A crystallographic route to understand drug solubility: the case of 4- aminoquinoline antimalarials

Most Active Pharmaceutical Ingredients (API) can be prepared in various crystalline forms [1] displaying largely different physical/chemical properties and bioavailability. Salt formation represents the most common and simplest chemical way to modify the overall features but also the toxicity and biopharmaceutical availability of a drug substance. However, it is often unclear how and why the chemical and crystallographic characters can cooperate in determining these changes. We here face the problem from the perspective of the antiplasmodial drug piperaquine (PQ, C29H32Cl2N6) [2]. Being highly lipophilic, both neutral PQ and its commercial hydrogen phosphate tetrahydrate salt are poorly soluble in water, resulting in a reduced oral bioavailability. We synthesized five novel PQ salts and characterized them by both single crystal X–ray diffraction methods and T-dependent (20 – 50 ºC) UV–Vis spectroscopy. Our aim was to explore possible relationships among non-covalent interaction networks in the crystals and measured solubilities. We also estimated changes in thermodynamic state functions related to the solvation process by DFT simulations, both in vacuo and in the solid state. We found that solubilities of PQ salts conform in most cases to the Hard and Soft Acid and Bases (HSAB) rules, i.e. less soluble compounds bear ions of comparable hardness. Crystal packing plays a far less important role, even though disorder-related entropic effects can influence the response of solubility to temperature. A possible take-home message is that intensive thermodynamic properties stem from a non-trivial cooperation several physicochemical effects. A first-principle understanding of the drug solubility cannot rely just on the description of the crystal packing, but must take into account the explicit evaluation of interaction energetics and pertinent electronic factors. [1] R. Hilfiker and M. von Raumer, Polymorphism in the Pharmaceutical Industry: Solid Form and Drug Development. 2019, Wiley-VCH, Weinheim (Germany). ISBN: 978-3-527-34040-8. [2] P. Sacchi, L. Loconte, G. Macetti, S. Rizzato and L. Lo Presti Crystal Growth Des. 2019. 19, 1399