title: Automated approach to couple solubility with final pH and crystallinity for pharmaceutical discovery compounds.
abstract: The design and validation of a novel high-throughput system for thermodynamic solubility determination requiring only 5 mg of sample is described. The system uses a sintered nickel filter assembly to recover excess solids from saturated solutions for rapid crystallinity assessment via powder X-ray diffraction (PXRD). Moreover, the system measures the pH of filtrates to provide a final pH value with the solubility measurement. The limit of detection for the UV-vis plate reader used on this system is approximately 0.001 mg/ml, while the practical upper limit is approximately 3 mg/mL. The solubility measurements of 60 proprietary Pfizer compounds were used to validate the nickel filter assembly against a more conventional polyvinylidenedifluoride (PVDF) filter. Additionally, a comparison was made between a subset of 10 compounds run on the automated system and a more traditional shake-flask method employing HPLC analysis. In both cases, a favorable comparison was obtained.
authors.affiliation: Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. Chris.Seadeek@Pfizer.com
authors.forename: Christopher
authors.initials: C
authors.lastname: Seadeek
authors.forename: Howard
authors.initials: H
authors.lastname: Ando
authors.forename: Shobha N
authors.initials: SN
authors.lastname: Bhattachar
authors.forename: Tycho
authors.initials: T
authors.lastname: Heimbach
authors.forename: Jason L
authors.initials: JL
authors.lastname: Sonnenberg
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Blackburn
mesh_terms: D001322:Autoanalysis; D001331:Automation; D002021:Buffers; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002851:Chromatography, High Pressure Liquid; D003460:Crystallization; D015195:Drug Design; D005374:Filtration; D006863:Hydrogen-Ion Concentration; D009532:Nickel / Q000737:chemistry; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011208:Powders; D012015:Reference Standards; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D013816:Thermodynamics; D014961:X-Ray Diffraction
chemical_list: D002021:Buffers; D004364:Pharmaceutical Preparations; D011208:Powders; D009532:Nickel