thesis mdt - copy

“DEVELOPMENT OF RAPIDLY DISINTEGRATING TABLETS FOR A

MODEL ANTI-EMETIC DRUG.”

By

SREENIVASA REDDY. N

Dissertation submitted to The Rajiv Gandhi University of Health Sciences,

Karnataka

In partial fulfillment of the requirements for the degree of

Master of Pharmacy in

Pharmaceutics

Under the guidance of

Dr.M.S Srinath

Department Of Pharmaceutics Government College Of Pharmacy.

No. 2, P. Kalinga Rao Road, Bangalore - 560027

January 2005

ACKNOWLEDGEMENT

In the name of God and my Guru, I bow myself to thank and acknowledge the

continued blessings showered on me to successfully complete my dissertation. I am deeply indebted to express my wholehearted gratitude and thanks to my

beloved mother, Smt. Sarojanamma, father Sri.Hanumantha Reddy and to whom I owe in a substantial measure in the successful completion of this subject.

It gives me immense pleasure to acknowledge, the help rendered to me by a host

of people, to whom I owe gratitude for the successful completion of my M.Pharm. The research work embodied in this dissertation has been carried out under the

supervision of my esteemed and most respected Guide, Head, Dept. of Pharmaceutics and Principal Prof.Dr.M.S. Srinath, Government College of Pharmacy, Bangalore. I take this golden opportunity to thank and express my sincere gratitude for his continuous encouragement, valuable suggestions, dynamic guidance, ever readiness to solve my problems, moral support and blessings shown on me throughout the period of this work.

I thank Assistant Professor Dr. N.G. Nanjunda swamy and lecturer Smt. B.P Manjula Dept., of Pharmaceutics, for their concern, cooperation and encouragement throughout the duration of the course.

I thank beloved and respected Prof. M.S.Harish, Head, Dept.of Pharmacology,

for his wholehearted concern, care and encouragement throughout the duration of the course.

I thank Assistant Professor Sri M. S. Niranjan, Sri Chandrashekar Javali

lecturer, Dept. of Pharmaceutical Chemistry, Govt. College of Pharmacy, Bangalore, for their encouragement and help.

I thank Dr. Shashidhara, Assistant Professor, Dept. of Pharmacognosy, for his

encouragement and moral support.

My regards to Prof. M. Lakshmana, Retd.-Principal of GCP, B’lore for his encouragement and support. And my regards to Dr. M. D. Karvekar for his care and encouragement. My special thanks to Asst. Professor Sri. Nagaraj, Sri. V. Ramakrishna and Sri Kalaskar, Lecturer, Govt. College of Pharmacy, Bangalore, for their encouragement and help. And my regards to Sri. Sathish, Sri Mukund, lecturers for their affection.

I would like to express my sincere and heartfelt thanks to Sri. C. Narendra,

Lecturer, Krupanidhi College of Pharmacy, Bangalore, for his kind help and sparing his precious time in carrying out the process of optimization.

i

I also acknowledge with heartfelt thanks M/s KAPL, Bangalore and

M/s EROS Pharma, Bangalore and M/s Ce-Chem Pharma, Bangalore for providing various excipients required for my work.

I thank Prof. Gopala Krishna Rao and Prof. Sanjay Pai, Dept. of Pharmachemistry, Al-Ameen College of Pharmacy, for their encouragement.

I take this opportunity to thank all the teaching and non-teaching staff Sri.

Prabhakar, Sri.LakshmiNagesh, SriNageshachar, SriThippeswamy, Smt.Veena and Librarians Smt.. B.K. Rohini and Smt. P. Aruna Sanjeeva Rao of Govt. College of Pharmacy, Bangalore, for their constant support and help.

At this juncture I would be failing, if I do not acknowledge the help of

Sri R. Chandrashekar., Chief Pharmacist, , Govt. Medical Stores, Bangalore, who was my moral and guiding supporter for my higher education.

I thank the Director and all the officials of Health Department, specially

Sri Dalappa, Sri Sreedhar, Sri Gopal and Sri Gopal reddy of DME for their timely support in permitting me to pursue M. Pharm.

My sincere thanks to Sri Nagaraj, Sri Ittagi (section Officers),

Sri Chandrappa, Sri Putnanjayya, Sri Shivalingaiah of Health Secretariat, M.S. Buildings, Bangalore for getting me permission to study M. Pharm.

I thank with highest regards to honorable Sri G. H. ThippaReddy, Sri Shankara

Reddy, Sri N. Surya Narayana Reddy, Members of Legislative Assembly, Sri G. Madhusudan, Member of Legislative Council and Sri K. Basavana Goud, Member of Parliament for their valuable support and help as always.

I thank my brothers Sri Basavaraj, Sri Gopal Reddy and my brother in law

Sri Gurudas Reddy, Sri Satishwar Reddy and their family members for their encouragement and support.

I sincerely acknowledge the special affection and moral support rendered by my brother-in-law Sri. C. S. Reddy and my sister Smt. Geetha all throughout my career in all the ways.

My sincere thanks to cousins specially Sri Anantha Reddy and Sri Nagaraj

Reddy for their valuable support in each and every movement. Mere words and acknowledgement cannot express the valuable help and

encouragement rendered by my friends specially Mr. Nataraj and Ms. Sindhu during my course and the kind help rendered by Mr.Prakash, Mr.Satish, Ms.Jayanthi, Mr.Satya, Mr.Somashekar, Mr.Vadivelan, Mr.Mahantesh, Mr.Suresh, Mr.Prathap,

ii

Mr.Ragavendra, Mr.Shreekant, Ms.Anusha, Ms.Malini, Ms.Nazia and Ms.Shameem.

I thank my seniors Mrs.Anitha, Mr.Siddu, Mr.Afrasim Moin, Mr.Sreenivasa Reddy, Mrs.Girija, Mr.Neelkant, Mr.Shalam, Mr.Badri, Mr.Harish, Mr.Suhas and Ms.Priya and others for their guidance and help.

I thank my juniors especially Mr.Rajesh and Mr.Sachin who were remembered for their support and help, during my course. I also thank Mr.Doddamani Mr.Nagesh, Ms.Vijaya, Mr.Pasha, Mr.Vathan, Mr.Ismail, Mr.Zarnappa, Mr.Naveen, Mr.Nagaraj, Ms.Aswini, Ms.Jaysheela, Mr.Ananth, Mr.Anne Gowda, Mr.Vageesh and Mr.Shabuddin for their kind support and help.

I remember at this juncture the cooperation rendered by my well wishers Sri. Suresh Shetty, Sri. Kalidas, Sri. Shantaram Shetty, Sri. Gurudev, Sri.Naganna and Sri. Rajiv for their moral support.

I also thank Mr. Arvind and Miss. Shweta of Cyber Arcade, Jayanagar in

designing and printing of my Research work. I am pleased to express my sincere thanks to my wife Smt. Prasanna Lakshmi

for her kind, heartfelt and moral support during my entire course, which cannot be expressed in mere words. With out her kind cooperation and sacrifice, it would have been impossible for me to complete my research project. I am happy that my son Master Srujan co-operated with me during my project work.

Finally, I take this opportunity to express my gratitude to all the people involved

directly or indirectly in the successful completion of this dissertation work. Date: Place: Bangalore (N. SREENIVASA REDDY)

iii

LIST OF ABBREVIATIONS USED Abs. : Absorbance

BP : British Pharmacoepia

CDR : Cumulative drug release

CLA : Cumulative loss account

Conc. : Concentration

CPVP : Crospovidone

DCP : Dicalcium Phosphate dihydrate

DT : Disintegration time

GIT : Gastro intestinal tract

g : gram

Hrs : Hours

HCl : Hydrochloric acid

HPC : Hydroxypropyl Cellulose

IP : Indian Pharmacoepia

IR : Infrared

mg : milligram

ml : milliliter

mm : millimeter

µg : microgram

µ l : microlitre

nm : nanometer

PA : Physical Appearance

%DC : Percentage Drug content

pH : Hydrogen ion concentration

ppm : parts per million

PVP : Poly Vinyl Pyrrolidone

Rf : Retention / resolution factor

RH : Relative Humidity

rpm : revolutions per minute

SEM : Standard error of mean

SSG : Sodium starch Glycolate

TLC : Thin Layer Chromatography

USP : United States Pharmacoepia

UV : Ultra Violet

Wt. : Weight

WT : Wetting Time

ABSTRACT

“DEVELOPMENT OF RAPIDLY DISINTEGRATING TABLETS FOR A MODEL

ANTI-EMETIC DRUG”

Sreenivasa Reddy N., Dr. M. S. Srinath, Government College of Pharmacy, Bangalore.

The present research work is an attempt to formulate and evaluate rapidly disintegrating tablets

of a model anti-emetic drug, Metoclopramide Hydrochloride prepared by direct compression

method.

The drug excipient compatibility studies were carried out. The tablets were formulated

by direct compression method, using directly compressible Mannitol, Dicalcium phosphate and

Avicel PH 200 as diluents. Crospovidone (5, 7.5, 10%), Crosscarmellose sodium (5, 7.5, 10%),

Low substituted hydroxy propyl cellulose (5, 7.5, 10%) and Sodium starch glycolate (10, 12.5,

15%) were used as disintegrants at different concentrations. Pregelatinized starch was used as a

binder in all the formulations to attain hardness. Aspartame was used as the sweetening agent.

The pre compression parameters like bulk density, tapped density, Carr’s Index and angle

of repose were determined. The post compression parameters like the hardness, thickness,

friability, weight variation, Disintegration time as per IP, wetting time and disintegrating time in

oral cavity for all the formulations were carried out. Crospovidone and Sodium starch glycolate

exhibited quicker disintegration of tablets than compared to those of Low substituted Hydroxy

propyl cellulose and Crosscarmellose sodium.

A 32 full factorial design was performed to study the effect of the formulation variables

on the DT and WT. Factors X2 (CPVP) were found to be significant for WT and factor X1 (SSG)

were found to be significant for DT. Interaction factors were found to be big for both the

responses. A numerical optimization was performed to find the optimum composition of RDT

and based on this an optimized formulation was arrived containing 5.13 mg of Sodium Starch

Glycolate and 12.5 mg of Crospovidone.

Finally it is concluded that the so developed formula holds good for Metoclopramide

Hydrochloride where rapid action is desired.

Keywords: Optimization; Disintegration; Metoclopramide Hydrochloride; Compression;

Hardness; Microcrystalline cellulose; Low- substituted hydroxy propyl cellulose.

TABLE OF CONTENTS

Chapter No. Title Page No.

1 Introduction 1

2 Objectives 14

3 Review of Literature 16

4 Methodology 38

5 Results 67

6 Discussion 100

7 Conclusion 109

8 Summary 110

9 Bibliography 112

iv

LIST OF TABLES

Sl.No Title

Page No.

1 Calibration curve of Metoclopramide Hydrochloride in 0.1N HCl. 45

2 Drug – Excipient compatibility studies- Rf values 48

3 Actual and coded values of factors 51

4 Runs designed in Actual and coded values 52

5 Dicalcium Phosphate based tablet formulations 53

6 Mannitol based tablet formulations 54

7 Avicel PH 200 based tablet formulations 55

8 Tablet formulations as per DOE 56

9 Carr’s index values 59

10 Pre-compression parameters of DCP formulations 67

11 Post- compression parameters of DCP formulations 67

12 Comparison between DT, DTO and WT. 68

13 Invitro release profile of DCP formulations at 5minutes 70

14 Invitro release profile of DCP formulations at 20 minutes 70

15 Pre-compression parameters of Mannitol formulations 72

16 Post- compression parameters of Mannitol formulations 72


18 Invitro release profile of Mannitol formulations at 5minutes 75

v

Sl.No Title

Page No.

19 Invitro release profile of Mannitol formulations at 20 minutes 75

20 Pre-compression parameters of Avicel PH 200 formulations 77

21 Post- compression parameters of Avicel PH 200 formulations 77


23 Invitro release profile of Avicel PH 200 formulations at 5minutes 80

24 Invitro release profile of Avicel PH 200 formulations at 20 minutes 80

25 Design and summary response data 83

26 ANOVA cubic model 84

27 Estimated regression coefficient 84

28 ANOVA Response Surface Cubic Model (Aliased) 86

29 Estimated regression coefficient 86

30 Optimized formula 89

31 Predicted solution of optimized formula 89

32 Pre-compression parameters of runs as per DOE 90

33 Post- compression parameters of runs as per DOE 90


35 Invitro release profile of runs as per DOE at 5minutes 93

36 Invitro release profile of runs as per DOE formulations at 20 minutes 93

37 Composition of optimized formulation 96

38 Pre-compression parameters of optimized formula 96

vi

Sl.No Title

Page No.

39 Post- compression parameters of optimized formula 96


41 Invitro release profile of optimized formula 97

42 Stability data of optimized formula stored at 25oC / 60% RH 99

43 Stability data of optimized formula stored at 40oC / 75% RH 99

44 Comparison of Precompression parameters of all the formulations 101

45 Comparison of Hardness of all the formulations 102

46 Comparison chart of predicted and actual values for optimized formulation 108

vii

LIST OF FIGURES

Sl.No Title

Page No.

1 IR spectrum of Metoclopramide Hydrochloride 42

2 UV spectrum of Metoclopramide Hydrochloride 43

3 Calibration curve of Metoclopramide Hydrochloride in 0.1N HCl 45

4 Schematic representation of Drug – excipient compatibility studies 46

5 TLC photograph of drug- Excipient compatibility studies. 49

6 Disintegration profile of DCP formulations 69

7 Dissolution profile of DCP formulations 71

8 Disintegration profile of Mannitol formulations 74

9 Dissolution profile of Mannitol formulations 76

10 Disintegration profile of Avicel PH 200 formulations 79

11 Dissolution profile of Avicel PH 200 formulations 81

12 Perturbation plot showing effect of Concentration of SSG on wetting time. 85

13 Perturbation plot showing effect of Concentration of CPVP on wetting time. 85

14 3-D graph showing combined effect of SSG and CPVP on wetting time 85

15 Perturbation plot showing effect of Concentration of SSG on DT 88

16 Perturbation plot showing effect of Concentration of CPVP on DT 88

17 3-D graph showing combined effect of SSG and CPVP on DT 88

18 Disintegration profile of runs as per DOE 92

19 Dissolution profile of runs as per DOE 95

20 Dissolution profile of optimized formula 98

21. Figure depicting Wetting time of Optimized formulation 98 a.

viii

Introduction

INTRODUCTION

RAPIDLY DISINTEGRATING TABLETS 1

Among the different routes of administration, the oral route of administration

continues to be the most preferred route due to various advantages including ease of

ingestion, avoidance of pain, versatility and most importantly patient compliance. The

different dosage forms include tablets and capsules. The important drawback of these

dosage forms for pediatric and geriatric patients is being difficulty in swallowing.

