盐酸厄洛替尼晶型研究

Study of Erlotinib Hydrochloride Polymorphism

目的:对盐酸厄洛替尼A晶型、B晶型进行鉴定,了解制剂过程对晶型稳定性的影响,确定A晶型盐酸厄洛替尼片的开发工艺。方法:通过X射线粉末衍射(XRD)、红外分光光度法(IR)、电镜扫描(SEM)和差式扫描量热分析(DSC),对两种晶型进行鉴定。通过XRD技术对晶型的转化进行研究,并比较两种晶型的理化性质及片剂在溶出介质中的溶出行为差异,对片剂的工艺开发进行初步研究。结果:两种晶型具有不同的晶型特征。A晶型溶解性好,溶出速度快,稳定性差;而B晶型具有较好的稳定性。湿法制粒中润湿剂的加入会导致A晶型转变为B晶型。结论:采用XRD、IR、SEM和DSC技术可以对药物晶型进行快速、准确的鉴定。以A晶型替代B晶型制备盐酸厄洛替尼片,采用干法制粒,但需改善包装,保证晶型的稳定性。

ABSTR ACT Objective: To identify the polymorph crystal A and B of erlotinib hydrochloride,to learn the influence of preparation process on crystal stability and to determine the development process of erlotinib hydrochloride tablets with polymorph A.Methods: X-ray diffraction(XRD),infrared spectrophotometry(IR),scanning electron microscopy(SEM) and differential scanning calorimetry(DSC) were applied to study the polymorph A and B of erlotinib hydrochloride for their physicochemical properties and the crystal transformation between A and B.In addition,in vitro dissolution tests were conducted to determine the dissolution profiles of each crystal form and the development process was also studied preliminarily.Results: Polymorph A and B demonstrated explicit disparity in crystal form characteristic,dissolution rate and stability,wherein polymorph A was thermodynamically unstable with better solubility and faster dissolution rate.Wetting agent added in wet granulation would transform crystal A into B.Conclusion: This study indicates that XRD,IR,SEM and DSC can be used to identify polymorphs rapidly and accurately.To develop erlotinib hydrochloride tablets of polymorph A by dry granulation process,the stability of polymorph should be ensured by improving packaging technology.