Pharmaceutical polymorphs: an electronic approach

描述（由申请人提供）：晶体多态性影响着药剂的许多性质（稳定性、熔点、硬度、溶解度等）和应用，因此详细分析药物的多态性并开发研究这一现象的新方法仍然是制药科学和工业的长期目标。在多态结构分析方面取得了许多重大进展，这些进展已导致成功的药物应用。另一方面，在现代分子/原子/电子水平上多态性的性质在许多方面仍不清楚。特别是，与多态性相关的晶体结构差异可以归因于分子间（原子间）相互作用，但直到最近，这种相互作用只有理论描述，并且在大多数情况下仅基于3d晶体结构模式得出相应的结论。在本项目中，我们提出了基于x射线衍射数据获得的电子密度分布的晶体分子间相互作用（包括其能量）影响的实验研究和新的定量评价，以及基于实验电子密度拓扑研究的分析方法。该项目的具体目标是：

DESCRIPTION (provided by applicant): Crystalline polymorphism impacts many properties (stability, melting point, hardness, solubility, etc.) and applications of pharmaceutical agents, therefore detailed analysis of pharmaceutical's polymorphism and development of new approaches to study this phenomenon are still the long-term objectives aims in pharmaceutical science and industry. Many significant advances have been made in the structural analysis of polymorphs that have led to successful pharmaceutical applications. On the other hand, the nature of polymorphism on the modern molecular/atomic/electronic level remains unclear in many respects. In particular, differences in crystal structure related to polymorphism can be ascribed to intermolecular (interatomic) interactions, but until recently, only theoretical descriptions of such interactions existed, and in most cases corresponding conclusions were made only on the basis of 3D-crystal structure pattern. In the present Project we propose experimental investigation and new quantitative evaluation of the effects of intermolecular interactions (including their energies) in crystals, based on the electron density distribution obtained from X-ray diffraction data, and new approach to its analysis based on the experimental electron density topology study. The specific aims of this project are: * To grow crystals of polymorphs of pharmaceutical compounds using different crystallization techniques. * To use high-resolution X-ray diffraction data to study electron density distribution in these polymorphs and to estimate their important properties (including energetic ones) directly from diffraction data. * To quantify interatomic (intermolecular) forces and partial energies that cause polymorphism using new approach - analysis of the electron density topology and its characteristics. * To develop and test new electronic approach for further analysis of known and new pharmaceuticals, and to get some insight on relation between polymorphs electronic structure, stability and bioactivity. We plan to grow polymorphs of five known pharmaceutical/bioactive compounds: acetaminophen, phenobarbital, diclofenac acid, glycine and thalidomide. Because properties, crystallization conditions, and crystal structures for these compounds are well documented, we have ample baseline data for comparison of our new results with known data, that will allow to use our approach in studies of new Pharmaceuticals.