Hydrogen Bond Synthons in the Interplay of Solubility and Membrane Permeability/Diffusion in Variable Stoichiometry Drug Cocrystals

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.