盐酸左西替利嗪片有关物质的色谱-质谱结构鉴定

目的：采用LC-MS技术对盐酸左西替利嗪片中有关物质进行结构鉴定。方法：采用Welch Xtimate C₁₈色谱柱（250 mm×4.6 mm，5 μm），以甲醇-四氢呋喃-磷酸盐溶液（磷酸二氢钠3.1 g，用水溶解稀释至1 000mL，用磷酸调节pH至2.9）（44.5：5.5：50）为流动相等度洗脱，对盐酸左西替利嗪片中有关物质进行分离；应用Kinetex C₁₈（100 mm×2.1 mm，1.7 μm）色谱柱，以水（含0.05%甲酸）-甲醇（含0.05%甲酸）流动相梯度洗脱，采用色谱-质谱（MSⁿ）技术测定离子准确质量并分析离子特征，结合对照品确证有关物质结构；结合处方分析，推测未知杂质结构，并揭示杂质产生的来源。结果：在所建立的条件下，盐酸左西替利嗪与其有关物质分离良好，检测出10个有关物质，并综合分析、鉴定了有关物质结构，推测其中最大的未知杂质为左西替利嗪与残留乙醇酯化生成的2-[2-[4-[（4-氯苯基）（苯基）甲基]哌嗪-1-基]乙氧基]乙酸乙酯，另2个较大未知杂质为是左西替利嗪的羧基与乳糖不同位置的羟基产生的酯化产物（R）-2-[2-[4-[（4-氯苯基）（苯基）甲基]哌嗪-1-基]乙氧基]乙酸乳糖酯。结论：本研究为盐酸左西替利嗪片的处方研究及制剂工艺提供指导。

Objective: To identify the related substances in levocetirizine hydrochloride tablets by LC-MS technique.Methods: A Welch Xtimate C₁₈ column(250 mm×4.6 mm, 5 μm)was adopted for the separation with a mixture of methanol, tetrahydrofuran and phosphate buffer(3.1 g of monobasic sodium phosphate in water, adjusted with phosphoric acid to a pH of 2.9)(44.5:5.5:50)as mobile phase by isocratic elution. A Kinetex C₁₈(100 mm×2.1 mm, 1.7 μm)column and gradient elution with water(with 0.05% formic acid)and methanol(with 0.05% formic acid)were applied in the LC-MS system. The structures of the related substances were speculated by LC-MS(MSⁿ)for accurate ion mass determination and elucidation, and further verified by spectroscopic analysis and prescription analysis.Results: Levocetirizine hydrochloride and the related substances were well separated under the established conditions. Ten related substances in levocetirizine hydrochloride tablets were characterized, the most abundant unknown impurity was determined as ethyl(R)-2-[2-[4-[(4-chlorophenyl) (phenyl)methyl)piperazin-1-yl)ethoxy)acetate, an esterified product of levocetirizine hydrochloride and ethanol, and the other two abundant unknown impurities were preliminarily determined as lactoseyl(R)-2-[2-[4-[(4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)ethoxy)acetate, esterified products of levocetirizine hydrochloride and lactose.Conclusion: The study provided valuable guiding principles for both formulation research and manufacturing process of levocetirizine hydrochloride tablets.

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