ABSTRACT
We determined the experimental solubility of CNS marketed drugs. Of the 98 drugs measured, greater than 90% had solubility >10 µM in pH 7.4 buffer. Only seven drugs had solubility <10 µM. Using these data, we established a solubility criterion to support CNS discovery. The implication of poor solubility with potential safety concerns and undesirable side effects are discussed.
Subject(s)
Central Nervous System Agents/chemistry , Pharmaceutical Preparations/chemistry , Drug Evaluation, Preclinical , Hydrogen-Ion Concentration , SolubilityABSTRACT
A rapid throughput octanol-water lipophilicity measurement based on 96-well shake-flask and LC/UV/APPI/MS is described. The method utilizes central liquid storage where compounds are stored as 10 mM solutions in dimethyl sulfoxide (DMSO). The DMSO is subsequently removed to generate solid like material used for LogD measurement. The removal of DMSO minimizes the concern for potential DMSO cosolvent effect on the measured value. Sample preparation is automated using a liquid handling workstation with 96-well pipetter. Both octanol and buffer phases are quantified using state of the art ultra-high pressure HPLC coupled with a superficially diffused core reversed-phase column and an atmospheric pressure photo ionization mass spectrometer. The throughput of the method is two days for a batch of 96 compounds. The method has been validated using 72 literature compounds with diverse ionization and LogD values ranging from -2 to +6. The observed coefficient of determination r(2) is 0.9973.
Subject(s)
Atmospheric Pressure , Dimethyl Sulfoxide/chemistry , High-Throughput Screening Assays/instrumentation , High-Throughput Screening Assays/methods , Mass Spectrometry/instrumentation , Mass Spectrometry/methods , Ultraviolet Rays , Buffers , Chromatography, Liquid , Hydrogen-Ion Concentration , Ions , Models, Chemical , Octanols/chemistry , Reproducibility of ResultsABSTRACT
A rapid throughput equilibrium solubility measurement is described. The method utilizes central liquid storage where compounds are stored as 10mM solution in dimethyl sulfoxide (DMSO). The DMSO is subsequently removed to generate solid like material used for solubility measurement. A full range of available technologies is used including automated liquid handling, automated data collection using both HPLC/UV and LC/MS/MS. The method is fully validated and has been used to measure solubility for over 20,000 compounds across all phases of drug discovery. A detailed discussion on data interpretation and comparison to traditional solubility measurement using solid material is presented. An in-house solubility predictive model has been developed from the vast data set and has been employed successfully as part of compound design resulting in over 30% reduction in the number of poorly soluble compound synthesized.
