Solvent selection for pharmaceuticals

Abstract The presence of solvents is essential in all steps of pharmaceutical processes (reaction, separation, and formulation). For toxicological reasons, drug manufacturers are increasingly required to minimize the number of solvents employed in pharmaceutical processes. In practice, the selection of solvents and antisolvents for pharmaceuticals mostly relies on experience, analogy and experimental testing. Our work aims to systematically investigate the solubility of pharmaceutical compounds and their intermediates in a wide range of solvents. We describe the development of solubility databases of mono- and bifunctional compounds that are based on the core molecular fragments of common drugs and contain substituents of gradually increasing polarity. The core fragments can be identified by a classification of drugs into pharmaceutical categories. Each of the solutes is studied in a series of pharmaceutical solvents of varying polarity and hydrogen bonding tendency. The utility of an example database is shown which uses the benzene ring as the core fragment and contains activity coefficient data of 13 monofunctional benzene derivatives in 17 solvents. The database was analyzed by the Modified UNIFAC (Dortmund) group contribution method and quantum-mechanical/COSMO-RS calculations. The testing shows the importance of polarization effects which are common between drug-like molecules and small polar solvents. The proposed approach can be useful to provide a systematic insight into solvent–solute interactions and for testing of new methods of solubility prediction.