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Pharmaceutical Research

, 35:79 | Cite as

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

  • Daniel S. Hsieh
  • Liang Luo
  • Yan Xu
  • Joshua D. Engstrom
  • Qi Gao
Research Paper
  • 98 Downloads

ABSTRACT

Purpose

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.

Methods

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.

Results

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.

Conclusions

The results from this application provide valuable input for process development and the risk analysis of the degradation of PVPVA.

KEY WORDS

alcoholysis degradation hydrolysis modeling PVPVA reaction kinetics 

ABBREVIATIONS

API

Active pharmaceutical ingredient

CSTR

Continuous stirred-tank reactor

HOAC

Acetic acid

IPA

Isopropyl alcohol

IPAC

Isopropyl acetate

GI

Gastrointestinal

M

Molarity

NMR

Nuclear magnetic resonance

PBPK

Physiologically based pharmacokinetic

PVPVA

Polyvinylpyrrolidone-co-vinylacetate

PVPVA-h

Hydrolyzed/Alcoholyzed Polyvinylpyrrolidone-co-vinylacetate

T50

Half of the residence time in stomach

VA

Vinyl acetate

NOTATION

KAPP

Apparent reaction rate constant

L

Reactor volume, Liter

MWPVPVA

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

W0

Initial weight of PVPVA, gram

[PVPVA]t = 0

PVPVA concentration at the beginning of reaction, Mole/Liter

T

Time, Minute

[VA]t = 0

Vinyl acetate concentration at the beginning of reaction, Mole/Liter

z in chemical structure

Number of repeating units for vinyl alcohol

Notes

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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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Daniel S. Hsieh
    • 1
  • Liang Luo
    • 1
  • Yan Xu
    • 1
  • Joshua D. Engstrom
    • 1
  • Qi Gao
    • 1
  1. 1.Drug Product Science & TechnologyBristol-Myers Squibb CompanyNew BrunswickUSA

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