Generic Tolbutamide Tablet Dissolution: Intralot and Interlot Variation

Dissolution profiles for 62 lots of tolbutamide tablets from six manufacturers have been characterized using the USP paddle-stirrer apparatus. Results of paddle-stirrer dissolution for percent drug dissolved at 10, 20, and 30min correlated well (r2 = 0.7444) with results from the USP rotating-basket test for 39 lots of tolbutamide. Interlot and intralot variability in tolbutamide dissolution was highly dependent on the manufacturer. For one product, the intralot range (for six paddle-stirred tablets) of percent drug dissolved after 30min was 50–68% while the maximum interlot range for mean dissolution was 58–104%. One lot failed to meet both the rotating-basket and the paddle-stirrer dissolution specifications. Tablet response to aging at 60, 75, and 98% relative humidity over time was also highly manufacturer specific. The innovator's product repeatedly dissolved well when fresh or aged at all humidities. Dissolution from some generic tablets was dramatically depressed by humidity aging, even after only 3 d. Pretreatment of tablets with simulated gastric fluid modified the dissolution profile of one poorly dissolving lot of tablets. Results indicate that manufacturing quality control is highly variable among tolbutamide tablets.