泊沙康唑晶型制备及甲醇-水体系中相图测定

Preparation of Polymorphs of Posaconazole and Determination of Phase Diagram in Methanol-water System

目的 制备泊沙康唑工艺相关的Form Ⅰ、Form Ⅲ、Form Ⅳ、Form S 4种晶型,研究上述晶型在甲醇-水体系中相互稳定性关系,并绘制相图。方法 采用溶液结晶法控制结晶溶剂、温度等析晶条件进行制备,并采用XRPD、DSC、TGA等方法表征4种晶型,采用晶型竞争试验的方法研究晶型在甲醇-水体系中的相对稳定性。结果 在甲醇-水体系中,泊沙康唑的晶型与水活度及温度密切相关。高水活度和低温更易于形成Form Ⅳ;高浓度甲醇和低温更易于形成Form Ⅲ;高水活度和高温更易于形成Form S;低水活度和高温更易于形成Form Ⅰ。结论 泊沙康唑在原料药结晶工艺及制剂处方工艺过程中存在转晶风险,制剂处方工艺中采用湿法造粒风险较高,因此在结晶工艺过程中确定析晶和洗涤时的甲醇优选范围对原料药和制剂生产过程中的晶型控制具有较强的指导意义。

OBJECTIⅣE To prepare four polymorphs(Form Ⅰ, Form Ⅲ, Form Ⅳ and Form S) related in industry process of posaconazole and to study their relative stability and the phase diagram in methanol-water system. METHODS Solution crystallization method were chosen to produce the forms through controlling solvents, temperature and other crystallization conditons. XRPD, DSC, TGA were used to characterize polymorphs. Competitive ripening were taken to study the relative stability in methanol-water system. RESULTS In methanol-water system, water activity and temperature were both key parameters for crystal controlling. Higher water activity and lower temperature were conducive to Form Ⅳ;higher concentration of methanol and lower temperature were conducive to Form Ⅲ;higher water activity and higher temperature were conducive to Form S;lower water activity and higher temperature were conducive to Form Ⅰ. CONCLUSION Posaconazole has the risk of crystal form transformation in the crystallization process of the raw material drug and the formulation process of the formulation,and the risk of wet granulation in the formulation process is relatively high. Therefore, determining the preferred range of methanol for crystallization and washing during the crystallization process, is useful for the crystal form control in the drug substance and formulation manufactural processes.