Automated approach to couple solubility with final pH and crystallinity for pharmaceutical discovery compounds.
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.
Seadeek
Christopher
C
Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. Chris.Seadeek@Pfizer.com
Ando
Howard
H
Bhattachar
Shobha N
SN
Heimbach
Tycho
T
Sonnenberg
Jason L
JL
Blackburn
Anthony C
AC
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
D002021:Buffers; D004364:Pharmaceutical Preparations; D011208:Powders; D009532:Nickel