Nearly 35% of the general population, especially the elderly patients and children

suffer from Dysphagia or difficulty in swallowing, which results in high incidence of

noncompliance and ineffective therapy. Swallowing problems also are very common in

young individuals because of their poorly developed muscular and nervous systems.

Other groups who may experience problems in swallowing conventional oral dosage

forms are the patients with tremors of extremities, mentally ill, developmentally disabled,

non co-operative patients and patients with reduced liquid intake plans or patients

suffering from nausea. The swallowing problems are also common in some cases such as

patients with motion sickness, sudden episodes of allergic attack or coughing and due to

lack of water.

To overcome these problems, formulators have considerably dedicated their effort

to develop a novel type of tablet dosage form for oral administration, i.e., one, which

disintegrates and dissolves rapidly in saliva without the need for drinking water. The

tablet is placed in the mouth, allowed to disperse or dissolve in the saliva. These tablets

Department of Pharmaceutics, GCP, B’lore-27.

1

Introduction usually dissolve within 15 seconds to 2 minutes. The faster the drug goes into solution,

the quicker the absorption and onset of clinical effect.

Less frequently, they are designed to be absorbed through the buccal and oesophageal

mucosa as the saliva passes into the stomach. In the latter case, the bioavailability of a

drug from rapidly disintegrating tablets may be even greater than that observed for other

standard dosage forms.

The rapidly disintegrating tablets also offer advantages over other oral dosage forms

such as effervescent tablets, suspensions, chewing gum or chewing tablets, which are

commonly used to enhance patient compliance. Effervescent tablets and suspensions

require preparatory steps before administration of the drug. The elderly, who often are

unable to chew large pieces of gum or tablets, sometimes experience unpleasant taste

when bitter drugs are consumed.

The advantages of rapidly disintegrating tablets are being recognized in both

industry and academia. Their growing importance was underlined recently when the

European Pharmacopoeia adopted the term Orodispersible tablet as a “tablet to be placed

in the mouth where it disperses rapidly before swallowing”.

The ideal rapidly disintegrating tablet technology should address the following:

Requires no water for oral administration, yet dissolve or disintegrate in the

mouth in a matter of seconds.

Allow high drug loading.

Bitter taste to be masked.

Have a pleasant mouth feel.

Leave minimal or no residue in the mouth after oral administration.


2

Introduction

Be portable without fragility concerns.

Exhibit low sensitivity to environmental conditions such as humidity and

temperature.

Allows the manufacture of tablets using conventional processing and packaging

equipment at low costs.

The techniques used in the preparation of rapidly disintegrating tablets are: -

CONVENTIONAL TECHNIQUES 1, 2

1. Tablet molding:

In this method, the delivery system is prepared in the form of tablets using water-

soluble additives, to allow the tablets to dissolve rapidly and completely in mouth.

All the ingredients of the formulation are passed through fine mesh, dry blended,

wetted with a hydro-alcoholic solvent and then compressed into tablets using low

compression forces.

2. Freeze drying (Lyophilization):

Lyophilization is a pharmaceutical manufacturing technology, which allows

drying of heat sensitive drugs and biologicals at low temperatures under conditions

that allow removal of water by sublimation. Lyophilization results in preparations,

which are highly porous, with a very high specific surface area, which dissolve

rapidly and show improved absorption and bioavailability.


3

Introduction 3. Spray drying:

Spray drying is a process by which highly porous, fine powders can be produced.

The composition contains a bulking agent (e.g. mannitol and lactose), a disintegrant

(e.g. sodium starch glycollate and croscarmellose sodium), an acidic ingredient (citric

acid) and/or alkaline ingredients (e.g. sodium bicarbonate) which when compressed

into tablets shows fast disintegration and enhanced dissolution.

4. Sublimation:

This method includes the addition of a sublime salt to the tableting components,

compressing the blend and removing the salt by the process of sublimation. The

active ingredient, a diluent, a sublime salt (ammonium carbonate, ammonium

bicarbonate), a binder and other excipients are blended and tablets are prepared.

5. Addition of Disintegrants:

Addition of disintegrants in fast dissolving tablets, leads to quick disintegration of

tablets and hence improves dissolution. Microcrystalline cellulose, cross-linked

Carboxymethylcellulose Sodium, cross-linked polyvinyl pyrrolidone and partially

substituted Hydroxypropyl cellulose, absorb water and swell due to capillary action

and are considered as effective disintegrants in the preparation of fast dissolving

tablets.


4

Introduction 6. Sugar-based excipient:

Sorbitol, mannitol, dextrose, xylitol, fructose, maltose, isomalt, and polydextrose

have been used as bulking agents. Because of their high aqueous solubility and

sweetness, which impart a pleasing mouth feel and good taste masking, nearly all

formulations for rapidly dissolving tablets contain sugar-based materials.

PATENTED TECHNOLOGIES:

7. ZYDIS

This technology converts the mixture of active ingredient and water dispersible

carrier materials into open matrix network that disintegrates rapidly using freeze-

drying process. The network is highly porous solid foam, which allows rapid

penetration of liquid and facilitates quick disintegration of the dosage unit. In Zydis

technology, drug is added to a solution of carrier material (preferably gelatin) to

obtain dispersion, and the dispersion is filled into preformed pockets of blister pack

by automatic means, and freeze dried to produce the final dosage form.

8. ORASOLV

This system essentially makes tablets that contain the taste masked active

ingredients and an effervescent disintegrating agent, which on contact with saliva,

rapidly disintegrates and released the active ingredient. The tablets are made by

direct compression at very low compression forces in order to minimize oral

dissolution time. The tablets produced are soft and friable.


5

Introduction 9. DURASOLV

The tablet made by this technology consists of a drug, fillers and a lubricant.

DuraSolv tablets are prepared by using conventionally tableting equipment and have

good rigidity. It is an appropriate technology for products requiring low amounts of

active ingredients.

10. FLASH DOSE

Flash dose tablets consists of self-binding shear form matrix termed as “floss”.

Shear form matrices are prepared by flash heat processing and are of two types.

Single floss or Unifloss, consisting of a carrier, and two or more sugar alcohols,

of which one is xylitol.

Dual floss consists of a first shear form carrier material (termed “base floss”,

contains a carrier and at least one sugar alcohol generally sorbitol), and a second

shear form binder matrix (“binder floss”, contains a carrier and xylitol).

In flash heat process, the feed stock (carbohydrates including sugars and

polysaccharides) is simultaneously subjected to centrifugal force and to a temperature

gradient, resulting in discrete fibers. The preformed matrices obtained are partially

crystallized and have good self-binding and flow properties. The so formed matrices

are complex crystalline structures with high specific surface area and result in rapid

dissolution rate of the drug. The shear form matrix is blended with drug and other

tableting ingredients, and compressed into tablets using conventional tableting

equipment. Flash dose tablets are soft, friable and hygroscopic dosage forms, which

require specialized packaging.


6

Introduction 11. WOW TAB

This process uses a combination of low mouldability saccharide (rapid

dissolution) and high mouldability saccharide (good binding property) to obtain a

rapidly melting strong tablet. The active ingredient is mixed with a low mouldability

saccharide (e.g. lactose, mannitol) and granulated with a high mouldability saccharide

(e.g. maltose, sorbitol) and compressed into tablets.

12. FLASHTAB

This technology involves the preparation of rapidly disintegrating tablet, which

consists of an active ingredient in the form of micro crystals. Drug micro granules

may be prepared by using the conventional techniques like coacervation; micro

encapsulation; extrusion-spheronization or simple pan coating method. The micro

crystals or micro granules of the active ingredient are added to the granulated mixture

of excipients prepared by wet or dry granulation, and compressed into tablets.

DIRECT COMPRESSION METHOD 3

Direct compression is the easiest method to manufacture rapidly disintegrating

tablets (RDTs) and fast-melting tablets (FMTs). The great advantage of direct

compression is its low manufacturing cost. It uses conventional equipment, commonly

available excipients and a limited number of processing steps.

In many cases the disintegrants used have a major role in the disintegration and

dissolution process of rapidly disintegrating tablets made by direct compression method.


7

Introduction The choice of a suitable type and an optimal amount of disintegrant is important for

ensuring a high disintegration rate. The addition of other formulation components such

as water-soluble excipients or effervescent agents can further enhance dissolution or

disintegration properties.

The understanding of disintegrant properties and their effect on formulation has

advanced significantly during the last few years, particularly regarding so called super-

disintegrants.

Caramella et al3 found that disintegration efficiency is based on the force-equivalent

concept (the combined measurement of swelling force development and amount of water

absorption). Force equivalence expresses the capability of force. The optimization of

tablet disintegration was defined by means of the disintegrant critical concentration.

Below this concentration, the tablet disintegration time is inversely proportional to the

disintegrant concentration. Above the critical concentration, the disintegration time

remains approximately constant or even increases.

OPTIMIZATION 4,5

The word optimize is defined as, to make as perfect, effective or functional as

possible. Optimization may be interpreted as to find out the values of controllable

independent variables, that gives the most desired value of dependent variables.

In the trial and error method, a lot of formulations have to be prepared to get a

conclusion, which involves lot of money, time and energy. These can be minimized by

the use of optimization technique.


8

Introduction Optimization process:

Generally optimization process involves the following steps.

1. Based on the previous knowledge or experience or from literature, the

independent variables are determined or set in the beginning.

2. Selection of a model based on the results of the factor screening.

3. The experiments are designed and are conducted.

4. The responses are analyzed by ANOVA, test on lack of fit, to get an empirical

mathematical model for each individual response.

5. The responses are screened by using multiple criteria to get the values of

independent variables.

Experimental design6

Experimental design is a statistical design that prescribes or advises a set of

combination of variables. The number and layout of these design points within the

experimental region, depends on the number of effects that must be estimated.

Depending on the number of factors, their levels, possible interactions and order of the

model, various experimental designs are chosen. Each experiment can be represented as

a point within the experimental domain, the point being defined by its co-ordinate (the

value given to the variables) in the space.


9

Introduction a) Factorial design

It is an experimental design, which uses dimensional factor space at the corner of

the design space. Factorial designs are used in experiments where the effects of different

factors or conditions on experimental results are to be elucidated. These are the design of

choice for simultaneous determination of the effect of several factors and their

interaction.

The simplest factorial design is the two-factorial design where two factors are

considered each at two levels, leads to four experiments, which are situated in 2-

dimensional factor space at the corners of a rectangle. If there are three factors, each at

two levels, eight experiments are necessary which are situated at the corners of an

orthogonal cube in a 3-dimensional space. The number of experiments is given by 2n,

where ‘n’ is the number of factors.

If the number of factors and levels are large, then the number of experiments

needed to complete a factorial design is large. To reduce the number of experiments,

fractional factorial design can be used (i.e., ½ or ¼ of the original number of experiments

with full factorial design).

The fitting of an empirical polynomial equation to the experimental result

facilitates the optimization procedure. The general polynomial equation is as follows:

Y = B0 + B1X1 + B2X2 + B3X3 +…+ B12X1X2 + B13X1X3 + B23X2X3 +…+ B123X1X3.

Where, Y is the response,

X1, X2, X3 are the levels (concentration) of the 1,2,3 factors

B1, B2, B3, B12, B13, B23, B123, are the polynomial coefficients.


10

Introduction B0 is the intercept (which represents the response when the level of all factors is

low).

b) Plackett – Burman design

It is a special fractional factorial design with K = m*4 experiment, for screening

of (K-1) variables, Where ‘K’ is the number of variables and ‘m’ is the number of

levels.

c) Star design

Star design is simply a 22 factorial design rotated over 450 angle in the space. A

center point is usually added, which may be replicated to estimate the experimental

error, so there will be three levels for each factor where quadratic effect can be

measured, but the interaction effect cannot be measured as that in case of factorial

design. In the star designs, 2k Factorial designs are rotated over 450 in (k-1) direction

in k-dimensional space with a replicated center point. ‘k’ is the number of factors in

the design. This results in 2k + Rc experiments, where Rc is the replicates of the

center point.

d) Central Composite design

A better design that combines the advantages of Factorial design or Fractional

factorial design and the Star design, is the central composite design (CCD) developed

by Box and Wilson. It is composed of


11

Introduction

• 2k Factorial design or 2(k-p) Fractional factorial design.

• 2*k Star design

This design enables the estimation of a full second-order model. The equation for

two factors is given by

E(y) = B0+B1X1+B2X2+B12X1X2+B11X12+B22X2

2

Validation of the model

The model is validated using ANOVA calculation, then the estimation pure

measurement error is done. The variance of these observations pooled over all to get an

estimate of pure error of variance. The F-test on regression and lack of fit will be useful

for judging descriptive properties of a model and the significance of model terms.

Predictions using the selected model

Once a model is selected and validated, the brute force method is applied for the

prediction of response. With the help of 3D-response surface or a 2D contour diagram,

the prediction is done using these graphs either by grid search or feasibility search

methods.


12

Introduction Software for designs and Optimization

Many commercial software packages are available which are either dedicated to

experimental design alone or are of a more general statistical type.

Software’s dedicated to experimental designs

Design Ease and Design Expert (Stat-ease)

ECHIP

CARD

Multisimplex

Software for general statistical nature includes

SAS

MINITAB

SYSTAT, etc.


13

Objectives

OBJECTIVE

Nausea and vomiting may be manifestations of a wide variety of conditions,

including pregnancy, motion sickness, gastrointestinal obstruction, peptic ulcer, drug

toxicity, myocardial infraction, renal failure and hepatitis. In cancer chemotherapy, drug

induced nausea and vomiting may occur so regularly that anticipatory vomiting occurs

when patients return for treatment before the chemotherapeutic agent is given. If not

controlled, the discomfort associated with drug – induced emesis may cause a patient to

refuse further chemotherapy.

Conventional tablets are available to treat nausea and vomiting, but swallowing

problems are common to 35% of population including patients suffering from

parkinsonism, head and neck surgery, motion sickness etc.

Metoclopramide hydrochloride is a substituted benzamide used for its prokinetic

and anti emetic properties. The drug is very useful in treating nausea and vomiting of

varied etiology, e.g. Nausea and vomiting associated with gastrointestinal disorders,

radiation sickness, hepatobiliary disorders, pre and postoperative periods and migraine.

