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 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*, II and III) and one chemically-initial concentration (lactam). 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.