formulation & evaluation of gastroretensive floating microsphere of cinnarizine
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RESEARCH ARTICLE Farha Amna Shaik et.al / IJIPSR / 1 (2), 2013, 252- 265
Department of Pharmaceutics ISSN (online): 2347-2154
Available online: www.ijipsr.com October Issue 252
FORMULATION AND EVALUATION OF TENOFOVIR DISOPROXIL
FUMARATE IMMEDIATE RELEASE TABLETS
1Farha Amna Shaik*,
2Shubhrajit Mantry
1M.Pharmacy Scholar, Kottam Institute of Pharmacy, Mahaboobnagar, AP, INDIA
2Assistant Professor, Kottam Institute of Pharmacy, Mahaboobnagar, AP, INDIA
Corresponding Author:
Farha Amna Shaik
Department of Pharmaceutics,
Kottam Institute of Pharmacy,
Erravally “X” Roads, Andhra Pradesh.509125
Email: [email protected]
Telephone: 91-9703483486
International Journal of Innovative
Pharmaceutical Sciences and Research www.ijipsr.com
Abstract
This investigation is undertaken with an aim to develop pharmaceutically equivalent, stable, cost
effective and quality improved formulation of Tenofovir Disoproxil Fumarate immediate release tablets.
The current study involves formulation and evaluation of Tenofovir Disoproxil Fumarate tablets,
comparison of dissolution rate of optimized formula with innovator‟s product and estimation of
similarity and difference factors. The similarity and dissimilarity factor obtained for Tenofovir
Disoproxil Fumarate was found to be within the limits. The formulation F-8 exhibited similar release
profile to that of innovators product at each time point. Hence, F-8 was considered as the best
formulation.
Key words: Tenofovir Disoproxil Fumarate, Immediate release tablets, Wet granulation method.
RESEARCH ARTICLE Farha Amna Shaik et.al / IJIPSR / 1 (2), 2013, 252- 265
Department of Pharmaceutics ISSN (online): 2347-2154
Available online: www.ijipsr.com October Issue 253
INTRODUCTION
Active pharmaceutical compounds (drugs) are used for the treatment of a disease or
for prophylactic purpose. An Active Pharmaceutical Ingredient (API) may exist
in solid, liquid or semisolid form. They are rarely prescribed to the patients as such i.e. without
adding excipients, since the desired effect may not be obtained. Earlier, it was thought that
excipients are inert in nature but, in recent time it is well known that excipients can greatly
modify the intended effect of a drug. The API and excipients are suitably processed in
pharmaceutical industry to convert them into dosage forms such
as tablet, capsule, suspension, solution, etc. The selection of excipients and processing of drug
excipients mixture is as important as API itself.
Patient acceptability can be improved by controlling the organoleptic properties. Dosage form
provides desired therapeutic level of a drug.
Preparation method of tablet [1-2]
Direct Compression
The term “direct compression” is defined as the process by which tablets are compressed directly
from powder mixture of API and suitable excipients. No pre-treatment of the powder blend by
wet or dry granulation procedure is required.
Manufacturing steps for direct compression
Direct compression involves comparatively few steps:
i) Milling of drug and excipients.
ii) Mixing of drug and excipients.
iii) Tablet compression
Wet Granulation
The most widely used process of agglomeration in pharmaceutical industry is wet granulation.
Wet granulation process simply involves wet massing of the powder blend with a granulating
liquid, wet sizing and drying.
RESEARCH ARTICLE Farha Amna Shaik et.al / IJIPSR / 1 (2), 2013, 252- 265
Department of Pharmaceutics ISSN (online): 2347-2154
Available online: www.ijipsr.com October Issue 254
Steps involved in the wet granulation
i) Mixing of the drug(s) and excipients
ii) Preparation of binder solution
iii) Mixing of binder solution with powder mixture to form wet mass.
iv) Coarse screening of wet mass using a suitable sieve (6-12 screens)
v) Drying of moist granules.
vi) Screening of dry granules through a suitable sieve (14-20 screens)
vii) Mixing of screened granules with disintegrant, glidant, and lubricant.
