.12. Different kinetic models applied to determine the release profile of

controlled release matrices of IBF consisting Ethocel

Sandard

Premium polymer of different viscosity grade, (meanSD of three

determinations)

152



Standard FP

Premium polymer of different viscosity grades, (meanSD of three

determinations)

153



Standard

Premium polymer of different grades and co-excipient HPMC

K100M, (meanSD of three determinations)

154



Standard FP

polymer of different grades and HPMC K100M, (meanSD of

three determinations)

155



Standard

Premium polymer of different grades and co-excipient Starch,

(meanSD of three determinations)

156



standard FP

polymer of different grades and co-excipient Starch, (meanSD of

three determinations).

157



Standard

simple Premium polymer of different grades and co-excipient

CMC, (meanSD of three determinations)

158



standard FP

polymer of different grades and co-excipient CMC, (meanSD of

three determinations).

159


controlled release matrices of KTF consisting Ethocel

simple

Premium polymer of different grades , (meanSD of three

determinations

160



FP polymer

of different grades, (meanSD of three determinations)

161

Table 4.22. Different kinetic models applied to determine the release profile of 162


Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page xvii


simple

Premium polymer of different grades and co-excipient HPMC

K100M, (meanSD of three determinations)



stand FP

polymer of different grades and co-excipient HPMC K100M,


163

Table 4.24 Different kinetic models applied to determine the release profile of


Standar

simple Premium polymer of different y grades and co-excipient

Starch, (meanSD of three determinations)

164



Standard

FP 7, 10, 100 polymers of different grades and co-excipient Starch,


165



standar

Simple Premium polymer of different grades and co-excipient

CMC, (meanSD of three determinations)

166



FP polymer

of different grades and co-excipient CMC, (meanSD of three

determinations)

167

Table 4.28. Stability indicating parameters (drug content, weight variation,

friability, hardness, % release after 24 hours and appearance) for

Ibuprofen matrices in ambient conditions (25oC and RH 65%)

170



Ibuprofen matrices in accelerated conditions (40oC and RH 75%)

171



Ketoprofen matrices in ambient conditions (25oC and RH 65%)

171



Ketoprofen matrices in accelerated conditions (40oC and RH 75%)

171

Table 4.32. Difference factor ƒ1 and Similarity factor ƒ2 calculated for

Ibuprofen controlled release matrix tablets, while comparing their

dissolution profile at different time intervals with dissolution

profile at zero time (pre-storage) during stability study

172

Table 4.33. Difference factor ƒ1 and Similarity factor ƒ2 calculated for

Ketoprofen controlled release matrix tablets, while comparing their

dissolution profile at different time intervals with dissolution

profile at zero time (pre-storage) during stability study

172


Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page xviii

Table 4.34. Pharmacokinetic parameters for Ibuprofen, following oral

administration of 300mg Reference and 300mg Test tablets of

Ibuprofen to two separate groups of rabbits (Mean±SD, n=12)

184

Table 4.35. Pharmacokinetic parameters for Ketoprofen, following oral

administration of 200mg Reference and 200mg Test tablets of

Ketoprofen to two separate groups of rabbits (Mean±SD, n=12)

185

Table. 6.1 Physical characteristics (size, polydispersity index and zeta

potential) of empty and drug loaded nanoparticles prepared from

various polymers by interfacial deposition method.

204


Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 1

Part-1

CHAPTER 1

INTRODUCTION

Efforts and Struggles of humankind to eradicate disease date back to early civilization.

To treat abnormalities of physiological life processes, pain and discomfort, natural

substances have been used. With the advancement of science, active ingredients of these

materials (the drug) were isolated and identified. Later on their mechanism of action was

determined. Now-a-days new drug candidates are used to treat diseases as effective tools.

Drug activity is the result of molecular interaction(s) in certain cells. It is necessary for

drug molecules to reach somehow the site of action after administration (oral, parenteral,

transdermal, etc.) at a sufficient concentration to show proper action. The scientific field

dealing with this issue is known as drug delivery.

1.1 Drug Delivery

“It is the process or method of administering active pharmaceutical ingredients (APIs) to

achieve a therapeutic or pharmacological effect in humans or animals” (Drug delivery,

2010; Ravi, 2008). Drug delivery today is at leading age of product development and

pharmaceutical science. Historically, the drug delivery field concentrated on introducing

and creating new forms of already established drugs. Now-a-days, drug delivery is being

used as a method or process of product life cycle management to prolong the product life

in market by providing improved version of drugs, as patents are getting ready to expire

(Definition, 2010). Drug delivery techniques or technologies are patent protected

formulation technologies which are used for the modification of drug release pattern,

absorption, distribution and elimination. Due to these technologies product safety,

efficacy and patient compliance are improved (Drug delivery, 2010; Ravi, 2008).

Basically the aim of the drug delivery is, to deliver the drug at right place, at the right

concentration for the right period of time. To achieve a safe and effective drug

concentration in body tissues, different drug delivery systems are developed.



1.2 Drug Delivery Systems

The drug delivery systems can be defined as “Systems for the delivery of drugs to target

the sites of pharmacological actions” (Drug delivery systems, 2010). The systems in their

own are not pharmaceutically active, but improve the safety and efficacy of the active

pharmaceutical ingredients that they carry.

The goal of the drug delivery systems is to deliver the specific amount of APIs to site of

action for attaining proper therapeutic response in the body (Gibaldi, 1997; Chiao et al.,

1995; Shargel et al., 2005; Aulton, 2002).

1.2.1 Traditional or conventional or immediate release drug delivery systems: These are

the systems which are characterized by rapid and unresrictracted drug release rates and

kinetics, usually leading to abrupt increase of drug concentration in body tissues followed

by a similar decrease, that may causes a dangerous approach to the toxic threshold or fall

down below therapeutic level (Grassi and Grassi, 2005).

1.2.2. Modified release drug delivery systems: These are the drug delivery systems in

which modification of the rate, site or kinetic behavior of release of active pharmaceutical

ingredients takes place for the achievement of specific therapeutic objectives. It cannot be

achieved with conventional dosage form similarly administered. These systems include

targeted drug delivery systems, delay or repeated drug delivery systems, prolonged or

extended drug delivery systems (e.g. controlled release, sustained release and long acting

dosage forms (Khan, 2007).

1.2.2.1. Controlled release drug delivery Systems: For many decades, treatment of

chronic diseases and acute illness has been accomplished by delivering drug to patient via

different types of pharmaceutical dosage forms, like tablets, capsules, injectable,

suppositories, syrups, creams, gels, etc. To achieve and maintain the drug concentration

within the effective therapeutic range, it is often necessary to take these dosage forms

(drug delivery systems) several times a day which may result fluctuations and saw-tooth



effects in drug blood levels and consequently undesirable toxicity and poor efficacy. Due

to these and other factors, like unpredictable absorption lead to the development of

controlled drug delivery systems (Tripathi, 2003; Chien, 1992).

Recently for controlling the rate of drug delivery, extending the duration of therapeutic

activity and/or targeting the delivery of drug to the tissue several technical advancements

have been made. For these systems various terminologies are used such as controlled

release, sustained release, prolonged release, time release etc. The term controlled release

implies to the reproducibility and predictability in drug release kinetics. This means that

the release of drugs from drug delivery systems proceeds at a rate profile that is not only

predictable kinetically but also reproducible from one unit to another (Tripathi, 2003;

Chien, 1992).

Two important aspects are included in the objectives of controlled release drug delivery

systems, namely spatial placement and temporal delivery of a drug. Spatial placement

deals with the targeting of a drug to a specific organ or tissue, while temporal delivery

relates to controlling the rate of the drug to the targeted tissues.

Controlled release drug delivery systems include any drug delivery system that “achieves

slow release of a drug over extended period of time” if the system can provide some

control wether of spatial or temporal in nature. In general controlled release drug delivery

attempts to:

1. Prolong drug action at a predetermined rate by maintaining a relatively constant

and effective drug levels in the boy with concomitant minimization of undesirable

side effects with a valley and peak kinetic profile.

2. Provide local drug action due to spatial placement of controlled release drug

delivery system adjacent to or in the diseased organ or tissue.

3. Targeting drug by using carriers or chemicals (Lee and Robinson, 1987).



The basic rationale for controlled drug delivery systems is to change the

pharmacokinetics and pharmacodynamics of APIs by modifying the molecular structure

and/or by using novel drug delivery systems.

Controlled release formulation can be classified as follow (Chiao et al., 1995; Shargel et

al., 2005; Aulton et al., 2002; Ansel et al., 2005; De Haan and Lerk, 1984; Caramella,

1995; Chien, 1985; Sala et al., 1997).

Reservoir systems or membrane controlled systems including:

enteric coated tablets,

coated granules,

capsules, and

microcapsules

Osmotic systems

Ion-exchange resins

Matrix tablets systems

Matrix system can be further classified as:

1. Inert monolithic matrix tablets system

2. Solvent activated matrix tablets system

The solvent system can be further sub-divided into the following two types

Gel- forming hydrophilic matrix tablets.

Erodible hydrophobic matrix system tablets.



These systems are shown in the following figure (Fig.1.1).

Figure 1.1 Schematic Representation of Reservoir Controlled System, Matrix

System and Osmotic system

1.2.2.1.1. Reservoir or membrane controlled systems: these systems are prepared with a

drug reservoir in which the API is either dispersed as solid particles, or as solution that

has been encapsulated by an outer rate controlling polymeric membrane that is usually

semipermeable membrane (Chiao et al., 1995; Aulton, 2002; Chien, 1985; Katz et al.,

1995; Imandis et al., 1998).

The reservoir systems are different from matrix systems because in these systems the

membrane does not erode and swell on hydration with passage of time (Chiao et al.,

1995; Aulton, 2002; Chien, 1985; Katz et al., 1995; Imandis et al., 1998). The rate of

drug release from these systems is first controlled by interfacial partitioning of the drug



from the reservoir into the membrane or by matrix controlled process (Chiao et al., 1995;

Aulton, 2002; Chien, 1985; Katz et al., 1995; Imandis et al., 1998).

The schematic presentation of drug release from reservoir systems is shown in the Fig.

1.2 (Reservoir, 2010; Rumiana and Assen, 2006).

Figure 1.2 Schematic presentation of drug release from reservoir or membrane

controlled drug delivery system.

The reservoir containing drug is encapsulated with a polymeric membrane through which

drug is released by means of diffusion. Constant or zero order release is mostly occurred

as shown in the Fig. 1.2.

1.2.2.1.2. Osmotic pump systems: These systems can be used as an alternative to

reservoir or membrane controlled systems. However, the energy source in these systems

which pushes the drug out of the systems is either, due to the drug properties or other

osmotic pressure generating substance included in the systems (Chiao et al., 1995;

Aulton, 2002; Chien, 1985; Katz et al., 1995; Imandis et al., 1998; Thombre et al., 2004;

Makhiji and Vavia, 2003).

In these systems the drug or active pharmaceutical ingredients are incorporated into water

soluble tablet core and then it is coated with semipermeable membrane (Chiao et al.,

1995; Aulton, 2002; Chien, 1985; Katz et al., 1995; Thombre et al., 2004).



The membrane used in these systems has the properties that only water can penetrate to

the tablet core, which dissolves the drug or active pharmaceutical ingredients or energy

producing source. It creates hydrostatic or osmotic pressure with in the delivery device,

which is used for the release of drug from the dosage form (Chiao et al., 1995; Aulton,

2002; Chien, 1985; Katz et al., 1995; Thombre et al., 2004).

Due to the diffusion of water into the device the release of drug from the system occurs

on the basis of an osmotic potential difference between the interior and exterior of the

device. In this case a constant drug release will occur until the concentration of drug or

energy producing source falls below saturation levels (Chiao et al., 1995; Aulton, 2002;

Chien, 1985; Katz et al., 1995; Thombre et al., 2004). The schematic presentation of drug

release from these systems is shown in Fig. 1.3, which shows the release of drug through

an opening in the coating following permeation of solvent into the device.

Figure 1.3 Osmotic pump system

1.2.2.1.3. Ion-exchange resins systems: These are the systems in which active

pharmaceutical ingredient or drug is bound to ion-exchange resins and forms a drug-



resin complex (Chiao et al., 1995; Aulton, 2002; Chien, 1985; Amsel et al., 1984; Anand

et al., 2001).

The resins which are used to form the backbone of drug delivery systems are cross-linked

water insoluble polymer containing the salt forming functional groups of anionic and

cationic nature which are repeated across the polymeric chain (Chiao et al., 1995; Aulton,

2002; Chien, 1985; Amsel et al., 1984; Sriwongjanya and Bodmeir, 1998). The release of

drug molecules from these systems take place by ion exchange in the gastrointestinal

tract and the drug molecules are allowed from drug-resins complex for dissolution

(Chien, 1985; Amsel et al., 1984; Anand et al., 2001).

The cross sectional diffusional area of these systems play a vital role to controlled the

rate and extant of drug release (Chiao et al.,1995; Aulton, 2002; Chien, 1985; Amsel et

al.,1984; Anand et al.,2001). A Schematic presentation of these systems is shown in Fig.

1.4 (Amsel et al., 1984).

Figure 1.4 Schematic presentation of Ion-exchange resigns system.

1.2.2.1.4. Matrix tablets systems: The term “matrix” indicates a three dimensional

network, more often polymeric, design and prepared for specific and particular



application containing APIs and other substances such as solvent and excipients

(Rumiana and Assen, 2006). These systems, due to low production costs and robustness

are the most commonly used type of controlled drug delivery systems, as controlled

release technology evolved with matrix technology and several articles in the 1950s and

1960s reported simple matrix tablets or monolithic granules (Nandita and Sudip, 2003;

Controlled-release, 2010). In 1952, Smith Kline and French introduced the first time

released formulation with the name of “Spansule” that launched a wide spread search for

other applications in the designs and of dosage forms or drug delivery systems (Helfand

and Cowen, 1983).

A matrix system is simply a homogenous mixture of drug particles within a polymer

matrix, often manufactured by simple direct compression method. Among the oral

controlled release technologies, matrix systems have often prominent popularity because

of low costs, simplicity, ease in manufacturing, high level of reproducibility, stability of

raw materials and dosage form, easy to scale-up and process validation. Controlled

release product development has made much easier then before because of the

technological advancements in the area of matrix formulation. It is reflected by large

number of patents filed each year and commercial success of different novel drug

delivery systems based on matrix technologies. The different types of matrix tablet

systems are further explained and reviewed.

Inert monolithic matrix tablets system: It is the simplest method to obtain an oral

sustained or controlled release dosage form, in which the drug is incorporated in

an inert matrix (Rowe, 1975). As the name indicates inert means non-interacting

with the biological fluids. The application of inert polymer tablets matrix dates

back to the mid 1950s, when the first matrix tablets containing soluble powder of

drug and the non-toxic , strong and coherent structure of resin was introduced

(Tablet and Method, 1959). Since the introduction of plastic matrix tablets these

preparations have gain considerable use.



During its passage through GIT these matrix tablets do not undergo disintegration

process like conventional tablets but remain intact and the skeleton can be

recovered in the faeces. The materials used in the preparation of these matrices

are mostly insoluble inert polymers and lipophilic materials. The first polymers to

be used for the preparation of matrix tablets were semi-synthetic polymers such as

polyethylene, polyvinylchloride, polymethyl methacrylate, polystyrene, polyvinyl

acetate, cellulose acetate, and ethylcellulose. The fat compound used such as,

carnauba wax, hydrogenated castor oil, and tristearin (Caramella, 1995). Now-a-

days research in this area focuses on natural biopolymers such as cellulose and

starch derivates, some of which can be consider semi-inert (ethycellulose).

Solvent activated matrix tablets: It is a collective term which is used for the

systems in which the interaction between polymer and water is responsible for

achieving controlled release. The interaction of polymer with water may include

plasticization, swelling, erosion or degradation of the polymer. The solvent matrix

tablets are used as a method to achieve a zero- order release, which was first

proposed by Hopfenberg (Hopfenberg and Hsu, 1996).

Depending on the nature of retarding or polymeric materials, the matrix system can be

also be divided into the following two types.

Gel-forming hydrophilic matrix tablets: These are gel-forming hydrophilic or

swellable heterogamous or homogenous systems in which the APIs are dispersed

in swellable hydrophilic polymer. Hydrophilic polymer forms a gel layer when

contacts with a liquid, which is essential for sustaining and controlling of drug

release from the matrices.

Gel-forming hydrophilic matrix tablets are plasticized by gastric fluid after

ingestion and then volume expansion and macromolecular chain relaxation take

place. Release of drug is governed by diffusion of the dissolved drug through the

swollen gel layer and generally shows a burst effect and leaching of drug

molecules present at the surface prior to formation of release-controlling gel.

Erodible hydrophobic matrix tablets: In erodible hydrophobic matrix tablets the

drugs are incorporated or dispersed in erodible hydrophobic materials. Release of



drug molecules from these systems is governed by erosion of the polymeric

materials

The schematic presentation of the drug release from erodible and non erodible matrix

tablets is shown in Figs.1.5 and 1.6 (Reservoir, 2010; Rumiana and Assen, 2006).

Figure 1.5 Schematic presentation of non-erodible matrix tablets

Figure 1.6 Schematic presentation of erodible matrix tablets



Fig.1.5 shows drug release from non-eroding matrix tablets. The drug is initially

dispersed in the matrix system, at time t=0 has 100% in the dosage form, and after

administration at time t=t some of the drug has been released and erosion of system has

accorded.

In contrast of drug release from non-eroding systems, the release from erodible systems

or tablets depends on the erosion or degradation of the polymeric materials, in which the

drug is dispersed or incorporated to achieve constant release rate as shown in the Fig. 1.6.

1.2.2.1.5. Oral controlled drug delivery: The majority of drug substances exist as

crystalline or amorphous powders. A delivery system is required to deliver the drug to the

action of site, effectively, safely and reliably. For the delivery of these substances

different routes are used like oral route, parental, rectal transdermal etc.

The oral route is the most frequently route for administration of drugs. Tablets form by

far the majority oral dosage form (Van der, 1997). Important reasons for their popularity

are the ease of their preparation on industrial scale and their convenience of application

(patient compliance). The majority of oral tablets formulations are presented in

conventional or immediate release (IR) dosage forms. Drugs administered with an IR

dosage forms exhibit fluctuations in plasma concentration of a drug, peaks and then

declines due to multiple dosing of the said dosage forms.

The use of multiple dosing with immediate release (IR) dosage forms has several

limitation, including the requirement that the patient follows a strict dosing regimen in

order for optimum therapeutic benefits to be achieved (Chiao et al., 1995; Shargel et al.,

2005; Aulton, 2002; Ansel et al., 2005).However, the need to adhere rigidly to a dosing

regimen often lead to non compliance and some time doses are missed. Thus the desired

therapeutic effects or outcomes are affected (Chiao et al., 1995; Shargel et al., 2005;

Ansel et al., 2005).

Doses frequency may lead to maximum toxic concentration and result in unwanted side

effect whereas, due to infrequent dosing sub-therpeutic level of drug in blood is achieved



(Chiao et al., 1995; Shargel et al., 2005; Aulton, 2002; Ansel et al., 2005). As low patient

adherence, more side effect and fluctuations in drug concentration following

administration of IR dosage forms lead to the development of controlled release

formulations. A hypothetical blood-level-time curve obtain after administering immediate

release dosage form and controlled release dosage form depicted in Fig. 1.7 (Nandita and

Sudip, 2003).

Figure 1.7 Plasma drug concentration profile Immediate Release (IR) and

Controlled Release (CR) Formulations, MEC= Minimum Effective Concentration

and MSC= Maximum Safe Concentration.

Oral controlled release dosage forms overcome the drawbacks of traditional or IR

formulations. As compare to IR formulations or dosage forms controlled release (CR)

tablets are not associated with alternating periods of toxic levels and sub-therapeutic

concentrations, and thereby improving the therapeutic efficacy and avoid side effects



(Saks and Gardner, 1998). This makes the controlled drug delivery systems suitable

especially for drugs which have plasma peaks levels associated with unwanted side

effects and for those which have short elimination half life. The reduce side effects and

lower dosage frequency of controlled release (CR) tablets shows more comfort, improved

patient compliance and more reliable tablets intake which is of special important for

those patients who are instructed to follow chronic medication regimen (Saks and

Gardner, 1998; Richter, 2004). The controlled drug delivery has the following advantages

over convention dosage forms.

Improved patient convenience and compliance due to low dosage frequency.

Reduction in fluctuation in steady-state and therefore better control of disease

condition and reduce intensity of systemic side effects.

Safety margin of high potent drug increased due to better control of plasma levels.

Maximum amount of drug is utilized because of reduction in total amount of dose

administered (Brahmankar and Sunil, 2001).

Furthermore, controlled release dosage forms have the capability to reduce

hospitalization cost because self administration is relatively easy.

Using controlled drug delivery, many pharmaceutical products available in market and

new molecular entities can be delivered in such a ways that not only improve its efficacy

and safety, but in some cases may improve its therapeutic procedures. As it is believed

that for improvement of therapeutic responses modification in release profile of a drug is

an effective method.

When feeling the need for novel oral controlled release technologies of delivery systems,

the time and cost associated with the process of drug development should be considered

and kept in mind. To introduce a new chemical entity (NCE) drug into market, mostly

takes more then 10 years and development costs more than 600-800 million dollars

(Malick, 1998). Due to huge costs and more time consumption on the development of

NCE drugs, the pharmaceutical industries believe in line extensions or modification of

existing products. The development costs and risks associated with line extensions are

lower as compare to NCE drugs. Line extensions based on advanced controlled release



systems or technologies may provide patent protection, which is an important point from

a product life cycle management point of view. For the generic pharmaceutical industries

controlled drug delivery or technology because of cheap excipient and low manufacturing

costs may provide to develop bioequivalent generic product at low costs as compared to

high priced originators.

Because of the above mentioned market drivers, the demand of safe, reliable and novel

controlled release drug delivery systems is continuously increasing.

1.2.2.1.6. Concepts in oral controlled release technologies: The driving force and idea

behind oral controlled release technologies is that with help of this technology plasma

levels of the drug can be optimized by controlling the delivery of drug from controlled

release dosage forms into gastro-intestinal tract (GIT). Control can be achieved by

developing simple sustained release formulations which release the drug at a specific rate

over a predetermined period of time. For those drugs which are inherently short acting, a

useful and reliable prolongation of pharmacological effect is sufficient and on the basis of

this idea many controlled drug delivery systems were developed in the 1980s.

As controlled release drug delivery systems provide a specifically designed dissolution

profile of the drug from the dosage forms, therefore for displaying the desire profile and

control over the drugs‟ absorption into the systemic circulation, different physicals and

chemicals approaches are applied to develop and produce such delivery systems (Qiu and

Zhang, 2000).

Some of the systems include: Insoluble, slowly eroding or swelling matrices; polymer

coated tablets, pellets, or granules; osmotically driven systems; systems controlled by ion

exchange mechanisms and various combinations of these approaches (Saikh et al., 1987a;

Saikh et al., 1987b; Tahar et al., 1995; Charman and Charman, 2002; Jeong and Park,

2008). Oral modified release (controlled release) formulations can be classified into



different ways. One is to differentiate between single unite dosage forms such as tablets

and capsules and the other one is multi-particulate dosage forms, like pellets or beads.

Among the oral controlled release technologies, matrix systems have often prominent

popularity because of low costs, simplicity, ease in manufacturing, high level of

reproducibility, stability of raw materials and dosage form, easy to scale-up and process

validation. Controlled release product development has made much easier then before

because of the technological advancements in the area of matrix formulation. It is

reflected by large number of patents filed each year and commercial success of different

novel drug delivery systems based on matrix technologies.

1.3. Preparation of Matrix tablets

A tablet can be described as an aggregate of smaller particles, which are strongly adhere

to each other. A large number of developments in the field of pharmaceutical ingredients,

the tablet machines have made tablet manufacturing a science and the tablets a most

favorite dosage form (Rasenak and Muller, 2002). Tablets are versatile drug delivery

systems, which are easy to manufacture and convenient to use (Chiao et al., 1995; Ansel

et al., 2005; Armstrong et al., 2002). The tablets possess relatively good stability

properties as compared to other pharmaceutical dosage forms such as suspension,

solutions (Jivraj et al., 2000).

There are three methods which are used for the preparation of tablets such as direct

compression (DC), and compression following wet granulation or dry granulation.

Generally there are three basic steps, which are involved in the preparation of tablets, viz.,

die filling, compression and the ejection and all these steps are shown in the Fig. 1.8

(Aulton et al., 2002; Banker and Rhodes, 1990).

The successful manufacture of tablets depends on appropriate balance between a brittle

fracture and plastic behavior within a formulation mix. These are dependent on the



compression characteristics of excipients and the APIs that are blended together to

achieve a particular uniform and acceptable dosage form (Armstrong et al., 2002; Jivraj

et al., 2000; Hiestrand et al.,1977; Imbert et al.,1997; Venkatesh et al.,1998).

Figure 1.8 Schematic presentation of the powder compression process using a single

punch press.

1.3.1. Direct compression method: The term direct compression refers the manufacturing

process, in which the tablets are compressed or compacted directly from powder blends

of drug and excipients without further manipulation (Aulton et al., 2002; Ansel et al.,

2005; Augsburger, et al., 2002; Gohel, 2005). In wet granulation method there is

granulation before compression, while in DC no granulation is required. It is easier than

wet granulation as fewer unit operations are used (Aulton et al., 2002; Ansel et al., 2005;

Augsburger, et al., 2002; Gohel, 2005). However, to avoid the formulation failure of this

method due to its simplicity some critical aspects, such as compressibility and flowability

the materials are seriously considered. As this method has some advantages and



disadvantages which are listed in the table 1.1 (Aulton et al., 2002; Ansel et al., 2005;

Augsburger, et al., 2002; Gohel, 2005).

Table 1.1 Advantages and disadvantages of direct compression method

Advantages Disadvantages

1. Fewer unit operations

2. Anhydrous process

3. No drying procedures

4. Faster dissolution rates achieved

5. Fewer excipients may be required

6. Economical

1. Particles segregations

2. APIs contents may be limited

3. Unsuitable for poor flowing APIs

4. Static charges on drug may lead to

5. Not applicable to low bulk density

materials

1.3.2. Wet granulation method: Wet granulation is a method of tablets preparation, in

which APIs are mixed with excipients and appropriate binding solution to form

agglomerate. From this agglomerate larger, multi-particulate entities called granules are

formed (Aulton et al.,2002; Augsburger et al.,2002; Wauters et al.,2002; Lister et

al.,2001; Iverson et al.,2001; Badway et al.,2000). In manufacturing of tablets by wet

granulation method, granulation is often an important step as segregation of the

components of the powder may be prevented or minimized by the formation of granules.

These granules also provide better flow properties to poweder blend (Aulton et al., 2002;

Augsburger et al., 2002; Wauters et al.,2002; Lister et al.,2001; Iverson et al.,2001;

Badway et al.,2000). As compared to the individual powder constituents of a blend

granules posses better compressibility and flow properties (Aulton et al., 2002;

Augsburger et al., 2002; Faure et al., 2001). The process of granules formation or

preparation can be divided in to three broad categories, such as wetting, nucleation and

consolidation and growth followed by attrition and breakage (Lister et al., 2001; Iverson

et al.,2001; Faure et al., 2001). During granules formation the wetting or nucleation stage

of granules starts when a binding solution or agent is brought into contact with the

powder materials to be granulated to form a nuclei (Lister et al., 2001; Iverson et al.,

2001; Faure et al., 2001). Then consolidation or granules growth starts after collision



between granules. The final stage attrition occurs as a result of wet or dried granular

materials fracturing or crumbling due to impact of wear or compaction and subsequent

powder handling throughout the manufacturing process (Lister et al., 2001; Iverson et al.,

2001; Faure et al., 2001). Like direct compression method this method also has some

advantages and disadvantages which are listed in table 2 (Aulton et al., 2002; Augsburger

et al., 2002).

Table 1.2 Advantages and disadvantages of wet granulation method

Advantages Disadvantages

1. Reduces air entrapment

2. Enhances fluidity and compatibility

3. Suitable for high does drugs

4. Reduces cross contamination and dust

5. Permits handling of powder without

loss of blend quality

6. Enhances wettability of an API

7. Drug stability and distribution during

drying

1. Each unit process adds complications

2. Large numbers of unit processes

3. Increases the problems and possible

operator errors

4. Difficult to control and validate

5. Potential adverse effects of

temperature

6. More costly than DC

1.4. Release mechanism of drug from matrix tablets or systems: The knowledge of drug

release mechanism is an important part of drug development process, because factors

affecting the drug release may vary and depending on the drug release mechanism of

drug delivery systems.The release mechanism of drug from different matrix systems is

different. The most important drug release mechanisms are diffusion, swelling,

dissolution, erosion and combination of dissolution and erosion. As shown in the Fig. 1.9

(Polymer for oral, 2010).



Figure 1.9 Presentation of release mechanisms of drug from matrix tablets

1.4.1 Diffusion: The release of drug from a porous monolithic matrix system or matrix

tablets is via leaching or diffusion mechanism (Fig. 1.10). The dispersed particles of drug

in the hydrophobic polymer matrix dissolve in the gastro-intestinal fluids and then release

of these particles take place from the matrix tablets by diffusion through already existing

porous network of pores and those pores which are formed by the dissolution of drug

particles(Qiu and Zhang, 2000; Crowley et al.,2004; Pohja et al.,2004). If drug loading is

increasing approximately 10-15%, a continuous structure forms and connecting all

particles (percolating drug network). If drug loading is lower then a proper fraction of the

drug may be surrounded by the polymer matrix (trapped fraction). In this case incomplete

release of drug would take place.

Higuchi and his co-workers developed a model for release mechanism of drugs from a

homogenous ointment base (Higuchi, 1961). However, modification in higuchi model

enabled the predication of drug release from a porous matrix tablets or systems with

connecting capillaries (Higuchi, 1963).



M = [Ds Ca (2C0 - Ca) t]1/2

(1.1)

where:

M is the amount of drug released per unit surface area

P is the porosity of the matrix

t tortuosity

Ca solubility of drug in release medium

C0 total amount of drug in a unit volume of matrix

DS diffusion co-efficient in release medium

The porosity factor (p) was introduced to correct for the volume fraction of the matrix

that is filled with water. The tortuosity factor (t) was required for further correction for

increase of the diffusional pathway of the drug in the porous structure.

Similarly, for pseudo- steady state (C0>>CS), where Cs, is the saturated concentration of

drug with in the matrix.

M = [2Ds Ca C0 t]1/2

(1.2)

As porosity is the matrix fraction existing in the form of channels or pores, through which

the surrounding liquid can penetrates.

For the purpose of the data treatment the equation (1.1) above can be reduced to:

M= k t1/2

(1.3)

Where k is a constant, if the release of drug from matrix system is diffusion controlled,

then the amount of drug release versus square root of time will be linear.

Tremendous studies have been performed to analyze the release mechanism of drug using

the Higuchi model of drug release (Desai et al., 1965; Fessi, 1978; Gurny et al., 1982;

Hernandez, 1994; Dabbagh, 1996).

The Higuchi model was actually developed for planar diffusion, but later on Korsmeyer

and Peppas introduced a simple exponential equation for describing the release



mechanism from other geometries, such as slabs, spheres and cylinders (Korsmeyer et al.,

1983).

Q = ktn (1.4)

Where Q (Mt/M∞) is fractional release, k constant n is the diffusional exponent. For

characterization of different release mechanisms, n value can be used (Costa and Sousa,

2001).

In the case of cylindrical, the exponent n has value of 0.45 for Fickian diffusion ( leading

to square root of time release kinetics), if n has value from 0.45 to 0.89 than it shows

non-Fickian anomalous transport (leading to first order release kinetics), if n value 0.89

shows non-Fickian case-II transport (leading to zero-order kinetics)

Figure 1.10 Idealized schematic presentation of leaching-based released mechanism (Bakker, 1987).

Water soluble drugs are released mainly by diffusion with a partial in put from erosion

while the anomalous diffusion results from the relaxation of the macromolecular polymer

chains (Melia, 1990).



1.4.2. Swelling: Drug release mechanism controlled by swelling is not easy process

because of macromolecular changes, such as chain relaxation and volume expansion take

place in polymer during release. Mostly, this release mechanism takes for those

controlled release systems in which water soluble drugs are dispersed in glassy polymer

matrices, such as HPMC (Colombo, 1993; Narasimhan, 2000).

When the polymeric matrix contacts with water or liquid, then swelling of polymer

occurs and the polymer changes from glassy state to rubbery state, forming a gel layer.

This process is also termed as the glassy-to-rubbery state transition of the polymer (Ju et

al., 1995; Karali et al., 1990). At this stage the core of the tablets remains essentially dry.

After formation of a gel layer, the dissolved drug can be transported because of increase

mobility of the polymeric chains. In case of a highly soluble and large dose drugs, burst

release takes place because of the presence of drugs on the surface of the matrix tablets.

The gel layer plays a rule to control additional water penetration and matrix

disintegration. The gel layer formation and drug dissolution is controlled by various

factors, such as water penetration, swelling, drug dissolution and diffusion, and matrix

erosion (Colombo et al., 1996; Colombo et al., 2000). The gel layer thickness and rate at

which forms can modify the release kinetics of the drug (Kanjicckal and Lopina, 2004).

As with the increase of the proportion of the polymer in the tablet matrix, gel formed

reduces the diffusion of the drug and prolong the erosion of the matrix (Ford et al., 1985).

1.4.3. Erosion: Mostly this release mechanism takes place in those systems in which the

drug disperses in hydrophilic polymeric matrix. Matrices swell and followed by polymer

and drug dissolution when contact with water or gastro-intestinal fluid. However, erosion

of the gel or polymer dissolution rate is faster than the diffusion of the drug in the gel

layer (Ford et al., 1987; Lee, 1985).

The erodible hydrophilic matrix, containing poorly water-soluble drugs, the release rate

can be controlled either by erosion or diffusion of the drug through the gel layer, but in



case of water-soluble drugs it can be controlled by erosion of the gel (Ford et al., 1985a;

Ford et al., 1985b; Lee, 1985).

Moreover, the strength of the gel layer impacts drug release. The matrices containing low

viscosity grade polymers lead to erosion release mechanism and zero-order kinetics

(Zuleger and Lippold, 2001), while those matrices containing high viscosity grade

polymers or high amounts of polymers are stable. In this case polymer dissolution is

negligible and drug release is primarily by Fickian diffusion following square root of

time kinetics (Zuleger and Lippod, 2001; Katzhendler et al., 1997; Pharm and Lee, 1994).

More often the release of drug occurs by both diffusion and erosion, leading to

anomalous transport (Zulger and Lippold, 2001).

Erosion is the major release mechanism for insoluble drugs, apart from their dose

(Rajabi-Siahboomi and Jordan, 2000; Li et al., 2005). There are two types of matrix

erosion mechanism, surface erosion and bulk erosion (Kanjickal and Lopina, 2004).

Those polymers which contain highly reactive functional groups (e.g. polyanhydrides)

undergo faster degradation than diffusion of water in the matrix, leading to surface

erosion. However, polymers with less reactive functional group, such as PLGA, undergo

bulk erosion.

1.5. Factors affecting release of drug from matrix tablets or systems

Factor affecting the release of drugs from matrix tablets are categorized in to two groups,

viz., formulation variables and process variables.

1.5.1. Formulation variables: In the preparation or formulation of the matrix systems,

the physicochemical characteristics of a drug, especially its solubility in water should be

considered before processing. Some recommendations are given in the table (Qiu and

Zhang, 2000). Apart of these other properties of drug affecting matrix systems include

drug stability in the system and at the site of its absorption, particles size, specific area

and pH dependent solubility of drug.



Table 1.3 Application of matrix for drug delivery systems.

Matrix systems Drug Release mechanism Drugs not recommended

Hydrophilic

Swellable / erodible

Erodible

Diffusion/Erosion

Erosion

Very soluble

Freely soluble

Hydrophobic

Monolithic

Multi-particulate

Erodible / Degradable

Diffusion

Diffusion

Erosion/Enzymatic

degradation

Practically insoluble

Freely soluble

1.5.1.1. Particle size of drug: In the case of moderately soluble drugs the effect of

particle size on the release mechanism of drugs from matrix systems or tablets is

important, because particle size greatly influences the release of drugs from matrices. As

diclofenac sodium particle size showed great effects on the release mechanism and rate

from HPMC tablets (Velasco et al., 1999). Depending on the penetration of dissolution

medium through the matrix tablets the particle of smallest size dissolve easily and

diffuses quickly through the matrix, while the larger particles are dissolved slowly and

are more prone to erosion at the matrix surface. Similar observations were shown in case

of less soluble drug, indomethacin (Ford et al., 1985).

1.5.1.2. Effect of drug-polymer ratio: Drug-polymer ratio has great effect on the release

of drugs from matrix tablets, as increase of drug-polymer quantity reduces the release rate

of drug from a system. Hydroxypropylmethylcellulose containing diclofenac sodium

showed a decreased release rate when the polymer and drug ratio was increased (Velasco

et al., 1999). This decrease in release rate was because of an increase in polymer

concentration and subsequently increases in viscosity of the gel and formation of the gel

layer with a longer diffusion path. Similar findings were observed by other researchers;

as in case of water soluble drug metoprolol decreased diffusional rate was observed with

increasing amount of HPMC (Rekhi et al., 1999).



By varying the polymer level, different drug release profile is observed. As different

metoprolol release profiles were observed by varying the Methocel K4M value (Nellore

et al., 1998). Similar observations were observed by Sung et al., as a wide range of drug

adinazolam mesylate release rate was observed when HPMC and lactose ratio was

changing (Sung et al., 1996).

1.5.1.3. Type of polymer: Polymer type is another factor which has an influence on the

release of drug from matrices. As different types of polymers are used for preparation and

formulation of extended release matrices, such Hydroypropyl methylcellulose (HPMC),

ethyl cellulose, eudragit etc. Each polymer is available in different grades, such as

different grades of HPMC are available, with different proportion of the hydroxypropyl

and methoxyl substitutions. Faster hydration takes place with increasing the amount of

hydrophilic hydroxypropyl groups as, Methocel®

K > Methocel®

E > Methocel® F. For

highly soluble drugs more hydrating grade of HPMC, methocel® K is preferred, because

for highly water soluble drug rapid hydration rate is necessary, as inadequate hydration of

polymer may lead to dose dumping because of fast penetration of gastric fluid into the

tablets core (Dow Pharmaceutical, 1996) The viscosity of the different grades of a

polymer also has an influence on the diffusion and mechanical properties of matrix

tablets. Higher viscosity gel layers showed a more tortuous and resistant barrier to

diffusion which resulted in slower release of a drug (metoprolol HCl) (Nellore et al.,

1998).

