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

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%

本研究以羟丙基-β-环糊精（hydroxypropyl-β-cyclodextrins，HPBCD）作为增溶剂与稳定剂，对酮康唑口服水溶液的处方工艺展开了考察。通过相溶解度实验发现，在pH 5.0的缓冲液中，酮康唑的溶解度随羟丙基-β-环糊精浓度的升高呈线性增长，符合A_L型相图特征。酮康唑与羟丙基-β-环糊精形成的包合物稳定常数为714.76 M⁻¹。基于该相图，可制备得到2% w/v的酮康唑水溶液。随后采用喷雾干燥法制备得到固体粉末。为筛选酮康唑溶液喷雾干燥的最优工艺参数，本研究采用Design-Expert 7.13软件进行优化实验，考察了进风温度与进料速率两个因素，每个因素设置三个水平。实验结果表明，最优工艺参数为进风温度120℃、进料速率3.5 mL/min。以喷雾干燥得到的酮康唑粉末、阿斯巴甜、糖精钠与黄原胶为原料，制备得到口服用干混剂。喷雾干燥粉末的X射线衍射谱与差示扫描量热图谱结果表明，其可能以无定形态存在，或是酮康唑与羟丙基-β-环糊精形成了包合物。对酮康唑口服溶液用干混剂进行加速稳定性考察，考察条件分别为40℃、75%相对湿度（RH）以及室温（30℃）；同时对复溶后的酮康唑溶液分别在40℃、75% RH、冷藏温度（2~8℃）与室温条件下进行为期90天的稳定性考察。为进行对照，本研究同时制备了USP 29版收载的酮康唑混悬剂，并对其稳定性进行考察。采用高效液相色谱法对剩余酮康唑含量进行测定。在考察周期内，复溶后的酮康唑溶液与口服溶液用干混剂中，酮康唑的残留量均不低于90%