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Soumik Ghosh et al. / International Journal on Pharmaceutical and Biomedical Research (IJPBR) Vol.

1(4), 2010, 124-131

FORMULATION AND EVALUATION OF SUSTAINED RELEASE DOSAGE FORM OF NIFEDIPINE HYDROCHLORIDE USING MULTI-UNIT CHITOSAN TREATED ALGINATE
Soumik Ghosh1*, Nansri Saha Ghosh2, Subal Debnath3, G. Ganesh kumar3, Raja Chakraborty4, Saikat Sen4.
Department of Pharmaceutics, Annamalai University, Annamalai Nagar - 608 002, Tamil Nadu, India. SSJ college of pharmacy, Vattinagula pally, Gandipet, .Rangareddy Dist., Hyderabad, A.P. 500 075. 3 Srikrupa Institute of Pharmaceutical Sciences, Vil. Velkatta, Kondapak (mdl), Dist. Medak, Siddipet, Andhra Pradesh 502 277. 4 Creative Educational Societys College of Pharmacy, Chinnatekur, Kurnool, Andhra Pradesh 518 218.
2 1

ABSTRACT The main objective of the present work was to develop sustained release matrix tablets of water soluble Nifedipine hydrochloride using multi-unit chitosan treated alginate. Sustained release formulation is the drug delivery system that is designed to achieve a prolonged therapeutic effect by contineously releasing medication over an extended period of time after administration of single dose. Here the release of orally administered drug depends on the residence time of dosage form in the GIT. In the sustained release formulation of Nifedipine as the dose administration is reduced, increases patient compliance. This formulation exhibit neither very slow nor very fast rates of absorption and excretion. The sustained release formulation of nifedipine is absorbed uniformly from the entire gastro-intestinal tract. It is administrated orally in relatively small dose of 20 mg. The addition of chitosan increased the swelling of multiple unit systems (MUS) in acidic conditions and reduced the drug release from MUS. The MUS retained in gastrointestinal tract (GIT) for more than 12 h and distributed throughout the GIT. This study demonstrates that the matrix type chitosan treated alginate MUS can be a good addition to sustained release tablets to deliver Nifedipine hydrochloride and expected to be less of an irritant to gastric and intestinal mucosa. Key Words: Nifedipine, Sustained release matrix, Multiple unit systems, Chitosan treated alginate. INTRODUCTION Nifedipine is a calcium channel antagonist, which is widely used as a coronary dilator in hypertension. It is a poorly soluble drug, its absorption from gastrointestinal tract (GIT) is rate limited. It has a short biological half-life of 4 hrs. When administrated orally via immediate-release solid dosage forms, absorption of nifedipine is poor1. Sustained release nifedipine is prepared as an extended-release-film coated tablet. The extended-release-film coated tablet contains a tablet core coated by a slow releasing layer composed of drug and the hydrophilic polymer. The outer slow releasing layer provides the initial drug release followed by drug release from the core of the tablet2. Drug release from such a tablet follows the first order kinetics. The use of multi-unit chitosan treated alginate is designed to release a poorly soluble drug by surface erosion as a consequence of the polymer erosion from matrix3. The sustained release dosage form of nifedipine can be evaluated in-vitro by USP Dissolution Test Apparatus using either rotating basket paddle or modified disintegration test apparatus. Assay is also another procedure carried for its evaluation. The components like diluent, binder, disintegrate and lubricant may be suspended and/or dissolved in a suitable vehicle according to their nature. The solids should represent at least 50 to 60 % of the suspension under constant stirring to maintain good distribution4,5. The slurry in pumped to an atomizing wheel, which whirls the material into

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Soumik Ghosh et al. / International Journal on Pharmaceutical and Biomedical Research (IJPBR) Vol. 1(4), 2010, 124-131 a stream of hot air. The heat removes the liquid carrier, and the solids fall to the bottom of the dryer as fine spherical granules ranging from as low as 10 to as high as 250 in diameter, the size depending on the speed of the wheel and the flow rate of the feed. The drug may be mixed with this base in proportion as high as 1 : 1. Nifedipine hydrochloride formulation using multi-unit chitosan treated alginate were prepared and compared as an oral controlled release system. The various parameter (alginate, chitosan, drug and excipients, the volume of external and internal phases and drying methods) properties were investigated. The addition of chitosan increased the drug loading capacity of the beads, and larger beads were obtained in the presence of chitosan. On the other hand, addition of chitosan in the formulation reduced the drug release from beads. The erosion of the beads was suppressed by chitosan treatment6.
Fig. 1: Schematic representation of a novel multi-unit chitosan treated alginate for sistained relese of a poorly soluble drug.

