title: A computational model for the prediction of aqueous solubility that includes crystal packing, intrinsic solubility, and ionization effects.
abstract: The optimization of aqueous solubility is an important step along the route to bringing a new therapeutic to market. We describe the development of an empirical computational model to rank the pH-dependent aqueous solubility of drug candidates. The model consists of three core components to describe aqueous solubility. The first is a multivariate QSAR model for the prediction of the intrinsic solubility of the neutral solute. The second facet of the approach is the consideration of ionization using a predicted pKa and the Henderson-Hasselbalch equation. The third aspect of the model is a novel method for assessing the effects of crystal packing on solubility through a series of short molecular dynamics simulations of an actual or hypothetical small molecule crystal structure at escalating temperatures. The model also includes a Monte Carlo error function that considers the variability of each of the underlying components of the model to estimate the 90% confidence interval of estimation.
authors.affiliation: Bristol-Myers Squibb, Co., Princeton, New Jersey 08543, USA. stephen.johnson@bms.com
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Johnson
authors.forename: Xue-Qing
authors.initials: XQ
authors.lastname: Chen
authors.forename: Denette
authors.initials: D
authors.lastname: Murphy
authors.forename: Olafur
authors.initials: O
authors.lastname: Gudmundsson
mesh_terms: D003460:Crystallization; D006863:Hydrogen-Ion Concentration; D007477:Ions / Q000737:chemistry*; D008956:Models, Chemical; D008962:Models, Theoretical; D015394:Molecular Structure; D009010:Monte Carlo Method; D004364:Pharmaceutical Preparations / Q000032:analysis / Q000737:chemistry*; D011237:Predictive Value of Tests; D021281:Quantitative Structure-Activity Relationship; D012995:Solubility; D018709:Statistics, Nonparametric; D014867:Water / Q000737:chemistry*
chemical_list: D007477:Ions; D004364:Pharmaceutical Preparations; D014867:Water