formulation and evaluation of gastroretentive bosentan monohydrate tablets using raft technology

FORMULATION AND EVALUATION OF

GASTRORETENTIVE BOSENTAN

MONOHYDRATE TABLETS USING RAFT

TECHNOLOGY

Presented by

MAMATHA. J

170615886004

Pharmaceutics

Under the guidance of

DR. K.V. RATNAMALA

CONTENTS

• Abstract

• Introduction

• Plan of work

• Literature review

• Drug profile

• Need of study

• Objectives of the study

• Experimental methodology

• Results and Discussion

• Publications

• References

Dr. K.V. Ratnamala Mamatha.J 2

ABSTRACTAim: The objective of the present study is to develop Bosentan monohydrate

gastroretentive tablets using raft technology with the aim to achieve controlled release

for the treatment of Pulmonary Arterial Hypertension (PAH).

Materials and methods: Floating tablets were prepared by direct compression method

using different concentrations of xanthan gum, chitosan, Carbopol 934 and methocel

E15. Pectin is used as raft forming agent. Drug, polymer and pectin were taken in

different ratios like (2:1:1); (1:1:1); (2:2:1). The prepared formulations were subjected

to pre-compression parameters like angle of repose, bulk density, tapped density,

Hausner’s ratio, Carr’s index and post-compression parameters like hardness, floating

time, floating lag time, raft strength and disintegration. Tablets were subjected to in-

vitro drug release in 0.1 N HCl (pH 1.2) for 12 hours.

Results and discussion: Drug-excipient compatibility study showed no interaction

between drug and excipients. Among the different combinations of polymers in

different ratios studied, F11 was found to be the best formulation showing 99.9% in

vitro drug release which includes drug, polymer and pectin in the ratio of 2:1:1

respectively. Stability study of the optimized formulation showed that the tablets were

stable at accelerated environmental conditions for 3 months. Hence from this study it

can be concluded that pectin can be used as raft forming agent for controlling the drug

release.

Key words: Raft technology, Floating drug delivery system, Bosentan monohydrate.


Introduction

Classification of Floating Drug Delivery:

(A) Effervescent FDDS

I. Gas generating system

II. volatile liquid containing system

(B) Non- Effervescent FDDS

I. Colloidal gel barrier system

II. Microporous compartment system

III. Floating microspheres

IV. Alginate floating beads.

(C) Raft forming system


RAFT FORMING SYSTEM:

A simple meaning of Raft is a flat structure, typically made of planks,

logs or barrels that floats on water and is used for transport or as a platform

for swimmers.

In the raft forming systems, a gel forming solution on contact with gastric

contents or fluid swells and forms a viscous cohesive gel containing

entrapped carbon dioxide bubbles and forms a layer which resembles same

as a raft in river.

The gel layer is of very low bulk density due to generation of carbon

dioxide bubbles within system which makes layer to float on gastric

contents.


PLAN OF WORKLiterature review

Selection of drug Selection of polymer

& Raft forming agent

Pre-compression parameters

Compression into tablet

Post-compression parameters

Comparison of optimized

formulation with marketed tablet

Stability study of optimized formulation Dr. K.V. Ratnamala Mamatha.J 7

Literature review

YEAR OF

PUBLIC

ATION

JOURNAL TITLE AND

AUTHOR

POLYMERS

USED

RESULT

2016

European

Journal of

Pharmaceutical

and Medical

Research

Preparation and

invitro

characterization of

bosentan

monohydrate

mucoadhesive

microspheres

Ch. S. Vijaya Vani

HPMC K4

M, HPMC

K100M,

Ethyl

Cellulose and

Carbopol

940P

Formulation

containing HPMC

K100M& Carbapol

940p is promising

for the controlled

oral delivery of

Bosentan

Monohydrate to

treat PAH.

2015

Journal of

Chemical and

Pharmaceutical

Research

Formulation and

evaluation of raft

forming sustained

release tablet

containing Ranitidine

Kanabar Vishvesh B.

et al

Sodium

alginate,

Aspartame,

Pectin,

Mannitol

Sodium alginate and

pectin achieved

good raft strength.


YEAR OF

PUBLICA

TION

JOURNAL TITLE AND

AUTHOR

POLYMERS

USED

RESULT

2015

International

Journal of

Pharmaceutical

Sciences and

Drug Research

Formulation and

Optimization of Raft

Forming Chewable

Tablet Containing

Lafutidine

Dasharath M. Patel

et al

Sodium

alginate,

Pectin, Guar

gum, Xanthan

gum, Isapgol

husk,Gellan

gum

F8 was found to be

the best

formulation which

includes sodium

alginate and pectin

in the ratio of 3:1.

