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Pathak N et al. / Pharmacie Globale (IJCP) 2011, 3 (08)

1 Pharmacie Globale (IJCP), Vol. 02, Issue 03

Available online at www.pharmacie-globale.info

PHARMACIE GLOBALE

INTERNATIONAL JOURNAL OF COMPREHENSIVE PHARMACY

FORMULATION AND OPTIMIZATION OF IMMEDIATE RELEASE TABLET OF AN

ANTIALCOHLIC DRUG BY DRY GRANULATION METHOD

Naveen Pathak*, Anuj Kumar, Vishal Methkar, Pankaj Pant and Rama Therdana Rao

Department of Formulation Research & Development, Jagsonpal Pharmaceuticals Limited, Rudrapur, U S Nagar, Uttarakhand, India.

Received: 27 December 2010; Revised: 15 February 2011; Accepted: 28 February 2011; Available online: 5 March 2011

INTRODUCTION

The tablet is the most widely used dosage form because ofits convenience in terms of self- administration,

compactness and ease in manufacturing. In

pharmaceutical industries, manufactures of generic tablets

are usually focused on the optimization of the excipientsmixture composition to obtain a product that meet

established standard.1,2 Direct compression of powders

requires materials exhibiting flowability and

compressibility. Those parameters become more critical

when the formulation contains large amounts of activesubstances with poor compressional properties. Spray-

dried extracts (SDEs) from medicinal plants are very fine,

light, and poorly compressible powders.3 additionally,

many plant constituents are sensitive to moisture and

heat. To overcome these problems, several alternativeshave been suggested, such as wet granulation using

nonaqueous solvents,4 direct compression of dried

extracts,5 and the use of different excipients to improve theextracts properties or formulation for direct

compression.4,5 However, few studies have examined theuse of dry granulation to enhance particle size and

consequently to improve flowability and compressibility

of such materials, dry granulation seems to be the most

appropriate technique because of the hygroscopicity of the

powder.6,7 Dry granulation can be achieved either by

slugging, using a tablet press, or by roll compaction.*Corresponding Author:

Naveen Pathak

Department of Formulation Research & Development,

Jagsonpal Pharmaceuticals Limited, Rudrapur,

U S Nagar, Uttarakhand, India.

Contact no: +91-9040658461, Email: [email protected]

The desired particle size distribution can be adjusted bymilling and sieving.8 The granulation parameters can

affect the mechanical (compressional) properties of the

granules, which subsequently can influence the tableting

behavior and tablet characteristics.9 Therefore, theevaluation of granule properties plays an important role in

the prediction of tablet characteristics.9,10 The Heckel plot

is the method most frequently used to evaluate the volume

reduction of materials when pressure is applied.11,12 It is

assumed that the densification of the powder columnfollows a first-order kinetics. Thus, the degree of material

densification is correlated to its porosity. Although theliterature reveals some limitations to the Heckels model13,

the model has often been applied to study powder

mixtures14,15 and to evaluate the parameters of granulemanufacture.9,16,17 Disulfiram is a drug used to support the

treatment of chronic alcoholism by producing an acute

sensitivity to alcohol. Trade names for disulfiram in

different countries are Antabuse and Antabuse

manufactured by Odyssey Pharmaceuticals. Disulfiram isalso being studied as a treatment for cocaine dependence,

as it prevents the breakdown of dopamine (a

neurotransmitter whose release is stimulated by cocaine);

the excess dopamine results in increased anxiety, higher

blood pressure, restlessness and other unpleasant

symptoms. Several studies have reported that it has anti-protozoal activity as well.17,18 In the present research,

based on the literature, patent search and the

compatibility studies of the excipients the most favorable

excipients were short listed. All the excipients chosen arewell known for their suitability and fitness of purpose.

ABSTRACTDisulfiram tablet is being developed for the treatment of chronic alcoholism following regulatory submissions.The proposed commercial formulation for Disulfiram tablet is an uncoated immediate release tablet. Double

strength (500/250 mg) is proposed for commercialization. This study presents a summary of the process

optimization of Disulfiram tablet. The purpose of this research is to prepare Disulfiram immediate release tablet

by dry granulation technique. In order to obtain the best, Optimized product six different formulations weredeveloped. Different filler, disintigrants and lubricants were taken as variables. Weight variation, thickness,hardness, friability, disintegration time; In-vitro release and pharmaceutical assay were studied as response

variables. Poor flow property was observed with the formulation containing less concentration of Colloidal

Silicon Dioxide during slugging. However, in the remaining four formulations containing constant concentration

of Colloidal Silicon Dioxide, improved flow property was observed due to absence of static charges during

slugging. The formulation D04 was selected as an optimized product. The different physical properties and in-

vitro release profile showed D04, best comparable with reference product. Optimization has been proven an

effective tool in product development.

