Purpose: Gabapentin is degraded directly into a high toxicity form known as gabapentin lactam (gaba-L) with a maximizing desire in mild pH and low humidity. This study reports the lactamization process of gabapentin, along with a detailed analysis of the energy landscape, geometry, and thermodynamic and kinetic preference of the process. To investigate the effect of the acidic/basic conditions on the energy landscape, the energy profiles were investigated for both protonation and deprotonation forms of gabapentin.
Methods: All the calculations were performed by using the density functional theory (DFT) and the G4MP2 levels of theory in the conductor-like polarizable continuum model, CPCM, and water as the solvent.
Results: The lactamization process is an intramolecular cyclization which results in formation of gabapentin-lactam. The chemically intact gabapentin exists in two forms of a stable, R, and a relatively disordered form, R*. The conversion of stable crystalline form R to the intact unstable isomer R* is considered as the primary step in the gabapentin degradation. The results exhibited that near the unstable geometry, R*, a transition state (TS), is 41.3 kcal/mol higher in energy than the optimized ground state, R* (4.1 kcal/mol). From the intrinsic reaction coordinates (IRC) computations, it can be concluded that this transition state led to the unstable R* in one direction and to gabapentin-lactam in the other.
Conclusions: The thermodynamic stability of the lactam form (-13.63 kcal/mol) clarifies the more thermal stability of gaba-L than its related gabapentin form and the experimental preference for the lactamization. The corresponding energy profile on protonation/deprotonation forms of gabapentin indicates the pH-dependent of the process and the rate reduction in out of the mild pH.
Keywords: Computational methods; Degradation mechanism; Gabapentin; Lactamization.
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