Development and validation of the analytical methods for determination of bromhexine hydrochloride and related impurities in novel orodispersible tablets

Bromhexine hydrochloride (BRX) is widely applied as an active pharmaceutical ingredient of oral solutions and tablets for the treatment of the infections of the respiratory tract. However, fulfillment of the present regulations, required for the registration process of BRX, might constitute a challenge, due to the occurrence of (3RS)-6,8-dibromo-3-cyclohexyl-3-methyl-1,2,3,4-tetrahydroquinazolin-3-ium, specified as impurity E by European Pharmacopeia. To overcome this issue, a novel BRX orodispersible tablets (ODT) with improved chemical stability were developed that contain low level of impurity E. Herein the analytical methods, elaborated for the determination of BRX and the related impurities in this product are presented. Stability of the product was tested at accelerated (ACC), intermediate (INT) and long-term (LT) conditions for ICH zones II and III. The degradant E was the most common impurity detected. In the samples stored in INT and LT conditions only a slight increase in the impurities and a slight drop in the assay of the BRX was observed, however the results did not exceed the pre-established acceptance criteria. In the samples stored at ACC conditions, an increase of the known impurities, including degradant E, degradant B and N-oxide, was noted. Noteworthily, even after three years of the product’s shelf-life, the level of the degradant E is still below 0.2 % which corresponds to the ICH identification threshold for the BRX related impurities.