2015

International

Journal of

Pharmaceutical

Sciences

Review and

Research

Preparation and

Evaluation of

Sustained Release

Matrix Tablets of

Bosentan by Using

Wet Granulation

Technique

Y. Ganesh Kumar et

al

Compritol 888

ATO,

Poloxamer-

407, and

Poloxamer-188

Formulation

containing

Poloxamer-407 is

the best in vitro

release of 97.5 %

in 12 hrs. The

release of drug

followed matrix

diffusion

mechanism.


YEAR OF

PUBLICA

TION

JOURNAL TITLE AND

AUTHOR

POLYMERS

USED

RESULT

2015

International

Journal of

Scientific &

Engineering

Research

Formulation and

Evaluation of Matrix

Membrane Moderated

Transdermal Patches

of Bosentan

Monohydrate

Revathi Mannam

HPMC K4M,

HPMC K15M,

HPMC

K100M and E

RL PO

Formulations using

HPMC produced

extended drug

release up to 12h,

addition of matrix

forming agent

further extended

the drug release up

to 24h.

2014

International

Journal of

Biopharmaceuti

cs

Development and

characterization of

matrix mini-tablets of

bosentan for

controlled drug

release

P. Ganga Jyothi et al

Carbapol and

polyethylene

oxide (PEO).

Formulation MT8

matrix mini-tablet

consists of 40mg

of Carbapol has

shown best result


YEAR OF

PUBLICA

TION

JOURNAL TITLE AND

AUTHOR

POLYMERS

USED

RESULT

2014

International

Journal of

Biological

&

Pharmaceutical

Research

Formulation and

evaluation of

matrix tablets of

bosentan for

controlled release

Anjaneyulu et al.

HPMC K15,

Eudragit

RSPO,

Karaya gum

and Guar

Gum

The formulation

containing karaya gum

was better and that

satisfied all the criteria

as controlled release

tablets.

2014

International

Journal of

Pharmacy and

Pharmaceutical

Sciences

Formulation

development and

in vitro

evaluation of

sustained release

matrix tablets of

bosentan by using

synthetic

polymers

Y.. Ganesh kumar

et al.

HPMC K 4

M, HPMC

K15 M

Formulation containing

Drug to polymer

(HPMC K 4 M) in ratio

1:0.5

gave the best in vitro

release of 96.3±0.53 in

12 hrs in simulated

intestinal fluid.


YEAR OF

PUBLICA

TION

JOURNAL TITLE AND

AUTHOR

POLYMERS

USED

RESULT

2014

International

journal of

pharmacy &

therapeutics

In vivo evaluation

of matrix mini-

tablets of bosentan

for controlled

release

V. Anjaneyulu et

al

Poly Ethylene

Oxide, Eudragit

RSPO, Guar

Gum and

Karaya gum

The mini matrix

tablets showed better

bioavailability

characteristic and

constant drug plasma

concentration while

comparing with a

commercial

conventional tablet

containing 62.5 mg of

Bosentan


SUMMARY OF LITERATURE REVIEW:

• Various types of formulations of Bosentan monohydrate like mucoadhesive

microspheres, matrix tablets, transdermal patches, matrix mini tablets have

been developed using synthetic polymers like HPMC K4M, HPMC K15M and

NaCMC. Among all the formulations Bosentan monohydrate mucoadhesive

microspheres showed drug release of 94.81% for 24 hrs.

• HPMC K4M is the ideal polymer for sustained drug release and also

compatible with Bosentan monohydrate.

• Raft technology has been used earlier to prepare sustained release tablets of

Lafutidine, Nizatidine and Ranitdine chewable tablets which showed ideal

drug release upto 12 hrs by using sodium alginate and pectin as raft forming

agents. Among the three formulations Nizatidine showed the drug release of

98.96% for 12hrs.

• When compared to other raft forming agents like Sodium alginate, Guar gum

and Isapgol, Pectin is known to be the best raft forming agent.

• Thus, from the literature review pectin has been selected as the raft forming

agent.


DRUG PROFILEBosentan is a dual endothelin receptor antagonist used in the treatment of

pulmonary artery hypertension (PAH). It is licensed in the United States, the

European Union and other countries by Actelion Pharmaceuticals for the

management of PAH under the trade name Tracleer.

