The Stabilizing Effect of Moisture on the Solid-State Degradation of Gabapentin

Abstract

Abstract. Gabapentin is known to undergo intramolecular cyclization to form a lactam (gaba-L) with concomitant loss of water. Gabapentin was milled in a planetary mill for 15-60 min. Unmilled and milled gabapentin were stored at 50°C with relative humidity ranged between 5% and 90%. The unmilled and milled samples were assayed for gabapentin and gaba-L by reversed phase-high-performance liquid chromatography and also subjected to powder X-ray diffraction, solid-state nuclear magnetic resonance and surface area analyses. The rates of lactamization in the milled gabapentin samples correlated to increased surface area, milling duration, and in-process lactam levels. This effect of milling could not be explained solely by the increase in surface area with increased milling time but was more likely due to increased regions of crystal disorder caused by the mechanical and thermal milling stresses. The lactamization rate of milled gabapentin samples was greatest in the presence of the lowest humidity conditions and dramatically decreased with increasing humidity. In particular, milled gabapentin appeared to be much more stable at humidity levels greater than 31% RH. This finding could not be attributed to the possibility of lactam hydrolysis at high humidity but rather to a competitive annealing process wherein milling-induced crystal defects were lost upon exposure to atmospheric moisture thereby stabilizing the milling-damaged drug substance.

Investigating Gabapentin Polymorphism Using Solid-State NMR Spectroscopy

“…Other research performed in the context of this project includes the work reported by Zong and coworkers (7). Additional reports are expected.…”

“…They milled form II for 15-60 min and stored the samples at 50°C, at relative humidity values ranging from 5% to 80%. The chemical instability, based on the amount of gabapentin lactam formed, was measured by reverse phase high-performance liquid chromatography (HPLC) (7). While milling did not cause any physical transformation, the amount of lactam formed increased with milling time.…”

Evaluation of In-Use Stability of Anticoagulant Drug Products: Warfarin Sodium

“…Loss of the integrity of the drug molecule at any stage may alter their physicochemical properties and therefore impact clinical outcome. If chemically degraded to toxic product, it may harm the patients instead of benefitting them …”

“…If chemically degraded to toxic product, it may harm the patients instead of benefitting them. 6 Warfarin sodium, an anticoagulant drug, has been widely used to treat various cardiovascular conditions and prevent clotting after medical intervention. 7 International normalized ratio (INR), which represents the effectiveness of the anticoagulant, is frequently monitored for patients on warfarin therapy.…”

Solid-State Characterization and Interconversion of Recrystallized Amodiaquine Dihydrochloride in Aliphatic Monohydric Alcohols

“…Various polymorphs, amorphous, hydrates, and solvates will have an impact on the physicochemical and mechanical properties of a drug substance. During manufacturing processes, there are many factors which will affect the solid-state characteristics of a drug such as temperature, light, humidity, pressure, processing time, and solvents (3)(4)(5). These factors will not only influence the physicochemical properties of the drug, but also on their efficacy (6)(7)(8)(9).…”