Comparison of a miniaturized shake-flask solubility method with automated potentiometric acid/base titrations and calculated solubilities

J Pharm Sci. 2005 Jan;94(1):1-16. doi: 10.1002/jps.20212.


Solubility is one of the most important parameters for lead selection and optimization during drug discovery. Its determination should therefore take place as early as possible in the process. Because of the large numbers of compounds involved and the very low amounts of each compound available in the early development stage, it is highly desirable to measure the solubility with as little compound as possible and to be able to improve the throughput of the methods used. In this work, a miniaturized shake-flask method was developed and the solubility results were compared with those measured by semiautomated potentiometric acid/base titrations and computational methods for 21 poorly soluble compounds with solubilities mostly in the range 0.03-30 microg/mL. The potentiometric method is very economical (approximately 100 microg of a poorly soluble compound is needed) and is able to create a pH/solubility profile with one single determination, but is limited to ionizable compounds. The miniaturized shake-flask method can be used for all compounds and a wide variety of media. Its precision and throughput proved superior to the potentiometric method for very poorly soluble compounds. Up to 20 compounds a week can be studied with one set-up. Calculated solubility data seem to be sufficient for a first estimate of the solubility, but they cannot currently be used as a substitute for experimental measurements at key decision points in the development process.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Buffers
  • Chemistry, Pharmaceutical*
  • Chromatography, High Pressure Liquid
  • Drug Compounding
  • Glyburide / chemistry
  • Hydrogen-Ion Concentration
  • Neural Networks, Computer
  • Pharmaceutical Preparations / chemistry*
  • Potentiometry*
  • Solubility


  • Buffers
  • Pharmaceutical Preparations
  • Glyburide