College of Pharmacy, University of Iowa, Iowa City, Iowa 52242, USA.
J Pharm Sci. 2012 Jun;101(6):2123-33. doi: 10.1002/jps.23115. Epub 2012 Mar 14.
Gabapentin degrades directly to gabapentin-lactam (gaba-L) in the solid state. The objective of this study was to formulate a drug degradation model that accounted for the environmental storage conditions and mechanical stress (prior to storage) on lactamization kinetics. The effects of mechanical stress on drug degradation kinetics were determined by milling gabapentin in a FRITSCH Planetary Micro Mill for 0 and 60 min. The resultant gabapentin powder was stored at 40 °C-60 °C and 5%-30% relative humidity. The rate of gaba-L formation was measured by high-performance liquid chromatography. An irreversible two-step autocatalytic reaction scheme was fit using nonlinear regression methods. The resultant kinetic model was used to predict the time-dependent concentration of degradant of gabapentin tablets prepared under various exemplary manufacturing conditions, thereby demonstrating the ability of the model to link manufacturing variation and chemical stability in solid-state gabapentin formulations.
在固态下，加巴喷丁直接降解为加巴喷丁内酰胺（gaba-L）。本研究的目的是建立一个药物降解模型，该模型考虑了环境储存条件和机械应力（储存前）对开环动力学的影响。通过在 FRITSCH 行星式微磨机中研磨加巴喷丁 0 和 60 分钟来确定机械应力对药物降解动力学的影响。所得加巴喷丁粉末在 40°C-60°C 和 5%-30%相对湿度下储存。通过高效液相色谱法测量 gaba-L 的形成速率。使用非线性回归方法拟合不可逆的两步自催化反应方案。所得动力学模型用于预测在各种示例制造条件下制备的加巴喷丁片剂的时变降解物浓度，从而证明了该模型能够将制造变化与固态加巴喷丁制剂中的化学稳定性联系起来。
