Dissolution control of highly soluble active pharmaceutical ingredients via cocrystallisation

Abstract

Crystal engineering involves the manipulation of intermolecular interactions to design functionalised crystalline materials and has proved to be an effective tool for the modification of physicochemical properties of active pharmaceutical ingredients (APIs). In the first section of this study, the aim was to systematically influence the rate of dissolution of a highly soluble active pharmaceutical ingredient using crystal engineering principles. Salicylic acid (SA) was employed as a model API to form multicomponent crystals with a series of selected cinchona alkaloids, namely quinine (QUIN), quinidine (QUID), cinchonine (CINC), cinchonidine (CIND), N-benzylquininium chloride (NBQUIN), N-benzylcinchonidinium chloride (NBCIND) and N-benzylcinchoninium chloride (NBCINC). The resulting novel crystalline forms were found to be salts, and were characterised using single crystal X-ray diffraction, powder X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis. The dissolution profiles of the salicylate salts, measured from an aqueous media using high performance liquid chromatography-mass spectroscopy, show a significant decrease in the rate of dissolution of SA. Subsequently, Hirshfeld surface analysis was used as a tool for quantitative and qualitative comparison of the crystal structures. This study indicates that the rate of dissolution can be successfully influenced by methodically adding extra hydrophobic groups onto the coformer. In the second section, we applied the information obtained from the SA studies to acetylsalicylic acid (aspirin, ASA). We sought to improve its thermal stability and dissolution via the formation of new solid forms with the aforementioned cinchona alkaloids. We successfully synthesized a novel drug-drug salt of an analgesic, non-steroidal antiinflammatory and antipyretic drug (ASA), and an antimalarial and analgesic drug (QUIN). The salt was formed both by using solution methods and liquid assisted grinding - a green chemistry technique. The salt exhibited physicochemical properties different from the parent drugs, and a reduced rate of dissolution.