Three-dimensional topological analysis of the experimental and theoretical electron density of a 5-fluorocytosine/isoniazid co-crystal

Abstract

Drug-drug cocrystals involve the combination of two or more active pharmaceutical ingredients (API) with their original chemical characteristics maintained without breaking or forming new covalent bonds, thus ensuring its effectiveness.[1] Its pharmaceutical properties are determined by the polarity of functional groups, the electrostatic potential and the available intermolecular interactions, which in turn are characterized by the three-dimensional arrangement and governed by its molecular electronic structure.[2] These molecular electron properties and their relationship with the charge density topology can be analysed by experimental and theoretical studies. In this manner, the experimental charge density analysis of the pharmaceutical drug-drug cocrystal involving the antimetabolite prodrug 5-Fluorocytosine (5-FC) and the tuberculostatic drug Isoniazid (INH), named 5FC-INH, [3] has been carried out based on the Hansen & Coppens aspherical multipolar model refinement,[4] using low temperature high resolution X-ray diffraction data ( (sin(θ max )/λ=1.15 Å -1 , 150K). The experimental model was compared with those derived from corresponding theoretical calculations for solid-state and gas-phase conditions using density functional theory (DFT)