Pharmaceutical polymorphs: an electronic approach

性状（由申请人提供）：结晶多晶型影响许多性质（稳定性、熔点、硬度、溶解度等）因此，深入分析药物的多晶型现象，开发新的研究方法，仍然是制药科学和制药工业的长期目标。在多晶型物的结构分析方面已经取得了许多重大进展，这些进展导致了成功的制药应用。另一方面，在现代分子/原子/电子水平上的多态性的性质在许多方面仍然不清楚。特别是，与多晶型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，这种相互作用的理论描述才存在，并且在大多数情况下，仅根据3D晶体结构模式得出相应的结论。在本项目中，我们提出了实验研究和新的定量评价的影响分子间相互作用（包括其能量）在晶体中，从X射线衍射数据获得的电子密度分布的基础上，和新的方法来分析其基于实验的电子密度拓扑结构研究。该项目的具体目标是： * 使用不同的结晶技术生长药物化合物的多晶型物的晶体。 * 利用高分辨X射线衍射数据研究这些多晶型物的电子密度分布，并直接从衍射数据估计它们的重要性质（包括能量性质）。 * 利用新的方法-电子密度拓扑结构及其特征分析，量化引起多态性的原子间（分子间）力和部分能量。 * 开发和测试新的电子分析方法，用于已知和新药物的进一步分析，并对多晶型物的电子结构、稳定性和生物活性之间的关系有一定的了解。 我们计划种植五种已知药物/生物活性化合物的多晶型物：对乙酰氨基酚，苯巴比妥，双氯芬酸，甘氨酸和沙利度胺。由于这些化合物的性质、结晶条件和晶体结构都有很好的记录，因此我们有充足的基线数据将我们的新结果与已知数据进行比较，这将允许在新药研究中使用我们的方法。

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.