As ethyl cellulose is used for the preparation of extended release matrices. The low

viscosity grades of ethyl cellulose are more compressible than the higher viscosity

grades. The matrices formulated with low viscosity grades resulting in harder and slower

release matrix tablets (Katikaneni et al., 1995; Shileout and Zessin, 1996; Upadrashta et

al., 1993).

1.5.1.4. Particle size of polymer: Polymer particles size has the impact on the release of

drugs from matrices. According to a study conducted on the release rate of diclofenac

sodium from HPMC, decreased release rate of diclofenac sodium was observed as there

was an increase in the particle size of HPMC (Velasco et al., 1999). According to one



another study, that in the case of polymer ethyl celloluse, that the characterization of

tablets prepared of polymer with different particle sizes revealed different release

profiles, using different particle sizes showed that the porosity of the tablets increased

with increase of particle size of polymer and resulted in faster drug release due to

increase porosity (Katikaneni et al., 1995).

1.5.1.5. Effect of fillers: Different fillers are used for increasing the volume of tablets.

These are having influence on the release of drugs from matrix tablets. Neullore et al

studied the influence of filler on the release rate of metoprolol matrix tablets containing

polymer methocel® K4M. They observed that filler solubility has an effect on the release

rate. A decreased release profiles of about 5-6 % after 6 hours was observed when the

filler was changed from lactose-microcrystalline cellulose to dicalcium phosphate

dehydrate (Nellore et al., 1998). According to another study, replacing the filler 100%

dicalcium phosphate dehydrate with 100% lactose showed an increase in metoprolol

release from matrix tablets containing methocel® K100LV(Sung et al.,1996).

1.5.1.6. Impact of ion-exchange resins: Ion-exchange resins can be used in the

formulation of matrix tablets as release modifiers. According to the study conducted by

Sriwongjanya and Bodmeier (Sriwongjanya and Bodmeier, 1998).They studied the

release of cationic drug propranolol from matrix tablets of HPMC containing drug

without resin, drug-resin complex and drug-resin physical mixture. They concluded

fastest release from a formulation free of resin.

1.5.1.7. Surfactants: The use of surfactants in the formulation of matrix tablets has the

influence on the release of drug. To study the effect of surfactants on the release rate of

drug from HPMC tablets Feely and Davis conducted a study, and they characterized the

ability of charged ionic surfactants to delay the release of oppositely charge bearing

drugs, such as chlormpheniramine maleate, sodium alkylsulphates, sodium salicylate and

cetylpiridinium bromide from HPMC containing tablets (Feely and Davis, 1988).



1.5.2. Process variables

The process variables, such compression force, tablet shape, table size have also effect on

the release of drug from matrix tablets.

1.5.2.1. Compression force: The compression force has a minimum effect on the release

profile of tablets but it has a significant effect on the hardness of matrix tablets. As

according to velasco and his colleagues that compression had a significant effect on the

hardness and minimal effect on the release of drug from HPMC tablets (Velasco et al.,

1999). According to their assumption that this change is due to relationship between

porosity of tablets and compression force. The less influence of compression force on the

release of drug from matrix tablets is due to that there is no dependency between the

porosity hydrated matrix tablets and initial porosity. The same observation were observed

by Rekhi and his colleagues that change in compression force or crushing strength

showed to have a low effect on the release of drug from matrix tablets of HPMC (Rekhi

et al.,1999).

1.5.2.2. Tablets size: Size of matrix tablets has also an influence on the release of drug, as

Siepman and his colleagues observed that tablets size has an impact on the release rate of

drug from matrix tablets. According to them the release of drug from matrix tablets of

different size, such as small, medium and large after 24 hours was, 99.8%, 83.1% and

50.9%, respectively. As according to them the maximum release from small tablets was

due to higher surface area and diffusion pathway. The diffusion pathways for small

tablets were smaller as compared to larger tablets (Siepmann et al., 1999).

1.5.2.3. Tablets shape: Like other process variables tablets shape has also impact on the

release of drug. According to Rekhi and his colleagues that the drug dissolution rate of

those matrix tablets which are undergoing diffusion and erosion mechanism is affected by

the size and shape (Rekhi et al., 1999). As according to their observations, 20-30%

increase in the dissolution rate of metoprolol tartrate tablets formulated with methocel®

K100LV was observed at each time point after the modification in the surface area from



concave shape to caplet shape. On the basis of these observations they suggested that for

possible lowest release the shape of the matrix tablet should be near to spherical.

Karasulu and his colleagues also studied the effect of shape on the release of drug

(Karasulu et al., 2000). According to another study conducted by Siepman and his

colleagues that the release rate of drug from flat shape was higher than regular shaped

cylinders with same volume. According to them, the difference in the release was due to

the difference in the surface area of the tablets (Siepmann et al., 1999).

1.6. Polymers used in the formulation of matrix tablets

1.6.1. Polymer: As the name indicates it is the combination of two Greek words “poly”

means many and “meros” means units/parts, so polymer is a compound or large molecule

which is formed by the combination of large number of simple small units or molecules

(monomers) (Polymer, 2010). The chemical reactivity and polymer properties depend on

the chemistry of the monomers and on the assembly of the monomers which are put

together (Jain, 2006). For the last few years, Polymer science has been the back bone for

the development and preparation of new dosage forms. Moreover, due to its

advancement, it has several applications in pharmaceutical sciences and used as coating

agent, adhesive, adjuvant, emulsifying agent and suspending agent, encapsulating agent,

drug carrier, thickness or viscosity enhancers, stabilizers, disintegrates, solubilizers,

gelling agents and bioadhesives (Udeala and Aly, 1998; Guo et al.,1989). For temporal or

spatial control of drug delivery polymeric systems are mostly intended to achieve (Jain,

2006). The different polymers which are used for the formulation of matrix tablets are

shown in table (1.4).



Table 1.4 Polymer used in the matrix tablets (Caramella, 1995; Ford et al., 1985a;

Korsmeyer and Peppas, 1981; Venkatraman et al., 2000).

Polymers Characteristics

Ethylcellulose, Polyethylene, Polyvinyl chloride,

Mehtyl-acrylate-methacrylate co-polymer, etc. Hydrophobic, inert

Carnauba wax: Stearyl alcohol, stearic acid,

polyethylene glycol.

Castor wax: Polyethylene glycol monostearate

Triglycerides, polyanhydrides,etc.

Hydrophobic, erodible

Methyl cellulose, Hydroxy propylmethyl cellulose,

Sodium carboxy methyl cellulose, Carboxy

polymethylene, Sodium alginate, carbopols, etc.

Hydrophilic

In line with scope of the present study, the Ethylcellulose derivative, Ethocel® will be

discussed in detail.

1.6.1.1. Polymer Ethocel®: Polymer ethocel

® is ethylcellulose derivative and

ethylcellulose is an ethyl ether of cellulose. It is commercially available, inert polymer

used widely for the preparation of matrix tablets of water soluble and poorly water

soluble drugs (Saikh et al., 1987a; Saikh et al., 1987b; Rekhi and Jambhekar, 1995). It is

also used in tablets technology as binder and hydrophobic coating agent for tablets and

graules (Desai et al., 2001; Chowhan, 1980; Sadeghi et al., 2001). It is also used in the

preparation of microcapsules and microspheres (Desai et al., 2001). It is also used for the

preparation of modified release matrix formulation (Pollock and Sheskey, 1996). Ethyl

cellulose derivatives, such as Ethocel® polymers are colorless, odorless, tasteless and

noncaloric. They have outstanding chemical and physical properties as shown in table

1.5.



Table 1.5 General properties of Ethocel® Standard polymers (Majewicz et al., 2002;

Ethocel, 2010).

Chemical names: Cellulose ethyl ether, ethyl ether of cellulose.

Chemical formula: C12H23O6 (C12H22O5) n C12H23O5

R= H or C2H5

Figure 1.11 Structure of ethylcellulose

Where “n” can be vary to provide a wide variety of molecular weights. Ethylcellulose is

available with different particle sizes, in different qualities. It is insoluble in water but

soluble in organic solvents, such as ethanol, ispropanol, metylene chloride, acetone etc.

Ethocel® standard premium and Ethocel

® standard FP premium are the two derivatives of

the Ethylcellulose which are used in the present study. Bothe these derivatives have have

different grades, used in the prepration of controlled release formulations.

Appearance White powder

Odor Odorless

Taste Tasteless

Density (bulk), g/cm3, Ethocel 0.3-0.4

Specific gravity, g/cm3 1.12-1.15

Melting point, 0C 165-173

0C

Refractive index 1.47



Table 1.6 Different grades of Ethocel® and their physical properties (Ethocel

premium, 2010).

Name of polymer Average particle

size (µm)

Viscosity

(cp)

Ehylcellulose

(%w/w)

Ethocel® standard premium 7 310 7 48.0-49.5

Ethocel® standard FP premium 7 6.1 7 48.0-49.5


Ethocel® standard FP premium 10 9.7 10 48.0-49.5

Ethocel® standard premium 20 ---- 20 48.0-49.5

Ethocel® standard premium 45 ---- 45 48.0-49.5


Ethocel® standard FP premium 100 41 100 48.0-49.5

As according to Khan and Zhu JB, that Ethocel® standard premium is the conventional

granular and Ethocel® standard FP premium is the newel finally milled form of

ethylcellulose and due to this property it is allowing the use of direct compression to

incorporate into the controlled release dosage forms (Khan and Zhu, 2001). Fine particle

ethylcellulose has shown a better efficiency as a release retarding matrix former (Agrawal

et al., 2003).

1.7. Excipients

According to International Pharmaceutical Excipients council, excipients can be defined

as “any substance other than the active pharmaceutical ingredient or prodrug that is

incorporated in the manufacturing process or is contained in a finished pharmaceutical

dosage form (Excipient, 2010). As excipients have been traditionally included or used in

different dosage forms as inert substances mainly to make up volume and help in the

manufacturing process. Mostly they are used in different dosage forms to fulfill the

specialized functions for improving drug delivery (Carien et al., 2009). According to

USP Pharmacopeia, the excipients are categorized, as binder, disintegrants, diluents,

lubricants, glidants, emulsifying agents, solubilizing agent, sweeting agent, coating agent,



and so forth. Moreover, the excipients should be stable, chemically inert, non-reactive

with drug and other excipients in the formulation. Different excipients, with different

names are available in the market, but in line with the scope of the present work, the

lactose, Magnesium stearate, Methocel®

(Hydorxyporpymethycellulose), starch,

Corboxymethycellulose, which are used as filler, lubricant and co-excipient, respectively,

will be discussed in detail.

1.7.1. Lactose: It is the most commonly used excipient which is used in tablets

technology as filler. It is a natural disaccharide found in milk, formed from galactose and

glucose. The name lactose is the combination of two Latin workds “lac” means milk and

“ose” means sugar, so it is also called milk sugar. Lactose was first dicoverd by Fabricci

Bartoletti in 1619 in milk and later on in 1980 Carl Wilhelm Scheele idintified it as sugar

(Linko, 1982). The gernal properties (Lactose, 2010) are given as follow:

Chemical formula: C12H22O11 (MW= 342.30)

Chemical name: 4-O-β-D-galactopyranosyl-D-glucose

Melting point: 222.8 0C

Figure 1.12 Structure of lactose

Mostly it is available in two isomeric forms alpha and beta, either in crystalline or

amorphous form (Tablets ingredients, 2010).



1.7.2. Magnesium stearate: It is a fine, impalpable white powder with a characteristic

metallic test and faint odour of stearic acid. It is widely used in, tablets and capsules

formation as lubricant at a varying concentration ranging from 0.25% to 5.0% w/w. It is

listed as non-toxic compound, but taking orally in large quantity may lead to laxative

effect because of mucosal irritation. It is stable compound and is non-reactive and

compatible with strong acids, alkalis and iron salts, but with product containing aspirin

and alkaloidal salts magnesium stearate can not be used (Rowe, 2003).

1.7.3. Methocel®: It is the propriety name for the methylcellulose derivative that is also

known as hydroxypropylmehtylcellulose (HPMC) or hypromellose. It is a mixed alkyl

hydroxyalkyl cellulos etiher containing methoxy or hydroxy group. Its hydration rate

depends on hydroxypropyl content. As with the increase in the hydroxypropyl content the

hydration rate also increases. Its solubility is pH independent (Deppa et al., 2008). It is

stable with in a wide pH range and resistant to enzymatic degradation (Hardy et al.,

2006). It has the chemical name cellulose, 2-hydroxypropy methyl ether. It is widely

accepted pharmaceutical excipient because of its availability in different molecular

weights and the effective control of gel viscosity is easily possible (Alderman, 1984).

Figure 1.13 Structure of Methocele (HPMC)

General structure of HPMC containing methoxyl (CH3-O-) and hydroxypropoxyl

(CH3CHOHCH2-O-) substituents. Where the R-group can be single or combination of

substituent. HPMC is white or creamy white, tasteless and odorless fibrous or granular



powder. It is non-toxic and non-irritating but ingestion in large quantity may lead to

laxative effect (Rowe, 2003). It is mostly used in the preparation of tablets and capsules

as coating agent, binder and modifier to control or extend the release of drug (Saha et al.,

2001). It is available in different viscosity grades, but higher viscosity grades are being

used in different concentration to retard or extend the release of a drug from tablets or

capsules. The viscosity of the polymer depends on the number of constituents on the

polymeric backbone and the length of the cellulose chain. Three viscosity grades of

HPMC (Methocel®

K100M, K15M and K4M) are used in the formulation of extended

release matrix (Ford, 1999). Due to its gelling property because it form diffusion and

erosion-resistant gel layer on hydration which is able to control drug release (Vasques et

al.,1992; Sung et al.,1996; Siepmann et al.,1999). This gel layer acts as a barrier

especially for high water soluble drugs. As on exposure to water it forms a gel layer and

retard the release of drug and the release of drug from these systems is due to Fickian

diffusion and matrix relaxation and erosion (Saha et al., 2001).

1.7.4. Starch: It is white stable powder. It is also known with different names such as,

soluble starch, corn starch, tapioca starch, amyldextrin, amylopectin, amylum, arrowroot

starch and etc. It is slightly water soluble, its melting point is around 250 0

C, but it

decomposed before its melting point is reached. It is represented with chemical formula

(C6H10O5)n. It is incompatible with strong oxidizing agent (Starch, 2010). Mostly two

types of starch viz., partially pre-gelatinized and fully pre-gelatinized starch is used as

binder, disintegrant and filler. The partially pre-gelatinized starch used as binder and

disintegrant while the fully pre-gelatinized starch loses its disintegrating properties and

only acts as binder (Tablet ingredients, 2010).

1.7.5. Carboxymethylcellulose (CMC): It is free flowing white to off white powder,

stable under ordinary condition and soluble in water. It has a melting point of 274 0C. It is

also called carboxymethyl ether (CMC, 2010; Corboxy methyl cellulose, 2010).



Figure 1.14 Structure of CMC

At low concentration CMC structure is rod-like, but at higher concentrations it entangles

to become a thermoreversible gel like structure because of overlapping and coiling up of

its molecules. It is more soluble in cold water and mostly used for controlling viscosity

without gel formation, due to this property it is used as thickener, emulsion stabilizer and

suspending agent (Corboxy methyl cellulose, 2010).

1.8. Solid dispersions

Solid dispersions (SDs) are defined as a range of pharmaceutical products with one or

more active ingredients homogenously dispersed in an inert carrier or matrix in a solid

state, prepared by the melting, solvent or melting-solvent methods (Damian et al., 2000;

Ford, 1986; Craig, 2002; Sethia and Squillante, 2003; Kauahal et al., 2004).

SDs are divided according to their physicochemical characteristics into three different

types. A broad distinction can be made based on the physical state of the drug within the

system, i.e. is it crystalline or amorphous. In eutectic and monotectic systems, both drug

and carrier are present in the crystalline state. In eutectic systems, the drug and carrier are

completely miscible in the liquid state, and when cooling their mixture with the eutectic

composition they form a microfine physical mixture with a lower melting point than the

drug or the carrier alone (Leuner and Dressman, 2000; Carig, 2002; Vippagunta et al.,



2007). In monotectic systems, the melting point of the carrier does not change with

incorporation of the active ingredients (Vippagunta, 2007). In eutectic drug/hydrophilic

carrier systems, the highly water soluble carrier dissolves quickly in an aqueous medium,

releasing very fine drug crystals and this drug size reduction has been noted to be

responsible for improved dissolution rate e.g. as observed for fenofibrate and loperamide

in solid dispersions with poly(ethylene glycols) (Law et al.,2003; Weuts et al.,2005a).

In the second type of SDs, the active ingredient may be dispersed as a separate

amorphous or crystalline phase or some combination of the two in glassy matrix (Carig,

2002; Vasconcelos et al., 2007). These types of SDs are mostly formed with amorphous

polymers, such as polyvinyl pyrolidone (PVP) (Van den Moorter et al., 1998; Sethia and

Squillante, 2004), or with semicrystlline materials, such as Poly ethylene glycol (PEG)

(Nair et al., 2002; Verheyen et al., 2002; Van den Moorter et al., 1998). Moreover,

complex formation might be possible with some carriers, such as PVP (Garekani et al.,

2003)

The third type of SDs is a solid solution in which the drug and carrier are totally miscible

with one another, and a result of specific molecular interactions, the drug is present as a

molecular dispersion within the carrier (Leuner and Dressman, 2000; Carig, 2002; Sethia

and Squillante, 2003, Kaushal et al.,2004; Vasconcelos et al.,2007).

1.8.1. Carrier used in solid dispersions: Different carriers which are used in the

preparation of SDs are mostly hydrophilic materials with varying physicochemical

characteristics, ranging from low molecular weight sugars to high molecular weight

polymers. The carriers materials which are commonly used for SDs are different grades

of PVP and PEG, either alone or in combination of surface active ingredients (Leuner and

Dressman, 2000; Sethia and Squillante, 2003; Kaushal et al., 2004). Other polymeric

materials which are used as carrier are, poly (acrylic acid) (PAA), poly (

vinylpyrrolidone-co-vinylacetate) (PVP/VA), povidone, Poloxamer and Pluronic F68 etc

(Broman et al., 2001; Weuts et al.,2005b; Matsumoto and Zogrfi, 1999; Vippagunta et



al.,2002; Ahuja et al., 2007; Nair et al., 2002); organic acids such as, citric acid and urea

(Ahuja et al., 2007); sugar such as chitosan, inulin, mannitol, sorbitol and glucosamine

(Asada et al., 2004; Ahuja et al., 2007) have been used as carriers in SDs. In the present

work Glucosamine HCl was used as carrier. As it is hydrophilic carrier, used as

dissoulution rate and solubility enhancer. The mechanism by which the solubility and

dissolution rate of the drug are increased using solid dispersion has several contributing

factors.

Firstly, the particle size of a drug is reduced to submicron size or molecular size where a

solid solution is obtained, this particles size reduction increase the solubility and

dissolution rate. Secondly, in some sample the drug is converted from crystalline to

amorphous form, which has high energetic state with increased solubility. Moreover, the

wettability of the drug particle can be improved by the dissolved hydrophilic carriers

(Ford, 1986).

1.8.2. Preparation of solid dispersions: Two methods are mostly used for the preparation

of solid dispersions such as melt (fusion) methods and solvent evaporation methods. Melt

(fusion) methods include traditional hot melting, melt extrusion, direct capsule filling,

compression moulding and hot spin melting (Leuner and Dressman, 2001). The solvent

methods include traditional solvent evaporation by spray or freeze-drying, supercritical

fluid technology, co-precipitation and spin-coating.

Part-2

1.9. Nanoparticles

In recent years tremendous efforts have been made to introduce nanotechnology for the

delivery of small molecular weight drugs and macromolecules such as proteins, peptides

and genes by either localized or targeted delivery to the site of interest (Moghimi et al.,

2001; Liu, 2007). Nanotechnology is referred to systems such as nanoparticles,

nanocapsules, micelles and conjugates of therapeutic agents. These systems are often



polymeric and submicron in size and they have multidimensional advantages in drug

delivery. These systems can be used for targeted drug delivery to improve the oral

bioavailability, to persist the drug/gene effect in site of action, to improve the solubility

of drug for intravenous administration, to prevent the instability of drugs against

enzymatic action with in the body (Moghimi et al., 2001).The nanometre size range of

these delivery systems provides prominent advantages for drug delivery. Due to sub-

cellular and submicron size, these particles can penetrate into deep tissues through

capillaries, cross the fenestration present in the liver epithelial lining and these

nanoparticles can be taken up by the cells (Vinagradov et al., 2002). They could show

controlled release properties due to the biocompatibility, pH, ion and temperature

sensibility and they can prove the utility of drugs and reduce drug side effects (Zonghua,

2008). Nanoparticles are spherical particles having smaller size less than 1um (Singh and

Lillard, 2009) as these are submicron-sized, colloidal vehicles that carry and release

drugs in a controlled way to the target site of action. Nanoparticles are different both, in

shape and in composition. Nanopaticles are different from their macroscopic/bulk

analogues due to increased surface area and quantum effects. a. Due to these quantum

effect and surface effects the optical, electrical, chemical and magnetic properties of

particles also change which ultimately affect the in vivo behaviour.

Nanoparticles are dispersed after preparation in a liquid and then these can be

administered for example via the parenteral route, oral route and/or transdermally.

Nanoparticles can be dried to a powder which can be used for pulmonary delivery.

Drug nanoparticles are the particles containing drug molecules and biocompatible

polymer (Kreuter, 1994; Couvreur et al., 1995; Kreuter, 1983). The drug can be

dissolved, entrapped, adsorbed, attached or encapsulated onto or into the nanoparticles.

Nanoparticles are classified into two groups on the basis of their structure. Nanocapsules

and Nanospheres (Allémann et al., 1993; Kreuter, 1994; Couvreur et al., 1995; Legrand

et al., 1999; Fresta et al., 1996). Nanocapsules consist of an oily core and polymeric

shell. The hydrophobic drug is contained in the oily core. Nanosphere has a matrix



structure in which polymer and drug are homogenously distributed. Some drug

containing nanoparticles are shown in the Fig 1.15.

Figure 1.15 (A) Matrix type nanoparticles where the drug molecules are homogenously

dispersed in the matrix, (B) Core shape nanoparticles, (C) Matrix type nanoparticles in

which drug molecules(crystals) are Imbedded in a polymer matrix.

1.9.1. Application of nanoparticles: For systemic drug delivery and for drug dissolution

modification both biodegradable and non-biodegradable nanoparticles have been studied

(Soppimath et al., 2001; Couvreur et al., 1995; Brannon-Peppas, 1995; Schmidt and

Bodmeier, 1999). Nanopaticles can be used for drug targeting and delivery (Chawla and

Amiji, 2002; Vauthier et al., 2003).

The nanoparticles prepared from natural and synthetic polymers have got great attention

due to its more stability and further opportunities for surface nanoengineering (Vanrell et

al., 2005; Vauthier et al., 2003). Moreover, nanoparticles can be used for controlled drug

delivery and site specific delivery by changing the polymer characteristics and surface

chemistry (Panyam et al., 2003; Kreuter, 1994). Nanoparticles have been very

significantly used in cancer therapy because they can extravasate from the leaky vessels

of tumours (Kallinteri et al., 2005). Nanoparticles are currently being studied as that they

can pass through the smallest capillaries because of its smaller size and its prolonged

duration in systemic circulation. To avoid rapid clearance by phagocytes, they can

penetrate tissue gap to reach the targeted site such as liver, spleen, lung, spinal cord and

lymph.They can improve the utility of drugs and reduce side effects (Zonghua, 2008).



Many studies have shown that nanoparticles have advantages over microparticles as drug

delivery systems (Linhardt, 1989). Micoparticles injected into tissue tend to stay where

they are placed and these can cause toxicity if used for chronic treatment. This was

observed in an experiment where 60um polymeric particles composed of a slowly

degrading polymer were injected at the sciatic nerve which was still found at the site after

eight weeks (Daniel, 2006). Microparticles 5, 25, 60 and 250um in diameter were

injected into the peritoneum of mice remained there for two weeks and an equal amount

of material but nanopaticles were injected and showed complete clearance from the

peritoneum in the same time frame (Daniel, 2006). Micropaticles mostly cause infarction

while the nanopaticles size is too small and don‟t cause emobolism and circulated in the

vasculature (Daniel, 2006).

The uses of biodegradable materials for the preparation of nanoparticles allow the

sustained and prolonged release of active entity at the site of action. Nanoparticles

formed from biodegradable polymers such as Poly DL-lactide co-glycolide (PLGA) and

Polylactide (PLA) have been developed for intracellular sustained drug delivery (Panyam

and Labhasetwar, 2003; Barrera et al., 1993; Davda and Labhasetwar, 2002)

1.9.2. Polymers used in nanoparticle preparation: Polymers are large molecules, which

are made up of simple repeating units. The name polymer is derived from Greek poly,

meaning „„many‟‟ and mer, meaning „‟part‟ (Stevens, 1999). Polymers are synthesised

from simple molecules called monomers by a process called polymerization (Stevens,

1999). A wide range of polymers are used for the formulation of nanoparticles, like

synthetic, natural, biodegradable and non-biodegradable (Chowdary and Srinivasa, 1997).

Biodegradable polymers are used for short term treatment and for long term therapy non-

biodegradable polymers are used for the preparation of nanoparticles such as for the

administration of vaccines and hormones (Roland, 1999). Biodegradable nanoparticles

are prepared from a variety of synthetic and natural polymers. Synthetic polymers such as



polyacrylates, polycaprolactones, polylactides and its copolymers with polyglycolides are

mostly used (Soppimath et al., 2001; Hans and Lowman, 2002). Natural polymers such

as albumin, gelatine, collagen, chitosan are used, too (Moghimi et al., 2001). Polymers

such as poly (D, L-lactide-co-glycolide) (PLGA) and polylactides (PLA) have been used

mostly for drug delivery (Jain, 2000; Langer, 1997). Poly-lactic acid (PLA), Poly glycolic

acid (PGA) and the copolymer as mentioned above PLGA are the biodegradable

polymers and no surgical removal is needed from the body (Indu et al., 2004). PLGA and

PLA have been approved by FDA but their disadvantages are their low drug

encapsulation and burst release phenomenon (Leo et al., 2004; Govender et al., 1999;

Govender et al., 2000). Also, the degradation products responsible for acidic conditions

at the surrounding tissues might affect drug bioavailability or cause tissue irritation or

inflammation. Another drawback is the need for surfactant during nanoparticle formation.

However, poly (glycerol adipate) consists of glycerol and adipic acid which is both

naturally metabolised in cells. Therefore the polymer is biodegradable and biocompatible

without any side effects (Kallinteri et al., 2005). The synthesis is achieved using a lipase

so the synthetic procedure has no harmful side products. The polymer can self-assemble

into nanoparticles in the absence of surfactants (Kallinteri et al., 2005). The main

advantage of PGA over PLGA and PLA is the ability of modification of the pendant

hydroxyl group on the polymer back bone. Thus, its physicochemical properties are

altered by introducing different functional groups (Puri et al., 2008).

1.9.2.1. Poly (glycerol adipate) PGA: It is novel co-polymer and is being synthesised by

the combination of glycerol and adipic acid which are both natural components.

For successful polycondensation reaction of PGA polymer lipase enzyme is used (Puri et

al., 2008). As mentioned above, this polymer is preferred than other polymers because of

its acylation properties.This polymer produces various acylated derivatives depending on

the percentage of the acylation of the pendant hydroxyl group (for example 0% PGA,

40%, 100%). This polymer and its derivatives are biodegradable and biocompatible; its

metabolites are used by the cell in Kerb‟s cycle. As discussed above the main advantage

as compare to other polymers is the absence of burst release phenomenon.



Figure 1.16 Structure of PGA and acylated PGA.

1.9.3. Nanoparticle preparation methods: For the preparation of nanoparticles several

methods are used such as emulsification solvent evaporation, interfacial polymer

deposition, spray drying, salting out, supercritical fluid expansion, complex coacervation.

Emulsification/solvent diffusion, emulsification/solvent evaporation, nanoprecipitation

and salting out methods are widely used methods (Pinto et al., 2006; Hans and Lowman,

2002; Soppimath et al., 2001; Qintanar et al., 1998).

1.9.3.1. Solvent Evaporation method: It is the most common method which is used for

the preparation of solid, polymeric nanoparticles. In this method the polymer dissolved in

water, immiscible volatile organic solvent is emulsified in presence of an aqueous phase.



Then, the organic solvent evaporates and polymeric nanoparticles are formed. This

method was described by Niwa et al and since it has been widely used for the preparation

of nanoparticles from different polymers. This method is used for the preparation of

nanoparticles containing polymers such as PLA and PLGA (Niwan et al., 1995). This

method has been successfully used for hydrophobic drugs. The drawback is the use of

surfactants which are difficult to remove. Polyvinyl alcohol (PVA) is mostly used as

emulsifier. As PVA remains on the surface of nanoparticles, its removal is very difficult

and due to the presence of PVA on the surface of nanoparticles, the biodegradability,

biodistribution, particle cellular uptake and drug release behaviours are affected (Scholes

et al., 1999).

1.9.3.2. Interfacial Polymer Deposition Method (IPD) or Nanoprecipitation Method:

Interfacial polymer deposition method is also called Nanoprecipitaton method because

the particle formation is based on precipitation and subsequent solidification of polymer

at the interface of solvent and non-solvent. Therefore, it is also called solvent

displacement method. This method was first introduced by Fessi and his co-workers

(Fessi et al., 1995). According to this, the polymer is dissolved in water miscible solvent

such as acetone, methanol and then it is added into an aqueous non-solvent under stirring.

The interfacial tension between the two phases is decreased because of the rapid diffusion

of solvent into the aqueous phase. Increase interfacial surface area is produced by the

turbulence and due to these small droplets of organic solvent is formed; the solvent

further diffuses into the aqueous phase. Then, polymer particles are formed from the

droplets. Thus, the polymer deposited at the interface plays a role for the particle

stability. Finally the solvent is evaporated.

The particle size prepared by this process varies from 100-500 nm. Drug encapsulation

occurs by dissolving a hydrophilic drug in the aqueous phase or a hydrophobic drug in

the organic phase. The advantages of the method are the lack of residual solvents and the

particles formed are in the nanometer range.



Figure 1.17 Schematic presentation of IDP (Interfacial Polymer Deposition method

1.9.3.3. Spray Drying Method: In this method fine nozzles are used while polymer and

drug are sprayed through the fine nozzles after being dissolved in organic solvent. Then,

after solvent evaporation, solid particles are formed. In this high temperature is used.

The particles prepared by using this process are mostly in micrometre size, due to high

temperature it creates problem during encapsulation of peptides and proteins. This

method is mostly used for the production and formulation of nanocrystals in industries.

1.9.3.4. Salting out Method: In this method, polymer precipitation is achieved via phase

separation by the addition of a salting out agent, e.g. electrolytes in case of acetone as a

solvent for polymer. This technique was introduced by Bindschaedler et al. in 1988

(Bindschaedler et al., 1988).

1.9.3.5. Supercritical fluid expansion method: This is a new approach for the

preparation of micron and nano sized particles (Dong and Feng, 2004). In this method

particles are formed free of organic solvent, and mild temperature is mostly used for

biological materials and the encapsulation of drugs for controlled release of therapeutic

agents is easier (Chattopadhyay and Gupta, 2002). Supercritical CO2 is used in this

technique under high pressure, it is termed rapid expension of supercrical solution.



1.9.3.6. Complex Coacervation Method: In this method spontaneous phase separation

occurs when two oppositely charged polyelectrolytes are mixed in an aqeous solution.

The process takes place at low temperature and in aqueous phase only. Particles of

nanometre or micrometer size are produced depending on the substrate and processing

parameters such as pH, ionic strength and polyelectrolyte concentration (Li and Zhang,

2002).

1.9. 4. Drug Release Mechanisms: The drug release may occur by desorption of surface

bound drug, diffusion through the nanoparticle matrix, but in case of nanocapsules,

(diffusion occurs through the polymer wall), nanoparticle matrix erosion, a combined

erosion diffusion process.

1.9.5. Methods of determination of drug release: Different method are used for In-Vitro

drug release determination from nanoparticles and some methods which have been

mostly used for release study are, Ultra filtration technique (Centrifugal), reverse

dialysais sac technique, dialysais bag technique, ultracentrifugation technique, side by

side diffusion cells with artificial or biological membrane. Dialysis technique is mostly

used and it is used for release study of drug from nanoparticles and colloidal suspensions

1.10. Model drugs

1.10. 1. Ketoprofen: Ketoprofen is anionic non-steroidal anti-inflammatory drug. Like

ibuprofen it is propionic acid derivative, which is used for the treatment and management

of rheumatoid disease (Dollery, 1991). It is one of the most useful NSAID drugs, has

received much attention in the last two decades. Its anti-inflammatory effect is

approximately 160 times that of aspirin (Guoa et al., 2006).



Figure 1.18 Structure of ketoprofen (C16H14O3, Molecular Mass 254.3 g/mol)

On the basis of its chemical structure different chemicals name are used for its

description such as, 2-(3-benzoylphenyl) propionic acid, (2RS)-2-(3-benzoylphenyl)

propionic acid, 2-(benzoyl-3-phenoyl) propionic acid, m-benzoylhydratropic acid, 3-

benzoly-α-methylbenzeneacetic acid, α-(benzoylphenyl) propionic acid, α-(3-

benzolyphenyl) propionic acid, (+)-(RS)-2-(3-benzoylphenyl) propionic acid (Dollery,

1991; BP, 2007; Moffat, 1986; Lund, 1994; Liversidge, 1981; Kantor, 1986; Vavra,

1987; Winholz, 1983; Delgado and Remers, 1998; Sweetman, 2002)

1.10.1.1. General description and properties: Ketoprofen is odourless, white crystalline

powder having sharp bitter teste (Dollery, 1991; Moffta, 1986; BP, 2007; Lund, 1994;

Sweetman, 2002). It has a melting point from 94 to 970C (BP, 2007; Lund, 1994;

Sweetman, 2002). It is practically insoluble or sparingly soluble in water, but freely

soluble in organic solvents, such as acetone, ethanol, methylene chloride, chloroform,

ether, benzene and etc (BP, 2007; Sweetman, 2002). As it is a weak monocarboxylic acid

(Sridevi and Diwan, 2002; Legen and Kristl, 2003), having dissociation constant, pKa, of

4.23 to 4.60 in water (Dollery, 1991; Lund, 1994; Legen and Kristl, 2003; Betge et al.,

2000; Hadgraft and Gossen, 2002; Corrigan et al., 2007). And 5.02 in aqueous solution of

pH 1.5 (de Jalon et al., 2000). Ketoprofen has two enantiomers, (S)-enantiomer and (R)-

enantiomer, which are both active and possess different biological activites (Sweetman,



2002; Liu et al., 2004). The (S)-enantiomer is used to relieve pain and inflammation,

while (R) - enantiomer is also used in toothpaste to treat peritoneal disease.

(R) - enantiomer (S) – enantiomer

Figure 1.19 Ketoprofen Enantiomers

1.10.1.2. History and synthesis: In the middle of the twentieth century dangerous

corticosteroids were used for the treatment of rheumatoid arthritis, then a safe anti-

inflammatory drug ibuprofen with simple molecular structure was synthesized by Dr.

Stewart Adams, after the discovery of ibuprofen in 1967 another safe drug ketoprofen of

the same group was synthesised by a French chemical company Rhône-Poulenc and later

on it was first approved in 1973 for clinical use in France and United Kingdom(Kantor,

1986; Vavra, 1987)

Different methods are used for the synthesis of ketoprofen, as shown in figs. 1.20, 1.21

and 1.22 the synthesis of ketoprofen starting from (3-carboxyl-phenyl)-2-propionitrile, 2-

(4-amenophenyl)- propionic acid and (3-benzoylphenyl)-acetonitrile, respectively.



Figure 1.20 Ketoprofen synthesized by starting from (3-carboxyl-phenyl)-2-propionitrile

(Liversidge, 1981).



Figure 1.21 Ketoprofen synthesized by starting from 2-(4-amenophenyl)- propionic

acid (Liversidge, 1981).



Figure 1.22 Ketoprofen synthesized by starting from (3-benzoylphenyl)-acetonitrile

(Liversidge, 1981).

1.10.1.3. Clinical and pharmacological aspects of Ketoprofen: In clinical practice

ketoprofen acts as anti-inflammatory and analgesic drug and it is also used widely for the

treatment of rheumatoid arthritis and osteoarthritis (Fossgreen et al., 1976). It is effective



like other NSAIDs and has anti-inflammatory, analgesic and anti-pyritic properties

(Dollery, 1991; Green, 2001).

1.10.1.4. Anti-inflammatory effects: Ketoprofen has shown anti-inflammatory activity

against acute inflammation, sub acute inflammation and chronic inflammation in several

animal models, such as rats, mice, rabbits, guinea pigs and pigeons (Kantor, 1986). Its

anti-inflammatory property is 20 time more potent than ibuprofen, 80 time more than

phenylbutazone and 160 times more than asprine (Dollery, 1991; Kantor, 1986).

1.10.1.5. Antipyretic and analgesic effect: It was shown that it is peripherally acting

analgesic drug in different animal models. It was also shown that in pain management it

is equivalent to indomethacin, slightly more potent than naproxen and 30 time more

potent analgesic than asprin (Kantor, 1986).

1.10.1.6. Mechanism of action: The pharmacodynamic activity of Ketoprofen, like other

NSAIDs, is presumed to be interference with the metabolism of arachidonic acid (Kantor,

1986). Arachidonic acid is the most important and abundant precursor of the eicosanoids.

It is a 20 carbon fatty acid containing four double bonds (Katzung, 2001). Free release of

arachidonic from memarane phospholipid is catalyzed by the enzymatic activation of

phospholipid A2. Then various forms of prostagalandin, such as prostaglandin D2 (PGD2),

prostaglandin E2 (PGE2), prostaglandin F2α (PGF2α), prostaglandin I2 (PGI2) and

thromboxane A2 (TXA2) are catalysed by cyclooxygenase (COX). Cyclooxygenase

(COX) is the main enzyme which plays a role in the formation of prostaglandin from

arachidonic acid (Howard and Delfontaine, 2004).

