Pattanayak Durga Prasad et al. IRJP 2 (3) 2011 121-124

IRJP 2 (3) Mar 2011 Page 121-124

INTERNATIONAL RESEARCH JOURNAL OF PHARMACY ISSN 2230 – 8407 Available online http://www.irjponline.com Research Article

DESIGN AND EVALUATION OF AN EXTENDED RELEASE TABLET DOSAGE FORM

OF CLASS-II DRUG, QUETIAPINE FUMARATE Pattanayak Durga Prasad1*, Narayan Una Lakshmi2, Dash Alok Kumar3, Mishra Jhansee3, Mishra

Manoj Kumar4 1S.P.S, BerhampurUniversity, Berhampur, Orissa, India

2I.G.I.P.S., Bhubaneswar, Orissa, India 3V.B.S.Purvanchal University, U.P., India

4B.P.R.I, Bhopal, M.P., India

Article Received on: 13/01/2011 Revised on: 18/02/2011 Approved for publication: 05/03/2011 *Durga Prasad Pattanayak, Email: durgaprasadpattanayak@yahoo.co.in ABSTRACT The scenario of pharmaceutical drug delivery is rapidly changing, but conventional pharmaceutical dosage forms are still dominating. Of all dosage forms, tablets are the manufacturer’s dosage form of choice because of their relatively low cost of manufacture, package, and shipment; increased stability and virtual tamper resistance. The main objective of the work is to develop a pharmaceutical equivalent, stable, robust and extended release tablets of Quetiapine. Which is orally administered ,very well tolerated side effect , lower incidence of EPS, improved depressed mood, high patient acceptability and satisfaction in recent era. To achieve this goal, various prototype trials were taken and evaluate with respect to various quality parameters such as bulk density, sieve analysis, drug uniformity and dissolution. KEYWORD: Extended release, Quetiapine , Hydroxypropylmethylcellulose, Polyethylene oxide, Seroquel tablet INTRODUCTION The aim of present work is to formulate a pharmaceutical equivalent dosage form of an Antipsychotic drug1,2. The objective of this research project was to develop an antipsychotic stable drug product which is as effective as other product, well tolerated and greater satisfaction by the patient .Also the in vitro drug release between In-house and the Pioneer drug product (SEROQUEL TABLETS) by ASTRAZENECA, USA study was done. MATERIALS AND METHODS Quetiapine fumarate from Concord biotech, Ahmedabad, Microcrystalline Cellulose supplier FMC Ireland/ Signet Chemical, Trisodium dihydrate as Buffering agent supplier FMC, Ireland/ Signet Chemical, Xantharal from BASF, Germany/ Signet Chemical, Magnesium stearate use as lubricant collect supplier Ferro, Portugal/ Signet Chemical, Lactose monohydrate a Diluents from FMC, Ireland/ Signet Chemical, Maltodextin a Diluent and polymer , Red iron Oxide & Yellow iron Oxide both are Colorant are collect from BASF, Germany/ Signet Chemical, Polyox and Methacrylate copolymer are use as Polymer supplier Coloforn asia limited, Sodium alginate Concord biotech, Ahmedabad, coating solution Ideal Cures Pvt. Ltd. Andheri(E),Mumbai, HPMC Hypermellose6 cps supplier Shin-Etsu,Japan / Signet chemical, PEG a Plasticizer supplier Merck/ Signet

Chemical, Talc Luzenac(Rio Tinto Italy)/ Signet Chemical. All the ingredients in respective formulae were passed through sieve no 80 to remove any aggregates present in powder. Then they were thoroughly triturated in a mortar and pestle to get a homogenous mix. The tablets were prepared by direct compression method3,4. Well-mixed powder was compressed using a ten-station rotary tablet compression machine (M/c Rimek Minipress Machinery Co. Pvt. Ltd.), at the hardness of nearly 5kg / cm2.are given in (Table-4). RESULT AND DISCUSSION Preformulation Study The present investigation was carried out to develop extended release tablet dosage form of Class -II drug, Quetiapine5. The Tablets were prepared by using different excipients. Compatibility Study: Drug–Excipient compatibility study of Quetiapine with different categories of excipients was carried out. The study was carried out at different conditions of temperature and humidity like 40°C/75%RH, 2–8°C, room temperature & found their physical appearance, impurity level and water content after 2 week, 4 weeks and compare with initial value. The result shows impurity level with some drug and excipient combination increases and also slight changes in appearance but

