A REVIEW ON VARIOUS ANALYTICAL METHODS USED IN DETERMINATION OF DISSOCIATION CONSTANT


Bebee Pathare, Vrushali Tambe, Vandana Patil

Abstract


Determination of dissociation constant for a drug capable of ionization within a pH range of 1 to 10 is important since solubility and consequently absorption, can be altered by orders of magnitude with changing pH. The dissociation constant [pKa] value, are essential for understanding many fundamental reactions in chemistry. These values reveal the deprotonation state of a molecule in a particular solvent. There is great interest in using experimental methods to calculate the pKa values for many different types of molecules. In this review the most valuable methods for determining accurate pKa values are presented. There are many diverse strategies for determining dissociation constant, so the main aim of the review is to discuss the available analytical methods.

 


Keywords


Dissociation constant, pH, potentiometric measurement, capillary electrophoresis, Deprotonation.

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References


Kristine SA, George CS. Theoretical Calculations of acid dissociation constant:a review article. J Annual Reports in Computational Chemistry 2010;6:113-38.

Aktas AH, Nurullah S, Guzide P. Spectrometric determination of pKa values for some phenolic compounds in acetonitrile-water mixture. J Acta Chim Slov 2006;53:214-8.

Niazi A, Ateesa Y, Jahanbakhsh G, Mikael K, Azemat S, Mahtab A. Spectrophotometrc determination of the dissociation constant of Fluorescein in Micellar Media. J Croat Chem Act 2009;82:753–9.

Shalaeva M, Jeremy K, Franco L, Andrea B. Measurement of dissociation constants (pKa Values) of organic compounds by multiplexed capillary electrophoresis using aqueous and cosolvent buffers. J of Pharm Sci 2007;1-24.

Kobra Z, Morteza A, Esmaeil A. Spectrophotometric determination of conditional acidity constant of some sulfonephthalein dyes as a function of anionic, neutral and cationic surfactants concentrations using rank annihilation factor analysis. Eurasian J Anal Chem 2009;4:314-27.

Magda FF, Sherine NK. Spectrophotometric determination of pKa’s of 1-hydroxybenzotriazole and oxime derivatives in 95% acetonitrile-water. J Chem Soc Pak 2011;33:324-32.

Marcin K, Marta W, Christopher SP, Paul AB. Macroscopic pKa calculations for fluorescein and its derivatives. J Chem Theory Comput 2006;2:1520-9.

Chandrul KK, Srivastava B. A process of method development:A chromatographic approach. J Chem Pharm Res 2010;2:519-45.

Tam KY, Hadley M, Patterson W. Multiwavelength spectrophotometric determination of acid dissociation constants part IV. water-insoluble pyridine derivatives. J Talanta 1999;49:539-46.

Hadjeb R, Barkat D. Arabian Determination of acid dissociation constants of some substituted salicylideneanilines by spectroscopy Application of the Hammett relation. J of Chemistry 2014;1-6.

Guzide PE, Hakan AA. Determination of the Dissociation Constant of Some Substituted Phenols by Potentiometric Method in Acetonitrile-Water Mixtures. SDU J of Sci (E-Journal) 2010;5:60-6.

John C, Karl B. High-throughput measurement of drug pKa values for ADME screening. J of Laboratory Automation 2003;8:55.

Brahmankar DM, Jaiswal SB. Biopharmaceutics & pharmacokinetics, 2nd edition. Vallabh prakashan;2009.p. 43.

Patrick JS. Martins Physical Pharmacy and Pharmaceuticals sciences, 5th edition. Indian edition.p. 201-02.

Leon L, Herbert AL, Joseph LK. The theory and practice of industrial pharmacy, 3rd edition. Varghese publishing house.p.185-6.

Jetse R, Arno VH, Antonie VL, Bram T. Development of Methods for the Determination of pKa Values. J Analytical Chemistry Insights 2013;3:53–71.

Beckett AH, Stenlake JB. practical pharmaceutical chemistry. 4th edition. part one, CBS publishers and distributors pvt ltd.p. 88.

Ravichandiran V, Devarajan V, Masilamani K. Determination of ionization constant (pka) for poorly soluble drugs by using surfactants:a novel approach. J Der Pharmacia Lettre 2011;3:183-92.

Badr MH, El-Halafawi MH, Abd El-al Zeid ER. Comparison Between the Effect of Ionic Strength on Acidity and Dissociation Constants of Humic Acids Extracted from Sewage Sludge and Nile Water Hyacinth Composts. Global J of Environmental Res 2012;6:36-43.

