Formulation of dry mixtures for oral solution of ketoconazole prepared by co-spray drying with hydroxypropyl-beta-cyclodextrins

Abstract

The formulation of ketoconazole as aqueous solutions for oral administration was investigated by using hydroxyprophy-β-cyclodextrins (HPBCD) as a solubilizer and stabilizer. From the phase solubility study, the solubility of ketoconazole in buffer solutions of pH 5.0 increased linearly as a function of HPBCD concentrations as type A[subscript L] phase diagram. The stability constant of inclusion complexse between ketoconazole and HPBCD was 714.76 M⁻¹. From the phase diagram the 2% w/v ketoconazole solution could prepared. Then dry powder was prepared by spray drying technique. To select the optimal condition for spray drying ketoconazole: solution, the optimization technique, by design expert version 7.13, was used and studied for 2 factors, inlet temperature and feed rate, with three levels for each. The results revealed that the optimal condition for this study is 120 ℃ for inlet temperature and 3.5 ml/min. for feed rate. Dry mixtures for oral administration were formulated with ketoconazole spray dried powders, aspartame, saccharin sodium and xanthan gum. The x-ray diffractogram and differential scanning calorimetric thermogram of spray dried powder might be due to the existence in an amorphous state or the formation of inclusion complexes between ketoconazole with HPBCD. Accelerated stability study of ketoconazole dry mixtures for oral solution were operated at 40 ℃ 75% RH and room temperrature 30 ℃ and ketoconazole reconstituted solutions at 40 ℃, 75% RH, refrigerated temperature (2-8 ℃) and room temperature were determined for 90 days. For comparison, ketoconazole suspension USP 29, was prepared and studied the stability. The remaining ketoconazole was analyzed by high performance liquid chromatography. Ketoconazole reconstituted solution and ketoconazole dry mixtures for oral solution had ketoconazole remained not less than 90%