Skip to main content
SpringerLink
Log in

Physicochemical Properties

  • Reference work entry
Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays

Abstract

Characterization of physicochemical properties attained strong interest in the pharmaceutical research area and is now a standard method. It is one of the key challenges to develop a pharmaceutical active ingredient into a drug, which combines biological activity with an appropriate physicochemical profile. Poor solubility in aqueous media is one of the major hurdles in the drug development process. Many promising drug candidates have failed simply due to inadequate solubility. The impact of solubility in drug discovery on biological assays, dosing and formulation, and intestinal absorption is discussed by Kerns et al. (2008).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 799.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 949.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References and Further Reading

  • Abraham MM, Chadha HS, Dixon JP, Leo AJ (1994) Hydrogen bonding. Part 9. The partition of solutes between water and various alcohols. J Phys Org Chem 7:712–716

    Article  CAS  Google Scholar 

  • Allen RI, Box KJ, Comer J, Peake C, Tam KY (1998) Multiwavelength spectrophotometric determination of acid dissociation constants of ionizable drugs. J Pharm Biomed Anal 17:699

    Article  PubMed  CAS  Google Scholar 

  • Alsenz J, Meister E, Haenel E (2007) Developlemt of a partially automated solubility screening (PASS) assay for early drug development. J Pharm Sci 96(7):1748–1762

    Article  PubMed  CAS  Google Scholar 

  • Avdeef A (2001) High - throughput measurements of solubility profiles. Pharmacokinetic Optimization in Drug Research: Biological, Physicochemical, and Computational Strategies, [LogP2000, Lipophilicity Symposium], 2nd, Lausanne, Switzerland, Mar. 5-9, 2000

    Google Scholar 

  • Avdeef A, Bucher JJ (1978) Accurate measurements of the concentration of hydrogen ions with a glass electrode: calibrations using the Prideaux and other universal buffer solutions and a computer-controlled automatic titrator. Anal Chem 50(14):2137–2142

    Article  CAS  Google Scholar 

  • Avdeef A, Comer JEA, Thomson SJ (1993) pH-Metric Log P. 3. Glass electrode calibration in methanol-water applied to pKa determination of water insoluble substances by potentiometric titration. Anal Chem 65(1):42–49

    Article  CAS  Google Scholar 

  • Bevan CD (2000) A high-throughput screening method for the determination of aqueous drug solubility using laser nephelometry in microtiter plates. Anal Chem 72:1781–1787

    Article  PubMed  CAS  Google Scholar 

  • Box K, Bevan C, Comer C, Hill J, Allan A, Reynold R (2003) High throughput measurement of pKa values in a mixed-buffer linear pH gradient system. Anal Chem 75(4):883–892

    Article  PubMed  CAS  Google Scholar 

  • Chen T-M, Shen H, Zhu C (2002) Evaluation of a method for high throughput solubility determination using a multi-wavelength UV plate reader. Comb Chem High Throughput Screen 5(7):575–581

    Article  Google Scholar 

  • Comer T, Box K (2003) High throughput measurement of drug pKa values for ADME screening. J Assoc Lab Autom 8(1):55–59

    Article  CAS  Google Scholar 

  • Comer J, Tam KY (2001) Lipophilicity profiles: theory and measurement. In: Testa B, van de Waterbeemd H, Folkers G, Guy R (eds) Pharmacokinetic optimization in drug research: biological, physicochemical and computational strategies. VHCA, Zurich, pp 275–304

    Chapter  Google Scholar 

  • Dehring KA, Workman HL, Miller KD, Mandagere A, Poole SK (2004) J Pharm Biomed Anal 36:447–456

    Article  PubMed  CAS  Google Scholar 

  • Dohta Y, Yamashita T, Horiike S, Nakamura T, Kukami T (2007) Anal Chem 79:8312–8315

    Article  PubMed  CAS  Google Scholar 

  • Dressman JB, Amidon GL, Reppas C, Shah VP (1998) Dissolution testing as a prognostic tool for oral drug absorption. Pharm Res 15(1):11–22

    Article  PubMed  CAS  Google Scholar 

  • Gluck SJ, Cleveland JA (1994) Capillary zone electrophoresis for the determination of dissociation constants. J Chromatogr A 680:49–56

    Article  CAS  Google Scholar 

  • Green C, McKee S, Saunders K (2004) A fully automated Kinetic solubility screen in 384-well Plate format using nephelometry, BMG, Application Note 117, http://www.bmglabtech.com/templates/applications/applications_sub.cfm?application_category_id=11%26application_subcategory_ selected_id=27

