formulation & evaluation of gastroretensive floating microsphere of cinnarizine

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.




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.




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,




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.




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




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.




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




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




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




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




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




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




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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formulation & evaluation of gastroretensive floating microsphere of cinnarizine

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