Pharmaceutical Research

, Volume 30, Issue 1, pp 203–217

Implementing Quality by Design in Pharmaceutical Salt Selection: A Modeling Approach to Understanding Disproportionation

  • Jeremy M. Merritt
  • Shekhar K. Viswanath
  • Gregory A. Stephenson
Research Paper

Abstract

Purpose

Salts of active pharmaceutical ingredients are often used to enhance solubility, dissolution rate, or take advantage of other improved solid-state properties. The selected form must be maintained during processing and shelf-life to ensure quality. We aimed to develop a model to quantify risk of disproportionation, where the salt dissociates back to the freebase form.

Methods

A mechanistic model based on thermodynamics was built to predict disproportionation. Stress testing of molecules in combination with excipients was used to benchmark model predictions. X-ray powder diffraction and solid-state NMR were used to quantify the formation of freebase experimentally.

Results

13 pharmaceutical compounds were screened in 4 formulations containing different combinations of excipients. The test set spanned molecules which did and did not disproportionate and also formulations which did and did not induce disproportionation. Model predictions were in qualitative agreement with the experimental data, recovering trends of how disproportionation varies with humidity, formulation excipients, base pKa and solubility of the API.

Conclusions

The model can predict the balance between different driving forces for disproportionation with limited experimental data resulting in a tool to aid in early-phase risk assessment and formulation design with respect to disproportionation.

KEY WORDS

disproportionation microenvironmental pH model pHmax quality by design 

Supplementary material

11095_2012_863_MOESM1_ESM.docx (192 kb)
ESM 1(DOCX 192 kb)

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Jeremy M. Merritt
    • 1
    • 2
  • Shekhar K. Viswanath
    • 1
  • Gregory A. Stephenson
    • 3
  1. 1.Chemical Product Research and DevelopmentEli Lilly and CompanyIndianapolisUSA
  2. 2.Eli Lilly & CoDC 4816, Eli Lilly and Co., Lilly Technology Center SouthIndianapolisUSA
  3. 3.Pharmaceutical Sciences Research and DevelopmentEli Lilly and CompanyIndianapolisUSA

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