Coating [3]
Coated tablets are defined as “tablets covered with one or more layers of mixture of various
substances such as natural or synthetic resins ,gums ,inactive and insoluble filler, sugar,
plasticizer, polyhydric alcohol ,waxes ,authorized colouring material and sometimes flavouring
material. Coating may also contain active ingredient. Substances used for coating are usually
applied as solution or suspension under conditions where vehicle evaporates.
Immediate release [3]
The term “immediate release” pharmaceutical formulation includes any formulation in which the
rate of release of drug from the formulation and/or the absorption of drug, is neither appreciably,
nor intentionally, retarded by galenic manipulations. In the present case, immediate release may
be provided for by way of an appropriate pharmaceutically acceptable diluents or carrier, which
diluents or carrier does not prolong, to an appreciable extent, the rate of drug release and/or
absorption. Thus, the term excludes formulations which are adapted to provide for “modified”,
“controlled”, “sustained”, “prolonged”, “extended” or “delayed” release of drug. In this context,
the term “release” includes the provision (or presentation) of drug from the formulation to the
gastrointestinal tract, to body tissues and/or into systemic circulation. For gastrointestinal tract
release, the release is under pH conditions such as pH=1 to 3, especially at, or about, pH=1. In
one aspect of the invention a formulation as described herein with a compound of formula (I), or
an acid addition salt thereof, in crystalline form releases drug under a range of pH conditions. In
another aspect of the invention a formulation as described herein with a compound of formula
(I), or an acid addition salt thereof, releases drug under pH conditions such as pH=1 to 3,
RESEARCH ARTICLE Farha Amna Shaik et.al / IJIPSR / 1 (2), 2013, 252- 265
Department of Pharmaceutics ISSN (online): 2347-2154
Available online: www.ijipsr.com October Issue 255
especially at, or about, pH=1. Thus, formulations of the invention may release at least 70%
(preferably 80%) of active ingredient within 4 hours, such as within 3 hours, preferably 2 hours,
more preferably within 1.5 hours, and especially within an hour (such as within 30 minutes), of
administration, whether this be oral or parenteral.
MATERIALS AND METHODS
Methods used in the formulation of TDF immediate release tablets:
1. Direct compression method &
2. Wet granulation method
Procedure for f-1(direct compression):
All the ingredients were weighed except Magnesium stearate and the mix was passed
through #40 mesh, and then mixed for 5 min in s blender.
The above mixture was then lubricated with Magnesium stearate which was initially
passed through sieve no 12 in blender for 2 mins.
Then the lubricated blend was compressed using 16.5 x 8mm size punches.
Procedure for f-2 to f-8(wet granulation):
API, MCC pH 101, Lactose monohydrate, Crospovidone were weighed and passed
through #40 meshes.
The above mixture was mixed in a poly bag for 10 minutes.
PG starch was added to sufficient quantity of purified water by stirring.
The binder solution was added to the dry mixture within 2 minutes with impeller speed
fast (600rpm).
The wet mass was mixed for 1min with impeller and chopper fast (600rpm).
The obtained wet mass was passed through #12 mesh.
The sieved mixture was dried using FBD and the temperature was maintained at 60˚ C.
until the moisture content in the blend comes to 1.0 to 2.0 %
The dried blend was passed through #18 mesh and then pre lubricated using MCC pH
102, crospovidone for 5 minutes and then lubricated with Magnesium stearate in bender
for 2mins.
Physical characteristics of the lubricated blend were carried out.
RESEARCH ARTICLE Farha Amna Shaik et.al / IJIPSR / 1 (2), 2013, 252- 265
Department of Pharmaceutics ISSN (online): 2347-2154
Available online: www.ijipsr.com October Issue 256
Then finally the lubricated blend was compressed using 16.5x8mm size, oval shape
punches.