Hence there is a need to develop rapidly disintegrating tablets, which disintegrates

in matter of seconds in the oral cavity, thereby reducing the time of onset of

pharmacological action.

The study was intended to select the best possible diluent - disintegrant combination

to formulate rapidly disintegrating tablets among the various diluents and disintegrants

used. Direct compression method was employed to formulate the tablets, because of its

cost effectiveness and due to reduced number of manufacturing steps.


14

Objectives

PLAN OF WORK:

1. Screening of various disintegrating agents for the preparation of rapidly

disintegrating tablets.

2. Formulation of rapidly disintegrating tablets by using different diluents,

disintegrants and other excipients.

3. Best disintegrating agents was further evaluated by using design of

experimental technique (DOE).

4. The results were subjected to ANOVA for the development of polynomial

models.

5. The best formulation was selected based on numerical optimization.

6. To study the Drug- Excipient compatibility.

7. Stability studies for the selected formulations.


15

Review of Literature

REVIEW OF LITERATURE

2.1 DRUG DATA 7

METOCLOPRAMIDE HYDROCHLORIDE Metoclopramide hydrochloride is a substituted benzamide used for its prokinetic and anti

emetic properties. It stimulates the motility of the upper gastrointestinal tract without

affecting gastric, biliary or pancreatic secretion and increases gastric peristalsis leading to

accelerated gastric emptying.

CHEMISTRY

Metoclopramide is a chlorobenzamide derivative chemically known as 4-amino-5-chloro-

N-(2-diethylaminoethyl)-2-methoxybenzamide hydrochloride monohydrate.

The structure is shown below:

Department of Pharmaceutics, GCP, Bangalore -27.

16


PHARMACOLOGY

The principle Pharmacological effects of Metocopramide Hydrochloride involve

the GI tract and CNS. Although structurally similar to Procainamide, Metoclopramide

HCl lacks significant local anesthetic activity.

The drug is a substituted benzamide, which stimulates the motility of upper GI

tract without affecting gastric acid secretion. It increases gastric peristalsis leading to

accelerated gastric emptying. Duodenal peristalsis is also increased which decreases

intestinal transit time.

It possesses parasympathomimetic activity as well as being a dopamine receptor

antagonist with a direct effect on CTZ has anti- emetic effect.

Mechanism of action:

Metoclopramide hydrochloride acts:

1) By blocking Dopamine receptors of Chemoreceptor Trigger Zone (CTZ).

2) By increasing frequency and depth of antral contractions and regularizing motility

between antrum and duodenal bulb, thus facilitating gastric emptying due to

dopaminergic receptor blockade, potentiation of cholinergic, muscarinic effects

and direct action on the smooth muscle

3) By blocking 5-HT receptors of CTZ, at higher concentrations.


17


PHARMACOKINETICS

Absorption:

Metoclopramide HCl is rapidly and completely absorbed after oral administration,

but hepatic first metabolism reduces its bioavailability to 75%.

Following oral administration of a single 10mg dose of the drug, peak plasma

Metoclopramide concentrations of 32-44ng/ml occurred at 1-2 hours. The onset of

Pharmacological actions of the drug on the GI tract is 1-3 minutes following i.v

administration, 10-15 minutes following i.m administration and 30 - 60minutes following

oral administration.

Distribution

Apparent volume of distribution of Metoclopramide Hydrochloride is 2.2 - 3.4

liters/ kg in adults. The drug crosses the Blood brain barrier and placenta. It is weakly

bound to plasma proteins.

Elimination

Elimination half life (t 1/2) is 4-6 hours. The t 1/2 is prolonged in patients with renal

failure. It is excreted in urine, about 85% of a dose being eliminated in 72 hours, 20-30%

as unchanged Metoclopramide and the remainders as sulfate or glucuronide conjugate.

About 5% of a dose is excreted in faeces via the bile.


18


INDICATIONS

Metoclopramide hydrochloride is used:

In disorders of decreased gastrointestinal motility such as gastorparesis or ileus.

In gastro –esophageal reflux disease.

In dyspepsia

To stimulate gastric emptying during radiographic examinations.

Parenterally in high doses for prevention of nausea and vomiting associated with

cancer therapy (Cisplatin induced).

Parenterally to facilitate intubation of small intestine in adults and children in

whom the tube (endoscope) does not pass through the pylorus with conventional

maneuver.

For the short term (upto 12 weeks) relief of symptomatic, documented gastro

esophageal reflux in adults who are not responding to conventional therapy alone.

Parenterally for the prevention of postoperative nausea and vomiting.

In the treatment of migraine to alleviate nausea and vomiting and gastric stasis.

CONTRAINDICATIONS

Recent GI surgery

Gastrointestinal hemorrhage, obstruction or perforation.

Drug intolerance

Pheochromocytoma (tumor of the adrenal medullary cells).

Tardive dyskinesia

Epilepsy


19


DOSING INFORMATION

1. For the relief of Symptomatic Gastroesophageal reflux: 10mg to 15mg orally

upto four divided doses, 30 minutes before each meal and at bedtime.

2. For the relief of symptoms associated with Diabetic gastorparesis: 10mg of

Metoclopramide 30 minutes before each meal and at bedtime for two to eight

weeks.

3. For the prevention of nausea and vomiting associated with emetogenic

Cancer chemotherapy: I.V infusions should be made slowly over a period of not

less than 15 minutes, 30 minutes before beginning cancer chemotherapy and

repeated every 2 hours for two doses, then every 3 hours for three doses.

4. To facilitate Small bowel intubation:

Patients of age 14 years and adults - 10mg of Metoclopramide base

6- 14 years of age - 2.5 to 5mg of Metoclopramide base

Under 6years - 0.1mg / kg of Metoclopramide base

ADVERSE EFFECTS

Metoclopramide is a Dopamine antagonist and may cause extra pyramidal

symptoms, which usually occur in acute dystonic reactions; these are more common in

children and young adults, especially if female and at daily doses above 500mcg per kg

body weight. Parkinsonism and tardive dyskinesia have occasionally occurred, usually

during prolonged treatment in elderly patients.


20


Other adverse effects include restlessness, drowsiness and diarrhoea, hypotension.

Hypertension, dizziness, headache and depression may occur and there are isolated

reports of blood disorders, hypersensitivity reactions (rash, bronchospasm) and

neuroleptic malignant syndrome.

Metoclopramide stimulates prolactin secretion and may cause galactorrhoea or

related disorders. Transient increases in plasma aldosterone concentartions have been

reported.


21


2.2 EXCIPIENT DATA 8

1} Mannitol

Synonyms:

Cordycepic acid, manita, manna sugar, mannite, Pearlitol.

Functional Category:

Tablet and capsule diluent, sweetening agent, tonicity agent, vehicle (bulking agent) for

lyophilized preparations.

Applications:

As a diluent in tablets (10-90% w/w). It is not hygroscopic and can be used with moisture

sensitive active ingredients. In the manufacture chewable tablet formulation because of

its negative heat of solution, sweetness, mouth feel.

Description:

White, odorless, crystalline powder, or free flowing granules. It has a sweet taste.

Solubility:

Freely soluble in water, practically insoluble in ether.

Storage conditions:

The bulk material should be stored in a well-closed container, in a cool, dry, place.

Incompatibilities:

Mannitol solution, 20 % w/v or stronger, may be salted out by potassium or sodium

chloride. It is incompatible with xylitol infusion & may form complexes with metals like

Fe, Al, and Cu.

Safety: When consumed orally in large amounts laxative effects may occur. Daily

ingestion of over 20 g is foreseeable


22


2} Dibasic Calcium Phosphate Dihydrate

Synonyms:

Cafos, dicalcium orthophosphate, Di-Cafos, Caltstar, DI-TAB, Emcompress.

Functional category:

Tablet and Capsule diluent.

Applications:

As a diluent in tablets (wet granulation and direct compression). The dihydrate &

anhydrous forms are nonhygroscopic at 250C and relative humidities up to about 90%.

Description:

White odorless, tasteless powder, or crystalline solid.

Solubility:

Practically insoluble in ethanol and water. Soluble in dilute acids.

Storage conditions:

The bulk material should be stored in a well-closed container in a cool, dry, place.

Incompatibilities:

Incompatible with Tetracyclines and Indomethacin. Due to its alkaline nature it should

also not be used with active ingredients that is sensitive to a pH of 7.3 or above.

Safety:

It is generally regarded as a nontoxic and nonirritant material. However, oral ingestion

of large quantities may cause abdominal discomfort


23


3} Microcrystalline Cellulose

Synonyms:

Avicel, cellulose gel, crystalline cellulose, E460, Emocel, Fobrocel, Tabulose, Vivacel.


Tablet and Capsule diluent, suspending agent, adsorbent, tablet disintegrant.

Applications:

As a diluent in tablets (wet granulation and direct compression) and capsule formulation.

It also has some lubricant and disintegrant property.

Description:

White-colored, tasteless crystalline powder composed of porous particles.

Solubility:

Slightly soluble in 5 % w/v Sodium hydroxide solution, practically insoluble in water,

dilute acids and most organic solvents.

Stability:

It is a stable, though hygroscopic material.

Storage conditions:

The bulk material should be stored in a well- closed container in a cool, dry, place.

Incompatibilities:

Incompatible with strong oxidizing agents.

Safety:

It is generally regarded as a nontoxic and nonirritant material


24


4} Crospovidone

Synonyms:

Cross-linked povidone, Kollidon CL, Polyplasdone XL, PVPP, Polyvinylpolypyrrolidone.


Tablet disintegrant.

Applications:

It is a water insoluble tablet disintegrant used at 2-5 % concentration in tablets,

prepared by wet and dry granulation method.

Description:

White to creamy-white, finely divided, free-flowing, practically tasteless, odorless,

hygroscopic powder.

Solubility:

Practically insoluble in water and most organic solvents.

Stability:

Crospovidone is stable.

Storage conditions:

Since it is hygroscopic it should be stored in an airtight container in a cool, dry, place.

Incompatibilities:

When exposed to a high water level it may form molecular adducts with some materials.

Safety:

It is generally regarded as a nontoxic and nonirritant material.


25


5} Croscarmellose Sodium

Synonyms:

Ac-Di-Sol, Cross-linked Carboxymethylcellulose Sodium, Modified Cellulose Gum,

Nymcel ZSX, Primellose, Solutab.


Tablet and Capsule disintegrant.

Applications:

As a disintegrant for tablets (wet granulation and direct compression), capsules and

granules at a concentration of 2- 5%.

Description:

Odorless, white-colored powder.

Solubility:

Insoluble in water, although it swells to 4 to 8 times its original volume on contact with

water.

Stability:

It is a stable though hygroscopic material.

Storage conditions:

It should be stored in a well-closed container in a cool, dry, place.

Incompatibilities:

Efficacy may be slightly reduced in formulations containing hygroscopic excipients

like sorbitol.

Safety: It is generally regarded as a nontoxic and nonirritant material. However,

ingestion of large quantities may have a laxative effect.


26


6} Sodium Starch Glycolate

Synonyms:

Carboxymethyl Starch, Explotab, Primogel


Tablet and capsule disintegrant

Applications:

As a disintegrant in tablet (wet granulation and direct compression) and capsules

formulations at a concentration of 2 - 8%.

Description:

White to off-white, odorless, tasteless, free-flowing powder.

Solubility:

Practically insoluble in ether, sparingly soluble in ethanol (95%). In water it swells up to

300 times its volume.

Stability:

It is a stable material.

Storage conditions:

It should be stored in a well-closed container to protect from wide variations in humidity

and temperature that may cause cracking.

Incompatibilities:

Incompatible with ascorbic acid.

Safety:


of large quantities may be harmful.


27


7} Pregelatinized Starch

Synonyms:

Compressible Starch, Instastarch, Lycatab PGS, Sta-Rx 1500, Prejel, Sepistab ST 200.


Tablet and capsule diluent, disintegrant, tablet binder.

Applications:

It is a modified starch used in capsule and tablet formulations as a binder, diluent &

disintegrant

Description:

It occurs as a moderately coarse to fine, white to off-white colored powder. It is odorless

and has a slight characteristic taste.

Solubility:

Practically insoluble in organic solvents. Slightly soluble to soluble in cold water,

depending upon degree of pregelatinization.

Stability:

It is a stable, though hygroscopic material.

Storage conditions:


Safety:


of large quantities may be harmful.


28


8} Aspartame

Synonyms:

Aspartyl phenyl amine Methyl Ester, equal, Canderel, Nutrasweet, Sancta, Tri-Sweet.


Sweetening agent.

Applications:

It is used as an intense sweetening agent in tablets powder mixes and vitamin

preparations. It enhances flavor systems, can be used to mask some unpleasant taste, and

has sweetening power of 180-200 times that of sucrose.

Description:

It occurs as white, almost odorless crystalline powder.

Solubility:

Slightly soluble in ethanol (95%), sparingly soluble in water. Solubility increases at

higher temperature and at more acidic pH

Stability:

It is stable in dry conditions. In presence of moisture, hydrolysis occurs. Degradation

also occurs during prolonged heat treatment.

Storage conditions:

Bulk material should be stored in a well- closed container, in a cool, dry, place.

Incompatibilities:

Incompatible with dibasic calcium phosphate & also with magnesium stearate.

Safety:

The WHO has set an acceptable daily intake of 40mg/kg body weight.


29


9} Magnesium Stearate

Synonyms:

HyQual, magnesium octadecanoate, stearic acid magnesium salt.


Tablet and capsule lubricant.

Applications:

It is primarily used as a lubricant in capsule and Tablet manufacture at concentrations

between 0.25-5.0%.

Description:

It is a fine, white, precipitated or milled, impalpable powder of low bulk density, having

a faint characteristic odor and taste. The powder is greasy to touch and readily adheres

to the skin.

Solubility:

Practically insoluble in ethanol, ethanol (95%), ether and water, slightly soluble in

benzene and warm ethanol (95%).

Stability:

Magnesium stearate is stable.

Storage conditions:


Incompatibilities:

Incompatible with strong acids, alkalis, iron salts and with strong oxidizing materials.


30


Safety: It is generally regarded as being nontoxic following oral administration.

However, oral consumption of large quantities may result in some laxative effect or

mucosal irritation.

10} Talc

Synonyms:

Magsil Osmanthus, Magsil Star, Purtalc, Steatite.


Glidant, tablet and capsule lubricant, anti- cackling agent.

Applications:

It is used as a lubricant in solid dosage forms (1-10%), in topical preparations as dusting

powder (90-99 %).

Description:

It is a very fine, white to grayish-white colored, odorless, impalpable, unctuous powder.

