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

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ABSTRACT

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.

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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.

Author information

Authors and Affiliations

  1. Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA

    Yi-Ling Hsieh, Grace A. Ilevbare, Bernard Van Eerdenbrugh & Lynne S. Taylor

  2. Laboratory for Pharmacotechnology and Biopharmacy, K.U. Leuven, Leuven, Belgium

    Bernard Van Eerdenbrugh

  3. Sirius Analytical, Sussex, UK

    Karl J. Box

  4. Eli Lilly and Company, Indianapolis, Indiana, USA

    Manuel Vincente Sanchez-Felix

  5. 575 Stadium Mall Dr., West Lafayette, Indiana, 47907, USA

    Lynne S. Taylor

Authors
  1. Yi-Ling Hsieh

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  2. Grace A. Ilevbare

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  3. Bernard Van Eerdenbrugh

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  4. Karl J. Box

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  5. Manuel Vincente Sanchez-Felix

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  6. Lynne S. Taylor

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Corresponding author

Correspondence toLynne S. Taylor.

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Hsieh, YL., Ilevbare, G.A., Van Eerdenbrugh, B.et al. pH-Induced Precipitation Behavior of Weakly Basic Compounds: Determination of Extent and Duration of Supersaturation Using Potentiometric Titration and Correlation to Solid State Properties.Pharm Res29, 2738–2753 (2012). https://doi.org/10.1007/s11095-012-0759-8

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