Ketoprofen also inhibits the lipoxygenase pathway of arachidonic acid cascade. The

lipoxygenase pathway is responsible for the production of leukotriens and non-cyclized

monohydroxy acids, which are promoting inflammation. The inhibition of lipoxygenase

pathway may attenuate cell mediated inflammation and thus retard the progression of

inflammation in inflamed joints. Ketoprofen also inhibits the production of bradykinin,

which is the chemical mediator of pain and inflammation. Ketoprofen also acts on the



lysosomal membranes and stabilizes the membranes and prevents the release of

lysosomal enzymes which are playing role in tissue destruction and damage during

inflammatory reactions (Hardman and Limbird, 2001; Vavra, 1987).

Figure 1.23 Prostaglandin (PGs) formation pathaway (Joan, 2003)

So ketoprofen acts on the cyclooxygenase (COX) and inhibits its synthesis because

ketoprofen is the powerful inhibitor of cyclooxygenase at concentrations well with in



therapeutic plasma concentration range (Kantor, 1986). This inhibition results in the

reduction of prostaglandins (PGE2 and PGF2α) production which is produced in the

different tissues (Dollery, 1991; Chan, 1983; Chan et al., 1982).

1.10.1.7. Therapeutic uses: Ketoprofen is used for the treatment of osteoarthritis,

rheumatoid arthritis, ankylosing spodylitis, bursitis, and tendinitis. It is also used for

painful and anti-inflammatory conditons, such as acute gout, soft tissue disorder, and to

reduce fever (Dollery, 1991; Delgado and Remers, 1998; de Jalon et al., 2000; Green,

2001).

It can be used in gynaecological conditions, such as dysmenorrhoea, pain related

relexation of utrine and post-partum pain in non-nursing women (Dollery, 1991). It is

used for the treatment and prophylaxis of migraine headaches. It is also used in the

traumatic and surgical situations where pain management is required, such as sports

injuries, dental extraction, and orthopaedic manipulation. It can be used as anti-

inflammatory, analgesic and antipyratic agent in infectious diseases

1.10.1.8. Contraindications: Ketoprofen is contraindicated in bronchospasmal condition

such as, rhinitis, asthma, nasal polyps (Dollery, 1991; Green, 2001). It is also

contraindicated in peptic ulceration and sever renal insufficiency (Dollery, 1991; Green,

2001).

1.10.1.9. Adverse reactions of ketoprofen: As ketoprofen inhibits cylcooxygenase

enzymes (COX1 and COX2), so the therapeutic effecs of ketoprofen are due to the

inhibition of COX2 enzymes and the unwanted side effects or adverse reactions are due to

the inhibition of COX1 enzymes (Villegas et al., 2004; Sweetman, 2002).

Ketoprofen has mild upper GI complaints such as, epigastric discomfort, nausea, and

dyspepsia and some times lower GI complaints are also involved such as diarrhea,

constipation and fluctuation (Dollery, 1991; Kantor, 1986; Vavra, 1987). Ketoprofen also



has some central nerve system (CNS) related side effects which are headache, vertigo,

dizziness, nervousness, tinnitus, depression, drowsiness, and insomnia. Some times

hypersensitivity reactions may occur such as angio oedema, fever, rashes, bronchospasm

and visual disturbances in some patients (Sweetman, 2002; Grahame, 1995).

Hematological adverse reactions of ketoprofen are anaemias, neutropenia,

thrombocytopenia, eosinophilia and agranulocytosis. It also causes nephritis and nephritic

syndrome and heart failure in elder patients may accrue (Evans and MacDonald, 1996;

Halpern, 1994; Grahame, 1995).

It has other adverse effects such increase blood urea nitrogen, photosensitivity,

pulmonary eosinophilia, pancreatitis, Stevens Johnson syndrome, colitis, and toxic

epidermal necrolysis, dermatitis (Dollery, 1991; Hardman and Limbird, 2001; Sweetman,

2002).

1.10.1.10. Ketoprofen interaction with other drugs: Ketoprofen has interaction with

other drugs such as aspire, warfarin, sulphonylurease, hydantoins, methotrexate, lithium,

cardiac glycosides, β-blockers, furosemide, angiotensin converting enzyme inhibitors,

probenecide, zidovudin (Dollery, 1991; Kantor, 1986; Vavra, 1987; Sweetman, 2002).

The concomitant use of ketoprofen with some drugs may cause sever adverse reactions

and gastrointestinal bleening and the risk of GI bleeding and ulceration may increase

when used corticosteroids, alcohol (Sweetman, 2002; Turner, 2001)

1.10.1.11. Pharmacokinetic of ketoprofen: Oral ketoprofen absorption is 94% ± 4

(Ketoprofen, 2010). Plasma protien binding of ketoprofen is 95% and volume of

distribution is about 0.1-0.2 l/kg (Ketoprofen, 2010). Plasma half life is about 1-3hours

(Ketoprofen, 2010). It is metablized in the liver. The main path way of its metabolism is

glucuronide conjugation along with minor hydroxylation pathway (Dollery, 1991;

Liversidge, 1981; Sweetman, 2002). Acyl-glucuronides formation is involved in the

metabolism of ketoprofen, which are excreted in the urine (Ishizaki et al., 1980). Acyl-



glucoronides are physiologically unstable and they are hydrolyzed back to parent

compound and accumulation of these metabolitis in the plasma can prolonged the

ketoprofen elimination (Verbeeck, 1990). The renal excrition of unmetabolized

ketoprofen is less than 10% (Ishizaki et al., 1980).

Figure 1.24 Ketoprofen metabolism pathways (Ishizaki et al., 1980).

1.10.1.12. Pharmaceutics of ketoprofen: It is available in different dosage forms such as,

tablets, capsules, injectable solutions, gels and suppositorie (Kantor, 1986).



Table 1.7 Ketoprofen dosage forms, route and strength

Dosage form Route Strength

Tablets Oral 50mg

Capsules Oral

50mg

75mg

100mg

Extended release ( tablets and capsules) Oral 100mg

200mg

Parenteral Intramuscular 100mg/2ml

Rectal Suppository 100mg

Topical Gel 2.5g/100g

1.10.1.13. Dose of ketoprofen for different disease conditions: The usual daily oral dose

of ketoprofen for rheumatic disorder is 100 to 200mg in 2 to 4 divided doses, but its

modified dosage form may be used once in a day. It may be used in suppository form at

night time in a dose of 100mg. For local pain relief a 2.5% gel may be applied on the

affected area 2 to 3 times a day for 10 days (Sweetman, 2002).

It may be given by deep intramuscular injection for soft tissue disorder, management of

pain after orthopedic surgery, and joint pain. The dose may be given in divided doses

after every 4 hours, up to a maximum dose of 200 mg in 24 hours, for up to three days.

1.10.2. Ibuprofen

Ibuprofen is propionic acid derivative of non-steroidal anti-inflammatory group of drugs,

which is used as analgesic and antipyretic agent (Baum et al., 1985; Herzfeldt and

Kümmel, 1983).

On the basis of chemical structure different names are given to describe ibuprofen, such

as, α- Methyl-4-(2-methylpropyl) benzeneacetic acid, [(±)-2-(4- isobulphenyl) propionic

acid] (Laura and Evangelos, 2007), (2-(4-isobulphenyl) propionic acid) (Philip et



al.,1999), (iso-butyl-propionic-phenolic acid) (A thesis, 2000), (2RS)-1[4-(2-methyl

propyl) phenyl] propionic acid (Rabia and Nousheen, 2010).

Figure 1.25 Structure of Ibuprofen (C13H18O2, Molecular Mass 206.3 g/mol)

1.10.2.1. General properties and description: Ibuprofen is white crystalline powder. It

has melting point from 74 to77 0

C (Ibuprofen, 2010). Slightly soluble in water but soluble

in organic solvents, such as methanol, ethanol, acetone etc (Ibuprofen, 2010). It has a half

life 1.8 to 2 hours (Gennaro, 1990). It has dissociation rate constant pKa, 5.3 (Herzfeldt

and Kummel, 1983). Like ketoprofen it has chiral carbon atom on the propionic side

chain and therfore, it also has two enantionmers, such as R (-)-ibuprofen and S (+)-

ibuprofen. S (+) – ibuprofen is pharmacologically 160 times more active than R (-) –

ibuprofen (Adams et al., 1976).

Basically, almost all of the pharmacological activity of ibuprofen comes from S (-) –

ibuprofen (Neupert et al., 1997).

The R (-) – ibuprofen is converted or inverted to S (+) – ibuprofen in vivo to the extent of

57-69% (Hutt and Caldwell, 1983; Cheng et al.,1994; Lee et al.,1985)



R (-)-ibuprofen S (+)-ibuprofen

Figure 1.26 Ibuprofen enantionmer

1.10.2.2. History and synthesis of ibuprofen: Ibuprofen was first derived in 1960s by

the research arm of Boot Group from propionic acid (Adams, 1992). And it was

discovered by Stewart Adams and his colleagues and they were patented in 1961s. It was

first launched in the United Kindom market in 1969s and in the United States in 1974s

for the treatment of rheumatoid artheritis. Boots was awarded for the this achievement

with Queen‟s Award Tehnical Achievement in 1987s (Ibuprofen, 2010). The two most

popular methods are used for the synthesis of ibuprofen, such as Boots Process and

Hoechst Process. The Boots process is the older one, it was developed by the Boots Pure

Drug company. And the other method which is called Hoechst process developed by

Hoechst company, in both process the synthesis of ibuprofen begins with isobutybenzene

as shown in the fig. 1.27.

1.10.2.3. Mechanism of action: Ibuprofen inhibits the synthesis of cyclooxygenase

(COX) enzymes (COX1 and COX2) (Vane and Botting, 1996; Neupert et al., 1997;

Oleson, 2009). As shown in the fig. 1.23 the ezymes COX1 and COX2 act as catalyste in

the production of prostaglandin and thromaxanes, which are involved in different

physiologic processes (Vane and Botting, 1996; Neupert et al., 1997). As prostaglandin is

responsible for the sensitization of pain receptors, and also plays a role in production of

inflammation and fever (Wahabi et al., 2005), and thus ibuprofen acts as indirect

analgesic by blocking the continues production of prostaglandin, the supression of



prostaglandin is also responsible for ibuprofen antipyratic activity (Vane and Botting,

1996).

Other possible mechanisms of action are the influence on lipoxygenase enzymes,

peroxisome proliferator-activated receptors and inhibiting cell signaling molecules such

as nuclear factor kappa B (Kukar and Golde, 2008).

Figure 1.27 Synthesis of ibuprofen by Boot process and Hoechst process (Synthesis

of Ibuprofen, 2010).

1.10.2.4. Therapuetic uses of ibuprofen: As it is widely used as analgesic, antipyretic and

anti-inflammatory agent (Wood et al., 2006; Nuzu, 1978; Adams et al., 1969).

It is mostly used in the treatment of mild to moderate pain related to headach,

dysmenorrhea, migrain, post-operative dental pain, mangement of sponylitis,

osteoartheritis, rehumatoid artheritis, and soft tissue disorders (Pottas et al., 2005).

Ibuprofen can be used in the management of Patent Duct Arterosus (PDA) (Kravs and

Pharm, 2005). It is used in the treatment of sever orthostatic hypotension as with other



NSAIDs (Zawada, 1982). It is also used in high dose for the reduction of inflammation in

Cystic Fibrosis (CF) (Mackey and Anbar, 2004; Rifai et al., 1996). It is also used for

prophylaxis of Alzheimers disease (Townsend and Pratic, 2005). It is used to lower the

risk of Parkinson‟s disease (PD) (Chen et al., 2005; Carrasco et al., 2005). It is also used

as chemo preventive agent in Breast Cancer (BC) (Harris et al., 1999).

1.10.2.4. Pharmacokinetic of Ibuprofen: Ibuprofen has oral bioavalability of 97% ± 2

(Pharmacokinetic of Ibuprofen, 2010). Its half life is 1.8-2hours and volum of distribution

0.1 l/kg and (Davies, 1998; Aarons et al., 1983; Paliwa et al., 1993). As there are two

enantiomers of ibuprofen, R(-) ibuprofen and S (+) – ibuprofen, both are metabolized to

in active hydroxy and corboxy metabolitis, two major metabolitis are 2-

hydroxyibuprofen and corboxyibuprofen (Mills et al.,1973; Tan et al.,2002; Burke et

al.,2006). All Phase I metabolitis of ibuprofen and intact enantiomer can be conjugated

with glucoronic acid and covert to phase II metabolitis (Kepp et al., 1997). Mostly two

enzymes are involved in the metabolism of ibuprofen enantiomers, such as CYP2C9 and

CYP2C8, S (+) – ibuprofen is metabolized by the enzyme CYP2C9 and R(-) ibuprofen is

metabolized by enzyme CYP2C8 (Leemann et al.,1993; Hamman et al.,1997).

1.10.2.5. Contraindications: Ibuprofen is contraindicated in individuals who are

hypersensitive to NSAIDs. It is also contraindicated in branchospasmal conditions, such

rhinitis, asthama and nasal polyps (Ibuprofen Drug monongraph, 2010; Oleson, 2009).

Ibuprofen should be used in caution in patients with hepatic diseases. It is also

contraindicated in patients with GI diseases such as ulcerative colitis, and peptic ulcer

disease (Green, 2001). It is also cotraindicated in patients having sever renal problems

(Green, 2001). It is also contraindicated in the pre-operativ pain related to coronary artery

bypass graft sugery. According to FDA it is pregnancy B category drug in first trimester

and D category in the third trimester dru because of potential constriction of the fetal

ductus arteriosus (Oleson, 2009).



1.10.2.6. Adverse reactions of ibuprofen: Like other NSAIDs, ibuprofen also has some

adverse reactions. The most common and major adverse reactions of ibuprofen are,

affects on the GI tract, the coagulation system and the kidney (Sweetman, 2002). It may

cause GIT bleeding, increase the risk of gastric ulcers and damage, renal failure, heart

failure, hyperkalaemia, confusion, bronchospasm, apoptosis, and epistaxis (Wolfe et al.,

1999; Oermarn et al., 1999; Gambero et al., 2005; Fulcher et al., 2003; Kennedy, 2001;

Kovesi et al., 1998; Durkin et al., 2006; Vale and Meredith, 1986). Ibuprofen has some

other adverse reactions but these are not most common, such as thrombocytopenia,

rashes, headache, blurred vision, dizziness, toxic amblyopia, edema and fluid retention,

nephritis, nephritic syndrome (Burke et al., 2006).

1.10.2.7. Interaction of ibuprofen: Ibuprofen has serious interactions like other NSAIDs

with drugs, such as aspirin, warfarin, lithium, oral hypoglycemic drugs, high does

methotrexate, antihypertensive drugs, β-blockers, angiotensin converting inhibitors, and

diuretics when used concomitantly (Hansen and Elliot, 2005). It has also interaction with

Desmopressin and thiopurines (Oselin and Anier, 2007; Garcia et al., 2003). Ibuprofen

interaction was observed with caffeine, naproxen, gemfibrozil, vericonazole and

fluconazole (Lόpez et al., 2006; Dooley et al., 2007; Tornio et al., 2007; Haynninen et

al., 2006; Rahman et al., 2005; Guindon et al., 2006).

Table 1.8 Dose of ibuprofen (Burke et al., 2006).

Patients Ibuprofen Doses

Adults

Analgesia n 200-400mg, every 4-6 hours

Anti-inflammatory 300mg, every 6-8 hours or

800mg, 3-4 times daily

Children Antipyretic 5-10mg/kg, every six hours or

(Max. 40 mg/kg per day)

Anti-inflammatory 20-40mg/ kg/day in 3-4 divided

doses



CHAPTER 2

REVIEW OF LITERATURE

2.1. MODIFIED RELEASE FORMULATION

2.1.1 Polymers for modified release formulations

Shah et al. (2011) developed controlled release matrix tablets of Ofloxacin, using

different grades of Ethocel® polymer.

Mesnukul et al. (2009) formulated the polyethylene glycol matrix tablets of

Indomethacin by mold technique, using hydroxypropylmethylcellulose (HPMC) polymer.

Chandira et al. (2009) developed a single tablet in which combination of Atorvastatin

and Gliclazide were used by wet granulation method, using HPMC 4000cps and HPMC

100cps as retardant polymers.

Tamizharasi et al. (2008) formulated and evaluated cephalexin microspheres, using

Eudragit. The in-vitro release profile indicated that cephalexine loaded Eudragit

microspheres provide sustained release over a period of 12 hours.

Gohel et al. (2008) fabricated the modified release press coated tablets of venlafaxine

hydrochloride, using hydroxypropylmethylcellulose (HPMC K4M) and (HPMC K100M)

polymers as release modifier in core and coat, respectively.

Shivkumar et al. (2008) formulated controlled release solid dispersion of dilclofenac

sodium in Eudragit SR and RL.

Suresh et al. (2007) developed ion-exchange resonates of propranolol hydrochloride,

using amberlite IR 120 by solvent evaporation method coated with polymer ethyl

cellulose.

Ribeiro et al. (2007) prepared Vinpocetine–cyclodextrin-tartaric acid multicomponent

complexes in HPMC matrix tablets. The drug release was evaluated for 12 hours.

Andrade-Vivero et al. (2007) increase the potential of poly (hydroxyethyl methacrylate),

pHEMA hydrogels as non-steroidal anti-inflammatory drugs delivery systems by using

the 4-vinyl-pyridine and N-(3-aminopropyl) methacrylamide.



Mayo-Pedrosa et al. (2007) prepared sustained release matrix plellets, using poly (N-

isopropyl acrylamide.

Diez-Sales et al. (2007) developed and formulated the matrix system of acyclovir, using

chitosan

Sotthivirat et al. (2007) formulated prednisolone controlled porosity osmotic pump

pellet formulation consisting of microcrystalline cellulose and sulfobutylether-β-

cyclodextrine. The influence of formulation and processing variables on the physical

characteristics of predinisolone was studied.

Tatavarti et al. (2006) developed a prototype matrix system consisting of trimethoprim,

hydroxypropylmethylcellulose and polymeric and nonopolymeric modulator.

Rigo et al. (2006) formulated swellable drug-polyelectrolyte matrices, using alginic acid.

Different parameters were studied such as solvent up-take, release kinetic, erosion and

dynamics of swelling.

Dashevsky et al. (2005) formulated and physicochemicaly evaluated extended release

pellets coated with Kollicoat SR 30 D, novel aqueous polyvinyl acetate dispersion for

extended release.

Santos et al. (2005) evaluated the compaction and compression of xanthan gum pellets of

Ibuprofen. Physical properties of pellets were evaluated.

Ribeiro et al. (2005) studied the impact of multicompartment complexation of

Vinpocetine with β-cyclodexrin, sulfobutylether β-cyclodextrin, tartaric acid,

polyvinylpyrrolidone and HPMC, on the design of controlled release hydrophilic HPMC

tablets.

Ceballos et al. (2005) developed the extended release theophylline matrix tablets, using

different pH-dependent (Eudragit L100, S100 and L100-55) and pH-independent

(Eudragit RLPO and RSPO) polymers combination by direct compression method.

Kim (2005) formulated extended release triple layer, donut-shaped tablets (TLDSTs).

The core tablets consisted of enteric polymers such as hydroxypropylmethylcellulose

acetate succinate, and the bottom and top layers made of hydrophobic polymer, ethyl

cellulose.



Miyazaki et al. (2004) studied jelly fig extract for sustained release tablets as a matrix

base.

Parojcic et al. (2004) developed hydrophilic matrix tablets, using Carbopol 971P and

71G. The influence of polymer level on drug release kinetics was evaluated.

Crowley et al. (2004) developed matrix tablets of water soluble drug guaifenesin by

either direct compression or hot melt extrusion, using ethy cellulose polymer. Different

physicochemical characteristics, drug dissolution and release kinetic were investigated.

Comolu et al. (2003) formulated the Ketoprofen microsponges, using Eduragit RS 100.

The impact of drug-polymer ratio on the physical properties as in vitro release rate of the

drug was studied.

Alock et al. (2002) evaluated a range of oligosaccharide ester derivatives as drug

matrices for controlled release

Mehta et al. (2001) fabricated and evaluated the multi-unit controlled release system of

poorly soluble thiazole bsed leukotriene D4 antagonist, using Eudragit L 100 55 and

Eudragit S100. In-vitro drug release from the pellets was evaluated.

Montouses et al. (1999) formulated theophylline extended-release spheres by extrusion-

spheronization of matrix granultions, using Gelucire 50/02 or 55/18. The release

mechanism of theophylline was Fickian diffusion.

Pather et al. (1998) developed sustained release theophylline tablets, using ethyl

cellulose polymer.

Codd and Deasy (1998) prepared two-layered novel bioadhesive antifungal lozenges

with an upper modified-release drug containing layer and a lower bioadhesive layer

composed of drum-dried waxy maize starch and Carbopol 980.

2.1.2. Development of modified release formulation

Shah et al. (2011) developed controlled release matrix tablets of Ofloxacin using

different grades of Ethocel® polymer

Conti et al. (2008) formulated swellable matrices of Diltiazem HCl, using a mixture of

HPMC and NaCMC. A matix containing a 1:1 mixture of NaCMC and HMPC exhibited

a significantly slower drug release rate than either polymer shows alone.



Lin et al. (2007) prepared sustained release tablets of asprin, using

polymethylmethacrylate. The drug release followed Fickian diffusion model.

Philip and Pathak (2006) formulated a nondisintegrating, controlled release, asymmetric

membrane capsular system of flurbiprofen. The influence of different formulation

varaibles was evaluated.

Savaşer et al. (2005) formulated diclofenac sodium tablets by wet granulation and direct

compression methods, using different ratio of HPMC and Chitosan.

Royce et al. (2004) prepared controlled release 6-N-Cyclohexyl-2-O-methyladenosine

formulations.

Uner and Altinkurt (2004) developed theophylline tablets using honey locust gum as a

hydrophilic matrix material.

Talan et al. (2004) formulated a once-daily extended release formulation of ciprofloxacin

Qui et al. (2003) prepared a once-daily controlled release matrix system of divalproex

sodium, using different rate controlling hydrophilic polymers.

Qui et al. (1998) formulated layered matrix system of pseudoephedrine hydrochloride for

zero-order sustained release.

Eddington et al. (1998) formulated hydrophilic matrix extended release metoprolol

tablets and dissolution data was analysized.

Ughini et al. (2004) prepared diclofenac sodium tablets and capsules, using a highly

substituted galactomannan from Mimosa scabrella Bentham, extracted from the seeds of

a Brazilian leguminous tree and xanthan.

Huang et al. (2004) developed and optimized the propranolol once-daily extended

release formulations containing HPMC, CMC and lactose.

Emami et al. (2004) developed sustained release matrix tablets of lithium carbonate,

using different types of polymer, including Carbopol, NaCMC and HPMC by either

direct compression or wet granulation.

Reddy et al. (2003) formulated once-daily sustained release matrix tablets of nicorandil,

using wet granulation method. HPMC, NaCMC and sodium alginate were used as matrix

materials, while ethanolic solutions of ethyl cellulose, Eudragit RL-100, Eudragit RS-100

and polyvinylpyrrolidone were incorporated as granulating agents.



Samani et al. (2003) prepared controlled release matrices of diclofenac sodium, using

different proportion of HPMC, Carbopol 940 and lactose.

Hasan et al. (2003) formulated and evaluated controlled release hydrophilic matrix

formulation of metoclopramide HCl, using chitosan and sodium alginate.

Makhija and Vavia (2002) prepared the once-daily sustained release matrix tablets of

Venlafaxine, using HPMC, cellulose acetate, Eudragit RSPO, ethyl cellulose polymers.

The effect of polymer ratio on in-vitro drug release and different physicochemical

parameters such as appearance, weight variation, and drug content were evaluated.

Espinoza et al. (2000) formulated a prolonged release formulation of Pelanserin, using

HPMC and citric acid.

Nellore et al. (1998) prepared extended release matrix tablets of metoprolol tartrate,

using several grades and levels of HPMC, filler and binder.

2.1.3. Formulation development via direct compression method

Shah et al. (2011) developed controlled release matrix tablets of Ofloxacin using

different grades of Ethocel® polymer

Yun-Tyng et al. (2007) formulated sustained-release tablets by direct compression

method.

Varshosaz et al. (2006) prepared matrix sustained-release tabltes of tramadol HCl by

direct compression method, using natural gums (xanthan and guar gums). Tablets were

evaluated physicochemically.

Miyazaki et al. (2006) formulated two kinds of theophylline dextran tablets by direct

compression method.

Vendruscolo et al. (2005) formulated extended release matrix tablets of theophylline,

using commercial xanthan (Keltrol®) and highly hydrophilic glatomannan from the seeds

of Mimosa scarbella by direct compression method.

Pose-Vilarnovo et al. (2004) formulated matrix tablets of diclofenac sodium and

sulphamethizole by direct compression method, using HPMC K4M.

Miyazaki et al. (2003) formulated three kinds of controlled release theophylline tablets,

using carboxymethyldextran, a mixture of carboxymethyldextrane and [2-(diethyl amino)

ethyl] dextran (EA) and mixture of dextran sulfate and EA by direct compression method.



Reza et al. (2003) prepared matrix tablets of theophylline, diclofenac sodium and

diltiazem HCl, using Kollidon SR, Carnauba was and HPMC-15cps by direct

compression method.

Siepmann et al. (2002) formulated tablets of chlorpheniramine maleate, propranolol

HCl, acetaminophen, and theophylline and diclofenac sodium by direct compression

method, using different grades of HPMC as matrix forming agent.

Capella and Landing (2002) developed a stable nitroglycerin tablets by direct

compression method.

2.1.4. Drug release mechanism and kinetics

Jeong et al. (2007) evaluated the release kinetics of polymer-coated/ion-exchange resin

complexes for sustained drug delivery.

Wu et al. (2005) mathematical models were developed to describe the transport

mechanism of water soluble drug (caffeine) from highly swellable and dissoluble

polyethylene oxide cylindrical tablets.

Fu et al. (2004) derived a working equation to calculate drug release from matrices

containing HPMC.

Koester et al. (2004) investigated the release kinetics of carbamazepine from HPMC

matrix tablets, using different mathematical models.

Ferrero et al. (2003) studied drug release kinetics and front moment from matrix tablets

of methacrylate copolymer. Data was analyzed mathematically, using Higuchi,

Korsmeyer and Peppas models.

Siepmann and Peppas (2001) studied different kinetic models to describe drug release

from pharmaceutical devices containing HPMC.

Bettini et al. (2001) studied the release mechanisms of different soluble drugs matrix

tablets contusing HPMPC. Diffusion, erosion and swelling mechanisms were studied.

Abrhamsson et al. (1998) investigated the erosion of two different compositions of

hydrophilic matrix tablets containing HPMC.

Khan and Zhu (1998a) studied Ibuprofen release from controlled-release tablets

containing ethylcellulose polymer, using different kinetics models.



2.1.5. Ibuprofen and Ketoprofen modified release formulations and nanoparticles

Gohel and Nagori (2009) prepared a novel colonic drug delivery system of Ibuprofen.

Capsules containing HPMC, adsorbate of eutectic mixture of Ibuprofen, methanol and

pregelatinized starch were coated with ethyl cellulose. The ethyl cellulose coated

capsules were incorporated into other capsules and the capsules were coated with

Eudragit S100. The in-vitro dissolution study was conducted.

Valot et al. (2009) prepared biocompatible Ibuprofen loaded-micrcapsules in the size

range from 20-60µm, using Eudragit RSPO or ethylcellulose, by the water in oil

emulsion-solvent evaporation method. The influence of different process parameters,

such as the volatile organic solvent, the oily core, the stirring rate on the properties of

microcapsules was investigated.

Chandran et al. (2008) designed and formulated controlled release matrix tablets of

Ibuprofen, using ethyl cellulose and cellulose acetate phthalate as the rate controlling

agents. The Ibuprofen release was extended for 14-16 hours.

Xiang et al. (2008) four different formulation of Ibuprofen nanostructured lipid carrier

were formulated using, Gelucire 44/14 by melted ultrasonic method. Investigated their in-

vitro and in-vivo properties.

Brabander et al. (2008) bioavailability of Ibuprofen from matrix mini-tablets containing

microcrystalline wax and starch derivative was investigated. Healthy human volunteers

were used for in-vivo evaluation.

Abbaspour et al. (2008) designed sustained-release Ibuprofen tablets which upon oral

ingestion rapidly disintegrated into sustained release pellets in which the integrity of the

pellets coat and core was preserved.

Adamo et al. (2008) prepared eight formulation containing model drug Ibuprofen in the

form of orally disintegrating tablets. By suitable combination of excipients it was thus

possible to obtain a delayed release of Ibuprofen using simple and conventional

techniques.

Golam and Reza (2008) prepared Ketoprofen pellets, using ammonio methacrylate

copolymer type A (Eudragit® RL 30 D) and ammonio methacrylate copolymer type B

(Eudragit® RS 30 D) as release rate retarding agents. The pellets were prepared by



extrusion spheronization techniques. The influence of physicochemical properties of the

polymers on the release profile of Ketoprofen from the pellets dosage form was also

investigated. The result obtained in this study revealed that proper selection of polymeric

materials based on their physicochemical properties was important in developing

sustained release pellets dosage form with suitable dissolution profile.

Norihiro et al. (2008) Assessed percutaneous penetration and pharmacological effect of

Ketoprofen after transdermal administration, compared to oral route of administration.

Microdialysis technique was used for skin and knee penetration of Ketoprofen, while for

in-vivo study retrodialysis technique was used. The results obtained, indicated that

transdermal patch formulation of Ketoprofen were useful.

Laura and Evangelos (2007) prepared loaded microspheres of Ibuprofen and in-vitro

drug release study was conducted.

Thompson et al. (2007) prepared Ibuprofen-loaded microspheres, using copolyesters.

Effect of various manufacturing parameters such as temperature, disperse phase volume

and polymer: drug ratio on morphology of microspheres was investigated.

Adi and Moawia (2007) encapsulated Ketoprofen particles with polyions and gelatin to

control the release of Ketoprofen in aqueous solutions. Ketoprofen release from the

coated microparticles in aqueous solution of different pH such as 1.4, 4.1 and 7.4 was

studied.

Burcu and Kandemir (2006) microspheres of Ibuprofen were prepared by modified

quasi-emulsion solvent diffusion method. The effect of different formulation factors such

as drug: polymer ratio, volume of solvents, polyvinyl alcohol concentration and type of

polymer on morphology, particle size distribution, drug loading capacity, micromeritical

characteristics and in-vitro drug lease profile were studied.

Nerurkar et al. (2005) developed Ibuprofen controlled-release matrix tablets, using

polymer blend of carrageenanas or cellulose ethers by direct compression method. The

influence of polymer on the drug release rate was studied. Linear release profile was

observed (r2 ≥ 0.96-0.99). The release of the Ibuprofen was sustained over 12-16 hours.



Kim et al. (2005) prepared a swelling-conrolled release delivery system of Ibuprofen,

using monoacrylate-poly (ethylene glycol)-grafted poly (3-hydroxyoctanoate) (PEGMA-

gPHO) copolymers.

Abbaspour et al. (2005) prepared Ibuprofen pellets, using Eudragit RL PO and RS PO

by extrusion-spheronization.

Maurizio et al. (2005) designed composite microcapsules of alginate/poly-L-

ornithine/alginate filled with biodegradable microspheres of Ketoprofen. Polyester

microspheres were developed by solvent evaporation technique. Different characteristics

such as encapsulation efficiency, particle size and in-vitro release were evaluated.

Helton et al. (2005) prepared two types of pellets of Diclofenac sodium and Ibuprofen,

using xanthan gum as sustained releasing agent by extrusion-spheronization technique.

Physical properties of pellets were evaluated

Tamer et al. (2004) developed sustained release suppositories containing Ibuprofen

microspheres, using hydrophilic polyethylene glycol 600 and whitepsol bases by solvent

evaporation method.

Al-Saidan (2004) prepared saturated solution of Ibuprofen, of different concetrations and

investigated their effect on permeation of Ibuprofen across rat epidermis. The

permeability study was also performed, using human epidermis and silastic membrane.

Fernández-Carballido et al. (2004) developed and optimized biodegradable PLGA

microspheres loaded with Ibuprofen for intraarticular administration. The formulation

was developed to provide in-vitro therapeutic concentration of Ibuprofen (8µg/ml) long

period of time.

Caroline et al. (2004) prepared hot melt extruded mini-matrices of Ibuprofen, using ethyl

cellulose and a hydrophilic excipient. Bioavailability study was performed using human

volunteers.

Costa et al. (2004) Ibuprofen pellets were developed and examined the effects of citric

acid and two common fillers (lactose and tricalcium phosphate) on the release profile

from pellets.



Luana et al. (2004) formulated new mucoadhesive patches of Ibuprofen for buccal

administration, using film-forming polymer, polyvinylpyrrolidone (PVP) and

mucoadhesive polymer, NaCMC.

Vueba et al. (2004) formulated and evaluated the hydrophilic matrix tablets of

Ketoprofen, using cellulose methyl cellulose, hydroxypropyl methylcellulose and

hydroxypropylcellulose as polymers, while lactose monohydrate and β-cyclodextrin as

diluents or fillers. The influence of cellulose ether polymer on the drug release was

evaluated. Different physicochemical characteristics, such as drug content, hardness,

weight variation, thickness, tensile strength, friability, swelling and release ratio were

determined. Polymers HPC and MC25 were found, not suitable candidates for the

preparation of modified release Ketoprofen matrix tablets, while HPMC K100M and

K15M were found good for modified release formulation of Ketoprofen. Different

Kinetic models such as zero-order, first-order, Higuchi and Korsmeyer-Peppas were used

for analysis of drug release profile, indicated that polymer type did not show any effect

on the rerlease mechanism of the drug. The formulations containing HPMC also showed

the higher MDT value.

Vostalova et al. (2003) formulated HPMC based hydrophilic matrix tablets of two drugs

with different solubility, well soluble diltiazem HCl and sparingly soluble Ibuprofen.

Barbara et al. (2003) prepared pH-sensitive physical mixture of Ibuprofen for site

specific delivery, using polymethacrylic acid-co-methylmethacrylate substituted with

different degree and types of fatty acids. In-vitro dissolution study was performed at

different pH levels.

Costa et al. (2003) prepared uncoated pellets of Ibuprofen. Both dependent an

independent models were used to assess the difference in dissolution profiles.

Brabander et al. (2003) formulated sustained release mini-matrices of Ibuprofen, using

ethyl cellulose as sustained release agent by hot-melt extrusion technique. The Ibuprofen

release from ethyl cellulose matrices was slow and other excipient such as HPMC and

xanthan gum were used to increase the release of Ibuprofen.



Manish et al. (2003) developed Ibuprofen beads with lower amount of excipient by a

single step novel melt solidification technique. Influence of different variables such as

speed of agitation and amount of cetyl alcohol was studied, using 32 factorial design.

Nadia et al. (2002) formulated Ibuprofen containing granules, using meltable hydrophilic

binder, poloxamer 188 and diluent, lactose by melt granulation.

Rosario et al. (2002) prepared polymeric nanoparticle suspension loaded with Ibuprofen,

using Eudragit RS 100. These suspensions were prepared for improving the availability

of Ibuprofen at the intraocular level. These nanosuspensions were made by modification

quasi-emulsion solvent diffusion technique.

Solinís et al. (2002) prepared sustained release matrix tablets of different enantiomers of

Ketoprofen, HPMC K100M as sustained release agent. Difference in the release profile

was observed due to chiral interaction of HPMC and Ketoprofen. HPMC showed more

interaction to S-enantiomer of Ketoprofen. Influence of formulation pH on the in-vitro

release profile of Ketoprofen was also studied. Diffusion study was also performed.

Roda et al. (2002) developed a new sustained release formulation of Ketoprofen

(Ibifen®) that gradually release Ketoprofen within 24 hours. For comparative in-vivo

study Ibifen® 200mg was administered to 12 human volunteer. Plasma profile was

compared with 200 mg Orudis retard® and two prompt release 100 mg Ibifen

®.

Vergote et al. (2002) in-vivo study of nanocrystalline Ketoprofen after oral

administration to drug was performed. No significant difference in AUC values was

noted between pellets formulation containing nanocrystalline or microcrystalline

Ketoprofen and commercially available prolonged release Ketoprofen formulation.

Perumal (2001) developed modified release microsphers of Ibuprofen by the emulsion

solvent diffusion technique. The in-vitro drug release and micromeritics propreties were

investigated.

Vergote et al. (2001) formulated controlled release pellets of Ketoprofen, using

NanoCyrstal colloidal dispersion. The in-vitro dissolution release pattern of wax based

pellets loaded with nanocrystalline Ketoprofen were compared with dissolution pattern of

wax based pellets loaded with microcrystalline Ketoprofen and commercially available



Ketoprofen sustained release formulation. Complete release of nanocrystalline

Ketoprofen was observed as compared to other formulations.

Sipahigil and Dortunҫ (2001) prepared and evaluated Verapamil and Ibuprofen

controlled release beads, using carrageenan by ionotropic gelation method. The effect of

different formulation factors such as drug content, polymer concentration, counterion

type and concentration and outer phase volume on particle size, encapsulation efficiency

in-vitro characteristics of beads were evaluated

Giunchedi et al. (2000) developed the hydrophilic matrix tablets of Ketoprofen, using

calcium gluconate, sodium alginate and HPMC in different ratios and combinations by

direct compression method. In-vitro release profile and erosion of the tablets were

investigated. The matrix tablets containing highest quantity of HPMC maintained their

capacity to release the drug for a longer period of time.

Claudia et al. (2000) prepared soy-lecithin aggregates for dermal use containing model

drug, Ketoprofen by compressed gas technique. After evaluation, it was concluded that

soy-lecithin aggregates were best candidates for new drug delivery in dermatology and

cosmetology.

Khan and Zhu (1999) formulated controlled-release matrix tablets of Ibuprofen, using

Carbopol 9334 P and blended mixture of Carbopol 934P and 971P, at different drug to

polymer ratio, by direct compression method. The effect of the proportion of the matrix

material and several co-excipients such as lactose, microcrystalline cellulose and starch

on the release mechanism was investigated.

