Hydrogen Bond Synthons in the Interplay of Solubility and Membrane Permeability/Diffusion in Variable Stoichiometry Drug Cocrystals Basanta Saikia, Pranita Bora, Rajiv Khatioda, and Bipul Sarma* Department of Chemical Sciences, Tezpur University, Tezpur 784028, India * S Supporting Information ABSTRACT: The bronchodilator drug theophylline (THP), though a BCS class-I drug, is considered as a representative compound to prepare variable stoichiometry cocrystals with isomeric aminobenzoic acids (o-ABA, m-ABA, and p-ABA) as coformers. Cocrystals are synthesized using crystal engineering principles through liquid-assisted mechanochemical grinding. Four different stoichiometry cocrystals of THP are isolated with o-ABA. Coformers m-ABA and p-ABA afforded only 1:1 cocrystals irrespective of crystallization media and different starting materials ratios. All cocrystal materials were subjected to aqueous solubility and diffusion/membrane permeability to examine drug biopharmaceutic properties to predict the in vivo performance of the drug. They exhibited different but improved solubility and modulated diffusion/membrane permeability when compared with pure THP. The interplay of drug solubility and membrane permeability that predicts the overall bioavailability is emphasized based on hydrogen bond synthons and solute···solvent interactions. Hirshfeld surface analysis was carried out in all cases to determine whether a correlation exists between permeability and drug-coformer interactions. ■ INTRODUCTION From intellectual property (IP) perspectives, polymorphs and cocrystal patents are given authoritative approval and thereby adding the responsibility to formulate a bioequivalent product which is physically and chemically stable and scale up manufacturable without losing desired properties. Hence, the synthesis of various solid-state forms and prior assessments of all physical and physicochemical characteristics such as solubility, dissolution rate, flowability, performance, and stability-related issues are of great importance to identify effective bioequivalent dosage forms. 1-10 By recommendation, cocrystals are crystalline solids, in association with an active pharmaceutical ingredient (API) with excipient(s) or co- former(s) designed at the molecular level to achieve drug product performance such as stability, bioavailability, patient acceptance, and other quality characteristics. Thereby different stoichiometry cocrystals ensure nonidentical drug perform- ances. To a large extent, polymorphs and in recent times drug cocrystals have been tested for the expected attributes such as stability issues, solubility, dissolution/permeability, hygrosco- picity, etc. 5,7,10-13 However, study on structure-property relationship of various stoichiometry drug cocrystals is limited. 14,15 Therefore, the present work sought to design and synthesize different stoichiometry cocrystals of the bronchodilator drug theophylline (THP) using a crystal engineering approach. We have chosen three commonly used and readily available coformers, i.e., isomeric mono amino- benzoic acids [o-aminobenzoic acid (o-ABA), m-aminobenzoic acid (m-ABA), and p-aminobenzoic acid (p-ABA)]. Despite polymorphism, isomeric aminobenzoic acids are also known to possess biological activities, primarily in metabolic processes and phytotoxicity. Four different stoichiometry cocrystals for THP·o-ABA including isobutanol as solvate and hydrates are isolated. Later two coformers, i.e., m-ABA and p-ABA, did not afford variable stoichiometry adducts except only solvent-free 1:1 cocrystals (Table 1). Spectroscopy, thermal analysis, powder X-ray diffraction, and single crystal X-ray structure determination were employed to characterize all cocrystals materials and then they were subjected to aqueous solubility and diffusion/membrane permeability determination. Jones et al. studied 1:1 nicotinamide·suberic acid cocrystal formation as an intermediate while synthesizing 1:2 cocrystals and emphasized the importance of mechanochemical grinding experiments to control cocrystal stoichiometry by modifying the stoichiometric ratio of reactants in the reactant mixture. 16,17 The cocrystal formation emphasized therein occurred in a stepwise manner by the formation and competition of various energy supramolecular synthons. Our attempts to isolate intermediate stoichiometry cocrystals in a stepwise mechanism were unsuccessful for THP·ABA systems. While there is an important role of competition and cooperation of supra- molecular synthons and crystallization media, different ratio starting materials on the formation of variable stoichiometry cocrystal is perceived. The synthesis, isolation, and character- Received: September 6, 2015 Revised: October 1, 2015 Published: October 5, 2015 Article pubs.acs.org/crystal © 2015 American Chemical Society 5593 DOI: 10.1021/acs.cgd.5b01293 Cryst. Growth Des. 2015, 15, 5593-5603