Pharmaceutical polymorphs: an electronic approach

描述(申请人提供)：晶型会影响许多性质(稳定性、熔点、硬度、溶解度等)。因此，对药物的多态进行详细的分析，并开发新的方法来研究这种现象，仍然是制药科学和工业的长期目标。在多晶型的结构分析方面取得了许多重大进展，导致了成功的药物应用。另一方面，现代分子/原子/电子水平上的多态性质在许多方面仍然不清楚。特别是，与多态有关的晶体结构的差异可以归因于分子间(原子间)相互作用，但直到最近，这种相互作用还只有理论描述，而且在大多数情况下，只有基于三维晶体结构模式才能得出相应的结论。在本项目中，我们提出了基于从X射线衍射数据获得的电子密度分布对晶体中分子间相互作用(包括其能量)的影响的实验研究和新的定量评估，以及基于实验电子密度拓扑研究的新的分析方法。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晶体。 *利用高分辨率X射线衍射数据研究这些晶型中的电子密度分布，并直接从衍射数据估计它们的重要性质(包括含能性质)。 *使用新的方法--电子密度拓扑及其特征分析--来量化引起多态的原子间(分子间)力和部分能量。 *开发和测试新的电子方法，以进一步分析已知和新的药物，并深入了解多晶型电子结构、稳定性和生物活性之间的关系。 我们计划培育五种已知药物/生物活性化合物的多晶型：扑热息痛、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已被很好地记录下来，我们有充足的基线数据用于将我们的新结果与已知数据进行比较，这将使我们能够在新药物的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.