Philip et al. (1999) prepared the S (+)-Ibuprofen mini-matrix tablets, using wet

granulation method. In-vitro drug release profile and mechanisms were studied.

Khan and Zhu (1998) developed Ibuprofen tablets, using surelease as granulating agent.

Wet granulation technique was used for the preparation of tablets. The influence of

several parameters such as levels of granulating agent, pH of dissolution media and

agitation speed on the release mechanism and release profile was investigated

Paul et al. (1998) formulated eutectic system of Ibuprofen and seven terpene skin

penetration enhancers were used to study.



Khan and Jiabi (1998) developed controlled-release matrix tablets of Ibuprofen, using

Carbopol 974P-NF, at different drug to polymer ratios by direct compression technology.

Nurten and Jülide (1997) designed controlled release osmotic pump system of

Ibuprofen, using polyethylene glycol 600 and sodium chloride as osmoting agents. In this

study, the influence of the delivery orifices and concentration of osmotic agents on the

release rate of Ibuprofen was evaluated.

Ntawukulilyayo et al. (1996) formulated two sustained release Ibuprofen formulation,

using xanthan gum and combination of xanthan gum and n-octenylsuccinate starch

(CL490) by direct compression method. In-vitro and in-vivo studies were conducted.

Blasi et al. (2007) formulated nanoparticles of Ketoprofen, using poly (lactide-co-

glycolide) polymer and physical interaction with drug was determined.

Eerikäinen et al. (2004) prepared Ketoprofen nanoparticles, using Acrylic Polymers

Prepared by an Aerosol Flow Reactor Method.

Thompson et al. (2004), prepared Ibuprofen-loaded microsphers, using novel

copolyesters.



CHAPTER 3

MATERIALS AND METHODS

3.1. MATERIALS

3.1.1. Chemical and reagent

The chemicals and reagents used in pre-formulation and formulation studies of

controlled release matrix tablets and solid dispersions are:

Model drugs Ibuprofen and Ketoprofen (Gratis sample by drug testing laboratory,

Peshawar, Abbott Laboratory, Pakistan, Sanofi-Aventis Pharmaceutical company,

Pakistan and Sigma, UK), Profenid SR® Ketoprofen 200mg tablets by Aventis

Pharmaceutical Company, Islamabad, Pakisstan and Ibuprofen Taiji SR® Ibuprofen 0.3g

(300mg) by China Pharmaceutical Company, Chongqing (Mainland), China (Purchased

from local market), Monobasic Potassium Phosphate (KH2PO4) (Merck, Germany),

Sodium Hydroxide (NaOH) (Merck, Germany), Magnesium Stearate (Solmom

Enterprise, Karachi, Pakistan), Lactose (BDH Chemical Ltd, UK), Different grades of

Ethyl Cellulose Polymer (Dow Chemical Co., Midland, USA), Hydroxypropyl methyl

cellulose (HPMC K100M) (Dow chemical Co., Midland, USA), Corboxy methyl

cellulose (CMC) (Merck, Germany), Starch (Merck, Germany), HPLC grade water

(Fisher, UK), Acetonitrile HPLC grade (Fisher, UK), Diethyl ether (Norway),

Orthophosphoric acid HPLC grade (Merck, Germany), Methanol, HPLC grade (Merck,

Germany), Ethanol (Fisher Scientific, UK), Double distilled water.

3.1.2 Instruments and equipment

Following instruments and equipment were used in this reaserch work.

UV/Visible Spectrophotometer (Shimadzu 1601, Japan), HPLC (Perkin Elmer, 200

series, USA; Millipore water, France), Dissolution apparatus (Pharma Test, PTWS-11/P,

Hunburg, Germany), Magnetic stirrer (VelpScientica, Germany), pH meter (Inolab,

Germany; Denver, USA), Analytical balance (Shimadzu, AX 200, Japan), Oven



(Mammert, Germany), Single punch tablets compression machine (Erweka, AR 400,

Germany), Fraibilator (Roche, Germany), Hardness tester (Erweka, Germany), Beaker,

test tubes, flasks (Pyrex, Japan; Fisherbrand, UK), Verniar caliper (Germany), Vacuum

filter assembly (Sartorius, Goettingen, Germany), Water distillation apparatus (IRMECO

GmbH, IM-100, Germany), Whatman filter paper (Whatman, Germany), Vacuum pump

(ILMVAC, Germany), Vortex mixer (Gyromixer, Pakland scientific, Pakistan),

Centrifuge machine (Helttich, Germany; Kubota, Janpan), Disposable Syringes (BD,

Pakistan), React vials (Greiner lavortechnik, Germany), Sonicator (Elma D78224,

Germany), Particle scanning distribution size analyzer (Horiba, LA-300, Japan), Shaking

water bath (Shel Lab, 1217-2E, USA), DSC instrument (Mettler Toledo DSC 822e,

Greifensee, Switzerland), FT-IR SpectrumOne spectrophotmer (Perkin Elmer, UK),

Stability Chamber (Ti-Sc-THH-07-0400, Faisalabad, Pakistan), Micropipette (20µl-

1000µl) (TreffLab, France; Gilson, France), Membrane filter paper (Sartorius AG,

Germany), Cannula (BD, Pakistan), Glass vials (Fisherbrand, UK), Glass pipettes

(Fisherbrand, UK), Pipette tips (Gilson, France), Microcentrifuge (Hettich, Micro 120,

Germany), Water bath (Grant, OLS 200, UK).

3.1.3 Animals:

Local breed rabbits of either sex (male and female) (Purchased from local market,

Lahore, Pakistan)

3.2 METHODS

3.2.1 Pre-formulation Studies

Pre-formulation studies were performed for both drugs (Ibuprofen and Ketopfrofen)

before development into matrix tables.

3.2.1.1 Drugs identity conformation: Conformation of the drug was done according

British Pharmacopeia (BP, 2007). Accordingly, the melting point, optical rotation and IR

spectra of the drug were determined, using digital melting point apparatus, optical

rotation and FT-IR machine, respectively. The results were compared with the standard

as given in British Pharmacopeia (2007).



3.2.1.2 Percentage purity determination of model drugs: Before formulation of matrix

tablets the Ibuprofen and Ketoprofen, samples were evaluated for their percentage purity.

The samples were compared with standards Ibuprofen and Ketopofen supplied by Abbott

Pharmaceutical Company, Karachi, Pakistan and Sanofi-Aventis Pharmaceutical

Company, Islamabad, Pakistan, respectively. In each case 50mg of drug was dissolved in

suitable quantity of phosphate buffer solution (pH 7.4) and the final volume (100ml) was

made with the same buffer solution. From this solution 1ml was taken and diluted up to

10ml. The absorbance of Ibuprofen was determined at λ max 223nm and that of

Ketoprofen at λ max 258nm using UV/Visible double beam spectrophotometer

(Shimadzu, 1601, Japan). The following formula was used for %age purity

determination:

%age Purity = )()(

)()(

SampleWstdAbsorbance

stdWSampleAbsorbance

× 100 (3.1)

Where, (std) = Standard, W = Weight.

3.2.1.3 Particles size analysis: The particles size analysis of the drugs was performed

with the Particle size analyzer (LA-300, HORIBA, Japan) using distilled water as a

circulating solvent. After setting different parameters (Circulation Speed: 2min, Ultra

sonic time: 5min, T%: 75%-85%, Form of distribution: standard, R.R.Index; 1.16-0.001)

small quantity of the drug was incorporated into the loading chamber and mean particles

size was determined.

3.2.1.4. Selection of suitable wavelength of model drugs: For this purpose 50 mg of

either drugs powder was dissolved in suitable volume of phosphate buffer solution (pH

7.4) in volumetric flasks and the final volume was made up to 100ml. The drug solution

was scanned between 190.0 nm to 500 nm using UV/Visible double spectrophotometer

(Shimadzu, 1601, Japan) and the λ mas was noted in each case.



3.2.1.5. Powder’s flow properties: The compactibility and flowability of a powder are

critical process parameters that must be determined and investigated prior to tablets

preparation. The flow properties of powders are affected by physicochemical and

mechanical properties of powder, in addition to operational processing conditions.

Moreover, the interparculate attractive forces between the components of powder may

affect the flow properties of powder (Li et al., 2004). Therefore, in order to maximize the

chances of success in formulation development accurate assessment and investigation of

the flow characteristic of powder is essential.

There are a number of methods which have been used for the assessment and

investigation of flow properties of powders such as Angle of Repose (Liu et al., 2001).

Compressibility Index (Liu et al., 2001; Kumar et al., 2001) and Hausner Ratio (USP,

2005; Li et at., 2004; Wong et al., 2002; Abdullah and Geldart, 1999)

3.2.1.6. Angle of Repose: Angle of repose is a parameter which is used for measurement

of characterization of powder flow and properties (Wong et al., 2002; Abdullah and

Geldart, 1999; Liu et al., 2004). A schematic representation of the angle of repose is

shown in the figure (3.1) (Wong et al., 2002).

Figure 3.1 Schematic representation of angle of repose

The funnel method was used for determination of angle of repose (α). The powders were

taken in a funnel. The funnels was fixed with a stand and bellow the funnel tip the Petri



dish was kept in such a way that the tip of the funnel was exactly at the center and just

above the apex of the heap of powder. The powders were fallen freely on to the Petri dish

and then measured the height of heap and diameter of the powder cone i.e. the diameter

of Petri dish and the following equation was used for calculation of angle of repose (α).

Tan (α) = base

heapofHeignt

5.0 (3.2)

Table 3.1 Angle of repose and flow properties according to B.P 2007.

Flow Property Angle of repose

Excellent 25-30

Good 31-35

Fair 36-40

Passable (May hung up) 41-45

Poor 46-55

Very poor 56-65

Very very poor >66

3.2.1.7. Compressibility index and Hausner Ratio: By measuring the bulk and taped

volume of powder, Compressibility Index and Hausner Ratio were determined. The

Husner value is the measure of propensity of the powder to be compressed and it is

determined using bulk and tapped bulk densities of a powder (USP, 2005). In this study,

first the powders were taken up to the volume of 100 ml in a graduated cylinder of 250ml

and it was the apparent or bulk volume (Vo) and then the cylinder was tapped on flat

surface until there was no further changes observed in powder volume, it was the final

volume or tapped volume (Vf) and the values were put in the following equations.

Compressibility Index = 100×

V

VfV (3.3)

Hausner Ratio = Vf

V (3.4)



Table 3.2 Compressibility Index and Hausner Ratio limits according to B.P 2007.

Compressibility Flow Character Hausner Ratio

1-10 Excellent 1.00-1.11

11-15 Good 1.12-1.18

16-20 Fair 1.19-1.25

21-25 Passable 1.26-1.34

26-31 Poor 1.35-1.45

32-37 Very poor 1.46-1.59

>37 Very very poor > 1.60

3.2.1.8. Differential scanning calorimetry (DSC) studies: The differential scanning

calorimetry (DSC) study was performed for the determination of drug interaction with

polymers and excipients, using DSC instrument (Mettler Toledo DSC 822e, Greifensee,

Switzerland) equipped with Stare computer program. Approximately 3-6mg of sample

was weighed in aluminum pan and then sealed with punched lid. The temperature ranged

between 20-300oC with heating rate of 10

oC/min under nitrogen gas flow.

3.2.1.9. Fourier transform Infrared (FT-IR) studies: The FT-IR spectra of pure,

Ibuprfofen, ketoprofen and its mixture with polymers and different excipients were taken

to observe the drug-polymer and excipient interaction, using FT-IR SpectrumOne

spectrophotometer (Perkin Elimer, UK) in the range of 650 to 4000 cm-1

. The sample of

several milligrams was placed on the stage of machine and then handle of the machine

was placed on the sample for generation of enough pressure. Then sharp peaks with

reasonable intensities were obtained. The spectra obtained were the result of 4 scans at 1

cm-1

resolution.

3.2.1.10. Preparation of Phosphate Buffer solutions (pH 7.4): For the preparation of

phosphate buffer solution (pH 7.4), firstly 0.2 M monobasic potassium phosphate

solutions and 0.2M sodium hydroxide (NaOH) solution were prepared. 0.2M monobasic

potassium phosphate solution was prepared by dissolving 27.218g of monobasic

potassium phosphate (KH2PO4) in 1000ml of double distilled water and 0.2M NaOH



solution was prepared by dissolving 8gram of NaOH in 1000ml of double distilled water,

followed by mixing the required volume of 0.2M sodium hydroxide and 0.2M monobasic

potassium, according to the United State Pharmacopeia (USP, 2007).

3.2.1.11. Construction of standard curves: For this purpose stock solutions of the model

drugs (Ibuprofen and Ketoprofen) were prepared in phosphate buffer solution of pH 7.4

having concentration of 0.2mg/ml and then from the stock solution of the respective drug

different dilutions were prepared. The standard curves were constructed by plotting

absorbance values of the dilutions against their respective concentrations.

3.2.1.12 Calculation of concentration of Ibuprofen and Ketoprofen: Regression

equations obtained from the standard curve of Ibuprofen and Ketoprofen were used for

the calculation of concentration of Ibuprofen and Ketopfofen.

Y= MC+B (3.5)

After rearranging the equation:

C= (Y-B)/M (3.6)

Where, Y = Absorbance of solution containing Ibuprofen and ketoprofen at λ max 223nm

and λ max 258nm, respectively.

M = Slope of Ibuprofen or Ketopfrofen Standard Curve of known concentrations

C = Concentration to be calculated

B = Intercept of the Curve

3.2.1.13 Solubility study: Solubility studies of Ibuprofen and Ketoprofen were performed

in different solvents (Phosphate buffer of pH 6.8, 7.2, 7.4, distilled water and 0.1N HCL)

at different temperatures (Room temperature (25oC), 37

oC and 40

oC) according to a

published method by Higuchi and Connors (1965). Accordingly, surplus amount (100mg)

of Ibuprofen and Ketoprofen were placed in 100ml volumetric flasks and then made the

final volume with the desired solvent up to 100ml. The flasks were sealed with aluminum

foils using rubber bands to avoid solvent loss. Then these flasks were kept on shaking

using thermostatically controlled shaking water bath (Shel Lab, 1217-2E, USA) for 24

hours at room temperature (25oC). The oscillation speed was kept at 100 oscillations per



minute. After 24 hours all flasks were kept undisturbed on flat surface for three hours. A

few ml supernatant from each flask was taken and filtered through membrane filter

(0.45µm). One ml each filtrate was diluted with the same solvent up to 25ml to achieve

suitable dilutions. The diluted samples were analyzed to determine the Ibuprofen and

Ketoprofen concentrations, using a UV/Visible double beam spectrophotometer

(Shimadzu, 1601, Japan) at λ max 223nm and 258nm, respectively. The calibration

curves were used for the determination of the quantity of soluble drug per ml. The same

procedure was repeated for other temperatures such as 37oC and 40

oC. All the solubility

measurements were performed in triplicate.

3.2.1.14. Preparation of solid dispersions: Solid dispersions of Ibuprofen Ketoprofen

were prepared with drug and carrier (Glucosamine HCL) ratio 1:1, 1:2 and 1:3 by weight,

using solvent evaporation technique (Prasad et al., 2010; Jain et al., 2009). The drug was

dissolved in ethanol followed by the addition of carrier dispersion in ethanol. The solvent

was then removed by evaporation keeping at 40o

C under stirring condition (100rpm) for

24 hours. The solid dispersions prepared were then collected and kept at room

temperature for 48 hours. Then the mass was pulverized in porcelain mortar and pestle

and passed through sieve no 100, and stored at room temperature in a desiccator until

further use.

3.2.1.15. Preparation of physical mixtures: For comparative studies of solid dispersions,

physical mixtures were also prepared. The physical mixtures prepared were having the

same composition of the solid dispersions; however, they were prepared by simple

trituration of drugs and carrier in porcelain mortar followed by thorough blending in poly

bags. The mixtures were then sieved and stored in desiccator at room temperature until

further evaluation.

The composition of physical mixtures and solid dispersions of the model drugs is shown

in tables 3.3 and 3.4.



Table 3.3 Composition of solid dispersions and physical mixtures of Ibuprofen

Formulation

Code Carrier Drug : Carrier Method

F1IBF Glucosamine HCL 1:1 Physical mixture (trituration)

F2 IBF Glucosamine HCL 1:2 Physical mixture (trituration)

F3 IBF Glucosamine HCL 1:3 Physical mixture (trituration)

F4 IBF Glucosamine HCL 1:1 Solid dispersion (solvent evaporation)



Table 3.4 Composition of solid dispersions and physical mixtures of Ketoprofen

Formulation

Code Carrier Drug : Carrier Method

F1KTP Glucosamine HCL 1:1 Physical mixture (trituration)

F2 KTP Glucosamine HCL 1:2 Physical mixture (trituration)

F3 KTP Glucosamine HCL 1:3 Physical mixture (trituration)

F4 KTP Glucosamine HCL 1:1 Solid dispersion (solvent evaporation)



3.2.1.16. Evaluation of solid dispersions and physical mixtures: The evaluation of solid

dispersion and physical mixture was performed using the following different techniques:

3.2.1.16.1. Determination of drug content: The drug content in each formulation was

determined by taking the solid dispersions or physical mixturesthe equivalent to 50mg of

the respective model drug (Ibuprofen or Ketoprofen) and transferring it to volumetric

flask of 100ml and then small volume of phosphate buffer (pH 7.4) was added to hydrate

the samples. Finaly the volume was made upto the mark. The samples were shaked for

some time to dissolve the drugs completely and were filtered carefully. The absorbance

values of standard (Ibuprofen and Ketoprofen standard, supplied by Abott Labortory,



Karachi, Pakistan and Sanofi Aventis, Pharmaceutical Company, Islamabad, Pakistan,

respectively) and the samples were determined at λmax 223 nm and 258nm for Ibuprofen

and Ketoprofen, respectively, using double beam spectrophotometer (UV-1601,

Shimadzu, Japan). Three reading were taken and then mean and standard deviation were

calculated.

3.2.1.16.2. Differential scanning calorimetry (DSC) studies: The differential scanning

calorimetry (DSC) study of carier Glucosamine, pure Ibuprofen, Ketoprofen, the solid

dispersions and physical mixtures of the model drugs was performed according to the

method described above in section 3.2.1.8, for determination of drugs-carrier interaction.

3.2.1.16.3. Fourier transform Infrared (FT-IR) studies: The FT-IR spectra of carrier

Glucosamine, pure Ibuprofen, Ketoprofen, the solid dispersions and physical mixtures

were taken to observe the drugs-carrier interation, using the same method as described in

section 3.2.1.9 of this thesis.

3.2.1.16.4. X-ray powder diffractometory studies: X-ray patterns of pure Ibuprofen, pure

Ketoprofen, physical mixtures and solid dispersions were taken using a Philips PW 1830

powder diffractometor (Philips, Eindhoven, Netherlands). The prepared samples were

exposed to Cu Kα radiation (λ= 1.5418 Å) in the range of 00

≤ 2θ ≤ 500. The step size was

0.050 and the time for each step was kept two secods.

3.2.1.16.5. Scanning electron microscope (SEM) analysis: Electron micrographs of

carrier Glucosamine, pure Ibuprofen, pure Ketoprofen, physical mixtures and solid

dispersions were obtained using scanning electron microscope (SEM; Joel JSM-5910,

Japan) operating at 10 kV. The samples were mounted on a metal stub using adhesive

tape with double sided and coated with gold for conductivity in an organ atmosphere

before observation. To study the morphology of active drugs, physical mixture and solid

dispersions, micrographs with different magnification were obtained.



3.2.1.16.6. Solubility measurement: The solubility measurements of pure Ibuprofen,

Ketoprofen, physical mixtures and solid dispersions in distilled water were performed

according to the well published method by Higuchi and Connors (1965), as described

above in section 3.2.1.13.

3.2.1.16.7. In –vitro dissolution studies: The in-vitro dissolution studies were performed

by USP method II (Paddle method) using eight stations dissolution apparatus Pharma

Test (PTWS-11/P, TPT, Hunburg, Germany) and the rotation speed of paddles was set at

100 r. p.m. Each station or flask of the dissolution apparatus was filled with 900ml of

distilled water, used as dissolution medium to study percentage dissolution of model

drugs (Ibuprofen and Ketoprofen), physical mixtures and solid dispersions. The

temperature of dissolution medium was kept 37oC ± 0.5

oC. Samples of five ml were

withdrawn at selected time intervals (5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100,

110, 120 min) with the help of syringes consisting of 0.45um filters. After each sampling

equal volume of fresh dissolution medium was replaced to maintain the dissolution

medium constant. Then after appropriate dilution the samples were analyzed for

Ibuprofen and Ketoprofen using double beam spectrophotometer (UV-1601, Shimadzu,

Japan) at λmax 223nm and 258nm, respectively. Percent drug dissolution of Ibuprofen

and Ketoprofen was calculated by using calibration standard curves of respective drugs.

The study was conducted in triplicate.

3.2.2 Formuation studies

3.2.2.1 Formulation of matrix tablets containing Ibuprofen and ketoprofen by direct

compression method: Matrix tablets of Ibuprofen and Ketoprofen were prepared using

polymers (Ethocel®

standard premium and Ethocel® standard FP premium) of different

viscosity grades, as drug release controlling agents. HPMC K100M, CMC, Starch and

Lactose were used as co-excipient to determine their influence on the release patterns and

release mechanism of the drugs and Magnesium stearate was use as lubricant. Direct

compression method was used for the preparation of matrix tablets and drug-to-polymer

ratio (D: P) was kept 10:1, 10:2 and 10:3.



Table 3.5 Different matrix tablets composition of Ibuprofen

D:P

Ratio

Drug Polymer Filler

(Lactose)

Lubricant Co-excipients

200 mg Ibuprofen -Ethocel matrices

10:1 100mg

7 Premium

10 mg 89 mg

0.5 %

------

7 FP Premium

1 mg

10 Premium

10 FP Premium

100 Premium

100 FP Premium

10:2 100mg

7 Premium

20 mg 79 mg 1 mg ------

7 FP Premium

10 Premium

10 FP Premium

100 Premium

100 FP Premium

10:3 100 mg

7 Premium

30 mg 69 mg 1 mg ------

7 FP Premium

10 Premium

10 FP Premium

100 Premium

100 FP Premium

200 mg Ibuprofen -Ethocel matrices having Co-excipients ( CMC, HPMC, Starch)

10:3 100mg

7 Premium

30 mg 48.3 mg

0.5 % 30 % of filler

7 FP Premium

1 mg 20.7 mg

10 Premium

10 FP Premium

100 Premium

100 FP Premium

All ingredients excepte magnesium stearate were mixed according to dilution principle of

powders and then polybags were used for further mixing. After this, for thorough mixing,

the powder mixtures were passed through No 30-mesh size screen and then the required

amount of magnesium stearate (0.5%) was added as lubricant and mixed well. Later on

each resultant mixture was passed twice through the same mesh screen, and then each

mixture was directly compressed into tablets, using single punch machine (Erweka,

Germany) equipped with 8 mm punch and die set. The composition of various

formulations is given in the tables 3.5 and 3.6.



Table 3.6 Different matrix tablets composition of Ketoprofen

D:P

Ratio Drug Polymer

Filler

(Lactose) Lubricant Co-excipients

200 mg Ketoprofen -Ethocel matrices

10:1 100mg

7 Premium

10 mg 89 mg

0.5 %

------

7 FP Premium

1 mg

10 Premium

10 FP Premium

100 Premium

100 FP Premium

10:2 100mg

7 Premium

20 mg 79 mg 1 mg ------

7 FP Premium

10 Premium

10 FP Premium

100 Premium

100 FP Premium

10:3 100 mg

7 Premium

30 mg 69 mg 1 mg ------

7 FP Premium

10 Premium

10 FP Premium

100 Premium

100 FP Premium

200 mg Ketoprofen -Ethocel matrices having Co-excipients ( CMC, HPMC, Starch)

10:3 100mg

7 Premium

30 mg 48.3 mg

0.5 % 30 % of filler

7 FP Premium

1 mg 20.7 mg

10 Premium

10 FP Premium

100 Premium

100 FP Premium

3.2.2.2. Physical evaluation of matrix tablets: In order to assess whether the tablets

fulfill the desired specifications of United States Pharmacopeia 2007. The USP range for

hardness, friability, thickness, diameter and drug content uniformity is 5-10kg/cm3,

0.8%, 2-4 mm, 4-13 mm and 90-110%, respectively (USP, 2007). Different physical and

dimensional tests such as weight variation, thickness and diameter, hardness test, content

uniformity and friability (Augsburger et al.,2002) were performed, as mentioned below.

3.2.2.2.1 Weight variation test: For this purpose 20 tablets were taken from each batch

and weighed individually, using analytical balance (AX-200, Shimadzu, Japan). The

mean and standard deviation were calculated, using computer based excel programme

and the results were recorded accordingly.



3.2.2.2.2 Thickness and diameter: The thickness and diameter of 20 tablets from each

batch were observed by varnier caliper (Varnier caliper, Germany) and then mean and

standard deviation were calculated.

3.2.2.2.3 Crushing strength or Hardness test: Crushing strength or Hardness of a tablet

is an indication of the resistance of the solid dosage form to withstand fracturing/ or

attrition (Alton, 2000). For this test, 10 tablets were taken from each batch and their

hardness was determined by using hardness tester (Erweka, Germany). The mean and

standard deviation were calculated and noted accordingly.

3.2.2.2.4 Friability test: It is evaluated under specific conditions. It is used to determine

whether any damage may occur to surface of tablets or whether lamination or tablet

failure may take place when a dosage form is subjected to a mechanical shock (USP,

2005; BP, 2002). Different official guidelines are given by USP and BP. To determine

the friability of the prepared matrix tablets, pre-weighed/de-dusted 20 tablets (W1) from

each formulation were used. For this test, Roche friabilator (Erweka, Germany) was used

at speed of 25 r.p.m for four minutes. Then the tablets were de-dusted well with the help

of a blower and re-weighed (W2) to determine the loss in their weight. Friability was

calculated using the following formula:

1

21%

W

WWF

×100 (3.7)

Where, W1= Initial weight of tablets; W2= Final weight of tablets

3.2.2.2.5 Content Uniformity Assay: For this purpose 10 tablets were taken randomly

from each batch and pulverized into powder, using pastle and mortar. The powder

samples equivalent to 20 mg of the drug were transferred to a volumetric flask (100ml)

followed by addition of a small volume of phosphate buffer (pH 7.4) to hydrate the

samples and final volume was made upto the mark. The samples were shaked for some

time to dissolve the drug completely and were passed through membrane filter paper

(0.45µm). The absorbance values of standar standard (Ibuprofen and Ketoprofen



standard, supplied by Abott Labortory, Karachi, Pakistan and Sanofi Aventis,

Pharmaceutical Company, Islamabad, Pakistan, respectively) and the samples were

determined at λmax 223 nm and 258nm for Ibuprofen and Ketoprofen, respectively,

using double beam spectrophotometer (UV-1601, Shimadzu, Japan). Three reading were

taken and then mean and standard deviation were calculated.

3.2.2.3. In vitro dissolution studies

In vitro dissolution studies were conducted for the determination of drug release rate

from the formulations to USP method-1 (basket method), using eight stations dissolution

apparatus Pharma Test (PTWS-11/P, TPT, Hunburg, Germany) and the rotation speed of

basket was set at 100 r.p.m. Each station or flask of the dissolution apparatus was filled

with 900ml of 0.2M phosphate buffer (pH7.4) used as dissolution medium to study the

release rate and pattern of drug from tablets matrices up to 24 hrs. The temperature of

dissolution medium was kept 37ºC ± 0.5ºC. Samples of five ml were withdrawn at pre-

dermined time of interval 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 and 24 hrs with the help of

syringes consisting of 0.45um filters. After each sampling equal volume of fresh

dissolution medium was replaced to maintain the dissolution medium constant. Then all

samples were diluted with the same buffer solution. The absobance values of model drugs

(Ibuprofen and Ketoprofen) were recorded, using spectorophtometerl (UV/Visible-1601,

Shimadzu, Japan) at λmax 223 and 258nm for Ibuprofen and Ketoprofen, respectively.

Finally percent release of drugs was calculated, using their respective calibration standard

curves. The release study for all formulations was conducted in triplicate.



Figure 3.2 Pharma-test dissolution apparatus

3.2.2.4. Drug Release kinetics

The following various kinetic models were applied on the data obtained from in vitro

dissolution studies of different matrix tablets formulations to determine the release

kinetics:

3.2.2.4.1 Zero-order kinetics (Xu and Sunada, 1995; Najib and Suleiman, 1985): Zero

order kinetic equation or model may be used for the constant release rate characterization

or representation of any active pharmaceutical ingredient (API) from a dosage form that

do not disintegrate or deaggregate (Costa and Lobo, 2001; Chang RK, 1986). Those

dosage forms which follow zero order kinetic, release the API in a constant amount per

unit time. To achieve prolong pharmacological action in sustained release dosage forms,

zero order model is an ideal kinetic model (Costa and Lobo, 2001; Chang RK, 1986).

This model is representing in the following equation.



W = k1t (3.8)

Where,

W = the amount of drug release at time = t

k1 = the zero-order release rate constant

t = time

3.2.2.4.2 First-order kinetics equation (Merchant et al., 2006; Avachat and Kotwal,

2007; Donbrow and Samueloy, 1980; Higuchi, 1963): The first order kinetic equation or

model was first proposed by Gibaldi and Feldman (Gibaldi and Feldman, 1967) and later

by Wagner (Wagner, 1969), where this model was used for description and

Characterization of absorption and release or elimination of certain drugs from biological

systems. This kinetic equation or model may be applied in those dissolution situation

where sink conditions exist (Wagner, 1969). This has shown in the following equation.

In (100-W) = In100-k2t (3.9)

Where,

W= the amount of drug release at time = t;

k2= the first order release rate constant

t= time

3.2.2.4.3 Hixon Crowel’s Equation(Erosion model) (Costa et al.,2003; Hixon and

Crowell, 1931): This model was developed by Hixon and Crowell (Hixon and Crowell,

1931). It is represented in the following equation.

(100-W)1/3

=1001/3

– k3t (3.10)

Where, W= the amount of drug release at time = t;

k3= a constant incorporating the surface volume relationship;



3.2.2.4.4 Higuchi’s Squre of Time Equation (Diffusion model) (Higuchi, 1963;

Korsmeyer et al., 1983): The Higuchi or Diffusion model describes the dissolution of

drugs in suspension from non-eroding matrix such as ointment base (Higuchi, 1963;

Higuchi, 1961). This model is also applicable for description of dissolution rates of other

pharmaceutical dosage forms other than ointment and also for description of dissolution

process and release mechanism of modified drug delivery systems (Higuchi, 1963;

Higuchi, 1961). The simple form of Higuchi model is shown in the following equation.

W = k4t1/2

(3.11)

Where,

W= the amount of drug release at time = t

k4= Higuichi dissolution rate constant

t= time

3.2.2.4.5 Power law equation or Korsmeyer- Peppas equation for mechanism of drug

release (Brabander et al., 2003; Korsmeyer et al., 1983; Rigter and Peppas, 1987): It is a

simple semi-empirical model that creates a relationship between drug release and elapsed

time with an exponential function. It is represented mathematically in the following

equation.

Mt / M∞ = k5t n

(3.12)

Where,

Mt / M∞= the fraction of drug release at time = t

k5= kinetic constant compromising the structural and geometric characteristics of the

device; n= the diffusion exponent for drug release

This model has been used for different systems in which the value for n is used to

describe different release mechanisms. For cylindrical matrix tablets if the n value is

equal to 0.45, then it indicates that the drug release mechanism is Fickian diffusion, and if

the n value is more than 0.45 and less than 0.89 it indicates that it is non-Fickian or



anomalous diffusion and if n value 0.89 is the indication of case II transport or typical

zero order release (Siepmann and Peppas, 2001) and greater than 0.89 is super case II

transport (Vueba et al., 2004)

Table 3.7 Interpretation of release exponent “n” in power law for release

mechanism of different geometries (Rigter RL and Peppas, 1987a; Retger and Peppas,

1987b). Exponent “n” for

Thin film Cylinder Sphere

Drug release mechanisms

≤ 0.5 ≤ 0.45 ≤ 0.43 Fickian diffusion

0.5 < n < 1.0 0.45 < n < 0.89 0.45 < n < 0.89 Anomalous

1.0 ≥ 0.89 0.85 Zero order

Note: The word cylinder refers to tablets

3.2.2.5 Testing dissolution equivalency

To test dissolution equivalency model independent method was used as such, suggested

by shah (Shah et al., 1998) and Fassihi and Pillay (Fissihi and Pillay, 1998). This model

was recommended for use by the US FDA (US FDA, 1997). Model independent method

is a simple approach to compare the dissolution profiles using difference factor ƒ1 and

similarity factor ƒ2. These are commonly known as ƒ1 and ƒ2 fit factors, originally

reported by Moore and Flanner (Moore and Flanner, 1996). To calculate the percent

difference between the two dissolution profile at each time point and relative error

between the two curves difference factor ƒ1 is used. The difference factor ƒ1 was

calculated using the following formula:



ƒ1 = (3.13)

Where “n” is the number of pull points, Rt is the dissolution profile of the reference

tablets at time t and Tt is the dissolution profile of the test tablets at the same time “t”.

The similarity factor ƒ2 is a measurement of the similarity in the percent dissolution

between the curves and logarithmic reciprocal square root transformation of the sum of

squared error.

The following formula was used for similarity factor ƒ2.

ƒ2 = 50 log (3.14)

Where n is the number of points collected, Rt and Tt are the percent drug released at each

time point for reference and test tablets, respectively. If the value of difference factor ƒ1

is close to zero and similarity factor is close to 100 then the release profiles between two

formulations are considered similar. Generally, ƒ1≤15 and ƒ2 ≥50 indicates an average

difference of not more than 10% at the sample time points. (Gohel and Panchal, 2002;

Shah et al., 1998; US FDA, 1997)

3.2.2.6. Accelerated stability and reproducibility studies

The selected optimized matrix tablets formulations of each drug were stored at room

temperature, using stability chamber (Ti-Sc-THH-07-0400, Pakistan) and also tested for

stability under the short term accelerated storage conditions. Short term stability study

was carried out under the International Commission for Harmonization (ICH) guidelines

for accelerated storage conditions i.e. at 40 ±2

oC and Relative humidity (HR) 75 ±5 %.

The tablets were evaluated for their physical appearance, hardness, friability, weight

variation, content uniformity, dissolution profile at predetermined intervals of 0, 1, 2, 3,

6, 9, and 12 months.



3.2.2.7. Preparation of matix tablets containing solid dispersions of model drugs

Solid dispersions of models drugs (Ibuprofen and Ketoprofen) corresponding to 100mg

of drugs, using Ethocel® standard 7 FP premium polymer as release controlling agent, at

D: P ratio 10: 3 were poured into die. Tablets were compressed according to the method

as described above in section 3.2.2.1 and physicochemical evaluation and in-vitro

dissolution study were carried out according to section 3.2.2.2 and 3.2.2.3, respectively.

3.2.2.8. In-vivo evaluation

3.2.2.8.1. Study Protocol and Design: The study protocol was approved by Research and

Ethical Committee. The Animal Scientific Procedure Act, 1986 was followed for the

procedure used. The pharmacokinetic parameters of the reference sustanined release

tablets and optimized controlled release test tablets for comparison were studied in two

animal groups, each comprising 12 rabbits in a parallel study design. The in-vitro and in-

vivo correlation was carried using suitable formulas. The dose study design has been

given in table (3.8)

Table 3.8 Dosing Schedule design of test tablets and reference tablets for

pharmacokinetics study

Treatment Description Dose

1 Ibuprofen Taiji SR®, Sustained release Ibuprofen tablets

(300 mg)

1 tablet

2 Test CR matrix tablets of Ibuprofen (300 mg) 1 tablet

3 Profenid SR®, Sustained release Ketoprofen tablets (200

mg)

1 tablet

4 Test CR matrix tablets of Ketoprofen (200mg) 1 tablet

Note: Treatment 1, 2, 3, and 4 with dose 1 tablet means that one tablet of each

formulation of test and reference was administered to each rabbit of the group (n=12)

As shown in the table (3.8). In the first trial period, each rabbit of one group (n=12) was

given reference tablets of Ibuprofen and each rabbit of the other group (n=12) was given



test tablets. And then after washout period of one week, each rabbits of both the groups

were given reference Ketoprofen tablets and test tablets.

3.2.2.8.2. Animals used for in-vivo studies: For in-vivo studies, local breed rabbits of

either sex, weighing 3 ± 0.5Kg were used as were used by Ishikawa (Ishikawa et

al.,2000) Maeda (Maeda et al.,1979) and Jing (Jing et al.,2006).

The rabbits were divided into two groups each one consisting 12 rabbits for assessment of

the pharmacokinetics evaluation of the test and reference formulations. The rabbits used

were kept on fasting for 24 hours before administration of test and reference tablets and

the same fasting condition was maintained until 24 hours post dosing. However, water

was allowed at libitum during this period.

3.2.2.8.3. Food, animal housing and maintenance for rabbits: The standard food was

given to the rabbits used for this study at least three days before administration of the

formulations. The standard food was prepared according to a published recipe composed

of 10% White fish meat, 18% Middlings, 20% Grass meal, 40% Bran (Kelley et al.,

1992)

3.2.2.8.4. Tablets administration to rabbits: For administration of tablets to rabbits 3ml

syringe with its barrel smoothly cut at the needle end to avoid the damage to oral mucosa

of rabbit was used. Before administration of tablets the rabbits were kept on fasting for

24hours and then the rabbits were shifted to wooden holder and tablets were administered

orally with help of syringe as mentioned. After conformation of tablets swallowing tap

water was given to rabbits with the help of 10ml syringe fitted with oral tube in order to

mimic human dosing.

3.2.2.8.5. Blood sample’s withdrawal or collection from rabbits: The blood samples of

1ml were collected in centrifuged tubes (Containing sodium heparin as anti-coagulant) at

0 (before dosing) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, 42 and 48 hours after

dosing via an in-dwelling cannula placed in the marginal ear vein (Fig. 3.3) of rabbits for

the test and reference formulations of Ibuprofen and Ketoprofen. The blood samples



collected were centrifuged for 15min at 3500 rpm and the plasma was transferred to new

glass tubes and kept frozen at -200 C until analysis.

