96 | P a g e International Standard Serial Number …. RPA131400238014.pdf96 | P a g e International...

96 | P a g e International Standard Serial Number (ISSN): 2319-8141

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International Journal of Universal Pharmacy and Bio Sciences 2(6): November-December 2013

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCES IMPACT FACTOR 1.89***

ICV 3.00*** Pharmaceutical Sciences RESEARCH ARTICLE……!!!

FORMULATION AND DEVELOPMENT OF IMMEDIATE RELEASE TABLET OF

AZATHIOPRINE DRUG BY DRY GRANULATION TECHNIQUE Singh D. K.

1, Yadav Sheela A.

2, Poddar S. S.

1*

1Department of Pharmaceutics, K.M. Kundnani College of Pharmacy, Mumbai-400005. India.

2Department of Pharmaceutics, H.K. College of Pharmacy, Mumbai-400102, India.

KEYWORDS:

Azathioprine,

Immunosuppressant, pH

dependent solubility

profile, Compatibility

studies.

For Correspondence:

Poddar S. S.*

Address: Department of

Pharmaceutics, K.M.

Kundnani College of

Pharmacy, Mumbai-

400005. India.

Email-ID:

[email protected]

ABSTRACT

The aim of the present work was to develop pharmaceutical tablet

dosage form of poorly water soluble an immunosuppressant drug

Azathioprine. This drug is used in organ transplantation and in the

treatment of arthritis. The purpose of the study was to prepare

Azathioprine immediate release tablets using roller compression

technique in order to meet dissolution profile in different media and

cost effective formulation. The blends were prepared and analyzed for

various physiochemical properties. In order to get the best and

optimized product ten different formulations were developed. Various

physical characterizations like weight variation, thickness, hardness,

friability, disintegration, assay of the tablets were studied. All the

parameters were found within the specified limit. In-vitro dissolution

study was done in water, pH 1.2, pH 4.5 acetate buffer and pH 6.8

phosphate buffer. Final formula was selected as the optimized

formulation on the basis of dissolution profile found satisfactory in all

dissolution medium as per USP specification (80% Q in 30 min.).

Final formulation was found stable.

mailto:[email protected]

- 97 - | P a g e International Standard Serial Number (ISSN): 2319-8141


INTRODUCTION:

Tablets are solid dosage forms containing pharmacologically active substances with or without

suitable diluents. They are most preferred form of medication both by pharmaceutical manufacturer

as well as physicians and patients. They offer safe and convenient way of active pharmaceutical

ingredients (API) administration with excellent physicochemical stability in comparison to some

other dosage forms, and also provide means of accurate dosing 1-3

. However manufacturing of tablets

is complex. Hence, careful consideration has to be given to select right process, and right excipients

to ultimately give a robust regulatory complaint product of good quality and high productivity. In

pharmaceutical industries, manufactures of generic tablets are usually focused on the optimization of

the excipients mixture composition to obtain a product that set up established standard. Direct

compression of powders requires materials exhibiting flowability and compressibility. Tablets

manufacturing parameters become critical when the formulation contains large amounts of active

substances with poor compressional properties 4-5

.

The desired particle size distribution can be adjusted by milling and sieving. The granulation

parameters can affect the mechanical (compressional) properties which subsequently can influence

the tabletting behavior and tablet characteristics. Therefore, the evaluation of granule properties

plays an important role in the prediction of tablet characteristics. The Heckel plot is the method most

frequently used to evaluate the volume reduction of materials when pressure is applied 6-7

. It is

assumed that the densification of the powder column follows first-order kinetics. The degree of

material densification is correlated to its porosity. Although the literature reveals some limitations to

the Heckel’s model, this model has often been applied to study powder mixtures and to evaluate the

parameters of granule manufacture 8-9

.

Azathioprine is an orally used immunosuppressant molecule [Figure 1]. It is Pale- yellow, odorless

crystalline powder insoluble in water and very slightly soluble in ethanol. It is used as an adjunct for

the prevention of the rejection of kidney allograft. The drug is used in conjunction with other

immunosuppressive therapy including local radiation therapy, corticosteroids, and other cytotoxic

agents. Azathioprine may be used for the treatment of conditions which involve derangement of the

immune system including chronic active hepatitis, severe rheumatoid arthritis, systemic lupus

erythematosus, dermatomyositis, pemphigus vulgaris, polyarteritis odosa, acquired haemolytic

anaemia, Crohn's disease and idiopathic thrombocytopenia 11-13

.