Rahmiye A, Ulviye O. Potentiometric and spectroscopic determination of acid dissociation constant of some phenols and salicylic acids. Tr J of Chemistry 1997;21:428-36.

Sandra B, Alka JMH, Dragana MP, Marija KM. Determination of pKa values of active pharmaceutical ingredients. J Trends in Analytical Chemistry 2007;26:1043-61.

Zhimin Q, Craig A, Potentiometric determination of acid dissociation constants (pKa) for human and veterinary antibiotics. J Water Res 2004;38:2874-90.

Vassilis E, Anna TK, Michael K. Determination of the dissociation constants of the cephalosporins, cefepime and cefpirome using UV spectrometry and pH potentiometry. J of Pharm and Biomedical Analysis 2003;31:1119-28.

Ray PC, Munichandraiah N, Das PK. Dissociation constants of some substituted cinnamic acids in protic solvents:measurements by hyper-Rayleigh scattering and potentiometric techniques. J Chemical Physics 1996;211:499-505.

Konstantin P, Hannu R, Lauri HJL. Guidelines for NMR measurement for determination of high and low pka values [IUPAC technical report]. Int Union of Pure and Applied Chemistry 2006;78:663-75.

Nicola S, Roberto B, Aurelien B, Simone U, Inmaculada RR, Alessandro A, et al. Boosting the Sensitivity of Ligand−Protein Screening by NMR of Long-Lived States. J of the American Chemical Society 2012;134:11076-9.

Aldino V, Joao M, Franklin LN, Eurico JC. Saturation-Transfer Difference (STD) NMR:A Simple and Fast Method for Ligand Screening and Characterization of Protein Binding. J of Chemical Edu 2011;88:990-4.

Chiara F, Stefano G, Peter G, Antonio S, Maria SM, Alberto V. Nuclear Magnetic Resonance as a tool for determining protonation constants of natural polyprotic bases in solution. J Analytical Biochemistry 1995;231:374-82.

Claudio D. NMR methods screening:theory and a comparison with other biophysical techniques. J Drug Discovery Today 2009;14:1051-7.

Julia V, Jun Q. Weak protein–protein interactions as probed by NMR spectroscopy. J Trends in Biotechnology 2006;24:22-7.

Lee F. NMR methods for the determination of protein–ligand;dissociation constants. Progress in Nuclear Magnetic Resonance Spectroscopy. J Organon Biosciences 2007;51:219-42.

Matthew DS, David SH, Gerard SH, Robert P. Estimating Protein-Ligand Binding Affinity Using High-Throughut Screening by NMR. A J of Combinatorial Chemistry 2008;10:948-58.

James EK, Walter JS, Paul BM. Determination of phosphate functional group acid dissociation constants of clindamycin 2-phosphate using “P Fourier transform NMR spectrometry. Int J of Pharm 1991;74:215-20.

Andrei B, Clifford AB, Sergio B, Carmen I, Exiquiel M. determination of acid dissociation constant of anomers of amino sugars by 1H NMR spectroscopy. J Carbohydrate Res 1997;298:163-72.

Xun CS, Slobodan J, Kiyoshi O, Nicolas DB, Nicholas ED, Gottfried O. Measurement of dissociation constants of high-molecular weight protein–protein complexes by transferred [15]N-relaxation. J Biomol NMR 2007;38:65-72.

Zoltan S, Marta K, Bela N. Determination of microscopic acid–base parameters from NMR–pH titrations. J Anal Bioanal Chem 2004;378:1428-48.

Bruce SH, Suzanne KC. Zero-Point Corrections for Isotropic Coupling Constants for Cyclohexadienyl Radical, C6H7 and C6H6Mu:Beyond the Bond Length Change Approximation. J Molecules 2013;18:4906-16.

Haixia R, Licheng W, Xusheng W, Xia L, Shengxiang J. Measurement of acid dissociation constants and ionic mobilities of 3-nitro-tyrosine and 3-chloro-tyrosine by capillary zone electrophoresis. J of Pharm and Biomedical Analysis 2013;1-20.

Matoga M, Laborde KE, Langlois MH, Dallet P, Bosc JJ, et al. Determination of pKa values of 2-amino-2-oxazolines by capillary Electrophoresis. J of Chromatography A 2003;984:253-60.

Laurent G, Yveline H, Alexandra G, Pierre AC, Jean LV. Determination of pKa values by capillary zone electrophoresis with a dynamic coating procedure. J Sep Sci 2005;28:2374-80.

Issam J, Hardcastle JE, Zhao K, Vermillion SR. General equation for calculating the dissociation constants of polyprotic acids and bases from measured retention factors in high performance liquid chromatography. J of Chromatography A 1997;762:63-72.

