INTRODUCTION:

Biopharmaceutical classification system (BCS) classified drugs based on the solubility and permeability. BCS class II drugs having low solubility and high permeability. The process of drug absorption occurs via dissolution. So it is important for drugs to increase the bioavailability. Many solubility enhancements techniques like micronisation, solvent evaporation technique, cogrinding, meltevaporation. meltcrystallisation, solid dispersions, microemulsion, hydrotrophy, precipitation, nanosuspensions are present. Among those solid dispersions is most widely used method^[1] Solid dispersions mean inserting poorly soluble drug in to inert hydrophilic matrix. Several water soluble carriers such as methyl cellulose, urea, lactose, citric acid, polyvinyl pyrrolidone and polyethylene glycols 4000 and 6000 are used as carriers for solid dispersion.

Clopidogrel bisulfate is an anti-platelet drug, inhibits the ability of platelets to clump together as part of a blood clot. Clopidogrel prevents blood clots by irreversibly binding to the P2Y12 receptor on platelets, preventing Adenosine Diphosphate (ADP) from activating platelets. It belongs to a class of drugs called P2Y12 inhibitors.

Clopidogrel is used for preventing strokes, heart attacks, and death in individuals who have had a previous stroke, unstable angina, and heart attack or have peripheral arterial disease (PAD).^[2]Drawback with this drug is its very low solubility (0.0099mg/ml) in biological fluids, which results in poor bioavailability after oral administration. In the present investigation to increase the solubility solid dispersion technique is adapted to the drug by using three hydrophilic carriers. Among them cornstarch: lactose showed best results compared to lactose and dextrose. In the future studies using these polymers many formulations can be developed^[3].

MATERIALS:

Clopidogrel bisulphate was obtained as a gift sample from Hetero Drugs, Hyderabad. Lactose, dextrose, and cornstarch were obtained as a sample from Girijan Co-operative Corporation Ltd, Srisailam. All other ingredients are of analytical grade.

METHODS:

Clopidogrel bisulphate solid dispersions were prepared with three polymers using co-grinding method. Clopidogrel bisulfate (75mg) triturated with different ratios of polymers lactose (1:5, 1:10, 1:15), dextrose (1:10,1:15) cornstarch: lactose (1:10, 1:15) 20 minutes to ensure uniform mixing in geometrical ratio. Calibration data of pure dug in water, pH1.2, pH6.8 buffer were given in Table 1 and 2. Composition of the formulation and dissolution data of the pure drug mixture and dissolution data of the drug with polymers were given in the Table 3 and 4 respectively.

Selection of the carrier^[^4,5]

· Be freely water-soluble with intrinsic rapid dissolution properties.

· Be nontoxic and pharmacologically inert

· Be heat stable with a low melting point for the melt method.

· Be soluble in a variety of solvents and pass through a vitreous state upon solvent evaporation for the solvent method.

· Be able to preferably increase the aqueous solubility of the drug.

Materials used as carriers for solid dispersions

S.NO	Class	Examples
1	Sugars	Dextrose, Sucrose, Galactose, Sorbitol, Maltose, Mannitol, Lactose
2	Acids	Citricacid, Succinicacid
3	Polymeric materials	Povidone, Polyethylene glycols, Hydroxy propyl cellulose
4	Insoluble polymers	Hydroxy propyl methyl cellulose, phthalate, Eudragit L-100
5	Surfactants	Polyoxyethylene sterate, Tweens and Spans

Standard solution:

75mg of Clopidogrel bisulphate was dissolved in methanol in a 50ml volumetric flask and the solution was made up to mark with methanol.

Procedure:

The standard solution of Clopidogrel bisulphate was subsequently diluted with 0.1N Hcl and p^H6.8 and water to obtain a series of solutions containing 5, 10, 15, 20, 30, 45, 50,60,70 µg of Clopidogrel per ml. The absorbance of the solutions was measured in ELICO-SL 150UV spectrophotometer at 240nm.

Calibration curve for three buffers showed difference in solubility pH1.2 > water > p^H6.8. Acidic ph showed more solubility than basic pH.solid dispersions studied In vitro dissolution studies in Ph6.8 buffer.

Preparation of solid dispersions:

The solid dispersions were prepared by co grinding method clopidogrel bisulphate were mixed in various ratios lactose (1:5, 1:10, 1:15), dextrose (1:10, 1:15) cornstarch: lactose (1:10, 1:15).

Method of preparation of dispersion by co grinding method^[^6,7]

The required quantities of drug and carrier as given in table 4 .were triturated in a mortar and pestle thoroughly for 20min.the obtained powder was sifted through sieve number 80, solid dispersion equivalent to 75mg Clopidogrel was filled in to capsules.