MATERIALS AND METHODS Raw materials Nifedipine USP, hyprornellose BP, lactose BP, microcrystalline cellulose BP, povidone BP, isopropyl alcohol BP/dichloromethane BP, colloidal anhydrous silica BP, magnesium sterate BP, chitosan treated alginate, titanium dioxide BP, purified talc BP, iron dioxide USP, propylene glycol BP, isopropyl alcohol BP/dichloromethane BP. Drug and solution preparation The excipient-1 (hyprornellose BP ) and excipient-2 (lactose BP) are filtered through 200 mesh nylon cloth and kept aside. The solvent mixture is used for rinsing finally. The excipient-3 (microcrystalline cellulose BP) used is dissolved in continuous stirring with the as one solvent mixture of Step-A. Now the drug nifedipine is dissolved slowly with stirring in above excipient solution of Step-B. The drug solution is divided in to part 1 and part 2. Preparation of chitosan treated alginate Chitosan was reacted with sodium alginate in the presence of tripolyphosphate for bead formation. Spherical beads were produced with diameter in the range 0.700.90 mm and 2085% encapsulation efficiency. Dry mixing and granulation7 The shifted materials are loaded into Rapid Mixer Granulation (RMG), The materials are mixed in RMG for 10 minutes at fast speed in impeller. Now the RMG is started with impeller speed Slow and the dry binder solution of part 1 is added into the RMG bowl through binder addition port while mixing. Now the chopper speed is increased to Fast and mixed for 50 seconds. All the dry binders solution is added. The stainless steel containers are rinsed with 200 mesh nylon cloth filtered solvent mixture and added to the RMG. The lid is opened and the materials

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Soumik Ghosh et al. / International Journal on Pharmaceutical and Biomedical Research (IJPBR) Vol. 1(4), 2010, 124-131 adhered to the walls and lids are scraped, the granules are checked and discharged the materials into fluid bed dryer (FBD) bowl with chopper and impeller at slow speed. Drying8 The FBD bowl containing the wet mass is placed under the retarding chamber. The proper locking of the bowl with the retarding chamber is checked. The material is air dried for 10 mins. Racking uniformity of a limit temperature 45 to 50C. The drying needed for air-drying, racking and hot air drying are recorded. Granulation Stage9 The granules of Stage 1 are loaded in to RMG. The materials are mixed for 1 min and granulated once again with impeller speed Slow and chopper at Fast speed while adding part 2 drug and binder solution. The stainless steel container is rinsed with solvent mixture and added to RMG. The materials are mixed with impeller and chopper at Fast speed and the readings are noted. The lid is opened and the granules are checked and the materials discharged into FBD bowl with chopper Fast speed and impeller at Slow speed. Wet Milling10 The Screen size 8.0 mm is fixed for multimill. The cleaned high-density polyethylene (HDPE) container is placed at the discharge end of multimill and the granules are collected and keep aside for 10 min. At every 5 min material samples are racked. The first sample of milled material is checked. The above milled granules of 8.0 mm are passed through 2.0 mm screen and keep aside for 10 mins. At every 5 min the sample are checked. The above milled granules of 2.0 mm are passed through 1.0 mm screen and keep aside for 10 min. At every 5 min the sample are checked. The above milled granules of 1.0 mm are passed through 0.5 mm screen and keep aside for 10 mins. At every 5 min the sample are checked. The FBD bowl containing the wet mass is placed under the retarding chamber. The proper locking of the bowl with the retarding chamber is checked. The filter bag is shaked after switching off the FBD. The regarding chamber is hammered gently and waited for few seconds for dust to settles before lacking out the bowl. Now the loss on drying (LOD) of the dried granules are checked. Sifting and Milling11 Mesh no. 30 are fixed to the sifter and 1.0 mm screen is fixed for multimill. The HDPE container is placed at the discharge end of sifter and multimill. The dried granules are sifted through 30 mesh sieve. The retention of sifter sieve is milled by using multimill with 1.0 mm screen with slow speed and knives in forward direction into double polythene lined HDPE drum. The samples are checked for any presence of foreign particles. Now the 1.0 mm screen milled granules are passed through 30 mesh sieve and collected the granules in clean double black colored polythene bag lined container. The sifted and milled granules are collected in cleaned HDPE container lined with double polyethelene bag. Blending12 The 30 mesh sifted granules of Step-VIII are loaded into the Conta-blender. Now excipient-4 (povidone BP) is loaded into blender. The material is started in inch mode and the leakage is checked. The materials are blended for 25 mins. Some amount of blend is taken and is mixed with excipient-5 (povidone BP) and loaded into the blender. Now the material is blended for 5 mins. The blended materials are unloaded and are kept in black double poly bag lined HDPE containers and are labeled and weights are recorded. Compression13 The upper punches, lower punches and dies are checked before starting the machine for the compression. The blended granules are loaded into machine hopper and the blended granules are compressed using 6.0 mm normal concave punches dies (plain on both sides). The machine is started by inching and is checked for any noise. The first two rounds of tablets are collected and destroyed by putting them in water. The machine is set to meet then required standard physical parameters and compressions of blended granules are continued. The in process parameters are checked at regular interval.

