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Predicting pHmax and Salt Disproportionation Risk for Basic Drugs
Xin Yao1, Mengqi Yu1, Fei Chen1
1Synthetic Molecules CMC, Research & Development, AbbVie Inc., North Chicago, Illinois60064, United States.
Molecular Pharmaceutics
|July 23, 2026
Summary
Predicting pharmaceutical salt pHmax using drug pKa and molecular weight improves salt screening efficiency. Disproportionation risk is linked to pHmax and excipient pHee, enabling systematic risk assessment for drug development.
Area of Science:
- Pharmaceutical Science
- Physical Chemistry
- Drug Development
Background:
- Pharmaceutical salts enhance drug bioavailability, with pHmax (maximum solubility pH) critical for stability.
- Predicting pHmax and salt disproportionation risk remains challenging, impacting material use and development timelines.
Purpose of the Study:
- To develop predictive models for pHmax based on molecular properties.
- To investigate the mechanism of salt disproportionation.
- To establish a systematic method for grading and predicting disproportionation risk.
Main Methods:
- Compiled pHmax data for 106 monosalts of 35 basic drugs.
- Developed a regression model correlating pHmax with drug pKa and molecular weights.
- Utilized differential scanning calorimetry (DSC) to assess disproportionation mechanisms.
- Defined and exemplified disproportionation risk levels based on pHmax and excipient equilibrium pH (pHee).
Main Results:
- pHmax strongly correlates with drug pKa and is influenced by molecular weights, enabling prediction with 74% accuracy within experimental error.
- Salt disproportionation was confirmed to be water-mediated, not solid-state.
- Disproportionation risk correlates with the pH difference (pHee - pHmax), increasing sharply for hygroscopic excipients.
Conclusions:
- A predictive model for pHmax can guide early-stage salt selection, reducing material consumption.
- Understanding disproportionation mechanisms and risks is crucial for stable pharmaceutical formulations.
- A workflow for predicting disproportionation risk aids in selecting appropriate excipients and salt forms.
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