Nucleation Mechanism of Organic Compound Crystals and Crystallization for Production of Nano-Medicine

1. 为了阐明有机化合物晶体成核的机理，研究了有机化合物BPPI(C16H12C12F3N302)多晶型物的结晶与溶液结构之间的关系。 B02形式的BPPI晶体从甲醇溶液中沉淀出来，并且B01形式从乙醇溶液中出现。我们将这些多晶型物的晶体结构与通过溶液的 NMR 分析确定的每种溶液结构进行了比较。结果发现，各溶液中的BPPI分子的构象与形成各多晶型物的BPPI分子的构象相似。成核前各溶液中形成的分子聚集体的结构也与各晶体结构相似。然而分子聚集体的结构与相应的晶体结构并不完全相同。这表明成核需要分子聚集体从某种随机结构向晶体结构进行结构转变，即结构转变步骤应该是成核。我们还得到了一个结果，提出了一个关于成核的新概念，即成核在溶液中的传播。 2．我们表明，即使在高过饱和度下，结晶过程中的微波照射也能抑制成核。控制成核抑制对于生产小尺寸和窄尺寸分布的晶体必须发挥重要作用。 3．我们开发了一种新型的毫升级连续结晶器，用于生产微晶体和不稳定多晶型物。我们可以以亚秒的平均停留时间操作该结晶器，而不会堵塞晶体。

1. In order to elucidate mechanism of crystal nucleation of organic compounds, the relationship between crystallization of polymorphs of an organic compound BPPI(C16H12C12F3N302) and the solution structure was investigated. The B02 form of BPPI crystals was precipitated from a methanol solution and the B01 form appeared from an ethanol solution. We compared crystal structures of those polymorphs with each solution structures determined by NMR analysis for solution. As a result, it was found that the conformation of BPPI molecules in each solution was similar to that of BPPI molecules forming each polymorph. The structure of molecular aggregates formed in each solution before nucleation was also similar to each crystal structure. However the structure of molecular aggregates was not completely the same as the corresponding crystal structure. This suggests that nucleation requires structure-transformation of molecular aggregates from a certain random structure to a crystal structure, namely the structure-transformation step should be the nucleation. We also obtained a result suggesting a novel concept about nucleation, that is the propagation of nucleation in solution.2. We showed that the irradiation of microwave during crystallization suppresses nucleation even under a high super-saturation. The controlled suppression of nucleation must play an important role for production of crystals with small size and a narrow size distribution.3. We developed a novel continuous crystallizer with a mL-scale for production of micro crystals and production of an unstable polymorph. We could operate this crystallizer at a mean residence time of sub-second without clogging of crystals.