中药浸膏粉玻璃化转变及其对固体制剂过程和稳定性的影响

Physicochemical properties of drugs have significant effects on the molding technique ,stability and bioavailability of solid dosage form. The descriptive indexes such as solubility ,crystal form of chemical drugs can not describe physicochemical properties of traditional Chinese medicine powdered extract because of its complexity and unacknowledged of constituents.At present, micromeritics indexs are applied to represent the physical property of traditional Chinese medicine powdered extract,but can not effectively guide in solving the key common problems such as collapse bed of fluidized bed granulation and sticky round of dry granulation that frequently taking place in the production. Based on theories of constitutes of traditional Chinese medicine powdered extract and solid dosage forms, characteristics of technical process, and glass transition of polymer, this topic propose the views that traditional Chinese medicine powdered extract and solid dosage forms exist glass transition that has significant effects on technical process, product quality and stability. From this new perspective, the researches on glass transition of traditional Chinese medicine powdered extract and solid dosage form, the major factors that influence glass-transition temperature of traditional Chinese medicine powdered extract and solid dosage form, influence law of glass-transition temperature on dry technology, molding process of solid dosage form, and stability of products, and building glass transition theory of Chinese medicine powdered extract and solid dosage form have guiding significance on solving adherence of spray drying, sticky round of dry granulation, collapse bed of fluidized bed granulation, cracking of pills and agglomerations of capsules and granules.

药物的物理性质明显影响固体制剂的成型工艺、稳定性和药物生物利用度等。由于中药浸膏粉成分复杂，未知成分多，采用类似化药的溶解度、晶体等难以准确描述其物理性质特点。目前主要运用粉体学指标来表征中药浸膏粉的物理性质，不能有效指导解决生产中容易出现的流化床制粒塌床、干法制粒粘轮等关键共性问题。本课题根据中药浸膏粉及其固体制剂的构成、工艺过程特点和聚合物玻璃化转变理论，提出中药浸膏粉及其固体制剂存在玻璃化转变，并且明显影响工艺过程、产品质量和稳定性的观点。从这个崭新的角度，研究中药浸膏粉及其固体制剂玻璃化转变，研究影响中药浸膏粉及其固体制剂Tg的主要因素、浸膏粉Tg对干燥工艺、固体制剂成型过程、产品稳定性等的影响规律，构建中药浸膏及其固体制剂玻璃化转变理论，对于解决中药喷雾干燥粘壁、流化床制粒塌床、干法制粒粘轮、丸剂干燥开裂及胶囊、颗粒剂储存结块等关键共性问题，优选制剂处方和工艺具有重要指导作用。

本课题根据中药浸膏粉及其固体制剂的组成特点，提出其存在玻璃化转变现象，并且明显影响工艺过程、产品质量和稳定性的观点。.首次采用DSC法，证实中药水提或醇提物及其固体制剂、中药丸剂（蜜丸、水丸、浓缩丸）普遍存在玻璃化转变现象，并系统考察了测定玻璃化转变温度（Tg）的影响因素，制定了具体操作规范，为玻璃化转变理论指导中药制剂的研发奠定基础。系统考察了浸膏性质（含水量、组分）、辅料性质（种类、用量等）、工艺参数等因素对浸膏粉Tg的影响。发现浸膏粉的Tg与其吸湿性、流动性、喷雾干燥粘壁、含水量、进风温度、醇沉浓度等密切相关。浸膏粉Tg越低，喷雾干燥粘壁、干法制粒粘轮、流化床制粒塌床越严重。以Tg为指标，通过添加辅料和调整工艺参数，是其有效的解决方法。在干法制粒中辅料、浸膏粉的简单混合不能明显提高混合物Tg，而选择合适溶剂将辅料和浸膏粉完全溶解、干燥则可能有效提高混合物Tg。首次采用质构仪建立了中药浸膏粉及其固体制剂结块的评价方法，结果表明浸膏粉Tg与其结块性密切相关。采用结块性指标（结块厚度比、平均结块强度）和内聚性指标（附着力总功、内聚力指数）能够较全面表征浸膏粉及其固体制剂的结块特性，并能指导筛选合理的辅料和工艺参数。以水分活度理论和玻璃化转变理论为基础，构建水分活度-平衡含水量-玻璃化转变温度的状态图，能够准确预测浸膏粉储存时保证稳定性的临界水分活度和临界含水量，对于选择储存条件具有重大指导意义。. 通过试验证明中药浸膏存在粉玻璃化转变、研究Tg的主要影响因素、以及对中药浸膏的干燥、成型、产品稳定性等的影响规律，构建中药浸膏及其固体制剂玻璃化转变理论，为解决中药喷雾干燥粘壁、流化床制粒塌床、干法制粒粘轮、胶囊、颗粒剂储存结块等关键共性问题，优选制剂处方与工艺、贮存条件提供了很好的理论指导和试验方法。