Identification of a Novel Impurity in Promethazine Hydrochloride Drug Substance and Tablets Using LC‐MS and NMR

ABSTRACT Promethazine hydrochloride is a phenothiazine derivative and is used for the treatment of antihistamine, antipsychotic, antiemetic, analgesic, anticholinergic, and sedative. During the routine analysis of promethazine hydrochloride, an unknown broad peak appeared using the related substances method indicated in the US Pharmacopeia. The separation method was optimized, and an unknown peak at a level of 0.11% was detected. Further study showed that the impurity could be detected in both USP reference standard and tablet samples, with the levels of 0.01% and 0.11%, respectively. In order to identify and characterize the impurity, high performance liquid chromatography‐tandem mass spectrometry technology was conducted to propose the chemical structure. 1D and 2D NMR were used to confirm the chemical structure of the unknown impurity as 1‐(10 H ‐[3,10′‐biphenothiazin]‐10‐yl)‐ N , N ‐dimethylpropan‐2‐amine. The formation of the impurity during the synthesis route was illustrated. The current study provided an optimized method for the quality control of promethazine hydrochloride drug substance and dosage forms.