School of Pharmacy
Compaction, Excipients, gabapentin, Kinetic model, phyico-chemical properties, Solid-state
Gabapentin is used in the treatment of seizures and neuropathic pain. Gabapentin undergoes intra-molecular cyclization to form a ÃŽÂ³-lactam. The product lactam is twenty times more toxic than gabapentin, causing seizures in animal models. The United States Pharmacopeia (USP) limits the content of lactam in gabapentin formulations to 0.4% w/w. A number of patents have been issued for solid dosage forms formulated to stabilize gabapentin. Despite these efforts, factors contributing to gabapentinÃ¢â‚¬â„¢s poor stability in the solid-state have not been explored completely.
It was hypothesized, that physicochemical properties of the excipients and compaction pressure will accelerate the solid-state degradation of gabapentin, increasing the kinetic rate constant for lactam formation. To test the hypotheses, binary mixtures and compacts of gabapentin with different excipients were prepared and stored under accelerated study conditions. The concentration of lactam and gabapentin was measured using a validated analytical method. A concentration dependent catalytic effect by the excipients was determined by mixing different concentrations of the excipient with gabapentin. The effect of excipient particle size was determined by mixing different size fractions of the excipient with gabapentin.
Significant degradation of unprocessed gabapentin in the presence of excipients strongly suggested a catalytic role of the excipients on gabapentinÃ¢â‚¬â„¢s degradation. The existing model was expanded to account for the observed catalytic effect of excipients. A relationship was developed between the rate constant for lactam formation and physical properties of the excipients (such as particle size, morphology, molecular weight, molecular cross sectional area and specific surface area). Along with the catalytic effect of the excipients, compaction pressure and powder properties of the excipients such as moisture content, particle size and yield pressure appeared to be other potential contributing factors affecting gabapentinÃ¢â‚¬â„¢s degradation.
Nevrekar, A. (2015). Development of a Kinetic Model to Investigate the Effect of Compositional Variation and a Processing Condition on the Solid-State Degradation of Gabapentin (Doctoral dissertation, Duquesne University). Retrieved from https://dsc.duq.edu/etd/1515