Carbocisteine is a commonly used expectorant drug. Currently, the reported detection methods for carbocisteine mainly include the electrochemical method, potassium bromated titration, kineticmethod, spectrometry, chromatography, HPLC-FLD precolumn derivation determination, HPLC-MS, etc. The advantages and disadvantages of each method were compared and analyzed in this paper, and it is found that HPLC was more suitable for the quality analysis of carbocisteine, which could serve as a reference for upgrading standard of carbocisteine content determination.

1.Wahl O, Holzgrabe U. Impurity profiling of carbocisteine by HPLC-CAD, qNMR and UV/vis spectroscopy[J]. J Pharm Biomed Anal, 2014, 95: 1-10. DOI: 10.1016/j.jpba.2014.02.012.

2.杨庆玺, 倪庆, 姬光东, 等. 羧甲司坦口服溶液联合莫西沙星治疗慢性支气管炎急性发作的临床研究[J]. 现代药物与临床, 2022, 37(9): 2035-2039. [Yang QX, Ni Q, Ji GD, et al. Clinical study of carbocysteine oral solution combined with moxifloxacin intreatment of acute attack of chronic bronchitis[J]. Drugs & Clinic, 2022, 37(9): 2035-2039.] DOI: 10.7501/j.issn.1674-5515.2022.09.023.

3.张惠燕. 羧甲司坦联合布地奈德治疗哮喘的疗效及对血清炎症因子的影响[J]. 中国药师, 2017, 20(1): 106-108. [Zhang HY. Clinical efficacy and effects on serum inflammatory factors of carbocisteine combined with budesonidein the treatment of asthma[J]. China Pharmacist, 2017, 20(1): 106-108.] DOI: 10.3969/j.issn.1008-049X.2017.01.029.

4.马瑞娟, 周凤, 田豆豆, 等. 黏液溶解剂羧甲司坦对急性呼吸道炎症的抑制作用[J]. 宁夏医科大学学报, 2022, 44(12): 1219-1222. [Ma RJ, Zhou F, Tian DD, et al.Inhibitory effect of mucolytic agent carbocisteine on acute respiratory inflammation[J]. Journal of Ningxia Medical University, 2022, 44(12): 1219-1222.] DOI: 10.16050/j.cnki.issn1674-6309.2022.12.007.

5.Hooper C, Calvert J. The role for S-carboxymethylcysteine (carbocisteine) in the management of chronic obstructive pulmonary disease[J]. Int J Chron Obstruct Pulmon Dis, 2008, 3(4): 659-669. https://pubmed.ncbi.nlm.nih.gov/19281081/.

6.杨晓雨, 陈东宇, 王红心, 等. 1990—2019年中国疾病负担趋势分析[J]. 医学新知, 2022, 32(5): 321-332. [Yang XY, Chen DY, Wang HX, et al. Trend analysis of disease burden in China from 1990 to 2019[J]. Yixue Xinzhi Zazhi, 2022, 32(5): 321-332.] DOI: 10.12173/j.issn.1004-5511.202201016.

7.杜秋凤, 蒋运兰, 李滔, 等. 慢性阻塞性肺疾病患者出院后30天内再入院风险预测模型的系统评价[J]. 中国循证医学杂志, 2024, 24(1): 49-55. [Du QF, Jiang YL, Li T, et al. Risk prediction models for readmission within 30 days after discharge in patients with chronic obstructive pulmonary disease: a systematic review[J]. Chinese Journal of Evidence-Based Medicine, 2024, 24(1): 49-55.] DOI: 10.7507/1672-2531.202306041.

8.李庭, 冯睿智, 彭丽桥, 等. 益活化痰方治疗慢性阻塞性肺疾病稳定期气虚血瘀痰阻证的临床研究 [J]. 华西医学, 2024, 39(4): 1-9. [Li T, Feng RZ, Peng LQ, et al. Efficacy and safety of Yi Huo Hua Tan granule in the treatment of stable chronicobstructive pulmonary disease (syndrome of qi deficiency with phlegm and bloodstagnation) [J]. West China Medical Journal, 2024, 39(4): 1-9.] DOI: 10.7507/1002-0179.202302084.

9.陈志博, 俞宁宁, 林圣乐. 吸入糖皮质激素对慢性阻塞性肺疾病合并社区获得性肺炎预后影响的回顾性研究[J]. 中国药师, 2023, 26(11): 279-285. [Chen ZB, Yu NN, Lin SL. Retrospective study of effect of inhaled corticosteroids on prognosis ofchronic obstructive pulmonary disease associated with community-acquiredpneumonia[J]. China Pharmacist, 2023, 26(11): 279-285.] DOI: 10.12173/j.issn.1008-049X.202311051.

