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:
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.
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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
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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
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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
5 pH 6.8 Phosphate buffer 0.119 29.75
6 pH 7.4 Phosphate buffer 0.118 29.50
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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
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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.
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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
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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].
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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
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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
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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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