Common name: Bosentan monohydrate

IUPAC name: 4-tert-Butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-

(pyrimidin-2-yl)pyrimidin-4-yl]benzene-1-sulfonamide

Molecular formula: C27H29N5O6S

Molecular weight: 551.614 g/mol

Molecular structure:


Appearance: Pale yellow to off-white solid

Density: 1.326 g/cm3

Solubility: Poorly soluble in water (1.0 mg/100 ml) and in aqueous solutions at

low pH (0.1mg/100 ml at pH 1.1 and 4.0; 0.2 mg/100 ml at pH 5.0). Solubility

increases at higher pH values.

LogP: 3.7

Pka value: 5.8

Biological half life: 5hrs

Bioavailability: 50%

Protein binding: >98%

Melting point: 107-110°C


Storage: -20ºC Freezer

BCS classification: Class II

Category: Endothelin receptor antagonist

•MEDICAL USE: Bosentan is used to treat people with moderate pulmonary

arterial hypertension and to reduce the number of digital ulcers — open wounds

especially on fingertips and less commonly the knuckles — in people with

systemic scleroderma.

• ADVERSE EFECTS: In addition to the risk of causing birth defects and of

causing liver damage, bosentan has a high risk of causing edema, pulmonary

veno-occlusive disease, decreasing sperm counts and decreases in hemoglobin

and hematocrit.


• MECHANISM OF ACTION:

Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by

binding to ETA and ETB receptors in the endothelium and vascular smooth muscle.

ET-1 concentrations are elevated in plasma and lung tissues of patients with

pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this

disease. Bosentan is a specific and competitive antagonist at endothelin receptor

types ETA and ETB. Bosentan has a slightly higher affinity for ETA receptors than

ETB.


NEED OF THE STUDY:

• Bosentan monohydrate is an Endothelin Receptor Antagonist used for the treatment of

Pulmonary Arterial Hypertension (PAH), a condition caused by narrowing of blood vessels

connected to and within the lungs.

• Gastro retentive drug delivery offers various potential advantages for drug with poor

bioavailability because their absorption is restricted to the upper gastrointestinal tract

(GIT) and they can be delivered efficiently thereby maximizing their absorption and

enhancing absolute bioavailability.

• Raft mechanism is a novel approach in which the drug is released in the upper part of

GIT slowly and continuously by the disintegration of the tablet and forming a layer on the

surface of the gastric contents.

• Bosentan monohydrate is poorly soluble at lower pH, as the pH increases the solubility

increases. Bosentan when formulated as the raft forming tablets, it forms raft at pyloric

sphincter, where the drug is poorly soluble and thereby the drug releases slowly towards

the proximal part of the intestine with an increase in the solubility and bioavailability.


OBJECTIVES OF THE STUDY:

• To formulate the gastroretentive tablets using a raft forming agent by direct

compression method

• To check the formulations for pre-compression and post-compression parameters

• To optimize the polymer and raft forming agent concentration

• To optimize a final formulation based upon the results

• To compare the optimized formulation with that of marketed formulation

• To study the stability of data of the optimized formulation


Experimental

methodology

Materials used:

• Bosentan monohydrate

• Xanthan gum

• Chitosan

• Carbopol 934

• Methocel E15

• Pectin

• Sodium bicarbonate

• Starch

• Lactose monohydrate

• Micro crystalline cellulose

• Magnesium stearate

• Talc


Methods

Preparation of stock solution

100mg of Bosentan monohydrate was accurately weighed and transferred to 100ml

of volumetric flask. To this little amount of 0.1N HCL was added and mixed

properly to dissolve the drug and made upto the mark by using 0.1N HCL to give

1000µg/ml (stock solution).

Standard calibration of Bosentan in 0.1N Hcl

From the stock solution 10ml was pippetted out and transferred into 100ml

volumetric flask and made upto the mark with 0.1N HCL to prepare 100µg/ml

which is called as working standard I. From the working standard I 10 ml was

pippetted out into 100ml volumetric flask and made upto the mark with 0.1N HCL

to prepare 10µg/ml which is called as working standard II. From the working

standard II dilutions were made using 2,4,6,8 and 10 ml of the solution to give

2,4,6,8 and 10µg/ml respectively. The absorbances of these solutions were measured

against blank at λmax 242nm in UV visible spectrophotometer.