10.Zheng JP, Kang J, Huang SG, et al. Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study[J]. Lancet, 2008, 371(9629): 2013-2018. DOI: 10.1016/S0140-6736(08)60869-7.

11.Pace E, CerveriI, LacedoniaD, et al. Clinical efficacy of carbocysteine in COPD: beyond the mucolytic action[J]. Pharmaceutics, 2022, 14(6): 1261. DOI: 10.3390/pharmaceutics14061261.

12.EP 11.0[S]. 2022: 2205.

13.中国药典2020年版. 二部[S]. 2020: 1761-1763.

14.JP XVIII[S]. 2021: 626-627.

15.赵冰璐, 张克良. 电流滴定法测定羧甲司坦及片剂的含量[J]. 黑龙江医药, 2000, 13(1): 10. [Zhao BL, Zhang KL. Determination of carboxymethylestan and tablets by amperometric titration[J]. Heilongjiang Medicine Journal,2000, 13(1): 10.] DOI: 10.3969/j.issn.1006-2882. 2000.01.009.

16.Kostara A, Tsogas GZ, Vlessidis AG, et al. Generic assay of sulfur-containing compounds based on kinetics inhibition of gold nanoparticle photochemical growth[J]. ACS Omega, 2018, 3(12): 16831-16838. DOI: 10.1021/acsomega.8b02804.

17.白秀峰, 主编. 生物药物分析[M]. 北京: 中国医药科技出版社, 2002: 274.

18.Rele RV, Patil SS. Ultra-violet spectrophotometric method for validation of carbocisteine from bulk drug and pharmaceutical formulation[J]. IntJPharma Bio Sci, 2013, 4(2): 847-851. https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=dd0eec2e0143388838686d472af2473e4430e6c1.

19.Walash M, El-Brashy A, Metwally MES, et al. Spectrophotometric and kinetic determination of some sulphur containing drugs in bulk and drug formulations[J]. Bull Korean Chem Soc, 2004, 25(4): 517-524. DOI: 10.5012/bkcs.2004.25.4.517.

20.Walash M, El-Brashy A, Metwally MES, et al. Spectrophotometric determination of penicillamine and carbocisteine based on formation of metal complexes[J]. Farmaco, 2004, 59(6): 493-505. DOI: 10.1016/j.farmac. 2003.11.016.

21.Srivastava A, Sharma V, Singh VK, et al. A simple and sensitive inhibitory kinetic method for the carbocisteinedetermination[J]. J Mex Chem Soc, 2022, 66(1): 57-69. DOI: http://dx.doi.org/10.29356/jmcs.v66i1.1654.

22.Walash M, EI-Brashy A, Metwally MES, et al. Fluorimetric determination of carbocisteine and ethionamide in drug formulation[J]. Acta Chimica Slovenica, 2004, 51(6): 283-291. http://dlib.si/details/URN:NBN:SI:DOC-B8K9H4X9.

23.Taha EA, Hassan NY, Aal FA, et al. Fluorimetric determination of some sulfur containing compounds through complex formation with terbium (Tb+3) and uranium (U+3)[J]. J Fluorescence, 2007, 17(3): 293-300. DOI: 10.1007/s10895-007-0172-6.

24.Megoulas NC, Koupparis MA. Ion-chromatographic determination of carbocisteine in pharmaceuticals based on non-suppressed conductimetric detection[J]. J Chromatogr A, 2004, 1026(1-2): 167-174. DOI: 10.1016/j.chroma.2003.10.111.

25.霍柱健, 吴凌涛, 林泽鹏, 等. 离子色谱法测定羧甲司坦中的氯乙酸[J]. 山东化工, 2016, 45(13): 87-89. [Huo ZJ, Wu LT, Lin ZP, et al. Determination of monochloroacetic acid in carbocistein by ion chromatography[J]. Chemical Industry, 2016, 45(13): 87-89.] DOI: 10.3969/j.issn.1008-021X.2016.13.029.

26.周远华, 方海顺, 苏广海, 等. 高效液相色谱法测定三种羧甲司坦制剂的含量[J]. 中国药品标准, 2017, 18(4): 264-270. [Zhou YH, Fang HS, Su GH, et al. Determine the content of carbocisteinepreparations by HPLC[J]. Drug Standards of China, 2017, 18(4): 264-270.] DOI: CNKI:SUN:YPBZ.0.2017-04-004.

27.颜元, 刘傲, 杨成, 等. 羧甲司坦微囊含量测定方法的研究[J]. 贵州医药, 2023, 47(5): 678-681. [Yan Y, Liu A, Yang C, et al. Study on content determination of carbocisteine microcapsules[J]. Guizhou Medical Journal, 2023, 47(5): 678-681.] DOI: 10.3969/j.issn.1000-744X. 2023.05.002.

