The noncovalent interactions arising from solute center dot center dot center dot solute (i.e., drug center dot center dot center dot drug, drug center dot center dot center dot neutraceutical, or drug center dot center dot center dot coformer) and solute center dot center dot center dot solvent play a significant role in predicting desired properties of an active compound. We demonstrated here the role of pi center dot center dot center dot pi interactions in the presence of hydrogen bonding, the two important cohesive and adhesive forces in the crystallization of small molecules to regulate certain physiochemical properties in their multicomponent crystals. Acridine was employed as a representative cocrystal partner with isomeric dihydroxybenzoic acids. The choice was intentional as with a single hydrogen bond acceptor acridine provides increased surface area to favor the stacking of p-frameworks at van der Waals separation (similar to 3.5 ) and herringbone C-H center dot center dot center dot pi interactions, and isomeric dihydroxybenzoic acids easily form COOH center dot center dot center dot N-acridine and O-HNacridine hydrogen bonds in competition. Structure elucidation of several cocrystals/salts underlines the influence of continuous and discrete pi center dot center dot center dot pi stacking and C-H center dot center dot center dot pi interactions supported by other hydrogen bonds on their physiochemical properties such as solubility, cell membrane permeation, and release behavior in vitro. Experiments were performed in various pH ranges (pH = 1.2 SAL and 7.4 PBS) in order to imitate human physiological conditions. Molecular packing and interaction energies suggest a significant contribution of pi center dot center dot center dot pi interactions in the modulation of property. In fact coformers conformational energy, lipophilicity, and Log P values were found to be valued contributors. Therefore, the present study anticipates the contribution towards understanding of the impact of pi center dot center dot center dot pi and C-H center dot center dot center dot pi interactions supported by hydrogen bonds on modulating physiochemical properties, essentially improving efficacy of a drug.