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Soumik Ghosh et al. / International Journal on Pharmaceutical and Biomedical Research (IJPBR) Vol. 1(4), 2010, 124-131 In process quality control parameters Appearance - Yellowish round tablets with plain biconvex surface both sides; Weight of 20 tablets - 1.630 g 2 % (1.597-1.663 g); Hardness - NLT 2.5 kg/cm; Thickness - 2.9 0.2 mm (2.7 to 3.1 mm); Friability - NMT 10 %; Individual weight variation - 81.5 mg 5% (77.43 mg to 85.57 mg). Fourty tablets are collected and are checked individually for any damages on upper and lower surface before continuing compression. The individual weight variation, appearance, thickness are checked those are collected at the start of compression and after every two hours of compression. The group weight variation, thickness, hardness are checked at every one-hour interval. After compression, the tablets are collected in black double polyethelene lined HDPE container. Coating suspension preparation14 Step I Exciepient 1 (hyprornellose BP ) is filtered through 200-mesh nylon cloth in a stainless steel vessel & excipients-6 (colloidal anhydrous silica BP) is added & stirred for 5 mins. Step II - 200-mesh nylon cloth filtered excipient 2 (lactose BP) is added to the above solution. Step III - A polymer is dispersed in the above solution of step 2 by adding slowly with constant stirring for period of 30 mins (lump formation is checked) Step IV- excipient 7 (magnesium sterate BP) & excipient 8 (chitosan treated alginate) are dispersed to the 200 mesh filtered solvent mixture of excipient 2 (lactose BP), excipient 9 (titanium dioxide BP) is added to it. Step V - the above excipients are milled through colloid mill with recirculation for 10 mins. Step VI - the milled dispersion of step V is added to polymer solution of step III under continuous stirring for 20 mins till uniform dispersion is obtained. Step VII - the above materials are passed through colloid mill with recirculation OFF. Step VIII - the milled solution is transferred to agitator vessel by filtering through 200 mesh nylon cloth. Coating15 Coating solution is stirred at frequent intervals for every 5 mins during the process of coating. The compressed tablets are loaded into the coating pan and rotated the coating pan by inching for dedusting & preheating of tablets. The heating of tablets is continued until the required bed temperature is obtained. The parameters for coating of tablets followed are, Peristaltic pump revolutions per minute (RPM) : 15-30 RPM; Inlet air temperature : 60-75C; Outlet air temperature : 38-45C; Atomization pressure: 3.0-6.0 kg/cm, Spray gun distance : 18-24 cm; Pan RPM : 7-11; Spray rate/gun : 200-260 gm/min. The tablets are dried for 15 mins after completion of coating at 1-2 RPM in coating pan. Then the tablets are air dried for 30 mins by keeping the inlet air ON without heaters before collecting the tablet in black double polyethelene bag lined HDPE drums. For calculating the weight buildup for tablets during coating the samples are collected before and after coating from different points of coating and 10-15 tablets are taken at each sampling point. The gross weights of 10 tablets are taken and the increase in weight is calculated. The coated tablets are inspected for orange peel, roughness of edge, surface erosion, colour variation, film cracking, peeling & tablets with black spots. The inspected tablets are collected in black double polyethelene lined HDPE labeled container. In process sample test -loss on drying16 Loss on drying calculated by using the following formula, {[w2]-[w3]* [100] / [w2] - [ w1]} w1 - weight of empty bottle in gm; w2 - weight of bottle with sample in gm; w3 - weight of bottle with sample after drying in gm. Loss on drying found 4.09, 4.06 and 3.91 % w/w for the Batch I, Batch II and Batch III respectively, were under the specification which is not more than 6.0 % w/w. Finshed product test Finshed product-test showed that Reddish brown, round film coated tablets with plain biconvex surface on both sides complies for all the three batches. Drug release test17, 18

