基于非晶体学分支生长的球形结晶机理及球晶形貌调控

球形结晶能够在结晶单元中一步制备功能性球晶颗粒，使产品同时具备高流动性、抗结块、直接压片等颗粒性能优势和高生物利用度、高纯度等晶体性能优势。但是球形结晶的机理和调控机制不清，技术开发面临挑战。本项目选用头孢噻肟钠、DL-丙氨酸等头孢类和氨基酸类药物有机分子作为模型物质，聚焦球晶成核、生长、聚结三个关键环节，综合运用核磁、在线拉曼和红外、原子力显微镜、粒子图像测速、分子模拟等分析手段，建立具有高分辨率、原位测量、在线监测、过程模拟优势的球形结晶表征体系，研究分子团簇、非晶体学分支、多级团聚体等多尺度结构的演变规律，从而揭示球晶颗粒形成机理，以此建立球晶成核动力学、非晶体学分支生长模型、动态组分多相流下的多重作用力聚结模型，明确成球关键控制因素-多尺度结构与行为-球晶形态的定量关系，理性制备具有直接压片、促溶、抗结块等功能的球晶颗粒，为晶体形貌开发提供新型的工业结晶技术支撑和调控策略。

Spherical crystallization is a novel strategy of regulating crystal morphology. It can prepare functional spherical particles in a single crystallization unit, which satisfies the major national demands of high-performance crystalline products and green solid production. The special structures of molecular clusters, non-crystallographic branches and multi-agglomerates have great impacts on nucleation, growth and agglomeration of spherical crystallization and determine the quality of spherical particles. It is challenging to characterize these dynamic, flexible and heterogeneous structures with sizes ranging from the molecular scale to the particle scale. Their behaviors cannot be fully explained by the traditional crystallization theories. This has become the bottleneck of spherical crystallization, which seriously limits the development of the technology. To solve this problem, the project focuses on the nucleation, growth and agglomeration of spherical crystallization with cefotaxime sodium and DL-alanine as the models. A high-resolution, in-situ, on-line and process-simulation characterization system would be established with on-line and off-line high-resolution devices (FTIR, IR, Raman, NMR, SEM, TEM, AFM, FBRM, PVM, etc.), high-throughput crystallization workstations (EasyMax、OptiMax and LabMax) and simulation techniques (molecular dynamics simulation and discrete element method simulation). According to the characterization system, the time and location dependent formation and behavior of molecular clusters, non-crystallographic branch and multi-agglomerates can be studied to further reveal the mechanism of spherical crystallization. Consequently, the mathematical models of nucleation kinetics, non-crystallographic branching, and agglomeration force in multi-liquid phases with dynamic composition would be proposed by the theories of classical and non-classical nucleation, rough growth, the Lifshitz-van der Waals acid-base approach. Thus the quantitative relationship among the key parameters, multi-scale structures and behaviors, and morphology of spheres can be further identified to achieve the rational preparation of functional spherical crystalline particles (e.g. direct tableting, dissolution promotion, and anti-caking). The study can help develop novel crystallization technology and strategy of regulating particle morphology.