Document Type

Dissertation

Date of Degree

Summer 2015

Degree Name

PhD (Doctor of Philosophy)

Degree In

Pharmaceutical Sciences and Experimental Therapeutics

First Advisor

Lee E. Kirsch

Abstract

Drug instability in solid dosage forms includes chemical or physical processes involving covalent or polymorphic transformations wherein different polymorphs possess crystal structure differences. Gabapentin chemically degrades by intramolecular cyclization to gabapentin-lactam (lactam) in the solid-state. Additionally, gabapentin undergoes polymorphic solid-state transformations. A kinetic model was developed to describe the environmental and excipient effects on chemical and physical instability associated with milling induced stress and subsequent storage under controlled temperature and humidity conditions.

Reaction mixtures were generated by co-milling gabapentin Form II with various excipients. The effects of environmental conditions were studied by storing reaction mixtures at 40-60 ºC and 5-50 %RH. The chemical and polymorphic compositions of the reaction mixtures were measured as a function of time using a combination of chromatographic method, 13C ssNMR and XRPD. Degradation 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.

In reaction mixtures composed of co-milled gabapentin and excipients, gabapentin was found to exist in three forms: anhydrous polymorph II and III and gabapentin-lactam. A fourth form (II*) was observed based on initial degradation kinetics and was hypothesized to be a crystal-disordered form generated by mechanical stress. The effect of environment moisture was to decrease the net rate of lactam formation by facilitating polymorphic transformation kinetics and crystal annealing. However, excipient blocked the catalytic moisture effect on polymorphic transformations. The key features of our model are first-order physical state transitions of II* and III to II, first-order degradation of II* to lactam and autocatalytic lactamization of II and III. 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 transitions, excipient primarily influenced the physical state transitions of II*and III → II through its ability to interact with humidity and the degree of contact between excipient and substrate.

Public Abstract

Solid-state drug degradation rates are complicated because drug molecules can exist in multiple states that are capable of undergoing both covalent and/or non-covalent changes at unique rates due in response to their mobility and environment. Systematic studies on the effects of composition (i.e. excipients) and manufacturing stress on drug stability in solid dosage forms are lacking. When drugs degrade to toxic degradants during their shelf-life predictive, quantitative models are needed to ensure drug product safety. The objective of our studies is to build a kinetic model that describes the environmental and excipient effects on chemical and physical instability associated with manufacturing-induced stress and subsequent storage under controlled temperature and humidity conditions using gabapentin as a model compound. Gabapentin chemically degrades to form gabapentin-lactam (lactam) in the solid-state. Lactam is a toxic degradation product, thus the established limit on lactam in gabapentin formulations is less than 0.4%. Kinetic models that describe the relationship between substrate, intermediate and degradation product were devised based on analysis of the concentration time profiles of gabapentin/excipient reaction mixtures. 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 kinetic model was shown to be robust and capable of describing the effects of temperature, humidity and excipient on rate constants associated with kinetics for each physical and chemical transition of gabapentin.

Keywords

publicabstract, Chemical stability, Crystal defects, Excipient effects, Mathematical model, Physical stability, Solid-state analytical techniques

Pages

xxi, 193 pages

Copyright

Copyright 2015 Radaduen Tinmanee

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