Exploring the shape influence on melting temperature, enthalpy, and solubility of organic grug nanocrystals by a thermodynamic model

This paper focuses on a thermodynamic model built to predict the reduction of organic drug melting temperature and enthalpy with nanocrystal size decrease. Indeed, this valuable information enables us to evaluate the increase of drug solubility, an aspect of paramount importance for poorly water-soluble organic drugs since a solubility increase is reflected in a bioavailability enhancement. In particular, the model considers the effect of nanocrystals shape (spherical, cylindrical, and parallelepiped-shaped) and morphology (from platelet to needle nanocrystals) on the melting temperature and enthalpy reduction with crystal size decrease. Nimesulide, a typical nonsteroidal and poorly water-soluble drug with anti-inflammatory action, has been chosen as a model drug to test model reliability. Model outcomes suggest that the reduction of melting temperature and enthalpy mainly depends on the ratio between crystals surface area and volume, i.e., on the ratio between the number of surface and bulk molecules constituting the nanocrystal network. The obtained prediction of solubility enhancement and the successful comparison with the outcomes obtained from a molecular dynamics approach, in terms of melting temperature and enthalpy decrease, have confirmed the reliability of the proposed model.