Pharmaceutical Research

, Volume 29, Issue 10, pp 2738–2753 | Cite as

pH-Induced Precipitation Behavior of Weakly Basic Compounds: Determination of Extent and Duration of Supersaturation Using Potentiometric Titration and Correlation to Solid State Properties

  • Yi-Ling Hsieh
  • Grace A. Ilevbare
  • Bernard Van Eerdenbrugh
  • Karl J. Box
  • Manuel Vincente Sanchez-Felix
  • Lynne S. TaylorEmail author
Research Paper



To examine the precipitation and supersaturation behavior of ten weak bases in terms of the relationship between pH-concentration-time profiles and the solid state properties of the precipitated material.


Initially the compound was dissolved at low pH, followed by titration with base to induce precipitation. Upon precipitation, small aliquots of acid or base were added to induce slight subsaturation and supersaturation respectively and the resultant pH gradient was determined. The concentration of the unionized species was calculated as a function of time and pH using mass and charge balance equations.


Two patterns of behavior were observed in terms of the extent and duration of supersaturation arising following an increase in pH and this behavior could be rationalized based on the crystallization tendency of the compound. For compounds that did not readily crystallize, an amorphous precipitate was formed and a prolonged duration of supersaturation was observed. For compounds that precipitated to crystalline forms, the observed supersaturation was short-lived.


This study showed that supersaturation behavior has significant correlation with the solid-state properties of the precipitate and that pH-metric titration methods can be utilized to evaluate the supersaturation behavior.


amorphous crystallization pH-Metric precipitation supersaturation 


Acknowledgments & Disclosures

The authors would like to thank Eli Lilly and Company for providing the Sirius instrument. Pfizer Inc. is acknowledged for providing a fellowship for YLH. BVE is a Postdoctoral Researcher of the 'Fonds voor Wetenschappelijk Onderzoek', Flanders, Belgium.


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Yi-Ling Hsieh
    • 1
  • Grace A. Ilevbare
    • 1
  • Bernard Van Eerdenbrugh
    • 1
    • 2
  • Karl J. Box
    • 3
  • Manuel Vincente Sanchez-Felix
    • 4
  • Lynne S. Taylor
    • 1
    • 5
    Email author
  1. 1.Department of Industrial and Physical Pharmacy, College of PharmacyPurdue UniversityWest LafayetteUSA
  2. 2.Laboratory for Pharmacotechnology and Biopharmacy, K.U. LeuvenLeuvenBelgium
  3. 3.Sirius AnalyticalSussexUK
  4. 4.Eli Lilly and CompanyIndianapolisUSA
  5. 5.West LafayetteUSA

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