Figure: 1. Structural formula of Azathioprine



In the present study, we made an attempt to develop a stable, formulation of oral immediate‐release

Azathioprine tablets with optimum properties. Drug-excipient compatibility study was carried out

before start the formulation development 14-16

. To achieve stable formulation, various formulation

of Azathioprine tablets were prepared by using roller compacted granule and evaluated with respect

to the various quality parameters in both process for granules (loss on drying, bulk density, tapped

density, compressibility index, Hausner’s ratio) and for finished product (average weight, weight

variation, tablet thickness, friability, hardness, disintegration time, drug content, dissolution studies)

17. On the basis of these parameters the formula was optimized and compared with the marketed

product. Then, the in-vitro dissolution profile of optimized Azathioprine tablets was compared with

the marketed product in different media and evaluated stability parameters at various atmospheric

conditions 18

. In the present research, based on the literature, patent search and the compatibility

studies of the excipients the most favorable excipients were short listed for manufacturing of robust

formulation. All the excipients chosen are well known for their suitability and fulfillment of

purpose. The objective of this work was to develop a stable, pharmaceutical equivalent, immediate

release, cost effective tablets of Azathioprine. To achieve this goal, various prototype trials were

taken and evaluated.

MATERIALS AND METHODS

Azathioprine was a generous gift from Sun pharmaceuticals Ltd., Mumbai, India. Lactose

monohydrate, (Pharmatose 200 M) from DMV Fontera, Germany/ Signet Chemicals,

Microcrystalline Cellulose, (Avicel PH 101) from FMC Biopolymer Ireland/ Signet Chemicals,

Corn starch (Corn starch 400 L) from Roquette USA, Sodium starch glycolate (Glycolis) from

Roquette frères, France; Pre-gelatinized starch, Roquette frères, France; Signet Chemicals,

Magnesium Stearate from Ferro corporation USA/ Signet Chemicals, and Stearic acid from

Stearinerie France/ Signet Chemicals All other chemicals and reagents used were either analytical

or pharmaceutical grades.

PREFORMULATION STUDY: 19

Solubility studies of Azathioprine

pH dependent solubility of Azathioprine in different media (Purified water, 0.1 N HCl, 0.01N HCl,

0.001N HCl, pH 4.5 Acetate Buffer, pH 6.8 Phosphate buffer, pH 7.4 Phosphate Buffer) at 37° C

was studied. Excess amount of Azathioprine was taken in 50 ml of above medium and dissolved

under sonication. The maximal solubility of Azathioprine in each medium was determined after

filtering the content and using UV method at 280 nm. All readings were made in triplicate. The

result was summarized in Table No. 1



Table 1: pH dependent solubility

Drug – Excipients compatibility study: 20-21

Drug – Excipients compatibility study was carried out with drug substance alone and combination

with excipients. The physical mixture of drug substance and excipients were prepared by mixing

separately and passing through 40 mesh. The ratio of drug and excipients was selected as in the

formulation. Sample were stored at room temperature and charged at 40º C /75% RH for 2 weeks

and 4 weeks. The result was summarized in Table No. 2

Table 2: Drug-excipients compatibility study

Sr.

No. Drug +Excipients

Condition

Room temp 40°C/75%RH

Initial

(impurity %)

2 week

(impurity %)

4 week

(impurity %)

1 Azathioprine (A) 0.004 0.006 0.039

2 A + Drug Lactose monohydrate 0.001 0.005 0.025

3 A + Microcrystalline Cellulose 0.002 0.003 0.058

4 A + Corn Starch 0.02 0.022 0.038

5 A + Croscarmellose sodium 0.02 0.018 0.029

6 A + Sodium starch glycolate 0.015 0.017 0.018

7 A + Crospovidone 0.001 0.002 0.018

8 A + Stearic acid 0.002 0.002 0.032

9 A + Magnesium Stearate 0.002 0.003 0.028

10 A + Coating material 0.001 0.023 0.037

Preparation of Azathioprine tablets 22

Immediate release tablet of Azathioprine were prepared by dry granulation technique. Accurately

weighed quantities of drug and intragranular materials (Azathioprine, Lactose monohydrate 200 M,

