Energy framework and solubility: a new predictive model in the evaluation of the structure–property relationship of pharmaceutical solid forms

Abstract

The active pharmaceutical ingredient (API) is a drug product's biologically active chemical substance that produces the desired therapeutic effects. Most APIs are small organic molecules commercially available as a crystalline solid phase. Crystalline drugs are preferred in oral dosage formulations for their high purity and stability. However, some commercial drugs have low aqueous solubility, reducing their bioavailability and requiring high doses of API. Thus, discovering/investigating solid crystalline forms or controlling/designing more soluble forms with optimized pharmaceutical properties can be challenging or suitable for the pharmaceutical industry and academia. In this sense, the present work proposes a new physicochemical approach consisting of the average framework energy (_framework) which is the average intermolecular interaction in crystalline solids to predict the modification of API solubility in new solid forms. This way, it was possible to correlate the intermolecular interactions of a given crystalline solid-state with its respective aqueous solubility. Overall, 60 crystalline forms are involved in this investigation derived from 25 distinct APIs. The results indicate that the average energy framework calculated and the aqueous solubility display a linear upward trend in the distribution of points, meaning that the greater the solubility, the lower the interaction energy. Such an approach is more evident in box plot-based drugs grouped by solubility range indicating a handy predictive model for drug solubility estimation based exclusively on energy framework features.