Effects of cyclodextrins for ophthalmic use on solubility and stability of 2% W/V ketoconazole solutions and lyophilized products

Abstract

The formulation of ketoconazole as aqueous solutions and lyophilized products for ophthalmic use was investigated by using cyclodextrins as a solubilizer and stabilizer. From the phase solubility study, the solubility of ketoconazole in buffer solutions increased as a function of hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD) concentrations as type A[subscript L] phase diagram. The stability constants of ketoconazole:HP-beta-CD inclusion complexes at pH 5 was much higher than that of ketoconazole: HP-gamma-CD inclusion complexes. The stability constants of HP-beta-CD complexes at pH 5 and pH 7 were 1263 and 6904 M[superscript 1]. Due to higher physical and chemical stabilities, the 2% w/v ketoconazole solutions and lyophilized products were prepared using HP-beta-CD at pH 7. Accelerated stability study at 50, 60 and 70 ํC, including 5 and 30 ํC was performed using high performance liquid chromatography to analyze the ketoconazole remaining. The color change which increased accordingly to the drug degradation could be detected by the determination of the absorbance at 410 nm. From the Arrhenius plot, the extrapolated shelf-lives of the formulation at refrigerator temperature and room temperature were 556 and 182 days, respectively. The extrapolated shelf-lives were longer than the observed shelf-lives, which were 111 and 107 days, respectively. Autoclaving of the solution was demonstrated to affect only 3% degradation. Moreover, the ketoconazole lyophilized products were more stable under the stressed condition at 45 ํC/ 75% relative humidity for three months than its solution form. The physiochemical characterization of 2% w/v ketoconazole solution showed the optimal pH of 7.06+-0.01, hypertonicity with 753+-12 miliosmole/kg and low viscosity at 2.50+-0.01 cps. The powder X-ray diffraction patterns and differential scanning calorimetric thermograms of ketoconazole lyophilized products revealed the formation of amorphous inclusion complexes between ketoconazole with HP-beta-CD. Furthermore, the sterile ketoconazole formulation did not produce ocular irritation and toxicity in the albino rabbits.