EVALUATION OF PRE-COMPRESSION PARAMETERS

Angle of repose

The angle of repose of blends was determined by the funnel method. The accurately

weighed blend was taken in funnel. The height of the funnel was adjusted in such a

way that the tip of the funnel touches the apex of the heap of the blend. The blend

was allowed to flow from the funnel on the surface. The diameter and height of the

heap formed from the blend was measured. The angle of repose was calculated

using following formula.

Tan θ = h/r

Where,

“h” is height of the heap and “r” is the radius of the heap of blends.

Bulk Density (BD)

An accurately weighed powder blend from each formula was lightly shaken to

break any agglomerates formed and it was introduced in to a measuring cylinder.

The volume occupied by the powder was measured which gave bulk volume.


Tapped bulk density (TBD)

An accurately weighed powder blend from each formula was lightly shaken to break

any agglomerates formed and it was introduced into a measuring cylinder. The

measuring cylinder was tapped until no further change in volume was noted which

gave the tapped volume.

Carr’s compressibility index

The Carr’s compressibility Index was calculated from Bulk density and tapped

density of the blend. A quantity of 2g of blend from each formulation was filled into

a 10mL of measuring cylinder. Initial bulk volume was measured and cylinder was

allowed to tap from the height of 2.5cm. The tapped frequency was 25±2 per min to

measure the tapped volume of the blend. The bulk density and tapped density were

calculated by using the bulk volume and tapped volume. Compressibility index was

calculated using the following formula:


DRUG-EXCIPIENT COMPATIBILITY STUDIES BY FTIR

In the preparation of Controlled Release tablet, drug and polymer may

interact as they are in close contact with each other, which could lead to

instability of drug. Preformulation studies regarding drug-polymer

interactions are therefore very critical in selecting appropriate polymers.

FT-IR spectroscopy was employed to ascertain the compatibility between

bosentan and selected polymers. The individual drug and drug with

excipients were scanned separately.

Procedure

Potassium bromide was mixed with drug and polymer in the ratio of 100:1

and pellet was prepared using KBr pellet press and spectrum was taken

using FTIR. FT-IR spectrum of bosentan was compared with spectrum of

bosentan and polymer mixture. Disappearance of bosentan peaks or shifting

of peak in any of the spectra was studied.


Preparation of raft forming tablets by direct compression method

Drug, polymer and other ingredients were weighed accurately. The

weighed ingredients were mixed thoroughly except the binder and

lubricant. Binder and lubricant were added before the compression. The

powder was poured into the die and compressed into the tablet.

Direct compression method: The term “direct compression” is defined as

the process by which tablets are compressed directly from powder blends

of API and suitable excipients. No pretreatment of the powder blend by

wet or dry granulation procedure is required.


Table 1: Formulation tableIngredients(mg) Formulations

F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12Drug 62.5 62.5 62.5 62.5 62.5 62.5 62.5 62.5 62.5 62.5 62.5 62.5

Sodium 45 45 45 45 45 45 45 45 45 45 45 45

bicarbonate

Starch 30 30 30 30 30 30 30 30 30 30 30 30

Pectin 62.5 62.5 62.5 62.5 62.5 62.5 62.5 62.5 31.25 31.25 31.25 31.25

Chitosan -- 62.5 -- -- -- 31.25 -- -- -- 31.25 -- --

Xanthum gum 62.5 -- -- -- 31.25 -- -- -- 31.25 -- -- --

Methocel E15 -- -- -- 62.5 -- -- -- 31.25 -- -- -- 31.25

Carbopol 934 -- -- 62.5 -- -- -- 31.25 -- -- -- 31.25 --

Lactose 20 20 20 20 20 20 20 20 30 30 30 30

monohydrate

Magnesium 5 5 5 5 6.5 6.5 6.5 6.5 6.5 6.5 6.5 6.5

stearate

Micro

Crystalline 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5

cellulose

Talc 5 5 5 5 5 5 5 5 6 6 6 6

Total wt.(mg) 300 300 300 300 270 270 270 270 250 250 250 250


EVALUATION OF TABLETS

Hardness test

Hardness indicates the ability of a tablet to withstand mechanical strength while

handling. The hardness of the tablets were determined using Monsanto Hardness

tester. It is expressed in Kg/cm2. Three tablets were randomly picked from each

formulation and the mean and standard Deviation values were calculated.

