Copyright (c) 2013 AJC
This work is licensed under a Creative Commons Attribution 4.0 International License.
Design of a Modified Kinetic Solubility Determination Method at Laboratory Level for Early Drug Discovery
Corresponding Author(s) : Gautam Singhvi
Asian Journal of Chemistry,
Vol. 25 No. 1 (2013): Vol 25 Issue 1
Abstract
Thermodynamic solubility is most often determined using the equilibrium shake flask method or the pH-metric method. But these methods are time consuming and less preferable at early drug discovery. Solubility determination by dimethyl sulfoxide widely used for kinetic solubility measurement at early drug discovery. The aim of this study is to design of a DMSO based solubility determination methods and find out the extent of validity of designed method with the shake flask method. A DMSO based method is designed and solubility determined at pH 1.2 and 6.8 at 25 ºC for model compound (hydrochlorothiazide). The solubility was also measured by shake flask method at pH 1.2 and 6.8 at 25 ºC. DMSO based solubility measured by two methods (i) titrimetric and (ii) spectrophotometric method under same conditions in both buffers. Solubility values obtained at pH 1.2 by DMSO titrimetric method, DMSO spectrophotometric method, and shake flask methods were found to be 1047, 1048 and 1109 μg/mL respectively. While values obtained at pH 6.8 by DMSO titrimetric method, DMSO spectrophotometric method and shake flask methods were found to be 1272, 1270 and 1154 μg/mL respectively. The results obtained by DMSO titrimetric and spectrophotometric methods were found not to be significantly different than results obtained by standard shake flask method as compared by t-test at 95 % confidence limit. Thus such a designed DMSO based method for solubility determination can be used at laboratory scale for preliminary solubility estimation in short time with minimum amount of drug at early drug discovery stage.
Keywords
Download Citation
Endnote/Zotero/Mendeley (RIS)BibTeX
- C. Lipinski, F. Lombardo, B.W. Dominy and P.J. Feeney, Adv. Drug Deliv. Rev., 23, 3 (1997).
- X.Q. Chen and S. Venkatesh, Pharm. Res., 21, 1758 (2004).
- R. Lobenberg, G.L. Amidon and M. Vieira, Solubility as a Limiting Factor to Drug Absorption. Oral Drug Absorption, Prediction and Assessment, Marcel Dekker, Inc., New York, NY, pp. 137-153 (2000).
- S.H. Yalkowsky and S.C. Valvani, J. Pharm. Sci., 69, 912 (1980).
- S.H. Yalkowsky and S. Banerjee, Aqueous Solubility, Methods of Estimation for Organic Compounds. Marcel Dekker, New York, NY (1992).
- A. Glomme, J. Marz and J.B. Dressman, J. Pharm. Sci., 94, 1 (2004).
- K.J. Box, G. Völgyi, E. Baka, M. Stuart, K. Takács-Novák and J.E.A. Comer, J. Pharm. Sci., 95, 1298 (2006).
- T. Higuchi and K.A. Connors, Adv. Anal. Chem. Inst., 4, 117 (1965).
- C. Lipinski, in eds.: H. Van de Waterbeemd, H. Lennernas and P. Artursson, Estimation of Solubility, Permeability, Absorption and Bioavailability. Drug Bioavailability. Wiley-VCH Verlag GmbH, Weinheim, pp. 215-231 (2003).
- A. Avdeef, Pharm. Pharmacol. Commun., 4, 165 (1998).
- C.D. Bevan, and R.S. Lloyd, Anal. Chem., 72, 1781 (2000).
- A. Avdeef, High-throughput Measurements of Solubility Profiles. Pharmacokinetic Optimization in Drug Research: Biological, Physicochemical and Computational Strategies, [LogP2000, Lipophilicity Symposium],
- nd, Lausanne, Switzerland, Mar. 5-9, (2000), pp. 305-325 (2001).
- E.H. Kerns and L. Di, Drug-Like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization, Academic Press (2008).
- E. Baka, J.E.A. Comer and K. Takács-Novák, J. Pharm. Biomed. Anal., 46, 335 (2008).
- L. Pan, Q. Ho, K. Tsutsui and L. Takahashi, J. Pharm. Sci., 90, 521 (2001).
References
C. Lipinski, F. Lombardo, B.W. Dominy and P.J. Feeney, Adv. Drug Deliv. Rev., 23, 3 (1997).
X.Q. Chen and S. Venkatesh, Pharm. Res., 21, 1758 (2004).
R. Lobenberg, G.L. Amidon and M. Vieira, Solubility as a Limiting Factor to Drug Absorption. Oral Drug Absorption, Prediction and Assessment, Marcel Dekker, Inc., New York, NY, pp. 137-153 (2000).
S.H. Yalkowsky and S.C. Valvani, J. Pharm. Sci., 69, 912 (1980).
S.H. Yalkowsky and S. Banerjee, Aqueous Solubility, Methods of Estimation for Organic Compounds. Marcel Dekker, New York, NY (1992).
A. Glomme, J. Marz and J.B. Dressman, J. Pharm. Sci., 94, 1 (2004).
K.J. Box, G. Völgyi, E. Baka, M. Stuart, K. Takács-Novák and J.E.A. Comer, J. Pharm. Sci., 95, 1298 (2006).
T. Higuchi and K.A. Connors, Adv. Anal. Chem. Inst., 4, 117 (1965).
C. Lipinski, in eds.: H. Van de Waterbeemd, H. Lennernas and P. Artursson, Estimation of Solubility, Permeability, Absorption and Bioavailability. Drug Bioavailability. Wiley-VCH Verlag GmbH, Weinheim, pp. 215-231 (2003).
A. Avdeef, Pharm. Pharmacol. Commun., 4, 165 (1998).
C.D. Bevan, and R.S. Lloyd, Anal. Chem., 72, 1781 (2000).
A. Avdeef, High-throughput Measurements of Solubility Profiles. Pharmacokinetic Optimization in Drug Research: Biological, Physicochemical and Computational Strategies, [LogP2000, Lipophilicity Symposium],
nd, Lausanne, Switzerland, Mar. 5-9, (2000), pp. 305-325 (2001).
E.H. Kerns and L. Di, Drug-Like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization, Academic Press (2008).
E. Baka, J.E.A. Comer and K. Takács-Novák, J. Pharm. Biomed. Anal., 46, 335 (2008).
L. Pan, Q. Ho, K. Tsutsui and L. Takahashi, J. Pharm. Sci., 90, 521 (2001).