溶液前聚体成核机理、模型与多晶型应用研究

It is of fundamental importance to control the crystal nucleation process precisely from solution crystallization for the creation and development of polymorphic crystalline materials with desired physical properties. However, the mechanism of polymorph nucleation process has not yet been fully understood, and the underlying theory based on the Classical Nucleation Theory (CNT) is still of great limited use. Therefore a complete understanding of the basis of the polymorph nucleation mechanism is urgently needed. Since there exhibit internal relationships between solution-state pre-nucleation associates and the solid-state structure of nucleated crystals, which has already been suggested by the researches on crystal engineering, two model compounds, the organic-soluble tolfenamic acid (TFA) and the aqueous-soluble methionine (MET) are selected in this project. The in situ spectroscopy techniques (ATR-FTIR, NMR, Raman, etc.) and analysis models, in conjunction with quantum mechanics methods and molecular simulation (the fist-principle treatments, density functional theory, etc.), are applied and developed to investigate the structures of pre-nucleation associates as well as the crystal nuclei of TFA and MET in organic and aqueous solutions, respectively. On the basis of the relationship between solution associates and nucleated structures of crystals, the molecular self-assemble pathways of polymorphic crystalline nucleation and the evolvement rule of crystal structure during the liquid-solid phase transition processes are revealed, and the nucleation mechanism of polymorphs is explored at the same time. The influences of external variables, which include out-field conditions, solvents, temperatures, and concentrations, as well as the templates on the structures of solution associates, are studied further, and consequently a new mathematical model for the description of the nucleation rate of polymorphs could be proposed. It can at least be used for the estimation of a range of possible nucleation rates by using those conditions occurring. At last, from the research discoveries in the current project, especially the nucleation mechanism of solution associates and the kinetic model of nucleation rate, a method based upon process modeling at the molecular scale will be developed to apply for the optimal control of the nucleation process of polymorphs, as well as that, the prediction of crystal structure could be achieved. In this way, theoretical guidelines will be obtained about the strategies for rational design of pharmaceutical polymorphs and reproducible preparations of crystalline materials.

溶液结晶成核过程的精准调控对于制备特定性能的多晶型材料至关重要，然而，目前有关多晶型成核的机理仍不清晰，传统的经典成核理论存在诸多局限。晶体工程学研究表明，晶体形成与溶液前聚体有关。本项目拟以溶于有机溶剂的托灭酸和水溶性的蛋氨酸为研究模型，开发原位在线的光谱学测定技术（ATR-FTIR，NMR，Raman等）和分析模型，结合量子力学和分子模拟方法，研究托灭酸在有机溶液和蛋氨酸在水溶液中的前聚体结构和晶核结构，揭示多晶型物质晶体成核的分子自组装机制和晶体结构演变规律，探讨多晶型成核机理；进一步研究外场条件、溶剂、温度、浓度及模板剂等对溶液前聚体的影响，构建多晶型成核动力学模型；基于溶液前聚体的成核机理与成核动力学模型，被用以开发分子尺度的过程模拟技术，应用于多晶型成核过程优化控制和晶体结构预测，提出药物多晶型的理性设计策略和晶体材料可控制备的理论指导方案。

现代制药行业不仅对原料药的化学纯度还对其晶体的物理（晶型）纯度进行了严苛的规定和要求，药物晶型的纯度会直接影响到药物的生物利用度、储存和药效。溶液结晶是晶型药物生产制造的主要手段，晶体成核作为溶液结晶过程的首要步骤，决定了药物多晶型的形成，其精准控制至关重要。然而，目前由于晶体成核的机理仍不完善，传统经典成核理论存在诸多局限，致使成核过程难以控制，高效晶型的精准制备仍难以实现。晶体工程学研究表明，晶核的形成与溶液前聚体有关，但是两者的关联仍不清晰。.本项目从多晶型成核的基础与应用研究两个维度，重点探讨溶液前聚体与成核多晶型之间的结构关联，补充和发展晶体成核理论，开发多晶型调控方法，实现药物多晶型的精准可控制备。项目选用了一系列羧酸类化合物包括非甾体抗炎药物托灭酸、苯甲酸、蛋氨酸等为模型物质，旨在构建溶液前聚体的定性和定量表征方法，探索溶液前聚体与成核晶体结构的普遍内在关联规律，利用全反射溶液红外（ATR-FTIR）和一维/二维核磁（NMR）等先进光谱分析技术，结合DFT量化理论计算，成功构建了溶液前聚体结构与性质的定性定量方法，揭示了溶液前聚体形成的本质；即由溶质-溶剂和溶质-溶质相互作用的竞争与协同共同决定；深入研究了溶液前聚体自组装与晶体介尺度成核机理，发现了前聚体自组装取决于分子间相互作用力的层级性，阐明了溶液前聚体与成核晶型结构基元的内在关联性，提出了基于短程有序长程无序溶液前聚体组装与重组的多步成核机理，补充和发展了经典成核理论；研究设计了一系列可溶性小分子添加剂和固相模板剂对溶液前聚体与晶体成核的调控规律，阐释了这些模板剂对前聚体形成和多晶型成核的不同作用机制，即主体嵌入和表面调控，实现了药物多晶型的精准制备。相关基础研究成果成功开发了“一种制备球形硫酸氢氯吡格雷晶型I的方法”专利技术，产品晶型稳定控制在介稳纯晶型I，显著提高了药物的溶解度和生物利用度，获得了2019 年中国专利金奖。

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