title: Identification of suitable formulations for high dose oral studies in rats using in vitro solubility measurements, the maximum absorbable dose model, and historical data sets.
abstract: The ability to define compound solubility targets that are predictive of good oral absorption at high dose preclinical studies (≥ 100 mg compound/kg animal) is of use in drug discovery and development. Two different approaches to identify these targets in preclinical formulations are evaluated herein. The first approach is the use of solubility values from in vitro formulation dilutions using biorelevant parameters for rats. These dilution/solubility results are applied to the maximum absorbable dose (MAD) model to predict compound exposure (AUC) from oral doses and allow the fraction of dose absorbed (F(abs)) calculation. The results from 26 such in vitro evaluations are compared to in vivo studies and discussed. The second approach is the analysis of in vivo AUC proportionality between 10 and 100 mg/kg doses for 28 compounds where only the compound solubility in neat formulation is known. Both assessments suggest similar threshold targets to remove solubility as an absorption limitation for any given compound. Specifically, compound solubility should be >2 mg/mL in aqueous surfactants and >15 mg/mL in cosolvent (PEG400) or pH-adjusted aqueous formulations. The results are a starting place for formulation rule-of-thumb solubility targets applied in discovery and development settings.
authors.affiliation: Basic Pharmaceutical Sciences, Merck Research Laboratories, Merck & Co, West Point, Pennsylvania 19486, United States. peter_wuelfing@merck.com
authors.forename: W Peter
authors.initials: WP
authors.lastname: Wuelfing
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kwong
authors.forename: John
authors.initials: J
authors.lastname: Higgins
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D012995:Solubility
chemical_list: D004364:Pharmaceutical Preparations; D011092:Polyethylene Glycols