Stoichiometric Control of Co-Crystal Formation by Solvent Free Continuous Co-Crystallization (SFCC)

摘要

Reproducible control of stoichiometry and difficulties in large-scale production have been identified as two of the major challenges to commercial uptake of pharmaceutical co-crystals. The aim of this research was to extend the application of SPCC to control stoichiometry in caffeine:maleic acid co-crystals. Both 1:1 and 2:1 caffeine:maleic acid co-crystals were produced by control of the feedstock composition and process conditions. It was also observed that formation of 2:1 stoichiometry co-crystals involved formation of a 1:1 co-crystal which was subsequently transformed to 2:1 co-crystals. The investigation of stoichiometric transformation revealed that although 1:1 co-crystals could be converted into 2:1 form with addition of excess caffeine, the reverse was not possible in the presence of excess maleic acid. However, conversion from 2:1 into 1:1 was only achieved by melt seeding with the phase pure 1:1 co-crystals. This investigation demonstrates that stoichiometric control can be achieved by SFCC by control of parameters such as extrusion temperature.