Effect of glycine/citric acid on the dissolution stability of hard gelatin capsules.

Gelatin capsule crosslinking is a well-known phenomenon that results in reduced dissolution of capsule products with the passage of time and/or under accelerated stability conditions. These studies describe one means of preventing capsule crosslinking by incorporating glycine and citric acid into a triamterene/hydrochlorothiazide 37.5/25 mg capsule formulation (triam/HCTZ). Triam/HCTZ without glycine and citric acid showed extensive capsule crosslinking and then failed the USP dissolution specification after a 4-week accelerated (40 degrees C/85% relative humidity [RH]) stability study. Triam/HCTZ containing glycine alone showed some improvement in the dissolution stability but did not prevent gelatin crosslinking. This formulation also failed dissolution specifications after a 4-week accelerated stability study. The same results were obtained when only citric acid was incorporated into the triam/HCTZ. However when glycine and citric acid were incorporated together into the triam/HCTZ, crosslinking was completely prevented. Dissolution profiles remained the same throughout 12-week accelerated stability studies, with little or no drop in the dissolution values throughout the test period. The above results were confirmed with follow-up studies using gemfibrozil and piroxicam as model drugs. Disintegration times for gemfibrozil and piroxicam capsule formulations without glycine and citric acid increased dramatically with observed pellicle formation, but there was little or no change in the disintegration time of the model drugs formulated with glycine and citric acid. The results of these studies demonstrated that when glycine and citric acid are present in some gelatin capsule formulations, pellicle formation or crosslinking of the capsule gelatin is prevented.