Dissolution instability of encapsulated marketed tablets

Abstract

For blinding purposes, 20 mg potency marketed tablets with some lactose monohydrate were encapsulated in size # 0 blue opaque capsule shells. After prolonged room temperature storage in HDPE bottles containing cotton and heat activated film seal, some of the capsule lots showed slower dissolution. No loss in potency was observed in these lots. When the contents of the capsules exhibiting the slower dissolution were transferred into fresh capsule shells, the original dissolution rate was observed. However, when aged tablet and fresh lactose monohydrate were transferred into the aged capsule shells, slower dissolution was observed. These observations indicated that the changes occurring in the capsule shells, rather than the capsule contents, were responsible for the decrease in dissolution. When the slow-dissolving capsules and ‘as is’ tablets were analyzed by HPLC, a peak corresponding to butylated hydroxytoluene (BHT) was observed. This BHT was probably an impurity in butylated hydroxyanisole (BHA), which was used in the marketed tablet formulation as an antioxidant. The amount of BHT detected in the encapsulated tablet formulation was significantly lower than the amount detected in ‘as is’ marketed tablets. BHT can degrade in the presence of oxygen and moisture to form 2,6-di-tert-butyl-4-hydroxy-benzaldehyde as the main degradant product. It is hypothesized that this aldehyde product cross linked the gelatin of the capsule shell resulting in the observed decrease in the dissolution of the encapsulated product. On the other hand, the encapsulated lot showing no decrease in dissolution showed comparatively less BHT, and the amount of BHT detected in capsules and ‘as is’ tablets were not significantly different.