Hardcastle JE, Vermillion SR, Zhao K, Jano I. Use of secondary equilibria in reversed-phase high-performance liquid chromatography for the determination of dissociation constants of polyprotic leukotrienes. J of Chromatography A 1997;763:199-203.

Markus M, Thomas E. Determination of pKa Values by Liquid Chromatography. J of Chromatographic Sci 2003;41:323-32.

William RA, Richard ET. Dissociation Constants for Carbonic Anhydrase-Sulfonamide Binding by High-Performance Liquid Chromatography. J Analytical Biochemistry 1984;137:302-6.

Huiling H, Tingting L, Lei Z. pKa determination of oxysophocarpine by reversed-phase high performance liquid chromatography. J Springer Plus 2013;2:1-5.

Marie IA. HPLC of Peptides and Proteins Methods and Protocols. J Methods in Molecular Biology 251:1-399.

Pavlova V, Petrovska JS. Simultaneous determination of amphetamine, methamphetamine, and caffeine in seized tablets by high-performance liquid chromatography. J Acta Chromatographica 2007;18:157-67.

Sameh M, Annette M. Affinity Chromatography:Principles and Applications, www.intechopen.com, 4-28.

Diego P, Leonides ES, Juan MM. Multi-Wavelength Spectrophotometric Determination of Propofol Acidity Constant in Different Acetonitrile-Water Mixtures. J Braz Chem Soc 2005;16:1054-60.

Kenneth BE. Second Harmonic Spectroscopy of Aqueous Nano-and Microparticle Interfaces. J Chem Rev 2006;106:1462-77.

David PS. Accurate hyper-Rayleigh scattering polarization measurements. J Review of Scientific Instruments 2011;82:113103.

Arumugam SR, Das PK. Padmanabhan B, Binding Constant Measurement by Hyper-Rayleigh Scattering:Bilirubin-Human Serum Albumin Binding as a Case Study. J Phys Chem B 2005;109:5950-3.

Sang HL, Man HC. Monoclonal antiboby production and characterization for the measurement of plasma high density lipoprotein. J of Korean Medical Sci 1996;11:390-6.

Murthy GS, Venkatesh N. Determination of kinetic parameters of epitope-paratope interaction based on solid phase binding:An inexpensive alternate to biospecific interaction analysis. J Bio Sci 1996;21:641-51.

Ferenc O, Judit O. A simple method for the determination of dissociation constants by displacement ELISA. J of Immunological Methods 2002;270:155-62.

Matthias CJ, Stefan S, Christoph ED, Renato Z. Label-free determination of protein–ligand binding constants using mass spectrometry and validation using surface Plasmon resonance and isothermal titration calorimetry. J of Molecular Recognition 2009;22:319-29.

Asta Z, Jurgita M, Lina B, Jelena J, Jolanta T, Vilma M, et al. Measurement of Nanomolar Dissociation Constants by Titration Calorimetry and Thermal Shift Assay – Radicicol Binding to Hsp90 and Ethoxzolamide Binding to CAII. Int J of Molecular Sci 2009;10:2662-80.

Berthod A, Carda BS. Determination of liquid–liquid partition coefficients by separation methods. J of Chromatography A 2004;1037:3–14.

Foley JP, May WE. Optimization of secondary chemical equilibria in liquid chromatography:variables influencing the self-selectivity, retention, and efficiency. J Anal Chem 1987;59:110-6.

Krisztina TN, Alex A. Interlaboratory study of log P determination by shake flask and potentiometric methods. J of Pharm and Biomedical Analysis 1996;14:1405-13.

Vezin WR, Florence AT. The determination of dissociation constants and partition coefficients of phenothiazine derivatives. Int J of Pharm 1979;3:231-7.

Jolanta K, Malgorzata C, Zbigniew K, Bychowska A, Krzysztof B, Jorg T, Piotr S. Application of spectroscopic methods for structural analysis of chitin and Chitosan. J Mar Drugs 2010;8:1567-636.

Dilek E. Calculation of acidity constants of some substituted thiazole derivatives using DFT and UV Spectroscopic Methods. J of Arts and Sci Say 2007;8:23-33.

Johannes O, Kelly C. Ultraviolet and visible absorption cross-sections for HITRAN. J of Quantitative Spectroscopy and Radiative Transfer 2003;82:491-504.

Beckett AH, Stenlake JB. Practical pharmaceutical chemistry. 4th ed. part two:CBS publishers and distributors pvt;Ltd. p. 275-98.