Microcrystalline Cellulose PH 101, Corn Starch, Croscarmellose sodium, Sodium starch glycolate,

Crospovidone, Stearic acid) were sifted through # 40 mesh and mixed in blender for 30 minutes. Dry

mix blend were compacted in a roller compacter. Compacts were sized with Multimill using screen

(1.5 mm). Then granules were sieved through #20 sieves. The extra granular materials were sifted

Sr. No. Media Solubility [mg/ml] mg/250 ml

1 Purified Water 0.125 31.25

2 0.1 N HCl 0.180 45.00

3 pH 4.5 acetate buffer 0.127 31.75

4 pH 5.5 Phosphate buffer 0.155 38.75





through #40 mesh. The # 20 sieve granules were blended with extra granular materials

(Microcrystalline Cellulose PH 102, Croscarmellose sodium or Sodium starch glycolate, or

Crospovidone,) and lubricated with Magnesium stearate (#60 mesh sifted). Compression was

performed with 8.0 mm round flat face beveled edges (FFBE) punches in a 16 station rotary tablet

press (Lab press, CIP Ahmedabad, India). Composition of prepared Azathioprine immediate release

tablets are presented in Table 3. Core tablets were coated with hydroxylpropyl methyl cellulose

polymer based coating materials in pan coater. Physical properties of granules of different

formulations were evaluated. The result was summarized in Table No. 4

Table 3: Unit dose formula:

S.No. Ingredients FD 1 FD 2 FD 3 FD 4

mg/tab mg/tab mg/tab mg/tab

Intragranular

1 Azathioprine 50.00 50.00 50.00 50.00

2 Lactose monohydrate 200 M 67.00 67.00 67.00 67.00

3 Microcrystalline Cellulose PH 101 54.00 40.00 40.00 40.00

4 Corn Starch 12.00 12.00 12.00 12.00

5 Croscarmellose sodium … 8.00 … …

6 Sodium starch glycolate … … 8.00 ...

7 Crospovidone ... …. … 8.00

8 Stearic acid 1.00 1.00 1.00 1.00

Extra granular

9 Microcrystalline Cellulose PH 102 15.00 15.00 15.00 15.00

10 Croscarmellose sodium … 5.00 … …

11 Sodium starch glycolate … … 5.00 …

12 Crospovidone … … … 5.00

Lubrication

13 Magnesium Stearate 1.00 1.00 1.00 1.00

Core tablet weight (mg) 200.00 200.00 200.00 200.00

Coating

14 Methylhydroxylpropyl cellulose 3.480 3.480 3.480 3.480

15 polyethylene glycol 400 0.092 0.092 0.092 0.092

16 Titanium dioxide (E171), 0.400 0.400 0.400 0.400

17 Iron oxide, yellow (E172) 0.028 0.028 0.028 0.028

Coated tablet weight (mg) 204.00 204.00 204.00 204.00



Evaluation of tablet properties

The formulated tablets were evaluated for uniformity of weight, thickness, hardness, friability and

disintegration time.

Thickness measurement:

It is carried out on 20 tablets by measuring thickness using vernier calipers.

Hardness determination

20 tablets were taken randomly and hardness was measured using Hardness tester (Electrolab India,

Ltd.). The mean hardness of 20 tablets of each formulation.

Friability test

33 tablets (equivalent to approx 6.50 gram) were weighed and placed in the Roche friabilator test

apparatus. The tablets were exposed to rolling and repeated impact, resulting from free falls within

the apparatus. After 100 revolutions the tablets were dedusted and weighed again. The friability was

determined as the percentage loss in weight of the tablets.

100 tabletsof weight final - tabletsof weight Initial

friability %

stelbat fo thgiew latinI

Disintegration test

Disintegration time was determined to ensure that the drug substance is fully available for

dissolution and absorption from the gastrointestinal tract. The tablets were examined using the

disintegration apparatus (Electrolab India). Six tablets were tested for each batch. The disintegration

time of tablets was compared to 15 minutes which is accepted as the general tablet disintegration

time.

