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Kinetic Modeling of API Oxidation: (2) Imipramine Stress Testing
Haoyang Wu1, Alon Grinberg Dana1,2, Duminda S Ranasinghe1
1Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
Molecular Pharmaceutics
|April 18, 2022
Summary
Computational chemistry models can predict active pharmaceutical ingredient (API) degradation, accelerating drug development. This study developed an ab initio kinetic model for oxidative degradation, successfully identifying key imipramine breakdown products.
Area of Science:
- Pharmaceutical Chemistry
- Computational Chemistry
- Chemical Kinetics
Background:
- Active pharmaceutical ingredient (API) chemical stability is crucial for drug safety and efficacy.
- Traditional stress testing for API stability is time-consuming and resource-intensive, especially in early drug development.
- Computational methods offer a potential solution for accelerated screening and enhanced stability studies.
Purpose of the Study:
- To develop and validate an ab initio predictive chemical kinetic model for API degradation.
- To investigate the free-radical oxidative degradation of imipramine.
- To compare computational predictions with experimental observations for API stress testing.
Main Methods:
- Utilized quantum chemical calculations and automated reaction mechanism generation.
- Developed an ab initio predictive chemical kinetic model for oxidative degradation.
- Conducted stress testing of imipramine in an azobis(isobutyronitrile) (AIBN) solution and compared with model predictions.
Main Results:
- The ab initio kinetic model successfully predicted the two major imipramine degradation products, iminodibenzyl and desimipramine.
- The model identified these key products within its top three predicted degradation products.
- Demonstrated the utility of predictive kinetic modeling in understanding API degradation pathways.
Conclusions:
- Ab initio chemical kinetic modeling combined with quantum chemical computations can effectively elucidate API chemical stability issues.
- This approach has the potential to significantly accelerate drug development and reduce costs.
- An automated digital workflow integrating first-principle models with data-driven methods and high-throughput experiments could transform API stability studies.