The obtained tablets were coated using opadry II blue coating solution
Table no.1 formulation table of TDF immediate release tablets
Materials F1
(mg)
F2
(mg)
F3
(mg)
F4
(mg)
F5
(mg)
F6
(mg)
F7
(mg)
F8
(mg)
Tenofovir disoproxil fumarate 302 302 302 302 302 302 302 302
Microcrystalline cellulose 137 190 148 139 135 130 126 123
Lactose anhydrous 148 - - - - - - -
Lactose monohydrate - 85 128 135 135 140 153 145
Crospovidone(intragranular) 15 10 12 14 - - - -
Croscarmellose
sodium(intragranular) 15 - - - 14 15 16 20
Pregelatinized starch 20 20 20 20 20 20 20 20
Water - Q.S Q.S Q.S Q.S Q.S Q.S Q.S
Microcrystalline cellulose(pH
102) - 25 21 19 24 23 13 21
Crospovidone(extragranular) - 10 12 14 - - - -
Croscarmellose
sodium(extragranular) - - - - 113 13 13.5 12.5
Magnesium stearate 13 8 7 7 7 7 6.5 6.5
Core tablet weight 650 650 650 650 650 650 650 650
Opadry blue II coat (2.3%) 15 15 15 15 15 15 15
Coated tablet weight 665 665 665 665 665 665 665 665
RESEARCH ARTICLE Farha Amna Shaik et.al / IJIPSR / 1 (2), 2013, 252- 265
Department of Pharmaceutics ISSN (online): 2347-2154
Available online: www.ijipsr.com October Issue 257
RESULTS & DISCUSSIONS:
Table.No.2 Standard calibration data of TDF in 0.1 HCL
Concentration (mcg/ml) Absorbance (260 nm)
0 0
3 0.127
6 0.265
9 0.368
12 0.512
15 0.628
18 0.756
Fig.No.1 Standard graph of Tenofovir Disoproxil Fumarate
Fourier Transforms Infrared Spectroscopy (FTIR) Studies:
The pure drug, physical mixtures and optimized formulations were subjected for FTIR analysis.
The samples were prepared on KBr-press (Sipra laboratories, Hyd). The samples were scanned
over a range of 4000-400 cm-1 using Fourier transformer infrared spectrophotometer Spectra
were analysed for drug polymer interactions.
RESEARCH ARTICLE Farha Amna Shaik et.al / IJIPSR / 1 (2), 2013, 252- 265
Department of Pharmaceutics ISSN (online): 2347-2154
Available online: www.ijipsr.com October Issue 258
Tab no.3 FTIR interpretation of Pure drug and excipients
S.No
Formulation
C=C
Stretching
Cm-1
C=O
Stretching
Cm-1
N-H
Stretching
Cm-1
C-H
Stretching
Cm-1
1 T+CCNa 1683.7 1683 3354.23 2905.7
2 T+MCCPH101 1667.3 1641.13 3446.16 2906.4
3 T+PS 1683.17 1640.82 3231.07 2937.12
4 T+LM 1678.02 1759.2 3342.10 2900.13
5
T+MCC
PH102 1682.07 1757.37 3230.77 2901.82
6 T+ALL 1661.58 1759.2 3381.42 2900.72
7 T+OB - - 3356.50 -
8 Drug(TDF) 1681.57 1756.73 3227.13 2902.4
D:\IR DATA\.279 DRUG - TDF T SOLID 9/19/2013
3227
.13
2986
.16
1756
.73 1681
.59
1508
.22
1421
.73
1275
.15
1185
.92
1102
.67
1032
.9798
4.78
952.2
5
891.2
883
3.10
789.1
7
655.2
3
100015002000250030003500
Wavenumber cm-1
2040
6080
100
Trans
mitta
nce [
%]
Page 1/1
Fig.No.2 FTIR Spectrum of Pure Drug Tenofovir Disoproxil Fumarate
RESEARCH ARTICLE Farha Amna Shaik et.al / IJIPSR / 1 (2), 2013, 252- 265
Department of Pharmaceutics ISSN (online): 2347-2154
Available online: www.ijipsr.com October Issue 259
D:\IR DATA\.271 T+CCNa SOLID 9/19/2013
3354
.23
2986
.46
2905
.77
1760
.83 1683
.71
1275
.66 1032
.37
893.4
5
832.5
278
9.52
654.4
8
100015002000250030003500
Wavenumber cm-1
2030
4050
6070
8090
100
Trans
mitta
nce [
%]
Page 1/1
Fig.No.3 FTIR Spectrum of TDF+Croscarmellose sodium
D:\IR DATA\.272 T+MCCPH-101 SOLID 9/19/2013
3446
.16
1760
.55
1667
.38
1273
.18 1031
