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

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 p...

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Bibliographic Details
Published in:Pharmaceutical research 2018-02, Vol.35 (2), p.39-12, Article 39
Main Authors: Tinmanee, Radaduen, Stamatis, Stephen D., Ueyama, Eji, Morris, Kenneth R., Kirsch, Lee E.
Format: Article
Language:English
Subjects:
Bayesian analysis
Biochemistry
Biomedical and Life Sciences
Biomedical Engineering and Bioengineering
Biomedicine
Catalytic converters
Chemistry, Pharmaceutical
Concentration time
Covalence
Crystallization
Drug Compounding - methods
Drug Stability
Excipients
Excipients - chemistry
Formulation and Manufacturing of Solid Dosage Forms
Gabapentin
Gabapentin - chemistry
Humidity
Kinetics
Mathematical models
Medical Law
Models, Chemical
Parameter estimation
Pharmacology/Toxicology
Pharmacy
Research Paper
Stress, Mechanical
Transition Temperature
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Summary: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 (II 0 *, II 0 and III 0 ) and one chemically-initial concentration (lactam 0 ). 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.
ISSN:0724-8741
1573-904X
DOI:10.1007/s11095-017-2285-1