Pathare B, Tambe V, Dhole S, Patil V. An update on various analytical techniques based on UV spectroscopy used in determination of dissociation constant. Int J Pharm 2014;4:278-85.

Carlos HRM, Christophe D. Rapid Determination of Ionization Constants [pKa] by UV Spectroscopy Using 96-Well Microtiter Plates. ACS Med. J Chem Letteres 2013;4:142-5.

Zhang JH, Liu Q, Chen YM, Liu ZQ, Xu CW. Determination of acid dissociation constant of methyl red by multi-peaks gaussian fitting method based on UV-visible absorption spectrum. J Acta Phys Chim Sin 2012;28:1030-6.

Peckel N, Guven O. Investigation of complex formation between poly [N-vinyl imidazole] and various metal ions using the molar ratio method. J Colloid Polym Sci 1999;277:570-3.

Allen RI, Box KJ, Comer JEA, Peake C, Tam KY. Multiwavelength spectrophotometric determination of acid dissociation constants of ionizable drugs. J of Pharm and Biomedical Analysis 1998;17:699-712.

Milan M, Zuzana F, Ales V. Thermodynamic dissociation constants of Rasagiline by the nonlinear regression and factor analysis of multiwavelength spectrophotometric pH titration data. J Chem Eng Data 2010;55:2707-13.

Milan M, Sylva B, Lubomir G. The thermodynamic dissociation constants of four non-steroidal anti-inflammatory drugs by the least-squares nonlinear regression of multiwavelength spectrophotometric pH-titration data. J of Pharm and Biomedical Analysis 2007;45:552-64.

Milan M, Dominika B, Tomas S, Ales V. The thermodynamic dissociation constants of silychristin, silybin, silydianin and mycophenolate by the regression analysis of spectrophotometric data. J Analytica Chimica Acta 2003;486:125-41.

Milan M, Tomas S, Ales V. The thermodynamic dissociation constants of losartan, paracetamol, phenylephrine and quinine by the regression analysis of spectrophotometric data. J Analytica Chimica Acta 2005;533:97-110.

Keisuke K, Miharu T, Sachiyo Y. Determination of dissociation constants of sparingly soluble phenothiazine derivatives by second-derivative spectrophotometry. J Analytica Chimica Act 1991;242:131-5.

Derya K, Mahir A. Determination of acidity constant of acid-base indicators by second derivative spectrophotometry. J of Chromatography A 2004;1037:3 –14.

Hajime I, Tsugikatsu O, Takashi H. Synthesis of sensitive pyridyihydrazone reagents and extraction spectrophotometric determination of trace nickel with 2-pyridinecarbaldehyde 2-[5-nitro]pyridylhydrazone. J Analytical Sci 1987;3:347-52.

Wahbi AM, EI –Yazbi FA, Barary MH, Sabri SM. Application of orthogonal functions to spectrophotometric analysis. Int J of Pharm 1993;92:15-21.

Abdel AW, Ekram H, Dalia H, Essam F, Magda B. Application of orthogonal functions to pharmaceutical analysis, generation of derivative curves. J Saudi Pharm 2005;13:14-3.

Filipp F, Dmitrij R. Density functional methods for excited states:equilibrium structure and electronic spectra, Chapter III of Computational Photochemistry, edited by M. Olivucci, Theoretical and Computational Chemistry, Elsevier, Amsterdam 2005;16:93–128.

Eduardo JD. DFT calculations of pKa’s for dimethoxypyrimidinylsalicylic based herbicides. J Chemical Physics Letteres 2009;471:133-5.

Zevatskii YE, Samoilov DV, Panina NS. Calculations of Dissociation Constants of Carboxylic Acids by Empirical and Quantum-Chemical DFT Methods. Russian J of General Chemistry 2009;79:944-52.

Hazarika P, Rajib LS, Karim M, Bezbaruah B, Kalita R, Medhi C. Prediction of pKa from basic principles;Ab initio and DFT studies on some molecules. Indian J of Chemistry 2009;48A:520-5.

Tadeusz M, Agustin GA. Formulation of the System of Isohydric Solutions. J of Analytical Sci Methods and Instrumentation 2012;2:1-4.

Tadeusz M, Boguslaw P, Agustin GA, Agnieszka D. A new sensitive method of dissociation constants determination based on the isohydric solution principle. J Talanta 2010;82:1965-73.

Senthilnithy R, Gunawardhana HD, De Costa MDP, Dissanayake DP. Absolute pKa determination for N-phenylbenzohydroxamic acid derivatives. J of Molecular Structure. THEOCHEM 2006;761:21-6.

