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.
- 1.Reintjes T (editor). Solubility enhancement with BASF pharma polymers, Solubilizer compendium, BASF; 2011.Google Scholar
- 4.Using METHOCEL Cellulose Ethers for Controlled Release of Drugs in Hydrophilic Matrix System, The Dow Chemical Company; 2000.Google Scholar
- 5.US FDA Inert Ingredients Database. Copovidone, Unique Ingredient Identifier: D9C330MD8B. (http://www.accessdata.fda.gov/scripts/cder/IIG/).
- 6.Rosenberg J, Reinhold U, Liepold B, Berndl G, Breitenbach J, Soumojeet G, Alani L. Solid pharmaceutical dosage form. Patent US 2005/0084529 A1. 2005.Google Scholar
- 7.KALETRA dosage forms and strengths, ABBOTT; 2016.Google Scholar
- 8.Helfferich FG. Kinetics of homogeneous multistep reactions, Elsevier; 2001.Google Scholar
- 9.BASF Pharma Ingredients & Services, Technical Information, Kollidon® VA64; 2011.Google Scholar
- 10.Applications of mechanistic modeling and simulations in compound and dosage forms selections by Eric Akwasi Mintah, Doctor Dissertation of Mercer University College of Pharmacy; 2017.Google Scholar
- 11.Zhao P. Report form the EM workshop on qualification and reporting of physiologically based pharmacokinetic (PBPK) modeling and simulation, CPT; 2017.Google Scholar
- 13.PubChem CID: 270885, National Center for Biotechnology Information, Bethesda, MD.Google Scholar
- 14.Guidance for Industry Food-Effect Bioavailability and Fed Bioequivalence Studies, U.S. Department of Health and Human Services, Food and Drug Administration. 2002.Google Scholar
- 15.Acid-catalyzed Hydrolysis reaction of poly(vinyl acetate), Sangsoo Park, Hisook Yoon, Polymer(Korea). 2005; 29(3): 304–307.Google Scholar
- 16.Bühler V. Polyvinylpyrrolidone excipient for the pharmaceutical industry, (9th revised edition) BASF. 2008, page 208.Google Scholar
- 17.Pilling MJ, Seakins PW. Reaction kinetics, Oxford; 1995.Google Scholar
- 18.Fogler HS. Elements of chemical reaction engineering, Fourth Edition, Prentice Hall; 2006.Google Scholar