Research On The Preparation Of Small-Molecule Cocrystals

Cocrystals are multi-component molecular crystals with specific structures and properties formed through intermolecular interactions of different molecules and are commonly used for medicines or explosives.As a new type of solid-state drug,cocrystals can significantly improve the physical and chemical properties of drugs and improve the bioavailability without damaging the pharmacology of drugs at the same time.Cocrystals are also stoichiometric diversity generally.The stoichiometric diversity of cocrystals has a significant effect on physicochemical properties and quality of drug cocrystals,which are directly related to the safety and efficacy of drugs.Therefore,the researches on new cocrystals preparation method and stoichiometry ratio of cocrystals play an important role in the development of drug industry.(1)Using cytosine-succinic acid cocrystal as the research system,we proposed a new preparation method of cocrystal based on the traditional neat-grinding method.Cytosine-succinic acid cocrystals were successfully prepared by neat-grinding and regrinding the pre-compression mixture of raw material respectively.The cocrystals morphology were characterized by X-ray powder diffraction,the compressibility of both raw materials and mixtures with different proportions were characterized by spiral micrometer.The effects of grinding time,mechanical external force and compressibility of raw materials on cocrystal formation were investigated.(2)Using urea-succinic acid cocrystal as the research system,the 1:1 urea-succinic acid cocrystal was successfully prepared by freeze-drying method and nano-mesoporous material loading method,which can not easily prepared by the traditional cocrystal preparation method.The products were characterized and identified by X-ray powder diffraction,Fourier transform infrared spectroscopy,Thermogravimetric analysis and Differential scanning calorimeter,Scanning electron microscopy.The effects of preparation method,solution proportion and other factors on the formation of urea-succinic acid cocrystal with different stoichiometry were investigated respectively.