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Polymorphic and Covalent Transformations of Gabapentin in Binary Excipient Mixtures after Milling-Induced Stress

  • Research Paper
  • Theme: Formulation and Manufacturing of Solid Dosage Forms
  • Published:
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Abstract

Purpose

The purpose of the research described herein was to develop a kinetic model for quantifying the effects of conditional and compositional variations on non-covalent polymorphic and covalent chemical transformations of gabapentin.

Methods

Kinetic models that describe the relationship between polymorphs and degradation product in a series of sequential or parallel steps were devised based on analysis of the resultant concentration time profiles. Model parameters were estimated using non-linear regression and Bayesian methods and evaluated in terms of their quantitative relationship to compositional and conditional variations.

Results

The model was constructed in which co-milling gabapentin with excipients determined three physically-initial concentrations (II0*, II0 and III0) and one chemically-initial concentration (lactam0). For chemical transitions, no humidity effect was present but the catalytic effects of excipients on the conversion of II and III➔lactam were observed. For physical transition, excipient primarily influenced the physical state transition of III➔II through its ability to interact with humidity.

Conclusions

This model was shown to be robust to quantitatively account for the effects of temperature, humidity and excipient on rate constants associated with kinetics for each physical and chemical transition.

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Abbreviations

II0 :

Initial concentration of gabapentin Form II

II0 * :

Estimated initial concentration of physically-disordered gabapentin Form II

III0 :

Initial concentration of gabapentin Form III

II➔III:

Physical state transition of gabapentin Form II➔III

II*➔II:

Physical state transition of physically-disordered gabapentin Form II*➔II

III➔II:

Physical state transition of gabapentin Form III➔II

II➔lactam:

Chemical degradation of gabapentin Form II➔lactam

II*➔lactam:

Chemical degradation of physically-disordered gabapentin Form II*➔lactam

III➔lactam:

Chemical degradation of gabapentin Form III➔lactam

AMASTK:

R-language based Advanced Modeling and Simulation Tool Kit

β:

Humidity sensitivity term in modified Arrhenius equation

13C CP/MAS NMR:

13C cross-polarization/magic angle spinning nuclear magnetic resonance

CaHPO4 :

Dibasic calcium phosphate dihydrate

Form II or II:

Gabapentin Form II

Form II* or II*:

Physically-disordered gabapentin Form II

Form III or III:

Gabapentin Form III

1H T1 :

Proton relaxation time in laboratory frame

HPC:

Hydroxy propyl cellulose

HPLC:

High-performance liquid chromatography

k1 :

Estimated rate constant for conversion of II*➔II

k2 :

Estimated rate constant for rapid conversion of II*➔lactam

k3 :

Estimated rate constant for the conversion of II➔lactam

k4 :

Estimated rate constant for the conversion of III➔lactam

k5 :

Estimated rate constant for polymorphic transformation of III➔II

lactam or L:

Gabapentin-lactam

Lactam0 or L0 :

Initial concentration of gabapentin-lactam

MCMC:

Markov Chain Monte Carlo

SiO2 :

Colloidal silicon dioxide

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Acknowledgments and Disclosures

Special thanks are given to the University of Iowa Central Nuclear Magnetic Resonance Facility.

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Authors and Affiliations

  1. Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, The University of Iowa, Iowa City, Iowa, 52242, USA

    Radaduen Tinmanee & Lee E. Kirsch

  2. Small Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, USA

    Stephen D. Stamatis

  3. Analytical and Quality Evaluation Research Laboratories, Pharmaceutical Technology Division, Daiichi Sankyo, Hiratsuka, Kanagawa, 254-0014, Japan

    Eji Ueyama

  4. The Lachman Institute for Pharmaceutical Analysis, Long Island University, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Brooklyn, New York, 11201, USA

    Kenneth R. Morris

Authors
  1. Radaduen Tinmanee
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  2. Stephen D. Stamatis
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  3. Eji Ueyama
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  4. Kenneth R. Morris
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  5. Lee E. Kirsch
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Corresponding author

Correspondence to Lee E. Kirsch.

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Guest Editors: Tony Zhou and Tonglei Li

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Tinmanee, R., Stamatis, S.D., Ueyama, E. et al. Polymorphic and Covalent Transformations of Gabapentin in Binary Excipient Mixtures after Milling-Induced Stress. Pharm Res 35, 39 (2018). https://doi.org/10.1007/s11095-017-2285-1

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  • DOI: https://doi.org/10.1007/s11095-017-2285-1

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