Friability test

It is the phenomenon whereby tablet surfaces are damaged and/or show evidence of

lamination or breakage when subjected to mechanical shock or attrition. The

friability of tablets was determined by using Roche Friabilator. It is expressed in

percentage (%). Ten tablets were initially weighed (Wt.initial) and transferred into

friabilator. The friabilator was operated at 25 rpm for 4 minutes or run up to 100

revolutions. The tablets were weighed again (Wt.final).

Weight variation test

The tablets were selected randomly from each formulation and weighed

individually to check for weight variation. To study weight variation, 20 tablets of

each formulation were weighed using an electronic balance and the test was

performed according to the official method.


Floating lag time

The buoyancy lag time was determined in the U.S.P. dissolution test apparatus II in the acid

environment. The time interval between the introduction of the tablet into the dissolution

medium and its buoyancy to the top of the dissolution medium is buoyancy lag time or

floating lag time.

Raft strength measurement by in-house method

Raft strength was estimated using the modified balance method. A double pan dispensing

balance was modified for raft strength measurement. One pan of the dispensing balance

was replaced with an L-shaped wire probe as shown in Figure 1. A tablet powder equivalent

to unit dose was transferred to150 mL of 0.1 N HCl maintained at 37°C in a 250 mL glass

beaker. Each raft was allowed to form around an L-shaped wire probe (diameter: 1.2 mm)

held upright in the beaker throughout the whole period (30 min) of raft development. Water

was added drop wise to the pan and the weight of water required to break the raft was

recorded.

Fig. 1: (a) Modified balance method (b) Wire probe for raft strength measurementDr. K.V. Ratnamala Mamatha.J 30

In vitro drug release studies

Drug release from the prepared tablets was determined up to 12 hrs using USP type

II (paddle type) dissolution test apparatus. 0.1 N HCl (900 ml) was used as

dissolution medium. The paddle was adjusted at 50 rpm and the temperature of

37±0.5°C was maintained throughout the experiment. Samples were withdrawn at

known time intervals and were replaced with same volume of fresh dissolution

media after each withdrawal. The samples were analyzed for drug release by

measuring absorbance using UV spectrophotometer.

STABILITY STUDIES:

Stability studies were conducted according to ICH guidelines. Optimized tablets

(formulation F11) were stored under 40±2°C/75%RH in humidity chamber for a

period of 3 months. After 3 months, the tablets were tested for disintegration, weight

variation, friability, hardness, floating time and in-vitro drug release studies.


RESULTS AND

DISCUSSION

Analytical Method for Construction of calibration curve

The absorption maxima for Bosentan monohydrate was found to be at 242 nm.

Fig 2: Absorption maxima of Bosentan monohydrate


242nm

The developed Spectrophotometric method obeyed Beer-Lambert’s law with linearity range

of 2-10 μg/ml. Calibration curve of Bosentan monohydrate in 0.1 N HCl (pH 1.2) was

constructed against the respective buffer as blank at λmax of 242 nm and are represented in

the below figure.


Concentration(µg/ml) Absorbance (n=3)

(Mean ± SD)

%CV

2 0.117±0.017 0.1529

4 0.221±0.03 0.1226

6 0.326±0.05 0.1424

8 0.418±0.07 0.1744

10 0.527±0.08 0.1618

Table 2: Standard curve values of Bosentan monohydrate in 0.1N HCL at λmax 242nm

y = 0.053x

R² = 0.998

0

0.1

0.2

0.3

0.4

0.5

0.6

0 2 4 6 8 10 12

Ab

sorb

an

ce

Conc.µg/ml

Fig 3: Standard curve of Bosentan monohydrate in 0.1N HCl


FTIR of pure drug

Determination of interaction between drug and excipients were performed using

FTIR. The FTIR of pure drug (Bosentan monohydrate) shows no interaction

between drug and excipients.

Table 3: FTIR of Bosentan monohydrate


Group Range in cm-1

N-H 2962

S=O 1718

Aromatic C-H Stretching 1579

C=C 1342

C-N Vibration 1170

O-H 1083

Fig 4: FTIR spectra of Bosentan monohydrate


Fig 5: FTIR spectra of Bosentan+Methocel E15


Fig 6: FTIR spectra of Bosentan+Xanthan gum


Fig 7: FTIR spectra of Bosentan+Chitosan


Fig 8: FTIR spectra of Bosentan+Carbopol


Table 4: Preformulation studies of all the formulations

Parameters F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12

Angle of

repose(°)