It adheres to the skin, is soft to touch, and free from grittiness.

Solubility:

Practically insoluble in dilute acids and alkalies, organic solvents and water.

Stability:

Talc is a stable material.

Storage conditions:


Incompatibilities:

Incompatible with quaternary ammonium compounds.


31


Safety:

Following oral ingestion talc is not absorbed systemically and may thus be regarded as

an essentially nontoxic material.


32


2.3(a) RAPIDLY DISINTEGRATING TABLETS.

1. Yunxia bi et al.,9 have formulated tablets which rapidly disintegrate in the oral cavity

using Microcrystalline cellulose and Low-substituted Hydroxypropyl cellulose as

disintegrants and Ethanzamide and Ascorbic acid as poorly and easily water soluble

model drugs, respectively.

2. Y. X. Bi, H. Sunada, et al.,10 have prepared rapidly disintegrating tablets using

microcrystalline cellulose as diluents, and cross-linked sodium Carboxymethyl cellulose

(Ac-Di-sol) Erythritol are selected as response variables, tablet porosity and parameters

representing the characteristics of formulations were selected as controlling factors and

the relation was determined by the polynomial regression method.

3. Simone Schiermeier, et al.,11 have formulated fast dispersible tablets which disintegrated

either rapidly in water to form a stabilized suspension or disperse instantaneously in the

mouth to be swallowed without the aid of water. They employed a rotatable central

composite design to predict the effects of the quantitative factors, Mannitol and

Crospovidone as well as compression force on the characteristics of the tablet.

4. Hisakadzy Sunada et al.,12 have developed rapidly disintegrating tablets using both direct

compression and wet compression methods. Tablet properties, such as, porosity, tensile

strength, wetting time and disintegrating time were evaluated, and the formulation and

disintegration mechanisms of the tablets were evaluated.

5. Akihiko Ito et al.,13 have developed rapidly disintegrating tablets for elderly patients with

impaired swallowing using agar powders and treated agar powders.

6. Tarasuya Ishikawa et al.,14 have prepared tablets which can rapidly disintegrate in saliva

using taste-masked granules, of drugs with bitter taste (ex. Pirenzepine HCl or


33


Oxybutynin HCl). The taste-masked granules were prepared using Eudragit E100 by

extrusion method.

7. Yoshiteru Watanabe et al., 15 have formulated rapidly disintegrating tablets comprising of

crystalline cellulose and low-substituted Hydroxypropyl cellulose (L-HPC).

8. S. Pandey et al.,16 have formulated and optimized fast dissolving tablets of Diclofenac

sodium by direct compression method, using super disintegrants such as cross linked

Carboxy methyl cellulose (Ac-Di-Sol), Sodium starch glycolate (Explotab) and

Crospovidone (Polyplasdone XL) in different concentrations. They reported that tablets

containing Ac-Di-Sol showed better disintegrating character along with rapid release.

9. Chowdary K P R, and Rao Raman N.,17 have carried out formulation and evaluation of

Piroxicam tablets with Piroxicam Pregelatinized Starch dispersions. Dispersions of

Piroxicam in Pregelatinized starch were prepared in different drug and carrier ratios and

were evaluated by X-Ray diffraction, differential thermal analysis and differential

scanning calorimetry studies. They claimed that all the tablets formulated with

Piroxicam-Pregelatinized starch physical mixtures, dispersions were found to contain

Piroxicam within 100 ± 5% of the labeled claim. Thus fast disintegrating tablet giving

rapid dissolution of the drug could be formulated employing Piroxicam Pregelatinized

starch dispersions by conventional wet granulation method

10. KPR Chowdary and Sujatha Rao.,18 have carried out the formulation and evaluation

of dispersible tablets of poorly soluble drugs. Dispersible tablets of three poorly soluble

drugs namely Sulfamethoxazole, Piroxicam and Oxyphenbutazone formulated with

Potato starch and Micro crystalline cellulose fulfilled all the official (BP) requirements

and gave fast and rapid dissolution of the medicament and they reported that the

dissolution followed first order kinetics.


34


2.3 (b) ANALYTICAL METHODS FOR ESTIMATION OF METOCLOPRAMIDE

HYDROCHLORIDE.

1. Harish Rao, Aroor AR, et al., 19 have developed a Fluorimetric method for the estimation

of Metoclopramide in pharmaceutical dosage forms.

2. Emmanuel J and Roy Mathew.,20 have carried out colorimetric estimation of

Metoclopramide Hydrochloride in pharmaceutical formulations. Metoclopramide after

diazotisation is coupled with Phloroglucinol, which shows maximum absorbance at 420

nm.

3. Bhatkar RG and Chondkar SK.,21 have developed a spectrophotometric method for the

determination of Metoclopramide Hydrochloride. The drug forms a complex with a

ammonium reineckate, which is soluble in acetone showing a maximum absorbance at

526nm.

4. Kamalapurkar OS and Chudasama JJ C.,22 have developed a spectrophotometric method

for the estimation of Metoclopramide Hydrochloride in pharmaceutical dosage forms.

The method is based on coupling of diazotised derivative of Metoclopramide with

Thymol resulting in a red chromophore.

5. In BP 2003,23 a Non-aqueous titrimetric method has been described for the determination

of Metoclopramide hydrochloride in pharmaceutical formulations.


35


2.3 (c) REVIEW OF OPTIMIZATION

1. Jesusa Joyce and et. al24., have reported an experimental design, the Central

Composite which was used for the optimization of a new filler / binder (Xylitab 200) for

direct compression, with aspirin as the model drug .the design consists of four

independent variables (filler / binder, drug, disintegrant, and compression force) in

varying amounts, and with crushing strength, friability, weight variation, etc as response

variables. Multiple regression in the form of a second-order polynomial was used to

determine meaningful relationships. In this study, the amounts of compression force and

disintegrant played an important role in controlling the response variables.

2. Renoux and et. al.25, have reported the use of the factorial design for the optimization of

direct compression tablets. A two- level factorial design was used to optimize the

rheological and preformulation properties of a directly compressed tablet formulation

containing 50 % active substance of plant origin. In preformulation tests, the directly

compressible excipients, lubricants, disintegrating agents and glidants were selected. The

optimum concentration of lactose, silicon dioxide colloidal (colloidal silica, Aerosil 200)

and magnesium stearate were then determined. The experimental design revealed a

marked influence of lactose and to a lesser extent of magnesium stearate, allowing the

optimization of these components. After direct compression of an optimized formulation,

mass regularity, friability and disintegrating time was found to be 501.87 mg, 0.16 % and

20 min. respectively.

3. Lipp and Heimann 26 reported a statistical approach to optimization of drying

conditions for a transdermal delivery system (TDDS). In order to optimize the drying

conditions of the TDDS containing 22% of the partly volatile penetration enhancer


36


(propylene glycol), the key factors like drying time and drying temperature were

optimized. Using the results of the statistical analysis of a 2-factorial experiment it was

reported that the amount of residual solvent, ethyl acetate was reduced below 0.02%

while the propylene glycol content of the transdermal system was kept at the desired 22%

level.

4. Lalla and Bhat 27 reported a 23 factorial design approach for the optimization of

Non-pareil seed preparation. Two different equipments were used for the process (i.e.,

coating pan and dish pelletizer). Eight batches of pellets were prepared from calcium

phosphate dibasic (dicalcium phosphate) by varying binder concentration, drying

interval, and pan / dish speed to optimize conditions for preparing Non-pareil seeds. The

pellets were evaluated for size, size distribution, density hardness, etc. Results indicated

that binder concentration, drying, and pan speeds are the critical factors determining

pellet properties.

5. Church, Zia and Rhodes 28 developed a novel extended release Sotalol Hydrochloride

tablet formulation, which possesses a unique combination of floatation and bio adhesion

for prolonged residence in the stomach. A two- factorial, central, composite Box-Wilson

experimental design was employed to develop and optimize the tablet formulation

containing 240 mg of Sotalol Hydrochloride. The ratio of two major bioadhesive agents,

Sodium Carboxymethylcellulose, and the ratio of two directly compressible agents,

diluents, Ethyl cellulose and Crospovidone were used as formulation variables for

optimizing tablet response parameters such as dissolution, bioadhesive capacity, tablet

density and required compression force for producing 6 kg/cm2 hardness.


37

Methodology

MATERIALS AND METHODS

The following excipients, chemicals and instruments were used for the formulation and

evaluation studies.

DRUG

Metoclopramide hydrochloride M/S Eros Pvt Ltd, Bangalore

M/S Ce-Chem laboratories, Bangalore

M/S KAPL Ltd, Bangalore

EXCIPIENTS

Dicalcium Phosphate M/S Eros Pvt Ltd, Bangalore


Mannitol M/S Eros Pvt Ltd, Bangalore


Avicel PH 200 M/S Eros Pvt Ltd, Bangalore


Aspartame Dr.Reddy’s labs, Hyderabad.

L-HPC Dr.Reddy’s labs, Hyderabad

Emcompress M/S Eros Pvt Ltd, Bangalore

Crospovidone M/S Eros Pvt Ltd, Bangalore


Croscarmellose sodium M/S Eros Pvt Ltd, Bangalore


Sodium starch glycolate M/S Eros Pvt Ltd, Bangalore


38

Methodology


Pregelatinized starch M/S KAPL Ltd, Bangalore

Magnesium stearate M/S Eros Pvt Ltd, Bangalore


Talc M/S Eros Pvt Ltd, Bangalore


INSTRUMENTS

Analytical balance National scientific works, Varanasi

Tablet punching machine Rimek RSB-4, minipress, Karnavati

(10 station) Engineering, Ahmedabad.

UV Visible spectrophotometer Elico UV-VIS Spectrophotometer

SL-159.

Monsanto hardness tester Praveen enterprises, Bangalore.

Friability testing apparatus Indian equipment corporation, Mumbai

Ovens Elite

Disintegration test apparatus Scientific

Dissolution test apparatus USP type 2

FT-IR spectrophotometer Shimadzu FT-IR 8400

TLC chamber Lab model


39

Methodology

PRE-FORMULATION STUDIES

METOCLOPRAMIDE HYDROCHLORIDE BP, IP, USP.23, 29, 30

PHYSICOCHEMICAL PROPERTIES

Structure:

Chemical name: 4-amino-5-chloro-N- (2-diethylaminoethyl)-2-

methoxybenzamide hydrochloride monohydrate.

Molecular Formula: C14H22Cl N3O2, HCl, H2O.

Molecular Weight: 354.3

Category: Anti-emetic.

Definition: Metoclopramide Hydrochloride contains not less

than 99.0% and not more than 101% of

C14H22Cl N3O2, HCl, H2O calculated with

reference to the anhydrous substance

Department of Pharmaceutics, GCP, Bangalore-27.

40

Methodology

Description: White or almost white crystals or crystalline

powder.

Solubility: Very soluble in water: freely soluble in ethanol

(95%); sparingly soluble in dichloromethane;

practically insoluble in ether.

Identification: a) Infra red absorption spectrometry.

b) UV spectroscopy

c) Thin Layer Chromatography.

Heavy metals: Not more than 20ppm.

Sulphated ash: Not more than 0.1%.

Storage: Store in well-closed, light resistant containers.

Assay: Tablet triturate equivalent to 250mg of

Metoclopramide Hydrochloride is dissolved in a

mixture of 50ml of ethanol and 5.0ml of 0.01M

Hydrochloric acid and titrated against 0.1M Sodium

hydroxide. The end point is determined

potentiometrically.

Each ml of 0.1M Sodium hydroxide is equivalent to

0.03363g of C14H22Cl N3O2, HCl, H2O.


41

Methodology

Figure 1: IR spectrum of Metoclopramide Hydrochloride.


42

Methodology

Figure 2: UV spectrum of Metoclopramide Hydrochloride in pH 1.2 buffer.

G.C.P

Mode : Spectrum Starting WL : 200.0nm Ending WL : 400.0nm Number of peaks detected: 3

0.402

Analyst: Sreenivasa Reddy N Date: 2/6/04 Sample: Metoclopramide Hydrochloride in 0.1 N HCL (pH1.2 buffer) Reference: Simulated gastric fluid (pH1.2 buffer) Concentration: 10mcg/ml Wavelength: 273.0 nm Absorbance: 0.402


43

Methodology

STANDARD GRAPH FOR METOCLOPRAMIDE HYDROCHLORIDE

Preparation of Simulated gastric fluid (pH 1.2 Buffer)

8.5ml concentrated hydrochloric acid and 0.8gm of sodium chloride were

dissolved in 1000ml of distilled water.

Instrument

Elico UV-Visible Spectrophotometer SL159.

Principle

Metoclopramide Hydrochloride showed maximum absorbance at 273 nm in 0.1N

Hydrochloric acid and obeyed Beer’s law at the concentration range between 2-25

mcg/ml.

Procedure

Stock solution

Weighed quantity of Metoclopramide Hydrochloride (100mg) was dissolved in

pH 1.2 buffer and the volume made up to 100ml with the same.

S.S I ⇒ 1000 mcg/ml.

10ml of Stock solution I was further diluted with 100ml of pH 1.2 buffer to get a working

standard S.S I ⇒ 100mcg/ml

Aliquots of 1.0, 3.0, 5.0, 7.0, 9.0,and 11.0ml of stock solution was pipetted into

50ml volumetric flask and the volume was made upto 50ml with pH 1.2 buffer. The

absorbance was measured at 273 nm against reagent blank (pH 1.2 buffer).


44

Methodology

Table 1: Calibration curve of Metoclopramide Hydrochloride in pH 1.2 buffer

Absorbance at 273nm Vol. of

SSII (ml)

Vol. made

Upto (ml)

Conc.

(mcg/ml) Trial I Trial II Trial III Avg. SEM

1.0 50 2 0.089 0.088 0.087 0.088 0.0006

3.0 50 6 0.241 0.241 0.239 0.240 0.0007

5.0 50 10 0.391 0.39 0.395 0.392 0.0015

7.0 50 14 0.549 0.547 0.549 0.548 0.0007

9.0 50 18 0.702 0.700 0.700 0.701 0.0007

11.0 50 22 0.856 0.855 0.857 0.856 0.0006

Figure 3:

Standard Curve of Metoclopramide Hydrochloride (pH 1.2 Buffer).

y = 0.0387x + 0.0063R2 = 0.9999

00.1

0.20.3

0.40.5

0.60.7

0.80.9

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Conc.(mcg/ml)

Abs

orba

nce


45

Methodology

COMPATIBILITY STUDIES

The proper design and formulation of a dosage form requires consideration of the

physical, chemical and biological characteristics of all drug substances and excipients to

be used in the fabricating the product. The drug and excipients must be compatible with

one another to produce a product that is stable, efficacious, attractive, and easy to

administer and safe.