Pattanayak Durga Prasad et al. IRJP 2 (3) 2011 121-124

IRJP 2 (3) Mar 2011 Page 121-124

except hypromellose all were compatible with Quetiapine. Excipients were considered compatible only if the total impuritties do not exceed 2–times the impurities of initial. API Characterization Study pH Dependent Solubility Study: pH of Quetiapine in 10% solution (water) found to slightly acidic. The pH dependent solubility study carried out by using different pH buffer solution ranging pH 1.2 (0.1 N HCl), pH 2.1 acid buffer, pH 4.5 acetate buffer, pH 5.5 acetate buffer and pH 6.8 phosphate buffer6. Study shows solubility of Quetiapine was more in pH 1.2 (0.1 N HCl) i.e. 17.17 mg/ml2. Water was used as dissolution medium as used by innovator (It is also added in USP recently) Sieve Analysis of API. The sieve analysis was carried out by using mechanical shaker shows the particle size of Quetiapine (which was used) were < 850um (99%). Powder Flow Properties: The flow properties of pure drug were carried out and the results indicate that drug shows poor flow. So, it was decided to overcome this problem by converting them to granules which was done by wet granulation technique using water binder to import good flow as well as compressibility3. Evaluation of Formulation Parameters Evaluation was divided in mainly Pre compression Parameters and Post compression Parameters6. This includes Loss on Drying of dried granules and final blend, bulk density, tapped density, Carr’s Index, Houser’s Ratio and sieve analysis in pre compression parameters and average weight, thickness, hardness, disintegration time and friability in post compression parameters. Pre Compression Parameters Loss on Drying (LOD) - As calculated, theoretical moisture content of drug and excipient which was 2%w/w, 80 LOD of dried granules maintained in that level NMT ± 2% variation by drying at 60°C and optimize drying time for achieve LOD in particular limit. Powder Flow Characteristics: Initially some flow problem arises in direct compression method. Powder Blend shows poor flow which causes weight variation, problem in content uniformity; But Wet Granulation Method shows good flow properties of granules and final blend. Bulk density in the range 0.58 – 0.57 gm/ml Tapped density in the range 0.619-0.643 gm/ml Hauser’s ration in the range 1.2-1.3 shows the good flow characteristics. Sieve Analysis: Sieve Analysis by Mechanical shaker shows there was good blend of fines and granules which result in good flow and reduces weight variation problems.

