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Relative humidity hysteresis in solid-state chemical reactivity: a pharmaceutical case study
Kenneth C Waterman1, Paul Gerst, Bruce C Macdonald
1Pfizer Global Research and Development, Groton, Connecticut 06340, USA. ken.waterman@freethinktech.com
Journal of Pharmaceutical Sciences
|October 14, 2011
Summary
Pharmaceutical product degradation rates show hysteresis, meaning exposure to high humidity can irreversibly increase reaction rates even after returning to low humidity. This impacts solid-state stability.
Area of Science:
- Pharmaceutical science
- Solid-state chemistry
- Chemical kinetics
Background:
- Solid-state reactions are crucial in pharmaceutical product stability.
- Understanding the impact of environmental factors like relative humidity (RH) on reaction rates is essential for drug formulation and storage.
- Previous studies have not fully elucidated the complex relationship between RH cycling and solid-state reaction kinetics.
Purpose of the Study:
- To investigate the effect of relative humidity (RH) cycling on the chemical reaction rate of solid-state product formation in a pharmaceutical context.
- To determine if RH-induced changes in reaction rates exhibit hysteresis.
- To explore potential mechanisms behind observed hysteresis.
Main Methods:
- Monitoring solid-state product formation rates under controlled relative humidity (RH) cycles.
- Employing a "high-low-high" (HLH) RH cycle (75%-21.5%-75%) and a "low-high-low" (LHL) RH cycle (21.5%-75%-21.5%).
- Comparing reaction rates at different RH levels and across RH cycles, and correlating with moisture sorption isotherms.
Main Results:
- The degradant formation rate was reversible under the HLH cycle, with the final 75% RH step rate matching the initial 75% RH step rate.
- Samples exposed to the LHL cycle exhibited a significantly higher product formation rate upon re-establishment of low RH compared to initial low RH conditions.
- Observed hysteresis in degradant formation rate was not explained by minimal hysteresis in the bulk moisture sorption isotherm.
Conclusions:
- High relative humidity (RH) exposure can induce hysteresis in solid-state pharmaceutical reaction rates, leading to increased degradation.
- The observed hysteresis is likely due to alterations at the solid-solid interface, potentially affecting solid-solution presence, material mechanical properties, or interfacial moisture content.
- These findings highlight the importance of considering RH history in assessing pharmaceutical stability and predicting product shelf-life.
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