Drug content study

Drug content of the manufactured tablets of each batch was determined by weighing and finely

grinding twenty tablets from each batch. Aliquot of this powder equivalent to 50 mg of Azathioprine

was accurately weighed, suitably extracted in 50 ml of in purified water. The resulting solution was

filtered, suitably diluted in water and analyzed by UV-Vis double beam spectrophotometer method

at 280 nm. The result were summarized in Table No. 5

In-vitro release studies

In-vitro release study of Azathioprine was carried out using USP 26 Type 2 dissolution test

apparatus, Electrolab TDT-06 P, Electrolab, India) at 37±1°C and 50 rpm using 900 ml purified

water. Aliquots were withdrawn at predetermined time intervals and were replenished immediately

with the same volume of fresh dissolution medium. Aliquots, following suitable dilutions, were

assayed by UV method at 280 nm. The result was summarized in Table No. 6. All readings were

made in triplicate.



Stability studies

Optimized formulations were exposed at room temperature and 40°C /75% Relative Humidity for 3

month. The results were summarized in Table No. 7 and 8. The tablets were withdrawn for analysis

of following parameters:

1. Drug release

2. Related substances

RESULTS AND DISCUSSION

Poorly water soluble immediate release tablets of Azathioprine were prepared via roller compaction

technique using Croscarmellose sodium, Crospovidone and Sodium starch glycolate (SSG) as super

disintegrates in different formulations. The lubricated blend of formulations FD1 to FD4 was

evaluated for Bulk density Tapped density, Carr’s index and Hausner’s ratio, which showed the

lubricated blend, has good flow property [Table 4] 23

. The values of different physical parameter of

blend were given in Table 5. The tablets obtained drug contents in the range of 95.98 to 101.05%.

This was within the acceptable limit. Hardness of tablet was found in the range of 55-70 N.

Friability was found to be below 1.0% which indicates good mechanical strength of the tablets 24

.

All the formulations found to have much faster dissolution when compared to the without

disintegrants [Table 6]. The disintegration time (DT) for the formulations prepared with sodium

starchglycolate, croscarmellose and crospovidone was found to be in the range of 1.55-3.5 minutes.

Among all the formulations F4 were showed promising result as the dissolution was comparable to

the reference product. Among all the formulations Sodium starch glycolate provide optimized drug

release when compared to croscarmellose Sodium and crospovidone. The drug release efficiency

established was in order of crospovidone > croscarmellose sodium > sodium starch glycolate. The

similarity factor (f2) result showed that among all the formulations F4 was more similar to the

marketed product. In-vitro drug release studies were performed with all formulations. The results are

accordingly tabulated in Table 6. The percentage drug release for the formulation F4 was found

100.28% at the end of 30 minutes. This formulation prepared with crospovidone was found to be the

optimized one. The optimized formulation containing 2.5% Crospovidone showed minimum

disintegration time and better drug release profile as compare to other formulations [Figure 2].

Table 4: Evaluation of lubricated blend

Parameters FD 1 FD 2 FD 3 FD 4

Loss on drying(w/w) 3.45 3.89 3.55 3.46

Bulk density(g/ml) 0.48 0.46 0.48 0.48

Tap density (g/ml) 0.63 0.60 0.61 0.63

Compressibility index (%) 23.81 23.33 21.31 23.81

Hausner’s ratio 1.31 1.30 1.27 1.31



Table 5: Physical parameters of coated Azathioprine Tablets

Parameters FD 1 FD 2 FD 3 FD 4

Thickness (mm) 3.17 3.14 3.22 3.14

Average Weight (mg) 205.00 204.00 205.00 204.00

Hardness (N ) 62.00 70.00 62.00 64.00

Friability (%) 0.24 0.27 0.29 0.19

Disintegration Time (min.) 4.30 2.45 2.44 2.48

Drug content (%) 95.98 101.05 99.67 100.28

Table 6: In-vitro drug release profiles in purified water.

