The molecular salt of pyrimethamine and fenbufen for enhancing dissolubility via an assisted efficacy-increasing approach of dual-drug salt formation: A combined study including theory analysis and experiment validation

Abstract

An approach of dual-drug salt formation assisted increase efficacy has been put forward with the aim of fully exploiting the benefits of NSAID fenbufen (HFB) in enhancing the dissolubility and efficacy of antimalarial drug pyrimethamine (PYR). The approach features the acidic property of HFB and PYR's alkalinity to generate the designed molecular salt via the neutralization reaction, thus making the solubility capacity of the two bulk drugs be concurrently heightened due to the salt formation effect, which, in turn, not only makes for enhancing PYR's bioavailability, but contributes to playing the fast and efficient antipyretic function of HFB serving as a fever-relieving medicine, thereby, conducing to increasing the therapeutic effect of PYR on malaria. Based on this approach, the objective dual-drug molecular salt PYR-HFB has been successfully attained and structurally authenticated by single-crystal X-ray diffraction and diversified analytical techniques. The single-crystal structure analysis demonstrates that the resulting heterodimer entity in the asymmetric unit of the molecular salt comprises a HFB anion and a PYR cation linked by robust charge-assisted hydrogen-bonds to construct an integral 3D supramolecular network, endowing the present molecular salt with the ability to respectively raise solubility and intrinsic dissolution rate up to 2.3- and 4.6-fold relative to parent drug PYR, which fulfills positive connections with theoretical forecasts involving Hirshfeld surface analysis, molecular electrostatic potential, theory of atoms in molecules and frontier molecular orbit. Therefore, this investigation not only affords a fire-new crystalline style with developing foreground for PYR, but supplies an insightful salt formation approach for perfecting both dissolubility and efficiency of antimalarial medicines at the molecular level by playing the characteristic and function of NSAIDs in treating malaria.