Study On The Parazinamide Cocrystals

Pharmaceutical cocrystals is a supramolecular compound composed by active pharmaceutical ingredient?API?and physically acceptable conformer?CCF?.This two components are fixed in a crystal lattice by hydrogen bonds and other non-covalent bonds.Cocrystals can improve the physicochemical properties and bioavailability of the API and then improve the efficacy.In this study,a series of Parazinamide-dihydroxybenzoic acid?PZA-DHBA?cocrystals were selected as the example for studying the screen,characterization,structure-property correlation and formation process of the pharmaceutical cocrystals.Firstly,three novel PZA-DHBA cocrystals were synthesized by liquid assisted grinding and the product were characterized by powder X-ray diffraction?PXRD?,differential scanning calorimetry?DSC?,Fourier transform infrared spectroscopy?FTIR?.High quality single crystals of the new cocrystals were successfully developed and the data of the structures were determined.And then the cocrystals were also prepared by slurry crystallization.Then the structural feature of the cocrystals was analyzed by Hirshfeld surface and intermolecular interaction energy computation.The melting point of the PZA-DHBA was investigated from the point of the physical property,contribution of different interactions to Hirshfeld surfaces and the hydrogen bonds network.The results show the melting point of this cocrystals is proportional to that of the CCF.The hydrogen bond interaction is the first factor in deciding the melting point of the cocrystals:all the elements to the hydrogen bond including the contribution,the number,the strength and the direction have an important effect on the melting point.In order to further understand the process of the cocrystal formation,process analytical technologies?PAT?including ATR-FTIR and in-situ Raman spectrometer?Raman?were applied to investigate the slurry crystallization process of the PZA-2,5-DHBA.The solubility product of PZA-2,5-DHBA cocrystal in acetonitrile at 30?was found to be 9.4×10^-4?mol/L?².During the slurry cocrystallization,there are 2 steps including PZA dissolution and crystallization.The PZA dissolution rate was fast.A metastable state occurred in nucleation.The cocrystal growth was found to be the rate-controlling step.