Time (min) Innovator FD 1 FD 2 FD 3 FD 4

0.00 0.00 0.00 0.00 0.00 0.00

5 77.08 58.12 68.21 78.52 75.23

10 85.80 62.28 71.28 84.21 87.25

15 91.00 65.25 77.25 85.94 93.10

20 97.52 68.21 78.28 88.52 96.22

30 99.44 71.28 78.32 89.74 98.25

45 101.25 75.85 82.90 92.25 99.82

60 101.70 88.97 87.55 95.88 100.8

Table 7: In-vitro drug release profiles of stability of test and innovator

Time (min) Innovator FD 4

0 0.00 0.00

5 74.25 76.24

10 83.20 85.84

15 90.27 92.33

20 95.24 96.25

30 97.25 98.25

45 100.30 99.22

60 100.24 99.37

In conclusion we had compared in-vitro dissolution profiles of optimized formulation of

Azathioprine tablet with the Reference Tablets in different dissolution media like purified water,

0.1 N HCl, pH 4.5 acetate buffer, pH 6.8 phosphate buffer. The comparison of in-vitro drug release

from optimized Azathioprine Tablets (formulation FD 4) with the Reference product has depicted

that the drug release from formulation FD 4 in 0.1 N HCl, pH 4.5 acetate buffer, pH 6.8 phosphate

buffer was similar to the innovator [Figure 3,4& 5].



Figure: 2 In-vitrorelease profile (Purified water) of formulation FD4 with reference product

(Mean ± SD, n = 6).

Fig. 3: In-vitro dissolution profiles (0.1 N HCl) of formulation FD4 and reference product

(Mean ± SD, n = 6).

Fig. 4: In-vitro dissolution profiles (PBS, pH 4.5 AB) of formulation FD4 and reference

product (Mean ± SD, n = 6).

0

20

40

60

80

100

120

0 10 20 30 40 50

% D

rug

Rel

ea

se

Time in min.

Dissolution Profile of Test Vs innovator

Innovator FD 1 FD 2 FD 3 FD 4

0

20

40

60

80

100

120

0 10 20 30 40 50

% D

rug R

elea

se

Time in min.

Dissolution Profile of Test Vs innovator 0.1 N

HCl

Innovator FD 4

0

20

40

60

80

100

120

0 10 20 30 40 50

% D

rug R

elea

se

Time in min.

Dissolution Profile of Test Vs innovator in

pH 4.5 acetate buffer

Innovator FD 4



Fig. 5: In-vitro dissolution profiles (PBS, pH 6.8) of formulation FD4 and reference product

(Mean ± SD, n = 6).

The optimized formulation were selected for accelerated stability studies and the tablets possessed

the same parameters even after the stressed conditions, indicating good stability properties. [ Figure

6].

Figure: 6. In-vitro release profiles of test compared with reference product in stability

condition.

Table 8: Stability study of test and innovator

Sr.

No. Drug product

Condition

Room Tempertaure 40°C/75%RH/3 month

Initial

% impurity

1 month

% impurity

3 months

% impurity

1 Azathioprine Tablets 0.088 0.961 1.097

2 Reference tablets 0.085 0.887 1.101

CONCLUSION

In conclusion, Azathioprine immediate release tablets were manufactured by dry granulation (Roller

compaction) technique. In order to obtain the best optimized product, different formulations were

developed. Various super disintegrant were taken as variables. The in-vitro dissolution studies

showed that drug release was in the following order of superdisintegrants crospovidone >

croscarmellose sodium > sodium starch glycolate. These results suggested that, in-vitro dissolution

020406080

100120

0 10 20 30 40 50

% D

rug R

elea

se

Time in min.

Dissolution Profile of Test Vs innovator in pH

6.8 phosphate buffer

Innovator FD 4

0

50

100

150

0 10 20 30 40 50

% D

rug R

elea

se

Time in min.

Dissolution Profile of Test Vs innovator

Innovator FD 4



was found similar to innovator with Formulation FD-4 and it was due to Crospovidone. Three month

stability data revealed that product is stable. From the above study it could be established that by

employing conventional diluents, super disintegrants, and lubricant an immunosuppressant

immediate release tablets of Azathioprine could be developed and commercialized for scale up.

ACKNOWLEDGEMENTS:

The authors are thankful to Sun pharmaceutical Ltd. for providing gift sample of Azathioprine, and

also to K M Kundnani College of Pharmacy for providing research facilities.

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