The use of capillary electrophoresis in the simultaneous determination of fixed-dose combination drugs for cardiovascular diseases

Document Type : Review Article


1 University of Medicine, Pharmacy, Science and Technology George Emil Palade Targu Mureș

2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Medicine, Pharmacy, Science and Technology of Targu Mureș

3 Department of Cell biology and Microbiology, Faculty of Pharmacy, University of Medicine, Pharmacy, Science and Technology of Targu Mureș


Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide and are usually multifactorial medical conditions. Usually cardiovascular patients must follow a complicated treatment scheme, containing several drugs. Fixed dose combinations (FDCs) are pharmaceutical formulations containing two or more active ingredients in a one pill. FDCs can add multiple benefits to the treatment of CVDs including increased patient compliance, elimination of some side effects and the simultaneous blockage of multiple pathogenic links. The great prevelance of FDCs in modern therapy brings the necessity of developing new analytical methods for the simultaneous analysis of their components. Capillary electrophoresis (CE) was shown to be as a complementary and attractive alternative to the more frequently used chromatographic methods. CE advantages relate to the high efficiency of separation, rapid method developement, short analysis time and relatively low operational costs. The most frequently used CE techniques in the analysis of FDCs are capilllary zone electrophoresis (CZE) for ionized analytes and micellar electrokinetic chromatography (MEKC) for neutral ones. The current article reviews application of CE in the analysis of FDCs used in the treatment of CVDs.


