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

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.

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.

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.

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.