  • Guttman A, Varoglu M, Khandurina J (2004) Multidimensional separations in the pharmaceutical arena. Drug Discovery 9(3):136–144

    Article  CAS  Google Scholar 

  • Hansch C, Leo A (1979) Substituent constants for correlation analysis in chemistry and biology. Wiley, New York

    Google Scholar 

  • Henchoz Y, Bard B, Guillarme D, Carrupt P-A, Veuthey J-L, Martel S (2009) Analytical tools for the physicochemical profiling of drug candidates to predict absorption/distribution. Annal Bioannal Chem 394:707–729

    Article  CAS  Google Scholar 

  • Hitzel L, Watt AP, Locker KL (2000) An increase throughput method for the determination of partition coefficients. Pharm Res 17(11):1389–1395

    Article  PubMed  CAS  Google Scholar 

  • Hongve D, Akesson G (1998) Comparison of nephelometric turbidity measurements using wavelengths 400–600 and 860. Water Res 32(10):3143–3145

    Article  CAS  Google Scholar 

  • Jander G, Blasius E (1995) Lehrbuch der analytischen und präparativen anorganischen Chemie 14. Auflage, S. Hirzel Verlag

    Google Scholar 

  • Jia Z, Ramstad T, Zhong M (2001) Medium-throughput pK a screening of pharmaceuticals by pressure-assisted capillary electrophoresis. Electrophoresis 22(6):1112–1118

    Article  PubMed  CAS  Google Scholar 

  • Kerns EH, Di L, Carter GT (2008) In vitro solubility assays in drug discovery. Curr Drug Metab 9:879–885

    Article  PubMed  CAS  Google Scholar 

  • Kerns EH (2001) High throughput physicochemical profiling for drug discovery. J Pharm Sci 90(11):1838–1858

    Article  PubMed  CAS  Google Scholar 

  • Kibbey CE, Poole SK, Robinson B, Jackson JD, Durham D (2001) An integrated process for measuring the physicochemical properties of drug candidates in a preclinical discovery environment. J Pharm Sci 90(8):1164–1175

    Article  PubMed  CAS  Google Scholar 

  • Law D, Kril SL, Schmitt EA, Fort JJ, Qiu Y, Wang W, Porter WR (2001) Physicochemical considerations in the preparation of amorphous ritonavir (poly(ethylene glycol) 8000 solid dispersions. J Pharm Sci 90(8):1015–1024

    Article  PubMed  CAS  Google Scholar 

  • Leo A, Hansch C, Elkins D (1971) Partition coefficients and their uses. Chem Rev 71(6):525–616

    Article  CAS  Google Scholar 

  • Lide DR, Frederikse HPP (1996) CRC handbook of chemistry and physics: special student edition, 77th edn. CRC Press, New York

    Google Scholar 

  • Lipinski CA, Franco L, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23:3–25

    Article  CAS  Google Scholar 

  • Lombardo F, Shalaeva MY, Tupper KA, Gao F, Abraham MH (2000) ElogPoct: a tool for lipophilicity determination in drug discovery. J Med Chem 43(15):2922–2928

    Article  PubMed  CAS  Google Scholar 

  • Lunn G, Schmuff NR (1997) HPLC methods for pharmaceutical analysis. Wiley-Intersciences, New York

    Google Scholar 

  • Miller JM, Blackburn AC, Shi Y, Melzak AJ, Ando HY (2002) Semi-empirical relationships between effective mobility, charge, and molecular weight of pharmaceuticals by pressure-assisted capillary electrophoresis: applications in drug discovery. Electrophoresis 23:2833–2841

    Article  PubMed  CAS  Google Scholar 

  • Minick DJ, Frenz JH, Patrick MA, Brent DA (1988) A comprehensive method for determining hydrophobicity constants by reversed-phase high-performance chromatography. J Med Chem 31(10):1923–1933

    Article  PubMed  CAS  Google Scholar 

  • Mirrlees MS, Moulton SJ, Murphy CT, Taylor P (1976) Direct measurement of octanol-water partition coefficients by high-pressure liquid chromatography. J Med Chem 19:615–619

    Article  PubMed  CAS  Google Scholar 

  • OECD, Paris (1981) Test guideline 107, Decision of the council C(81) 30 final http://www.raell.demon.co.uk/chem/logp/logppka.html

  • Pagliara A, Khamis E, Thrinh A, Carupt PA, Tsai RS, Testa B (1995) Structural properties governing retention mechanisms on RP-HPLC stationary phases used for lipophilicity measurements. J Liquid Chromatogr 18:1721–1745

