title: Novel high/low solubility classification methods for new molecular entities.
abstract: This research describes a rapid solubility classification approach that could be used in the discovery and development of new molecular entities. Compounds (N=635) were divided into two groups based on information available in the literature: high solubility (BDDCS/BCS 1/3) and low solubility (BDDCS/BCS 2/4). We established decision rules for determining solubility classes using measured log solubility in molar units (MLogSM) or measured solubility (MSol) in mg/ml units. ROC curve analysis was applied to determine statistically significant threshold values of MSol and MLogSM. Results indicated that NMEs with MLogSM>-3.05 or MSol>0.30mg/mL will have ≥85% probability of being highly soluble and new molecular entities with MLogSM≤-3.05 or MSol≤0.30mg/mL will have ≥85% probability of being poorly soluble. When comparing solubility classification using the threshold values of MLogSM or MSol with BDDCS, we were able to correctly classify 85% of compounds. We also evaluated solubility classification of an independent set of 108 orally administered drugs using MSol (0.3mg/mL) and our method correctly classified 81% and 95% of compounds into high and low solubility classes, respectively. The high/low solubility classification using MLogSM or MSol is novel and independent of traditionally used dose number criteria.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.
authors.forename: Rutwij A
authors.initials: RA
authors.lastname: Dave
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA. Electronic address: memorris@buffalo.edu.
authors.forename: Marilyn E
authors.initials: ME
authors.lastname: Morris
mesh_terms: D001702:Biopharmaceutics / Q000379:methods*; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000145:classification*; D012995:Solubility
chemical_list: D004364:Pharmaceutical Preparations
keywords: Analytical chemistry; Computational ADME; Computer aided drug design; High throughput technologies; In silico modeling; ROC curve analysis; Solubility