Bibliography of pKa Determinations:Abstracts


	Text Size: A A CombiSep™ pKa Determinations Literature References using Capillary Electrophoresis (CE) for pKa Determinations Determination of acid dissociation constants by capillary electrophoreis. Salwa Poole^a, Sneha Patel^a, Karen Dehring^a, Heather Workman^a, Colin F. Poole^b. ^a Discovery Technologies, Pfizer Global Research and Development, Ann Arbor MI, ^b Department of Chemistry, Wayne State University Detroit MI J. Chromagr., A 2004, 1037:445-454 Abstract: Capillary Electrophoresis affords a simple, automated approach for the measurement of pKa values in the range 2-11 at a throughput of less than 1 hour per sample per instrument. Agreement with literature values is usually within 0.20 log units with a precision better than 0.07 log units. The attractive features of capillary electrophoresis for pKa measurements are (1) conventional instrumentation with a high level of automation are suitable for all measurements; (2) because it is a separation method samples need not be of high purity; (3) samples of low water solubility with suitable chromophores are easily handled (detection limits in µM range); (4) sample consumption per measurement is in the microgram range; and (5) since only mobilities are measured, exact knowledge of concentrations is not needed. The general approach can be extended to pKa measurements in aqueous-organic solvent mixtures and non-aqueous solvents with suitable calibration. The widespread use of absorbance detection in capillary electrophoresis means that the sample must have a suitable chromophore for detection. The main source of controllable error is the accuracy of buffer standardization and their stability in use, and uncontrollable error, the retentive interactions of the sample with the column wall. The latter seems to be a rare problem in practice for typical operating conditions. Semi-empirical relationships between effective mobility, charge, and molecular weight of pharmaceuticals by pressure-assisted capillary electrophoresis: Applications in drug discovery. Jonathan M. Miller, Anthony C. Blackburn, Yi Shi, Andrew J. Melzak, Howard Y. Ando. Pharmaceutical Research and Development, World Wide Pharmaceutical Sciences, Pfizer Global Research and Development, Ann Arbor M Electrophoresis., 2002, 23, 2833-2841 Abstract: Relationships between effective mobility (m_eff), calculated charge (Z_c) and molecular weight (MW) are semi-empirically derived from pharmaceuticals using pressure assisted capillary electrophoresis (PACE). We determined that m_eff at 12 different pH points (2.0-11.4) of 66 pharmaceutical-like compounds ranging in MW from 79 to 825 g/mol. Plots of the observed meff values versus Z_c/MW^x (where x is a fractional coefficient) gave linear relationships. For anions, it was found that the best correlation (R²=0.9666) exists when the fractional coefficient is equal to 0.4920, resulting in the equation m_eff = 0.1863 (Z_c/MW^0.4920). For cations, the best linear relationship (R²=0.9861) gave the equation m_eff = 0.3888 (Z_c/MW^0.6330). The m_eff,(Z_c/MW^x) relationships were then applied to (i) developing a technique for selecting an appropriate pH to achieve optimal separation of pharmaceuticals and (ii) determining the maximum charge a molecule in the pH range of determination of negative log of the dissociation constants (pKa) by PACE, thus enabling the correct choice of model equation to be automated without structure analysis. Detrmination of pKa values of bais new drug substances by CE Gabriel A. Caliaro, Camy A. Herbots. Lilly Development Centre, Biopharmaceutics and Drug Delivery, Mont-ST-Guibert, Belgium Journal of Pharmaceutical & Biomedical Analysis, 26, (2001) 427-434 Abstract: During the discovery phase for chemical entities as potential new drugs, the determination of pKa values can be a very valuable parameter in the selection process. In general, at the very beginning, only small amounts of these active pharmaceutical ingredients (API) are available for analytical characterization. One drawback of traditional methods such as titration and UV Spectroscopy is that they require large amounts of high purity material. As an alternative technique, a method by capillary electrophoresis (CE) which is based on migration times or mobilities of the ionic species over a range of pH values has been evaluated for the determination of pKa. From the relationship between measured mobilities and pH of electrolyte, an S shaped curve was obtained and pKa values determined for some new API entering the screening phase. On the basis of our experience, the pKa determination by CE of early phase compounds can easily be performed with a very small quantity of material and in addition with insoluble compounds. pKa values, similar to those earlier observed by potentiometric titration or computational calculations, were obtained. The reported technique using CE can easily be automated and is able to cope with the high throughput needed at the screening stage of lead optimization.

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