Lionel V, Claude K, Giovanni B, Stephan S, Jean YP. Mat-pKa calculation tool development for evaluation of acidity constants from solubility profiles-large study of 41 compounds. Int J of Pharmaceutics 2012;437:137-55.

Lewis GA. determination of dissociation constant of sparingly soluble compounds from solubility data. Int J of Pharmaceutics 1984;18:207-12.

Sung HK, Young SN. Determination of dissociation constant of thymol blue with Diode-laser/ fibre-optic thermal lensing spectroscopy. J Bull Korean Chem Soc 1998;19:822-4.

Paul DC. Surface and interfacial dissociation constants:apparent vs. absolute, Colloids and Surfaces. J Physicochemical and Engineering Aspects 1994;89:103-8.

Thakur A. QSAR study on benzenesulfonamide dissociation constant pKa:physicochemical approach using surface tension. J Arkivoc 2005;xiv:49-58.

Petr B, Danuse P, Petrb T, Petr B, Milan K, Zdenek S, Radim V. Determination of the first dissociation constant of 6-benzylaminopurine A comparison methods. J Analytica Chimica Acta 2000;421:221-9.

Leonard SR, Gicela L, Cathy G, Stephen GS. Fluorimetric determination of dissociation constants of sparingly soluble amino and hydroxy aromatic compounds. J Analytica Chimica Acta 1979;106:81-7.

Nathan W, Luedtke YT. Fluorescence-Based Methods for Evaluating the RNA Affinity and Specificity of HIV-1 Rev–RRE Inhibitors. J Biopolymers 2003;70:103–19.

Linda P, Mylene G, Peter B. Determination of equilibrium dissociation constant in fluorescence polarization. J of Molecular Screening 2001;6:141-50.

Wiczlng P, Struck LW, Siluk D, Markuszewski MJ, Kaliszan R. The simultaneous determination of hydrophobicity and dissociation constant by liquid chromatography–mass spectrometry. J PBA-RDPA Bologna 2013.

Lucie J, Fabienne S, Francoise S, Martine C. Improved Accuracy of Low Affinity Protein–Ligand Equilibrium Dissociation Constants Directly Determined by Electrospray Ionization Mass Spectrometry. J American Society for Mass Spectrometry 2012;23:908-22.

Wortmann A, Matthias CJ, David T, Martin B, Renato Z, Binding constant determination of high-affinity protein–ligand complexes by electrospray ionization mass spectrometry and ligand competition. J of Mass Spectrometry 2008;43:600-8.

Jaroslava S, Sonal M, Alexander M, Thomas L, Ales S. Microchip-ESI-MS Determination of Dissociation Constant of the Lysozyme-NAG3 Complex. J Electrophoresis 31 2010;15:1-24.

Kurt B, Per-OE, Johan R. Noncovalent electrospray ionization mass spectrometry:a powerful tool in drug discovery. J Biovitrum, Rapid Communication in Mass Spectrometry 2002;16:2054-9.

Emily AS, William DT, Laura LK, Robert MC. Surface Plasmon Resonance Imaging Studies of Protein-Carbohydrate Interactions. J AM CHEM SOC 2003;125:6140-8.

Claudia H, Stephan D, Friedrich WH. Determination of Kinetic Data Using Surface Plasmon Resonance Biosensors Methods in Molecular Medicine. J Molecular Diagnosis of Infectious Diseases 94:299-320.

Joseph AL. Studying noncovalent protein complexes by electrospray ionization mass spectrometry. Mass Spectrometry Reviews 1997;16:1–23.




About this article

Title

A REVIEW ON VARIOUS ANALYTICAL METHODS USED IN DETERMINATION OF DISSOCIATION CONSTANT

Keywords

Dissociation constant, pH, potentiometric measurement, capillary electrophoresis, Deprotonation.

Date

01-09-2014

Additional Links

Manuscript Submission

Journal

International Journal of Pharmacy and Pharmaceutical Sciences
Vol 6, Issue 8, 2014 Page: 26-34

Online ISSN

0975-1491

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796 Views | 96 Downloads

Authors & Affiliations

Bebee Pathare
Department of pharmaceutics, P. E. S’s, Modern College of Pharmacy [for ladies], Borhadewadi, Moshi, Pune 412105 India
India

Vrushali Tambe
Department of pharmaceutics, P. E. S’s, Modern College of Pharmacy [for ladies], Borhadewadi, Moshi, Pune 412105 India
India

Vandana Patil
Department of pharmaceutics, P. E. S’s, Modern College of Pharmacy [for ladies], Borhadewadi, Moshi, Pune 412105 India
India


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