药物球形粒子工业结晶过程机理与应用研究

Fine particles are often needed in pharmaceutical industry because of superior dissolution kinetics and, potentially, higher bioavailability. However, processing challenges such as filtration and drying, as well as complications originating from formulation, could jeopardize the benefit of small particles. Spherical crystallization is a size-enhancement approach which facilitates many of the API and drug product processing steps while not compromising the solubilisation properties of the initial fine particles. Materials from spherical agglomeration offer the advantage of high bulk density, good flowability, and satisfactory compactability all of which are required for direct-tableting. The spherical crystallization process as part of the API synthesis is normally inexpensive from a commercialization perspective, but the lack of knowledge on the fundamental principles (e.g. mechanisms, kinetics) of this technique often limits its application in pharmaceutical industry. In this study, water-soluble drug Clopidogrel sulfate and poorly water-soluble drug Azithromycin will be used as model compounds. A systematic study on the mechanisms, processing, and applications will be conducted based on the general design concept of industrial crystallization to enable application of spherical crystallization in pharmaceutical manufacturing. The mechanism of nucleation, growth, and secondary process involved with spherical agglomeration (SA) and quasi-emulsion solvent diffusion (QESD) are to be investigated to provide some general guidelines for the screening and selection of anti-solvent, bridge liquid, and additives. This knowledge is a key element for the development of controlled-released drug-polymer composite particles or a novel spherical crystallization method for the production of metastable crystal form with large-size spherical particles. The solution thermodynamic phase diagram, population balance model, and RBF neural network model will be built to direct the process simulation and scale-up implementation of pharmaceutical spherical crystallization. The research results will provide unprecedented understanding and new insights into the technology framework for the design and preparation of novel functional materials (low-sensitivity explosive of spherical RDX particles, high-efficiency energy materials of spherical lithium iron phosphate particles, etc.).

药物细晶有较好的溶解性和生物利用度，但过滤、干燥困难，制剂过程复杂。利用球形结晶技术能增大粒度改进分离效率，并保留细晶溶解特性，产品堆密度、流动性和可压缩性大为提高，可用于直接压片，有很好应用前景，但由于缺乏系统理论指导，该技术工业化应用极少。本项目以水溶性原料药氯吡咯雷硫酸氢盐和难溶性原料药阿奇霉素为模型，借鉴工业结晶研究方法，系统开展球形结晶机理、过程与应用研究。通过探讨球形聚集（SA）和准乳液溶剂扩散（QESD）两种球形结晶过程成核、生长以及二次过程机理，提出反溶剂、架桥剂、添加剂等筛选的指导原则，开发具有缓控释效果的功能性药物球形颗粒，设计制备大颗粒介稳晶型药物的球形结晶过程；构建热力学相图、过程粒数衡算方程和神经网络经验模型，以指导药物球形结晶过程模拟及过程放大。本项目成果可为新型功能材料（如低敏性球形RDX炸药或高效能球形磷酸鉄锂能源材料等）的设计与制备提供研究思路和技术支撑。

球形晶体可被定义为：将晶体直接转变成紧实的球形来提高产品的流动性，溶解度和可压缩性的过程。球形晶体的优势在于出色的物理化学性质（溶解度、溶解速率、生物利用度、稳定性等）及微观性质（堆密度、流动性、可压缩性等），在压片工艺中可以直接跳过造粒及后续干燥步骤，实现直接压片。本项目成果也可为新型功能材料（如低敏性球形RDX 炸药或高效能球形磷酸鉄锂能源材料等）的设计与制备提供研究思路和技术支撑。. 本项目研究了药物球形结晶机理。主要包括氯吡格雷硫酸氢盐、头孢克肟、碳酸锂、阿托伐他汀钙、L-色氨酸、头孢噻肟钠、琥乙红霉素、泮托拉唑钠、盐酸头孢甲肟等物质的球形结晶的机理研究。通过过程在线监测及离线检测，对球形晶体的形成过程进行连续化的全程观测及关键点的重点研究；通过接触角测定、计算晶体粘附过程的界面张力和吉布斯自由能变化，分析固液界面张力与毛细管压力在晶体聚集中的作用；通过考察搅拌、温度、溶液粘度和固含量对稳定成核过程的影响研究晶体聚集中的扩散效应。基于以上基础研究，揭示了包括球形聚集、球形生长、准乳液扩散等的成球过程机理，建立了球形聚集的溶剂-反溶剂-架桥剂的筛选原则。重点研究了球形结晶热力学，包括：测定药物在不同溶剂和混合溶剂中的溶解度，筛选合适的溶剂和反溶剂；建立溶剂-反溶剂-架桥剂在不同温度下的等温三元相图，筛选合适的架桥剂和溶剂配比；测定不同溶液的粘度，建立溶液热力学模型；测定球形结晶过程的介稳区和诱导期，开展药物球形结晶过程工艺参数优化研究。建立典型药物，如氯吡格雷硫酸氢盐，的动力学及粒数衡算模型，以此找到药物球形结晶过程模拟及过程放大的规律；通过以上热力学及动力学的结晶过程研究，设计新型药物球形结晶过程用于制备可直接压片的药物球晶和具有缓控释效果的功能性药物球形颗粒，控制药物晶型并制备大粒径药物介稳晶型球晶。