Figure 3.3 Marginal ear vein of rabbit

3.2.2.9. Extraction of drugs from plasma

3.2.2.9.1. Extraction procedure for Ibuprofen and Ketoprofen from plasma: For the

extraction of drugs from the plasma a simple one step liquid liquid extratction procedure

was used. For the extraction of Ibuprofen from plasma the method used by

Ntawukulilyayo et al (Ntawukulilyayo et al., 1996) was used with slight modification.

Briefly, 500µl of plasma containing drug Ibuprofen was taken into a glass tube with

Teflon lined screw cap and 4ml hexan/ether mixture (4:1, v/v) was used as extracting

solvent. For Ketoprfofen extraction the method reported by Satterwhite and Boudinot

(Satterwhite and Boudinot, 1988) was used with some modification. In this the same

volume of plasma (500µl) was taken and then the samples were extracted with 4ml

diethyl ether. Then the samples prepared were vortexed 1-5 minutes with help of vortex

mixer (Gyromixer, Pakistan). After vortex mixing the samples were centrifuged 3500

rpm for 15 minutes by centrifuge (Kubota, Japan). Then the upper supernatant layer was



transferred into React vial (React vial, Germany). Then the extraction solvents were

evaporated to dryness under nitrogenous atmosphere at 40o C. The resulting residues in

react vial were reconstituted with 100µl of respective mobile phases for Ibuprofen and

Ketoprofen.

3.2.2.10. HPLC analysis of drugs in rabbit plasma

For the determination and analysis of Ibuprofen and Ketoprofen concentration in plasma

the already published methods were used with slight modification.

3.2.2.10.1. Analysis of plasma Ibuprofen concentration: The Ibuprofen plasma samples

were analyzed, using a reversed-phase high performance liquid chromatographic (HPLC)

technique according to the method reported by (Paul et al.,1998) with slight modification.

Briefly, the HPLC system comprised of an HPLC (Perkin Elmer series 200, USA) with

binary pump solvent delivery system (Perkin Elmer Series 200, USA), UV/ Visible

variable wave length detector (Perkin Elmer Series 200, USA), Integrator NCI 900,

Degasser (Perkin Elmer Series 200, USA) and TCNav software. The samples of 20µl

were injected with the help of 50µl syringe into a 20µl sample loop in Rheodyne

injection port. The eluted chromatographic peaks were detected at λ max 220nm by UV

detector (Perkin Elmer Series 200, USA), using a reverse phase C-18 (ODS Hypersil, 4.6

×250mm, 5µm) stainless steel analytical column (Thermo Electron Corporation, UK)

fitted with a refillable guard column. The solvent used were degassed with help of

sonicator (Elma D 78224, Germany) before operation of HPLC and the pH of the mobile

was adjusted by pH meter (Inolab Series, Germany). The mobile phase consisted of

acetonitrile and phosphate buffer (60:40 v/v) with pH 3.0 ±0.2 was used. The pH of the

mobile phase was adjusted with orthophosphoric acid. The mobile phase prepared was

filtered through the 0.45µl membrane filter (Sartorius, Germany) and was then degassed

by ultrasonication. The analysis of was performed isocratically with mobile phase flow

rate of 1.0ml/min. And then quantification was done by linear regression equation

derived from standard curve.



3.2.2.10.2. Analysis of plasma Ketoprofen concentration: The chromatographic analysis

of Ketoprofen samples was performed using the same HPLC system and procedure which

were used for Ibuprofen, but the mobile phase composition and the λ max for eluted

chromatographic peaks detection were different. The Ketoprofen in plasma was

determined according to the method described by Roda et al (Roda et al., 2002). For the

elution of Ketoprofen the mobile phase consisted of acetonitrile and 0.1M KH2PO4

(40:60 v/v) was used. The pH was adjusted to apparent pH 3.5 with H3PO4. The peaks

were detected at λ max 254nm.

3.2.2.11. Pharmacokinetic analysis

The most common pharmacokinetic parameters such as peak plasma concentration

(Cmax), time to reach maximum plasma concentration (Tmax) and total area under the

plasma concentration-time curve (AUC0-∞) were determined from the plasma

concentration time profile of the reference and test formulation for twelve rabbits. The

peak plasma concentration (Cmax) and time of its occurrence (Tmax) were calculated

directly from each plasma concentration data (Weiner, 1981). The plasma concentration-

time data for both drugs Ibuprofen and Ketoprofen in each animal was analyzed by well-

known pharmacokinetic computer software, WinNolin® Ver 5.2.1(Pharsight Corporation,

Mountain View, CA, USA). The total area under the plasma concentration-time curve

(AUC0-∞) was estimated by adding the area from time zero to the last sampling time

(AUC0-t) and the area from the last sampling point to infinity (AUCt-∞). The (AUC0-∞)

and momen plasma level time curves (AUMC) were calculated by trapezoidal method.

The ratio of (AUCt-∞) and (AUMC) was used for the calculation of mean residence time

(MRT). The (AUCt-∞) was determined by dividing the last measurable plasma drug

concentration with total elimination rate constant (Kel). All other parameters such as

terminal rate constant (Lz), half-life (t1/2), clearance (Clt), volume of distribution (Vd)

were calculated using the following formulas:

t1/2= In2/Lz, Cltotal= Dose/(AUC0-∞), and Vd= Cltotal/Lz, respectively.



3.2.2.11.1. In-vitro and In-vivo correlation: The in-vitro and in-vivo correlation was

determined by plotting the percent drug absorbed (Fa) against percent drug released (Fr).

The values of percent drug released were taken from the in-vitro release data while

percent drug absorbed was determined by using Wagner and Nelson equation (Wagner

and Nelson, 1964).

Fa (3.16)

Where,

Fa= fraction of drug absorbed;

Ct= plasma drug concentration at time = t

Kel= the total elimination rate constant;

AUC0-t= area under the curve between time zero and time t;

AUC0-∞= area under the curve between tie zero and infinity

3.2.2.12. Statistical analysis

The parameters obtained were further processed for individual rabbit statistically for

getting mean and standard deviation and level of significance, using computer based

programs SPSS 17.



CHAPTER 4

RESULTS AND DISCUSSION

Ibuprofen and Ketoprofen are Non-steroidal anti-inflammatory drugs, used for

rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute musculoskeletal injury

and dysmenorrhea. Due to their short half-life, dosage frequency, patient non-compliance

and side effects such as gastrointestinal disturbance, peptic ulceration and gastrointestinal

bleeding, they are considered to be good candidates for formulation into controlled

release dosage forms. Different drug delivery systems were developed such as controlled

release matrices, solid dispersionS and nanoparticle to avoid the above mentioned

problems.

4.1. Drugs identity conformation studies

During the preformulation studies, both drugs were evaluated physically in order to

confirm their identity, using British Pharmacopoea, 2007 as reference standard. As shown

in table 4.1, the melting point and optical rotation for Ibuprofen are 76.1oC and 0.03,

respectively and for Ketoprofen the melting point determined is 94oC, which are within

BP limits.

Table 4.1 Results of identity conformation tests

Chemical Test

performed

Result Official limit Comments

Ibuprofen Melting point

&

Optical rotation

76.1 °C

&

+ 0.03

75 to 78°C

&

-0.05° to + 0.05°

Identity

confirmed

Ketoprofen Melting point

94oC

94 to 97oC

Identity

confirmed

For further conformation FT-IR spectra for both drugs were taken and compared with the

standard spectra given in BP, 2007.



Figure 4.1 FT-IR spectra of (a) BP Standard (b) Pure Ibuprofen sample

Figure 4.2 FT-IR spectra of (a) BP Standard (b) Pure Ketoprofen sample

Table 4.2 Percentage purity of Ibuprofen and Ketoprofen

Drug Absorbance %age purity

determined

BP 2007 limit comments

Ibuprofen Sample= 2.232

Standard= 2.237

99.78

99% to 101% Within limit

Ketoprofen Sample= 3.01

Standard= 3.019

99.701 99% to 101% Within limit



As shown in Figs. 4.1 and 4.2, the FT-IR spectra of Ibuprofen and Ketoprofen samples

were similar, in all respects, to standard spectra of the same drugs as given in the BP,

2007, indicating the identity conformation and purity of the samples/model.

Table 4.2 shows the % age purity of the sample Ibuprofen and Ketoprofen as compared to

those of the BP standards. It may be observed that the % age purity of the sample drugs

lies within the acceptable BP limits.

4.2. Particle size analysis

After determination of percentage purity of the drugs, particle size analysis was

performed because particle size and size distribution of any drug play an important role in

the release pattern as well as the release mechanism of a drug from controlled release

formulations (Velasco et al., 1999). The details about mean particles size and size

distribution of Ibuprofen and Ketoprofen are shown in the Figs. 4.3 and 4.4. As shown

the mean particle size distribution for Ibuprofen was 38.30µm while that for Ketoprofen

the 24.35µm. So it indicated that both drugs are suitable candidate for controlled release

formulations.

Figure 4.3 Particle size distribution of Ibuprofen



Figure 4.4 Particle size distribution of Ketoprofen

4.3. Selection of suitable wavelength for model drugs (Ibuprofen and Ketoprofen)

The UV spectra of Ibuprofen and Ketoprofen in phosphate buffer solution (pH 7.4) are

shown in Figs. 4.5 and 4.6.

Figure 4.5 UV/Visible spectra of Ibuprofen with different wave lengths in phosphate

buffer solution pH 7.4



Figure 4.6 UV/Visible spectra of Ketoprofen with different wave lengths in


The spectra demosnstrate primery maximas (peaks) at 223nm and 217nm for Ibuprofen

and Ketoprofen, respectively, while secondry maximas (peaks) for Ibuprofen and

Ketoprofen are shown at 264nm and 258nm, respectively. In case of Ibuprofen, the

primary maxima (223nm) was selected as suitable wavelength for further analysis due to

clear peak and stable and maximum absorbance at this wavelength, as shown in Fig. 4.5.

However, in case of Ketoprofen a secondry maximum (258nm) was selected because of

stability and maximum absorbance at this wave length (Fig. 4.6).

4.4. Powder’s flow properties

In order to obtain optimum flow of powder from bulk storage containers or hoppers into

dies and for achieving reproducible matrix tablets with acceptable content uniformity,

blends of each formulation and pure Ibuprofen and Ketoprofen were evaluated for

compressibility index, Hausner Ratio and angle of repose, before matrix tablets

formulation.



As problem in flowability can cause variations in die filling and result in tablets that vary

in weight, drug content and strength; to ensure uniform feed from hopper into dies for

achieving reproducible tablets with acceptable content uniformity, weight variation and

physical consistency an optimum flow of powder blends is must (Navaneethan et al.,

2005) These studies were conducted according to BP, 2007.

As shown in table 4.3, the compressibility index, Hausner Ratio and angle of repose for

pure Ibuprofen are 28±0.03%, 1.39±0.02 and 48.5±0.03, respectively, indicating poor

flow properties and for pure Ketoprofen, the vlues of the said parameters viz.

compressibility index, Hausner Ratio and angle of repose were 31±0.01%, 1.45±0.01 and

49.7±0.02, respectively (table 4.4), conforming poor flow properties. For improvement of

flow properties, 0.5% magnesium stearate was added as lubricating agent during mixing

of the formulation ingredients for all formulations, which showed good results and

improved flow properties of the powder blends. The same remedy has been prescribed by

the B.P and U.S.P to resolve such problems in flow properties of powders.

As shown in table 4.3, the values of the above mentioned parameters changed

significantly in favor of better flow properties, where the compressibility index for

Ibuprofen formulations became 12.3±0.03% to 14.8±0.01%, the Hausner Ratio as

1.112±0.02 to 1.17±0.02 and the angle of repose as 32.1±0.03 to 34.9±0.04, indicating

better flow properties. Similar improvements in flow properties for all formulation of

Ketoprofen blended magnesium stearate were observed (table 4.4), where the values of

the flow parameters changed significantly and the compressibility index became

12.4±0.04% to 15±0.02%, the Hausner Ratio as 1.121±0.03 to 1.18±0.02 and angle of

repose as 32.2±0.02 to 35±0.01, indicating better flow properties. These improvements in

flow properties of the powder samples were attributed to the addition of magnesium

stearate which is used as lubricating agent (Row, 2003).



Table 4.3 Micromeritics or flow properties of pure Ibuprofen and formulation blends

S/NO Formulation D:P Ratio Co-

Excipients

Compressibility

Index (%)

(Mean±SD)

Hausner

Ratio

(Mean±SD)

Angle of

Repose

(Mean±SD)

1 Pure Ibuprofen - - 28±0.03 1.39±0.02 48.5±0.03

2 Ethocel® Standard 7P 10:1 Nil 14.8±0.01 1.167±0.03 34.9±0.04

3 Ethocel® Standard 7 FP -do- Nil 14.4±0.01 1.152±0.01 34.6±0.01

4 Ethocel® Standard 7P 10:2 Nil 14±0.03 1.154±0.03 34±0.01




8 Ethocel® Standard 7P -do- HPMC 14.6±0.01 1.17±0.02 35±0.01

9 Ethocel® Standard 7 FP -do- HPMC 14.3±0.05 1.163±0.02 34.9±0.03

10 Ethocel® Standard 7P -do- CMC 13.3±0.04 1.123±0.05 33.4±0.01

11 Ethocel® Standard 7 FP -do- CMC 13.1±0.03 1.123±0.04 33.1±0.02

12 Ethocel® Standard 7P -do- Starch 12.9±0.04 1.123±0.04 33±0.04

13 Ethocel® Standard 7 FP -do- Starch 12.7±0.01 1.112±0.03 33±0.01




17 Ethocel® Standard10 FP -do- Nil 13.6±0.03 1.13±0.02 33.7±0.05

18 Ethocel® Standard 10 P 10:3 Nil 13.4±0.02 1.132±0.02 33.4±0.02


20 Ethocel® Standard 10 P -do- HPMC 14.5±0.04 1.16±0.03 34.9±0.03



23 Ethocel® Standard 10 FP -do- CMC 13±0.04 1.12±0.03 33±0.03

24 Ethocel® Standard 10 P -do- Starch 12.8±0.03 1.122±0.03 32.9±0.03

25 Ethocel® Standard 10 FP -do- Starch 12.6±0.02 1.121±0.03 32.8±0.03






31 Ethocel® Standard 100 FP -do- Nil 13±0.02 1.12±0.04 32.1±0.03



34 Ethocel® Standard 100 P -do- CMC 13.1±0.04 1.121±0.02 33.2±0.04



37 Ethocel® Standard 100 FP -do- Starch 12.3±0.03 1.2±0.01 32.30.03



Table 4.4 Micromeritics or flow properties of pure Ketoprofen and formulation blends

S/NO Formulation D:P Ratio Co-

Excipients

Compressibility

Index (%) Hausner Ratio

Angle of

Repose

1 Pure Ketoprofen - - 31±0.01 1.45±0.01 49.7±0.02

2 Ethocel® Standard 7P 10:1 Nil 15±0.02 1.17±0.05 35±0.01






8 Ethocel® Standard 7P -do- HPMC 14.7±0.01 1.18±0.02 35±0.01




12 Ethocel® Standard 7P -do- Starch 13±0.03 1.124±0.03 33.1±0.05


14 Ethocel® Standard 10P 10:1 Nil 14.8±0.02 1.18±0.03 35±0.01


16 Ethocel® Standard 10P 10:2 Nil 13.9±0.02 1.154±0.04 34±0.03

17 Ethocel® Standard10 FP -do- Nil 13.7±0.03 1.14±0.01 33.8±0.01



20 Ethocel® Standard 10 P -do- HPMC 14.6±0.02 1.17±0.02 35±0.01




24 Ethocel® Standard 10 P -do- Starch 12.9±0.01 1.123±0.03 33±0.02










34 Ethocel® Standard 100 P -do- CMC 13.2±0.03 1.122±0.03 33.3±0.01

35 Ethocel® Standard 100 FP -do- CMC 13±0.04 1.121±0.02 33±0.03





4.5. Differential scanning calorietry (DSC) studies

To investigate interactions between the drugs, polymers and different excipients, DSC

studies were conducted. Figure 4.7 shows DSC curves of pure Ibuprofen and its physical

mixtures with polymer ethyl cellulose ether and different co-excipients. A sharp

endothermic peak at 76.94oC was observed for pure Ibuprofen at the temperature

corresponding to its melting point (Fig. 4.7a). As shown, the endothermic peak of

Ibuprofen in its mixtures with either the polymers or the coexipients did not show any

major change as compared to that of the pure drug (Fig.4.7a-d), indicating no possible

interaction.

Figure 4.7 DSC thermogram of pure Ibuprofen (a) and physical mixtures of

Ibuprofen with polymer ethylcellulosel, magnesium stearate, lactose, using co-

excipients; HPMC (b); starch (c); and CMC (d).

Differential scanning calorimetry (DSC) studies were also performed for Ketoprofen to

investigate possible drug-polymers and excipients interactions. The DSC thermograms of

pure Ketoprofen and its physical mixtures with poymer and co-excipients are shown in

the figure 4.8. The thermal curve of ketoprofen (Fig. 4.8a) showed a single endothermic



peak at 94oC, corresponding to the melting point of ketorpfen (Mudit et al., 2010). As

shown in figure (4.8a-d) the endothermic peaks of ketoprofen in the physical mixture of

polymer ethylcellulose and different co-excipients such as lactose, magnesium sterate,

hydroxypropylmethylcellulose (HPMC), starch and corboxymethylcellulose (CMC) were

found at the same temperature as that of pure ketoprofen. This indicated that no possible

chemical interaction was found between ketoprofen and polymer and different excipients.

Our results are supported by findings in other studies previously conducted by several

invistigators (Shivakumar et al., 2006; Khan and Zhu, 1998; Nagarsenkar and Shenal,

1996).

Figure 4.8 DSC thermogram of pure Ketoprofen (a) and physical mixtures of

Ketoprofen with polymer ethylcellulosel, magnesium stearate, lactose, using co-




4.6. Fourier transform infrared (FT-IR) studies

For further analysis FT-IR spectra of pure drugs and their respective physical mixtures

were also taken to assure the compatibility between pure drug and its physical mixtures

with polymer ethylcellulose and different excipients such lactose, magnesium stearate,

hydroxypropylmethylcellulso (HPMC), starch and corboxymethylcellulose (CMC). The

FT-IR spectrums of pure ibuprofen, its physical mixture with polymer ethylcellulose

ether and different excipients such as lactose, magnesium stearate,

hydroxypropylmethylcellulso (HPMC), starch and corboxymethylcellulose (CMC) are

shown in Figure 4.9a-c. Pure ibuprofen showed sharp characteristic peaks at 1706 cm-1

which corresponds to the carboxyl acid (COOH) present in ibuprofen. Other smaller

peaks in the region 1200-1000 cm-1

are the indication of benzene ring (Socrates, 1994).

As the sharp, characteristic peaks of ibuprofen did not change in physical mixture with

polymer and different excipients, indicating no possible interaction.

Figure 4.9 FT-IR spectra of of pure Ibuprofen (a) and physical mixtures of

Ibuprofen with polymer ethylcellulosel, magnesium stearate, lactose, using co-




Similarly, FT-IR spectra of pure ketoprofen (Fig. 4.10a) showed characteristic symmetric

carbonyl peaks at 1693.8 cm-1

and 1654.0 cm-1

due to dimeric carboxylic and ketonic

group stretching vibrations, respectively (Sancin et al.,1999; Mura et al.,1998). The

characteristic acid corbonyl stretching band of ketoprofen unchanged in formulation with

polymer ethylcellulose and different excipients such as lactose, magnesium,

hydroxypropylmethylcellulso (HPMC), starch and corboxymethylcellulose (CMC) as

shown (Fig.4.10a-d). Hence, from these studies it was conformed that no possible

interaction was found between drug, polymer and different excipients. On the other hand,

another study was performed by Shivakumar et al (2008) who conducted FT-IR study for

investigation the chemical interaction between Ketoprofen and cellulose acetate and

Eudragit. According to their findings no chemical interaction was found because the IR

spectra of Ketoprofen and microcapsules were identical.

Figure 4.10 FT-IR spectra of pure Ketoprofen (a) and physical mixtures of

Ketoprofen with polymer ethylcellulosel, magnesium stearate, lactose, using co-




4.7. Construction of standard curves

For further analysis and determination of solubility of drugs in different solvents,

standard curves were prepared for both drugs (Ibuprofen and Ketoprofen). The average

absorbance values of drug solutions with different concentration, in phosphate buffer (pH

7.4), are shown in tables 4.5-4.5 and and standard curves in Figs. 4.11-4.12. The straight

lines with R2 value of 0.9997 and 0.9998 for Ibuprofen and Ketoprofen were obtained,

respectively.

Table 4.5 Absorbance and concentration of Ibuprofen for different dilutions.

S. No Cont. (mg/ml) Abs1 Abs2 Abs3 Avg. Abs

1 0 0 0 0

2 0.00125 0.08 0.079 0.081 0.080

3 0.00312 0.160 0.162 0.158 0.160

4 0.00625 0.303 0.303 0.303 0.303

5 0.0125 0.586 0.585 0.587 0.586

6 0.025 1.166 1.166 1.168 1.167

Figure 4.11 Standard Curve for Ibuprofen in phosphate buffer 7.4



Table 4.6 Absorbance and concentration of Ketoprofen for different dilutions.

S. No Cont. (mg/ml) Abs1 Abs2 Abs3 Avg. Abs

1 0 0 0 0 0

2 0.00125 0.105 0.105 0.105 0.105

3 0.00312 0.206 0.205 0.207 0.207

4 0.00625 0.421 0.421 0.421 0.421

5 0.0125 0.847 0.847 0.847 0.847

6 0.025 1.700 1.702 1.698 1.700

Figure 4.12 Standard Curve for Ketoprofen in phosphate buffer 7.4



4.8. Solubility studies

The concentrations (mg/ml) of Ibuprofen and Ketoprofen determined from solubility

studies in phosphate buffer solutions (pH 6.8, 7.2 and 7.4), distilled water and 0.1 N HCL

solutions at 25oC, 37

oC and 40

oC are shown in tables 4.5 and 4.6.

As shown in tables 4.7 and 4.8, the solubility of the drugs (Ibuprofen and Ketoprofen) is

higher in phosphate buffer solution of pH 7.4 as compared to other solvents. Ibuprofen

and Ketoprofen are weekly acidic drugs with pKa value 5.3 and 4.6, respectively. This

increase in solubility of Ibuprofen and Ketoprofen in phosphate buffer solution of pH 7.4

may be due to weekly acidic properties of both these drugs, as the solubility of weak

acidic or basic drugs is often pH dependent. Solubility of weak acidic drug is increased

with increase in pH of the solvent (Loyd et al., 2005a).

Moreover, with the increase in temperature the solubility of both the drugs was enhanced

in different in all solvents as shown in tables 4.7 and 4.8. This increase in solubility of

drugs may be due to absorption of heat, as most chemical absorb heat when they are

dissolved and are said to have positive heat of solution, resulting in increased solubility

with an increase in temperature (Loyd et al., 2005b)

Table 4.7 Solubility of Ibuprofen in different solvents at different temperatures.

S/NO Solvent Temp Conc. Determined

(Mean±SD)

1 Phosphate Buffer 6.8 PH

25 °C 0.847±0.005

37 °C 0.856±0.003

40 °C 0.867±0.002


25 °C 0.928±0.002

37 °C 0.931±0.009

40 °C 0.940±0.002


25 °C 0.990±0.007

37 °C 0.999±0.006

40 °C 1.00±0.008

4 Distilled Water

25 °C 0.276±0.007

37 °C 0.285±0.003

40 °C 0.295±0.001

5 0.1N HCL solution

25 °C 0.027±0.005

37 °C 0.045±0.005

40 °C 0.053±0.009



Table 4.8 Solubility of Ketoprofen in different solvents at different temperatures.

4.9. Preparation of solid dispersions

Different methods such as salt formation, solubilization, particle size reduction, complex

formation, solvent evaporation, etc. are used to prepare solid dispersions to enhance the

dissolution rate and thereby improve the bioavailability of poorly water soluble drugs

(Galia et al., 1998), however, in this study solvent evaporation method was used due to

its inherent ease of handling and no more steps were required. The solid dispersions of

model drugs (Ibuprofen and Ketoprofen) with different drug and carrier ratios were

prepared. The respective physical mixtures with the same drug and carrier ratios were

prepared by simple trituration method for comparative evaluation.

For conformation of uniform dispersion of drug in solid dispersions and physical

mixtures drug content analysis was performed and it was found between 99.57±0.7 %

and 101.3 ±0.32 %. All the solid dispersions and physical mixtures indicated the high

content and uniformly dispersion of drugs. These findings conformed that the solvent

evaporation method appears to be reproducible for development and preparation of solid

dispersions. Similar studies were conducted by Prasad (Prasad et al., 2010; Rosario et al.,

S/NO Solvent Temp Conc.determined

(Mean±SD)


25 °C 0.853±0.003

37 °C 0.858±0.007

40 °C 0.869±0.004


25 °C 0.938±0.007

37 °C 0.941±0.004

40 °C 0.944±0.005


25 °C 0.978±0.003

37 °C 0.998±0.004

40 °C 0.999±0.004

4 Distilled Water

25 °C 0.421±0.004

37 °C 0.425±0.002

40 °C 0.431±0.003

5 0.1N HCL solution

25 °C 0.158±0.001

37 °C 0.163±0.003

40 °C 0.169±0.003



2002) who prepared solid dispersions of Tebinanfine hydrochloride and NSAIDs by the

same method obtaining good results in terms of content analysis and uinform distribution

of the drugs used.

4.9.1. Solubility study: As shown in table 4.9, the aqueous solubility study of pure

Ibuprofen, pure Ketoprofen, their physical mixtures and solid dispersions was performed

in distilled water. The study showed that solubility of Ibuprofen and ketoprofen enhanced

in presence of carrier (Glucosamine HCL). This effect of solubility enhancement was

more prominent in case of solid dispersions as compared to that of their respective

physical mixtures. The enhancement of drugs solubility in presence of solid dispersions

may be due to conversion of drugs to amorphous form as amorphic forms of drug are

more soluble than their crystalline form (Parsad et al., 2010; Khan and Zhu, 1998). The

increase in solubility of drugs in solid dispersions might also be due to good wettability

and dispesrability (Khan and Zhu, 1998).

Table 4.9 Solubility data of different Ibuprofen and Ketoprofen formulations.

Formulations Solubility (mg/ml)

Ibuprofen

IBF Pure

F1 IBF

F2 IBF

F3 IBF

F4 IBF

F5 IBF

F6 IBF

0.285

0.297

0.313

0.333

0.320

0.357

0.398

Ketoprofen

KPT Pure

F1 KPT

F2 KPT

F3 KPT

F4 KPT

F5 KPT

F6 KPT

0.321

0.335

0.355

0.377

0.465

0.501

0.555

4.9.2. Differential scanning calorimetry (DSC) studies: Differential scanning

calorimetric (DSC) studies of pure ibuprofen, ketoprofen, their physical mixtures and



solid dispersions were conducted to investigate the crystillinity and drugs carrier

interaction. The DSC run of the pure Ibuprofen and carrier (glucosamine HCL) show

sharp endothermic peaks around 76.94oC and 210

oC, corresponding to the melting point

of Ibuprofen and Glucosamine HCL, respectively (Fig. 4.13a-d).

Figure 4.13 DSC Thermograms of (a) Glucosamine; (b) Pure ibuprofen; (c) Physical

mixture; and (d) Solid dispersions of ibuprofen with glucosamine.

Figure 4.14 DSC Thermograms of (a) Glucosamine; (b) Pure ketoprofen; (c)

Physical mixture; and (d) Solid dispersions of ketoprofen with glucosamine.



The endothermic peak of Ibuprofen is of very high intensity, showing the crystalline form

of ibuprofen. The DSC thermograms of Ibuprofen-carrier (Glucosamine HCL) physical

mixture and solid dispersions showed both the endothermic peaks (Fig. 4.13c-d) with

some changes in the characteristics of the peaks shown by individual components; for

example the endothermic peaks of physical mixture and solid dispersions lost its

sharpness and distinctive appearance. It showed that no possible interaction was found

between drug and carrier but the loss of peaks sharpness may be due to conversion from

crystalline form to amorphous form of the drug.

As shown in (Fig. 4.14a-d), the DSC studies of pure Ketoprofen, its physical mixture and

solid dispersions exhibited similar interactive effects as found in case of Ibuprofen. The

pure Ketoprofen and carrier (Glucosamine HCL) showed sharp endothermic peaks round

94oC and 210

oC, corresponding to their melting points, while the DSC thermograms of

Ketoprofen in physical mixture and solid dispersions (Fig. 4.14c-d) did not exhibit any

major change in the endothermic peaks except disappearance of sharpness, indicating

occurance of no possible interaction between Ketoprofen and Glucosamine HCL.

Our results are supported by findings in other studies previously conducted by several

invistigators (Khan and Zhu, 1998; Nagarsenkar and Hira, 1996).

4.9.3. Fourier transform Infrared (FT-IR) studies: For the conformation of interaction

between drugs and carrier in presence of physical mixtures and solid dispersions FT-IR

studies were performed. The FT-IR spectrums of pure Ibuprofen, and Ibuprofen-

Glucosamine physical mixtures and solid dispersions were obtained as shown in the Fig.

4.15a-d. Pure Ibuprofen showed sharp characteristic peaks at 1706 cm-1

which

corresponds to the carboxyl acid (COOH) present in ibuprofen. Other smaller peaks in

the region 1200-1000 cm-1

are the indication of benzene ring (Socrates, 1994). These

peaks can also be seen in the ibuprofen-carrier physical mixture and solid dispersions, but

in this case IR spectrum for Ibuprofen-carrier mixture and solid dispersion shows the

overlapping of carboxyl acid group (Fig. 4.15c-d). Therefore, it can be concluded that no

chemical interaction occurred between Ibuprofen and glucosamine HCL.



Figure 4.15 FT-IR spectra of (a) Glucosamine; (b) Pure ibuprofen; (c) Physical

mixture; and (d) Solid dispersions of ibuprofen with glucosamine.

Figure 4.16 FT-IR spectra of (a) Glucosamine; (b) Pure ketoprofen; (c) Physical

mixture; and (d) Solid dispersions of ketoprofen with glucosamine.



Pure ketoprofen crystals show two carbonyl absorption bands at 1694.4 cm

-1 and 1654.2

cm-1

, indicating carboxyl carbonyl and ketonic carbonyl stretching, respectively (Sancin

et al., 1999, Mura et al., 1999) as shown in Fig. 4.16a-d. The characteristics stretching

band of pure ketoprofen with Glucosamine in physical mixture and solid dispersions did

not change, and on the basis of these observations no possible interaction was observed

between ketoprofen and Glucosamine HCL. The same findings were observed by other

researchers (Shivkumar et al., 2008).

4.9.4. X-ray diffractometory studies: Figure (4.17a-c) shows the diffractograms of pure

Ibuprofen, Ibuprofen-carrier physical mixture and solid dispersion.

Figure 4.17 X-ray diffractograms of (a) Pure Ibuprofen; (b) Physical mixture; and

(c) Solid dispersions of Ibuprofen and glucosamine.

The diffractograms of pure Ibuprofen with numerous distinctive peaks showed that the

drug is highly crystalline in nature, confirms the DSC studies as shown in figure (4.13b).

Four peaks with high intensity were present in the diffractogram of Ibuprofen around 17o,

20o, 23

o and 25

o along with some other peaks of lower intensity. The same peaks were



present in the diffractogarm of Ibuprofen-carrier physical mixture and solid dispersions,

but with lower intensity. This indicates that Ibuprofen crystallinity has been diminished.

As compared to pure Ibuprofen and physical mixture of Ibuprofen-carrier, the peaks in

the diffractogram of solid dispersions were of much reduced intensities, indicating the

amorphous nature of the Ibuprofen in presence of solid dispersions.

While in case of Ketoprofen, as shown in Figure (4.18a-c) different peaks with high

intensity were present in the diffractogram around 13o, 14

o, 18

o, 23

o, 24

o, 26

o and 29

o

along with some other peaks of lower intensity. The same peaks were present in the

diffractograms physical mixture and solid dispersion but with low intensities, indicating

the conversion of crystalline form of pure Ketoprofen to amorphous form in presence of

physical mixture and solid dispersions. Moreover, the peak intensity of Ketoprofen was

much more reduced as compared to pure Ketoprofen and physical mixture, as shown in

Figure 4.18b-c. Our results confirm the findings of other researchers (Shivakumar et al.,

2008; Nagarsenkar and Hira, 1996).

Figure 4.18 X-ray diffractograms of (a) Pure ketoprofen; (b) Physical mixture; and

(c) Solid dispersions of ketoprofen and glucosamine.



4.9.5. Scanning electron microscope analysis: Figure 4.19a-d shows the scanning

electron micrographs of Glucosamine HCL, pure Ibuprofen, Ibuprofen-carrier physical

mixture and solid dispersions of Ibuprofen with glucosamine HCL. After analysis, the

scanning electron microscopy (SEM) revealed that Glucosamine has prismatic shape

(polygonal) and pure Ibuprofen has irregular crystalline shape. Both of these crystals can

easily be identified in the physical mixture, as shown in the Figure 4.19c. In physical

mixture, there are numerous small crystals of Ibuprofen which are responsible for more

solubility and enhanced dissolution rate as compared to pure compound, while in case of

solid dispersions the crystals of Ibuprofen are in smallest size and they have irregular,

circular and plate like shapes. The dissolution rate of Ibuprofen in solid dispersions was

rapid and more as compared to pure Ibuprofen and physical mixture because the particle

shape irregularity and small particle size increased the specific surface area and enhanced

the dissolution rate (Javadzadeh and Nokhodchi, 2009).

Figure 4.19 Scanning electron photomicrographs of (a) Carrier (Glucosamine HCL); (b)

Pure Ibuprofen; (c) Physical mixture of Ibuprofen-Glucosamine HCL; (d) Solid dispersion

of Ibuprofen-Glucosamine HCL.



Similar SEM results were produced for Ketoprofen as shown in Fig. 4.20a-d.

Glucosamine and pure Ketoprofen has prismatic shape (polygonal) and irregular shape

crystals, respectively. The SEM analysis showed that relatively smaller polyhedral

crystalline forms of Glucosamine and Ketoprofen are clearly visible in physical mixture,

as shown in Fig. 4.20c, the Ketoprofen has smallest, irregular, circular and plate like

crystals in solid dispersions, which are responsible for enhanced dissolution rate. Similar

studies were conducted Nagarsenkar and Hira, (1996) and Shivakumar et al. (2008). Our

results confirm their findings.

Figure 4.20 Scanning electron photomicrographs of (a) Carrier (Glucosamine

HCL); (b) Pure Ketoprofen; (c) Physical mixture of Ketoprofen-Glucosamine HCL;

(d) Solid dispersion of Ketoprofen-Glucosamine HCL.



4.9.6. In –vitro dissolution studies: The dissolution profiles of pure Ibuprofen, Ibuprofen

physical mixtures and solid dispersions prepared with Glucosamine HCL are shown in

Figs. 4.21 and 4.22. It is shown that pure Ibuprofen has the slowest dissolution rate and

22.3% of drug was dissolved after 120 minutes, while in case of physical mixtures and

solid dispersions with different Drug: Carrier ratios (1:1, 1:2 and 1:3) the dissolution rate

was linearly increased and 25%, 29.65, 32.8% and 27.1%, 40.75, 43.3% of drug was

dissolved after 120 minutes from formulations F1 IBF, F2 IBF, F3 IBF and F4 IBF, F5

IBF, F6 IBF, respectively. The fastest dissolution rate was obtained for the formulation

(F6 IBF) with the D: C ratio of 1:3 in carrer concentration dependent manners. The fast

and rapid dissolution rate of Ibuprofen in solid dispersion may be due to the presence of

Ibuprofen in amorphous form which is revealed by the results of different techniques as

mentioned above. On the other hand it may be that if the percentage of carrier is too high,

this may lead to increase in solubility and dissolution rate due to absence of crystallinity

of drug (Ford, 1986).

Figure 4.21 In-vitro dissolution profiles of pure Ibuprofen and physical mixture with

different drug-carrier (Glucosamine HCL) ratio; F1 IBF (1:1); F2 IBF (1:2); F3 IBF

(1:3)



Figure 4.22 In-vitro dissolution profiles of pure Ibuprofen and solid dispersions with

different drug-carrier (Glucosamine HCL) ratio

Similar study was performed for Ketoprofen and the dissolution profile of pure

Ketoprofen and Ketoprofen physical mixtures and solid dispersions with Glucosamine

HCL are depicted in Figs. 4.23 and 4.24. As shown 27.3% of pure Ketoprofen was

dissolved after 120 minutes, while in case of physical mixtures and solid dispersions with

different Drug: Carrier ratios (1:1, 1:2 and 1:3) the dissolution rate was linearly increased

and 30%, 33.1% and 34.2% and 32.5%, 42.7% and 46.9% of drug was dissolved after

120 minutes from formulations F1 KTP, F2 KTP, F3 KTP and F4 KTP, F5 KTP, F6

KTP, respectively. As shown in Figs. 4.23 and 4.24 the Ketoprofen dissolution rate from

formulations containing the same carrier with the same D: C ratios followed the same

dissolution rate pattern as described above in case of Ibuprofen, which further

authenticates the more prominent and effective role of the carrier Glucosamine HCl in

enhancing the dissolution rate of drugs such as IBF and KTP. The fast and rapid

dissolution rate of Ketoprofen in solid dispersions may be due to the presence of

Ketoprofen in amorphous form which is revealed by the results of different techniques as

mentioned above. On the other hand it may be that if the percentage of carrier is too high,

this may lead to increase in solubility and dissolution rate due to absence of crystallinity

of drug (Ford, 1986).



Figure 4.23 In-vitro dissolution profiles of pure Ketoprofen and physical mixture

with different drug-carrier (Glucosamine HCL) ratio.

Figure 4.24 In-vitro dissolution profiles of pure Ketoprofen and solid dispersion with

different drug-carrier (Glucosamine HCL) ratio.

4.10. Physicochemical Assessment of Matrix Tablets

In order to assess whether the specific dosage form fulfills the desired specifications

different physicochemical, dimensional and quality control tests, such as weight

variation, thickness and diameter, hardness test, content uniformity and friability test

must be performed on solid dosage forms (Augsburger et al.,2002). These tests are

performed to ensure that tablets will have sufficient mechanical strength to tolerate forces

encountered during, packaging, shipping and handling. Moreover, test must be performed



to ensure, whether the tablets are physically and chemically stable to deliver the precise

amount of drug at the desired dissolution rate when administered by a patient. Any

change in these characteristics may significantly affect the safety and efficacy of the

product (Hwang et al., 2001).

