核苷酸类晶体多晶型成核机制及其调控的多尺度研究

Solution nucleation is a key process affecting the design and precise preparation of crystals. It is of great theoretical significance and application value to achieve precise regulation of crystallization process owing to polymorphic nucleation mechanism and mesoscopic fluid dynamics simulation. Based on the basic idea of crystal polymorphism, this project uses four kinds of nucleotides as research objects to study the key scientific problems of microscopic mechanism and mesoscopic kinetics of crystal transformation in different crystal nucleation processes. It is proposed to relate solution chemistry with nucleation mechanism to study the effect of solution environment on different crystal nucleation processes. Structural chemical characterization and microscopic simulation methods are used to investigate the intermolecular forces and crystal configurations of the solvent environment during nucleation. The effect is to reveal the microscopic mechanism of crystallization in different crystal nucleation processes, and provide a theoretical basis for the design of polymorphic drug solid crystallization process. Under the premise of clear microscopic mechanism in nucleation process, the solution environment, additives, self-assembly. The interfacial interaction between the assembled membrane and different crystal nucleus, based on mesoscopic computational fluid dynamics simulation (LBM), to explore the regulation of the medial kinetics of different crystal transformation processes; regulation of nucleotide crystal polymorphs provide the basic theory and optimization ideas of the system.process of nucleation, the interfacial interaction between solution environment and nuclei in different morphologies was investigated. Based on Mesoscopic Computational Fluid Dynamics simulations(CFD-LBM), mesoscopic regulation of different solid forms during the transformation were explored; provide the systematic basic theory and optimization rule for the regulation of the diversity of nucleotide morphological solid forms. To study the mechanism of different microfluidic fields on the self-assembly path of polymorphic drug nucleation process, explore the general rule of microfluidic field regulation of drug solids diversity, and use Fluent software to simulate the interface between solution and crystal nucleus in microfluidic field. Changes in action and supersaturation and the effect of macrofluids on the final morphology of the drug polymorph. The research mentioned above, provides the systematic basic theory and optimization rule for the regulation of the diversity of morphological solid forms of drugs.

溶液成核是影响晶体设计与精准制备的关键过程。多晶型成核分子机理和介观流体力学模拟研究对于实现结晶过程的精准调控，具有重要的理论意义与应用价值。本项目基于晶体多晶型可调控的基本思路，以4种核苷酸为研究对象，开展不同晶型成核过程中微观作用机制及晶型转化介观动力学规律的关键科学问题的研究。拟将溶液化学与成核机理相关联，研究溶液环境对不同晶型成核过程的影响，采用结构化学表征以及微观模拟手段，考察溶剂环境对成核过程中分子间作用力、晶体构型的影响，以揭示晶体不同晶型成核过程中的微观作用机制，为多形态药物固体结晶过程的设计提供理论基础；在明确成核过程中微观作用机制的前提下，考察溶液环境、添加剂、自我组装膜与不同晶型晶核的界面作用，基于介观计算流体力学的模拟手段（LBM），探索不同晶型转化过程中介观动力学的调控规律；为核苷酸类晶体多晶型的调控，提供系统的基础理论和优化思路。

多晶型现象广泛存在于固体化合物中，在材料、能源、食品、医药等领域有着广泛的应用，尤其是在医药行业，药物晶型具有不同的晶体结构常表现出溶解度、溶出速率、生物利用度、储存和药效等差异，其纯度决定药物一致性评价的成败，受到制药监管部门的严苛规定与要求。然而制备性能优异 、疗效好的药物晶体产品 离不开对结晶过程的控制，了解多晶型之间转化的可能性以及转化机理，对结晶过程精准调控具有重要理论意义与应用价值。核苷酸类药物存在普遍的多晶现象，且在医药、食品等领域有着广泛的应用，但在实际工业生产过程中依然存在众多问题，例如红外不合格，晶体比重轻，堆密度小、流动性差等问题。对于核苷酸类药物多晶型的筛选、成核机制以及多晶型转化机制等问题，目前为止尚未明确。因此本项目针对上述问题，以UMP、GMP为例，进行了深入研究。建立起DFT理论计算的方法在核苷酸类药物多晶型的研究过程中应用。首先我们利用理论计算对模型药物进行了刚柔性分析，证明了其多晶型的可能性。探索了UMP钠盐结晶水合物的层状结构的特征以为微观晶体分析，证实了UMP钠盐层状结构均为C2221空间群的正交晶系，与结晶水数量无关。证明了UMPNa•7H2O结晶水合物之间在一定的湿度介导下易发生晶型转化，存在湿度介导的晶型转化。研究发现GMP钠盐在晶型转化过程中存在严重的油析现象，针对此问题，绘制了GMP三相相图，从热力学角度阐述了形成了油析的原因，考察了温度、pH、溶液溶度等因素对转晶过程中油析现象的影响，基于DFT理论计算，发现了GMP晶型转化过程中油析现象的产生是由pH诱导的GMP3-离子产生的，而GMP3—异丙醇的结合力大于GMP3—水。以上研究能够为我们清楚的认识核苷酸药品多晶型现象以及精准调控提供一定的理论指导以及调控思路。