If the excipients are new and not been used in formulations containing the active

substance, the compatibility studies are of paramount importance.

Figure 4: Schematic representation of Drug- Excipient compatibility studies

Drug

M eTLC

Excipients

No Interaction

Method

Drug and excipients

samples were analysed

and seven weeks as pe

Department of Pharm

1:1 ixtur

Interacti

in 1:1 ratio were mixed and stored in glass vi

for compatibility by Thin Layer Chromatograph

r the method described below.

aceutics, GCP, Bangalore-27.

Recommendexcipients

on
Alternative Excipients?
als at 500C. The

y after one, three

46

Methodology

Stationary phase: Thin plate of Silica gel G having thickness of 0.25cm.

The plates were activated at 1050C for 30min prior to

use.

Mobile phase: Benzene: Methanol: Ammonia (75:25:0.25)

Separation technique: Ascending

Reference solution: 5mg of Metoclopramide hydrochloride was shaken with

5ml of methanol, decanted and used for spotting

Test solution: Drug-Excipient mixture equivalent to 5mg of

Metoclopramide HCl was shaken with 5ml of methanol,

decanted and used for spotting

Procedure: - 10µl of reference and test solutions were applied as spots on the dry

activated plate. The solvent system was allowed to run upto a desired height; the plates

were removed and allowed to dry. The dry plates were then exposed to iodine vapors in a

chamber to observe the spots. The plates ere then removed and the Rf values calculated.

Rf = Distance of the solute from the starting point Distance of the solvent from the starting point


47

Methodology

Table 2: Drug- Excipient compatibility – Rf values.

Spot No. Sample Rf values

A Drug 0.44

B Drug + Avicel PH 200 0.44

C Drug + Dibasic Calcium Phosphate 0.44

D Drug + Mannitol DC 0.44

E Drug + L-HPC 0.44

F Drug + Crospovidone 0.44

G Drug + Croscarmellose Sodium 0.44

H Drug + Sodium Starch Glycolate 0.44

I Drug + Pregelatinized starch 0.44

J Drug + Aspartame 0.44

K Drug + Magnesium stearate 0.44

L Drug + Talc 0.44


48

Methodology

Figure 5: TLC profile of compatibility studies after 7 weeks.

A G H I J K L

A Drug

B Drug + Avicel PH 200

C Drug + Dibasic Calcium Phosphate

D Drug + Mannitol DC

E Drug + L-HPC

F Drug + Crospovidone

G Drug + Croscarmellose Sodium

H Drug + Sodium Starch Glycolate

I Drug + Pregelatinized starch

J Drug + Aspartame

K Drug + Magnesium stearate

L Drug + Talc


49

Methodology

FORMULATION OF TABLETS

DIRECT COMPRESSION METHOD

The tablets were formulated employing direct compression method using 8mm

flat-faced punches. It is the process by which tablets are compressed directly from

mixtures of the drug and excipients without preliminary treatment such as granulation.

The steps involved are as follows:

Drug

Filler

Disintegrant

Sweetening agent Blending Compression

Lubricant

Glidant

Experimental Design

Factorial design is an experimental design technique, by which the factor involved and

their relative importance can be assessed. In the present study, the runs or formulations,

which are designed based on 32 full factorial design containing 2 factors evaluated at

three levels and the experimental trials were, performed at all possible combinations.


50

Methodology

The two independent formulation variables evaluated include:

Factor A: Amount of SSG in milligram (X1) (5, 12.5, 20)

Factor B: Amount of CPVP in milligram (X2). (5, 8.75, 12.5)

32 full factorial design was considered, according to the model totally 11

experiments were conducted with three replicates of center point.

Table 3: Actual and coded values of the factors

Model Actual values Coded values

Factor Low level Mid level High level low mid High

Factor -A 5 12.5 20 -1 0 +1

Factor-B 5 8.75 12.5 -1 0 +1

The coded levels are calculated using the following formula:

X - The average of the two levels

Level = Half the difference of the level


51

Methodology

Table 4: Runs Designed In Actual and Coded Values

Coded values Actual values Runs Type

Factor A Factor B Factor A Factor B

1 CentEdge 0 1 12.50 12.50

2 Center 0 0 12.50 8.75

3 Fact -1 1 5.00 12.50

4 CentEdge -1 0 5.00 8.75

5 Fact -1 -1 5.00 5.00

6 CentEdge 1 0 20.00 8.75

7 Fact 1 1 20.00 12.50

8 Fact 1 -1 20.00 5.00

9 Center 0 0 12.50 8.75

10 Center 0 0 12.50 8.75

11 CentEdge 0 -1 12.50 5.00


52

Table 5: Dibasic Calcium Phosphate based tablet formulations.

*INGREDIENTS D1 D 2 D 3 D 4 D 5 D 6 D 7 D 8 D 9 D10 D11 D12

Metoclopramide HCl 10 10 10 10 10 10 10 10 10 10 10 10

Calcium phosphate dibasic 190.5 188.0 185.5 190.5 188.0 185.5 190.5 188.0 185.5 185.5 183.0 180.5

Cross Povidone 5 7.5 10 - - - - - - - - -

Croscarmellose Sodium - - - 5 7.5 10 - - - - - -

L-HPC - - - - - - 5 7.5 10 - - -

Sodium Starch Glycolate - - - - - - - - - 10 12.5 15

Pregelatinized Starch 31.5 31.5 31.5 31.5 31.5 31.5 31.5 31.5 31.5 31.5 31.5 31.5

Aspartame 5 5 5 5 5 5 5 5 5 5 5 5

Magnesium Stearate 4 4 4 4 4 4 4 4 4 4 4 4

Talc 4 4 4 4 4 4 4 4 4 4 4 4

TOTAL 250 250 250 250 250 250 250 250 250 250 250 250

*All the quantities expressed are in mg / tablet

.

53

Table 6: Mannitol based tablet formulations.

*INGREDIENTS M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12


Mannitol 190.5 188 185.5 190.5 188 185.5 190.5 188 185.5 185.5 183. 180.5

Cross Povidone 5 7.5 10 - - - - - - - - -


L-HPC - - - - - - 5 7.5 10 - - -



Aspartame 5 5 5 5 5 5 5 5 5 5 5 5


Talc 4 4 4 4 4 4 4 4 4 4 4 4

TOTAL 250 250 250 250 250 250 250 250 250 250 250 250

*All the quantities expressed are in mg / tablet.

54

Table 7: Avicel PH200 based tablet formulations.

*INGREDIENTS A1 A2 A3 A4 A5 A6 A7 A8 A9 A10 A11 A12


Avicel PH200 190.5 188 185.5 190.5 188 185.5 190.5 188 185.5 185.5 183. 180.5

Cross Povidone 5 7.5 10 - - - - - - - - -


L-HPC - - - - - - 5 7.5 10 - - -



Aspartame 5 5 5 5 5 5 5 5 5 5 5 5


Talc 4 4 4 4 4 4 4 4 4 4 4 4

TOTAL 250 250 250 250 250 250 250 250 250 250 250 250

*All the quantities expressed are in mg / table.

55

Table 8: Runs as per DOE using Avicel PH 200 as diluent.

*INGREDIENTS R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11

Metoclopramide HCl 10 10 10 10 10 10 10 10 10 10 10

Avicel PH200 178 185.5 174.25 178 163 166.75 174.25 170.5 174.25 181.75 170.5

Cross Povidone 5 5 8.75 12.5 12.5 8.75 8.75 12.5 8.75 8.75 5

Sodium Starch Glycolate 12.5 5 12.5 5 20 20 12.5 12.5 12.5 5 20

Pregelatinized Starch 31.5 31.5 31.5 31.5 31.5 31.5 31.5 31.5 31.5 31.5 31.5

Aspartame 5 5 5 5 5 5 5 5 5 5 5

Magnesium Stearate 4 4 4 4 4 4 4 4 4 4 4

Talc 4 4 4 4 4 4 4 4 4 4 4

TOTAL 250 250 250 250 250 250 250 250 250 250 250


56

Methodology

EVALUATION PARAMETERS

Precompression Parameters

1. Bulk Density (Db):

It is the ratio of total mass of powder to the bulk volume of powder. It was

measured by pouring the weighed powder into a measuring cylinder and the volume

was noted. It is expressed in gm/ml and is given by

Where, M is the

mass of powder 0

b VMD =

V0 is the Bulk volume of the powder.

2. Tapped Density (Dt):

It is the ratio of total mass of powder to the tapped volume of powder. The tapped

volume was measured by tapping the powder to constant volume. It is expressed in

gm/ml and is given by

Where, M is the mass of powder

tt V

MD =

Vt is the tapped volume of the powder.


57

Methodology

3. Angle of Repose:

The frictional forces in a loose powder can be measured by the angle of repose, θ.

This is the maximum angle possible between the surface of a pile of powder and the

horizontal plane.

tan θ = h / r

θ = tan-1 (h / r)

Where, θ is the angle of repose

h is the height in cms

r is the radius.

The powder mixture was allowed to flow through the funnel fixed to a stand at

definite height. The angle of repose was then calculated by measuring the height and

radius of the heap of powder formed.

4. Carr’s Index (I):

It indicates the ease with which a material can be induced to flow. It is expressed

in percentage and is given by

100

DDDI

t

bt ×−

=

Where, Dt is the tapped density of the powder.

Db is the bulk density of the powder.


58

Methodology

Table 9: Carr’s index values

Carr’s index (%) Type of flow

5 – 15 Excellent

12 – 18 Good

18 – 23 Fair to passable

23 – 35 Poor

35 – 38 Very poor

> 40 Extremely poor

Post compression Parameters

5. Hardness:

The hardness of the tablet was determined using a Monsanto hardness tester. It is

expressed in Kg / cm2.

6. Friability (F):

The friability of the tablet was determined using Roche Friabilator. It is expressed

in percentage (%). 10 tablets were initially weighed (Winitial) and transferred into the

friabilator. The friabilator was operated at 25 rpm for four mins. The tablets were

weighed again (Wfinal). The percentage friability was then calculated by:


59

Methodology

100W

WWFinitial

finalinitial ×−

=

7. Weight Variation:

Ten tablets were selected randomly from the lot and weighed individually to

check for weight variation. IP limit for weight variation in case of tablets weighing

upto 250mg is ± 7.5%

8. Thickness:

The thickness of the tablets was measured by screw gauge. It is expressed in mm.

9. Disintegration Time:

The Invitro disintegration time was determined using disintegration test apparatus.

A tablet was placed in each of the six tubes of the apparatus and one disc was added

to each tube. The time in seconds taken for complete disintegration of the tablet with

no palpable mass remaining in the apparatus was measured in seconds.

10. Disintegration time in oral cavity:

The disintegration time in the oral cavity of human volunteers was measured by

placing the tablet on the tongue until no lumps remain. It is expressed in seconds.


60

Methodology

11. Wetting Time:

A piece of tissue paper folded twice was placed in a small petri plate (internal

diameter = 6.5 cm) containing 10ml of water. A tablet was placed on the paper, and

the time for complete wetting of the tablet was measured in seconds. The method was

slightly modified by maintaining water at 37o C (Photograph in next page)

12. Assay:

10 tablets were weighed and triturated. The tablet triturate equivalent to 10 mg of

the drug was weighed accurately, dissolved in pH 1.2 buffer and diluted to 100 ml

with the same. Further dilutions were done suitably to get a concentration of 10 mcg /

ml with simulated gastric fluid pH 1.2. Absorbance was read at 273 nm against the

reagent blank, and the concentrations of Metoclopramide hydrochloride in mcg / ml

was determined by using the regression equation.

Y = 0.0387x + 0.0063

Drug content in mg / tablet = conc. mcg / ml * dilution factor

% Drug content = drug content in mg * 100 / label claim.


61

Methodology

13. Invitro dissolution studies:

The Invitro dissolution study was carried out in USP dissolution test apparatus type 2

(paddle)

Dissolution Medium : 900ml of simulated gastric fluid

Temperature : 37 ± 0.5 o C

RPM : 50

Tablets taken : 2 tablets were weighed & taken for study

Volume withdrawn & replaced : 5 ml every five minutes.

λ max : 273 nm

Beer’s range : 2 –25 mcg /ml.

14. Optimization

The runs or formulations, which are designed based on 32 full factorial designs, are

evaluated for the response variables. The response values are subjected to multiple

regression analysis to find out the relationship between the factors used and the response

values obtained. The response values subjected for this analysis are;

1. Wetting time (WT) in seconds.

2. Disintegration time (DT) in seconds.


62

Methodology

The Wetting time and Disintegration time were chosen for analysis of the following

relationship:

1. To study the effect of amount of SSG

2. To study the effect of amount of CPVP.

3. To study the combined effect of SSG and CPVP.

STATISTICAL ANALYSIS

The effect of formulation variables on the response variables were statically evaluated by

applying one-way ANOVA at 0.05 level using a commercially available software

package Design of Experiments® 6.05 (Stat Ease, USA). The design was evaluated by

quadratic model, which bears the form of equation (1).

Y= b0 + b1 X1+ b2 X2 + b3 X1 X2 + b4 X12 + b5 X2 2 eq-1

Where y is the response variable, b0 the constant and b1, b2, b3…b5 is the regression

coefficient. X1 and X2 stand for the main effect; X1X2 are the interaction terms, show

how response changes when two factors are simultaneously changed. X12, X2

2 are

quadratic terms of the independent variables to evaluate the nonlinearity. The results of

this analysis are presented in the table.

Using the regression coefficient of the factors, the polynomial equation for the response

is constructed. Only significantly, contributing factors are considered for the equation

generation.


63

Methodology

Desirability Details

The method makes use of an objective function, D (X), called the desirability function. It

reflects the desirable ranges for each response (di). The desirable ranges are from zero to

one (least to most desirable respectively). The simultaneous objective function is a

geometric mean of all transformed responses:

If any of the responses or factors falls outside their desirability range, the overall function

becomes zero. For simultaneous optimization each response must have a low and high

value assigned to each goal.

Maximum:

di = 0 if response < low value

0 < di < 1 as response varies from low to high

di = 1 if response > high value

Minimum:


1 <di < 0 as response varies from low to high


Target:


0 < di < 1 as response varies from low to target

1 < di < 0 as response varies from target to high


Range:



64

Methodology

di = 1 as response varies from low to high


STABILITY STUDIES

INTRODUCTION

In any rational design and evaluation of dosage forms for drugs, the stability of

the active component must be a major criterion in determining their acceptance or

rejection.