28.2±

0.15

31.5±

1.25

30.2±

0.55

29.0±

1.27

29.1±

1.65

24.1±

1.58

24.6±

1.56

26.5±

1.84

25.5±

2.23

27.1±

1.26

22.6±

1.65

28.2±

2.35

Bulk

density(g/cc)

0.74±

0.25

0.49±

0.15

0.47±

0.82

0.56±

0.87

0.59±

0.54

0.45±

0.98

0.45±

0.65

0.54±

1.58

0.54±

1.98

0.59±

1.66

0.43±

1.25

0.58±

0.64

Tapped

density(g/cc)

0.87±

0.12

0.56±

0.12

0.58±

1.25

0.64±

1.55

0.62±

1.69

0.64±

2.36

0.64±

2.48

0.56±

2.65

0.76±

2.88

0.59±

1.25

0.46±

1.08

0.68±

1.86

Hausner's ratio 1.09±

1.23

1.12±

1.57

1.11±

1.38

1.14±

1.22

1.03±

0.54

1.54±

1.25

1.62±

2.36

1.08±

2.35

1.45±

1.32

1.62±

1.25

0.93±

1.02

1.98±

0.24

Carr's

compressibility

index

19.05

±0.15

17.1±

0.125

20.5±

0.42

12.5±

0.145

14.95

±1.02

28.6±

1.25

26.6±

2.03

0.55±

1.54

29.19

±2.04

11.69

±1.02

6.52±

1.02

19.65

±1.02

All the values are expressed as mean ± S.D. n=3


Table 5: Post compression parameters

Formulations Disintegration

time(sec)

Hardness

(kg/cm²)

Floating lag

time(sec)

Floating

time(hrs)

Raft

strength(gms)

F1 48.33±2.94 3.33±1.25 24±1.27 12.3±0.47 4.2±0.12

F2 40±1.08 3.5±0.74 11.33±1.25 12.3±1.25 2.6±0.15

F3 391.3±2.3 3.79±0.85 7.67±1.25 13.67±1.25 2.5±0.11

F4 320.67±2.5 3.243±0.77 19.67±2.05 14±1.63 4.9±0.02

F5 40.67±0.9 3.273±0.43 23.33±2.68 14±0.82 4.6±0.65

F6 50.67±1.25 2.97±0.62 17±2.16 14.3±1.7 4.8±0.12

F7 383.67±2.7 3.63±0.48 13±2.94 15.3±0.47 3.5±1.65

F8 334.67±1.18 3.863±0.3 22.67±2.05 14.3±0.47 4.1±1.24

F9 38±1.35 3.5±0.52 14.67±2.05 14.67±0.47 5.2±1.25

F10 45±2.74 3.813±0.69 14±0.82 13±0.82 4.9±0.36

F11 394.67±1.5 4.573±0.74 16±0.82 15±0.82 5.6±1.45

F12 337.67±1.4 4.48±0.55 21±1.63 13.3±1.25 4.8±1.32



Table 6: In vitro drug release:


