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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

Pharmaceutical Research volume 35, Article number: 79 (2018) Cite this article

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.

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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

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

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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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Authors and Affiliations

  1. Drug Product Science & Technology, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey, 08903, USA

    Daniel S. Hsieh, Liang Luo, Yan Xu, Joshua D. Engstrom & Qi Gao

Authors
  1. Daniel S. Hsieh
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  2. Liang Luo
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  3. Yan Xu
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  4. Joshua D. Engstrom
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  5. Qi Gao
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Corresponding author

Correspondence to Daniel S. Hsieh.

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Commemoration

The authors would like to dedicate this article to our dear colleague, Dr. John Crison, who passed away in Oct. 2016. John initiated this study by combining an in vitro kinetic model with a physiological-based pharmacokinetic model (GastroPlus™) to assess the potential in vivo fate of PVPVA used in a formulation.

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Hsieh, D.S., Luo, L., Xu, Y. et al. 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. Pharm Res 35, 79 (2018). https://doi.org/10.1007/s11095-017-2305-1

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  • DOI: https://doi.org/10.1007/s11095-017-2305-1

KEY WORDS

  • alcoholysis
  • degradation
  • hydrolysis
  • modeling
  • PVPVA
  • reaction kinetics