title: Substituent effect on the thermodynamic solubility of structural analogs: relative contribution of crystal packing and hydration.
abstract: Thermodynamic analysis of the solubility of benzoylphenylurea (BPU) derivatives was conducted to investigate the relative importance of crystal packing and hydration for improving solubility with minor structural modification. The contribution of crystal packing to solubility was evaluated from the change in Gibbs energy on the transition from the crystalline to liquid state. Hydration Gibbs energy was estimated using a linear free-energy relationship between octanol-water partition coefficients and gas-water partition coefficients. The established solubility model satisfactorily explained the relative thermodynamic solubility of the model compounds and revealed that crystal packing and hydration equally controlled solubility of the structural analogs. All hydrophobic substituents were undesirable for solubility in terms of hydration, as expected. On the other hand, some of these hydrophobic substituents destabilized crystal packing and improved the solubility of the BPU derivatives when their impact on crystal packing exceeded their negative influence on hydration. The replacement of a single substituent could cause more than a 10-fold enhancement in thermodynamic solubility; this degree of improvement was comparable to that generally achieved by amorphous formulations. Detailed analysis of thermodynamic solubility will allow us to better understand the true substituent effect and design drug-like candidates efficiently.
authors.affiliation: Analytical Development Research, Eisai Product Creation Systems, Eisai Company Ltd., Kamisu, Ibaraki 314-0255, Japan; Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Sakyo, Kyoto 606-8502, Japan. Electronic address: s3-ozaki@hhc.eisai.co.jp.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Ozaki
authors.affiliation: Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Sakyo, Kyoto 606-8502, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Sakyo, Kyoto 606-8502, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Shirai
authors.affiliation: Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Sakyo, Kyoto 606-8502, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kano
mesh_terms: D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D004355:Drug Stability; D057927:Hydrophobic and Hydrophilic Interactions; D016014:Linear Models; D008956:Models, Chemical; D044367:Phase Transition; D010671:Phenylurea Compounds / Q000737:chemistry*; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D013696:Temperature; D014867:Water / Q000737:chemistry*
chemical_list: D010671:Phenylurea Compounds; D014867:Water
keywords: calorimetry; crystal packing; drug design; hydration; log P; solubility; thermodynamics