Evaluation of solid dispersions:

The solid dispersions prepared were evaluated by the dissolution studies

Dissolution rate studies:

The dissolution rate testing of different Clopidogrel capsule formulations in table 5 was studied using USPXX1 dissolution rate testing apparatus (basket type) the basket was rotated at a speed of 50rpm and the dissolution fluid (900ml 6.8PHmedium) was maintained at a temperature of 37.5˚±0.5˚c.at specific time intervals a 5ml aliquot withdrawn and replaced to maintain sink condition. The obtained samples were analyzed at 240nm^[^8-10]

The dissolution profiles of Clopidogrel bisulphate solid dispersions from various formulations are given in the tables 6 and 7 and graphs 4, 5 and 6.

CONCLUSION:

Solid dispersions of Clopidogrel bisulphate prepared using cornstarch: lactose by co grinding method showed better dissolution than the pure drug. Cornstarch: lactose showed more solubility of drug compared to dextrose and lactose.

ACKNOWLEDGEMENT:

The authors are thankful to Chalapathi Institute of Pharmaceutical Sciences for providing facilities for bringing out this work.

Table 1: Calibration of Clopidogrel bisulphate in water at 240nm

S. NO	Concentration (ug/ml)	Trail I	Trail II	Trail III	Absorbance
1	5	0.280	0.271	0.269	0.273
2	10	0.382	0.369	0.389	0.380
3	15	0.487	0.479	0.483	0.483
4	20	0.584	0.562	0.568	0.571
5	25	0.678	0.658	0.668	0.668
6	30	0.785	0.783	0.775	0.781
7	35	0.869	0.864	0.864	0.865
8	40	0.890	0.899	0.890	0.895

Table 2: Calibration of Clopidogrel bisulphate in P^H1.2 at 240nm

S. NO	Concentration(ug/ml)	Trail I	Trail II	Trail III	Absorbance
1	10	0.215	0.248	0.218	0.227
2	20	0.326	0.354	0.325	0.335
3	30	0.434	0.478	0.445	0.452
4	40	0.545	0.578	0.567	0.563
5	50	0.658	0.689	0.680	0.675
6	60	0.741	0.798	0.790	0.776
7	70	0.849	0.890	0.891	0.876

Table 3: Calibration of Clopidogrel bisulphate in P^H6.8 at 240nm

S. NO	Concentration(ug/ml)	Trail I	Trail II	Trail III	Absorbance
1	10	0.194	0.256	0.239	0.229
2	20	0.304	0.345	0.340	0.331
3	30	0.426	0.458	0.451	0.447
4	40	0.575	0.560	0.568	0.567
5	50	0.686	0.654	0.689	0.676
6	60	0.796	0.780	0.784	0.786
7	70	0.898	0.894	0.890	0.894

Table 4: Amount of Clopidogrel bisulphate and carriers in solid dispersions

S. No	Formulation	Amt of drug (mg)	Amount of carrier (mg)
1	L1(1:5)	75	375
2	L2(1:10)	75	750
3	L3(1:20)	75	1500
4	D1(1:10)	75	750
5	D2(1:15)	75	1125
6	CS:L1(1:10	75	750
7	CS:L2(1:15)	75	1125

Table 5: List of different Clopidogrel capsule formulations

S. No.	Formulation	Composition
1	A	Pure drug( CL.G)
2	B	Pure drug in 0.1Hcl
3	C	Pure drug in 6.8 buffer
4	L1	CL.G:LACTOSE(1:5)
5	L2	CL.G:LACTOSE(1:10)
6	L3	CL.G:LACTOSE(1:20)
7	D1	CL.G:DEXTROSE(1:10)
8	D2	CL.G:DEXTROSE(1:15)
9	CS:L1	CL.G:CORNSTARCH:LACTOSE(1:10)
10	CS:L2	CL.G:CORNSTARCH:LACTOSE(1:15)

Table 6: Dissolution profiles of Clopidogrel bisulphate from capsules containing pure drug in a different mediums

S.NO	Time(mts)	%Clopidogrel dissolved
S.NO	Time(mts)	Water	Ph1.2	Ph6.8
1	5	29.493	63.122	17.4
2	10	32.083	72.618	18.72
3	20	36.309	84.669	21.96
4	30	42.316	87.076	22.8
5	45	48.681	90.28	24.12

Figure 1: Calibration curve of a drug in acidic medium

Figure 2 : calibration curve of a drug in water

Figure 3 : calibration curve of a drug in basic medium

Figure 4 : Comparison of pure drug dissolution in three mediums

S. NO	Time (mts)	%Clopidogrel bisulphate dissolved
S. NO	Time (mts)	L1	L2	L3	D1	D2	CS:L1	CS:L2
1	5	42.744	53.04	69.72	58.08	59.28	52.44	58.32
2	10	46.272	57.12	77.04	64.68	69.12	62.88	66.24
3	20	49.452	60.24	78.96	71.64	76.08	66.84	80.88
4	30	54.456	63.12	84.12	77.61	83.04	83.76	93.12
5	45	57.852	72.6	95.52	84.12	97.68	84.24	99.09