A novel method for the prediction of the activity coefficient in pharmaceutical-solvent systems is introduced. The method infers that the concept of segment interactions applies not only to components, but to the functional groups that comprise the component; more specifically, the popular modified UNIFAC (Dortmund) [1] functional groups. In the present work, four basic segment interactions are considered, that include hydrophobic (dispersive), hydrophilic, as well as positive and negative polarity. The predictive model was applied to a set of structurally diverse, complex pharmaceuticals, and compared to popular qualitative solubility prediction methods such as NRTL-SAC Chen and Song [2] and the UNIFAC based methods. Furthermore, the Akaike Information Criterion [3] and Focused Information Criterion [4] were used to establish the relative quality of the solubility predictions of various predictive models, with the new model exhibiting favourable results. The temperature dependence provided by the new model was also investigated. (C) 2015 Elsevier B.V. All rights reserved.