.99
895.5
9
830.5
3
100015002000250030003500
Wavenumber cm-1
5060
7080
9010
0
Trans
mitta
nce [
%]
Page 1/1
Fig.No.4 FTIR Spectrum of TDF+Microcrystalline cellulose-101
Fig.No.5 FTIR Spectrum of TDF+Pregelatinized starch
D:\IR DATA\.273 T+PS SOLID 9/19/2013
3231
.07 2986
.48 2935
.12
1759
.58
1683
.17
1508
.5014
69.29
1421
.44
1274
.99
1102
.41
1032
.4598
6.56
893.7
7
832.1
0 654.0
7
100015002000250030003500
Wavenumber cm-1
4050
6070
8090
100
Trans
mitta
nce [
%]
Page 1/1
RESEARCH ARTICLE Farha Amna Shaik et.al / IJIPSR / 1 (2), 2013, 252- 265
Department of Pharmaceutics ISSN (online): 2347-2154
Available online: www.ijipsr.com October Issue 260
D:\IR DATA\.275 T+LM SOLID 9/19/2013
3526
.47
3342
.10
2984
.6929
33.29
2900
.13
1761
.82 1678
.02 1422
.73
1275
.14
1095
.41
1034
.00
894.6
1
782.1
0
100015002000250030003500
Wavenumber cm-1
5060
7080
9010
0
Trans
mitta
nce [
%]
Page 1/1
Fig.No.6 FTIR Spectrum of TDF+Lactose monohydrate
D:\IR DATA\.276 T+MCC-102 SOLID 9/19/2013
3230
.77
2986
.28
1757
.31
1682
.57
1508
.5814
71.01
1421
.92
1275
.14
1102
.90
1033
.0198
5.09
952.7
9
891.6
883
3.17
789.3
5
655.5
8
100015002000250030003500
Wavenumber cm-1
2030
4050
6070
8090
100
Trans
mitta
nce [
%]
Page 1/1
Fig.No.7 FTIR Spectrum of TDF+Microcrystalline cellulose-102
D:\IR DATA\.278 T+OB SOLID 9/19/2013
3675
.55
3356
.50
2985
.97
1761
.84
1676
.60
1275
.53
1102
.68
1030
.65
952.6
2
891.6
283
3.49
789.2
1 668.4
4
100015002000250030003500
Wavenumber cm-1
5060
7080
9010
0
Trans
mitta
nce [
%]
Page 1/1
Fig.No.8 FTIR Spectrum of TDF+Opadry ii blue
RESEARCH ARTICLE Farha Amna Shaik et.al / IJIPSR / 1 (2), 2013, 252- 265
Department of Pharmaceutics ISSN (online): 2347-2154
Available online: www.ijipsr.com October Issue 261
D:\IR DATA\.277 T+ALL SOLID 9/19/2013
3381
.42
2985
.47
2900
.72
1759
.23
1661
.58 1422
.92
1275
.40
1032
.52
892.7
5
100015002000250030003500
Wavenumber cm-1
6570
7580
8590
9510
0
Tran
smitta
nce [
%]
Page 1/1
Fig.No.9 FTIR Spectrum of TDF+Mixture of Excipients
Differential scanning calorimetry (dsc):
Approximately 2-6 mg of pure drug (TDF) and selected formulations were taken in aluminum
pan, sealed with aluminum cap and kept under nitrogen purging (atmosphere). The samples were
scanned from 300-300°C with the scanning rate of 30°C/min using differential scanning
calorimeter.
Fig.No.10 DSC Thermogram of Pure drug Tenofovir Disoproxil Fumarate
Fig.No.11 DSC Thermogram of Best formulation F-8
RESEARCH ARTICLE Farha Amna Shaik et.al / IJIPSR / 1 (2), 2013, 252- 265
Department of Pharmaceutics ISSN (online): 2347-2154
Available online: www.ijipsr.com October Issue 262
Pre-Formulation Parameters [4, 5, 6]
Precompression parameters such as bulk density, tapped density, angle of repose, Carr‟s index
and Hausner ratio which are evaluated for prepared tablets are given in following table:
Evaluation of tablet: [7, 8]
Weight variation:
Twenty tablets were randomly selected from each batch individually weigh, the average weight
and standard deviation of 20 tablet calculated (Krishanaiah et al., 2003). Table no-6
Thickness:
The thickness of the tablet was measured by using digital venire caliper, twenty tablets from each
batch were randomly selected and thickness was measured (The British Pharmacopoeia, 2005).