Keywords: Disulfiram, Optimization, Dry granulation technique, Immediate release tablet, Slugging.

Research Article

ISSN 0976-8157

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Each excipient is controlled by pharmacopeial

specification and are the same or similar to those used in

the reference innovators product. The object of the

development programme was to produce a generic tablet

which was robust, stable and of an acceptable formulationwhen compared to the reference original product, thereby

fulfilling the requirements of essential similarity to the

innovator or reference product.

The major objective of the product optimization stage is

to ensure that the product could be selected for furtherdevelopment (the intended commercial product).

MATERIALS AND METHODSDisulfiram (Apicore Pharma Pvt. Ltd, Baroda, India),

Colloidal Silicon Dioxide (200, Evonik Industries GMBH),

Lactose Anhydrous (Super tab 21 AN, DMV Fonterra),Microcrystalline Cellulose (PH112, FMC Biopolymer),

Stearic Acid (Spezoil, JRS Pharma Germany), Magnesium

Stearate (Ferro Signet), Silicified Microcrystalline

Celuulose (SMCC-90, SMCC-50, JRS Pharma Germany),

Sodium Starch Glycollate (Glycolis-Type A, RoqutteFrance). All other chemicals and reagents used were either

analytical or pharmaceutical grades.Solubility studies of Disulfiram

Maximal solubility of Disulfiram in different media

(Purified water, 2%w/w SLS in purified water, 0.01N HCl,

pH 4.5 Acetate Buffer, pH 6.8 CitroPhosphate buffer, pH

7.6 CitroPhosphate Buffer) was studied. Excess amount ofDisulfiram was taken in 50 ml of above medium and

dissolved by triplicate sonication. The maximal solubility

of Disulfiram in each medium was determined at different

time intervals (0, 15, 60, 120min) after filtering the

content using Chromatographic method at 254nm.

Preparation of Disulfiram tablets

Immediate release tablet of Disulfiram were prepared by

dry granulation technique using different hydrophilic and

hydrophobic polymers. Accurately weighed quantities of

presieved drug and intragranular materials (colloidalsilicon dioxide, lactose anhydrous, microcrystalline

cellulose, sodium starch glycolate, stearic acid) were

mixed & slugs were prepared, then passed with Multimillscreen (1.5). The granules were sieved through #20

sieves. The final granules were blended with extragranularmaterials (lactose anhydrous, sodium starch glycolate &magnesium stearate) and compressed using 12.7 mm

round flat standard concave punches on 12- station rotary

tablet press (Labpress, CIP Ahmadabad, India). Three

batches of tablets were prepared for each formulation.

Composition of prepared Disulfiram immediate releasetablets are presented in Table 1. Physical properties of

granules of different formulations were determined.

(Table 2)Table 1. Formulae used in the preparation of tablets

Ingredients D01 D02 D03 D04 D05 D06

Disulfiram USP 500 500 500 500 500 500

Colloidal Silicon Dioxide 3 10 20 20 20 20Lactose Anhydrous

(super tab 21 AN)

183 172 180 154 *** 156

Lactose Anhydrous

(super tab 22 AN)

*** *** *** *** 156 ***

Microcrystalline Cellulose

Ph-112

*** *** 40 60 60 60

Silicified Microcrystalline

Cellulose-90

60 60 *** *** *** ***

Sodium Starch Glycolate

(Glycolis-Type A)

6 10 12 14 14 14

Stearic Acid (Speziol) 4 4 4 6 4 6

Magnesium Stearate 4 4 4 6 6 4

Tablet Weight(mg) 760 760 760 760 760 760

Table 2. Physical properties of granules of different formulations

Properties D01 D02 D03 D04 D05 D06Angle of repose 28.20.04 27.60.06 28.60.02 26.00.03 23.90.09 27.50.03

Bulk density (gm/ml) 0.540.02 0.550.08 0.530.02 0.540.03 0.550.03 0.530.04

Tapped density (gm/ml) 0.680.04 0.690.03 0.680.03 0.690.02 0.690.02 0.680.04

Compressibility Index 27.01.06 26.11.07 25.771.37 21.651.25 23.521.52 24.830.98

Hausners ratio 1.360.09 1.300.18 1.350.24 1.270.20 1.310.19 1.330.20

Evaluation of tablet properties

The formulated tablets were evaluated for uniformity of

weight, thickness (micrometer, USSR), hardness, friability

and disintegration time.

