Pharmaceutical Cocrystals And Salts Of Tautomeric Drug Molecule

An active pharmaceutical ingredient (API) compound can exist in several different solid forms, such as polymorphs and amorphous forms of pure API compounds, hydrates, solvates, salts and cocrystals. Each form may display unique physicochemical properties such as solubility, stability, bioavailability, and manufacturability. Some APIs with highly desirable molecular pharmacological properties may never realize their maximum potential due to the unfavorable physicochemical properties. Thus, it is necessarily to screen out suitable solid form of an API to ensure satisfied properties. Cocrystal and organic salt forms have being attracted significant interest in the pharmaceutical industry and crystal engineering as their remarkable improvement on the physicochemical properties and bioavailabilities of APIs. This context aims at the design of cocrystals and salts of tautomeric drugs. The tautomeric drug we selected is the sulfa drug sulfamethazine (SMT). We firstly study the formation mechanism of SMT/saccharin (SAC) complexes, which can exist in either 1:1 salt or 1:1 cocrystal form. We also performed cocrystallization of SMT with some acidic organic molecules. A variety of characterization methods have been used to confirm resulting products, and the physicochemical properties of these novel crystalline complexes have also been investigated.(1) The preparation of the salt of SMT and SAC has been repeated by using solvent evaporation method. Also, a cocrystal was obtained by changing the solvent and experimental condition. X-ray single crystal diffraction indicates both forms possess the same main intermolecular interaction site but the locations of the acidic proton are different. Theoretical calculations have been taken to testify the contributions of intra-and intermolecular interactions on the energy relationship of both forms. The solvent-mediated phase transformation experiments were carried out for the comparison of Gibbs free energies of these two complexes. All solid products were transformed into cocrystal form, indicating SMT-SAC cocrystal, relative to SMT-SAC salt, is located at the lower Gibbs free energy state at room temperature. This conclusion is also supported by the higher solubility of SMT-SAC salt than that of SMT-SAC cocrystal.(2) Three salts and two cocrystals have been obtained by co-crystalizing SMT with the selected acidic organic molecules (acesulfame (AH), anhydrous oxalic acid (OA), maleic acid (MA),2,6-dihydroxybenzoic acid (DBA), gentisic acid (DHA,) and phthalic acid (PHA)). These new crystalline complexes all demonstrated enhanced solubilities. Single-crystal for the samples have been obtained by using solvent evaporation method. These complexes were further characterized by using powder X-ray diffraction (PXRD), differential sacanning calorimetry (DSC) and solid-state nuclear magnetic resonance (ssNMR). Basing on these knowledge, spectroscopic characteristics and structural features of SMT crystalline complexes were summarized.