Polymorphism in drug compounds can cause significant problems for industrial-scale production and so a method for restricting the conformational freedom of the target compound whilst retaining desired chemical properties is highly beneficial to the pharmaceutical industry. Co-crystallisation is commonly used to alter the structure of an active pharmaceutical ingredient (API) without affecting its activity. A comprehensive co-crystal screen of four fenamic acid derivatives affords a strictly limited number of co-crystals. These show no evidence of polymorphism, although some of the parent APIs exhibit significant polymorphism. Two of these co-crystals, of mefenamic acid and tolfenamic acid with 4,4′-bipyridine, were previously unknown and are studied using X-ray diffraction. Co-crystals from this screen are fully characterised and display comparable solubility and stability with respect to the parent APIs; no phase transformations have been identified. A range of crystallisation techniques, including cooling and grinding methods, are shown to afford single polymorphic forms for each of the co-crystals.
Wittering, K., Agnew, L., Klapwijk, A. R., Robertson, K., Cousen, A., Cruickshank, D., & Wilson, C. (2015). Crystallisation and physicochemical property characterisation of conformationally-locked co-crystals of fenamic acid derivatives. CrystEngComm, 17(19), 3610-3618. https://doi.org/10.1039/C5CE00297D