As summarized in tables 4.10 and 4.11, the prepared matrix tablets containing model

drugs (Ibuprofen and Ketoprofen), polymer ethyl cellulose of different viscosity grades

and co-excipients, at several drugs to polymer ratio of 10:1, 10:2 and 10:3, were

evaluated for their physicochemical properties and appearance. Table 4.10 shows the,

weight variation, hardness, friability, thickness, diameter and drug content tests results,

applied to controlled release matrix tablets of Ibuprofen with Ethocel® standard 7, 10 and

100 premium and Ethocel® standard 7, 10 and 100 FP premium with or without co-

excipient ( HPMC, CMC and starch). All these tests were performed in strict compliance

of Good Laboratory Practice (GLP). Orgnolaptically, the tablets were having smooth

surfaces and were elegant in appearance. As shown in table 4.10, the average weight for

all formulations is 199.01±0.403mg to 200.95±0.401mg, indicating low weight variation,

which is within acceptable range of United States Pharmacopeia. Similar study was

conducted by Tiwari et al (2003). They prepared controlled-release formulations of

tramadol HCL, using HPMC K100M and calculated the weight variation of each

formulation. All the tablets prepared showed acceptable in-house specifications for

weight variation. The average hardness, friability, thickness, diameter and drug content

given in the table 4.10 are 6.98±0.041 kg/cm3 to 7.16±0.096 kg/cm

3, 0.11±0.01% to

0.29±0.05%, 3.4±0.032 mm to 3.51±0.031 mm, 7.985±0.031 mm to 7.995±0.035 mm

and 98.09±2.322% to 100.311±2.031%, respectively. The results obtained for the

physicochemical testing of all formulations divulged that the prepared matrix tablets

comply with the USP standards. The USP range for hardness, friability, thickness,

diameter and drug content uniformity is 5-10kg/cm3, 0.8%, 2-4 mm, 4-13 mm and 90-

110%, respectively (USP, 2007).

The hardness of matrix tablets containing FP grades was more as compared to the tablets

containing Premium grades. Moreover, it was observed that tablets containing FP grades



polymer (Ethocel® standard 7, 10 and 100 FP premium) were less thick as compared to

tablets containing Premium grades (Ethocel® standard 7, 10 and 100 premium). This is

probably due to fine particle size of FP grades which facilitates the compression of tablets

resulting into production of thinner tablets. These results conform the finding of Khan

and Median (2007), that Ethocel® standard FP premium tablets were more compressible,

harder and less thick as compared to tablets containing Ethocel® standard premium

because of the fine particle size of FP grades. The results showed that tablet diameter was

almost similar for all formulations because diameter of the tablets was not affected by the

polymer, lubricant, co-excipients as well as viscosity grade of polymer. On the other

hand, another study was performed by Ghorab et al (2004) who prepared meloxicam

tablets, using β-cyclodextrin as a vehicle, either alone or in blends with lactose, by direct

compression and wet granulation and subjected to thickness and diameter tests.

According to their findings no effect on diameter of tablets was observed with changing

the concentration of different excipients.

The same physicochemical tests were repeated for the assessment of controlled release

matrices of Ketoprofen. The tablets obtained were elegant in appearance and were having

smooth surfaces. The results of the average weight, hardness, friability, thickness,

diameter and drug content determination of the tablets are given in table 4.11. The

average weight, hardness, friability, thickness, diameter and drug content are

199.85±0.234 mg to 200.85±0.231 mg, 6.93±0.092 kg/cm3 to 7.17±0.095 kg/cm

3,

0.11±0.03% to 0.29±0.03%, 3.42±0.032 mm to 3.505±0.039 mm, 7.985±0.037 mm to

7.995±0.022 mm and 98.012±3.103% to 100.213±2.343, respectively. All formulations

were found to be uniform in weight, hardness, friability, thickness, and diameter and drug

content within acceptable limits of BP and USP. The results showed that no significant

variations were observed in physical tests applied except hardness and thickness. The

tablets containing FP grades were harder and less thick than the tablets containing

Premium grades of polymer. As mentioned above, this might be due to fine particle size

of FP grades. These results conform the finding of Khan and Median (2007).



Table 4.10 Physicochemical characteristics of Ibuprofen controlled release matrices

S/NO Polymer D:P

Ratio

Co-

Excipi

ents

Wt variation

test (mg)

n=20

(Mean±SD)

Hardness

test(kg/cm3

)

n=10

Mean±SD

Friability

test (%)

n=3

Mean±SD

Thickness

(mm)

n=20

(Mean±SD)

Diameter

(mm)

n=20

(Mean±SD

)

Drug content

(%)

n=3

(Mean±SD)

1 Etho Std 7 10:1 Nil 199.01±0.403 7.11±0.056 0.21±0.02 3.5±0.021 7.99±0.032 100.211±2.03

2 Etho Std 7FP -do- Nil 199.01±0.305 7.13±0.032 0.11±0.01 3.4±0.054 7.99±0.035 99.216±2.035

3 Etho Std 7 10:2 Nil 199.03±0.201 7±0.092 0.28±0.01 3.5±0.034 7.985±0.03

1

99.223±2.023

4 Etho Std 7FP -do- Nil 200.02±0.203 7.14±0.095 0.12±0.03 3.4±0.032 7.99±0.036 99.212±2.037

5 Etho Std 7 10:3 Nil 199.7±0.403 6.99±0.049 0.25±0.04 3.5±0.032 7.99±0.035 99.231±2.043

6 Etho Std 7FP -do- Nil 200.02±0.303 7.16±0.096 0.12±0.01 3.4±0.022 7.995±0.03

2 98.09±2.825

7 Etho Std 7 -do- HPMC 199.05±0.421 6.98±0.041 0.24±0.04 3.5±0.032 7.99±0.036 99.025±2.143

8 Etho Std 7FP -do- HPMC 200.15±0.432 7.11±0.045 0.13±0.02 3.49±0.031 7.99±0.038 100.01±2.194

9 Etho Std 7 -do- CMC 200.04±0.321 6.99±0.043 0.29±0.02 3.495±0.039 7.995±0.03 99.032±2.213

10 Etho Std 7FP -do- CMC 199.85±0.323 7.11±0.049 0.12±0.05 3.4±0.032 7.985±0.03 99.08±2.211

11 Etho Std 7 -do- Starch 199.83±0.423 7±0.085 0.19±0.03 3.5±0.032 7.99±0.038 99.311±3.125

12 Etho Std 7FP -do- Starch 199.1±0.432 7.12±0.037 0.12±0.01 3.41±0.31 7.99±0.025 99.09±2.212

13 Etho Std 10 10:1 Nil 199.83±0.328 7.01±0.095 0.24±0.02 .5±0.032 7.99±0.033 99.221±2.035

14 EthoStd10FP -do- Nil 200.82±0.342 7.12±0.095 0.11±0.03 3.4±0.038 7.99±0.039 99.125±2.036

15 Etho Std 10 10:2 Nil 200.03±0.329 7.01±0.056 0.2±0.03 3.5±0.042 7.99±0.035 100.231±2.01

16 EthoStd10FP -do- Nil 200.75±0.432 7.12±0.098 0.14±0.01 3.4±0.046 7.995±0.03 99.211±2.033

17 Etho Std 10 10:3 Nil 200.01±0.521 7±0.085 0.23±0.04 3.505±0.039 7.995±0.02 99.311±1.912

18 EthoStd10FP -do- Nil 199.1±0.321 7.13±0.045 0.12±0.06 3.49±0.031 7.995±0.05 98.22±1.387

19 EthoStd 10 -do- HPMC 199.1±0.445 6.98±0.049 0.25±0.02 3.51±0.031 7.99±0.032 100.041±2.82

20 EthoStd10FP -do- HPMC 200.05±0.321 7.12±0.075 0.16±0.03 3.49±0.031 7.99±0.032 99.08±1.365

21 EthoStd 10 -do- CMC 199.75±0.543 7.02±0.096 0.21±0.02 3.49±0.31 7.995±0.02 99.152±3.19

22 EthoStd10FP -do- CMC 200.07±0.354 7.11±0.077 0.15±0.03 3.4±0.032 7.99±0.032 99.012±2.198

23 EthoStd 10 -do- Starch 200±0.454 7.01±0.076 0.21±0.04 3.51±0.031 7.995±0.02 99.05±2.355

24 EthoStd10FP -do- Starch 199.1±0.459 7.13±0.046 0.12±0.01 3.45±0.023 7.99±0.024 99.011±3.106

25 EthoStd 100 10:1 Nil 200.65±0.465 7.0±0.096 0.23±0.04 3.5±0.033 7.99±0.031 99.212±2.032

26 EthoStd100FP -do- Nil 200.43±0.232 7.11±0.092 0.12±0.01 3.43±0.067 7.99±0.035 100.311±2.03

27 EthoStd 100 10:2 Nil 200.85±0.234 7.0±0.095 0.23±0.04 3.5±0.043 7.995±0.03 99.215±2.031

28 EthoStd100FP -do- Nil 199.95±0.204 7.11±0.095 0.14±0.06 3.45±0.067 7.99±0.031 99.111±2.038

29 EthoStd 100 10:3 Nil 199.8±0.507 7±0.085 0.21±0.01 3.5±0.035 7.99±0.035 98.09±2.322

30 EthoStd100FP -do- Nil 199.9±0.506 7.11±0.098 0.18±0.01 3.42±0.022 7.995±0.02 99.22±1.321

31 EthoStd 100 -do- HPMC 200.95±0.401 6.98±0.042 0.25±0.02 3.5±0.031 7.99±0.024 99.211±2.165


33 EthoStd 100 -do- CMC 200.05±0.365 6.99±0.099 0.27±0.02 3.5±0.034 7.99±0.032 100.012±2.15

34 EthoStd100FP -do- CMC 199.95±0.54 7.11±0.075 0.15±0.01 3.4±0.045 7.99±0.033 99.231±2.217

35 EthoStd 100 -do- Starch 200.1±0.498 6.98±0.048 0.29±0.05 3.5±0.037 7.985±0.03 100.03±2.102

36 EthoStd100FP -do- Starch 199.05±0.35 7.12±0.099 0.17±0.01 3.49560.032 7.985±0.03 99.02±2.171



Table 4.11 Physicochemical characteristics of Ketoprofen controlled release matrices.

S/N Formulation D:P

Ratio

Co-

Excipie

nts

Weight

variation test

(mg)

n=20

(Mean±SD)

Hardness

test

(kg/cm3)

n=10

Mean±SD

Friability

test (%)

n=3

(Mean±SD)

Thickness

(mm)

n=20

(Mean±SD)

Diameter

(mm)

n=20

(Mean±SD)

Drug content

(%)

n=3

(Mean±SD)

1 Etho Std 7 10:1 Nil 200.01±0.501 7.02±0.083 0.23±0.03 3.5±0.022 7.99±0.031 99.217±2.234

2 Etho Std 7FP -do- Nil 199.01±0.602 7.11±0.023 0.15±0.01 3.496±0.065 7.995±0.022 100.03±2.201

3 Etho Std 7 10:2 Nil 200.03±0.301 6.99±0.095 0.24±0.03 3.5±0.023 7.995±0.022 100.213±2.34

4 Etho Std 7FP -do- Nil 200.01±0.101 7.14±0.091 0.16±0.01 3.497±0.023 7.995±0.022 100.04±2.321

5 Etho Std 7 10:3 Nil 199.9±0.308 6.97±0.048 0.25±0.03 3.5±0.032 7.99±0.031 99.211±2.037

6 Etho Std 7FP -do- Nil 200.05±0.605 7.17±0.095 0.17±0.01 3.495±0.022 7.995±0.022 98.09±2.823

7 Etho Std 7 -do- HPMC 200.05±0.394 6.97±0.048 0.25±0.01 3.5±0.032 7.99±0.031 99.024±2.172

8 Etho Std 7FP -do- HPMC 200.15±0.587 7.02±0.042 0.18±0.02 3.49±0.031 7.99±0.031 100.01±2.193

9 Etho Std 7 -do- CMC 200.05±051 6.98±0.042 0.26±0.02 3.495±0.039 7.995±0.022 99.032±2.523

10 Etho Std 7FP -do- CMC 199.95±0.394 7.11±0.042 0.17±0.03 3.42±0.032 7.985±0.037 99.09±2.213

11 Etho Std 7 -do- Starch 199.85±0.489 7±0.082 0.26±0.01 3.5±0.032 7.99±0.031 99.312±3.121

12 Etho Std 7FP -do- Starch 200.1±0.447 7.12±0.032 0.13±0.01 3.43±0.31 7.995±0.022 99.07±2.201

13 Etho Std 10 10:1 Nil 199.85±0.489 6.93±0.092 0.27±0.01 3.5±0.024 7.995±0.022 99.09±2.206

14 EthoStd10FP -do- Nil 199.82±0.345 7.11±0.03 0.15±0.0.4 3.5±0.027 7.99±0.031 99.04±2.301

15 Etho Std 10 10:2 Nil 200.05±0.483 6.97±0.093 0.27±0.05 3.48±0.046 7.99±0.031 100.07±2.201

16 EthoStd10FP -do- Nil 199.75±0.483 7.12±0.034 0.15±0.02 3.499±0.029 7.99±0.031 99.217±2.503

17 Etho Std 10 10:3 Nil 200.01±0.512 6.97±0.093 0.25±0.01 3.505±0.039 7.995±0.022 99.321±1.994

18 EthoStd10FP -do- Nil 200.1±0.447 7.12±0.082 0.12±0.03 3.49±0.031 7.995±0.022 98.22±1.322

19 EthoStd 10 -do- HPMC 200.1±0.447 6.97±0.048 0.26±0.05 3.51±0.031 7.99±0.031 98.041±2.813


21 EthoStd 10 -do- CMC 199.85±0.489 7.0±0.095 0.21±0.03 3.49±0.31 7.995±0.022 99.122±3.183

22 EthoStd10FP -do- CMC 200.05±0.394 7.11±0.074 0.14±0.04 3.47±0.032 7.99±0.031 99.012±2.135

23 EthoStd 10 -do- Starch 200±0.459 7.01±0.074 0.2±0.01 3.51±0.031 7.995±0.022 99.03±2.356

24 EthoStd10FP -do- Starch 200±0.459 7.12±0.042 0.12±0.04 3.49±0.022 7.995±0.022 98.012±3.103

25 EthoStd 100 10:1 Nil 200.85±0.483 6.97±0.093 0.23±0.03 3.5±0.076 7.99±0.031 100.07±2.298

26 EthoStd100FP -do- Nil 200.85±0.231 7.11±0.089 0.15±0.01 3.498±0.022 7.985±0.037 99.07±2.522

27 EthoStd 100 10:2 Nil 199.85±0.234 7±0.098 0.27±0.03 3.5±0.028 7.99±0.031 100.07±2.431

28 EthoStd100FP -do- Nil 199.95±0.203 7.12±0.01 0.14±0.04 3.499±0.035 7.985±0.037 99.237±2.201

29 EthoStd 100 10:3 Nil 199.9±0.553 7±0.082 0.25±0.01 3.5±0.032 7.99±0.031 98.08±2.327

30 EthoStd100FP -do- Nil 199.9±0.553 7.11±0.082 0.15±0.02 3.495±0.022 7.995±0.022 98.22±1.322

31 EthoStd 100 -do- HPMC 199.95±0.51 6.98±0.042 0.28±0.01 3.505±0.022 7.995±0.022 99.221±2.163


33 EthoStd 100 -do- CMC 200.05±0.394 6.99±0.088 0.27±0.02 3.5±0.032 7.99±0.031 100.042±2.15

34 EthoStd100FP -do- CMC 199.95±0.51 7.11±0.074 0.11±0.03 3.495±0.032 7.99±0.031 98.231±2.211

35 EthoStd 100 -do- Starch 200.1±0.447 6.98±0.042 0.29±0.03 3.5±0.032 7.985±0.037 100.03±2.113

36 EthoStd100FP -do- Starch 200.05±0.394 7.13±0.095 0.17±0.03 3.495±0.039 7.985±0.037 99.04±2.136



4.11. In-vitro dissolution study of directly compressed matrix tablets

An ideal extended release tablet should release the requisite quantity of drug with

predetermined kinetics, in order to uphold effective drug plasma concentration. To

achieve this, the tablet should be formulated in such a way to release the drug in

predetermined and reproducible manner. To achieve the predetermined release profile,

various formulation factors like polymer, polymer concentration, polymer grades and

excipients should be modified to get the required release (Saravanan et al., 2002). The in-

vitro dissolution study was carried out to examine the release profile of model drugs

(Ibuprofen and Ketoprofen) from the formulations containing polymer ethyl cellulose of

different viscosity grades (Ethocel® standard 7, 10 and 100 premium and Ethocel

®

standard 7, 10 and 100 FP premium). Moreover, the effect of polymer concentration and

partial incorporation of co-excipients (HPMC, CMC and starch) on the release profile of

model drugs from different formulations was also studied.

4.11.1. Effect of Ethocel® viscosity grade (Molecular weight) on drug release: The

release profiles of Model drugs (Ibuprofen and Ketoprofen) from Ethocel® matrices with

different viscosity grades, at D: P ratios of 10:3 are shown in Figs. 4.25 and 4.26. It can

be observed that Ethocel® 7-cp showed the slowest release rate and Ethocel

® 100-cp the

fastest release rate among the formulations studied. This is because that tablets containing

Ethocel®

with higher viscosity grades (granular polymer with larger particle size and thus

higher porosity) might not have produced a matrix with pores or openings small enough

to trap the drug and retard its release rate. The reason cited is that the smaller particle size

and fragmentation rate of Ethocel® with lower molecular weight (viscosity grade) are

more effective than those with higher molecular weights (higher viscosity) (Nystrem and

Alderborn, 1993).



Figure 4.25 Release profile of Ibuprofen from Ethocel

® matrices with different

viscosity grades and D: P ratio of 10:3.

These results ratify the findings of Shlieout and Zessin. (1996) and that of Upadrashta et

al. (1993) that ethylcellulose with lower viscosity grades produce slower release rates.

However, our results oppose the declaration of Shaikh et al. (1987a and 1987b) stating

that higher the viscosity grades of ethylcellulose the slower the release of water soluble

and sparingly soluble drugs from the tablets.

Figure 4.26 Release profile of Ketoprofen from Ethocel

® matrices with different

viscosity grades and D: P ratio of 10:3.



4.11.2. Effect of drug-to- polymer (D: P) ratio on release rate: Figs. 4.27 to 4.32 show

the percentage release of model drugs (Ibuprofen and Ketoprofen) in 24 hours from

matrix tablets containing ethylcellulose derivative polymer, Ehocel® standard premium

(7, 10 and 100) and Ethocel® standard FP premium (7,10 and 100) at different D:P ratios.

It can be observed that an increase in the quantity of Ethocel® decreased the drug release

rates. This might be due to the strength of matrix because the matrix at higher amount of

Ethocel®

should be, expectedly, stronger. This kind of matrix would cause a reduction of

water or solvent penetration through the micropores and drug diffusion, resulting in

slower release rate. Similar study was performed by Velasco et al. (1999). They observed

that release rate of Diclofenac sodium from matrix tablets containing HMPC was reduced

by an increase in the amount of the polymer. Our results also conform the findings of

Espinoza et al. (2000), showing that slower release rates of Pelanserin HCL were

observed with higher HPMC proportion.

Figure 4.27 Release profiles of Ibuprofen from Ethocel® standard 7 premium and

Ethocel® standard 7 FP premium matrices with different D: P ratios.



Figure 4.28 Release profile of Ibuprofen from Ethocel® standard 10 premium and

Ethocel® standard 10 FP premium matrices with different D:P ratios.

Figure 4.29 Release profiles of Ibuprofen from Ethocel® standard 100 premium and




Figure 4.30 Release profiles of Ketoprofen from Ethocel® standard 7 premium and


Figure 4.31 Release profiles of Ketoprofen from Ethocel® standard 10 premium and

Ethocel® standard 10 FP premium matrices with different D:P ratios.



Figure 4.32 Release profiles of Ketoprofen from Ethocel® standard 100 premium

and Ethocel® standard 100 FP premium matrices with different D: P ratios.

4.11.3. Ethocel® standard premium vs. Ethocel

® standard FP premium: Figures 4.33

and 4.34 show the comparative release patterns of model drugs (Ibuprofen and

Ketoprofen) from the matrix tablets containing Ethocel® Standard 7 premium and 7 FP

premium, Standard 10 premium and 10 FP premium, Standard 100 premium and 100 FP

premium polymers at 10: 3, D:P ratio. It could be observed that Ethocel®

standard FP

polymers had a more pronounced effect on the release rates of Ibuprofen and Ketoprofen

from all the formulations studied as compared to to simple Ethocel® standard premium

polymers. As shown in Fig. 4.33, granular Ethocel® Standard 7, 10 and 100 Premium

released 50% of Ibuprofen after 10, 8 and 6 hours, respectively.

On the other hand Ethocel® Standard 7, 10 and 100 FP Premium with similar D: P ratio

(10:3) released 50% of the drug after 18, 12 and 10 hours, respectively. As shown the

Ethocel® FP polymers extended the release rates of the drug more efficiently than the

conventional granular forms (Ethocel® Standard Premium), indicates that particle size of

the polymer has more effective role in controlling/retarding the release rate of the model

drugs. This effect of Ethocel®

standard FP grades might be due to the small particle size



and decreased porosity as compared to the granular Ethocel® Standard Premium grades of

polymer. Our results also conform the finding of Katikaneni et al. (1995), where tablets

prepared of polymer ethylcellulose with different particle sizes, revealed different release

profiles and showed that the porosity of the tablets increased with increase of particle size

of polymer and resulted in faster drug release. It may be seen that 100% drug was

released from all formulation after 24 hours, however, the percentage release from

formulation containing Ethocel® standard 7 FP Premium was 95.5% after 24 hours. This

distinctive effect of polymer Ethocel® standard FP 7 Premium could be due to the

smallest or fine particles size of the polymer as compared to all other types of the

granular as well as FP grades of Ethocel®, used in this study. Similar findings were

observed by Khan and Meidan (2007) in a previous study.

As demonstrated in Fig. 4.34, the Ketoprofen release from matrix tablets containing the

same polymers with the same D: P ratio followed the same release patterns as observed in

case of Ibuprofen, which further authenticates the more effective role of Ethocel® FP

grades, sepecially of the Ethocel®

standard 7 FP premium polymer in controlling the

release rate of drugs such as Ibuprofen and Ketoprofen.

Figure 4.33 Release profiles of Ibuprofen from Ethocel® standard 7, 10 and 100

premium and Ethocel® standard 7, 10 and 100 FP premium matrices with D: P ratio

10:3.



Figure 4.34 Release profiles of Ketoprofen from Ethocel® standard 7, 10 and 100

premium and Ethocel® standard 7, 10 and 100 FP premium matrices with D: P ratio

10:3.

4.11.4. Influence of co-excipietns on drug release rate: Preparation of tablets may

require the addition of co-excipients to acquire the tablets with appropriate size and

properties or to modify the drug release rates. Therefore, the influence of different co-

excipients, such as HPMC K100M, CMC and Starch was studied on the release rates of

model drugs (Ibuprofen and Ketoprofen) from the matrix tablets containing Ethocel®

Standard 7, 10, and 100 Premium and Ethocel®

Standard 7, 10 and, 100 FP Premium, at

D:P ratio 10:3. The release study was performed after physicochemical evaluation of all

formulation containing co-excipients. Tablets with acceptable physical properties were

obtained in all cases, studied. Moreover, excellent content uniformity was observed in all

the tablets with the above mentioned co-excipients.

As depicted in Figs. 4.35 to 4.46, all the co-excipients used in this study showed

significant enhancement in the drugs release rates from the tablets formulated. Drugs

release was found to be most rapid from tablets containing co-excipients as compared to

those without co-excipients. As shown in the figures, 90% of Ibuprofen was released



after 18, 12 and 10 hours from the formulations containing Ethocel® Standard 7, 10 and

100 Premium, respectively, on the other hand, the amount (90%) of the drug was released

after 24, 18 and 12 hours from the formulations having Ethocel® Standard 7, 10, and 100

FP Premium, respectively. It can also be seen from the same Figs. (4.35-4.40), that all

formulations with co-excipients displayed much higher release rates of the Ibuprofen.

The formulations containing Ethocel® Standard 7, 10, and 100 Premium and Ethocel

®

Standard 7, 10, and 100 FP Premium with co-excipient HPMC K100M, showed fast

release of Ibuprofen, as 90% of drug was released after 8, 6, 5, 18, 12 and 10 hours,

respectively. However, when CMC and Starch were used as co-excipients the release

rates of the drug were further increased, where 90% of the drug was released only within

2-3hours.

The same procdure was repeated for the tablet formulations containing Ketoprofen. It can

be observed form the figures 4.41-4.46 that 90% of Ketoprofen was released from the

formulations containing Ethocel® Standard 7, 10, 100 Premium and Ethocel

® Standard 7,

10 and 100 FP Premium after 7, 6, 5 and 24, 18, 12 hours, respectively. But after

incorporation of HMPMC K100M as co-excipient to the formulation containing Ethocel®

Standard 7, 10, 100 Premium and Ethocel®

Standard 7, 10 and 100 FP Premium, the

release rates were increased and 90% of Ketoprofen was released after 6, 5, 4, 12, 10 and

8 hours, respectively. Much faster release the drug was observed from the tablets when

CMC and Starch were replaced as co-excipients and 90% of the drug was released within

2-3 hours.

As the release rates of the model drugs (Ibuprofen and Ketoprofen) from the formulations

containing HPMC K100M as co-excipient was fast as compared to formulation without

co-excipients, but it was more extended as compared to formulations containing co-

excipients CMC and Starch. This more extended release may be due to the less hydration

capacity of HPMC K100M (Luana et al., 2004), but the higher release rates from the

tablets having HPMC K100M as compared to the formulations containing Ethocel®



standard Premium and Ethocel® FP Premium without co-excipient may be due to the

development of osmotic pressure because HPMC creates osmotic forces following

penetration of water with in matrices. These results conform the finding of Alderman.

(1984), Ford et al. (1987), Khan GM and Zhu. (1998a and 1998b) and Gohal et al. (2003)

that HPMC in small quantity may act as channeling agent and can increase the release

rate.

As shown in the figures, more than 90% of drug is released within 2-3hours from the

formulation containing starch as co-excipient, it is because that starch is insoluble in

water and due to insoluble nature of starch it may cause non-uniformity of polymeric

material around the drug and due to this property mostly imperfection in membranes

takes place, which causes the quick release of drug from tablets and it may be due to

water-swellable nature of starch in water. Similar findings were reported by Khan and

Zhu. (1998b) who quoted that reason for enhancement of drug from formulations

containing starch could be the water-swellable property of starch and due to this property;

it might cause to rupture the polymeric membrane around the drug contents and causing

the enhancement of drug release rate.

The same findings were observed when CMC was used as co-excipient (Figs. 4.41-4.46)

where the entire drug was released from the formulations containing CMC within 2

hours. These results might be attributed to the relatively lower viscosity of CMC which

led to low swellability and rapid dilution and erosion of the diffusion gel layer

(Alderman, 1984; Hamdy et al., 2007). It may also be due to the disintegrating property

of CMC (Khan and Rhodes, 1975; Shah and Jarwoski, 1981), and the disintegration

properties might contribute to this effect. Furthermore, this drastic release may be due to

the water soluble property of CMC because according to Khan and Zhu. (1998b) the

water soluble co-excipient may break up the polymeric membrane around the drug

contents due to the creation of osmotic forces within matrices, causing higher release rate

of drug.



Figure 4.35 Influence of partial replacement (30%) of lactose with various co-excipients

(HPMC K100M, CMC and Starch) on release profiles of Ibuprofen from tablets containing

Ethocel® standard 7 premium with D: P ratio, 10:3.



Ethocel® standard 7 FP premium with D: P ratio, 10:3.






Figure 4.38 Influence of partial replacement (30%) of lactose with various co-

excipients (HPMC K100M, CMC and Starch) on release profiles of Ibuprofen from

tablets containing Ethocel® standard 10 FP premium with D: P ratio, 10:3.




(HPMC K100M, CMC and Starch) on release profiles of Ketoprofen from tablets

containing Ethocel® standard 7 premium with D: P ratio, 10:3.



containing Ethocel® standard 7 FP premium with D: P ratio, 10:3.





containing Ethocel® standard 10 premium with D: P ratio, 10:3.



containing Ethocel® standard 10 FP premium with D: P ratio, 10:3.




(HPMC K100M, CMC and Starch) on release profile of Ketoprofen from tablets containing



(HPMC K100M, CMC and Starch) on release profile of Ketoprofen from tablets containing




4.12. In-vitro release study of the matrix tablets containing solid dispersions

Solid dispersions of model drugs (Ibuprofen and Ketoprofen) showing better dissolution

rate were formulated into matrix tablets, using Ethocel® standard 7 FP premium, at D: P

ratio 10: 3. Ethocel® standard 7 FP premium was selected for preparation of these

formulations due to its more effective role in controlling the release rate of drugs

Ibuprofen and Ketoprofen as mentioned above. As shown in Figs. 4.47 and 4.48, the

formulated matrix tablets containing solid despersions of model drugs showed complete

(100%) release of Ibuprofen and Ketoprofen in 12 and 8 hours, respectively, whereas the

matrix tablets of Ibuprofen and Ketoprofen were found to release 87.6% and 95.4% of

drug after 24 hours, respectively. The fast and rapid release of drugs in solid dispersions

form could be due to the presences of drugs in amorphous form. These results well

conform to those obtained in this study, from the DSC, X-ray diffractometry, IR and

SEM. The other factors such as absence of aggregation, good wettability and

dispersability might contribute to the increase in release rate (Parsad et al., 2010)

Figure 4.47 Comparative dissolution release profile of Ibuprofen and Ibuprofen solid

desperisons from matrix tablets containing Ethocel® standard 7 FP premium polymer.



Figure 4.48 Comparative dissolution release profile of Ketoprofen and Ketoprofen solid

desperisons from matrix tablets containing Ethocel® standard 7 FP premium polymer.

4.13. Analysis of drugs release kinetics

Tables 4.12 to 4.27 show the data of the parameters of the kinetic models (Zero-order

kinetics, First-order kinetics, Hixon Crowel‟s Cube-root Equation, Higuchi‟s Square Root

of Time Equation and Power Law Equation) as applied to test formulations for model

drugs (Ibuprofen and Ketoprofen) release profiles from tablets containing Ethocel®

Standard Premium and Ethocel® Standard FP Premium polymers of different grades, at

different D: P ratios with or without and co-excipients (HPMC K100M, Starch and

CMC). Based on the kinetic models, linear relation was found for all the formulations

containing conventional Ethocel® Standard Premium polymers, at different D: P ratios.

Among them, the Ethocel® Standard 10 and 100 Premium polymers demonstrated

maximum r values, at D: P ratios of 10:2 and 10:3, when the release data was fitted to Eq.

5 but the best linear relation as well as maximum r values were found for Ethocel®

Standard 7 Premium, as compared to Ethocel® Standard 10 and 100 Premium, when the

percentage release data for both drugs (Ibuprofen and Ketoprofen) was fitted to the same

equation 5 (Power Law equation).



However, in case of tablets containing Ethocel®

Standard FP Premium (the lattest among

the ethyl cellulose ether derivative polymers), at different D: P ratios, good linear relation

was observed in all the cases when the data was fitted to any one of the above equations

(Eqs. 1-5) and the best linear relation with maximum r values was observed for Ehtocel®

Standard 7 FP Premium, at D: P ratio of 10:3. Nevertheless, maximum linearity was

found for all formulations when the data was fitted to Eq. 5.

In case of formulations containing co-excipients, linear relation was found for

formulations containing co-excipient HPMC K100M along with Ethocel® Standard FP 7

Premium, at D: P ratio 10:3, when the data was fitted to Eq. 1-5. However, fluctuations

were observed in the release mechanisms of drugs in those formulations containing other

co-excipients, such as CMC and Starch when the data was fitted to the said equations

(Eqs. 1-5) and non-linear relation was found with minimum r values.

As shown in the tables 4.12 to 4.27 majority of the formulations have diffusional

exponent value “n” in between 0.469 and 0.855, indicating that these formulations follow

non-fickian anomalous release mechanism (n value between 0.45 and 0.89). This means

that the drug is released in pure diffusion controlled mechanism coupled with swelling

and erosion mechanisms; while the remaining formulations showed „„n‟‟ value less than

0.45. This smaller value may be due to drug diffusion partially through swollen matrix

and water filled pores in the formulation (Roshan et al., 2008). The formulations

containing Ethocel®

standard FP 7 Premium showed better release kinetics as compared

to other formulations containing different grade of ethylcellulose polymer and

formulations containing co-excipients, as shown in tables 4.12 to 4.27.





Sandard Premium polymer of

different viscosity grade, (meanSD of three determinations).

Formulation

IBF:Ethocel

W=k1t

k1SD r1

(100-W)=ln100-k2t

k2SD r2

(100-W)1/3=1001/3-k3t

k3SD r3

W=k4t1/2

k4SD r4

Mt/M=k5tn

k5SD r5 n

Ibuprofen- Ethocel

standard 7 Premium

10:1

9.7339.042

0.9321

0.3140.152

0.9212

0.3390.117

0.9301

8.3517.864

0.9321

0.0160.048

0.9531

0.632

10:2

5.2661.841

0.9582

0.1180.040

0.9521

0.1500.037

0.9513

5.8662.537

0.9532

0.0760.152

0.9632

0.721

10:3

4.5681.160

0.9853

0.0960.033

0.9652

0.1190.027

0.9762

5.3622.171

0.9854

0.2080.412

0.9941

0.758

Ibuprofen Ethocel

standard 10 Premium

10:1

9.8329.751

0.8639

0.2990.165

0.9174

0.3390.114

0.9324

8.3778.250

0.9639

0.0110.032

0.9603

0.618

10:2

6.0372.553

0.963

0.1340.035

0.9224

0.1710.033

0.9415

6.3952.935

0.9631

0.0560.121

0.9929

0.721

10:3

5.3151.909

0.941

0.1120.030

0.9247

0.1480.036

0.9163

5.9102.361

0.9751

0.0800.165

0.9912

0.722

Ibuprofen- Ethocel

standard 100 Premium

10:1

9.76810.484

0.7966

0.3490.200

0.6755

0.3720.153

0.7557

8.2299.150

0.7955

0.0090.027

0.973

0.583

10:2

6.903 4.224

0.9539

0.1780.076

0.7995

0.2120.052

0.8701

6.8944.911

0.9541

0.0320.070

0.9878

0.712

10:3

6.42.999

0.9604

0.1450.047

0.7892

0.1830.039

0.8661

6.6233.597

0.9654

0.0430.089

0.9899

0.716





Standard FP Premium

polymer of different viscosity grades, (meanSD of three determinations).

Formulation

IBF:Ethocel

W=k1t

k1SD r1

(100-W)=ln100-k2t

k2SD r2

(100-W)1/3=1001/3-k3t

k3SD r3

W=k4t1/2

k4SD r4

Mt/M=k5tn

k5SD r5 n

Ibuprofen- Ethocel

standard 7 FP Premium

10:1

6.1613.138

0.9494

0.1290.033

0.9778

0.1670.036

0.9612

6.4613.326

0.9494

0.0500.104

0.9682

0.715

10:2

5.0381.490

0.9236

0.1000.034

0.9681

0.1310.025

0.9517

5.7722.218

0.9236

0.1790.353

0.992

0.775

10:3

3.6130.490

0.9932

0.0750.039

0.9935

0.0890.026

0.9901

4.5322.016

0.9992

0.5571.103

0.9995

0.855

Ibuprofen- Ethocel


10:1

6.6633.222

0.9453

0.1590.059

0.9254

0.1970.041

0.9767

6.8043.688

0.9653

0.0380.082

0.9893

0.715

10:2

5.371.805

0.9614

0.1130.033

0.6599

0.1400.025

0.9862

5.9612.188

0.9714

0.1320.267

0.9924

0.761

10:3

3.8870.347

0.9746

0.0720.032

0.9856

0.0980.030

0.9845

4.9672.490

0.9846

0.4120.774

0.9944

0.762

Ibuprofen- Ethocel


10:1

6.9053.873

0.9616

0.1720.060

0.8263

0.2100.045

0.8922

6.8794.289

0.9616

0.0310.066

0.9902

0.704

10:2

6.4240.013

0.9612

0.1370.043

0.7837

0.1730.031

0.8659

6.6763.586

0.9641

0.0790.170

0.9897 0.755

10:3

4.7261.558

0.9882

0.1000.046

0.9082

0.1280.033

0.9021

5.5393.251

0.8922

0.1960.403

0.9935

0.772





Standard Premium polymer

of different grades and co-excipient HPMC K100M, (meanSD of three

determinations).

Formulation

IBF:Ethocel

W=k1t

k1SD r1

(100-W)=ln100-k2t

k2SD r2

(100-W)1/3=1001/3-k3t

k3SD r3

W=k4t1/2

k4SD r4

Mt/M=k5tn

k5SD r5 n

Ibuprofen- Ethocel

standard 7 Premium and HPMC K100M

10:3

8.8067.046

0.9163

0.2470.111

0.8821

0.2890.075

0.8176

7.9116.275

0.9061

0.0180.045

0.9184

0.666

Ibuprofen- Ethocel

standard 10 Premium and HPMCK100M

10:3

9.431 8.732

0.8648

0.2860.145

0.755

0.3180.110

0.8275

8.0997.695

0.8654

0.0110.029

0.9824

0.623

Ibuprofen- Ethocel


10:3

9.321 8.519

0.8523

0.3040.151

0.7637

0.3350.116

0.8312

8.0387.643

0.8552

0.0080.021

0.9791

0.600





Standard FP polymer of

different grades and HPMC K100M, (meanSD of three determinations).