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Soumik Ghosh et al. / International Journal on Pharmaceutical and Biomedical Research (IJPBR) Vol. 1(4), 2010, 124-131 RPM of dissolution apparatus : 50; PH of dissolution medium : pH 6.8 buffer; Volume of dissolution fluid : 900 ml; Temperature of water bath : 37C; Sampling interval : 3 hrs. Exactly 330.9 gm of dibasic sodium phosphate and 38.0 gm of citric acid are transferred to 1000 ml volumetric flask, water is added to dissolve and 10 ml of phosphoric acid is added and diluted with water to make up the volume. Dissolution medium was prepared by mixing 125 ml of buffer concentrate and 1000 ml of 10 % sodium lauryl sulphate solution and diluted to 10 litres, pH is adjusted to 6.8. Standard prepared by transferring 22.3 mg of nifedipine working standard into 100 ml volumetric flask. It is dissolved and diluted with methanol and mixed. From the above solution 5 ml was transferred to 50 ml volumetric flask and diluted to volume. Sample prepared by taking 6 tablets individually in 6 dissolution flasks containing 900 ml of dissolution medium that has been equilibrated to 37C. The apparatus is started and samples are collected at specified time. The samples is withdrawn from a zone midway between the surface of the medium and top of the rotating blade and not less than 1 cm from vessel wall and filtered through 0.48 membrane filter after discarding the first 5 ml. Assay of Nifedipine hydrochloride Nifedipine content of the pellets was determined by UV spectrophotometry. The formulation (100 mg) were dissolved in 100 mL of methanol, and the resultant solution was diluted to obtain a 10 mg/mL nifedipine hydrochloride concentration. This solution was analyzed spectrophotometrically at 237 nm, and nifedipine content of 100 mg was determined. RESULTS AND DISCUSSION Drug release test were carried out at 3, 6 and 12 hrs, showed that at 12 hrs maximum on average 92.8, 91.5 & 82.5 % drug released for the Batch I, II & III respectively. Whereas, batch I showed maximum upto 92.8% drug release indicatese the beast batch of formulation.
Table 1: Drug release test at 3, 6 and 12 hrs.

Drug release test at hrs At 3 hrs

Specification Between 10% and 30%

Batch I Max: 20% Min: 11% Avg: 14.2%

Batch II Max: 24% Min: 14% Avg: 17.5% Max: 50% Min: 43% Avg: 46.5% Max: 98% Min: 87% Avg: 91.5%

Batch III Max: 21% Min: 13% Avg: 17.5% Max: 52% Min: 40% Avg: 47.2% Max: 85% Min: 80% Avg: 82.5%

At 6 hrs

Between 40% and 65%

Max: 50% Min: 40% Avg: 44.5%

At 12 hrs

Not less than 80%

Max: 98% Min: 86% Avg: 92.8%

It showed that the U.V absorption spectra of both standard and sample preparation exhibit maxima at the same wavelength corresponds to that in the standard, complies for the Batch I, Batch II and Batch III. Analysis of parameters for diameter, thickness, average weight, hardness and uniformity of weight satisfies the stable formulation. Diameter of the tablets found on an average 6.00 mm for all three batches. Thickness found to be 3.00 mm, average weight 85.60, 85.72, 86.10 for the Batch I, II & III respectively. Hardness 3.7, 4.00, 3.8 for the Batch I, II & III respectively. Uniformity of weight complies the IP specification for all the batches.

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Soumik Ghosh et al. / International Journal on Pharmaceutical and Biomedical Research (IJPBR) Vol. 1(4), 2010, 124-131
Table 2: Analysis of parameters for diameter, thickness, average weight, hardness and uniformity of weight.