1. de Cates AN, Farr MR, Wright N, Jarvis MC, Rees K, Ebrahim S, Huffman MD. Fixed-dose combination therapy for the prevention of cardiovascular disease. Cochrane Database Syst Rev. 2014 Apr 16;4(4):CD009868. doi: 10.1002/14651858.CD009868.
2. Huffman MD, de Cates AN, Ebrahim S. Fixed-dose combination therapy (polypill) for the prevention of cardiovascular disease. JAMA. 2014 Nov 19;312(19):2030-1. doi: 10.1001/jama.2014.13616.
3. Sanz G, Fuster V. Fixed-dose combination therapy and secondary cardiovascular prevention: rationale, selection of drugs and target population. Nat Clin Pract Cardiovasc Med. 2009 Feb;6(2):101-10. doi: 10.1038/ncpcardio1419.
4. Gupta P, Patel P, Štrauch B, Lai FY, Akbarov A, Gulsin GS, et al. Biochemical Screening for Nonadherence Is Associated With Blood Pressure Reduction and Improvement in Adherence. Hypertension. 2017 Nov;70(5):1042-1048. doi: 10.1161/HYPERTENSIONAHA.117.09631.
5. Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med. 2007 Aug;120(8):713-9. doi: 10.1016/j.amjmed.2006.08.033
6. Du LP, Cheng ZW, Zhang YX, Li Y, Mei D. The impact of fixed-dose combination versus free-equivalent combination therapies on adherence for hypertension: a meta-analysis. J Clin Hypertens (Greenwich). 2018 May;20(5):902-907. doi: 10.1111/jch.13272.
7. Webb AJ, Rothwell PM. Effect of dose and combination of antihypertensives on interindividual blood pressure variability: a systematic review. Stroke. 2011 Oct;42(10):2860-5. doi: 10.1161/STROKEAHA.110.611566.
8. Benjamin IJ, Kreutz R, Olsen MH, Schutte AE, Lopez-Jaramillo P, Frieden TR, et al. Fixed-dose combination antihypertensive medications. Lancet. 2019 Aug 24;394(10199):637-638. doi: 10.1016/S0140-6736(19)31629-0.
9. Hughes AD. One pill, four questions: what we still need to know about reducing cardiovascular risk with combination therapy. Cochrane Database Syst Rev. 2014;(4):ED000079. Published 2014 Apr 16. doi:10.1002/14651858.ED000079
10. Chrysant SG. Using fixed-dose combination therapies to achieve blood pressure goals. Clin Drug Investig. 2008;28(11):713-34. doi: 10.2165/00044011-200828110-00005
11. Suntornsuk L. Recent advances of capillary electrophoresis in pharmaceutical analysis. Anal Bioanal Chem. 2010 Sep;398(1):29-52. doi: 10.1007/s00216-010-3741-5.
12. Toraño JS, Ramautar R, de Jong G. Advances of capillary electrophoresis in the life sciences. J Chromat B. 2019;1118-1119:116-36. doi: 10.1016/j.jchromb.2019.04.020
13. Altria KD. Overview of capillary electrophoresis and capillary electrochromatography. J Chromat A. 1999;856(1-2):443-63. doi: 10.1016/S0021-9673(99)00830-4
14. Gordon M, Huang X, Pentoney S, Zare R. Capillary Electrophoresis. Science. 1988;242(4876):224-228. Retrieved October 10, 2020, from
15. Maguregui MI, Jimenez RM, Alonso RM. Simultaneous determination of the β-blocker atenolol and several complementary antihypertensive agents in pharmaceutical formulations and urine by capillary zone electrophoresis. J Chrom Sci. 1998;36(10):516-522. doi: 10.1093/chromsci/36.10.516
16. Hillaert S, De Grauwe K, Van den Bossche W. Simultaneous determination of hydrochlorothiazide and several inhibitors of angiotensin-converting enzyme by capillary electrophoresis. J Chromatogr A. 2001 Jul 27;924(1-2):439-49. doi: 10.1016/s0021-9673(01)00714-2.
17. Quaglia MG, Donati E, Carlucci G, Mazzeo P, Fanali S. Determination of losartan and hydrochlorothiazide in tablets by CE and CEC. J Pharm Biomed Anal. 2002 Aug 1;29(6):981-7. doi: 10.1016/s0731-7085(02)00138-3.
18. Hillaert S, Van den Bossche W. Simultaneous determination of hydrochlorothiazide and several angiotensin-II-receptor antagonists by capillary electrophoresis. J Pharm Biomed Anal. 2003;31(2):329-339. doi: 10.1016/S0731-7085(02)00643-X
19. Balesteros MR, Faria AF, de Oliveira MA.
Determination of losartan associated with chlorthalidone or hydrochlorothiazide in capsules by capillary zone electrophoresis. J Braz Chem Soc. 2007;18(3):554-8. doi: 10.1590/S0103-50532007000300009
20. Çelebier M., Altınöz S. Development of a capillary zone electrophoresis method for the indirect determination of olmesartan medoxomil and determination of hydrochlorothiazide in synthetic tablets. Hacettepe Univ Eczacı Fak Derg. 2007;2:119-130.
21. Stăcescu Ș., Hancu G., Gagyi L., Soare R.M., Kelemen H. Simultaneous determination of hydrochlorothiazide and telmisartan from pharmaceutical preparations using capillary electrophoresis. Studia UBB Chemia. 2017;52(2):189-98. doi: 10.24193/subbchem.2017.2.14
22. Ion V, Imre S, Cârje AG, Muntean DL. Analytical performance of an hplc and cze methods for the analysis and separation of perindopril erbumine and indapamide. Acta Med Marisiensis. 2016;61(4):324-327. doi: 10.1515/amma-2015-0073
23. Al Azzam K, Elbashir AA, Elbashir MA, Saad B, Abdul Hamid S. Simultaneous determination of atenolol and chlorthalidone in pharmaceutical preparations by capillary-zone electrophoresis. Anal Lett. 2009;42(10):1458-1470. doi: 10.1080/00032710902961065
24. Al Azzam KM, Saad B, Aboul‐Enein HY. Simultaneous determination of atenolol and amiloride in pharmaceutical preparations by capillary zone electrophoresis with capacitively coupled contactless conductivity detection. Biomed Chrom. 2010;24(9):948-953. doi: 10.1002/bmc.1390
25. Al Azzam KM, Saad B, Aboul‐Enein
HY. Simultaneous determination of atenolol, chlorthalidone and amiloride in pharmaceutical preparations by capillary zone electrophoresis with ultraviolet detection. Biomed Chrom. 2010;24(9):977-981. doi: 10.1002/bmc.1395
26. Alnajjar AO, Idris AM, Attimarad MV, Aldughaish AM, Elgorashe RE. Capillary electrophoresis assay method for metoprolol and hydrochlorothiazide in their combined dosage form with multivariate optimization. J Chromatogr Sci. 2013 Jan;51(1):92-7. doi: 10.1093/chromsci/bms107.
27. Alnajjar AO. Validation of a capillary electrophoresis method for the simultaneous determination of amlodipine besylate and valsartan in pharmaceuticals and human plasma. J AOAC Int. 2011 Mar-Apr;94(2):498-502. PMID: 21563683.
28. Inglot TW, Gumieniczek A, Komsta Ł, Związek R. Densitometry, video-scanning and
capillary electrophoresis for determination of valsartan and amlodipine in a combined dosage form: A comparative study. Acta Chromatogr. 2013;25(1):47-58. doi: 10.1556/AChrom.25.2013.1.2
29. Modroiu A, Hancu G, Vlad RA, Stăcescu Ș, Soare R, Kelemen H. Simultaneous
determination of amlodipine and telmisartan from pharmaceutical products by way of capillary electrophoresis. Curr Issues Pharm Med Sci. 2016;29(1):42-46. doi: 10.1515/cipms-2016-0010
30. Hefnawy MM, Sultan M, Al-Johar H. Development of capillary electrophoresis technique for simultaneous measurement of amlodipine and atorvastatin from their combination drug formulations. J Liq Chromatogr Relat Technol. 2009;32(20):2923-2942. doi: 10.1080/10826070903320681
31. Alnajjar AO. Simultaneous determination of amlodipine and atorvastatin in tablet formulations and plasma using capillary electrophoresis. LC GC Europe. 2012;3:130-38.
32. Mircia E, Balaci T, Hancu G, Ion V,
Cârje A. Simultaneous determination of amlodipine and atorvastatin by capillary electrophoresis from fixed pharmaceutical formulations. Farmacia. 2016;64(3):398-402.
33. Salim MM, Ebeid WM, El-Enany N, Belal F, Walash M, Patonay G. Simultaneous determination of aliskiren hemifumarate, amlodipine besylate, and hydrochlorothiazide in their triple mixture dosage form by capillary zone electrophoresis. J Sep Sci. 2014 May;37(9-10):1206-13. doi: 10.1002/jssc.201301140.
34. Attimarad M, Nagaraja SH, Al-Dhubaib BE, Nair AB, Venugopala KN. Capillary Electrophoresis: MEKC assay method for simultaneous determination of olmesartan medoxomil, amlodipine besylate and hydrochlorothiazide in tablets. Indian J Pharm Educ Res. 2016;50(2):188-195. doi: 10.5530/ijper.50.2.35
35. Ebeid W, Salim M, Elkady E, Elzahr A, El-Bagary R, Patonay G. Simultaneous determination of valsartan, amlodipine besylate and hydrochlorothiazide using capillary zone electrophoresis (CZE). Pharmazie. 2015 Jun;70(6):368-73. PMID: 26189296.
36. Ahmed HM, Belal TS, Shaalan RA, El Yazbi FA, Elonsy SM. Validated capillary zone electrophoretic method for simultaneous analysis of benazepril in combination with amlodipine besylate and hydrochlorothiazide. Acta Chromatogr. 2020;32(4):219-227.