28.陈秀琳, 许永鹏. 高效液相色谱法测定羧甲司坦颗粒中羧甲司坦的含量[J]. 海峡药学, 2002, 14(4): 43-44. [Chen XL, Xu YP. Determination of carbocisteine in carbocisteine granules by HPLC[J]. Strait Pharmaceutical Journal, 2002, 14(4): 43-44.] DOI: 10.3969/j.issn.1006-3765.2002.04.024.

29.李锐, 骆海春, 路雪芳. 高效液相色谱法测定羧甲司坦片的含量[J]. 中国药师, 2006, 9(6): 505-507. [Li R, Luo HC, Lu XF. Determination of carbocisteinetabletes by HPLC[J]. China Pharmacist, 2006, 9(6): 505-507.] DOI: 10.3969/j.issn.1008-049X.2006.06.010.

30.Argekar AP, Raj SV, Kapadia SU. Simultaneous determination of cephalexin and carbocisteine from capsules by reverse phase high performance liquid chromatography (RP-HPLC)[J]. Anal Lett, 1997, 30(4): 821-831. DOI: 10.1080/00032719708006427.

31.Fanigliulo A, Filippis PD, Curcuruto O, et al. Development and validation of a stability indicating method for S-carboxymethyl-L-cysteine and related degradation products in oral syrup formulation[J]. J Pharm Biomed Anal, 2015, 115: 39-47. DOI: 10.1016/j.jpba.2015.06.031.

32.余琼娥, 叶放. HPLC测定羧甲司坦及其制剂有关物质[J]. 药物分析杂志, 2006, 26(2): 260-262. [Yu QE, Ye F. HPLC determination of the related substances in carbocisteine and its preparation[J]. Chinese Journal of Pharmaceutical Analysis, 2006, 26(2): 260-262.] DOI: CNKI:SUN:YWFX.0.2006-02-035.

33.谭少云, 叶放, 陈溪. HPLC法测定羧甲司坦无糖口服溶液中羧甲司坦的含量及有关物质[J]. 广东药 学院学报, 2009, 25(1): 52-55. [Tan SY, Ye F, Chen X. Assay of carbocysteine and its related substances in carbocysteine sugar-free oral solution[J]. Journal of Guangdong Pharmaceutical College, 2009, 25(1): 52-55.]DOI: 10.16809/j.cnki.1006-8783.2009.01.017.

34.李可鹏, 胡梅, 晁若冰. 羧甲司坦中杂质的分离和鉴定[J]. 药物分析杂志, 2014, 34(4): 707-710. [Li KP, Hu M, Chao RB. Separation and identification of impurities in carbocisteine[J]. Chinese Journal of Pharmaceutical Analysis, 2014, 34(4): 707-710.] DOI: CNKI:SUN:YWFX. 0.2014-04-028.

35.赵雪梅, 黄秀明. 反相离子对色谱法测定羧甲司坦的含量及有关物质[J]. 中国药品标准, 2007, 8(2): 60-63. [Zhao XM, Huang XM. Determination of the content and the related substances of carbocisteine by reversed ion-pairphase HPLC[J]. Drug Standards of China, 2007, 8(2): 60-63.] DOI: 10.3969/j.issn.1009-3656.2007.02.021.

36.Vispute AC, Patil VA, Patil DA. RP-HPLC method for simultaneous estimation of amoxicillin and carbocisteine in dosage forms[J]. Der Pharmacia Lettre, 2013, 5(1): 327-333. https://www.researchgate.net/publication/289397048_RP-HPLC_method_for_simultaneous_estimation_of_amoxicillin_and_carbocisteine_in_dosage_forms.

37.Mankar SS, Younas M. Development of analytical method for simultaneous estimation of amoxicillin and carbocisteine in solid dosage form by RP-HPLC[J]. Int J Phar Sci Res, 2020, 11(4): 1674-1682. DOI: 10.13040/IJPSR.0975-8232.11(4).1674-1682.

38.Orlovic D, Radulovic D, Vujic Z. Determination of S-carboxymethyl-L-cysteine, methylparaben and their degradation products in syruppreparations[J]. Chromatographia, 2004, 60(5-6): 329-333. DOI: 10.1365/s10337-004-0371-0.

39.陈秀琳, 郑小力. HPLC-ELSD法测定羧甲司坦颗粒中羧甲司坦的含量[J]. 中国药品标准, 2006, 7(3): 62-64. [Chen XL, Zheng XL. Determination of carbocisteine in carbocisteine granules by HPLC-ELSD[J]. Drug Standards of China, 2006, 7(3): 62-64.] DOI: 10.3969/j.issn.1009-3656.2006.03.032.

40.EI-Hay SSA, Sheikh RE, Ali M, et al. Aneco-friendly HPLC method for concurrent determination of carbocisteine, guaifenesin, and oxomemazine in their combined formulations[J]. Talanta Open, 2023, 8(5): 1002331-1002338. DOI: 10.1016/j.talo.2023.100233.

