Thermodynamic Studies On The Phase Purity And The Formation Enthalpies Of The Pharmaceutical Co-crystals

At present,the research on pharmaceutical co-crystals mainly focuses on the preparation,screening,characterization and solubility determination of co-crystals,but there are few studies on the purity and thermodynamic data of co-crystals.The purity of the co-crystals phase directly affects its bioavailability,and the thermodynamic data of the drug(such as the enthalpy of melting,the enthalpy of dissolution,etc.)can be used to understand the stability of the drug and the intermolecular interaction.It can be seen that the purity and thermodynamic data of the co-crystal play an important role in the development and design of the pharmaceutical co-crystals.Therefore,this paper is devoted to the study of these two aspects.The specific research contents are as follows:Chapter Ⅰ: This chapter is the introduction of this paper,which mainly introduces crystal engineering,supramolecular chemistry and pharmaceutical co-crystals,including the development of crystal engineering and supramolecular chemistry and their applications in pharmaceutical co-crystals;Definition,preparation and characterization of pharmaceutical co-crystals.Finally,the significance of the research is elaborated.Chapter Ⅱ and III: Theophylline(THP),isoniazid(INH),isonicotinamide(INA),carbamazepine(CBZ)and pyrazinamide(PZA)were selected as active pharmaceutical ingredients,and p-hydroxybenzoic acid(PHBA),oxalic acid(OXA),p-aminosalicylic acid(PASA)and p-coumaric acid(PCA)were selected as coformers.Eight kinds of pharmaceutical co-crystals were successfully prepared by solution evaporation method it was characterized by powder diffraction,infrared spectroscopy,thermal analysis,elemental analysis and scanning electron microscopy.After characterization,information about the structure,thermal behavior and morphology of the co-crystals was obtained,which laid the foundation for the subsequent research.Chapter Ⅳ: In this chapter,the purity of isoniazid-p-hydroxybenzoic acid(INH-PHBA),isoniazid-p-aminosalicylic acid(INH-PASA),pyrazinamide-p-hydroxybenzoic acid(PZA-PHBA)and isonicotinamide-p-hydroxybenzoic acid(INA-PHBA)co-crystal prepared by solution method and grinding method were compared and analyzed by differential scanning calorimetry(DSC),After the conclusion that the purity of co-crystals prepared by solution method is higher,the purity values of the above four kinds of co-crystals were measured by DSC,and the influence of single component impurity and multi-component impurity on DSC curve was studied.It was found that the existence of impurity can significantly change the shape of DSC curve,and the thermal effect of some phase transition peaks on DSC curve has a linear relationship with the impurity content.Finally,the sensitivities of DSC,powder diffraction and IR to the purity of co-crystal phase were compared and analyzed.The results show that DSC has the most obvious response to the purity of co-crystals phase,and it has the potential to be used in the quantitative detection of the purity of co-crystals phase.Chapter Ⅳ: This chapter improves the precision dissolution-reaction calorimeter,and uses it to determine the molar dissolution enthalpies of eight co-crystals and APIs at 298.15 K.Then the reaction enthalpy change of each co-crystals was calculated according to Hess law.And from the perspective of thermodynamics,the energy change and mechanism of co-crystals formation are briefly analyzed.In addition,taking the pyrazinamide-p-hydroxybenzoic acid(PZA-PHBA)co-crystal as an example,the density functional theory(DFT)was used to simulate the reaction enthalpy change and the hydrogen bonds in the process of PZA and PHBA crystals forming the PZA-PHBA co-crystal.The results of the simulation are consistent with the one of the solution calorimetry experiments.