INTRODUCTION:

Ketoconazole is synthetic antifungal agent, Imidazole derivative, chemically it is piperazine, 1-acetyl-4-(4-[2-92,4-dichlorophenyl)-2-(1H-1imidazole-1-yllmethyl)-1,3dioxolan-4-yl)methoxy) phenyl]-cis. Ketoconazole is used in the local and systemic candidacies, cryptococosis. Ketoconazole fall under Class II Compound as per the biopharmaceutical classification system (BCS). Class II means high permeability and low solubility. Ketoconazole soluble in DMSO (scbt.com) (20 mg/ml warm) in ethanol (20 mg/ml warm) in water (≤1 mg/ml) (scbt.com) due to poor water solubility of drug it is challenging task to enhance solubility and dissolution rate.

Ketoconazole was use as a model drug. Literature reveals that ketoconazole classified in BCS Class II means high permeability and low solubility. ^{1, 2, 3}Ketoconazole is poorly soluble means lipophilic compound pKa 6.51 and 2.94⁴ means moderately weak acid. Best absorb s in acid (at pH3).

Enhancement of oral bioavailability of such poorly water soluble drug remain challenging task. Solid dispersion method used for improving dissolution, solubility and bioavailability. Solid dispersion consist of hydrophilic matrix and lipophilic drug ^5,6 The increase in the dissolution rate of ketoconazole may be due to increase in wetting, hydrophilic nature of the carrier as well as reduction in drug particle size. ^{5, 7, 8} It is possible to improve its bioavailability by increasing its aqueous solubility.

Ketoconazole which is a poorly water‐soluble drug shows poor solubility or poor wet ability which leads to decrease in bioavailability.⁹ Solid dispersion is one of the unique approaches, to

Increase the solubility, dissolution and absorption of poorly soluble drugs.^10,11In SDs technique dissolution rate can be improved by increasing the surface area and thereby reducing the particle size.¹²

MATERIALS:
Ketoconazole was received as gift sample from Aurobindo Pharma Ltd, Hyderabad. PEG 4000, PEG 6000 from Loba Chem Ltd. Mumbai. All other chemicals and reagents used in this study were of analytical grade.

Physical mixture:

Drug and carrier (PEG 4000, PEG 6000 and urea) in ratio of 1:1,1:2,1:4,1:6,1:8 and 1:10 respectively were geometrically mix by using spatula. Prepared mixture triturated by using mortar and Pestle for 5 minutes. Prepared mixture finally passed through an 80 mesh screen and stored.

METHOD:

Solid dispersion prepared by different methods such as solvent evaporation method, kneading method, fusion method; melt solvent method out of that solvent evaporation method was used.

Solvent Evaporation Method:

Drug and carrier (PEG 4000, PEG 6000 and urea) in ratio of 1:1,1:2,1:4,1:6,1:8 and 1:10 respectively were dissolved in minimum volume of organic solvent (Dichloromethane) with continuous stirring. The solvent was then evaporated at 45 ⁰C with continuous stirring to obtain solid residue in a flask, If necessary vacuum pump was used to evaporate solvent. Prepared solid dispersion was kept in refrigerator for about 5 min and allowed to solidify. The hardened mixtures were then powdered in mortar, sieved through an 80 mesh screen and stored in desiccators at room temperature.

FORMULATIONS:

Solid dispersions prepared with Drug with PEG 4000, Drug with PEG 6000and Drug with Urea in different weight ratios 1:1,1:2,1:4,1:6,1:8,1:10

Evaluation of ketoconazole solid dispersions

Percent practical yield ¹³

Percentage practical yield were calculated to know about percent yield of the method, thus it helps in selection of appropriate method of production. Solid dispersions were collected and weighed to determine from the following equation.

Practical yield (%) = [Practical Mass (Solid dispersion) / Theoretical Mass (Drug+ Carrier)] × 100

Drug content ¹⁴

The Physical mixture and solid dispersion equivalent to 200 mg of model drug were taken and dissolved separately in 100 ml of methanol. The solutions were filtered and were further diluted such that the absorbance falls within the range of standard curve. The absorbances of solutions were determined at 254 nm by UV‐visible spectrophotometer. The actual drug content was calculated using the following equation as follows:

% Drug content =

Actual ketoconazole content in weight quantity of solid dispersion

------------------------------------------------------------------------------X 100

Theoretical amount of ketoconazole solid dispersion

INVITRO DISSOLUTION STUDIES:

The dissolution studies were performed using USP Type I (Basket) dissolution test apparatus. The sample equivalent to 200mg ketoconazole solid dispersion was placed in basket. Dissolution vessel containing 800 ml 0.01NHCl maintained at 37°C and stirred at 100 RPM. The samples were collected periodically and replace with a fresh dissolution medium. After filtration, the concentration of ketoconazole was determined by UV-visible spectrophotometer at 254 nm.