Weight variation test

The variation of the weight of individual tablet is a valid

indication of the drug content. 5 weight variation studiesof 20 tablets were done and resulting deviations were

determined. (table 3)

Thickness measurement

It is carried out on 20 tablets by measuring thickness

using vernier calipers. Mean and standard deviation were

determined. (table 3)

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 is

shown in table 3.

Table 3. Physico-chemical properties of tablets of different formulationsProperties Reference D01 D02 D03 D04 D05 D06

Thickness (mm) 6.960.65 6.960.78 6.960.95 6.960.35 7.060.21 6.960.65 6.960.76

Weight Variation 7.600.05 7.600.03 7.600.09 7.600.08 7.600.02 7.600.05 7.600.08

Drug content (%) 99.20.40 99.20.60 99.20.80 99.20.60 99.40.40 99.20.40 99.20.30

Hardness (kg/cm2 ) 1100.10 1100.10 1100.10 1100.10 1100.20 1100.10 1100.20

Friability (%) 0.4 0.3 0.35 0.55 0.5 0.6 0.5

Disintegration Time (min.) 2.000.45 7.000.43 6.000.44 4.000.42 2.100.41 3.000.453 3.350.46

Friability test

Friability was determined on 20 tablets. Tablet samples

were weighed accurately and placed in fribilator(Electrolab India Ltd). After 100 rotations (4 min at 25

rpm) loose dust was removed from the tablets. Finally

tablets were wighed. The loss in weight indicates the

ability of the tablets to withstand the wear. The

percentage friability was determined by using following

formula:

Disintegration test

Disintegration time was determined to ensure that thedrug substance is fully available for dissolution and

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higher as compared to the reference product. About 2-5 %

concentration of sodium starch glycolate is generally

recommended in tablet preparation. Here it was utilized in

concentration 3.8% because in the presence of sodium

starch glycolate, tablet disintegrated rapidly.

Disulfiram does not possess excellent fluidity. The

lubricant is added in the formulation because it prevents

the adhesion of tablet material to the machine parts suchas punches and dies, reduce inter particle friction and

facilitates the ejection of tablets from the cavity. It ishydrophobic and may retard the dissolution of a drug

from solid dosage form; the lowest possible concentration

is therefore used in such formulation. Here compressiontakes place twice, once during slugging & another during

final compression, so two lubricants used in process

during slugging (stearic acid) & during final compression

(magnesium stearate). In this study stearic acid &

magnesium stearate were selected as lubricants inconcentration of (0.75%) each.

The optimized batch of Disulfiram tablet formulation D04

was studied for the different physical parameter and In-

vitro release profile in the above media. Results of alldeveloped formulation were within the acceptable ranges

of values as given in official compendia but it was

observed that the physical properties of D04 were best

comparable with marketed preparation. The in-vitro

release (Table 5) of Disulfiram from both the optimized

formulation D04 and marketed product were found

similar.

Dry granulation methods can be used alternatively fordirect compression method, because of the lower

compressibility index and poor flow properties of drug

candidate although number of research article are

available which are evident that the wet granulation is a

preferred method of tableting. Optimization technique is agood tool for preparing better quality of dosage form. This

is widely used in developing optimal dosage form andbetter process of manufacture.

CONCLUSIONDisulfiram immediate release tablets were prepared by

dry granulation technique. In order to obtain the best,Optimized product six different formulations were

developed. Different filler, disintigrants and lubricants

were taken as variables. An optimized product has been

formulated by varying the above variables and

determining their effect on physical/mechanicalproperties of the final product. Lower compressibility and

poor flow of drug candidate was overcome by dry

granulation (slugging).

ACKNOWLEDGMENTAuthors are thankful to Jagsonpal pharmaceutical Ltd.

Rudrapur for providing technical support, necessary

facility, equipment and material.

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