The pre-formulation of pharmaceutical cocrystals and salts is a concept of crystal engineering that has emerged as a promising technique for drug development in pharmaceutical industry. Recent introduction of pharmaceutical cocrystals in regulatory guidelines of US Food and Drug Administration (FDA) made them one of the potential alternatives when salt preparation is not feasible. Apart from generally regarded as safe (GRAS) coformers, drug‑drug and drug‑nutraceutical cocrystals are recent additions to pharmaceutical cocrystal family that have additional health benefits. Indeed, preparation of salt forms is a routine practice to deal with inadequacies associated with the active pharmaceutical ingredient (API) and happens to be a potentially reliable method. Amongst them, drug-drug and drug-nutraceutical cocrystals have drawn significant importance in the recent past as they reduce drug load and cost effects during multiple disease diagnosis. However, one has to be prudent in the selection of drug molecules, the presence of complementary hydrogen bond synthon, disease management during multiple disease therapy, etc. that play important roles in their preparation. That is the reason why drug–drug cocrystals are scarce in the literature compared to pharmaceutical cocrystals containing GRAS coformers and salt forms. Herein, we discuss case studies preferably the reported drug‑drug, drug‑nutraceutical cocrystals, and a few salts with an emphasis on their role in physicochemical property modulation.

Theophylline medications are used as bronchodilators that relax the muscles in the breathing tubes. Issues relating to the hydration behaviour and moisture stability of this drug are well-known. Seven new cocrystals of theophylline with phenols, and isomeric hydroxybenzoic acids are synthesized. Solvent assisted mechanochemical synthesis is employed in order to synthesize the cocrystal materials. Single crystal structures are obtained for all cocrystals and furthermore they are characterized thermally, spectroscopy and by powder X-ray diffraction. The hydrogen bonding and crystal packing features are examined and found to be comparable to reported cocrystals/salts of theophylline or its molecular analogues, i.e. caffeine and theobromine. The solubility of these cocrystals are determined using UV-vis spectroscopy and correlated with the hydrogen bond synthon energies computed on Gaussian using DFT. The occurrence probability of the hydrogen bond synthons are examined with the Cambridge Structural Database (CSD). An important observation is that the phenol coformers facilitate water assimilation in the crystalline lattice since they offer a weaker O–H⋯N_imidazole H bond synthon over the stronger COOH⋯N_imidazole H-bond available in hydroxybenzoic acid coformers. The presence of the –COOH group prevents water incorporation and provides added physical stability to the cocrystal at highly humid conditions. The results show the feasibility of cocrystal design of a drug to tune its physical properties based on hydrogen bond synthons.

Stoichiometric variation in organic cocrystals, their synthesis, structure elucidation and properties are discussed. Accountable reasons for the occurrence of such cocrystals are emphasised.