    Article  CAS  Google Scholar 

  • Pan L, Ho Q, Tsutsui K, Takahashi L (2001) Comparison of chromatographic and spectroscopic methods used to rank compounds for aqueous solubility. J Pharm Sci 90(4):521–529

    Article  PubMed  CAS  Google Scholar 

  • PSOL (PION) http://www.pion-inc.com/pSOL.htm

  • Rafols C, Fuguet E, Reta M, Gilbert C, Roses M, Bosch E (2008) Critical evaluation of buffering solutions for pKa determination by capillary electrophoresis. Electrophoresis 29(13):2841–2851

    PubMed  Google Scholar 

  • Silveston R, Kronberg B (1994) Accurate measurements of solubility and thermodynamic transfer quantities using reversed-phase liquid-liquid chromatography. J Chrom 659(1):43–56

    Article  CAS  Google Scholar 

  • Sirius analytics: application and theory guide, http://www.sirius-analytical.com/books.htm

  • Slater B, McCormack A, Avdeef A, Comer JEA (1994) pH-Metric log P. 4. Comparison of partition coefficients determined by Shake-Flask, HPLC, and potentiometric methods. J Pharmaceut Sci 83:1280–1283

    Article  CAS  Google Scholar 

  • Strasburg R, Franck E, Bastin A, Kenseth J (2003) High throughput determination of pKa values of compounds by multiplexed, absorbance-based, vacuum modulated capillary electrophoresis. In: HPCE 2003, San Diego

    Google Scholar 

  • Tam KY, Takacs-Novak K (2001) Multi-wavelength spectrophotometric determination of acid dissociation constants: a validation study. Anal Chim Acta 434:157–167

    Article  CAS  Google Scholar 

  • Tam KY, Allen Ri, Box KJ, Comer JEA, Peake C (1998) Multiwavelength spectrophotometric determination of acid dissociation constants of ionizable drugs. J Pharm Biomed Anal 17:699–712

    Article  PubMed  Google Scholar 

  • Taylor PJ (1990) In: Hansch C, Sammer G, Taylor JB (eds) Comprehensive medicinal chemistry, vol IV. Pergamon, Oxford, p 241

    Google Scholar 

  • TREGA, Bioscience, iDEA version 1.2, users guide, 9880 Campus Point drive, San Diego

    Google Scholar 

  • Unger KK (ed) (1994) Handbuch der HPLC, Teil 1. GIT Verlag, Darmstadt

    Google Scholar 

  • Unger SH, Cooks JR, Hollenberg JS (1978) Simple procedure for determining octanol-aqueous partition, distribution, and ionization coefficients by reversed-phase high-pressure liquid chromatography. J Pharm Sci 67:1364–1367

    Article  PubMed  CAS  Google Scholar 

  • Valko K (2004) Application of high-performance liquid chromatography based measurements of lipophilicity to model biological distribution. J Chromatogr A 1037:299–310

    Article  PubMed  CAS  Google Scholar 

  • Valko K, Bevan C, Reynolds D (1997) Chromatographic hydrophobicity index by fast-gradient RP-HPLC: a high-throughput alternative to log P/log D. Anal Chem 69:2022

    Article  PubMed  CAS  Google Scholar 

  • Van De Hulst HC (1981) Scattering and extinction experiments as a tool, Light scattering by small molecules. Wiley, New York, pp 381–428

    Google Scholar 

  • Waterbeemd H, Folkers G, Guy R (2001) Pharmacokinetic optimisation in drug research: biological, physicochemical and computational strategies. Zürich, Switzerland

    Google Scholar 

  • Zhou L, Yang L, Tilton S, Wang J (2007) Development of a high throughput equilibrium solubility assay using miniaturized shake-flask method in early drug discovery. J Pharm Sci 96(11):3052–3071

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Sanofi Deutschland GmbH, Industriepark Hoechst, Frankfurt am Main, Germany

    Dr. Heiko Tietgen & Michael Walden

Authors
  1. Dr. Heiko Tietgen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Walden
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Heiko Tietgen .

Editor information

Editors and Affiliations

  1. Sanofi Pharma Deutschland GmbH, A company of the Sanofi-Aventis Group Industriepark Hoechst, Frankfurt am Main, Germany

    Jochen Maas

  2. Dieburg, Germany

    Franz J. Hock

  3. Idstein, Germany

    Dieter Mayer

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer-Verlag Berlin Heidelberg

About this entry

Cite this entry

Tietgen, H., Walden, M. (2013). Physicochemical Properties. In: Vogel, H.G., Maas, J., Hock, F.J., Mayer, D. (eds) Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-25240-2_48

Download citation

Publish with us

Policies and ethics

Search

Navigation