Post Compression Parameters Weight Variation: Initially in same trails, weight variation observed, but in final trial tablet ranging 600-603mg (Target wt –600mg/Tablet) for 200 mg which is less than 5% indicates that the variation in the weight of the tablets is within standard official limits. Thickness Evaluation: Thickness of tablets was observed by Vernier Caliper. Thickness of Tablet does not show any measurable deviation in both strengths. Hardness Test : Hardness of the tablet was measured in ‘Newton’ unit in digital harness tester The hardness of tablets found to be uniform within range 120 N to 140 N for 200mg Friability Test: The friability was carried out by using Roche Friabilator. The percentage friability of tablet was ranging 0.03% - 0.08% for 200mg. They are less than the standard limit of 1% indicates that the prepared tablets are mechanically stable. Drug Content Uniformity In the initial trials drug content uniformity found outside limit but, after that each trials drug contents ranging from 98% - 101.2% which is within the range of 92.5 – 105% for Quetiapine. It indicates uniform distribution of drug in the tablets of each formulation. Dissolution Studies The release rate of Quetiapine was determined using USP XXIV (model DISSO, M/s Labindia) rotating paddle method (Apparatus II). The dissolution test was performed using 900ml of 0.1 N HCl, 37± 0.50C at 50 RPM. 5ml sample was withdrawn hourly from the dissolution medium for 12 hours, and replaced with fresh medium7,8. The samples were filtered through Whatman filter paper no. 41. After suitable dilution solution’s absorbance was measured at 313 nm using a double beam UV spectrophotometer (Shimadzu 1700). Release rate are shown in (Table-1, 2 and 3). Exposure Study Exposure studies were carried out of selected trial. In exposure study, our trial and innovator formulation was subjected to different environmental stress conditions like 80° for 2 days and in autoclave at 121°C for 15 min. The result shows similar behaviour between our trial and innovator in different conditions. Stability Study The stability studies of final trial was done for 3 months by packing in HDPE container in humidity chamber 40°C/75% RH.8,9 The result given in table for 1 month, 2 months, 3 months show. All parameters of formulation including physical parameters, impurity profile, content uniformity or dissolution profile were within specification limit.9 So it indicates optimized formulation were stable. All in all, in these different steps

Pattanayak Durga Prasad et al. IRJP 2 (3) 2011 121-124

IRJP 2 (3) Mar 2011 Page 121-124

formulation and development study of Quetiapine tablet was successfully accomplished and results were found also satisfactory. CONCLUSION In the present investigation, an attempt was made to formulate bioequivalent dosage form of extended release of Quetiapine fumarate. The study was aimed at developing tablet formulation with in vitro dissolution profile identical to innovator product Seroquel XR.The study involved formulation, evaluation and in vitro release profile of Quetiapine in order to understand the dissolution behaviour as well as for calculating dissimilarity (f1) and similarity (f2) factors10..Evaluation of developed formulations for various pre compression and post compression parameters was done.. Stabilities studies on the optimized tablet formulation at different stability storage conditions were observed. A physicochemically stable film coated extended release tablet formulation of Quetiapine fumarate was successfully design11. Physical attributes of tablets such as percentages weight variation, friability, drug content uniformity, all of which were found to be within pharmacopoeial limits. In vitro drug dissolution that demonstrated drug release in manner quite identical to Seroquel. Least dissimilarity (f1) factor value and highest similarity (f2) factor value indicating that the developed product has the capacity to pass in vivo bioequivalence test. In conclusion, a stable film coated

extended release tablet of Quetiapine was successfully developed that has in vitro drug release character identical to the innovator’s product Seroquel. REFERENCES 1. Chatterjee CC. Human Physiology. Vol I, Medical Allied

Agency; Kolkata; 2004. 2. Indian pharmacopoeia, Vol II. Government of India, Ministry of

Health and Family Welfare. Published by the Controller of Publicatons; Delhi; 1996.

3. The theory and practice of industrial pharmacy, Leon Lachman ,Hearbert A. Lieberman and Joseph L. Kangi-third edition, 2003.

4. Rowe RC, Shesky PJ, Weller PJ. Handbook of Pharmaceutical Excipients. 4th ed. London; Pharmaceutical Press; 2003.

5. Chein YW. Novel Drug Delivery Systems, 2nd ed, Marcel Dekker, New York, 2005, 157-63.

6. Mathematical modelling and in vitro study of controlled drug release via a highly swellable and dissoluble polymer matrix: polyethylene oxide with high molecular weights. J Controlled Release 2005; 102: 569–581.

7. Vyas SP, Khar RK. Controlled Drug Delivery: Concept and Advances 1st ed. Vallabh Prakashan; Delhi; 2002.

8. Moore JW and Flanner HH. Mathematical comparison of dissolution profiles. Pharm Tech 1996; 20: 64–74.

9. Martindale. The Complete Drug Reference. 34th ed. London; Pharmaceutical press; 2002.

10. Maggi L, Segale L, Torre ML, Machiste EO and Conte U. Dissolution behaviour of hydrophilic matrix tablets containing two different polyethylene oxides for the controlled release of a water-soluble drug. Dimensionality study. Biomaterials 2002; 23: 1113–1119.

