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The total entropy of melting for a variety of compounds is estimated by a modification of Walden's rule. This modification accounts for the effects of both molecular rotational symmetry and molecular flexibility upon entropy. The simple semiempirical equation gives an average error of 12.5 J/K·mol when applied to more than 930 different compounds.

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The objective of this paper was to identify oral bioavailability enhancing approaches for a poorly water-soluble research compound during drug discovery stages using minimal amounts of material. LCQ789 is a pBCS (preclinical BCS) Class II compound with extremely low aqueous solubility (<1 µg/mL) and high permeability, therefore, resulting in very low oral bioavailability in preclinical species (rats and dogs). A number of solubility and/or dissolution enhancing approaches including particle size reduction, solid dispersions, lipid-based formulations and co-crystals, were considered in order to improve the compound's oral bioavailability. High-Throughput Screening (HTS) and in silico modeling (GastroPlus™) were utilized to minimize the compound consumption in early discovery stages. In vivo evaluation of selected physical form and formulation strategies was performed in rats and dogs. Amongst the formulation strategies, optimized solid dispersion and lipid-based formulation provided significant improvement in drug dissolution rate and hence, oral bioavailability. In addition, a significant impact of physical form on oral bioavailability of LCQ789 was observed. In conclusion, a thorough understanding of not only the formulation technique but also the physical form of research compounds is critical to ensure physical stability, successful pharmacokinetic (PK) profiling and early developability risk assessment.

Experimental entropy of melting values for physical property estimation schemes, such as solubility and vapor pressure, are not readily available. In this study a semiempirical equation, which contains two molecular parameters, is used to estimate the total entropy of melting for a variety of pharmaceutically and environmentally relevant compounds. A database of experimental entropy values consisting of over 370 different compounds was compiled from literature. A molecular rotational symmetry number and a molecular flexibility number for each compound were defined. The simple equation does very well in predicting the total entropy of melting for the complex set of molecules with an average error of 21%.