Time (hrs) F1 F2 F3 F4 F5 F6

0.5 7.58±0.8 8.1±0.7 5.76±0.5 7.29±1.2 14.7±0.9 15.7±0.64

1 13.1±1.2 17.4±0.8 16.14±1.8 12.6±0.8 25±1.6 27.58±0.6

2 24.4±0.6 22.7±1.0 25.7±1.2 16.1±1.2 33.3±1.4 33.38±0.53

3 34.3±1.1 26.6±0.8 28.4±0.7 24.3±0.9 38.5±08 39.38±1.96

4 35.4±1.3 32.6±0.9 32±0.4 29.2±1.3 46.2±08 44.18±3.3

5 36±0.95 34.9±0.5 33.2±0.4 31.2±0.8 49.2±0.8 49.25±1.0

6 37.3±0.4 37.8±1.5 35.5±0.8 33±0.5 55.1±1.1 54.34±2.0

7 38.5±0.8 41.5±1.0 38.6±0.9 35.2±2 56.9±1.2 58.1±0.8

8 42.1±0.7 42.2±0.4 44.6±2.1 41.1±1.3 60.7±1.3 62.03±0.4

9 43.5±0.5 44.3±0.3 51.1±0.6 43.4±0.4 65.3±0.9 64.6±0.47

10 44.7±1.1 46.2±0.7 53.8±1.3 44.8±1 68.2±0.8 67.31±1.7

11 47.4±1.0 50.2±1.7 57±0.4 54±1.1 70.2±0.8 71.7±1.1

12 54±0.05 55.6±2.2 58.2±0.5 56.8±3 75.4±0.7 77.1±1.8

Time (hrs) F7 F8 F9 F10 F11 F12

0.5 14.52±0.6 14.94±0.6 15.6±0.1 14.55±1.4 16.88±0.9 13.85±1.2

125.14±1.4 24.49±2.0 27.7±0.7 27.57±0.8 25.4±1.8 27.3±0.9

232.6±3 31.93±3.0 39.2±0.5 38.31±1.1 37.5±1.5 35.5±2.2

337±4 37.26±2.0 57.08±1.6 57.4±1.2 53.74±1.3 41.8±1.5

444.41±1.8 43.93±3.6 66±1.7 62.4±1.4 58.75±0.9 55.09±0.8

548.4±1.0 47.35±2.8 65.57±0.5 66.16±0.7 63.4±1.4 65.25±0.8

653.4±2.5 53.85±2.8 67.9±1.0 69.49±2.0 66.9±1.3 67.08±1.7

7 55.97±3.1 55.98±2.5 72±2.6 73.64±2.4 72.4±2.0 73.8±1.5

8 59.3±2.3 60.67±1.4 76.46±0.3 77.5±1.4 76.9±1.8 76.7±1.2

9 63.11±3.1 65.45±0.6 82.3±0.6 82.37±0.7 81.87±1.7 80.6±1.3

10 64.97±2.8 67.1±1.0 86.4±0.8 86.48±0.9 87.2±0.2 87±0.2

11 69.02±3.27 68.8±1.4 90.2±1.0 91.78±3.1 94.25±2.1 92.67±2.0

12 75.4±0.1 75.4±0.7 95.87±0.5 96.7±1.4 99.9±1.2 95.5±0.9



0

10

20

30

40

50

60

70

80

90

0 2 4 6 8 10 12 14Cu

mu

lati

ve %

of

dru

g r

elea

sed

Time(hrs)

F1

F2

F3

F4

F5

F6

Fig 9: CUMULATIVE % OF DRUG RELEASE OF ALL FORMULATIONS (F1-F6)


Fig 10: CUMULATIVE % OF DRUG RELEASE OF ALL FORMULATIONS (F7-F12)


0

20

40

60

80

100

120

0 2 4 6 8 10 12 14

Cu

mu

lati

ve %

of

dru

g r

elea

sed

Time(hrs)

F7

F8

F9

F10

F11

F12

Comparison of the optimized formulation (F11) with marketed formulation

The invitro drug release of optimized formulation F11 was compared with that of

the marketed film coated tablets (BOSENTAS) containing 62.5mg of Bosentan

Monohydrate per tablet. The comparative invitro release profiles is shown below.

The marketed formulation released 91% of the drug within one hour where as the

optimized formulation (F11) released 99.9% for a period of 12 hrs. This shows that

the drug release was controlled from the optimized formulation for 12 hrs because

of slow release and increased gastrointestinal retention of the prepared tablets.

Fig 11: Comparison of F11 and Bosentas


0

25

50

75

100

0 2 4 6 8 10 12 14Cu

m%

of

dru

g r

elea

sed

Time (hrs)

Bosentas

F11

Model dependent kinetics of optimized formulation F11:


R² = 0.6115

-2

-1

0

1

2

3

0 2 4 6 8 10 12 14

Lo

g c

um

% o

f d

rug

rem

ain

ing

Time(hrs)

First order plot

R² = 0.9257

0

20

40

60

80

100

120

0 2 4 6 8 10 12 14

Cu

m %

of

dru

g

rele

ase

d

Time (hrs)

Zero order plot

R² = 0.9931

0

20

40

60

80

100

0 1 2 3 4

Cu

m %

of

dru

g

rele

ase

d

√Time (hrs)

Higuchi model

R² = 0.787

n= 0.254

0

0.5

1

1.5

2

2.5

-0.4 -0.2 0 0.2 0.4 0.6 0.8 1 1.2

Lo

g c

um

% o

f d

rug

rem

ain

ing

Log Time

Korsmeyer peppas


STABILITY STUDY:

Table 6: Post compression parameters after stability studies (40±2°C/75%RH)


Time Disintegration

(sec)

Hardness

(Kg/cm²)

Floating time

(hrs)

Cum % of drug

released

Before stability 394.67±1.5 4.573±0.74 15±0.82 99.9±1.2

After 1 month 393.17±0.5 4.73±0.22 15±0.18 97.41±1.25

After 2 months 390.15±2.41 4.61±1.24 15±0.88 95.96±1.34

After 3 months 391.5±1.02 4.63±1.2 16±1.22 94.12±1.32

0

20

40

60

80

100

120

0 2 4 6 8 10 12 14

Cu

mu

lati

ve %

of

dru

g r

elea

sed

Time (hrs)

Before stability

After 1 month

After 2 months

After 3 months


DISCUSSION:

From the present study, the following points can be drawn:

All the formulations have fulfilled the official limit for physicochemical

parameters like weight variation, floating time, hardness and friability.