Stability of a drug can be defined as the ability of a particular formulation, in a

specific container, to remain within its physical, chemical, therapeutic and toxicological

specifications.

Or

Stability of a drug can be defined as the time from the date of manufacture and the

packaging of the formulation, until its chemical or biological activity is not less than a

predetermined level of labeled potency and its physical characteristics have not changed

appreciably or deleteriously.


65

Methodology

4.6.2 OBJECTIVE OF THE STUDY

The purpose of stability testing is to provide evidence on how the quality of a

drug substance or drug product varies with time under the influence of a variety of

environmental factors such as temperature, humidity and light, enabling recommended

storage conditions, re-test periods and shelf-lives.

Generally, the observation of the rate at which the product degrades under normal

room temperature requires a long time. To avoid this undesirable delay, the principles of

accelerated stability studies are adopted.

The International Conference on Harmonization (ICH) Guidelines titled

“stability testing of New Drug substance and products” (QIA) describes the stability test

requirements for drug registration applications in the European Union, Japan and the

United States of America.

ICH specifies the length of study and storage conditions.

Long-Term Testing: 250 C ± 20 C / 60% RH ± 5% for 12 Months

Accelerated Testing: 400 C ± 20 C / 75% RH ± 5% for 6 Months

Stability studies were carried out at 250 C / 60% RH and 400 C / 75% RH for the

optimized formulation for 2 months.

Method

The selected formulations were packed in amber-colored bottles, which were

tightly plugged with cotton and capped. They were then stored at 250 C / 60% RH and

400 C / 75% RH for 2 months and evaluated for their physical appearance, drug content

and drug excipient compatibility at specified intervals of time.


66

RESULTS

Table 10: Pre-compression parameters of Dibasic Calcium Phosphate formulations

PARAMETERS D1 D 2 D 3 D 4 D 5 D 6 D 7 D 8 D 9 D10 D11 D12

Bulk Density (g/cc) 0.79 0.83 0.84 0.88 0.72 0.8 0.85 0.79 0.76 0.73 0.83 0.88Tapped Density (g /cc) 0.65 0.68 0.69 0.71 0.61 0.67 0.69 0.62 0.59 0.58 0.69 0.71

Angle of Repose (θ) 32.4 35.3 33.2 37.3 36.5 33.5 36.3 32.5 33.0 34.0 33.4 33.8Carr’s Index (%) 17.722 18.07 17.86 19.32 15.28 16.25 18.82 21.52 22.37 20.55 16.87 19.32

Table 11: Post compression parameters of Dibasic Calcium Phosphate formulations.


Hardness (kg / cm2) 3.5 4.0 3.5 4.0 3.5 4.0 4.0 3.5 4.0 3.8 3.5 3.8Friability (%) 0.21 0.23 0.19 0.19 0.18 0.21 0.20 0.18 0.16 0.19 0.23 0.25

Thickness (mm) 3.07 2.98 2.79 2.81 2.79 2.90 3.01 2.96 9.90 2.88 2.93 2.96Drug content (%) 95.65 96.68 98.47 98.98 99.74 100.26 97.95 96.68 97.44 96.48 98.98 97.44Weight Variation 239 mg to 253 mg (IP limit: 231.25 mg to 268.75 mg)

67

Table No. 12 Comparison between Disintegration Time, Disintegration time in Oral cavity, and Wetting time.


Average* 35.67 32.00 30.67 55.00 49.00 46.00 59.67 58.00 54.87 45.00 43.00 37.00DT in oral

cavity in (sec)

SEM n = 3 0.333 0.577 0.667 0.577 0.577 1.155 0.882 0.577 0.333 0.577 0.577 0.577

Average* 35.67 34.00 25.00 48.00 43.00 41.00 59.00 51.00 47.67 46.00 43.33 40.67Wetting time (sec) SEM

n = 3 0.333 0.577 0.577 0.577 0.577 0.577 0.577 0.577 0.333 1.528 0.882 0.333

Average* 39.67 35.33 29.00 65.00 52.00 54.0 77.00 45.00 37.00 50.00 45.67 40.67DT in (sec) SEM

n = 3 0.882 0.667 0.577 0.577 0.577 0.577 0.577 0.577 1.528 0.577 0.333 0.333

*Average of 3 trials

68

0

20

40

60

80

100

D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11 D12

Dis

inte

grat

ion

Tim

e (s

ec)

In Vitro DT Wetting Time DT in Oral Cavity

Figure 6: DISINTEGRATION PROFILE OF DCP FORMULATIONS

69

Results

Department of Pharmaceutics, GCP, B’lore-27 .66

Results

In Vitro Release rate profile of Dibasic Calcium Phosphate formulations in simulated gastric fluid (pH 1.2) after 5 and 20 mins

Table No. 13

Formulations Absorbance Conc. (mcg /ml)

Conc. (mg / 5ml)

Conc. (mg/900ml) CLA CDR

%CDR after 5

mins D1 0.370 9.525 0.048 8.573 0 8.573 89.581 D2 0.361 9.284 0.046 8.356 0 8.356 86.409 D3 0.348 8.936 0.045 8.042 0 8.042 81.646 D4 0.373 9.606 0.048 8.645 0 8.645 87.326 D5 0.370 9.525 0.048 8.573 0 8.573 85.987 D6 0.368 9.472 0.047 8.525 0 8.525 84.992 D7 0.370 9.525 0.048 8.573 0 8.573 87.568 D8 0.370 9.525 0.048 8.573 0 8.573 88.655 D9 0.367 9.445 0.047 8.501 0 8.501 87.274 D10 0.370 9.525 0.048 8.573 0 8.573 88.931 D11 0.373 9.606 0.048 8.645 0 8.645 87.326 D12 0.399 10.303 0.052 9.273 0.0946 9.367 94.619

Table No. 14


Conc. (mg / 5ml)


%CDR after 20

mins D1 0.399 10.303 0.052 9.273 0.0946 9.367 97.881 D2 0.402 10.383 0.052 9.345 0.0966 9.442 97.638 D3 0.412 10.651 0.053 9.586 0.0927 9.679 98.264 D4 0.409 10.571 0.053 9.514 0.0975 9.611 97.086 D5 0.399 10.303 0.052 9.273 0.0946 9.367 93.954 D6 0.401 10.357 0.052 9.321 0.0943 9.415 93.871 D7 0.399 10.303 0.052 9.273 0.0946 9.367 95.682 D8 0.393 10.142 0.051 9.128 0.0946 9.222 95.372 D9 0.399 10.303 0.052 9.273 0.0946 9.367 96.173 D10 0.393 10.142 0.051 9.128 0.0942 9.222 94.682 D11 0.396 10.223 0.051 9.200 0.0950 9.295 93.891 D12 0.396 10.223 0.051 9.200 0.0946 9.295 95.430

Department of Pharmaceutics, GCP, B’lore-27. 70

Results

Figure 7: Dissolution Profile of Dicalcium Phosphate Formulations in Simulated Gastric Fluid (pH 1.2) after 5 and 20 minutes.

0

20

40

60

80

100

120

D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11 D12

%C

DR

After 5mins After 20 mins


Table 15: Pre-compression parameters of Mannitol formulations

72

PARAMETERS M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12



Table 16: Post compression parameters of Mannitol formulations


Hardness (Kg / cm2) 2.8 3.0 2.8 3.0 2.8 2.8 3.2 3.0 3.0 2.8 3.0 3.2Friability (%) 0.59 0.40 0.64 0.58 0.52 0.63 0.56 0.58 0.60 0.65 0.57 0.58

Thickness (mm) 4.14 4.01 4.02 4.01 4.05 4.08 4.11 4.10 4.15 4.02 4.15 4.10Drug content (mg) 97.95 100.51 98.47 98.78 97.19 96.68 95.65 98.88 96.68 94.38 95.91 96.16 Weight Variation 239 mg to 253 mg (IP limit: 231.25 mg to 268.75 mg)

Table No. 17 Comparison between Disintegration Time, Disintegration time in Oral cavity, and Wetting time.

73



cavity in (sec)

SEM n = 3 0.333 0.333 0.333 0.333 0.577 0.577 0.577 0.577 0.577 0.333 0.333 0.333


n = 3 0.577 0.667 0.000 0.333 0.000 0.333 0.000 0.333 0.667 0.667 0.333 0.333


n = 3 0.882 1.764 2.186 0.882 0.667 0.000 0.667 0.333 0.667 1.155 0.882 0.333

* Average of 3 trials

0

20

40

60

80

100

M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12

Dis

inte

grat

ion

Tim

e (s

ec)

In Vitro DT Wetting Time DT in Oral Cavity

Figure 8: DISINTEGRATION PROFILE OF MANNITOL FORMULATIONS

74

Results


Results

In Vitro Release rate profile of Mannitol formulations in simulated gastric fluid (pH 1.2) after 5 and 20 mins

Table No. 18


Conc. (mg / 5ml)


%CDR after 5

mins M1 0.38 9.794 0.049 8.814 0 8.814 90.033 M2 0.361 9.284 0.046 8.356 0 8.356 83.142 M3 0.362 9.311 0.047 8.380 0 8.380 84.903 M4 0.376 9.686 0.048 8.718 0 8.718 88.325 M5 0.374 9.633 0.048 8.669 0 8.669 89.284 M6 0.371 9.552 0.048 8.597 0 8.597 88.996 M7 0.385 9.928 0.050 8.935 0 8.935 90.709 M8 0.361 9.284 0.046 8.356 0 8.356 83.558 M9 0.365 9.391 0.047 8.452 0 8.452 84.948 M10 0.378 9.740 0.049 8.766 0 8.766 88.545 M11 0.374 9.633 0.048 8.669 0 8.669 88.015 M12 0.369 9.499 0.047 8.549 0 8.549 87.680

Table No. 19


Conc. (mg / 5ml)


%CDR after 20

mins M1 0.401 10.357 0.052 9.321 0.1001 9.421 96.231 M2 0.418 10.812 0.054 9.731 0.0975 9.829 97.797 M3 0.408 10.544 0.053 9.490 0.0967 9.587 97.128 M4 0.414 10.705 0.054 9.635 0.0998 9.734 98.626 M5 0.409 10.571 0.053 9.514 0.0979 9.612 98.989 M6 0.399 10.303 0.052 9.273 0.0973 9.370 96.997 M7 0.407 10.517 0.053 9.466 0.1008 9.566 97.121 M8 0.42 10.866 0.054 9.779 0.0975 9.877 98.769 M9 0.414 10.705 0.054 9.635 0.0971 9.732 97.806 M10 0.415 10.732 0.054 9.659 0.1001 9.759 98.574 M11 0.409 10.571 0.053 9.514 0.0979 9.612 97.583 M12 0.407 10.517 0.053 9.466 0.0970 9.563 98.079


Results

Figure 9: Dissolution Profile of Mannitol Formulations in Simulated Gastric Fluid (pH 1.2) after 5 and 20 minutes.

75

80

85

90

95

100

105

M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12

%C

DR

After 5 mins After 20 mins


Table 20: Pre-compression parameters of Avicel formulations

PARAMETERS A1 A2 A3 A4 A5 A6 A7 A8 A9 A10 A11 A12



Table 21: Post compression parameters of Avicel formulations.


Hardness (Kg / cm2) 3.0 3.2 3.2 3.2 2.8 3.2 3.1 3.0 2.8 2.8 3.0 3.2Friability (%) 0.49 0.51 0.59 0.39 0.48 0.41 0.51 0.48 0.49 0.52 0.48 0.50

Thickness (mm) 2.30 2.15 2.18 2.20 2.19 2.21 2.31 2.22 2.24 2.23 2.32 2.40Drug content (%) 96.93 95.91 94.37 97.44 97.95 95.91 97.44 96.93 96.16 99.49 95.91 96.93Weight Variation 239 mg to 253 mg (IP limit: 231.25 mg to 268.75 mg)

77

Table 22: Comparison between Disintegration Time, Disintegration time in Oral cavity, and Wetting time.



cavity in (sec)

SEM n = 3 0.333 0.577 1.155 0.577 0.667 0.577 0.577 0.577 0.333 0.667 0.333 0.333


n = 3 0.333 0.333 0.667 0.667 0.333 0.333 0.667 0.333 0.33 0.333 0.333 0.667


n = 3 0.577 0.333 0.577 0.333 0.333 0.667 0.333 0.577 0.333 0.667 0.333 0.667

78

0

10

20

30

40

50

60

A1 A2 A3 A4 A5 A6 A7 A8 A9 A10 A11 A12

Dis

inte

grat

ion

Tim

e(se

c)

DT WT DTO

Figure 10: DISINTEGRATION PROFILE OF AVICEL PH 200 FORMULATIONS

79

Results


Results

In Vitro Release rate profile of Avicel PH 200 formulations in simulated gastric fluid (pH 1.2) after 5 and 20 mins

Table 23:


Conc. (mg / 5ml)


%CDR after 5

mins A1 0.385 9.928 0.050 8.935 0 8.935 92.21 A2 0.368 9.472 0.047 8.525 0 8.525 88.89 A3 0.370 9.525 0.048 8.573 0 8.573 90.81 A4 0.365 9.391 0.047 8.452 0 8.452 86.78 A5 0.361 9.284 0.046 8.356 0 8.356 85.35 A6 0.355 9.123 0.046 8.211 0 8.211 85.62 A7 0.369 9.499 0.047 8.549 0 8.549 87.77 A8 0.365 9.391 0.047 8.452 0 8.452 87.23 A9 0.364 9.365 0.047 8.428 0 8.428 87.61 A10 0.374 9.633 0.048 8.669 0 8.669 87.13 A11 0.366 9.418 0.047 8.476 0 8.476 88.39 A12 0.355 9.123 0.046 8.211 0 8.211 84.74

Table 24:


Conc. (mg / 5ml)


%CDR after 20

mins A1 0.410 10.598 0.053 9.538 0.1001 9.638 99.46 A2 0.398 10.276 0.051 9.249 0.0970 9.346 97.45 A3 0.395 10.196 0.051 9.176 0.0967 9.273 98.23 A4 0.405 10.464 0.052 9.417 0.0974 9.515 97.69 A5 0.411 10.625 0.053 9.562 0.0974 9.660 98.67 A6 0.402 10.383 0.052 9.345 0.0958 9.441 98.44 A7 0.408 10.544 0.053 9.490 0.0970 9.587 98.43 A8 0.405 10.464 0.052 9.417 0.0965 9.514 98.18 A9 0.402 10.383 0.052 9.345 0.0959 9.441 98.14 A10 0.415 10.732 0.054 9.659 0.0986 9.757 98.06 A11 0.411 10.625 0.053 9.562 0.0981 9.660 100.73 A12 0.408 10.544 0.053 9.490 0.0958 9.586 98.92


Results

Figure 11: Dissolution Profile of Avicel PH 200 Formulations in Simulated Gastric Fluid (pH 1.2) After 5 and 20mins

75

80

85

90

95

100

105

A1 A2 A3 A4 A5 A6 A7 A8 A9 A10 A11 A12

%C

DR



Results

OPTIMIZATION

The runs or formulations, which are designed based on central composite design,

are evaluated for the response. The response values are subjected to multiple regression

analysis to find out the relationship between the factors used and the response values

obtained. The response values subjected for this analysis are;

1. Wetting time in seconds.

2. Disintegration time in seconds.

The duration of Wetting time and Disintegration time were chosen for the analysis

of the following relationship:

1. To study the effect of amount of SSG

2. To study the effect of amount of CPVP.

3. To study the combined effect of SSG and CPVP

The multiple regression analysis was done using design expert 6.05 (STAT-

EASE) software, which is specially meant for this optimization process. The results of

this analysis are presented in the table 31.