Parameters Diameter

Specification The diameter of individual tablet should be in the range of 5.80 mm to 6.20 mm

Batch-I Max: 6.08 mm Min: 5.98 mm Avg: 6.0 mm

Batch-II Max: 6.04 mm Min: 5.96 mm Avg: 6.0 mm Max: 3.06 mm Min: 2.94 mm Avg: 3.0 mm 85.72 mg

Batch-III Max: 6.11 mm Min: 6.05 mm Avg: 6.1 mm Max: 3.01 mm Min: 2.97 mm Avg: 3.0 mm 86.10 mg

Thickness

The thickness of individual tablet should be in the range of 2.70 mm to 3.10 mm

Max: 3.04 mm Min: 2.98 mm Avg: 3.0 mm

Average Weight Hardness

Average weight of 20 tablets should be in the range of 84.39 mg to 89.61 mg The hardness of individual tablet not less than 2.5 kg/cm

85.60 mg

Max: 4.08 kg/cm Min: 3.3 kg/cm Avg: 3.7 kg/cm

Max: 4.48 kg/cm Min: 3.6 kg/cm Avg: 4.0 kg/cm Complies

Max: 4.25 kg/cm Min: 3.3 kg/cm Avg: 3.8 kg/cm Complies

Uniformity of weight

When 20 tablets are weighted not more than 2 of the individual weight deviate from average weight by more than 7.5% w/w and no. of the tablets deviates by more than 15.0% w/w.

Complies

Assay value found 19.53, 19.84 and 19.67 % w/w for the Batch I, Batch II and Batch III respectively, were under the specification which is not less than 19.0 mg and not more than 21.0 mg.
Fig. 1: In process sample test - loss on drying Fig. 2: Drug release test at 3 hrs.

LOSS ON DRYING
4.2 4 3.9 3.8 BATCH 1 BATCH 2 BATCH NUMBER BATCH 3

DRUG RELEASE TEST AT 3 HRS


20 15 10 5 0 BATCH 1 BATCH 2 BATCH 3 BATCH NNUMBER AVG DRUG RELEASE

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L.O.D

4.1

Soumik Ghosh et al. / International Journal on Pharmaceutical and Biomedical Research (IJPBR) Vol. 1(4), 2010, 124-131
Fig. 3: Drug release test at 6 hrs. Fig. 4: Drug release test at 12 hrs.

DRUG RELEASE TEST AT 6 HRS


AVG DRUG RELEASE

DRUG RELEASE RATE AT 12 HRS


95 90 85 80 75 BATCH 1 BATCH 2 BATCH 3 BATCH NUMBER AVG DRUG RELEASE

48 46 44 42 BATCH 1 BATCH 2 BATCH 3 BATCH NUMBER

Fig. 5: Diameter

Fig. 6: Thickness

DIAMETER
AVG THICKNESS
AVG DIAMETER 6.15 6.1 6.05 6 5.95 BATCH 1 BATCH 2 BATCH NUMBER BATCH 3

THICKNESS
4 3 2 1 0 BATCH 1 BATCH 2 BATCH NUMBER BATCH 3

Fig. 7: Average weight

Fig. 8: Thickness

AVERAGE WEIGHT
AVG HARDNESS

HARDNESS
4.1 4 3.9 3.8 3.7 3.6 3.5 BATCH 1 BATCH 2 BATCH NUMBER BATCH 3

86.2 86 85.8 85.6 85.4 85.2 BATCH 1 BATCH 2 BATCH NUMBER BATCH 3

AVG WEIGHT

Fig. 9: Assay

ASSAY
ASSAY RESULT 19.9 19.8 19.7 19.6 19.5 19.4 19.3 BATCH 1 BATCH 2 BATCH NUMBER BATCH 3

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Soumik Ghosh et al. / International Journal on Pharmaceutical and Biomedical Research (IJPBR) Vol. 1(4), 2010, 124-131 CONCLUSION Sustained release dosage form of nifedipine using multi-unit erosion matrix eudragit evalution data satisfies the formulation for the further in vivo study and highly probable multipurpose use. Drug release test at 12 hours showed maximum for Batch I in an average 92.8%. Analysis of parameters for diameter, thickness, average weight, hardness and uniformity of weight under the limit of the Pharmacetica for its effective formulation purpose. REFERENCES
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