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Salt Stability – The Effect of pHmax on Salt to Free Base Conversion

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Abstract

Purpose

The aim of this study was to investigate how the disproportionation process can be impacted by the properties of the salt, specifically pHmax.

Methods

Five miconazole salts and four sertraline salts were selected for this study. The extent of conversion was quantified using Raman spectroscopy. A mathematical model was utilized to estimate the theoretical amount of conversion.

Results

A trend was observed that for a given series of salts of a particular basic compound (both sertraline and miconazole are bases), the extent of disproportionation increases as pHmax decreases. Miconazole phosphate monohydrate and sertraline mesylate, although exhibiting significantly different pHmax values (more than 2 units apart), underwent a similar extent of disproportionation, which may be attributed to the lower buffering capacity of sertraline salts.

Conclusion

This work shows that the disproportionation tendency can be influenced by pHmax and buffering capacity and thus highlights the importance of selecting the appropriate salt form during the screening process in order to avoid salt-to-free form conversion.

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Abbreviations

API:

Active pharmaceutical ingredient

PXRD:

Powder X-ray diffraction

RH:

Relative humidity

TGA:

Thermogravimetric analysis

TSPd:

Tribasic sodium phosphate dodecahydrate

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Acknowledgments

The Dane O’Kildsig Center for Pharmaceutical Processing Research is acknowledged for providing funding for this project. Pfizer Inc is thanked for providing a fellowship for Yi-Ling Hsieh. Sheri L. Shamblin, Kenneth C. Waterman, and Evgenyi Y. Shalaev, are thanked for the helpful discussions. Chris Seadeek is acknowledged for assisting in salt screens.

Author information

Author notes

  1. Yi-Ling Hsieh

    Present address: Novartis Pharmaceutical Corporation, 201 Industrial Rd., San Carlos, California, 94070, USA

Authors and Affiliations

  1. Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Dr., West Lafayette, Indiana, 47907, USA

    Yi-Ling Hsieh & Lynne S. Taylor

  2. Eli Lilly & Co, 1400 W. Raymond St., Indianapolis, Indiana, 46221, USA

    Jeremy M. Merritt

  3. Pfizer Global Research and Development, Eastern Point Road, MS 8156-007, Groton, Connecticut, 06340, USA

    Weili Yu

Authors
  1. Yi-Ling Hsieh
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  2. Jeremy M. Merritt
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  3. Weili Yu
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  4. Lynne S. Taylor
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Corresponding author

Correspondence to Lynne S. Taylor.

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Hsieh, YL., Merritt, J.M., Yu, W. et al. Salt Stability – The Effect of pHmax on Salt to Free Base Conversion. Pharm Res 32, 3110–3118 (2015). https://doi.org/10.1007/s11095-015-1691-5

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  • DOI: https://doi.org/10.1007/s11095-015-1691-5

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