Using the regression coefficient of the factors, the polynomial equation for the response

is constructed. Only significantly, contributing factors are considered for the equation

generation.


82

Results

Table 25 : Design and Summary Response Data

Run TYPE SSG CPVP WT DT

1 CentEdge 12.50 12.50 45 20

2 Center 12.50 8.75 40 15

3 Fact 5.00 12.50 17 19

4 CentEdge 5.00 8.75 31 19

5 Fact 5.00 5.00 28 18

6 CentEdge 20.00 8.75 37 14

7 Fact 20.00 12.50 50 28

8 Fact 20.00 5.00 38 23

9 Center 12.50 8.75 37 14

10 Center 12.50 8.75 37 13

11 CentEdge 12.50 5.00 20 19

SSG: Sodium Starch Glycolate CPVP: Crospovidone


83

Results

Response: WT Table 26: ANOVA for Response Surface Cubic Model

Source Sum of Squares DF Mean Square F Value Prob >F Model 962.48 7 137.50 20.37 0.0156

A 18.00 1 18.00 2.67 0.2010 B 312.50 1 312.50 46.30 0.0065 A2 5.70 1 5.70 0.84 0.4259 B2 22.80 1 22.80 3.38 0.1634 AB 132.25 1 132.25 19.59 0.0214 A2B 200.08 1 200.08 29.64 0.0122 AB2 80.08 1 80.08 11.86 0.0411

Residual 20.25 3 6.75 - - Lack of fit 14.25 1 14.25 4.75 0.1611

Pure 6.00 2 3.00 - - Cor Total 982.73 10 - - -

Table 27: Estimated Regression Coefficient

Factor Coefficient Estimate DF Intercept 37.00 1 A- SSG 3.00 1

B- CPVP 12.50 1 A2 -1.50 1 B2 -3.00 1 AB 5.75 1 A2B -12.25 1 AB2 7.75 1

Final Equation in Terms of Coded Factors: W = +37.00 +3.00 * A +12.50* B-1.50* A2 -3.00 * B2 +5.75* A * B -12.25* A2 * B +7.75 * A * B2


84

Results

Figure12: Perturbation plot showing effect of Concentration of SSG on wetting time.

DESIGN-EXPERT Plot

WT

X = A: SSG

Design Points

Actual FactorB: Cpvp = 8.75

5.00 8.75 12.50 16.25 20.00

17

25.25

33.5

41.75

50

A: SSG

WT

One Factor PlotWarning! Factor involved in an interaction.

22

Figure 13: Perturbation plot showing effect of Concentration of CPVP on wetting time.

DESIGN-EXPERT Plot

WT

X = B: Cpvp

Design Points

Actual FactorA: SSG = 12.50

5.00 6.88 8.75 10.63 12.50

16.1349

25.0674

34

42.9326

51.8651

B: Cpvp

WT


22

Figure 14: 3-D graph showing combined effect of SSG and CPVP on wetting time.

DESIGN-EXPERT Plot

WTX = B: CpvpY = A: SSG

16.25

25.05

33.85

42.65

51.45

W

T

5.00

6.88

8.75

10.63

12.50

5.00

8.75

12.50

16.25

20.00

B: Cpvp A: SSG


85

Results

Response: DT Table 28: ANOVA Response Surface Cubic Model (Aliased)

Source Sum of Squares DF Mean F Value Prob >F Model 194.55 7 27.79 41.69 0.0055

A 12.50 1 12.50 18.75 0.0227 B 0.50 0.75 0.4502 - - A2 15.83 23.75 0.0165 - - B2 76.63 114.95 0.0017 - - AB 4.00 6.00 0.0917 - - A2B 1.33 2.00 0.2522 - - AB2 48.00 72.00 0.0034 - -

Residual 2.00 3 0.67 - - Lack of fit 0.000 1 0.000 0.000 1.0000

Pure 2.00 2 1.00 - - Cor Total 196.55 10 - - -

Table 29:Estimated Regression Coefficients

Factor Coefficient Estimate DF Standard Intercept 14.00 1 0.42 A- SSG -2.50 1 0.58

B- CPVP 0.50 1 0.58 A2 2.50 1 0.51 B2 5.50 1 0.51 AB 1.00 1 0.41 A2B 1.00 1 0.71 AB2 6.00 1 0.71


86

Results

Final Equation in Terms of Coded Factors:

DT =

+14.00

-2.50 * A

+0.50 * B

+2.50 * A2

+5.50 * B2

+1.00 * A * B

+1.00 * A2 * B

+6.00 * A * B2


87

Results

Figure 15: Perturbation plot showing effect of Concentration of SSG on DT.

DESIGN-EXPERT Plot

DT

X = A: SSG

Design Points

Actual FactorB: Cpvp = 8.75

5.00 8.75 12.50 16.25 20.00

12.3139

16.2354

20.1569

24.0785

28

A: SSG

DT


2

2

2

2

Figure 16: Perturbation plot showing effect of Concentration of CPVP on DT.

DESIGN-EXPERT Plot

DT

X = B: Cpvp

Design Points

Actual FactorA: SSG = 12.50

5.00 6.88 8.75 10.63 12.50

13

16.75

20.5

24.25

28

B: Cpvp

DT


2

2

2

2

Figure 17: 3-D graph showing combined effect of SSG and CPVP on disintegration time

DESIGN-EXPERT Plot

DTX = B: CpvpY = A: SSG

13.335

17.0012

20.6675

24.3338

28

D

T

5.00

6.88

8.75

10.63

12.50

5.00

8.75

12.50

16.25

20.00

B: Cpvp A: SSG


88

Results


89

Using the polynomial equations, the optimized formulations were obtained for the

response parameters. In the trial runs the optimized formulations were arrived using

numerical optimization in design expert 6.05 VERSION.

The data for the formulation variables, the response parameters and the constraints placed

on them are as follows.

Table 30: Optimized formula

Constraints

Upper Name Goal Lower

limit Upper limit

Lower weight

Upper weight

SSG is in range 5 20 1 3 Cpvp is in range 5 12.5 1 3 WT minimize 17 50 1 5 DT minimize 13 28 1 5

Table 31: Predicted solution of optimized formula

Solutions

Number SSG (mg)

CPVP (mg) WT (sec) DT (sec)

Desirability (R2)

1 5.13 12.50 16.9997 18.9582 0.776

Table 32: Pre-compression parameters of runs as per DOE. PARAMETERS R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11

Bulk Density (g/cc) 0.79 0.83 0.84 0.88 0.72 0.8 0.85 0.79 0.76 0.73 0.83Tapped Density (g /cc) 0.65 0.68 0.69 0.71 0.61 0.67 0.69 0.62 0.59 0.58 0.69

Angle of Repose (θ) 32.2 34.3 32.2 36.3 35.5 34.5 38.3 33.5 31.0 33.0 32.4Carr’s Index (%) 18.72 17.07 18.86 17.32 16.28 18.25 17.82 20.52 21.37 19.55 18.87

Table 33: Post compression parameters of runs as per DOE. .

PARAMETERS R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11

Hardness (Kg / cm2) 3.5 3.5 3.5 3.5 3.5 3.5 3.5 3.4 3.5 3.5 3.4 Friability (%) 0.4 0.32 0.16 0.16 0.16 0.16 0.24 0.32 0.24 0.24 0.32

Thickness (mm) 4.09 4.1 4.08 4.08 4.06 4.11 4.08 4.07 4.12 4.11 4.13Drug content (%) 98.21 100.51 98.98 99.56 99.21 98.91 99.49 99.87 100.01 100.12 98.54 Weight Variation 241 mg to 254 mg (IP limit: 231.25 mg to 268.75 mg)

90

Table 34: Comparison between Disintegration Time, Disintegration time in Oral cavity, and Wetting time.

PARAMETERS R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11

Average* 12.67 27.67 19.67 12.67 16.67 13.33 17.65 19.00 21.00 18.64 18.67DT in oral

cavity in (sec)

SEM n = 3 0.333 0.333 0.333 0.333 0.333 0.667 0.333 0.577 0.000 0.333 0.333

Average* 36.33 49.00 44.00 38.33 39.33 37.00 27.67 17.33 54.33 19.00 30.67Wetting time (sec) SEM

n = 3 0.667 0.557 0.577 0.667 0.667 0.000 0.333 0.333 0.333 0.577 0.333

Average* 17.67 29.33 25.33 17.33 19.67 16.33 21.67 23.67 26.33 21.67 2.67DT in (sec) SEM

n = 3 0.333 0.667 0.333 0.333 0.333 0.667 0.333 0.333 0.333 0.333 0.333

91

Figure 18: DISINTEGRATION PROFILE OF RUNS AS PER DOE.

0

10

20

30

40

50

60

R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11

Dis

inte

grat

ion

time

( sec

s)

DT WT DTO92

Results


Results

In Vitro Release rate profile of Runs as per DOE in simulated gastric fluid (pH 1.2) after 5 and 20 mins

Table No. 35


Conc. (mg / 5ml)


%CDR after 5

mins R1 0.370 9.525 0.048 8.573 0 8.573 87.30 R2 0.361 9.284 0.046 8.356 0 8.356 83.14 R3 0.367 9.445 0.047 8.501 0 8.501 85.95 R4 0.368 9.472 0.047 8.525 0 8.525 86.81 R5 0.365 9.391 0.047 8.452 0 8.452 85.98 R6 0.368 9.472 0.047 8.525 0 8.525 86.54 R7 0.368 9.472 0.047 8.525 0 8.525 85.68 R8 0.365 9.391 0.047 8.452 0 8.452 84.95 R9 0.355 9.123 0.046 8.211 0 8.211 84.74 R10 0.379 9.767 0.049 8.790 0 8.790 89.79 R11 0.368 9.472 0.047 8.525 0 8.525 86.54

Table No. 36


Conc. (mg / 5ml)


%CDR after 20

mins R1 0.395 10.196 0.051 9.176 0.0967 9.273 94.43

R2 0.405 10.464 0.052 9.417 0.0974 9.515 94.67

R3 0.405 10.464 0.052 9.417 0.0967 9.514 96.20

R4 0.393 10.142 0.051 9.128 0.0965 9.224 93.93

R5 0.403 10.410 0.052 9.369 0.0961 9.465 96.29

R6 0.409 10.571 0.053 9.514 0.0965 9.610 97.57

R7 0.398 10.276 0.051 9.249 0.0970 9.346 93.92

R8 0.405 10.464 0.052 9.417 0.0974 9.515 95.63

R9 0.382 9.847 0.049 8.862 0.0938 8.956 92.43

R10 0.412 10.651 0.053 9.586 0.0990 9.685 98.93

R11 0.409 10.571 0.053 9.514 0.0965 9.610 97.57

Department of Pharmaceutics, GCP, B’lore-27 93

Results

Figure 19: Dissolution Profile of runs as per DOE in Simulated Gastric Fluid

(pH 1.2) after 5 and 20 minutes.

0

20

80

60

40

100

R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11

%C

DR



Results

Table 37: Composition of the optimized formula.

*INGREDIENTS R

Metoclopramide HCl 10

Avicel PH200 177.87

Cross Povidone 12.5

Sodium Starch Glycolate 5.13

Pregelatinized Starch 31.5

Aspartame 5

Magnesium Stearate 4

Talc 4

TOTAL 250


Table 38: Pre-compression parameters of optimized formulation.

PARAMETERS R Bulk Density (g/cc) 0.88

Tapped Density (g /cc) 0.71 Angle of Repose (θ) 36.3

Carr’s Index (%) 17.32

Table 39: Post compression parameters of optimized formulation.


PARAMETERS R Hardness (Kg / cm2) 3.5

Friability (%) 0.16 Thickness (mm) 4.08 Drug content (%) 99.56 Weight variation 240 –253mg

Results

Table 40: Comparison between Disintegration Time, Disintegration time in Oral cavity,

and Wetting time.

PARAMETERS R

Average* 12.67 DT in oral

cavity in (sec)

SEM (±) n = 3 0.333

Average* 38.33 Wetting time (sec) SEM (±)

n = 3 0.667

Average* 17.33 DT in (sec) SEM (±)

n = 3 0.333

Table 41: Dissolution profile of runs as per DOE.

Time (minutes) Absorbance Conc.

(mcg /ml)Conc.

(mg / 5ml)Conc.

(mg/900ml) CLA CDR

%CDR

0 0 0 0 0 0 0 0

5 0.365 9.391 0.047 8.452 0 8.452 84.95

10 0.391 10.088 0.050 9.080 0.0470 9.127 91.72

15 0.405 10.464 0.052 9.417 0.0974 9.515 95.63

20 0.389 10.035 0.050 9.031 0.1497 9.181 92.27


Results

Figure 20: Dissolution profile of optimized formulation.

0

20

40

60

80

100

120

0 5 10 15 20 25

Time ( in minutes)

% C

DR


Results

Stability Studies

Table 42: Stability data of optimized formulation stored at 250C / 60%RH

Optimized formulation Time in days

PA %DC

0 +++ 100.01

30 +++ 100.01

60 ++ 99.90

PA: Physical appearance +++: Same as on ‘0’ day

%DC: Percentage Drug content ++: Slight change in appearance

Table 43: Stability data of optimized formulation stored at 40o C / 75 % RH

Optimized formulation Time in days

PA %DC

0 +++ 100.01

30 +++ 100.01

60 ++ 99.90

PA: Physical appearance +++: Same as on ‘0’ day

%DC: Percentage Drug content ++: Slight change in appearance


Results


Discussion

DISCUSSIONS

The present study was carried out to develop rapidly disintegrating tablets of

Metoclopramide Hydrochloride by direct compression method. Hence it was necessary to

find suitable excipients with good compactability and disintegrating ability.

