目的: 建立RP-HPLC法同时测定米氮平的起始物料米氮醇的9个有关物质(杂质1~9)。方法: 采用Apollo C18色谱柱(250 mm×4.6 mm,5 μm),以0.02 mol·L-1磷酸二氢钾溶液-0.1%磷酸(30∶70)为流动相A,甲醇为流动相B,梯度洗脱(0~20 min,90%A→68%A;20~50 min,68%A;50~50.01 min,68%A→90%A;50.01~60 min,90%A),流速为1.0 mL·min-1,柱温为40 ℃,检测波长为210 nm(杂质1、5)和260 nm(杂质2、3、4、6、7、8、9),进样量为30 μL。结果: 米氮醇及9个有关物质实现完全分离,并与其他化合物达到良好的分离;杂质1~9的线性范围分别为0.49~9.81 μg·mL-1(r=0.999 6)、0.46~9.24 μg·mL-1(r=0.999 2)、0.47~9.44 μg·mL-1(r=0.999 7)、0.51~10.11 μg·mL-1(r=0.999 5)、0.46~9.19 μg·mL-1(r=0.999 8)、0.50~10.07 μg·mL-1(r=0.999 7)、0.50~9.91 μg·mL-1(r=0.999 8)、0.50~10.05 μg·mL-1(r=0.999 8)、0.50~10.08 μg·mL-1(r=0.999 7);9个有关物质的平均加样回收率(n=9)分别为99.1%、100.4%、98.8%、98.3%、98.8%、100.0%、100.4%、100.9%、99.2%。检测不同时期生产的9批米氮醇原料,杂质8的含量分别为0.19%、0.18%、0.19%、0.27%、0.23%、0.13%、0.14%、0.12%、0.11%,其他杂质均未检出。结论: 本法专属性好,灵敏度高,准确度高,耐用性好,可用于米氮醇有关物质的质量控制。
Objective: To establish a RP-HPLC method for the simultaneous determination of 9 related substances(impurities 1-9) in mirtazol, the starting material of mirtazapine. Methods: Apollo C18 column(250 mm×4.6 mm, 5 μm) was adopted, the mobile phase consisted of 0.02 mol·L-1 potassium dihydrogen phosphate solution with 0.1% phosphoric acid (30∶70) and methanol with gradient elution(0-20 min, 90%A→68%A; 20-50 min, 68%A; 50-50.01 min, 68%A→90%A; 50.01-60 min, 90%A) at a flow rate of 1.0 mL·min-1. The column temperature was 40 ℃, the detection wavelengths were 210 nm (impurities 1, 5) and 260 nm(impurities 2, 3, 4, 6, 7, 8, 9), and the injection volume was 30 μL. Results: Mirtazol and 9 related substances were completely separated and well separated from other components; the linear ranges of impurities 1-9 were 0.49-9.81 μg·mL-1(r=0.999 6), 0.46-9.24 μg·mL-1(r=0.999 2), 0.47-9.44 μg·mL-1(r=0.999 7), 0.51-10.11 μg·mL-1(r=0.999 5), 0.46-9.19 μg·mL-1(r=0.999 8), 0.50-10.07 μg·mL-1(r=0.999 7), 0.50-9.91 μg·mL-1(r=0.999 8), 0.50-10.05 μg·mL-1(r=0.999 8), 0.50-10.08 μg·mL-1(r=0.999 7), respectively.The average recovery rates(n=9) of 9 related substances were 99.1%, 100.4%, 98.8%, 98.3%, 98.8%, 100.0%, 100.4%, 100.9%, 99.2%, respectively. Detecting 9 batches of mirazol produced in different periods, the contents of impurity 8 were 0.19%, 0.18%, 0.19%, 0.27%, 0.23%, 0.13%, 0.14%, 0.12%, 0.11%, respectively. Other impurities were not detected. Conclusion: This method has good specificity, high sensitivity, high accuracy, and good durability. It can be used for quality control of miridonol-related substances.
[1] 马立强. 米氮平联合重复高频经颅磁刺激治疗抑郁焦虑共病患者的临床疗效观察[J].中国实用医药, 2020, 15(4):126
MA LQ.Observation of the clinical efficacy of mirtazapine combined with repetitive high-frequency transcranial magnetic stimulation in the treatment of patients with comorbid depression and anxiety[J].China Pract Med,2020,15(4):126
[2] 赵丽军. 米氮平治疗老年失眠伴抑郁症的临床效果观察[J].世界睡眠医学杂志, 2019(12):1690
ZHAO LJ. Clinical effect of mirtazapine in the treatment of senile insomnia with depression[J].World J Sleep Med, 2019(12):1690
[3] KUYPER AM, HONIG A. Treatment of post-myocardial infarction depressive disorder[J].Expert Rev Neurother,2008,8(7):1115
[4] 安震. 抗抑郁药物的作用特点与临床应用[J].齐齐哈尔医学院学报, 2008, 29(14):1749
AN Z. The action characteristics and clinical application of antidepressants[J].J Qiqihar Med Coll, 2008,29(14):179
[5] 张红胜. 不同剂量米氮平联合草酸艾司西酞普兰片治疗抑郁伴焦虑的疗效分析[J].心理月刊, 2020, 15(2):5
ZHANGHS. Efficacy of different doses of mirtazapine combined with escitalopram oxalate on depression and anxiety[J].Psychologies, 2020,15(2):5
[6] 高聪聪, 范筱. 米氮平联合匹维溴胺治疗肠易激综合征的效果及对患者抑郁程度的影响[J].临床医学研究与实践, 2020, 5(2):2
GAO CC, FAN X. Effect of mirtazapine combined with pinaverium bromide on irritable bowel syndrome and its influence on the degree of depression of patients[J].Clin Res Pract, 2020,5(2):2
[7] 司天梅, 方贻儒, 李涛,等. 米氮平治疗抑郁障碍的临床使用[J].中国心理卫生杂志, 2014, 28(8):634
SI TM, FANG YR, LI T, et al. Consensus of mirtazapine in treatment of depression[J].Chin Mental Health J, 2014, 28(8):634
[8] DE BOER T. The pharmacologic profile of mirtazapine[J].J Clin Psychiatry,1996,57(Suppl 4):19
[9] 张丽娜. 米氮平与曲唑酮治疗抑郁障碍的疗效与神经递质的关系[D].呼和浩特:内蒙古医科大学,2020
ZHANG LN. Relationship between Efficacy and Neurotransmitters of Mitazapine and Trazodone in the Treatment of Depression[D].Hohhot:Inner Mongolia Medical University,2020
[10] 梁冬冬. 抗抑郁症新药米氮平的合成工艺研究[D].沈阳:沈阳药科大学, 2004
LIANG DD. Study on Synthetic Technology of the New Antiderressant Drug-Mritazapine[D].Shenyang:Shenyang Pharmaceutical University,2004
[11] LAMAZZI C, DREAU A, BUFFERNE C, et al. Microwave-induced by-products in the synthesis of 2-(4-methyl-2-phenylpiperazinyl)pyridine-3-carbonitrile[J].Tetrahedron Lett, 2009, 50(31):5402
[12] EP 10.0. VolⅢ[S].2020:3278
[13] USP 43-NF 38[S].2020:2976
