Download - 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.
Dr. K.V. Ratnamala Mamatha.J 3
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
Dr. K.V. Ratnamala Mamatha.J 5
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.
Dr. K.V. Ratnamala Mamatha.J 6
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.
Dr. K.V. Ratnamala Mamatha.J 9
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.
Dr. K.V. Ratnamala Mamatha.J 10
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
Dr. K.V. Ratnamala Mamatha.J 11
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.
Dr. K.V. Ratnamala Mamatha.J 12
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
Dr. K.V. Ratnamala Mamatha.J 13
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.
Dr. K.V. Ratnamala Mamatha.J 14
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:
Dr. K.V. Ratnamala Mamatha.J 15
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
Dr. K.V. Ratnamala Mamatha.J 16
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.
Dr. K.V. Ratnamala Mamatha.J 17
• 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.
Dr. K.V. Ratnamala Mamatha.J 18
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.
Dr. K.V. Ratnamala Mamatha.J 19
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
Dr. K.V. Ratnamala Mamatha.J 20
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
Dr. K.V. Ratnamala Mamatha.J 22
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.
Dr. K.V. Ratnamala Mamatha.J 23
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.
Dr. K.V. Ratnamala Mamatha.J 24
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:
Dr. K.V. Ratnamala Mamatha.J 25
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.
Dr. K.V. Ratnamala Mamatha.J 26
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.
Dr. K.V. Ratnamala Mamatha.J 27
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
Dr. K.V. Ratnamala Mamatha.J 28
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.
Dr. K.V. Ratnamala Mamatha.J 29
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.
Dr. K.V. Ratnamala Mamatha.J 31
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
Dr. K.V. Ratnamala Mamatha.J 33
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.
Dr. K.V. Ratnamala Mamatha.J 34
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
Dr. K.V. Ratnamala Mamatha.J 35
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
Dr. K.V. Ratnamala Mamatha.J 36
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
Dr. K.V. Ratnamala Mamatha.J 37
Fig 5: FTIR spectra of Bosentan+Methocel E15
Dr. K.V. Ratnamala Mamatha.J 38
Fig 6: FTIR spectra of Bosentan+Xanthan gum
Dr. K.V. Ratnamala Mamatha.J 39
Fig 7: FTIR spectra of Bosentan+Chitosan
Dr. K.V. Ratnamala Mamatha.J 40
Fig 8: FTIR spectra of Bosentan+Carbopol
Dr. K.V. Ratnamala Mamatha.J 41
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
Dr. K.V. Ratnamala Mamatha.J 42
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
All the values are expressed as mean ± S.D. n=3
Dr. K.V. Ratnamala Mamatha.J 43
Table 6: In vitro drug release:
Dr. K.V. Ratnamala Mamatha.J 44
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
All the values are expressed as mean ± S.D. n=3
Dr. K.V. Ratnamala Mamatha.J 45
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)
Dr. K.V. Ratnamala Mamatha.J 46
Fig 10: CUMULATIVE % OF DRUG RELEASE OF ALL FORMULATIONS (F7-F12)
Dr. K.V. Ratnamala Mamatha.J 47
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
Dr. K.V. Ratnamala Mamatha.J 48
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:
Dr. K.V. Ratnamala Mamatha.J 49
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
Dr. K.V. Ratnamala Mamatha.J 50
STABILITY STUDY:
Table 6: Post compression parameters after stability studies (40±2°C/75%RH)
Dr. K.V. Ratnamala Mamatha.J 51
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
Dr. K.V. Ratnamala Mamatha.J 52
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.
Dr. K.V. Ratnamala Mamatha.J 53
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.
Dr. K.V. Ratnamala Mamatha.J 55
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.
Dr. K.V. Ratnamala Mamatha.J 56
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.
Dr. K.V. Ratnamala Mamatha.J 55
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.
Dr. K.V. Ratnamala Mamatha.J 56