New insight into the properties of indomethacin pharmaceutical cocrystals

In the last years, the synthesis of co-crystals containing active pharmaceutical ingredients (APIs) has become the new frontier of the crystal engineering due to the great opportunity to modify the physico-chemical properties of solid forms of drugs. Actually, the pharmaceutical co-crystals display intermolecular motifs and hence crystal structure different from the pure API component, and consequently can exhibit diverse specific physical properties, such as solubility and dissolution rate. Since the therapeutic efficacy of a pharmaceutical formulation depends on its bioavailability, i.e. the absorption extent and rate of the active pharmaceutical ingredient into the bloodstream following its administration, the solubility and dissolution properties of cocrystals can allow to increase the bioavailability of poorly water soluble APIs. Even though it is currently believed that the co-crystallization strategy should not induce changes on the pharmacological profile of the APIs, it is not yet clear whether a co-crystal would be defined as a physical mixture or as a new chemical entity. In order to clarify these aspects, we chose indomethacin as guest poorly aqueous soluble molecule and compared its properties with those of its cocrystals obtained with 2-hydroxy-4-methyl-pyridine (cocrystal 1), 2-methoxy-5-nitroaniline (cocrystal 2) and saccharine (cocrystal 3). In particular, we evaluated via HPLC analysis the API dissolution profile, its ability to permeate across intestinal cell monolayers (NCM460) and its oral bioavailability in rat using the pure drug, its cocrystals and their parent physical mixtures [1]. This interdisciplinary study has shown for the first time that different effects can be induced by co-crystals and their parent physical mixtures on a biologic system, and at the same time has raised serious concerns about the use of co-crystal strategy to improve API bioavailability without performing appropriate investigations.