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

有机化合物晶体的成核机理及纳米药物生产的结晶

基本信息

批准号：
17560664
负责人：
OOSHIMA Hiroshi
金额：
$ 2.37万
依托单位：
Osaka City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

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.

1。为了阐明有机化合物的晶体成核的机理，研究了有机化合物BPPI（C16H12C12F3N302）结晶的关系与溶液结构之间的关系。从甲醇溶液中沉淀出BPPI晶体的B02形式，并从乙醇溶液中出现B01形式。我们将这些多晶型物的晶体结构与通过NMR分析确定的每个溶液结构进行了比较。结果，发现每种溶液中BPPI分子的构象与形成每个多晶型物的BPPI分子的构象相似。在成核之前，在每个溶液中形成的分子聚集体的结构也与每个晶体结构相似。但是，分子聚集体的结构与相应的晶体结构并不完全相同。这表明成核需要从某个随机结构到晶体结构的分子聚集体的结构转换，即结构转化步骤应该是成核。我们还获得了一个关于成核的新概念的结果，即溶液中成核的传播2。我们表明，在结晶过程中，微波的照射即使在高超饱和度下也会抑制成核。对成核的受控抑制对于生产尺寸较小且尺寸分布狭窄的晶体必须起重要作用。3。我们开发了一种新型的连续结晶器，具有ML尺度，用于生产微晶和不稳定的多晶型物。我们可以在不堵塞晶体的情况下在平均次秒的平均停留时间操作该结晶器。