Screening solubility

Solubility screens using LC/MS detection do not require an ultra-pure sample of the test compound due to the selective detection of the mass spectrometer. Mass spectrometric detection offers high selectivity and low detection limits, which eliminates the need to develop complex chromatographic methods. The LC/MS-based solubility screen surpasses the traditional HPLC/UV-based equilibrium solubility assay with increased throughput, minimal manual intervention, and high sensitivity and selectivity. 

Y Sugaya, T Yoshiba, T Kajima, Y Ishihama. Development of solubility screening methods in drug discovery. Yakugakuzasshi 122 237-246 (2002). 

Green C, McKee S, Saunders K A fully automated Kinetic solubility screen in 384-well Plate format usinig nephelometry. BMG, Application Note 117... 

Bevan et al. [97] have developed a solubility screen for. small amounts of compounds (10 pi of a 10 mM DMSO solution) on a 96 well plate format by applying reversed-phase HPLC with a fast gradient elution. The DMSO solutions of the compounds are dispensed into a 96 well microtitre plate format at a known concentration (typically 10 mM). Duplicate plates are prepared each containing 10 pi of a 10 mM DMSO solution. For the so-called standard plate the DMSO solution is diluted with known amounts of solvent possibly dissolving the compounds (methanol or DMSO). The wells on the so-called sample plate are diluted with the same known amounts of aqueous buffer used in the enzyme-assay screens. The compounds having poor aqueous solubility will eventually precipitate out in the wells of the sample plates. The precipitation and the equilibrium formation between the saturated solution and the solid can be promoted by applying sonication. Before HPLC analysis of the wells of the standard... 

Alsenz, J., Meister, E. andHaenel, E. (2007) Development of a partially automated solubility screening (PASS) assay for early dmg development. Journal of Pharmaceutical Sciences, 96 (7), 1748-1762. 

Yamashita, T. et al., High-speed solubility screening assay using ultra-performance liquid chromatography/mass spectrometry in drug discovery, J. Chromatogr. A., 1182, 72, 2008. 

Effectiveness of designing for adequate aqueous solubility depends on whether chemistry protocol development or chemistry production is rate determining. If chemistry production is rate determining, there will be excess validated protocols relative to library production. This means that protocols can be prioritized as to the attractiveness of the compound solubility profile and the least attractive protocols from a solubility perspective may never be translated into actual library production. However, often protocol development and not library production is the rate-determining step. This eventuality is unfortunate because there is an understandable reluctance to discontinue chemistry synthetic efforts due to poor experimental solubility profile if considerable chemistry effort has already been expended. Consider the following situation. The effort toward library production is 70% complete. The experimental solubility profile is poor. Would you discontinue completion of library synthesis because of poor solubility if 70% of the chemistry effort had already been completed So a key issue becomes how much chemistry experimental effort takes place before exemplars are experimentally profiled in solubility screens ... 

Thus, we regard the solubility of the substrates and/or products in the respective IL as a key for the design of the IL. Because of the huge number of possible ILs, only limited solubility data is available in the literature. An experimental solubility screening for each process is time consuming and expensive. Therefore, a fast computational a priori screening is necessary. The conductor-like screening model for real solvents (COSMO-RS) is a flexible tool that is able to predict the solubility of solutes in the IL. 

The a priori solubility screening can be utilized to optimize a chemical reaction in a SILP catalyst system. This was shown in Chapter 4, where the results of the propene hydrogenation could be correlated to the substrate solubility in the respective IL. Further, this model can be applied on technical systems (e.g., selective... 

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