Importance of Solvent Selection for Stoichiometrically Diverse Cocrystal Systems: Caffeine/Maleic Acid 1:1 and 2:1 Cocrystals

Phase diagrams of cocrystals often show a highly unsymmetrical
nature. The solvent has an important impact on the overall aspect
of these diagrams. In this paper, we show how the solvent affects
the composition of the stoichiometric solid phase nucleated. Suitable
conditions for nucleation and growth of a single 2:1 caffeine/maleic
acid cocrystal are obtained in ethyl acetate, showing comparable solubility
toward both caffeine and maleic acid. Through a full kinetic screen,
we were able to identify, for the first time, reproducible conditions
for the spontaneous crystallization of the 2:1 phase in solution.
Furthermore, during the screening experiments, a hithertho unknown
form of the 1:1 cocrystal phase was encountered. Structural X-ray
diffraction analyses of both the 2:1, as well as the 1:1 polymorphic
phases, show an out of plane maleic acid compound. The carboxylic
acid groups are oriented in such a manner to promote intermolecular
formation of hydrogen bonded synthons.