Objective: To establish a new high performance liquid chromatography method for the determination of related substances of propranolol hydrochloride,to improve the related substance detection method in the quality standard of propranolol hydrochloride in the 2020 edition of the“ Chinese Pharmacopoeia” (Part Two),and to evaluate drug quality. Methods: A new alkaline chromatography column system was used instead of the mixed ion pair method. CERI L-column3 C18(250 mm×4.6 mm,5 μm) was chosen. The buffer pH and organic phase were optimized and 230 nm wavelength which was more sensitive than that of previous method was used. The new method was validated and used to analyze the impurities and determine the structure of the unknown impurities. Results: This method could not only effectively separate the three known impurities (impurity A,B and C),but also solve the overlapping problem of the α-naphthol peak and propranolol peak in the pharmacopoeia methods. A large unknown impurity found in some samples was confirmed with comprehensive structure and synthesis process analysis. This substance was determined to be the isomer of propranolol hydrochloride (named β-isoform). It was synthetic by-products produced by β-naphthol within the synthetic substrate of propranolol hydrochloride -α-naphthol. This β-isoform could not be detected by the methods currently used in pharmacopoeias from various countries. Conclusion: The improved method is sensitive,specific, simple and accurate. It can effectively investigate the composition and content of related substances of propranolol hydrochloride. It provides data reference for the revision of its quality standards.
ZHANG Shu-dong, WU Ke-chun, ZHANG Zhi-jun, WU Zhao-wei, WANG Lin, SUN Yi, ZHANG Zhe, HU Qin
. Establishment of detection method for related substances of propranolol hydrochloride and study of an unknown impurity β-isomer*[J]. Chinese Journal of Pharmaceutical Analysis, 2021
, 41(9)
: 1519
-1533
.
DOI: 10.16155/j.0254-1793.2021.09.05
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