Preformulation

In the preformulation study, it was found that the estimation of Metoclopramide

Hydrochloride by UV spectrophotometric method at λmax 273.0 nm in 0.1N Hydrochloric

acid had good reproducibility and this method was used in the study. The correlation

coefficient for the standard curve was found to be closer to 1, at the concentration range,

2- 25 mcg/ml.. The regression equation generated was y = 0.0387x + 0.0063.

Drug-excipient compatibility studies

Thin Layer Chromatography was carried out to check for the possible drug-

excipient interaction. The Rf values of the drug and excipients used in the study were

similar. This established that the drug (Metoclopramide Hydrochloride) and all the

excipients used in the study showed no interaction between them and indicated that they

were compatible with each other. The photograph and Rf values are given in page no.

(Fig 5, Table No 2).

Department of Pharmaceutics, GCP, B’lore-27

100

Discussion

Formulation and Evaluation of rapidly disintegrating tablets

In direct compression method, Mannitol, Dicalcium phosphate, and Avicel PH

200 were selected as directly compressible diluents25. Crospovidone, Croscarmellose

sodium, Sodium starch glycolate and Low-substituted Hydroxypropyl cellulose were

used as disintegrants. In all the formulations, Pregelatinized starch was used as a binding

agent to attain hardness. Aspartame was used as a sweetening agent. Magnesium

stearate and talc were used as lubricant and glidant respectively.

Precompression parameters

The precompression parameters for the formulations, formulated by direct

compression method are as given below:

Table 44: Comparison of Precompression parameters of all the formulations.

Formulations

Parameters Mannitol (M1-M12)

DCP (E1-E12)

Avicel PH 200 (A1-A12)

Bulk Density (g/cc) 0.61 – 0.69 0.64 – 0.73 0.49 – 0.63 Tapped Density (g / cc) 0.52 - 0.6 0.49 – 0.58 0.39 – 0.49

Carr’s Index (%) 8.20 – 20.0 18.31 – 25.0 20.41 – 26.98

Angle of Repose (θ) 320 - 380 320 - 390 300 - 390

The Carr’s Index values indicate that-

1. Mannitol powder mixtures showed good flow properties

2. Dicalcium Phosphate powder mixtures showed fair flow properties


101

Discussion

3. Avicel PH 200 powder mixtures showed poor flow properties for the ingredients used

in the study.

The Angle of repose values indicate that all the formulations showed acceptable flow

properties.

Physical properties of tablets

Hardness

The hardness was determined for all the formulations and the results were as

follows.

Table 45: Comparison of Hardness of all the formulations.

Formulations Hardness (kg/ cm2)

Mannitol 4.0

DCP 3.5

Avicel PH 200 4.0

The hardness of all the formulations was kept at 3.0 ± 1 kg / cm2 to compare the

disintegration time between the formulations.

Friability

The percentage friability of all the formulations were found to be not more than

0.6 %, which is well within the 1 % limit. The results of friability indicated that the

tablets were mechanically stable.


102

Discussion

Weight variation

The weights of the tablets were between 239.0 mg to 258.0 mg. As the weight of

tablets was 250 mg, the acceptable weight variation range is between 232.5 mg to 267.5

mg (± 7.5 %). Hence all the tablet formulations were within the pharmacoepial limits.

Assay

The percentage drug content of all the tablets was found to be between 94.37 %

and 100.51 % of Metaclopramide Hydrochloride, which was within the acceptable limits.

Disintegration time as per IP, Wetting time and Disintegration time in Oral cavity was

determined for all the formulations.

Disintegration Time as per IP

Disintegration time as per IP, for all the formulations was found to be within 77

seconds, which was well within IP limit. (IP limit is 180 seconds)

Formulations with Crospovidone and Sodium starch glycolate as disintegrants

exhibited quicker disintegration of tablets than compared to Croscarmellose sodium &

low-substituted Hydroxypropyl cellulose. It indicated that amongst the disintegrants used

Sodium starch glycolate and Crospovidone were better disintegrants to formulate rapidly

disintegrating tablets by direct compression method for Metaclopramide Hydrochloride

than Croscarmellose sodium and L-HPC. This can be attributed to the extent of water

uptake and consequently the strong swelling power of these disintegrants caused


103

Discussion

sufficient hydrodynamic pressure to induce complete disintegration. These disintegrants

swell to a large extent when they come in contact with water to disintegrate tablets and

has a fibrous nature that allows intraparticulate, as well as extraparticulate, wicking of

water even at low concentration levels (10%).

Wetting time

Wetting time, for all the formulations was found to be within 59 seconds.

Formulations with Crospovidone and Sodium starch glycolate as disintegrants exhibited

quicker Wetting time of tablets than compared to Croscarmellose sodium & Low-

substituted Hydroxypropyl cellulose. It indicated that amongst the disintegrants used,

Sodium starch glycolate and Crospovidone were better disintegrants to formulate rapidly

disintegrating tablets by direct compression for Metaclopramide hydrochloride than

Croscarmellose sodium and L-HPC. This may be due to the low porosities of these

disintegrants.

Disintegration Time in Oral Cavity

It was observed that all the tablets disintegrated in oral cavity within 69 seconds.

• Tablets prepared with Avicel PH 200 as diluent disintegrated in oral cavity

between 19.33 seconds and 27 seconds.

• Tablets prepared with Dicalcium Phosphate as diluent disintegrated in oral cavity

between 32 seconds and 59.67 seconds.

• It was found that tablets prepared with Mannitol as diluent took longer time (40

second to 70.67 seconds) to disintegrate in oral cavity than other diluents used in


104

Discussion

the study. The disintegration time in oral cavity in case of Mannitol formulations

was between 40 second to 70.67 seconds.

Rapid disintegration of tablets containing Avicel PH 200 as diluent was attributed to the

penetration of water into the hydrophilic tablet matrix by means of capillary action of the

pores and by subsequent disruption of the hydrogen bonds24.

Dissolution rate study

The dissolution study was carried out using 900 ml of simulated gastric fluid as

dissolution medium at 50 rpm at 370C ± 0.50C in USP Type II apparatus. All the

formulations showed rapid dissolution rate and the percentage cumulative drug release

(%CDR) after 5 minutes was more than 81.64 % and complete dissolution was achieved

within 20 minutes.

Optimized Formulations

Using the polynomial equations, the optimized formulations were obtained for the

response parameters. In the trial runs, the optimized formulations were arrived using

numerical optimization in design expert 6.05 VERSION.

Rapidly disintegrating tablets are gaining importance as new drug delivery systems.

These dosage forms dissolve or disintegrate in oral cavity without the need of water or

chewing. A number of superdisintegrants are available in the market, which markedly

improve tablet disintegration by swelling and exerting sufficient pressure in the tablet to

break it apart into small segments. Selection of an appropriate superdisintegrant depends

up on its concentration in decreasing the DT of a tablet. Hence, an optimization technique


105

Discussion

was adapted. The tablets were prepared following 32 full factorial designs. For rapid drug

dissolution, the carrier material should be highly soluble in the dissolution medium;

hence, lactose was chosen as carrier material, which is highly soluble. Crospovidone, an

effective disintegrant and also has bioadhesive property is expected to prolong the

residence time of the drug at the oral mucosa and their by increasing the absorption. In

this study, the effect of formulation variables: the amount of SSG and crospovidone was

chosen as independent variables. The dependent (response) variables include wetting

time and DT. For the generation of polynomial models, only coefficients found to be

significant (p<0.05) were used.

Effect of formulation variables on WT

The cubic model for Y1 (WT) was found to be significant with an F value of 20.37 (p<

0.0156).

Y1 = 37.00 + 12.50 X2 + 5.75 X1X2 -12.25 X12 X2

+ 7.75 X1X22

In this case, only factor X2 and its interaction with X1 and X2 were found to be

significant. Increase in the amount of crospovidone, increases the WT. The relation ship

between the variables was further elucidated using Response surface plot (Figure 10).

At lower level of X1 and X2, the WT time was found to be 27.25 seconds and as the

concentration of CPVP is increased from low to higher level the WT decreased to 16.25

seconds. Similarly, if the concentration of CPVP was increased from low to higher value

the WT increased from 37.25 to 49.25 by keeping the concentration of SSG at higher

level. High value of WT in case of crospovidone may be due to it’s binding property.


106

Discussion

Effect of formulation variables on disintegration time

The Model F-value of 41.69 implies the model is significant. There is only a 0.55%

chance that a "Model F-Value" this large could occur due to noise.

Values of "Prob > F" less than 0.0500 indicate model terms are significant.

In this case A, A2, B2, AB2 are significant model terms.

Y3 = 14.00 – 2.50 X1 + 2.50 X12 + 2.50 X2

2 + 6.00 X1X22

The coefficient X1 shows negative sign; on increasing the concentration of crospovidone

a decrease in DT is observed. High concentration of crospovidone leads to swelling and

water uptake, which subsequently facilitate disintegration. The interaction effect between

X1 and X2 are shown in Response surface plot (Figure 7). At low concentration of

crospovidone and if 5 mg of MCC were used, then the DT were found to be 18 sec and

19 seconds when the concentration of Crospovidone is increased. Similarly the DT

decreases from 23.00 seconds to 28.00 seconds, if 20 mg of SSG were used and

crospovidone was increased from 5 to 12.50 mg. The results conveyed us that, factor X2

has significant effect on DT than that of X1. Presence of high amount of crospovidone

wicking is facilitated and known to have an optimum concentration regarding

disintegrating time.

The data of pure error and lack of fit are summarized in ANOVA table, which can

provide a mean response and an estimate of pure experimental uncertainty. The residuals

are the difference in the observed and predicted value. Since, the computed F values were

respectively less than the critical F value, which denotes non-significance of lack of fit.


107

Discussion

A numerical optimization technique by the desirability approach was used to

generate the optimum setting for the formulation using minimizing WT and DT.

The optimized formulations were prepared using the various criteria as mentioned in the

earlier section and the formulations were evaluated for the various responses.

Optimization results therefore obtained were included in the following table.

Table 46: Comparison chart of predicted and actual values for optimized formulation.

Formulation WT DT

Predicted Actual Predicted Actual Opt form

16.997 17.20 18.958 19.10

Stability studies

The formulations had a residual drug content of more than 97% after 2 months

when stored at 25oC / 60% RH and 40oC / 75%RH. These results indicated that the

selected formulations were stable. Also, the aged samples showed no change in the

Physical appearance, hardness or drug content.

The drug excipient compatibility studies indicated that there was no change in the Rf

values of the drug and the excipient.


108

Conclusion

CONCLUSION

In the present work, an attempt was made to develop rapidly disintegrating tablets

of Metoclopramide Hydrochloride

From the study conducted, the following conclusions are drawn:

Amongst the various combinations of diluents and disintegrants used in the study,

tablets that were formulated (direct compression) using Crospovidone and Sodium starch

glycolate exhibited quicker disintegration of tablets than compared to those of L-HPC

and Crosscarmellose sodium.

Based on the optimization results it is concluded that the objective of

formulating Rapidly Disintegrating Tablets containing Metoclopramide

Hydrochloride has been achieved with success.

SCOPE FOR FURTHER STUDIES

1. The so developed formula can be adopted to formulate Rapidly

Disintegrating Tablets containing highly water soluble drugs, where

desired action is required in short time. Example: Salbutamol and

Terbutaline Sulphate for the treatment of Bronchitis.

2. The work can be extended to invivo studies by using Rabbit as animal

model and carry out the invitro and invivo Correlation studies.

3. The work can be extended to study the effect of compression pressure,

shape and diameter of the tablet and size of particles (based on mesh

screen).

Department of Pharmaceutics, GCP, B’lore-27 109

Summary

SUMMARY

The present study is an attempt to select the best possible diluent - disintegrant

combination to formulate rapidly disintegrating tablets of Metoclopramide

Hydrochloride, which disintegrates in matter of seconds in the oral cavity, thereby

reducing the time of onset of pharmacological action.

Mannitol, Dicalcium phosphate, and Avicel PH 200 were selected as directly

compressible diluents. Crospovidone, Croscarmellose sodium, Sodium starch glycolate

and Low-substituted Hydroxypropyl cellulose were used as disintegrants. In all the

formulations, Pregelatinized starch was used as a binding agent to attain hardness.

Aspartame was used as a sweetening agent. Magnesium stearate and talc were used as

lubricant and glidant respectively.

The results of the drug – excipient compatibility studies revealed that there was

no chemical interaction between the pure drug and excipients.

Direct compression method was employed to formulate the tablets, because of its

cost effectiveness and due to reduced number of manufacturing steps.

The precompression parameters like bulk density, tapped density, Carr’s ‘index

and angle of repose were determined. All the 36 formulations showed acceptable flow

properties.

The postcompression parameters like the hardness, thickness, friability and weight

variation, disintegration time, wetting time, disintegration time in oral cavity and Invitro

release were carried out and the values were found to be within IP limits.


110

Summary

The percentage drug content of all the tablets was found to be between 94.37 %

and 100.51 % of Metaclopramide hydrochloride, which was within the acceptable limits.

From the data obtained, it is observed that Formulations with Crospovidone and

Sodium starch glycolate as disintegrants exhibited quicker disintegration and wetting

time of tablets than compared to Croscarmellose sodium & low-substituted

Hydroxypropyl cellulose. It indicated that amongst the disintegrants used Sodium starch

glycolate and Crospovidone were better disintegrants to formulate rapidly disintegrating

tablets by direct compression method for Metaclopramide hydrochloride.

Based on the preliminary experiment Crospovidone and Sodium starch

glycolate were found to be the best disintegrating agents in the formulation of

Rapidly disintegrating tablets. But, appropriate amount of SSG and CPVP were found

to affect the DT. Hence, a 32 factorial design of experiment was performed by which

the amount of Crospovidone and Sodium starch glycolate was considered as

independent variables. As per the DOE totally 11 possible combinations were

performed with3 centre points to find out the lack of fit and errors due to experiments.

The response parameters were fitted to cubic model to access the effect of

formulation variables. Based on the polynomial equation and response surface plots,

the optimized formulation was arrived by using desirability function. The so

developed optimized formulation was further challenged with experimentation and

was found that, the predicted values were in close agreement with the actual values,

indicating the validation of the model.


111

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