Design,Preparation And Characterization Of Chlorothiazide Cocrystals And Hydrochlorothiazide Cocrystal

Cocrystal is composed of two or more carefully selected organic molecules,which may exhibit a different crystal compared to the single component.Cocrystals often have some novel structural feature,and in-depth study of crystal structure feature and weak interactions is of great significance for perfecting the cocrystal crystallization mechanism.In this paper,two drugs with similar structures ——chlorothiazide and hydrochlorothiazide,were selected as model drugs to study the structural feature of the cocrystals.First,the electrostatic potential of the surface of chlorothiazide and hydrochlorothiazide molecules are analyzed to determine the possible interaction sites and their strength.Then,with the guidance of amine-carboxylate supramolecular synthon,11 amino acids with lower molecular weights were selected as cocrystal formers,and the cocrystals were screened by the grinding method,characterized by single crystal X-ray diffraction,powder X-ray diffraction,differential thermal scanning calorimetry,infrared and other means,it was confirmed that 5 new cocrystals were obtained,which were chlorothiazide-sarcosine cocrystal,Chlorothiazide-DL-proline cocrystal,chlorothiazide-L-proline cocrystal hydrate,chlorothiazide-D-proline cocrystal hydrate,and hydrochlorothiazide-sarcosine cocrystal.Analysis of the hydrogen bond length indicates that there is no proton transfer between the molecules,indicating that the crystal obtained are cocrystal.Among them,chlorothiazide-sarcosine cocrystal,chlorothiazide-DL-proline cocrystal and hydrochlorothiazide-sarcosine cocrystal have very similar structural feature,showing similar intermolecular interactions and crystal packing.Crystal Explorer software and wave function analysis software Mulitiwfn were used to analyze the intermolecular interaction between molecules in the cocrystal.