title: Development of a partially automated solubility screening (PASS) assay for early drug development.
abstract: A medium-throughput, compound-saving, thermodynamic solubility assay for early drug development was developed. Solid compound suspended in heptane was used for simple, time-saving, and flexible compound distribution into 96-well plates, with minor risk to generate new physical forms during dispensing. Low volume, well-stirred incubation vessels were generated by using a combination of V-shaped wells, well caps, and vertically inserted stir bars. This allowed solubility determination up to 100 mg/mL in 40-80 microL volumes in aqueous and nonaqueous, low- and high-viscosity solvents. After removal of residual solid through syringe filters mounted on microtiter plates, the filtrate was quantified by ultra performance liquid chromatography (UPLC) using a 1.2 min gradient. Combined with a robotic liquid handling system, throughput was 45 samples per hour and >600 solubility measurements per week. Results from the partially automated solubility screening (PASS) assay correlated well with reported solubility values (r2 = 0.882). The PASS assay is useful for compound-saving, thermodynamic solubility measurement at the discovery-development interface where maximal solubility in many commonly used solvents needs to be determined. PASS results provide a basis for the identification of formulation strategies, the selection of appropriate excipients, and for the prediction of the potential in vivo behavior of compounds.
authors.affiliation: Preclinical Research, Pharma Division, F. Hoffmann-La Roche Ltd., CH-4002 Basle, Switzerland. Jochem.Alsenz@roche.com
authors.forename: Jochem
authors.initials: J
authors.lastname: Alsenz
authors.forename: Eva
authors.initials: E
authors.lastname: Meister
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Haenel
mesh_terms: D001331:Automation; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D015195:Drug Design; D004867:Equipment Design; D005374:Filtration; D008832:Microchemistry; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D015203:Reproducibility of Results; D012995:Solubility; D012997:Solvents / Q000737:chemistry*; D013678:Technology, Pharmaceutical / Q000295:instrumentation / Q000379:methods*
chemical_list: D004364:Pharmaceutical Preparations; D012997:Solvents