Solubility high-throughput measurements

Avdeef, A. High-throughput measurements of solubility profiles. In Pharmacokinetic Optimization in Drug Research Biological, Physicochemical and Computational Strategies, Testa, B., Van de Waterbeemd, H., Folkers, G., Guy, R. (eds.), VHCA, Zurich and Wiley-VCH, Weinheim, 2001, pp 305-325. 

Avdeef, A., High-throughput measurements of permeability profiles, in van de Waterbeemd, H. Lennemas, H. Artursson, P. (eds.), Drug Bioavailability. Estimation of Solubility, Permeability, Absorption and Bioavailability Wiley-VCH Weinheim, 2003 (in press)... 

Dehring, K.A. et al. 2004. Automated robotic liquid handling/laser-based nephelometry system for high throughput measurement of kinetic aqueous solubility. J. Pharm. Biomed. Anal. 36 447. 

Avdeef A. (2001) High-throughput measurements of solubility profiles,... 

Comer, J.E.A. 2004. High-throughput measurements of log D and pK. In Drug bioavailability Estimation of solubility, permeability, absorption and bioavailability, eds. H. van de Waterbeemd, H. Lennernas, P. Artursson, R. Mannhold, H. Kubinyi, and G. Folkers, 21. Weinheim Wiley-Verlag. 

Dehring KA, Workman H, Miller K, Mandagere A, and Poole S. Automated Robotic Liquid Handling/Laser-based System for High Throughput Measurement of Kinetic Aqueous Solubility. /P/tam Biomed Anal 2004 35 447-456. 

Figure 6.10 High-throughput solubility-pH determination of chlorpromazine. The horizontal line indicates the set upper limit of solubility, where the compound completely dissolves and solubility cannot be specified. The points below the horizontal line are measured in the presence of precipitation and indicate solubility. The solubility pH curve was collected in the presence of 0.5 vol% DMSO, and is affected by the cosolvent (see text). [Avdeef, A., Cun Topics Med. Chem., 1, 277-351 (2001). Reproduced with permission from Bentham Science Publishers, Ltd.]...

High-throughput solubility measurements have been developed which can be used in early discovery [9, 20-22]. 

As a key first step towards oral absorption, considerable effort has been directed towards the development of computational solubility prediction [26-30]. However, partly due to a lack of large experimental datasets measured under identical conditions, today s methods are not sufficiently robust for reliable predictions [31]. Nonetheless, further fine-tuning of these models can be expected since high-throughput data have become available for their construction. 

Therefore, a continued interest exists in the role of pKa in absorption, which often is related to its effect on lipophilicity and solubility. New methods to measure pKa values are being explored [36], e.g., using electrophoresis [37], and an instrument for high-throughput pKa measurement has recently been announced [38]. 

Typically, MS does not play an important role in solubility measurement because UV and nephelometric plate readers provide high throughput and are sufficiently sensitive for most compounds. 

MS has recently been used to measure compounds with significant levels of impurities and solubilities below the quantitation limits of other methods. Guo et al.46 described the use of LC/MS for solubility measurements in buffer solutions in a 96-well plate. Fligge et al.47 discussed an automated high-throughput method for classification of compound solubility. They integrated a Tecan robotic system for sample preparation in 384-well plates and fast LC/MS for concentration measurement. This approach is limited by LC/MS throughput. 

Solubility and permeability were measured by a high throughput solubility assay and parallel artificial membrane permeation assay (PAMPA), respectively [56], The assays categorized 14 out of 18 drugs based on the BCS consistent with their known solubility and permeability characteristics [56],... 

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