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。当晶体药物和环糊精的物理混合物在玻璃安瓿中加热时，发现形成了包合晶体。根据这一发现，我们开发了“密封加热法”作为制备环糊精包合物的新方法。这种方法在不需要任何溶剂方面有很大的优点。本课题通过对密封加热条件与分子行为关系的研究，明确了环糊精的结晶度和体系中的水分含量将是包裹体形成的重要因素。在二甲基- β -环糊精与萘或1-金刚烷醇的体系中，密封加热过程提供了与共沉淀具有不同晶体结构的包合物。由于结晶过程的不平衡，导致了亚稳态的出现。通过研磨使胆酸结晶不定形，而与某些药物共磨则提供结晶样品。通过粉末x射线衍射、热分析和光谱分析，发现胆酸通过共磨与多种客体化合物形成包合物，并进一步阐明了化合物结构和混合摩尔比的影响。研究了旋光性化合物砾岩在研磨和加湿过程中的理化变化。砾岩和外消旋物的熔点差异以及晶体结构中的氢键特征与砾岩和外消旋物容易转变为外消旋物有关。当晶体药物与多孔材料（如多孔纤维素和受控孔玻璃）混合时，药物容易变形，化学稳定性发生变化。澄清了这导致药物通过气态吸附到添加剂的微孔中的现象。在机理方面，得到了一些有趣的结果。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