溶剂介导快速相转化的分子机制和可控制备研究

Solution crystallization and phase transformation are the key adjustments and controls in preparation of the target crystal form and crystal shape. Solvent – mediated phase transformation is the most common method for polymorphism screening. But few studies have been reported on solvent-mediated rapid phase transformation which requires only a few seconds or even microseconds for the process. The entire transformation process is so fast that the conventional detection methods can't complete the process of monitoring and data collecting. The existing theory is also can’t explain the transformation phenomenon precisely. Therefore, this project uses sulfadiazine, sulfamerazine and sulfamethoxazole as the model compounds. Experiments, quantum chemistry calculation, molecular dynamics simulation in combination with spectrum analysis will be used to analyze the mechanisms of rapid dissolution of metastable phase and instantaneous nucleation and growth of stable phase. Through the research above, it is expected to elucidate the mechanism of dissociation and diffusion of solute molecules during dissolution, to reveal the intermolecular interactions such as solute-solvent, solute-solute molecular and the interaction sites between solute and crystal planes, to find out the molecular assembly rules between the metastable and stable phase. The research results of this project will provide theoretical basis for solvent-mediated rapid phase transformation, solvent screening, polymorphism control and crystal preparation.

溶液结晶和相转化是晶型和晶习调控的关键手段，溶剂介导转化是晶型筛选最常用的一种方法，然而关于转化时间只需要几秒甚至几微秒的溶剂介导快速相转化的研究却很少报道。由于转化过程非常迅速，导致常规分析手段无法完成过程监测和数据信息的采集，现有理论也不能合理解释该转化过程。因此，本项目选择磺胺嘧啶、磺胺甲基嘧啶和磺胺甲恶唑3种物质为研究模型，采用实验研究、分子模拟与光谱分析相结合的方法，开展亚稳相迅速溶解机制和稳定相瞬间成核和生长的机理。旨在阐明1）溶解过程中亚稳相溶质分子解离和扩散的机理；2）溶质-溶剂分子和溶质-溶质分子的相互作用，溶质分子-晶面的识别位点和组装机制；3）相转化前后两相分子组装规律的联系，为晶体的可控制备、溶剂的筛选和溶剂介导快速相转化机理提供理论基础和科学依据。

晶型和晶习是药物安全性和有效性的本质要素，有机药物晶型和晶习的精准制备和研究契合国家新药创制需求，由于我国药企相关科研人员对药物的晶型认识不够透彻，导致很多药物产品存在晶型和晶习的问题。需要对药物的晶型筛选、晶型转化和晶习调控进行系统研究，加快推进我国“仿制药一致性评价”工作。.本项目通过磺胺嘧啶、磺胺甲嘧啶、磺胺甲恶唑、嘧霉胺晶型和溶剂化合物的预测与筛选，不同晶型之间的转化进行研究，结果表明利用COSMOtherm可以快速有效筛选溶剂制备得到溶剂化合物，为溶剂化合物的设计提供理论依据；溶剂化合物的形成主要取决于溶剂分子的氢键受体能力、分子大小和形状；通过在线和离线分析表明，溶剂化物脱溶剂形成的产品晶型受多种因素影响，包括分子间相互作用大小、分子体积大小、分子无序性等，而溶剂化合物与产物晶体结构之间的相似性没有必然联系；溶剂化物通过溶剂介导快速转化，可以迅速得到形貌和晶习可控的无溶剂化合物，利用这种方法制备得到了块状和棒状的磺胺嘧啶、磺胺甲嘧啶和磺胺甲恶唑晶体，产品的堆密度、流动性和后处理性能明显提升。