目的: 建立硫酸吗啡片中有关物质的HPLC检测方法。方法: 采用Symmetry C18色谱柱(150 mm×4.6 mm,5 μm),以庚烷磺酸钠溶液(取庚烷磺酸钠1.01g,加水1 000 mL溶解,用磷酸调节pH至2.6)为流动相A,甲醇为流动相B,梯度洗脱,流速1.5 mL·min-1,柱温35 ℃,检测波长230 nm,进样量20 μL。结果: 硫酸吗啡与各杂质以及各杂质间均能达到很好分离。硫酸吗啡质量浓度在2.026~2 532 μg·mL-1范围内线性关系良好(r=0.999 9);杂质A、B、C、D、E、F质量浓度分别在0.195~5.847、0.305~17.080、0.154~6.172、0.198~5.929、0.473~6.626、0.420~6.294 μg·mL-1范围内线性关系良好,相关系数分别为0.999 8、0.999 9、0.999 8、0.999 8、0.999 8、0.999 9。硫酸吗啡检测限为0.068 μg·mL-1,杂质A、B、C、D、E、F检测限分别为0.059、0.092、0.047、0.060、0.143、0.127 μg·mL-1;硫酸吗啡定量限为0.224 μg·mL-1,杂质A、B、C、D、E、F定量限分别为0.195、0.305、0.154、0.198、0.473、0.420 μg·mL-1。3批样品共检出6个主要杂质,其中包括杂质A、B、D、E、F和1个未知杂质,均未检出杂质C,其他杂质均符合相应限度规定。结论: 本法可准确检测硫酸吗啡片中杂质A、B、C、D、E、F。
Objective: To establish an HPLC method for the detection of related substances in morphine sulfate tablets. Methods: Symmetry C18(150 mm×4.6 mm, 5 μm) chromatographic column was adopted. Sodium heptane sulfonate solution(1.01 g of sodium heptane sulfonate was dissolved in 1 000 mL of water, and the pH was adjusted to 2.6 with phosphoric acid.) was used as mobile phase A, and methanol was used as mobile phase B.Using gradient elution, the flow rate was 1.5 mL·min-1, the column temperature was 35 ℃, the detection wavelength was 230 nm, and injection volume was 20 μL. Results: Morphine sulfate could be well separated from the impurities, and the impurities could also be separated well. Morphine sulfate had a good linear relationship in the range of 2.026-2 532 μg·mL-1(r=0.999 9). The mass concentrations of impurities A, B, C, D, E, and F were within the range of 0.195-5.847,0.305-17.080, 0.154-6.172, 0.198-5.929, 0.473-6.626, and 0.420-6.294 μg·mL-1, respectively. The linear relationship was good, and the correlation coefficients were 0.999 8, 0.999 9, 0.999 8, 0.999 8, 0.999 8, 0.999 9, respectively. The detection limit of morphine sulfate was 0.068 μg·mL-1, and the detection limits of impurities A, B, C, D, E, and F were 0.059, 0.092, 0.047, 0.060, 0.143, 0.127 μg·mL-1. Morphine sulfate quantification limit was 0.224 μg·mL-1, and the detection limits of impurities A, B, C, D, E, F were 0.195, 0.305, 0.154, 0.198, 0.473, 0.420 μg·mL-1, respectively. Six major impurities were detected in the three batches of samples, including impurities A, B, D, E, F and an unknown impurity, but no impurity C was detected. Other impurities were conformed to the corresponding limits. Conclusion: This method can determine impurities A, B, C, D, E, F in morphine sulfate tablets.
