Solubility high-throughput

Bevan, C. D., Uoyd, R. S. A high-throughput screening method for the determination of aqueous drug solubility using laser nephelometry in microtiter plates. Anal. Chem. 2000, 72,1781-1787. 

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. 

Huuskonen, J. Estimation of aqueous solubility in drug design. Comb. Chem. High-Throughput Screen. 2001, 4, 311-316. 

The graphically deduced constants are subsequently refined by a weighted nonlinear least squares procedure [472]. Although the potentiometric method can be used in discovery settings to calibrate high-throughput solubility methods and computational procedures, it is too slow for HTS applications. It is more at home in a preformulation lab. 

A high-throughput method using a 96-well microtiter plate format and plate UV spectrophotometry has been described [26]. Solubilities at a single pH, or at <12 pH values can be determined, using one of two methods. 

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.]...

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)... 

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]. 

The next section describes the utilization of //PLC for different applications of interest in the pharmaceutical industry. The part discusses the instrumentation employed for these applications, followed by the results of detailed characterization studies. The next part focuses on particular applications, highlighting results from the high-throughput characterization of ADMET and physicochemical properties (e.g., solubility, purity, log P, drug release, etc.), separation-based assays (assay development and optimization, real-time enzyme kinetics, evaluation of substrate specificity, etc.), and sample preparation (e.g., high-throughput clean-up of complex samples prior to MS (FIA) analysis). 

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