Determination of pKa Values by Liquid Chromatography

Abstract

In this paper, we investigate the potential of a high-performance liquid chromatography technique to determine pKa values of drug candidates that show poor solubility in water. The determination of pKa values by this method is in principle not new, but it exhibits simplicity, requires lower quantities of drugs and solvents, and minimal analysis time. The method is an alternative to existing methodology, in which this determination is not readily feasible.

Solubility Advantage of Amorphous Pharmaceuticals: II. Application of Quantitative Thermodynamic Relationships for Prediction of Solubility Enhancement in Structurally Diverse Insoluble Pharmaceuticals

“…Due to its low solubility, it was difficult to obtain an unambiguous fit to the pH-solubility profile. The pK a reported in Table I is consistent with the pH-solubility profile obtained here as well as the pK a obtained by Manderscheid and Eichinger (21).…”

A Graphite‐Polyurethane Composite Electrode for the Analysis of Furosemide

“…Experimental values obtained by different techniques estimate pK 1 % 0.5 from octanol/water partition measurements [3] and pK 2 ¼ 3.9; 3.8; 3.65 or 3.6, determined by aqueous solution titration; mixed solvents titration; octanol/ water partition and solubility methods respectively [3]. Using liquid chromatography a 3.9 value has been assigned to the carboxylic acid dissociation [4].…”

“…The structure of the neutral form of furosemide is shown in Figure 1; the protonated form has four ionizable acid groups [3,4]. It is soluble in alkaline media, as well as in organic solvents such as acetone and methanol; however, it has a very low solubility in water and acidic aqueous solutions [2].…”

Measurement of Dissociation Constants (pKa Values) of Organic Compounds by Multiplexed Capillary Electrophoresis Using Aqueous and Cosolvent Buffers**Advanced Analytical Technologies, Inc. (Formerly CombiSep), 2711 South Loop Drive, Suite 4200, Ames, IA 50010.

“…There have been a number of methods employed for pK a measurements based on solubility, potentiometric titration, 7-10 spectrophotometry, [11][12][13][14] HPLC [15][16][17] and, most recently, on capillary electrophoresis (CE). [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] The solubility method is of limited accuracy and potentiometric titrations typically require mg amounts of pure sample with a throughput of 20-40 min per compound.…”