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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ibers JA. Gabapentin and gabapentin monohydrate. Acta Crystallogr, Section C: Cryst Struct Commun. 2001;C57:641–3.
Pesachovich M, Singer C, Pilarski G. Preparation of gabapentin. WO98/28255, 25 pp. 1998
Reece HA, Levendis DC. Polymorphs of gabapentin. Acta Crystallogr, Section C: Cryst Struct Commun. 2008;C64(3):o105–8.
Kearney AS, Mehta SC, Radebaugh GW. The effect of cyclodextrins on the rate of intramolecular lactamization of gabapentin in aqueous solution. Int J Pharm. 1992;78(1):25–34.
Hsu CH, Ke WT, Lin SY. Progressive steps of polymorphic transformation of gabapentin polymorphs studied by hot-stage FTIR microspectroscopy. J Pharm Pharmaceut Sci. 2010;13:67–77.
Brago D, Grepioni F, Maini L, Rubini K, Polito M, Brescello R, et al. Polymorphic gabapentin: thermal behavior, reactivity and interconversion of form in solution and solid-state. New J Chem. 2008;32:1788–95.
Lin SY, Hsu CH, Ke W. Solid-state transformation of different gabapentin polymorphs upon milling and co-milling. Int J Pharm. 2010;396:83–90.
Zour E, Lodhi SA, Radebaugh GW. Stability studies of gabapentin in aqueous solutions. Pharm Res. 1992;9(5):595–600.
Zambon E, Giovanetti R, Cotarca L, Pasquato L. Mechanistic investigation on 2-aza-spiro[4,5]decan-3-one formation from 1-(aminomethyl)cyclohexylacetic acid (gabapentin). Tetrahedron. 2008;64(28):6739–43.
Cutrignelli A, Denora N, Lepedota A, Trapani A, Laquintana V, Latrofa A, et al. Comparative effects of some hydrophilic excipients on the rate of gabapentin and baclofen lactamization in lyophilized formulations. Int J Pharm. 2007;332(1–2):98–106.
Chawla M, Raghuvanshi R, Rampal A. Sustained release oral tablets of gabapentin and process for their preparation. WO 2005/020978 A1, 23 pp. 2005
Augart H, Gebhardt U, Herrmann W. Lactam-free amino acids. US 6,054,482, 5 pp. 2000
Singer C, Pilarski F, Pesachovich M. Stable gabapentin containing more than 20 ppm of chlorine ion. WO 01/97612 A1, 24 pp. 2001
Manikandan R, Gogia A, Roy S, Makik R. Gabapentin tablets and methods for their preparation. WO 2004/032905 A1, 17 pp. 2004
Sherman B. Solid compositions comprising gabapentin having improved stability. WO 2004/014356, 10 pp. 2004
Chawla M, Raghuvanshi R, Rampla A. Stable sustained-release oral dosage forms of gabapentin and process for preparation thereof. WO 2005/077332 A2, 20 pp. 2005
Yande V, Kulkarni S, Narasimharaghavan S, Meenakshisunderam S. Stable liquid formulation of antiepileptic agents. WO 2007/107835 A2, 9 pp. 2007
Lloret P. Solid pharmaceutical composition of gabapentin. WO 2007/128495, 25 pp. 2007
Volpe DA, Gupta A, Ciavarella AB, Faustino PJ, Sayeed VA, Khan MA. Comparison of the stability of split and intact gabapentin tablets. Int J Pharm. 2008;350(1–2):65–9.
Gupta A, Ciavarella AB, Sayeed VA, Khan MA, Faustino PJ. Development and application of a validated HPLC method for the analysis of dissolution samples of gabapentin drug products. J Pharm Biomed Anal. 2008;46(1):181–6.
Steiner K, Herrmann W, Baumagarten Z, Crone G. Process for the preparation of cyclic amino acids and intermediates useful in the process. US 5068413, 8 pp. 1991
Inman EL, Tenbarge HJ. High-low chromatography: estimating impurities in HPLC using a pair of sample injections. J Chromatogr Sci. 1988;26:89–94.
Geibel W, Hartenstein J, Herrmann W, Witzke J. Process for the preparation of 1-aminomethyl-1-cyclohexaneacetic acid. US 5091567, 12 pp. 1992
Bryans J, Morrell A. Novel stereoselective processes for the preparation of gabapentin analogues. WO 9914184, 19 pp. 1999
Author information
Authors and Affiliations
Corresponding author
Additional information
Guest Editors: Robin Bogner, James Drennen, Mansoor Khan, Cynthia Oksanen, and Gintaras Reklaitis
An erratum to this article can be found at http://dx.doi.org/10.1208/s12249-011-9692-0
Rights and permissions
About this article
Cite this article
Zong, Z., Desai, S.D., Kaushal, A.M. et al. The Stabilizing Effect of Moisture on the Solid-State Degradation of Gabapentin. AAPS PharmSciTech 12, 924–931 (2011). https://doi.org/10.1208/s12249-011-9652-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1208/s12249-011-9652-8