Combining an In Vitro Kinetic Model with a Physiologically-Based Pharmacokinetic Model to Assess the Potential In Vivo Fate of Polyvinyl Pyrrolidone-Vinyl Acetate Copolymers
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To understand hydrolysis and alcoholysis of polyvinylpyrrolidone-co-vinylacetate (PVPVA) during formulation and storage, elucidate the reaction mechanism, establish an intrinsic kinetic model, and apply this model coupled with GastroPlus™ modeling to predict the amount of PVPVA degradation in vivo.
The experimental approach includes the detection of the polymer reaction by solution nuclear magnetic resonance (NMR) and the measurement of reaction product concentration via gas chromatography (GC). The theoretical approach includes the establishment of the intrinsic kinetic model and the application of GastroPlus™ to predict the degree of PVPVA degradation.
The kinetic model established is a first order reaction between PVPVA and 2-propanol (IPA) or water under an acidic condition. The application of this kinetic model shows that between 1.7 and 6.8 mg of degradant is formed in the GI tract for a 850 mg dose of PVPVA.
The results from this application provide valuable input for process development and the risk analysis of the degradation of PVPVA.
KEY WORDSalcoholysis degradation hydrolysis modeling PVPVA reaction kinetics
Active pharmaceutical ingredient
Continuous stirred-tank reactor
Nuclear magnetic resonance
Physiologically based pharmacokinetic
Half of the residence time in stomach
Apparent reaction rate constant
Reactor volume, Liter
Molecular weight of PVPVA
- m in chemical structure
Number of repeating units for vinyl acetate
- n in chemical structure
Number of repeating units for N-Pyrrolidone
Initial weight of PVPVA, gram
- [PVPVA]t = 0
PVPVA concentration at the beginning of reaction, Mole/Liter
- [VA]t = 0
Vinyl acetate concentration at the beginning of reaction, Mole/Liter
- z in chemical structure
Number of repeating units for vinyl alcohol
ACKNOWLEDGMENTS AND DISCLOSURES
The authors are grateful for colleagues and project team members, especially Dr. San Kiang and Dr. Chiajen Lai, at Bristol-Myers Squibb Co. for providing support to accomplish this work. Special thanks are also given to Dr. Yidan Lan and Dr. Shaukat Ali at BASF for providing samples and technical support.
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