Ambroxol hydrochloride (AMB) and bromhexine hydrochloride (BRO) are classic expectorants and bronchosecretolytic pharmaceuticals. In 2022, both AMB and BRO were recommended by medical emergency department of China to alleviate cough and expectoration for symptoms caused by COVID-19. The reaction characteristics and mechanism of AMB/BRO with chlorine disinfectant in the disinfection process were investigated in this study. The reaction of chlorine with AMB/BRO were well described by a second-order kinetics model, first-order in both AMB/BRO and chlorine. The second order rate reaction constant of AMB and BRO with chlorine at pH 7.0 were 1.15 × 10 2 M −1 s −1 and 2.03 × 10 2 M −1 s −1 , respectively. During chlorination, a new class of aromatic nitrogenous disinfection by-products (DBPs) including 2-chloro-4, 6-dibromoaniline and 2, 4, 6-tribromoaniline were identified as the intermediate aromatic DBPs by gas chromatography-mass spectrometry. The effect of chlorine dosage, pH, and contact time on the formation of 2-chloro-4, 6-dibromoaniline and 2, 4, 6-tribromoaniline were evaluated. In addition, it was found that bromine in AMB/BRO were vital bromine source to greatly promote the formation of classic brominated DBPs, with the highest Br-THMs yields of 23.8% and 37.8%, respectively. This study inspired that bromine in brominated organic compounds may be an important bromine source of brominated DBPs.
Min Zhou,Wei Wu,Hong Pu,Feng Chen,Chaofan Yi,Yuande Long
A long-term stability study using high performance liquid chromatography (HPLC) revealed an unidentified impurity in the bromhexine hydrochloride injection, which was employed as a mucolytic agent . Investigations into stress degradation and elemental impurities revealed one of the elemental impurities Fe 3+ in this injection as the primary generator of these impurities. This impurity, named N-carboxymethyl bromhexine, was a product formed during drug–excipient interaction between bromhexine and tartaric acid with Fe 3+ . The structure of the impurity was identified through ultra-high-performance liquid chromatography with diode array detector (UHPLC-DAD), liquid chromatograph mass spectrometer (LC-MS). Further, the formation mechanism of the impurity was discussed. Overall, this study elucidates the cause, origin, and mechanism of an unknown impurity in bromhexine hydrochloride injection, providing a basis for quality control for bromhexine hydrochloride injections and drug products containing both amine and tartaric acid.
危险品化学品经营许可证（带存储）