The stabilizing effect of moisture on the solid-state degradation of gabapentin

Zhixin Zong, Salil D. Desai, Aditya M. Kaushal, Dewey H. Barich, Hong Shian Huang, Eric J. Munson, Raj Suryanarayanan, Lee E. Kirsch

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)924-931
Number of pages8
JournalAAPS PharmSciTech
Issue number3
StatePublished - Sep 2011


  • drug degradation kinetics
  • gabapentin
  • lactamization
  • moisture effect
  • solid-state stability

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