11. Kiss D, Süvegh K, Marek T, Dévényi L, Novák Cs and Zelkó R. Tracking the physical aging of poly (ethylene oxide): A technical note. AAPS PharmSciTech 2006; 7 (95): 118-125.

Table 1: Reference Product Profile

Time(min)

% Drug release Unit-1 Unit-2 Unit-3 Mean RSD

0 0 0 0 0.0 0.0 1 48.9 47.8 49.6 48.77 1.86 2 48.1 50.9 53.5 50.83 5.31 4 56 59.4 54.4 56.6 4.51 6 65.8 71.2 73.9 70.3 5.87 8 75.2 82.4 85.5 81.03 6.52 10 82.7 93.7 92.2 89.53 6.66 12 89.3 97.3 96.5 94.37 4.67 16 98.1 99.1 101 99.4 1.48 18 101.2 99.9 100 100.37 0.72 24 101.4 106.4 100.1 102.63 3.24

Table 2: Test product profile

Time

(min)

% Drug Released Unit-1 Unit-2 Unit-3 Mean RSD

0 0 0 0 0.0 0.0 1 48.7 55.6 48.4 50.9 8.0 2 49.9 59.2 50.6 53.23 9.73 4 54.6 59 55 59.53 13.78 6 62.9 80.5 62.3 68.57 15.08 8 70.4 92 69.1 77.17 16.67 10 77 97.6 74.2 83.93 15.41 12 84.3 99.4 83.5 89.7 10.6 16 96.8 101.4 97.2 98.47 2.59 18 98.8 102.6 99.3 100.23 2.06 24 102.8 104.2 100.4 102.45 1.88

Pattanayak Durga Prasad et al. IRJP 2 (3) 2011 121-124

IRJP 2 (3) Mar 2011 Page 121-124

Table 3: Dissolution Profile

Time in minute

% of Dissolution (Tt-Rt)

(Tt-Rt) 2 Reference-Rt Test (Tt)

0 0 0 0 0 1 48.77 50.9 2.1 4.41 2 50.83 53.23 2.4 5.76 4 56.6 59.53 2.9 8.41 6 70.3 68.57 1.7 2.89 8 81.03 77.17 3.9 59.21 10 89.53 82.93 6.6 43.56 12 94.37 89.07 5.3 28.09 16 99.4 98.47 0.9 0.81 18 100.37 100.23 0.1 0.01 24 102.63 102.47 0.2 0.04 sum 793.8 782.6 19.6 384.16

Table 4: Quetiapine XR Tablets

B.NO C216-19A C216-19B C216-20 C216-21 C216-22 C216-23 Base granules

with MCC and extragranular

Base granules with MCC and extragranular

Base granules with MCC and extragranular

Base granules withintra and extragranular MCC ,20% Polymer

Base granules with intra and extragranular MCC ,25% Polymer

Base granules with mannitol

Quetiapine 230.5 230.5 230.5 230.5 230.5 230.5 MCC(Avicel 101) 102.5 102.5 82.5 102.5 102.5 77.5 SodiumCitrate dihydrate 75 75 75 75 75 75 Mannitol 0 0 0 0 0 25 Mg Stearate 12 12 12 12 12 12 Polyox WSR 303 80 60 100 54 67 80 Polyox WSR N750 100 120 0 66 0 0 MCC102(Avicel 102) 0 0 0 60 30 0 Polyox WSR N80 0 0 100 0 83 100 Purified water qs qs qs qs qs qs Total weight 600 600 600 600 600 600

Figure 1: Molecular Structure - Quetiapine fumarate

Source of support: Nil, Conflict of interest: None Declared