Solubility prediction of paracetamol and salicylic acid: The role of intramolecular hydrogen bonds

Intramolecular hydrogen bonds (IMHBs) are non-covalent interactions formed between a hydrogen atom covalently bonded to an electronegative atom and another electronegative atom within the same molecule. The formation of these bondshas a pronounced effect on conformation and thermodynamic properties. In particular, IMHBs play an important role in modulating solubility through the internal locking of polar groups that would otherwise interact with the solvent. However,few thermodynamic models account for IMHB interactions, leading to discrepanciesbetween predicted and experimental solubilities for compounds where such interactions are significant. In this work, an effective IMHB model is developed within the SAFT-γ Mie approach and applied to predict the solubility of two IMHB-formingmolecules, paracetamol and salicylic acid, in 30 solvents. Non-polar, polar, and hydrogen bonding solvents are considered, and the solubility in pure and mixed-solvent systems is studied. To account for the formation of IMHBs, second-ordergroups are defined, in which association sites involved in IMHB are considered saturated and hence excluded from intermolecular interactions. Within the model the sites are effectively “switched off”, so that the second-order IMHB groups have fewer sites than their first-order counterparts. All other, like and unlike, parameters of the second-order IMHB groups are identical to those of corresponding first-order groups. Considering paracetamol and salicylic acid in pure and mixed solvents, we find that the SAFT-γ Mie IMHB approach successfully captures the influence of IMHB formation in the prediction of solubility. We report improved accuracy insolid–liquid solubility calculations for 48 of the 67 mixtures investigated using this effective treatment to account for the formation of IMHBs. Thus, the approach presented serves to support molecular and process design by improving the solubility prediction of complex drug–solvent mixtures, reducing the need for additional experimental data.