FIG.1 Standard curve of Ketoconazole

FIG.2 Dissolution profile of SDs of Drug: PEG 4000

FIG.3 Dissolution profile of SDs of Drug: PEG 6000

Table No.1: Percentage drug release of Drug: PEG 4000, Drug: PEG 6000, Drug: Urea

	Drug: PEG 4000						Drug: PEG 6000
Formulation	F1	F2	F2	F4	F5	F6	F7	F8	F9	F10	F11	F12
Ratio Time (Min.)	1:1	1:2	1:4	1:6	1:8	1:10	1:1	1:2	1:4	1:6	1:8	1:10
0	0	0	0	0	0	0	0	0	0	0	0	0
10	20	22	20	9	15	7	17	16	19	40	12	19
20	35	32	32	15	25	19	33	30	39	51	22	29
30	49	48	47	32	36	30	45	43	40	59	24	40
40	62	66	61	38	47	43	65	54	51	71	33	48
50	79	78	74	52	54	45	79	69	60	83	36	57
60	88	89	88	60	59	54	86	74	65	90	43	60

	Drug: Urea
Formulation	F13	F14	F15	F16	F17	F18
Ratio Time (Min.)	1:1	1:2	1:4	1:6	1:8	1:10
0	0	0	0	0	0	0
10	17	16	45	30	23	47
20	31	44	71	54	50	71
30	41	60	86	59	56	74
40	51	77	92	65	61	78
50	64	92	94	70	70	77
60	73	94	99	75	74	84

FIG.4 Dissolution profile of SDs of Drug: Urea

RESULT AND DISCUSSION:

Solid dispersions of ketoconazole were prepared by solvent evaporation using carriers like PEG‐4000, PEG‐6000, Urea. In the present work, total 18 formulations were prepared and their complete detail shown in Table No.1.

Percent practical yield:

The results of percent practical yield of ketoconazole SDs.The % Practical yield of the prepared solid dispersions was found in the range of 86.50 ‐ 97.53%. The maximum yield was found 97.53% in F3 formulation.

Drug content:

The actual drug content of all the 18 formulations of Ketoconazole SDs. The drug content of the prepared Solid dispersions were in the range of 86.37 ‐ 100.03% indicating the application of the present methods for the preparation of Solid dispersions with high content uniformity. The maximum % drug content was found 100.03% in F3 formulation.

Dissolution Studies:

Dissolution of ketoconazole from its pure drug was about 41% in 60 minutes. Solid dispersion brings the drug in close contact with the hydrophilic polymer. The increased dissolution rate can thus be explained as being due to increased wettability and dispersibility of ketoconazole. Dissolution profiles of ketoconazole SDs are shown in Table No.1. SDs of ketoconazole showed a significant increase in the release profile as compared with physical mixture and pure ketoconazole. SDs with Drug: PEG 4000 for ratio 1:1, 1:2, 1:4 were showing 88% .89%, 88% drug dissolved in 60 minutes. In SDs with Drug: PEG 4000 with ratios (1:2) was showing faster dissolution profile. Similar drug release profiles were observed from Drug: PEG 4000 ratio 1:1 to 1:4.

For SDs with Drug: PEG 6000 ratios 1:1,1:6 were 86%,90% drug dissolved in 60 minutes,

For SDs with Drug: Urea for ratios 1:2, 1:4 were %, 97%respectively drug dissolved in 60 minutes. Similar drug release profile were observed from

Drug: Urea ratio 1:2 to 1:4 ratios were 94%, 99% drug dissolved in 60 minutes. Dissolution study of solid dispersions revealed that there was a marked increase in the dissolution rate of ketoconazole by using hydrophilic carrier. Solid dispersions of drug: urea containing ratio from1:2 to 1:4 were showing faster dissolution. The increase in the dissolution rate of ketoconazole may be due to increase in wetting, hydrophilic nature of the carrier.

ABBREVATIONS:

SD: Solid dispersion

BCS: Biopharmaceutical classification system.

DMSO: Dimethyl sulphoxide

PEG: Polyethylene Glycol

OGD: Office of generic drug.

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Received on 01.04.2016 Modified on 23.04.2016

Res. J. Pharm. Dosage Form. & Tech. 2016; 8(3): 173-176.

DOI: 10.5958/0975-4377.2016.00023.9