Hardness:
Hardness was measured using Pfizer hardness tester, for each batch three tablets were tested
(The United State of Pharmacopoeia, 1995). (Table no-6)
Friability:
Twenty tablets were weight and placed in the Roche friabilator and apparatus was rotated at 25
rpm for 4 min. After revolution the tablets were dusted and weighed. (Chaudhari PD, 2005).
In-vitro disintegration test:
The test was carried out on 6 tablets using Tablet disintegration tester. Distilled water at 37 ˚C±
2˚C was used as a disintegration media and the time in seconds taken for complete disintegration
of the tablet with no palable mass remaining in the apparatus was measured.
Table.No.4 Post-compression parameters for F-1to F-8
Formula Average
weight(mg)
Thickness
(mm)
Hardness
(Kg/cm2)
Friability
(%)
Disintegration
Time
F-1 660 6.12 4.20 1.21 4min 21sec
F-2 667 6.08 4.10 0.79 5min 19sec
F-3 664 6.03 4.15 0.43 5min 14sec
F-4 666 6.05 4.00 0.28 4min 56sec
F-5 670 6.02 4.20 0.24 4min 49sec
F-6 661 6.06 4.00 0.19 4min 31sec
F-7 663 6.01 4.10 0.24 4min 29sec
F-8 668 6.04 4.10 0.11 3min 58sec
RESEARCH ARTICLE Farha Amna Shaik et.al / IJIPSR / 1 (2), 2013, 252- 265
Department of Pharmaceutics ISSN (online): 2347-2154
Available online: www.ijipsr.com October Issue 263
Table.No.5 Dissolution profile of formulations (F-1 to F-8)
Time(min) F-1 F-2 F-3 F-4 F-5 F-6 F-7 F-8
0 0 0 0 0 0 0 0 0
5 10.40 26.40 27.22 28.64 30.80 31.70 34.21 34.27
10 20.11 45.10 45.88 47.20 48.90 50.30 50.74 62.75
15 31.34 55.80 56.40 59.14 59.60 61.25 63.50 75.60
20 42.41 69.20 70.93 71.71 72.86 75.45 80.84 86.98
30 61.60 81.80 83.28 85.52 88.60 90.33 92.65 94.82
40 73.65 91.62 93.12 93.60 93.80 94.40 95.10 97.20
45 80.15 93.23 94.10 94.24 94.52 94.90 96.40 98.75
Fig.No.12 In-vitro dissolution profile of Fig.No.12 In-vitro dissolution profile of
TDF formulations F-1 to F-4 TDF formulations F-5 to F-8
Table.No.6 Comparision of In-vitro Drug release profile of (Tenofovir Disoproxil
Fumarate) best formulation F-8 with Marketed product
TIME %CDR OF
INNOVATOR
%CDR OF F-8
0 0 0
5 3.3 34.27
10 65.8 62.75
15 73.9 75.60
30 95.6 94.82
45 96.8 98.75
RESEARCH ARTICLE Farha Amna Shaik et.al / IJIPSR / 1 (2), 2013, 252- 265
Department of Pharmaceutics ISSN (online): 2347-2154
Available online: www.ijipsr.com October Issue 264
Fig.No.14 Plot for comparison of In-vitro Drug release F-8 with marketed product
CONCLUSION:
Drug and excipient compatibility studies by FTIR reveal that there is no chemical or physical
interaction. Pre formulation studies of Tenofovir Disoproxil Fumarate are within the acceptable
literature limits. The hardness, friability, thickness, average weight, in-vitro disintegration time
and in-vitro release were uniform and reproducible. Based on the results of the above mentioned
tests F8 was selected as the best formulation as it showed drug release profile matching with the
Innovator product. Stability studies were performed for this batch under accelerated testing
conditions. The product was evaluated for assay and dissolution and the results obtained were
found to be within the specified limits indicating the product is stable. The Tenofovir Disoproxil
Fumarate immediate release tablets showed fickian mechanism following zero order kinetics.
ACKNOWLEDGMENT
The authors are thankful to by “Kottam institute of pharmacy” Erravally „X‟ road,
Mahaboobnagar-509125(A.P.) INDIA, for completion of this work.
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Available online: www.ijipsr.com October Issue 265
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