41.杨婷婷, 袁峰泉, 金荣庆, 等. 绿色分析技术及其在药物分析中的应用研究进展[J]. 药物分析杂志, 2015, 35(12): 2070-2075. [Yang TT, Yuan FQ, Jin RQ, et al. Advances in green analytical techniques and theirapplications in pharmaceutical analysis[J].Chinese Journal of Pharmaceutical Analysis, 2015, 35(12): 2070-2075.] DOI: 10.16155/j.0254-1793.2015.02.

42.Rashed NS, Zayed S, Abdelazeem A, et al. Development and validation of a green HPLC method for the analysis of clorsulon, albendazole, triclabendazole and ivermectin using monolithic column: assessment of the greenness of the proposed method[J]. Microchem J, 2020, 157(Pta1): 1050691-10506910. DOI: 10.1016/j.microc.2020.105069.

43.王秀中, 王清清, 宋海峰, 等. 衍生化技术在氨基酸分析中的应用进展[J]. 药物分析杂志, 2010, 30(6): 1162-1166. [Wang XZ, Wang QQ, Song HF, et al. Application progress of derivatization technology in amino acids analysis[J]. Chinese Journal of Pharmaceutical Analysis, 2010, 30(6): 1162-1166.] DOI: CNKI:SUN:YWFX.0.2010- 06-064.

44.Brockmller J, Staffeldt B, Roots I. Evaluation of proposed sulphoxidation pathways of carbocysteine in man by HPLC quantification[J]. Eur J Clin Pharmacol, 1991, 40(4): 387-392. DOI: 10.1007/BF00265849.

45.毕惠嫦, 钟国平, 汤铮, 等. 高效液相色谱法测定人血浆中羧甲司坦浓度[J]. 中国医院药学杂志, 2005, 25(9): 828-830. [Bi HC, Zhong GP, Tang Z, et al. Determination of carbocisteine in human plasma by HPLC[J]. Chinese Journal of Hospital Pharmacy, 2005, 25(9): 828-830.] DOI: 10.3321/j.issn:1001-5213.2005.09.016.

46.王晓娟, 王荣, 邓冲, 等. 柱前衍生HPLC-FLD法测定人血浆中羧甲司坦[J]. 药物分析杂志, 2008, 28(3): 372-375. [Wang XJ, Wang R, Deng C, et al. HPLC-FLD precolumn derivation determination of carbocisteine in human plasma[J]. Chinese Journal of Pharmaceutical Analysis, 2008, 28(3): 372-375.] DOI: 10.16155/j.0254-1793.2008.03.028.

47.Anacardio R, Cantalini MG, De Angelis F, et al. Quantification of S-carboxymethyl-(R)-cysteine in human plasma by high-performance ion-exchange liquid chromatography/atmospheric pressure ionization mass spectrometry[J]. J Mass Spectrom, 1997, 32(4): 388-394. DOI: 10.1002/(SICI)1096-9888(199704)32:4<388::AID-JMS462>3.0.CO;2-8.

48.刘靖, 秦崇臻, 李慧, 等. HPLC-MS/MS测定人血浆中羧甲司坦的浓度及其生物等效性研究[J]. 中南药学, 2012, 10(2): 114-117. [Liu J, Qin CZ, Li H, et al. HPLC-MS/MS method for the determination of carbocisteine in human plasma and its bioequivalence[J]. Central South Pharmacy, 2012, 10(2): 114-117.] DOI: 10.3969/j.issn.1672-2981.2012.02.011.

49.Chen XY, Zhong DF, Han Y, et al. Determination of carbocysteine in human plasma by liquid chromatography/tandem mass spectrometry employing precolumn derivatization[J]. Rapid Commun Mass Spectrom, 2003, 17(3): 192-196. DOI: 10.1002/rcm.894.

50.Bi HC, Zhao LZ, Zhong GP, et al. High-throughput determination of carbocysteine in human plasma by liquid chromatography/tandem mass spectrometry: application to a bioequivalence study of two formulations in healthy volunteers[J]. Rapid Commun Mass Spectrom, 2006, 20(7): 1153-1160. DOI: 10.1002/rcm.2422.

51.李婵, 傅强, 杨建婷, 等. HPLC-MS法测定人血浆中羧甲司坦浓度[J]. 西安交通大学学报(医学版), 2009, 30(4): 518-520. [Li C, Fu Q, Yang JT, et al. Determination of carbocisteine concentration in human plasma by HPLC-MS[J]. Journal of Xi'an Jiaotong University(Medical Sciences), 2009, 30(4): 518-520.] DOI: CNKI:SUN: XAYX.0.2009-04-034.