阿达帕林的多晶型筛选和制备与表征研究

Polymorphism screening,preparation and identification of adapalene

目的:本实验系统研究了阿达帕林存在的多晶型现象,制备获得晶型样品,并采用现代技术方法进行表征,研究数据为该药品的晶型质量控制提供科学依据。方法:采用化学的重结晶法、快速溶剂去除法与物理的晶格破坏法等晶型筛查技术方法,筛查发现阿达帕林存在多晶型现象并制备出4种晶型样品;利用粉末X射线衍射法、差示扫描量热法、热重法、红外光谱法分别对4种晶型物质状态进行了表征分析;通过影响因素实验探讨4种晶型的稳定性与晶型转变规律;通过溶解性实验比较不同晶型的溶解性差异。结果:本研究制备获得4种晶型物质,其中2种为首次发现新晶型物质状态;晶型表征方法学研究发现粉末X射线衍射技术可有效区分4种晶型物质,差示扫描量热法、热重法可用于区分新晶型与已知晶型,红外光谱法可用于区分晶Ⅲ型与其他晶型;晶型稳定性研究结果表明晶Ⅱ型为稳定晶型,其他晶型属亚稳定晶型,可在不同条件下向晶Ⅱ型发生转变;溶解性实验结果表明晶Ⅳ型具有最佳的溶解性,其溶解速率和溶解度显著优于其他3种晶型。结论:阿达帕林药物存在着多晶型现象,不同晶型样品的稳定性、溶解性存在差异,在生产过程中必须对阿达帕林晶型进行控制。新发现的晶Ⅳ型为优势药用晶型,但其稳定性较差,需进一步通过制剂技术研究来确保其晶型物质状态的稳定。

Objective： To systematically study the polymorphism of adapalene,prepare and characterize the different forms by modern analytical technique for providing scientific data for the quality control of the polymorphic in this drug. Methods： Recrystallization, fast solvent removal, ball milling and other polymorphism screening techniques had been used. Four forms of polymorphies were found and prepared. The powder X-ray diffraction（ PXRD）,differential scanning calorimetry（ DSC）,thermogravimetric analysis（ TGA） and infrared spectrometry（ IR） were introduced for characterization analysis. Furthermore,the stability and the transformation rules were explored. The solubility of different forms was investigated and compared. Results： Four forms of adapalene were prepared,including two forms reported for the first time. The results indicated that PXRD could be used to identify four different forms effectively; the DSC and TG to identify two new forms and known forms; and the IR to identify form Ⅲ and the other forms. Moreover,form Ⅱ was the stable form,and the other forms were metastable forms which could transform to form Ⅱ eventually. The solubility experiment showed that the form Ⅳ performed best,and the dissolution rate and solubility were remarkably better than the others. Conclusion： The adapalene has polymorphism. As the difference among the stability and solubility of three solvate-free forms,the quality control of the polymorphic should be emphasized during the preparation process. The new form Ⅳ is advantage pharmaceuticalform,which needs further pharmaceutical technology exploration to ensure its stability.