Formulation

IBF:Ethocel

W=k1t

k1SD r1

(100-W)=ln100-k2t

k2SD r2

(100-W)1/3=1001/3-k3t

k3SD r3

W=k4t1/2

k4SD r4

Mt/M=k5tn

k5SD r5 n

Ibuprofen- Ethocel

standard 7 FP Premium and HPMC K100M

10:3

4.2990.753

0.9921

0.0890.036

0.9908

0.1080.026

0.9951

5.1711.880

0.9923

0.3100.631

0.9961

0.761

Ibuprofen- Ethocel


10:3

5.8872.546

0.9522

0.1240.039

0.743

0.1580.030

0.9387

6.3443.270

0.9513

0.0890.176

0.9887

0.759

Ibuprofen- Ethocel


10:3

6.631 3.904

0.9473

0.1590.070

0.7937

0.1910.048

0.8604

6.7924.973

0.9479

0.0570.120

0.9901

0.748





Standard Premium

polymer of different grades and co-excipient Starch, (meanSD of three

determinations).

Formulation

IBF:Ethocel

W=k1t

k1SD r1

(100-W)=ln100-k2t

k2SD r2

(100-W)1/3=1001/3-k3t

k3SD r3

W=k4t1/2

k4SD r4

Mt/M=k5tn

k5SD r5 n

Ibuprofen- Ethocel

standard 7 Premium and Starch

10:3

11.36715.197

0.6923

0.4520.314

0.689

0.4740.229

0.7189

9.04112.102

0.6959

0.0150.052

0.9485

0.537

Ibuprofen- Ethocel


10:3

11.41218.118

0.6152

0.4720.333

0.4383

0.4790.279

0.536

8.84014.366

0.6144

0.0100.031

0.9715

0.515

Ibuprofen- Ethocel


10:3

11.54317.572

0.6103

0.5300.412

0.3591

0.5160.308

0.4994

8.88313.956

0.6112

0.0070.024

0.9517

0.469





standard FP polymer of

different grades and co-excipient Starch, (meanSD of three determinations).

Formulation

IBF:Ethocel

W=k1t

k1SD r1

(100-W)=ln100-k2t

k2SD r2

(100-W)1/3=1001/3-k3t

k3SD r3

W=k4t1/2

k4SD r4

Mt/M=k5tn

k5SD r5 n

Ibuprofen- Ethocel

standard 7 FP Premium and Starch

10:3

9.0987.628

0.9107

0.2540.112

0.8882

0.2980.078

0.9202

8.0566.628

0.9119

0.0180.050

0.9743

0.657

Ibuprofen- Ethocel


10:3

9.5019.110

0.8352

0.3040.148

0.7697

0.3380.121

0.8221

8.1268.081

0.8343

0.0110.030

0.9764

0.607

Ibuprofen- Ethocel


10:3

9.64910.376

0.7982

0.3500.205

0.6645

0.3720.154

0.7509

8.1619.170

0.7965

0.0080.023

0.9759

0.580





Standard simple Premium

polymer of different grades and co-excipient CMC, (meanSD of three

determinations).

Formulation

IBF:Ethocel

W=k1t

k1SD r1

(100-W)=ln100-k2t

k2SD r2

(100-W)1/3=1001/3-k3t

k3SD r3

W=k4t1/2

k4SD r4

Mt/M=k5tn

k5SD r5 n

Ibuprofen- Ethocel

standard 7 Premium and CMC

10:3

6.92616.420

0.3339

0.6730.678

0.4048

1.0270.835

0.2624

4.86711.625

0.3331

0.0000.000

0.7495

0.092

Ibuprofen- Ethocel


10:3

6.57716.778

0.2127

1.0360.932

0.0079

0.9900.860

0.0685

4.52411.921

0.2123

0.0000.000

0.7051

0.075

Ibuprofen- Ethocel


10:3

6.44616.686

0.1987

1.0340.939

0.0049

0.9930.870

0.0587

4.41911.861

0.2984

0.0000.000

0.6972

0.071





standard FP polymer of

different grades and co-excipient CMC, (meanSD of three determinations).

Formulation

IBF:Ethocel

W=k1t

k1SD r1

(100-W)=ln100-k2t

k2SD r2

(100-W)1/3=1001/3-k3t

k3SD r3

W=k4t1/2

k4SD r4

Mt/M=k5tn

k5SD r5 n

Ibuprofen- Ethocel

standard 7 FP Premium and CMC

10:3

8.14116.140

0.4125

0.6280.628

0.3982

0.8920.652

0.3958

5.71911.434

0.4128

0.0000.000

0.844

0.128

Ibuprofen- Ethocel


10:3

7.74 17.846

0.2849

0.9060.720

0.0804

0.9010.722

0.1635

5.34412.144

0.2749

0.0000.000

0.7818

0.106

Ibuprofen- Ethocel


10:3

7.59317.725

0.2712

0.9200.746

0.06

0.9120.740

0.142

5.23812.599

0.2717

0.0000.000

0.7728

0.101





simple Premium polymer of

different grades, (meanSD of three determinations).

Formulation

KTF:Ethocel

W=k1t

k1SD r1

(100-W)=ln100-k2t

k2SD r2

(100-W)1/3=1001/3-k3t

k3SD r3

W=k4t1/2

k4SD r4

Mt/M=k5tn

k5SD r5 n

KTF- Ethocel

standard 7 Premium

10:1

9.14611.727

0.8146

0.4450.257

0.8364

0.4710.217

0.8391

7.49110.275

0.8146

00 0.009

0.9823

0.417

10:2

8.987510.362

0.9098

0.4020.192

0.9236

0.4360.176

0.9086

7.5329.093

0.9298

0.0010.001

0.9851

0.449

10:3

9.076610.1347

0.9343

0.2960.160

0.9633

0.3230.126

0.9211

8.0569.443

0.9343

0.0240.071

0.9873

0.662

KTF- Ethocel

standard 10 Premium

10:1

9.081 11.901

0.7218

0.4380.245

0.5694

0.4710.216

0.6621

7.42010.080

0.7219

0.0000.001

0.9813

0.406

10:2

9.29511.049

0.7462

0.4150.197

0.6736

0.4500.186

0.7268

7.6459.319

0.7465

0.0000.001

0.9829

0.436

10:3

7.7910.043

0.8142

0.3220.174

0.7452

0.3470.140

0.7961

8.3278.901

0.8147

0.0200.059

0.9869

0.633

KTF- Ethocel

standard 100 Premium

10:1

9.02811.585

0.8225

0.4170.207

0.8945

0.4680.215

0.6581

7.2969.667

0.7029

0.0000.000

0.9814

0.387

10:2

9.28811.504

0.8275

0.4310.220

0.8159

0.4620.201

0.6482

7.5999.755

0.7243

0.0000.000

0.9842

0.424

10:3

9.710.275

0.8621

0.3360.192

0.8069

0.3580.149

0.7717

8.2639.222

0.9876

0.0150.046

0.9847

0.619





FP polymer of different

grades, (meanSD of three determinations).

Formulation

KTF:Ethocel

W=k1t

k1SD r1

(100-W)=ln100-k2t

k2SD r2

(100-W)1/3=1001/3-k3t

k3SD r3

W=k4t1/2

k4SD r4

Mt/M=k5tn

k5SD r5 n

KTF- Ethocel


10:1

8.337 7.179

0.9016

0.2740.101

0.9014

0.3160.094

0.9805

7.4486.637

0.9216

0.0030.008

0.9898

0.571

10:2

8.09755.191

0.985

0.1790.050

0.9892

0.2190.037

0.9976

7.5654.067

0.975

0.0710.185

0.9945

0.741

10:3

4.7931.454

0.9923

0.0930.017

0.9904

0.1280.022

0.997

5.6691.063

0.9923

0.1670.343

0.9991

0.843

KTF- Ethocel


10:1

8.031 6.332

0.9176

0.2610.093

0.9277

0.3050.088

0.9082

7.2695.836

0.9176

0.0030.007

0.9891

0.568

10:2

8.4156.362

0.9319

0.2250.092

0.9502

0.2600.067

0.9022

7.6935.862

0.9319

0.0340.086

0.9769

0.704

10:3

5.8822.271

0.957

0.1180.032

0.9679

0.153.022

0.9335

6.3252.561

0.957

0.1260.265

0.9982

0.776

KTF- Ethocel


10:1

8.5377.539

0.8773

0.2960.112

0.8182

0.3420.111

0.619

7.4596.857

0.8773

0.0020.004

0.9819

0.528

10:2

8.9017.082

0.8151

0.2620.114

0.8399

0.2880.078

0.9025

7.8916.289

0.9151

0.0250.065

0.9829

0.684

10:3

6.6433.153

0.9119

0.1440.058

0.9783

0.1770.037

0.9632

6.8323.806

0.9219

0.0880.188

0.9853

0.771





simple Premium polymer of

different grades and co-excipient HPMC K100M , (meanSD of three

determinations).

Formulation

KTF:Ethocel

W=k1t

k1SD r1

(100-W)=ln100-k2t

k2SD r2

(100-W)1/3=1001/3-k3t

k3SD r3

W=k4t1/2

k4SD r4

Mt/M=k5tn

k5SD r5 n

KTF- Ethocel


10:3

9.7509.438

0.813

0.3110.152

0.7634

0.3430.124

0.8183

8.2638.167

0.8323

0.0140.042

0.6979

0.612

KTF- Ethocel


10:3

9.70510.472

0.7998

0.3460.214

0.6451

0.3660.157

0.7442

8.2219.301

0.7876

0.0110.033

0.9702

0.596

KTF- Ethocel


10:3

7.1724.483

0.9536

0.1850.082

0.8004

0.2180.053

0.8773

7.0494.901

0.9532

0.0370.081

0.9861

0.723





stand FP polymer of

different grades and co-excipient HPMC K100M, (meanSD of three

determinations).

Formulation

KTF:Ethocel

W=k1t

k1SD r1

(100-W)=ln100-k2t

k2SD r2

(100-W)1/3=1001/3-k3t

k3SD r3

W=k4t1/2

k4SD r4

Mt/M=k5tn

k5SD r5 n

KTF- Ethocel


10:3

6.092.564

0.9836

0.1310.036

0.9615

0.1680.028

0.9585

6.4462.946

0.9636

0.0730.151

0.9924

0.745

KTF- Ethocel

standard 10 FP and HPMC K100M

10:3

6.9773.900

0.9625

0.1710.063

0.8324

0.2060.043

0.8956

6.9683.825

0.9637

0.0440.097

0.9914

0.730

KTF- Ethocel

standard 100 FP and HPMC K100M

10:3

7.1724.483

0.9536

0.1850.082

0.8004

0.2180.053

0.8773

7.0494.901

0.9512

0.0370.081

0.9867

0.723





Standar simple Premium

polymer of different y grades and co-excipient Starch, (meanSD of three

determinations).

Formulation

KTF:Ethocel

W=k1t

k1SD r1

(100-W)=ln100-k2t

k2SD r2

(100-W)1/3=1001/3-k3t

k3SD r3

W=k4t1/2

k4SD r4

Mt/M=k5tn

k5SD r5 n

KTF- Ethocel


10:3

3.6888.171

0.1953

1.0410.890

0.0313

1.0501.005

0.0815

2.4745.853

0.1952

0.0000.000

0.8373

0.037

KTF- Ethocel


10:3

0.2539.270

0.0052

1.3061.632

0.026

1.2461.584

0.0074

0.0486.565

0.0052

0.0000.000

0.2768

0.004

KTF- Ethocel


10:3

3.6149.330

0.1767

1.1441.054

0.0056

1.0981.068

0.047

2.4436.679

0.1723

0.0000.000

0.7529

0.035





Standard FP 7, 10, 100

polymers of different grades and co-excipient Starch, (meanSD of three

determinations).

Formulation

KTF:Ethocel

W=k1t

k1SD r1

(100-W)=ln100-k2t

k2SD r2

(100-W)1/3=1001/3-k3t

k3SD r3

W=k4t1/2

k4SD r4

Mt/M=k5tn

k5SD r5 n

KTF- Ethocel


10:3

6.0952.564

0.9636

0.1310.036

0.7615

0.1680.028

0.8585

6.4462.946

0.9612

0.0730.151

0.9914

0.745

KTF- Ethocel


10:3

3.7147.890

0.209

1.0110.864

0.038

1.0300.986

0.0915

2.4715.668

0.2213

0.0000.000

0.8693

0.039

KTF- Ethocel


10:3

3.7319.086

0.1718

1.1671.077

0.2007

1.1021.058

0.0286

2.5166.990

0.1732

0.0000.000

0.7664

0.037





standar Simple Premium

polymer of different grades and co-excipient CMC, (meanSD of three

determinations).

Formulation

KTF:Ethocel

W=k1t

k1SD r1

(100-W)=ln100-k2t

k2SD r2

(100-W)1/3=1001/3-k3t

k3SD r3

W=k4t1/2

k4SD r4

Mt/M=k5tn

k5SD r5 n

KTF- Ethocel

standard 7 Premium and CMC 10:3

2.1486.306

0.0174

1.223 1.215

0.0382

1.1761.254

0.0078

1.3834.519

0.0172

0.0000.000

0.6721

0.010

KTF- Ethocel


10:3

2.1566.344

0.0201

1.2611.247

0.0411

1.1941.268

0.008

1.3934.544

0.0232

0.0000.000

0.6637

0.012

KTF- Ethocel


10:3

2.0616.182

0.0083

1.2511.269

0.0566

1.1941.290

0.0182

1.3134.428

0.0076

0.0000.000

0.6201

0.001





FP polymer of different

grades and co-excipient CMC, (meanSD of three determinations).

Formulation

KTF:Ethocel

W=k1t

k1SD r1

(100-W)=ln100-k2t

k2SD r2

(100-W)1/3=1001/3-k3t

k3SD r3

W=k4t1/2

k4SD r4

Mt/M=k5tn

k5SD r5 n

KTF- Ethocel


10:3

2.7857.541

0.0869

1.3751.410

0.0453

1.1991.212

0.0009

1.8365.394

0.8543

0.0000.000

0.734

0.021

KTF- Ethocel


10:3

2.947.975

0.0972

1.1591.090

0.0007

1.1251.137

0.0102

1.9475.722

0.0932

0.0000.000

0.7183

0.023

KTF- Ethocel


10:3

2.8927.912

0.0731

1.2191.162

0.0147

1.1541.169

0.0004

1.9095.656

0.0712

0.0000.000

0.7023

0.020



4.14. Selection of the optimized test tablets

The Ibuprofen and Ketoprofen formulations containing Ethocel® standard 7 FP premium,

at D:P ratio 10:3 were selected as the optimized and the best formulations on the basis of

their prolonged release rates of 87.66% and 95.4% of Ibuprofen and Ketoprofen,

respectively, after 24 hours (Figs. 4.25 to 4.46). The formulations also followed near to

zero order release profile, as shown in tables 4.12 to 4.27. These formulations were

further used for stability study and in- vivo evaluation.

4.15. Reproducibility and accelerated stability study

The selected tablets (best formulations) were stored for stability study in ambient

conditions or room temperature (temperature = 25 0C and Relative humidity 65%) as well

as at accelerated storage conditions (400C and RH 75%) for one year. The tablets were

evaluated for their physical appearance, hardness, friability, weight variation, content

uniformity and dissolution profile at predetermined intervals of time 0 (pre-storage), 1, 2,

3, 6, 9 and 12 months. As shown in tables 4.28 and 4.29, the percent drug content for

Ibuprofen in ambient conditions or room temperature at 0 time (pre-storage) and after 1,

2, 3, 6, 9 and 12 months are 101±3, 101±2, 100±1, 100.1±2, 99.5±2, 99±2 and 99±1, and

in accelerated conditions as 101±3, 100±1, 99.5±1, 99.2±2, 99±3 and 99±1, respectively

showing no significant difference in drug content. The weight variation in both

conditions in ambient and accelerated conditions at the same time interval was noted to

be 199.85±0.421, 199.05±0.12, 199.1±0.231, 199.12±0.121, 200.05±0.231,

200.05±0.654, 200.01 and 199.85±0.421, 200±0.12, 200.01±0.231, 200.02±0.121,

200.05±0.231, 200.1±0.654, 200.15±0.132, respectively. The friability for optimized

Ibuprofen formulation in ambient conditions was noted to be 0.12±0.01, 0.13±0.0.5,

0.13±0.02, 0.12±0.09, 0.14±0.01, 0.14±0.02, 0.14±0.03 and in accelerated conditions it

was 0.12±0.01, 0.14±0.0.6, 0.14±0.09, 0.14±0.01, 0.15±0.01, 0.15±0.01 and 0.15±0.02 at

0 time (pre-storage) and after 1, 2, 3, 6, 9 and 12 months, respectively. Moreover,

hardness was also evaluated at 0 time (pre-storage) and after 1, 2, 3, 6, 9 and 12 months

in ambient and accelerated conditions and the results obtained are 7.15±0.092,

7.15±0.098, 7.15±0.043, 7.16±0.012, 7.17±0.017, 7.17±0.091, 7.17±0.098 and



7.15±0.092, 7.15±0.012, 7.16±0.043, 7.16±0.052, 7.16±0.019, 7.17±0.078, 7.17±0.099,

respectively. The percentage release profile at 0 time (pre-storage) and after 1, 2, 3, 6, 9

and 12 months was also studied in ambient and accelerated conditions and the results

obtained are 87.91±0.111, 87.01±0.213, 86.09±0.112, 86.05±0.123, 86.04±0.12,

86.01±0.312, 86±0.114 and 87.91±0.111, 87.06±0.341, 86.08±0.431, 86.07±0.123,

86.05±0.171, 86.02±0.211, 86.01±0.141, respectively. The whitish appearance was

retained the whole year.

Similar stability studies were performed for optimized Ketoprofen matrix tablets. As

shown in tables 4.30 and 4.31, no significant changes were observed in the percent drug

content in ambient conditions (101±1, 100.5±2, 100.5±1, 100±2, 99.85±1, 99.5±1, 99±2);

weight variation (200±0.123, 199.85±0.13, 199.85±0.141, 200±0.122, 200.05±0.231,

200.1±0.113, 200.75±123); percent friability (0.14±0.02, 0.15±0.0.1, 0.15±0.03,

0.16±0.08, 0.16±0.05, 0.16±0.01, 0.16±0.02); hardness (7.14±0.093, 7.14±0.095,

7.15±0.031, 7.15±0.0141, 7.16±0.0117.17±0.012, 7.17±0.0312); percent drug release

(94.9±0.121, 94.5±0.214, 94.5±0.112, 94.5±0.121, 94.1±0.11, 94±0.316, 93.9±0.125) and

appearance (whitish), tested at 0 time (pre-storage) and after storage at 1, 2, 3, 6, 9 and 12

months, respectively and same results were found when the tablets were stored in

accelerated conditions. Moreover, no significant effects were observed in accelerated

conditions on the percent drug content (101±1, 100.5±1, 100±2, 99.5±2, 99.1±2, 99.1±1,

99±2); weight variation (200±0.123, 200±0.568, 200±0.145, 200±0.172, 200.05±0.231,

200.1±0.112, 200.1±0.112); percent friability (0.14±0.02, 0.15±0.07, 0.15±0.09,

0.16±0.04, 0.16±0.08, 0.16±0.09, 0.17±0.01); hardness (7.14±0.093, 7.15±0.098,

7.15±0.0842, 7.17±0.095, 7.17±0.098, 7.17±0.101, 7.17±0.123); percent release

(94.9±0.121, 94.5±0.124, 94.5±0.234, 94.5±0.157, 94.1±0.217, 94.1±0.452, 94±0.161);

appearance (whitish), tested at 0 time (pre-storage) and after storage at 1, 2, 3, 6, 9 and 12

months, respectively

As shown (tables 4.28 to 4.31), no significant difference was noted in the % drug

released. This indicates that controlled release matrix tablets of Ibuprofen and Ketoprofen



were reliable and reproducible. Also the release kinetics remained unchanged up to one

year of storage in ambient and accelerated conditions and no significant changes were

observed in all physical characteristics, suggesting that Ibuprofen and Ketoprofen were

stable in Ethocel® standard 7 FP premium polymer compressed tablets. These results are

similar to a previously reported study of Chandran et al. (2008), wherein no significant

changes were observed in physical characteristics and release profiles of Ibuprofen

matrix tablets after storage for one year.

Difference factor ƒ1 and Similarity factor ƒ2 were also calculated as shown in tables 4.32

and 4.33 during stability studies for Ibuprofen and Ketoprofen controlled release matrix

tablets at different time intervals after 1, 2, 3, 6, 9 and 12 months, while comparing the

release profile with dissolution profiles at zero time (pre-storage). As shown in tables

4.32 and 4.33 the difference factor ƒ1 for Ibuprofen and Ketoprofen matrix tablets in

ambient and accelerated conditions was in the range of 0.014-0109 and 0.011-0.101,

respectively, while similarity factor ƒ2 was in the range of 96.305-99.161 for Ibuprofen

and 98.856-99.809 for Ketoprofen, indicating a good level of equivalence of dissolution

profiles determined at 0 time (pre-storage) and after storage at 1, 2, 3, 6, 9 and 12 months.

Generally, ƒ1 up to 15 and ƒ2 > 50 indicates similar dissolution profile (Shah et al., 1998;

US FDA, 1997).

Table 4.28 Stability indicating parameters (drug content, weight variation, friability,

hardness, % release after 24 hours and appearance) for Ibuprofen matrices in ambient

conditions (25oC and RH 65%).

Reading taken for

determination of

stability

Drug

content(%)

n= 3

(mean±SD)

Weight variation

test (mg)

n=20

(Mean±SD)

Friability

test (%)

n=3

(Mean±SD

Hardness

test kg/cm3)

n=10

(Mean±SD

% Release after

24 hours

n=3

(Mean±SD)

Appearance

(Colour)

At 0 time (prestorage) 101±3 199.85±0.421 0.12±0.01 7.15±0.092 87.91±0.111 Whitish

After 1 month 101±2 199.05±0.12 0.13±0.0.5 7.15±0.098 87.01±0.213 Whitish

After 2 months 100±1 199.1±0.231 0.13±0.02 7.15±0.043 86.09±0.112 Whitish

After 3 months 100.1±2 199.12±0.121 0.12±0.09 7.16±0.012 86.05±0.123 Whitish



After 12 months 99±1 200.01 0.14±0.03 7.17±0.098 86±0.114 Whitish




hardness, % release after 24 hours and appearance) for Ibuprofen matrices in accelerated


Reading taken for

determination of

stability

Drug content

(%)

n= 3

(mean±SD)

Weight variation

test (mg)

n=20

(Mean±SD)

Friability

test (%)

n=3

(Mean±SD

Hardness

test (kg/cm3)

n=10

(Mean±SD

% Release after

24 hours

n=3

(Mean±SD)

Appearance

(Colour)

At 0 time (prestorage) 101±3 199.85±0.421 0.12±0.01 7.15±0.092 87.91±0.111 Whitish

After 1 month 100±1 200±0.12 0.14±0.0.6 7.15±0.012 87.06±0.341 Whitish







hardness, % release after 24 hours and appearance) for Ketoprofen matrices in ambient


Reading taken for

determination of

stability

Drug

content (%)

n= 3

(mean±SD)

Weight variation

test (mg)

n=20

(Mean±SD)

Friability

test (%)

n=3

(Mean±SD

Hardness

test (kg/cm3)

n=10

(Mean±SD

% Release after

24 hours

n=3

(Mean±SD)

Appearance

(Colour)

At 0 time (prestorage) 101±1 200±0.123 0.14±0.02 7.14±0.093 94.9±0.121 Whitish

After 1 month 100.5±2 199.85±0.13 0.15±0.0.1 7.14±0.095 94.5±0.214 Whitish


After 3 months 100±2 200±0.122 0.16±0.08 7.15±0.0141 94.5±0.121 Whitish


After 9 months 99.5±1 200.1±0.113 0.16±0.01 7.17±0.012 94±0.316 Whitish

After 12 months 99±2 200.75±123 0.16±0.02 7.17±0.0312 93.9±0.125 Whitish


hardness, % release after 24 hours and appearance) for Ketoprofen matrices in accelerated


Reading taken for

determination of

stability

Drug

content (%)

n= 3

(mean±SD)

Weight variation

test (mg)

n=20

(Mean±SD)

Friability

test (%)

n=3

(Mean±SD

Hardness test

(kg/cm3)

n=10

(Mean±SD

% Release after

24 hours

n=3

(Mean±SD)

Appearanc

e

(Colour)

At 0 time (prestorage) 101±1 200±0.123 0.14±0.02 7.14±0.093 94.9±0.121 Whitish

After 1 month 100.5±1 200±0.568 0.15±0.07 7.15±0.098 94.5±0.124 Whitish

After 2 months 100±2 200±0.145 0.15±0.09 7.15±0.0842 94.5±0.234 Whitish

After 3 months 99.5±2 200±0.172 0.16±0.04 7.17±0.095 94.5±0.157 Whitish



After 12 months 99±2 200.15±121 0.17±0.01 7.17±0.123 94±0.161 Whitish



Table 4.32 Difference factor ƒ1 and Similarity factor ƒ2 calculated for Ibuprofen controlled release

matrix tablets, while comparing their dissolution profile at different time intervals with dissolution

profile at zero time (pre-storage) during stability study.

Time Difference factor ƒ1 Similarity factor ƒ2

25oC/RH 65% 40

oC/RH 75% 25

oC/RH 65% 40

oC/RH 75%

After 1 month 0.014 0.01 99.064 99.161

After 2 months 0.121 0.12 96.597 96.565

After 3 months 0.112 0.13 96.468 96.533

After 6 months 0.111 0.11 96.436 96.468

After 9 months 0.109 0.107 96.338 96.370

After 12 months 0.103 0.109 96.305 96.338

Table 4.33 Difference factor ƒ1 and Similarity factor ƒ2 calculated for Ketoprofen controlled release

matrix tablets, while comparing their dissolution profile at different time intervals with dissolution

profile at zero time (pre-storage) during stability study.

Time Difference factor ƒ1 Similarity factor ƒ2

25oC/RH 65% 40

oC/RH 75% 25

oC/RH 65% 40

oC/RH 75%

After 1 month 0.011 0.011 99.809 99.809

After 2 months 0.011 0.011 99.809 99.809

After 3 months 0.011 0.011 99.809 99.809

After 6 months 0.012 0.012 99.254 99.254

After 9 months 0.014 0.012 99.064 99.254

After 12 months 0.101 0.012 98.856 99.064

The selected formulations were further used for in-vivo studies. In this case the sustained

release tablets of Ibuprofen and Ketoprofen available in market were used as reference, as

the strength of SR Ibuprofen and SR Ketoprofen available in market was 300mg and

200mg, respectively, so the test formulations were developed according to market

strength, for this purpose the same D:P ratio was used (10:3). Therefore, controlled

release matrix tablets of Ibuprofen and Ketoprofen were developed containing 300mg

Ibuprofen and 200 mg Ketoprofen active. After satisfactory physical evaluation and in-

vitro dissolution studies the tablets were used for in-vivo evaluation. As shown in Fig.

4.49, the in-vitro dissolution studies depicted that more than 90% of drug was release

from reference SR tables of Ibuprofen in 18 hours, while 90% of drug was released from



test tablets in 24 hours. Similar comparative studies were performed for SR Ketoprofen

tablets available in market and test tablets. As shown in Fig. 4.50, more than 90% of drug

was released in 18 hours from reference tablets of Ketoprofen, while from the test tablets

more than 90% of drug was released in 24 hours. It can be seen that both test tablets of

Ibuprofen and Ketoprofen had a slower in-vitro release when compared with the

commercially available reference products.

Figure 4.49 Drug-release profiles for Ibuprofen from test and reference tablets up to 24

hours.

Figure 4.50 Drug-release profiles for Ketoprofen from test and reference tablets up

to 24 hours.



4.16. In-vivo evaluation

Selecting the formulations for in-vivo evaluation was done after a inclusive in-vitro

development study. Figures 4.51 to 4.56 are typical chromatograms of standard solution

containing 5µg/mL of Ibuprofen and Ketoprofen, rabbit plasma spiked with 10µg/mL of

Ibuprofen and Ketoprofen, rabbit plasma collected from blood withdrawn 4 hours after

administration of test tablets of Ibuprofen and Ketoprofen. As shown, sharp peaks with

retention times of 7.3min and 5.2min for Ibuprofen and Ketoprofen are observed,

respectively. The mean absolute recovery of Ibuprofen and Ketoprfen determined from

six aliquot samples was more than 90% at 0.25µg/mL to 10µg/mL. The mean plasma

concentration curve was found to be linear with correlation coefficient R2 of 0.9988 and

0.9992 for Ibuprofen and Ketoprofen, respectively (Figs. 4.57 and 4.58).



Figure 4.51 A representative chromatogram of standard solution consisting of

5µg/mL of Ibuprofen



Figure 4.52 A representative chromatogram of Ibuprofen extracted from a sample

of rabbit plasma spiked with 10µg/mL of Ibuprofen.



Figure 4.53 A representative chromatogram of Ibuprofen extracted from a sample

of rabbit plasma with drawn 4 hours after administration of Ibuprofen Test tablet.



Figure 4.54 Representative chromatogram of standard solution consisting of

5µg/mL of Ketoprofen



Figure 4.55 A representative chromatogram of Ketoprofen extracted from a sample

of rabbit plasma spiked with 10µg/mL of Ketoprofen.



Figure 4.56 A representative chromatogram of Ketoprofen extracted from a sample

of rabbit plasma with drawn 4 hours after administration of Ketoprofen Test tablet



Figure 4.57 Standard curve for Ibuprofen in plasma.

Figure 4.58 Standard Curve for Ketoprofen in plasma.

The mean plasma concentration versus time profiles of reference and test tablets of

Ibuprofen and Ketoprofen are shown in figures 4.59 and 4.60, respectively. As shown,

the in-vivo plasma concentration for both test and reference formulations of Ibuprofen



and Ketoprofen are reflective of a slow and extended release rate of drug absorption.

However, more extended release rates were observed in case of test formulations

compared to reference formulations of Ibuprofen and Ketoprofen, as for reference

formulations the active moieties remained in the body for 30 hours, while for test

formulations the active moieties remained in the body for longer period of 42 hours.

The pharmacokinetic parameters based on the plasma level time curve are presented in

tables 4.34 and 4.35. The two tailed t-test was applied on results using SPSS 12.0

software to test for the treatment effect i.e. Test tablets vs reference tablets. As shown in

table 4.34, the mean elimination rate constants (Kel) of reference SR Ibuprofen tablets and

test tablets were 0.274±0.311 h-1

and 0.0767±0.006 h-1

, respectively and significant

difference (P<0.05) in Kel values of the two formulations was found. The mean half-life

(t1/2) of Ibuprofen reference and test tablets were 4.858±2.301 and 9.913±1.032,

respectively and significant difference was observed (P<0.001). The mean Tmax values for

reference and test tablets of Ibuprofen were 3±0.003 hours and 4±0.001 hours and Cmax

were 414.21±3.211µg/mL and 411.03±1.322 µg/mL. Statistical analysis showed

significant difference between Tmax values of reference and test tablets (P<0.05), while

there was no significant difference observed between Cmax values of reference and test

tablets of Ibuprofen (P>0.05).

Figure 4.59 Mean plasma concentration of Ibuprofen from test tablets and reference

tablets (n=12).



Figure 4.60 Mean plasma concentration of Ketoprofen from test tablets and


In this study the values of AUC0-t for reference and test tablets were noted 3391.54±70.04

µg.hr/mL and 6593.9±48.43 µg.hr/mL, respectively and statistically significant difference

was noted between reference and test formulations (P<0.001). The mean resident time

(MRT0-t) values, calculated for reference and test tablet of Ibuprofen were 3.647±0.76

hours and 13.053±0.43 hours, respectively and significant difference was observed

(P<0.0001). Similarly, the mean volume of distribution (Vd) values for reference and test

formulations were 0.609±0.002 Litters and 0.612±0.001 Litters, respectively, and no

significant difference was observed (P>0.05). The mean of total clearance, calculated for

reference tablets was higher 0.087±0.003µg×hr/(µg/mL) than that of test tablets

0.05±0.0002µg×hr/(µg/mL) with significant difference (P<0.05). The means apparent

volume of distribution at steady state (Vss) values and absorption rate constant for

reference and test formulations were 0.71±0.004 Litters and 0.698±0.001 Litters and

0.348±0.213 and 0.478±0.321, respectively and no significant difference was observed

(P>0.05). Similar in-vivo study for Ibuprofen mini matrices was conducted by Caroline et

al. (2004), using human volunteers, but our results were contradicting with their findings.

This might be due to subject difference, as in our study rabbits were used as experimental

animals while they had used human volunteers for their in-vivo evalution.



Table 4.34 Pharmacokinetic parameters for Ibuprofen, following oral administration of

300mg Reference and 300mg Test tablets of Ibuprofen to two separate groups of rabbits

(Mean±SD, n=12).

Pharmcokinetic parameters calculated for Reference Tablets

(Ibuprofen, 300mg)

Test Tablets

(Ibuprofen, 300mg)

Elimination rate constant (Kel) (hr-1

) 0.274±0.311 0.077±0.006

Half-life (t1/2) (hours) 4.858±2.301 9.913±1.032

Time of maximum plasma concentration (tmax) (hours) 3±0.003 4±0.001

Maximum plasma concentration (Cmax) (µg/ mL) 414.21±3.211 411.03±1.322

Area under curve (AUC0-t) (µg×hr/mL) 3391.54±70.04 6593.9±48.43

Mean residence time (MRT0-t) (hours) 3.647±0.76 13.053±0.43

Volume of distribution (Vd) (Liters) 0.609±0.002 0.612±0.001

Clearance (Cl) (µg×hr/(µg/mL) 0.087±0.0031 0.049±0.0002

App. vol of distribution at steady state (Vss) (µg/(µg/mL) 0.710±0.004 0.698±0.001

Absorption rate constant (Ka) 0.348±0.213 0.478±0.321

Similarly, table 4.35 represents mean values of pharmacokinetic parameters obtained

after oral administration of reference SR and test tablets of Ketoprofen to rabbits (n=12).

The elimination rate constant (Kel) of the experimental formulation was significantly

lower 0.080±0.134 h-1

than the corresponding value of reference formulation

0.380±0.213 h-1

, combined with significant difference (P<0.001) in half-life (t1/2), as half-

life for reference was noted to be 4.133±1.431hr, while that for test formulation it was

10.309±2.103 hr. Maximum plasma concentration (Cmax) of reference formulation was

283.42±2.431 µg/mL, while that for test formulation it was 281.77±1.321 µg/mL and no

significant difference was observed (P>0.05). As shown in fig () the maximum plasma

peak reference was not significantly higher than that of test formulation, but reach in

short time as compared to test formulation. As Tmax for reference was noted 2±0.001 hr,

while that for test 4±0.002 hr. statistically, there is significant difference between Tmax of

reference and test formulations (P<0.05). In this study the values of AUC0-t for reference

and test formulations were observed 1596.24±64.21 µg.hr/mL and 4159.36±37.21

µg.hr/mL, respectively and statistically, significant difference was noted between

reference and test formulations (P<0.001). The mean resident time (MRT0-t) values,

calculated for reference and formulations of Ketoprofen were 2.631±0.45 hours and

12.469±0.57 hours, respectively and significant difference was observed (P<0.0001).



Similarly, the mean volume of distribution (Vd) values for reference and test

formulations were 0.741±0.003 Litters and 0.745±0.001 Litters, respectively, and no

significant difference was observed (P>0.05). The mean of total clearance, calculated for

reference tablets was higher 0.124±0.001 µg×hr/(µg/mL) than that of test tablets

0.045±0.001 µg×hr/(µg/mL) with significant difference (P<0.05). The means apparent

volume of distribution at steady state (Vss) values and absorption rate constant for

reference and test formulations were 0.827±0.001 Litters and 0.743±0.004 Litters and

0.455±0.113 and 0.568±0.211, respectively and no significant difference was observed

(P>0.05). Similar study was also performed by Roda et al. (2002), using human

volunteers and evaluated different pharmacokinetic parameters. Our results were different

in respect of different pharmacokinetic parameters. This might be due to subject

difference, as in our study rabbits were used as experimental animals while they had used

human volunteers for their in-vivo evaluation.

Table 4.35 Pharmacokinetic parameters for Ketoprofen, following oral administration of

200mg Reference and 200mg Test tablets of Ketoprofen to two separate groups of rabbits

(Mean±SD, n=12)

Pharmcokinetic parameters calculated Reference Tablets

(Ketoprofen, 200mg)

Test Tablets

(Ketoprofen, 200mg)

Elimination rate constant (Kel) (hr-1

) 0.380±0.213 0.080±0.134

Half-life (t1/2) (hours) 4.133±1.431 10.309±2.103

Time of maximum plasma concentration (tmax) (hours) 2±0.001 4±0.002

Maximum plasma concentration (Cmax) (µg/mL) 283.42±2.431 281.77±1.321

Area under curve (AUC0-t) (µg×hr/mL) 1596.24±64.21 4159.36±37.21

Mean residence time (MRT0-t) (hours) 2.631±0.45 12.469±0.57

Volume of distribution (Vd) (Liters) 0.741±0.003 0.745±0.001

Clearance (Cl) (µg×hr/(µg/mL) 0.124±0.001 0.045±0.001

Apparent volume of distribution at steady state (Vss)

(µg/(µg/mL))

0.827±0.001 0.743±0.004

Absorption rate constant (Ka) 0.455±0.113 0.568±0.211

Relatively wide inter subjects (rabbits) variation was observed in the values of AUC0-t,

which could be attributed to difference in body weight and drug disposition among

subjects (rabbits).



4.17. In-vitro and in-vivo correlation

In-vitro and in-vivo correlation (IVIVC) is an analytical mathematical model used for

unfolding the relationship between an In-vitro behavior of a product and corresponding

In-vivo response. Typically, the In-vitro behavior is the rate or extent of a drug release,

while the In-vivo is the plasma drug concentration (US FDA, 1997).

Five correlation levels such as, level A, B, C, D and E have been introduced for the In-

vitro and In-vivo correlation in the FDA guidance (US FDA, 1997). The level A

correlation is the best class of correlation and reports a point-to-point relationship

between In-vitro dissolution rate and In-vivo absorption rate of the drug from the dosage

form (US FDA, 1997). Therefore, to demonstrate a IVIVC, fraction of percent drug

absorbed (Fa, Y-axis) was plotted against fraction of percent drug released (Fr, X-axis)

(Amir et al., 2010).The values of percent drug released were obtained from In-vitro

release data and percent drug absorbed was calculated, using the well-known Wagner and

Nelson equation (Wagner and Nelson, 1964). As shown in figures 4.61 and 4.62, a good

in-vitro and in-vivo correlation of level A was achieved for test formulations of Ibuprofen

and Ketoprofen with coefficient of determination (R2) 0.9658 and 0.9643, respectively,

which indicate that the formulations were successful enough for further clinical

evaluation and promotion. However, the reference SR formulations of Ibuprofen and

Ketoprofen showed less linearity with coefficient of determination (R2) 0.8651 and

0.7868, respectively (Figs. 4.63 and 4.64) Moreover, Ibuprofen and Ketoprofen test

formulations showed good linear relationship between In-vitro drug released and In-vivo

drug absorption, prolonged MRT0-t and t1/2 values as compared to reference formulations.



