Analysis of Molecular Interactions in Solid Pharmaceuticals

研究了固体药物分散体中药物的结晶状态以及药物与添加剂之间的分子相互作用。当结晶药物与环糊精的物理混合物在玻璃瓶中加热时，可形成包合物晶体。自这一发现以来，我们发展了“密封加热法”作为一种制备环糊精包合物的新方法。该方法不需要任何溶剂，具有很大的优势。通过对封闭加热条件与分子行为关系的研究，阐明了环糊精的结晶度和体系中的水分含量是包合物形成的重要因素。在二甲基β-环糊精与萘或金刚烷醇的体系中，封闭加热提供了与共沉淀法不同的晶体结构的包合物。人们认为转移瘤…由于结晶过程的非平衡，胆酸的结晶出现了更多的非平衡状态，胆酸的结晶被研磨成非晶态，而与某些药物共研磨则得到结晶样品。从粉末X射线衍射、热分析和光谱分析中发现，胆酸与多种客体化合物通过共研磨形成包合物，进一步阐明了化合物结构和混合摩尔比的影响，并研究了光学活性化合物在研磨和增湿过程中凝聚体的物理化学变化。凝聚体向外消旋化合物转化的容易程度被认为与凝聚体和外消旋化合物熔点的差异以及晶体结构中的氢键特征有关。当结晶性药物与多孔材料如多孔纤维和可控孔玻璃混合时，药物容易无定形，化学稳定性发生变化。结果表明，这导致了药物以气态吸附到添加剂微孔中的现象。在机理方面，取得了一些有趣的结果。较少

Crystalline state of drugs and molecular interaction between drugs and additives in solid pharmaceutical dispersions have been investigated.When a physical mixture of crystalline drug and cyclodextrin was heated in a glass ampoule, inclusion complex crystals were found to be formed. Since this findings, we have developed the "Sealed-Heating Method" as a new methodology for preparing cyclodextrin inclusion complex. This method have a great advantage in terms of no need of any solvent. In the present project, it was clarified through the investigations about the relationship between sealed-heating conditions and molecular behavior that the degree of crystallinity of cyclodextrin and moisture content in the system will be important factors for inclusion formation.In the systems of dimethyl-beta-cyclodextrin with either naphthalene or 1-adamantanol, sealed-heating process provided a inclusion compound having different crystal structure from coprecipitation. It was considered that a metasta … More ble state appeared due to the non-equibrium process of crystallization.Crystals of cholic acids were amorphised by grindig, while co-grinding with some drugs provided crystalline samples. From powder X-ray diffraction, thermal analysis and spectroscopies, cholic acids were found to form inclusion complexes with a variety of guest compound by means of co-grinding, and further effects of structure of the compounds and mixing molar ratio were clarified.We also investigated physico-chemical change of conglomerate of optically active compounds during the process of grinding and humidifying. The ease of transformation from the conglomerate to the racemic compound was considered to be correlated to the difference of melting points between conglomerate and racemic compound and the hydrogen-bonding feature in the crystal structure.When mixing a crystalline drug with porous materials such as porous cellulose and controlled pore glass, the drug was easily amorphisted and the chemical stability was changed. It was clarified that this resulted in the phenomena of adsorption of drug into the micro-pore of the additives through gaseous state. With regard to the mechanisms, some interesting results were obtained. Less