An investigation into co-crystal processing and solid-liquid phase equilibria

In this work, the processing and manufacturing of co-crystals have been investigated for two systems of sulfamethazine (SMT), with respective coformers, salicylic acid (SA) and 3methylsalicylic acid (3mSA), both in 1:1 stoichiometry. Slurry conversion crystallization is demonstrated as a successful route for the manufacture of pure co-crystal. This technique involves equilibrating the solid co-crystal components and solvent in a specific ratio at a certain temperature. In any solvent, guided by the ternary phase diagram, as long as the overall composition is in the region where co-crystal is the most stable solid phase, pure co-crystal can be obtained by this technique. The phase diagrams for these co-crystals have been determined and analyzed in different solvents and at different temperatures. For model system 1, 1:1 SMT-SA co-crystal, ternary phase diagrams in three solvents- methanol, acetonitrile and 7:3 (v/v) dimethylsulfoxide (DMSO)-methanol mixture, and at three temperatures were constructed. For model system 2, 1:1 SMT-3mSA, phase diagrams in methanol and acetonitrile, at 30 oC were constructed. SMT3mSA formed a new co-crystal wherein its crystal structure was solved and it was thoroughly characterized. The SMT-SA co-crystal showed congruent dissolution in acetonitrile but dissolved incongruently in the other two solvents, whereas the SMT-3mSA co-crystal showed incongruent dissolution in both methanol and acetonitrile. The choice of solvent is shown to have a strong impact on the appearance of the ternary phase diagram and affects the dissolution behavior of the co-crystal, significantly. Temperature did not show a significant effect in the 20 oC temperature range studied for SMT-SA co-crystal. The thermodynamics of both the cocrystals were investigated. The values for Gibbs energy of co-crystal formation were negative signifying the thermodynamic stability of the co-crystal over a mixture of pure components. A relation between the size of the region where the co-crystal is the stable solid phase in the ternary phase diagram and the relative solubility (solubility ratio) of coformer to API was uncovered. SMT was found to form solvates with three solvents- dimethylsulfoxide, N,Ndimethylacetamide and N,N-dimethylformamide, all in 1:1 stoichiometry. The solvates were characterized by various analytical techniques and their solubility was determined in their respective solvents at 25 oC. The solubility of the solvates was much higher than the solubility of SMT in common solvents like water and methanol. Desolvation experiments produced the monomorphic pure crystalline SMT. The desolvation temperature and the enthalpy of desolvation were much lower than the melting temperature and the enthalpy of vaporization of the pure solvent, respectively, suggesting weaker bonding in the solvates than in pure solvents. Microwave-assisted slurry conversion for co-crystal manufacture was evaluated and compared to conventional slurry crystallization at same temperature keeping other conditions identical. Microwave technique not only increased the rate of co-crystal formation but also proved to be scalable at least up to 20 g. Three new co-crystals, SMT-nicotinamide, sulfamerazine (SMR)anthranilic acid and SMR-salicylamide were discovered and characterized thoroughly. The cocrystals increased the equilibrium concentration of drug in solution as compared to pure APIs. A difference in stability, reactivity and rate of co-crystal formation between the two sulfa drugs was observed and discussed via Hirshfeld analysis and interaction energy calculations.