Figure 4.61 Percent of drug absorbed (Fa, Y-axis) plotted against percent of drug

released (Fr, X-axis) at times 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 and 24 hours to

show the In-vitro and In-vivo correlation of Ibuprofen Test tablets.



show the In-vitro and In-vivo correlation of Ketoprfofen Test tablets.





show the In-vitro and In-vivo correlation of Ibuprofen Reference tablets.



show the In-vitro and In-vivo correlation of Ketoprofen Reference tablets.

Nanoparticles of Propionic Acid Derivatives By: A.Wahab


CHAPTER 5

NANOPARTICLES MATERIALS AND METHODS

5.1. MATERIALS

5.1.1. Chemical and reagent

The chemicals and reagents used for nanoparticles preparation are.

Ibuprofen sodium salt, Ibuprofen and Ketoprofen (Sigma, UK), Poly glycerol adipate

(0% C-18 PGA), Modified 40% C-18 PGA and Modified 100% C-18 PGA (Provided by

Dr. Paraskevi Kallinteri), Tween 0.01% (Sigma, UK), Sepharose (Sigma, UK) Acetone

(Fisher Scientific, UK), Methanol (Fisher Scientific, UK), HPLC grade water (Fisher,

UK), Acetonitrile HPLC grade (Fisher, UK), Ethanol (Fisher Scientific, UK), Sodium

Hydroxide (NaOH) (Sigma, UK), Monobasic Potassium Phosphate (KH2PO4) (Sigma,

UK).

5.1.2. Instrumentation and equipment

The following instruments and equipment were used in this research work.

Glass Vials (Fisherbrand, UK), Glass pipettes (Fisherbrand, UK), Accurate pipette

(micropipette) (Gilson, France), Pipette tips (Gilson, France), Nitrogen Pump and

Cylinder (Boc, UK), Beakers, Flasks, Gloves, Magnetic stirrers, Stands, test tubes

(Fisherbrand, UK), Eppendorfs (Eppendorf, UK), Size Exclusion Chromatography

column and plastic tubing for SEC (Coludin: GE Healthcare, France), Fraction Collector

and Pump P1 ( GE Healthcare, France), Viva Spin Centrifuge tubes (Sartorius Stedim

Biotech, Germany), Dialysis Membrane (M.W. cut off 12-14kDa), (SLS,UK), Hot Plate

(IKA WERK, RT 10 P,Germany), Fume hood (UK), Freez Drier (SCANVAC,

DENMARK), Bench Centrifuge (Hettich Rotina, 3812, Germany), Microcentrifuge

(Hettich, Mikro 120, Germany), HPLC (Millipore water, France), GPC (PL-GPC50Plus,

Varian), Water bath (shaker)(Grant, OLS 200, UK), Sonicator (Ultrawave, UK), Balance

(Sartorious, ED1245, Germany), Vapour Venting Wash Bottles (Bibby Sterilin, UK),

Parafilm M (PARAFILM, Chicago), Marvlen Zitasizer (Marveln, nano ZS, UK), pH



meter (Denver, USA), DSC instrument (Mettler Toledo DSC 822e, Greifensee,

Switzerland), FT-IR SpectrumOne spectrophotmer (Perkin Elmer, UK).

5.2. METHODS

5.2.1. Nanoparticles formulation

5.2.1.1. Differential scanning calorimetry (DSC) studies: The differential scanning

calorimetry (DSC) study was performed for the determination of drugs interaction with

polymer, using DSC instrument (Mettler Toledo DSC 822e, Greifensee, Switzerland)

equipped with Stare computer program according to the method described above in

section 3.2.1.8.

5.2.1.2. Fourier transform Infrared (FT-IR) studies: The FT-IR spectra of pure

Ibuprofen, pure ketoprofen, pure Ibuprofen sodium salt and polymers, were taken to

observe the drugs-carrier interation, using FT-IR SpectrumOne spectrophotometer

(Perkin Elimer, UK), using the same method as described in section 3.2.1.9 of this thesis.

5.2.1.3. Preparation of Stock Solution: Polymer (20 mg/ml in acetone) and drug

(4mg/ml) stock solutions were prepared. Drugs used were Ibuprofen, Ibuprofen sodium

salt and Ketoprofen. Ibuprofen and Ketoprofen were dissolved in Methanol while

Ibuprofen sodium salt was dissolved in deionised water.

5.2.1.4. Preparation of Empty Nanoparticles: Nanoparticles were prepared using the

interfacial deposition method (Fessi et al., 1965). Empty particles were prepared by

adding dropwise the polymer solution (20 mg in 2 ml of acetone) into 5ml deionised

water under mild stirring at room temperature. The dispersion was left in the fume hood

overnight for the organic solvent to evaporate. Then, agglomerated polymer was

separated from the particles by centrifugation at 5000rpm for five minutes and then

particles were passed through PD-10 column with distilled water as an eluent. Particle

size, polydispersity index and zeta-potential were determined using NanoZS by Malvern.

5.2.1.5. Preparation of drug-loaded particles: For the formation of nanoparticles loaded

with the lipophilic drugs, 1 ml of drug stock solution was mixed with 1 ml polymer

solution in a glass vial and then the organic solvents were evaporated using nitrogen gas



stream till the formation of a matrix in the vial. Then, that was dissolved in 2ml of

acetone which was added dropwise in 5 ml of distilled under mild stirring at room

temperature. Then, the particle dispersion was left in the fume hood overnight for the

organic solvent to evaporate. In case of the water-soluble Ibuprofen sodium salt, 1ml of

drug solution in water was added in 4 ml of distilled water. To that solution, 2 ml of

polymer solution (20 mg) was added. Polymer aggregates were separated from the

particles by centrifugation as mentioned above.

5.2.1.6. Separation of free drug from nanoparticles: Nanoparticles were separated from

the free drug using size exclusion chromatography Sepharose 4B-CL (16mm x 24 cm)

Fig. 5.1. Distilled water was used as an eluent. Fractions of 1 ml were collected at a flow

rate 1ml/min. The fractions that contained the nanoparticles were pooled together, the

exact volume was measured and the preparation was split in half. One half was freeze

dried so to estimate the drug incorporation while the other half was placed in dialysis

bags to study the drug release.

Figure 5.1 Size Exclusion Chromatography column packed with Sepharose 4B-CL.

Column length ~24 cm, diameter 16 mm

5.2.1.7. Freeze-drying study: For freeze-drying the glass vials were weighed before and

after placing the samples for freeze drying. The difference of the two weights (weight

after – weight before) was the mass of the freeze dried polymer + drug matrix.



5.2.1.8. Drug Release study: For the determination of drug release from the

nanoparticles, the samples were concentrated to approximately 2.5ml in viva spin

concentrators at 11,000 r.p.m at 25C0 for 30 minutes Fig. 5.2.

Figure 5.2 Viva spine Concentrator tubes

Then, the samples were transferred in dialysis bags and put into a glass vial with 2ml of

0.01% Tween. The samples were placed in a shaking water-bath (25 oscillation, 37°C)

and drug release study was carried out for 17 days. Samples (2ml) were withdrawn at

various time intervals (0 min, 15 min, 30 min, 1hr, 2hr, 3hr, and then daily till 17 days)

while they were replaced with fresh 0.01% Tween solution.

The analysis of the samples was carried out using HPLC. All formulations were prepared

in triplicate for statistical purposes.

5.2.1.9. HPLC analysis of the nanoparticles: Percentage drug release from polymer

nanoparticles was determined using HPLC (Waters, Millipore Instrument), consisting of



Waters 717plus autosampler, Waters 486 UV-detector, Waters 600 controller and

GALAXIE Varian software. An analytical column (Lichrospher C-18) was used.

The mobile phase for ibuprofen analysis was 0.05M phosphate buffer (pH:

3.5)/acetonitrile (30/70 v/v) respectively. Detection wavelength was 220nm and the drug

retention time was 3.9 minutes.

The moblile phase for ketoprofen was 0.05M phosphate buffer (pH: 7.4)/acetonitrile

(22/78 v/v). The drug was detected at 258nm while the retention time was 4.1nm.

The mobile phase for ibuprofen sodium salt was 0.05M phosphate buffer (pH:

6.5)/acetonitrile (66/34 v/v). The drug was detected at wavelength 236nm and the

retention time was 4.1 minutes.

5.2.1.10. Preparation of standard solutions and construction of calibration curves: So

for construction of calibration curves, stock solutions of all three drugs were prepared

with concentration of 1mg/ml in HPLC grade solvents. From these stock solutions

reference solutions of 0.25ppm, 0.5ppm, 1ppm, 2ppm, 5ppm and 10ppm were prepared.

Then standard curve for all three drugs were constructed using HPLC (Figs. 5.3, 5.4 and

5.5).

Figure 5.3 Standard curve for Ibuprofen



Figure 5.4 Standard curve for Ketoprofen

Figure 5.5 Standard curve for Ibuprofen sodium salt



5.2.1.11. Determination of drug loading: In order to estimate the drug loading on the

nanoparticles, the following process was carried out: the freeze-dried samples containing

ibuprofen and ketoprofen were first dissolved in 0.5 ml of methanol and 1 ml of acetone

(1:2 v/v) and then diluted with same solvent upto 10ml for HPLC anaylsis, but in case of

ibuprofen sodium salt water and acetone was used for dissolution of freeze-dried sample

with the same ratio (1:2 v/v) as mentioned above.



CHAPTER 6

NANOPARTICLES RESULTS AND DISCUSSION

6.1. Drug-polymer interaction studies

6.1.1. Differential scanning calorimetry (DSC): To investigate the possible interactions

between drugs and polymers DSC studies were performed. Figures 6.1, 6.2 and 6.3 depict

DSC curves of each drug alone, polymer and drug-polymer combination (mixture)

separately.

The thermal curves or peaks of pure Ibuprofen, polymer PGA (Poly glycerol adipate) and

drug-polymer combination are depicted in Fig. 6.1a-c. A sharp endotherm (Tpeak=

76.94oC) was observed for pure ibuprofen at the temperature corresponding to its melting

point (Fig. 6.1c). The polymer peak was observed at 37.18oC which is the melting point

of PGA polymer (Fig.6.1a). As shown, the thermogram of ibuprofen did not show any

major change in the endothermic peak with the polymer PGA (Fig. 6.1b), indicating no

possible interaction but the broadness and low melting point of polymer indicates that the

polymer has amorphous structure.

Figure 6.1 DSC thermograms of (a) PGA polymer; (b) Ibuprofen-polymer (PGA);

(c) pure Ibuprofen.



The thermal curves of pure ketoprofen, polymer and ketoprofen-polymer (PGA) are

reported in Fig. 6.2a-c. The thermogram of ketoprofen showed a single endothermic peak

at 94oC, corresponding to the melting point of this drug (Fig. 6.2c). The DSC themogram

for Ketoprofen-polymer combination (mixture) showed prominent peaks at the same

temperature range as their melting points (Fig. 6.2b). There were not extra thermal events

found in the corresponding thermograms and the ketoprofen signal appears unaffected,

which means that there is no incompatibility between ketoprofen and polymer PGA.

Figure 6.2 DSC thermograms of (PGA polymer); (b) Ketoprofen-polymer (PGA)

mixture; (c) pure Ketoprofen.

The DSC thermogram of ibuprofen sodium salt and its combination with polymer PGA,

40% C18 PGA, and 100% C18 PGA are shown in the Fig. 6.3a-d. The pure ibuprofen

sodium salt shows two endothermic peaks at 197.76oC and 100.57

oC, indicating melting

point and the loss of crystal water (dehydration peak), respectively (Fig. 6.3d). It is

obvious that the mixture of drug with all polymers did not show any peaks indicating

possible interaction between the two components, while mixtures of Ibuprofen sodium

salt with the said polymers showed disappearance of sharp melting peak and dehydration

peak. Thus on the bases of these observations it can be concluded that Ibuprofen sodium



salt has possible interaction with polymers. The same findings were observed by other

investigator Gruber et al. (2009) about Ibuprofen sodium salt.

Figure 6.3 DSC thermograms of (a) Ibuprofen sodium salt-Polymer (100% C-18

PGA) mixture; (b) Ibuprofen sodium salt-Polymer (40%C-18 PGA) mixture; (c)

Ibuprofen sodium salt-Polymer (PGA C-18) mixture; (d) Ibuprofen sodium salt

pure.

6.1.2. Fourier transforms infrared spectroscopy (FT-IR): To rule out any possible

interaction between different drugs, such as ibuprofen, ketoprofen, and mixtures of these

drugs with the polymers used, FT-IR study was performed.

The FT-IR spectrums of pure ibuprofen, polymer and ibuprofen-polymer (PGA)

combination (mixture) were obtained as shown in the Fig. 6.4a-c. Pure ibuprofen showed

sharp characteristic peaks at 1706 cm-1

which corresponds to the carboxyl acid (COOH)

present in ibuprofen. Other smaller peaks in the region 1200-1000 cm-1

are the indication

of benzene ring (Socrates, 1994). These peaks can also be seen in the ibuprofen-polymer

(PGA) mixture, but in this case IR spectrum for ibuprofen-polymer (PGA) mixture shows

the overlapping of carboxyl acid group (Fig. 6.4b). Therefore, it can be concluded that no

chemical interaction occurred between ibuprofen and polymer (PGA).



Figure 6.4 FT-IR spectra of (a) PGA polymer; (b) Ibuprofen-polymer (PGA)

mixture; (c) pure Ibuprofen.

Similar results were observed for the combination of Ketoprofen with the polymer.

Infrared spectra of ketoprofen, as well as those of ketoprofen-polymer (PGA) mixture are

depicted in Fig. 6.5a-c. Pure ketoprofen crystals show two carbonyl absorption bands at

1694.4 cm-1

and 1654.2 cm-1

, indicating carboxyl carbonyl and ketonic carbonyl

stretching, respectively (Sancin et al., 1999, Mura et al., 1999) as shown in Fig. 6.5a.

PGA polymer also contains carboxyl carbonyl group, therefore the IR spectra showed

overlapping carboxyl vibration of carboxyl group at 1694.4 cm-1

. The characteristics

stretching band of pure ketoprofen with polymer did not change, and on the basis of these

observations it may be suggested no possible interaction was observed between

ketoprofen and polymer (PGA).



Figure 6.5 FT-IR spectra of (PGA polymer); (b) ketoprofen-polymer (PGA)

mixture; (c) pure Ketoprofen

Ibuprofen sodium salt peaks of FT-IR are shown in Fig. 6.6a-d. Pure ibuprofen sodium

salt shows a peak at 1697.6 cm-1

, indicating the carbonyl stretch (COOH). Figure 6.6a-c

showed a significant difference in the FT-IR spectra of ibuprofen sodium salt and its

mixture with polymers when compared with spectra of pure ibuprofen sodium salt. The

characteristic carbonyl-stretching band of ibuprofen sodium salt was changed in the case

of ibuprofen sodium salt-polymer mixtures. This study revealed that there was a possible

interaction between ibuprofen sodium salt and polymers, as the change was from lower

wave number to higher wave number, indicating the change from more crystalline form

to amorphous.



Figure 6.6 FT-IR spectra of (a) Ibuprofen sodium salt-Polymer (PGA C-18)

mixture; (b) Ibuprofen sodium salt-Polymer (40%C-18 PGA) mixture; (c)

Ibuprofen sodium salt-Polymer (100 C-18 PGA) mixture; (d) pure Ibuprofen

sodium salt.

6.2. Preparation of empty and drug loaded nanoparticles

The main objective of this study was to prepare ibuprofen, ibuprofen sodium salt and

ketoprofen nanoparticles using the newly synthesized polymer PGA (poly glycerol

adipate) (Kallinteri et al., 2005) and its acylated derivatives in absence of surfactant. As

mostly surfactants are used as stabilizing agent for nanoparticles. But the removal of

surfactants from nanoparticles surface is not easy and the presence of surfactants on the

surface of nanoparticles may cause toxicity (Vu-giang et al., 2004)

Empty and drug-loaded nanoparticles of Ibuprofen, Ibuprofen sodium salt and

Ketoprofen were prepared, using biodegradable polymer, Poly (glycerol adipiate) (PGA)

and its acylated derivatives 40% C-18 PGA and 100%C-18 PGA by interfacial deposition

method without using surfactans (Fessi et al., 1995). Empty nanoparticles and drug-



loaded nanoparticles of Ibuprofen sodium salt were successfully developed with polymer

PGA and its acylated derivatives, while massive aggregartion and precipitation was

observed during the preparation of drug-loaded nanoparticles of Ibuprofen and

Ketoprofen with acylated derivaties 40% C-18 PGA, 100% C-18 PGA and combination

of PGA with 40% C-18 PGA and 100% C-18 PGA. The aggregation or precipitation may

be due to lipophilicity of polymer as 0% PGA is less lipophilic than its acylated

derivatives. The increased lipophilicity (hydrophobicity) may cause a subsequent increase

in the aggregation number of polymer molecules leading to a rapid precipitation (Puri et

al., 2008)

6.2.1. Physical evaluation of nanoparticles: The size, zeta potential and polydispersity

of empty as well as loaded nanoparticles were determined. The zeta potential is an

indicator of surface charge, which determines particles stability in the dispersion using

the principle of elecrophoretic mobility in electric field. Polydisperity index is the

dimensionless number indicating the width of the size distribution (Chandr et al., 2010).

The average particle size of empty nanoparticles 0% C-18P PGA, 40% C-18 PGA,

combination of 0% C-18 PGA with 40% C-18 PGA and 100% C-18PGA were found to

be in the range of 197.07±2.6 nm, 240.5±3.061 nm, 234.6±3.58 nm, 252.4±3.732 nm,

respectively, while drug-loaded nanoparticles of Ibuprofen and Ketoprofen with 0% C-18

PGA were having average particle size 207.333±3.85 nm and 202.6±2.18 nm,

respectively. Moreover, drug-loaded nanoparticles of Ibuprofen sodium salt with 0% C-

18 PGA, 40% C-18PGA, combination of 0% with 40% C-18 PGA and 100% C-18 PGA

were found to be in the range 192.767±3.204 nm, 231.33±2.804 nm, 226.933±2.312 nm,

and 240.633±2.150 nm, respectively. As shown in the Table 6.1 that the particle size of

empty nanoparticles of 0% C-18 PGA was smaller than the loaded nanoparticles of

Ibuprofen and Ketoprofen with 0% C-18PGA. This increase in size may be due to

packing arrangement of the drug in the polymeric matrix. Some authors have reported

that larger size of drug loaded particles than empty particles is due to the presence of drug

in the polymeric matrix based on the assumption that presence of drug in the matrix is

responsible for expansion of matrix volume and hence size (Stolnik et al., 1995). It may



also depend on the properties of different functional groups of polymer. As ibuprofen and

ketoprofen are sparingly soluble drugs and increase in the number of hydrophobic

domains was found to be associated with larger nanoparticles (Piskin, 1995).While in

case of ibuprofen sodium salt the nanopaticles formed with 0% PGA, 40% C-18 PGA,

combination of 0% C-18 PGA with 40% C-18 PGA and 10% C-18PGA were smaller

than empty nanoparticles as shown in Table 6.1. There could be two possibilities for this

difference in particle size: Change in the aggregation number of polymer molecules or

change in the particles density due to interaction between drug and polymer, but in this

case it is more likely to be due to drug-polymer interaction (Fig. 6.3a-d). As some time

interaction between drug and polymer may cause more compact and condense particles, it

may be due to the solubility of drug, as ibuprofen sodium salt is water soluble, it may

also play a role at the interface; there could be a steep concentration gradient at the

interface or migration of drug from more viscous phase, both leading to a decrease in the

interfacial tension and turbulence leading to rapid diffusion of acetone from organic

phase and result in more compact and condensed particles. The particles size data suggest

that it is possible to prepare the biodegradable nanoparticles of ketoprofen, ibuprofen and

ibuprofen sodium salt by interfacial deposition method without using surfactant. The zeta

potential for all empty and drug-loaded nanoparticles was -27.37 mV to -33.8mV and

polydispersity index was 0.116 to 0.860 as shown in the Table 6.1. As no more change in

the zeta potential and polydispersity was observed, but there was a slightly increased

negative zeta potential value with increase of acylation and incorporation of drug. This

increase in the negative value of zeta potential might be due to surface localization of

drug molecules (Alejandro et al., 1999).



Table 6.1 Physical characteristics (size , polydispersity index and zeta potential) of

empty and drug loaded nanoparticles prepared from various polymers by

interfacial deposition method.

Polymer Empty particles (+) Ibuprofen sodium salt (+) Ibuprofen (+) Ketoprofen

Size nm (SD) Polydispersity index

ζ-Potential mV(SD)

Size nm ( SD) Polydispersity index

ζ-Potential mV(SD)

Size nm (SD) Polydispersity index

ζ-Potential mV (SD)

Size nm (SD) Polydispersity

index

ζ-Potential mV (SD)

0%PGA-12kDa

197.07(2.6) 0.116

-27.37(2.011)

192.767(3.204) 0.148

-28.3(0.6)

207.33(3.85) 0.197

-29.57(1.42)

202.6(2.18) 0.185

-28.27(2.7)

40%C18-12kDa

240.5(3.06)

0.116

-28.67(1.96)

231.33(2.804)

0.132

-29.27(1.65)

-------

--------

-------

--------

0%+40%C18-12kDa

234.6(3.58)

0.176

-31.37(2.05)

226.93(2.312)

0.152

-32.2(0.4)

-------

-------

-------

--------

100%C18-12kDa

252.4(3.732)

0.189

-33.3(3.676)

240.633(2.150)

0.86

-33.8(1.308)

------

--------

-------

--------



6.3. Drug loading

As shown in the Fig. 6.7, the average amount of drug bound per mg of polymer was

determined. Ibuprofen and Ketoprofen loading on 0% C-18 PGA was 17.53± 7.15 µg/mg

and 19.6 ± 5.83µg/mg, respectively. Ibuprofen sodium salt loading on 0% C-18 PGA,

40%C-18PGA, combination of 0% with 40% C-18 PGA and 100% C-18 PGA was

10.59± 2.09, 18.28 ± 5.39, 14.12 ± 1.29 and 19.6 ± 2.7, respectively. As shown in

Fig.4.71 increase in acylation increase led to increase in drug loading for Ibuprofen

sodium salt. As maximum loading of Ibuprofen sodium salt was observed on 100% C-18

PGA.This maximum loading might be due to more interaction of drug with 100% C-18

PGA confirmed by different studies such as DSC and FT-IR. As the higher the

percentage of acyl groups, the greater the expected interactions between drug and

polymer (Puri et al., 2008). Similar finding were observed by other investigators

(Panyam et al., 2003). However, the exact opposite trend was observed for Ibuprofen and

Ketoprofen. As the loading of Ibuprofen and Ketoprofen on 0% C-18 PGA was more as

compared to Ibuprofen sodium salt. This might be due to some binding between drugs

and polymer that depends upon the collective properties of the two. As the drug loading

is not only the matter of drug-polymer interaction but it depends on the mechanism of

polymer assembly into nanoparticles (Kallinteri et al., 2005). It might be due to drug and

polymer nature as Ibuprofen and Ketoprofen are lipophilic drugs and Ibuprofen sodium

salt is hydrophilic. The loading of Ibuprofen and Ketoprofen was more on 0% C-18 PGA

which is less lipophilic as compared to its acylated derivatives, while loading of

Ibuprofen sodium salt on 100% C-18 PGA as compared to 0% C-18 PGA.



Figure. 6.7 Average drug contents on each plolymer

6.4. In-vitro drug release study

The in-vitro release profile of ibuprofen, ketoprofen and ibuprofen sodium salt from 0%

C-18 PGA, 40% C-18PGA, combination of 0% C-18 PGA with 40% C-18 PGA and

100% C-18 PGA are shown in Figures 6.8 and 6.9. As shown in Figures the drug release

from these particles is biphasic phenomenon but in some case triphasic profile is also

observed. In some formulations there is initial rapid removal of drug from nanoparticles,

it may be due to the loosely bonding of drugs to the surface of nanoparticles, mostly, and

this initial release is rapid and uncontrolled, termed burst release (Tse et al., 1999). The

initial release after 15 minutes of ibuprofen and ketoprofen from 0% C-18 PGA

nanoparicle was 7.09±0.7% and 2.54±1.13%, respectively and the release of Ibuprofen

sodium salt from different nanoparticles of 0% C-18PG, 40% C-18PGA, combination of

0% with 40%C-18PGA and 100% C-18PGA was 3.6±0.42%, 2.53±0.403%,

10.05±0.85% and 1.74±0.3%, respectively. The initial burst release in case of ibuprofen

from 0% C-18 PGA and Ibuprofen sodium salt from combination of 0% and 40% C-18

PGA may be the due to surface localization of drug. Other factors contributing to initial

burst release are larger surface area, high diffusion coefficient and low viscosity of matrix

(Akinobu, 2002). The release from other formulations was slow and no initial burst

release phenomenon was observed. At the end of in-vitro drug release study (17 days),



100% drug was released from all nanopartilces but on the basis of statistical calculation

the t50% for ibuprofen and ketoprofen from 0% C-18 PGA was 2 and 3 days, respectively,

but for ibuprofen sodium salt from 0% C-18PGA, 40%C-18PGA, combination of 0% and

40% PGA, and 100% C-18PGA was 4, 6, 2 and 3 days, respectively. Most commonly it

is reported that particles with higher drug loading have a fast release rate mainly

attributed to surface localization. (Peng, 2006). As shown in the Figs. 6.8 and 6.9, the

drug loading of ibuprofen, ketoprofen on 0%C-18PGA, and that of ibuprofen sodium salt

on 100%C-18 PGA is more as compare to other formulations.

Figure. 6.8 The release behavior of various formulations (the results are the mean

and standard deviation of three determinations).



Figure. 6.9 The release behavior of various formulations (the results are the mean

and standard deviation of three determinations).

Conclusion By: A.Wahab


OVER ALL CONCLUSIONS

During the preformulation studies our results confirmed that no possible

interaction was found between the drugs (Ibuprofen and Ketoprofen) and

differenent polyemers and excipietns.

Solid Dispersions of Ibuprofen and/or Ketoprofen with Glucosamine HCl

markedly enhanced the dissolution rates and solubility of the drugs. Moreover,

DSC, FT-IR, X-ray diffractometory and SEM studies revealed the confirmation of

solid dispersions and that no possible interactions take place between the carrier

and drugs.

Ethocel polymers can be used for successful development of controlled-release

matrix tablets of sparingly soluble drugs such as Ibuprofen and Ketoprofen, using

direct compression method.

Ethocel polymers with lower viscosity grades are more compressible than their

counterparts with higher viscosity grades.

Particle size and concentration of the polymer are the determining factors in

controlling the release of Ibuprofen and Ketoprofen from the tablets.

Ethocel standard FP premium polymers are more efficient than conventional

Ethocel Standard premium polymers in extending and controlling the release rates

of the drugs. Our results revealed that Ethocel standar 7 FP premium showed

more effective role in controlling the release of drugs such as Ibuprofen and

Ketoprofen.

Conclusion By: A.Wahab


The release mechanisms of Ibuprofen and Ketoprofen from the tablets are

changeable, depending mainly on the particle size and amount of the polymer

used in the formulations.

Replacement of portions of lactose within the tablet formulation by the co-

excipients such as HPMC K100M, CMC and starch enhance the release rates of

Ibuprofen and Ketoprofen.

Matrices composed of Ethocel® standard 7 FP premium provide suitable

environment for stability of Ibuprofen and Ketoprofen like drugs and optimized

formulations demonstrating good stability of the Ibupofen and Ketoprofen in

Ethocel matrix tablets.

In-vivo pharmacokinetic parameters of test formulations showed more extended

release rates as compared to reference formulations of Ibuprofen and Ketoprofen.

Moreover, the test formulations showed good linear relationship between In-vitro

drug release and In-vivo drug absorption, and prolonged MRT0-t and t1/2 values as

compared to reference formulations.

Nanoparticles of the Ibuprofen and Ketoprofen with PGA (Poly glycerol adipate)

and its acylated derivates 40% C-18 PGA and 100% C-PGA could be used for

successful development of controlled release formulations of the drugs.

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List of publications

1. Abdul Wahab, Gul Majid Khan, Muhammad Akhlaq, Nauman Rahim Khan, Abid Hussain, Haroon Khan and

Muhammad Farid Khan (2011). Formulation and Evaluation of Controlled Release matrices of Ketoprofen and

influence of different Coexcipients on the Release Mechanism (Published in international journal “Die

Pharmazie”, Germany) Vol. 66: 677–683. Impact factor 1. (HEC recognized)

2. Abdul Wahab, Gul Majid Khan, Muhammad Akhlaq, Nauman Rahim Khan, Abid Hussain (2011). Pre-

formulation investigation and in vitro evaluation of directly compressed ibuprofen-ethocel oral controlled release

matrix tablets: A kinetic approach (Published in African journal of pharmacy and pharmacology). Vol. 5(19): 2118-2127. . Impact factor 0.667. (HEC recognized)

3. Muhammad Akhlaq, Gul Majid Khan and Abdul Wahab, Nauman Rahim Khan, Abid Hussain, Waqas Rabbani

(2011). Effect of ether derivative cellulose polymers on hydration, erosion and release kinetics of diclofenac

sodium matrix tablets. ( Published, in Archive of Pharmacy Practice) Vol.2(3): 123-128. (HEC recognized)

4. Muhammad Akhlaq, Gul Majid Khan, Abdul Wahab, Hamdy Abdelkader, Raid Alany, Abid Hussain and

Nauman Rahim Khan (2011). Physicochemical characterization and in-vitro evaluation of flubiprofen oral

controlled release matrix tablets: Role of ether derivative polymer ethocel (Published in African journal of

Pharmacy and Pharmacology) Vol. 5(7): 862-873. . Impact factor 0.667. (HEC recognized)

5. Abdul Wahab, Muhammad Akhlaq, Waqas Rabbani, Asim Rehman, Abid Hussain, Kifayatullah Shah and Gul

Majid Khan (2010). Innovative transdermal drug delivery systems and technology: A review of current trends

with futuristic prospective (Published in GomaL, University, Journal of research) Vol. 26(2): 25-32. (HEC

recognized)

6. Khan Haroon, Khan Muhammad Farid, Wahab Abdul, Hussain Abid (2011). Cytosolic fraction of Glutathione

level after addition of aluminum metal human blood (Published in international journal of research and

Ayurveda and pharmacy) Vol. 2(2): 550-555. (HEC recognized)

7. Murad Ali Khan, Abdul Haleem Shah, Azhar Maqbool, Shakoor Ahmad, Zia Urrahman, Abdul Wahab (2011).

Epidemiological survey of scabies skin disease among different migrants in Khyber Pukhthoonkhwa, Pakistan

(published in IJCRB) Vol. 3 (2): 1378-1390. (HEC recognized)

8. Shah Shefaat Ullah, Shah Kifayat Ullah, Wahab Abdul, Khan Haroon, Khan Gul Majid (2011). Formulation

and evaluation of directly compressed ofloxacin-ethocel controlled release tablets: A kinetic approach (Published

in IJRAP) Vol. 2 (3): 801-809. (HEC recognized)

9. Nauman Rahim Khan, Gul Majid Khan, Abdul Wahab, Abdul Rahim Khan , Akhlaq Ahmad, Abid Husssain,

Asif Nawaz (2011). Formulation, Physical, In vitro and Ex-vivo evaluation of transdermal hydrogels of

Ibuprofen containing turpentine oil as penetration enhancer ( Published in Die Pharmazie, Germany ) Vol.

66(11): 849-852. . Impact factor 1. (HEC recognized)

10. Muhammad Akhlaq, Gul Majid Khan, Abdul Wahab, Arshad Khan, Abid Hussain, Asif Nawaz, Hamdy

Abdelkader (2011). A simple High-Performance Liquid Chromatographic practical approach for determination

of Flurbiprofen (Published in, Journal of Advance pharmaceutical technology and research) Vol. 2(3): 151-155. .

Impact factor 0.332. (HEC recognized) 11. Muhammad Akhlaq, Gul Majid Khan, Abdul Wahab, Abid Hussain, Arshad Khan and Asif Nawaz (2011).

Formulation and In-vitro evaluation of Flurbiprofen Controlled release matrix tablets using cellulose derivative

polymers. (published in, Pakistan journal of pharmacy) Vol. 21-23(1and 2): 3-9. (HEC recognized)



12. Muhammad Rafiq, Abdul Wahab, Nisar-ur-Rehman, Abid Hussain and Said Muhammad (2010) . In vitro and

in vivo evaluation of two sustained release formulations of diltiazem HCl (Published in African journal of

pharmacy and pharmacology) Vol. 4(9): 678-694.. Impact factor 0.667. (HEC recognized)

13. Haroon Khan, Syed Umer Jan, Hashmatullah,M Farid Khan, Kamran Ahmad Khan, Asim Ur Rehman And

Abdul Wahab (2010). Effect of Lithium on The chemical status of Glutathione in whole Blood (especially in

plasma and cytosolic fraction in human) (Published in Pakistan journal of Pharmaceutical Sciences Vol. 23

(2):188-193. Impact factor 0.728. (HEC recognized)

14. Rehan Zafar Paracha, Haroon Khan, Muhammad Farid Khan, Zahid Rasul Niazi, Kamran, Ahmad Khan, Syed

Ummar Jan, Barkat Ali, Hashmat Ullah, Abdul Wahab (2010). Concentration and time dependent effect of zinc

chloride on glutathione level in aqueous medium (Published in GomaL, University, Journal of research) Vol.

26(2): 9-14. (HEC recognized)

15. Haroon Khan, Muhammad Farid Khan, Rehan Zafar Paracha, Kamran Ahmad Khan, Hashmat Ullah, Syed Umer

Jan, Zahid Rasul Niazi, Saif Ullah Mehsud and Abdul Wahab (2010). Effect of aluminum metal on the

chemical status of Glutathione in aqueous medium (Published, in GomaL, University, Journal of research) Vol.

26(1): 13-19. (HEC recognized)

16. Muhammad Farid Khan, Haroon Khan, Rehan Zafar Paracha, Hashmat Ullah, Gul Majid Khan, Usman Zafar

Parach, Saif Ullah Khan, Abdul Wahab, Kamran Ahmad Khan (2008). Effect of Silver metal on the chemical

status of Glutathione in aqueous medium (Published in GomaL, University, Journal of research) Vol. 24(2): 8-

12. (HEC recognized)

17. Haroon Khan, Muhammad Farid Khan, Naseem Ullah, Muhammad Mukhtiar, Naheed Haque, Barkat Ali, Abdul

Wahab, Arshad Farid, Kamal Shah. Effect of aluminium acetyl acetone on the chemical status of glutathione by

influential parameters in aqueous medium. (Published, in International journal of basic medical sciences and

pharmacy) Vol.1, No.1: 23-26. (HEC recognized)

18. Nauman Rahim Khan, Gul Majid Khan, Abdul Rahim Khan, Abdul Wahab, Muhammad Akhlaq, Abid Hussain

(2012). Formulation, Physical, In vitro and Ex-vivo evaluation of Diclofenic diethylamine matrix-patches

containing turpentine oil as penetration enhancer (Published in African journal of Pharmacy and Pharmacology).

Vol. 6(6):434-439. . Impact factor 0.667. (HEC recognized)

19. Abid Hussain, Gul Majid Khan, Shefaat Ullah Shah, Kifayat Ullah Shah, Nauman Rahim, Abdul Wahab and

Asim-ur-Rehman. Development of Novel Ketoprofen transdermal patch: Effect of Almond oil as penetration

enhancers on in-vitro and ex-vivo penetration of ketoprofen through rabbit skin (Published, in Pakistan journal

of pharmaceutical sciences). Vol. 25(1): 227-232. . Impact factor 0.728. (HEC recognized)

20. Abdul Wahab, Marco Favretto, Onyeagor, Gul Majid Khan, Dynnis Douroumis, Casely-Hayford, Paraskevi

Kallinteri (2012). Development of poly(glycerol adipate) nanoparticles loaded with non-steroidal anti-

inflammatory drugs (Accepted in Journal of Microencapsulation). Impact factor 1.738. (HEC recognized)



21. Abdul Wahab, Gul Majid Khan, Muhammad Akhlaq, Nauman Rahim and Abid Hussain, Haroon khan, Saif

Ullah Mehsud. Preparation and evaluation of solid dispersions of Ibuprofen using Glucosamine HCl as a carrier

(Accepted in Die Pharmazie). . Impact factor 1. (HEC recognized)

22. Abid Hussain, Gul Majid Khan, Syed Umer Jan, Shefaat Ullah Shah, Kifayatullah Shah,

Muhammad Akhlaq, Nauman Rahim Khan, Asif Nawaz and Abdul Wahab (2012). Effect of

olive oil on transdermal penetration of flurbiprofen from topical gel as enhancer. (Published in

Pakistan journal of pharmaceutical sciences) Vol. 25(2): 365-369. Impact factor 0.728. (HEC

recognized)

23. Abdul Wahab, Gul Majid Khan, Muhammad Akhlaq, Nauman Rahim and Abid Hussain, Haroon khan, Saif

Ullah Mehsud. Preparation and solid state characterization and evaluation of Ketoprofen-Glucosamine HCl

solid dispersions: A novel approach (Submitted)

24. Muhammad Akhlaq, Gul Majid Khan, Abdul Wahab. To Investigate a Simple and Rapid Approach for In-Vitro

In-Vivo Evaluation of Diclofenac Sodium Controlled Release Matrices Using Albino Rabbits (Submitted)

25. Abid Hussain, Gul Majid Khan, Nauman Rahim Khan, Muhammad Akhlaq, Abdul Wahab and Asif.

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capability of Olive oil. (submitted)

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containing turpentine oil as penetration enhancer (Submitted)

formulation and evaluation of controlled release matrices of...

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