不同厂家生产罗红霉素原料药的表征及其片剂制剂溶出的比较研究

目的：对国内市售5个厂家的罗红霉素原料药进行固体形态和理化性质表征，并按照同一处方压制片剂，考察对应的溶出曲线，探讨不同厂家生产的原料药的固体形态和理化性质差异对制剂产品溶出行为的影响。方法：采用X射线粉末衍射（XRPD）分析、扫描电镜（SEM）分析、差热热重（DTG）分析、粉末溶解速率分析方法对5种罗红霉素原料药进行了表征，并研究其在高温（60℃）、高湿（90% RH）条件下的稳定性，最后考察对应片剂的溶出曲线差异。结果：5个厂家的罗红霉素原料药之间晶型状态存在显著差异，可根据XRPD表征结果分为A和B类。2类晶型在高温（60℃）和高湿（90% RH）条件下储存都保持稳定；但将A和B类晶型放置在水中时，B类稳定，A类不稳定，并会转化为B类；同时2类晶型在水中溶解曲线存在差异。A、B 2类晶型原料药所制得片剂的溶出曲线也存在不可重合现象。结论：本研究通过XRPD法、SEM法、DTG法、粉末溶解速率法来鉴别5种市售罗红霉素原料药差异，药品稳定性、压片成型性、溶出度等分析结果表明B晶型为优势晶型，粉末晶型的差异会影响罗红霉素片剂溶出曲线。本研究揭示了制剂开发前处方前研究的重要性，且为罗红霉素原料药质量控制和制剂原料药筛选提供了科学依据。

Objective:To investigate the characteristics and physiochemical properties of five roxithromycin active pharmaceutical ingredients (APIs) in solid-sates from different domestic manufactures, and dissolution profiles of their tablets.Methods:X-ray powder diffraction (XRPD) analysis, scanning electron microscope (SEM) analysis, differential thermal & gravimetric (DTG) analysis were used to characterize the solid-states;solubility in water and stability under high temperature (60℃) and high humility (90%RH) conditions were studied;dissolution profiles of the corresponded tablets were also investigated.Results:The differences in the solid-states of five roxithromycin APIs were classified into types A and B according to XPRD data.Both types of the APIs were stable under the high temperature and the high humidity storage conditions.However, type A crystals underwent a solution-mediated phase transformation when placed in water and transformed into type B;in addition, a significant difference in the solubility behaviors between two types of APIs in water was showed.Finally, inequality in the dissolution profiles of the corresponded five formed tablets was demonstrated.Conclusion:The differences among these raw materials were detected by XRPD, SEM, DTG and dissolution methods.Stability, tablet formulation and dissolution test showed that type B is an advantage form and the roxithromycin dissolution profiles can be affected by the APIs crystal form.This study reveals the importance of pre-formulation study before formulation development, and provides the basis information and the selective materials for roxithromycin tablet generic.

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