DESIGN AND SYNTHESIS OF MULTICOMPONENT ANTIMALARIAL COCRYSTALS THROUGH STRUCTURAL INEQUIVALENCE AND COMBINATORIAL APPROACHES

Abstract

The low water solubility issue of antimalarial drugs is a challenge that calls for an urgent improvement and development of new formulations because the limited bioavailability causes the need for high dosages, variability in clinical response, emergence of resistance and efficacy problems. Recent advances in knowledge of crystal engineering present the possibility to design and synthesize higher order cocrystals (HOCs) with improved properties through structural inequivalence and combinatorial approaches, using synthesized binary precursor cocrystal model that allows the inclusion of a molecule with stronger bonding energy. This research aim is to synthesize improved multicomponent pharmaceutical cocrystals of antimalarial drugs as fixed dose combination formulations through structural inequivalence approach using the insoluble antimalarial active pharmaceutical ingredients (APIs) of artermisin quinoline, and antifolate derivatives, such as artemether, primaquine, mefloquine, sulfadoxine etc. Structural inequivalence start with design of stoichiometry binary cocrystal precursor as ABB* from cocrystallization of selected APIs, A + B. Here, the weakly bonded B* situated in more than one crystallographic space (asymmetric unit) i.e. Z' ³ 2 is substituted at bonding point by the inclusion of API (C) that present stronger noncovalent energy, and homologate to a ternary ABC HOC. The successful inclusion of C to design ternary system may require exploiting the chemical differences using the complementarity from combinatorial synthesis, API shape-size mimicry, and synthon hierarchy approaches. Structure-property studies, screening and characterization will be analyzed using X-ray diffraction, spectroscopic techniques, and integrated to acoustic levitator among others. Thermodynamic models and theories on non-covalent interaction such as electron density functions and distance-dependent contacts will aid study of molecular complexity. Finally, drug properties of pharmaceutical interest such as stability, solubility and dissolution of the obtained antimalarial pharmaceutical cocrystals will be investigated. This study is expected to advance the current knowledge in this field, improve supramolecular synthetic approaches, and contribute to the development of better antimalarial formulations.