IR spectra indicated the absence of probable chemical interaction between the

drug and polymers used in different proportions.

According to in-vitro release studies, the release rate was sustained with

decreasing the concentration of polymer.

In-vitro dissolution studies showed that tablets of Bosentan in 2:1:1 proportion,

prepared by direct compression is the best formulation to increase controlled effect

due to the polymer and pectin concentration.

The optimized formulation F11 gave the best in vitro release of 99.9±1.2 in 12 hrs

in 0.1N Hcl. The drug release followed zero order and Fickian diffusion controlled

release.


CONCLUSION

• It shows that carbopol and pectin are the suitable excipients for the preparation of Bosentan

monohydrate gastroretentive tablets using raft technology.

• Bosentan monohydrate is soluble at higher pH or at alkaline pH. The raft forming tablets

makes the drug to be released in the pyloric sphincter where the drug is poorly soluble and

thereby the released drug passes through the intestine and gets absorbed in the alkaline pH.

• Thus the bioavailability of the drug can be improved by the formation of Bosentan

monohydrate raft forming tablets.

FUTURE SCOPE:

• Bosentan monohydrate gastro retentive tablets of raft technology can be marketed by

performing all the required pharmacokinetic and pharmacodynamic studies.

• The stability of the formulation can be further increased by adding required quantity of

suitable stabilizer if required.


Publications:

Research article:

Mamatha J, Ratnamala K V. “Formulation And Evaluation Of Gastroretentive

Bosentan Monohydrate Tablets Using Raft Technology”. International Journal of

Pharmacy & Pharmaceutical Research.

Article was accepted by the journal and was going to be published in January.

Review article:

Mamatha J, Ratnamala K V. “Cessation of Smoking By Nicotine Replacement

Therapy”. Journal of Pharmacy Research. 2017, 11(5), 414-418.


References

1. Ganesh kumar Y. Sreekanth J, Satyavati D. (2015) Preparation and Evaluation of

Sustained Release Matrix Tablets of Bosentan by Using Wet Granulation Technique.

International Journal of Pharmaceutical Sciences Review and Research. 31(2), 155-161.

2. Anjaneyulu V, Gnanaprakash K, Chandrasekhar K B. (2014) In vivo evaluation of

matrix mini-tablets of Bosentan for Controlled Release. International Journal of

Pharmacy & Therapeutics. 5(5), 324-329.

3. Tapan kumar panda, Debajyoti das, Lalatendu panighahi. (2016) Development of

Multiple-unit Mucoadhesive Sustain Release Mini-tablets of Bosentan. International

Journal of Pharmacy and Pharmaceutical Sciences.8(10), 235-241.

4. Vijaya Vani1 CH S and Vidyavathi Maravajala. (2016) Preparation and invitro

characterisation of Bosentan monohydrate Mucoadhesive Microspheres. European

Journal of Pharmaceutical and Medical Research. 3(5), 340-350.

5. Momin Shiraz Mohammad Shafi, Ravindra Bhanudas Saudagar. (2015) Solubility

Enhancement of Bosentan monohydrate using Mixed hydrotropy. International Journal

of Institutional Pharmacy and Life Sciences. 5(3), 319-330.


6. Ramdas T. Dolas, Dr. Avinash Hosmani, Sachin B. Somwanshi. (2015) Raft Technology

for Gastro Retentive Drug Delivery. International Journal Of Pharmacy And

Pharmaceutical Research. 3(1), 232-252.

7. Elham Ghasemian, Parisa Motaghian, Alireza Vatanara. (2016) D-optimal Design for

Preparation and Optimization of Fast Dissolving Bosentan Nanosuspension. Advanced

Pharmaceutical Bulletin. 6(2), 211-218.


formulation and evaluation of gastroretentive bosentan monohydrate tablets using raft technology

Health & Medicine