混合溶剂对喷雾干燥制备伊曲康唑固体分散体物理性质的影响

Influence of the Cosolvent Composition on the Physical Properties of Itraconazole Solid Dispersion Prepared by Spray Drying

关键词:  伊曲康唑  喷雾干燥  混合溶剂  固体分散体  物理稳定性

Key words:  itraconazole  spray drying  cosolvent  solid dispersion  physical stability

摘要:

目的 研究二氯甲烷-乙醇混合溶剂组分比对喷雾干燥制备伊曲康唑固体分散体物理性质的影响。方法 采用HPLC测定室温下伊曲康唑在不同体积比的二氯甲烷-乙醇混合溶剂中的平衡溶解度。以PVP VA64为载体，体积比分别为100：0、90：10、70：30、50：50的二氯甲烷-乙醇混合液为溶剂，采用喷雾干燥法制备伊曲康唑固体分散体，通过扫描电镜、差示扫描量热法、接触角测定仪和体外溶出试验对制得的固体分散体进行表征。采用差示扫描量热法考察固体分散体在90℃放置48，96，192 h后的物理稳定性。结果 伊曲康唑溶解度的大小取决于二氯甲烷-乙醇混合溶剂的组成，在不同体积比的二氯甲烷-乙醇混合溶剂中的溶解度差别很大。喷雾干燥制得的4种伊曲康唑固体分散体均为无定形固体分散体，具有单一的玻璃化转变温度、不同的形态和润湿性。体外溶出试验表明相对于原料药，制备得到的4种伊曲康唑固体分散体溶出速率显著提高。90℃高温加速稳定性试验放置后的固体分散体显示不同的物理稳定性。结论 二氯甲烷-乙醇混合溶剂组分比会对喷雾干燥制备伊曲康唑固体分散体的物理性质产生显著影响，其原因是由于伊曲康唑在混合溶剂中的溶解度差异会导致药物沉淀析出的时间不同，并进一步影响药物在固体分散体中的分布行为和物理稳定性。

Abstract:

OBJECTIVE To investigate the influence of cosolvent composition[different volume ratio of dichloromethane (DCM) and ethanol (EtOH)] on the physical properties of itraconazole (ITRA) solid dispersion prepared by spray drying.METHODS The equilibrium solubility of ITRA in DCM and EtOH mixtures of different ratios at room temperature was measured using HPLC method. Four different solvent compositions including DCM:EtOH (100:0, 90:10, 70:30, 50:50) were selected to prepare spray-dried solid dispersion with VA64 PVP as carrier. The spray-dried powders were characterized using scanning electron microscopy, differential scanning calorimetry(DSC), contact angle goniometer and in vitro dissolution study. The physical stability of the samples was accessed with DSC by storing the samples at 90℃ for 48, 96 and 192 h. RESULTS The solubility of ITRA was highly dependent on the composition of cosolvent, and the solubility of ITRA in DCM and EtOH mixtures of different ratios was significantly different. ITRA formulations processed with 4 different solvent compositions were all amorphous, with single glass transition temperatures, different morphology and wettability. Compared with the pure drug, the dissolution rates of ITRA solid dispersions were improved significantly. Spray-dried powders stored at accelerated stability condition (90℃) showed significant differences in the physical stability.CONCLUSION Cosolvent for spray drying has a remarkable influence on the physical properties of ITRA solid dispersion. The difference in the physical properties was attributed to the different ITRA solubility in cosolvent leading to a different drug precipitation time in spray drying droplets, which further influence the drug distribution behavior and physical stability of solid dispersion.