Pharmaceutical Hydrates: Prevalence, Properties and Progress

[摘要] Among pharmaceutical solids, hydrates are a commonly chosen crystalline form for commercialization. Compared to their anhydrous counterparts, hydrates are often more stable due to strong hydrogen bonding networks between water and pharmaceutical molecules. However, this stability atypically comes with the tradeoff of lower solubility, and research is needed to uncover novel pharmaceutical forms displaying both optimal solubility and stability. This dissertation focuses on both common and unconventional methods of hydrate crystal modification in order better understand limitations of current approaches in the field as well as chart promising directions for future research. Polymorphism, the ability of a molecule to pack into multiple crystal forms, can produce novel forms with unique physical and chemical properties. Extensive analysis of crystal forms published in the Cambridge Structural Database, however, alludes to an observed low prevalence of hydrate polymorphism among known structures, indicating this route is not ideal for hydrate modification. This analysis does, however, uncover new areas of future research such as the physical basis for the prevalence of phase transitions in crystalline salts, and understanding the increased occurrence of cocrystal polymorphism in the last decade. Beyond polymorphism, other experimental methods, such as precise control of water available during crystallization, can also have an effect on the crystal form achieved. With the antileukemia compound mercaptopurine, this method results in the discovery of a hemihydrate crystal form, which displays superior solubility and bioavailability compared to the commercially used monohydrate form, as well as decreased conversion in aqueous media compared to the known anhydrate form. The hemihydrate also displays the highest known dehydration temperature for any non-salt organic molecule reported in the literature (240 degrees C). Extensive material characterization from experimental methods and theoretical calculations explains the physical basis for these properties, with the hemihydrate water molecules residing in electrostatically shielded pockets within the structure. Controlling water present during crystallization of the antifungal compound miconazole also allows for the discovery of a novel hemi(hydrogen peroxide) solvate. Characterizations such as thermogravimetric analysis, and Karl Fisher titration, along with chemical reactivity tests with triphenylphosphine verify the absence of water and presence of hydrogen peroxide within the structure. X-ray diffraction reveals the similar, but not isostructural, packing of the solvate in comparison to the known hemihydrate form. Incorporation of the fungicidal hydrogen peroxide in combination with the fungistatic miconazole molecules in a stable solid form should allow for more effective pharmaceutical formulations.Solid form antifungal susceptibility methods are currently under development to determine the efficacy of this solvate in comparison to the other known solid forms of miconazole.

[发布机构] University of Michigan

[效力级别] polymorph

[关键词] pharmaceutical hydrate;polymorph;Chemistry;Science;Chemistry