[1] 汤洋. 吗啡耐受和痛敏的μ受体机制:伤害性感受器μ受体的阻断可预防耐受而不影响吗啡镇痛[J].中国疼痛医学杂志, 2018, 24(8):576
YANG Y. μ-receptor mechanisms of morphine tolerance and pain sensitivity:block of nociceptor μ-receptors prevents tolerance without affecting morphine analgesia[J].Chin J Pain Med, 2018, 24(8):576
[2] 王天学, 张敏娟, 魏文芝, 等. 盐酸吗啡片溶出度测定方法的改进[J].西北药学杂志, 2018, 33(6):789
WANG TX, ZHANG MJ, WEI WZ, et al. Improvement of dissolution method for the dissolution of morphine hydrochloride tablets[J].Northwest Pharm J, 2018, 33(6):789
[3] 张博, 孙莉. 吗啡耐受机制的研究进展[J].北京医学, 2020, 42(3):239
ZHANG B, SUN L. Research progress on the mechanism of morphine tolerance[J].Beijing Med J, 2020, 42(3):239
[4] 侯炳军, 刘健. 吗啡镇痛机制的研究进展[J].临沂医学专科学校学报, 2003, 25(5):356
HOU BJ, LIU J. Research progress of morphine analgesia mechanism[J].J Linyi Med Coll, 2003, 25(5):356
[5] 田丽. 探究吗啡与咪达唑仑联合对急危重症患者ICU内镇痛镇静的效果[J].影像研究与医学应用, 2017, 1(12):206
TIAN L. To investigate the effect of morphine combined with midazolam on analgesia and sedation in ICU of acute and critical patients[J].J Imag Res Med Appl, 2017, 1(12):206
[6] 刘敬东, 徐迎军. 小剂量吗啡联合咪达唑仑镇静治疗重症手足口病的疗效观察[J].中国医刊, 2018, 53(11):1296
LIU JD, XU YJ. Efficacy of low dose morphine combined with midazolam sedation in the treatment of severe hand, foot and mouth disease[J].China J Med, 2018, 53(11):1296
[7] 孙永兴, 熊军, 王惠军. 盐酸氢吗啡酮复合咪达唑仑镇痛镇静在成人眼底手术中的应用[J].中国医药导刊, 2015, 17(3):274
SUN YX, XIONG J, WANG HJ. Analgesia and sadition of hydromorphone combined midazolum in adult retinal surgery[J].China J Med Guide, 2015, 17(3):274
[8] 卢海燕. 右美托咪啶复合盐酸氢吗啡酮对颈丛阻滞麻醉下甲状腺手术患者的镇痛及镇静效果的影响[J].临床医学, 2016, 36(5):77
LU HY. Effect of dexmedetomidine combined with hydromorphone hydrochloride on analgesia and sedative effect of thyroid surgery patients under cervical plexus block anesthesia[J].Clin Med, 2016, 36(5):77
[9] 梁晓南. 芬太尼致呼吸抑制的可能机制研究[D].北京:军事科学院, 2019
LIANG XN. The Possible Mechanism of Respiratory Depression Induced by Fentanyl[D].Beijing:Miltary Science, 2019
[10] WALSH SL, PRESTON KL, STITZERML, et al. Clinical pharmacology of buprenorphine:ceiling effects at highdoses[J].Clin Pharmacol Ther, 1994, 55(5):569
[11] CARLEZON WA JR, BÉGUIN C, KNOLL AT, et al. Kappa-opioid ligands in the study and treatment of mood disorders[J].Pharmacol Ther, 2009, 123(3):334
[12] 陈碧. 盐酸氢吗啡酮对阿片类药物耐受的癌痛患者爆发痛治疗的临床疗效及安全性研究[D].杭州:杭州师范大学, 2019
CHEN B. A Prospective Randomized Comparative Study to Evaluate the Efficacy and Safety of Hydromorphone in Opioid-Tolerance Cancer Patients with Breakthrough Pain[D].Hangzhou:Hangzhou Normal University, 2019
[13] 杨园, 李苗, 王姗姗, 等. 盐酸西替利嗪片有关物质分析[J].药物分析杂志, 2019, 39(12):2136
YANG Y, LI M, WANG SS, et al. Analysis of related substances in cetirizine hydrochloride tablets[J].Chin J Pharm Anal, 2019, 39(12):2136
[14] 中华人民共和国药典2020年版. 二部[S].2020:1573
ChP 2020. Vol Ⅱ [S].2020:1573
[15] WS1-(X-012)-99国家食品药品监督管理局药品标准[S].1999
WS1-(X-012)-99 The State Food and Drug Administration Drug Standard[S].1999
[16] BP 2020. VolⅡ[S].2020
[17] 王夕静, 常春, 温秀红, 等. HPLC法测定盐酸莫西沙星的有关物质[J].药物分析杂志, 2020, 40(11):2048
WANG XJ, CHANG C, WEN XH, et al. Related substances analysis for moxifloxacin hydrochloride by HPLC[J].Chin J Pharm Anal, 2020, 40(11):2048
[18] 黄诺哲, 黄莹, 严全鸿. HPLC法测定拉莫三嗪中的有关物质[J].药物分析杂志, 2020, 40(3):495
HUANG NZ, HUANG Y, YAN QH. Determination of related substances of lamotrigine by HPLC[J].Chin J Pharm Anal, 2020, 40(3):495
[19] 杨浩天, 宋浩静, 吴茵, 等. HPLC法测定塞来昔布原料药有关物质[J].药物分析杂志, 2019, 39(1):164
YANG HT, SONG HJ, WU Y, et al. Determination of related substances in celecoxib raw meterial by HPLC[J].Chin J Pharm Anal, 2019, 39(1):164
[20] 陈忠兰, 吴先富, 王瑾, 等. 克霉唑有关物质检查色谱条件的优化[J].药物分析杂志, 2019, 39(9):1694
CHEN ZL, WU XF, WANG J, et al. Optimization of the chromatographic conditions for detecting related substances in clotrimazole[J].Chin J Pharm Anal, 2019, 39(9):1694
