Application of Continuous Wavelet Transform Coupled with Zero-crossing Technique for the Simultaneous Spectrophotometric Determination of Sacubitril and Valsartan in Tablet Dosage Form

Document Type : Original Article


1 Department of Chemistry, Arak Branch, Islamic Azad University, Arak, Iran

2 R&D Department, Tehranchemie Co., Tehran, Iran


A rapid, simple, precise, accurate, and environmentally friendly spectrophotometric method was developed and validated for simultaneous determination of Sacubitril and Valsartan in their combined dosage form, using continuous wavelet transform (CWT) and zero-crossing techniques without using organic solvents and the time-consuming extraction step.Initially, UV spectra of two pure components in water were processed via various mother wavelet families. Then, applying zero-crossing technique, the optimum points were found to obtain appropriate calibration curves for each point. The calibration curves were linear for both Sacubitril and Valsartan. The validation of these methods was investigated by analyzing several synthetic mixtures with known concentrations. Applying one-way analysis of variance (ANOVA) test and Fisher pairwise comparisons, the following were found to yield the best results: Discrete Meyer (dmey) wavelet functions with scaling factor of 61 at 232 nm and Symlet5 (sym5) with 48 at 232 nm for Sacubitril and Meyer (meyr) with 50 at 272 nm, meyr with 59 at 247 nm, Daubechies (db5) with 53 at 237 nm, and sym5 with 59 at 226 nm for Valsartan. The mean recovery values in synthetic mixtures were between 99.09% and 101.16% using the proposed methods, where relative standard deviation (RSD) not more than 1.23% proved to have good precision. The obtained results from the commercial tablets, applying the developed methods, were compared to those yielded by HPLC method by one-way ANOVA test.According to the results, they were in good agreement and showed no significant differences, thereby suggesting successful determination in accordance with green chemistry.


1. McMurray J.J.V., Trueman D., Hancock E., Cowie M.R., Briggs A., Taylor M., Mumby-Croft J., Woodcock F., Lacey M., Haroun R., Deschaseaux C., 2017. Cost-effectiveness of sacubitril/valsartan in the treatment of heart failure with reduced ejection fraction. Heart. 1–7.
2. Minguet J., Sutton G., Ferrero C., Gomez T., Bramlage P., 2015. LCZ696: a new paradigm for the treatment of heart failure?. Expert Opin Pharmacother. 16(3), 435-446.
3. Yandrapalli S., Andries G., Biswas M., Khera S., 2017.  Profile of sacubitril/valsartan in the treatment of heart failure: patient selection and perspectives. Vasc Health Risk Manag. 13, 369–382.
5. Packer M., 2016. Kicking the tyres of a heart failure trial: physician response to the approval of sacubitril / valsartan in the USA. Eur J Heart Fail. 1-9.
6. McMurray J.J.V., Packer M., Desai A. S., Jianjian Gong M.P.H., Lefkowitz. M. P., Rizkala A. R., Rouleau J. L., Shi V.C., Solomon S.D., Swedberg K., Zile M.R., 2014. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 371(11), 993-1004.
7. Kaplinsky E., 2016. Sacubitril/valsartan in heart failure: latest evidence and place in therapy. Ther Adv Chronic Dis. 7(6), 278–290.
8. Langenickel T.H., Tsubouchi C., Ayalasomayajula S., Pal P., Valentin M.A., Hinder M., Jhee S., Gevorkyan H., Rajman I., 2016. The effect of LCZ696 (sacubitril/valsartan) on amyloid-β concentrations in cerebrospinal fluid in healthy subjects. Br J Clin Pharmacol. 00, 1-13.
9. Bavishi C., Messerli F.H., Kadosh B., Ruilope L.M., Kario K., 2015. Role of neprilysin inhibitor combinations in hypertension: insights from hypertension and heart failure trials. Eur Heart J. 36, 1967–1973.
10. U.S. Food & Drug Administration. https://www. (Accessed 5 Sep, 2018).
11. RxList. (Accessed 5 Sep, 2018).
12. Scientific Reports. https : // www. nature. Com /articles /srep27909/ figures/1 (Accessed 5 Oct, 2018).
13. Heydari R., 2008. A New HPLC Method for the simultaneous determination of acetaminophen, phenylephrine, dextromethorphan and chlorpheniramine in pharmaceutical formulations. Anal Lett. 41(6), 965–976.
14. Heydari R., Shamsipur M., Naleini N., 2013. Simultaneous determination of EDTA, sorbic acid, and diclofenac sodium in pharmaceutical preparations using high-performance liquid chromatography. AAPS Pharm Sci Tech. 14 (2), 764-769.
15. Heydari R., Mousavi M., 2016. Simultaneous determination of saccharine, caffeine, salicylic acid and benzoic acid in different matrixes by salt and air-assisted homogeneous liquid-liquid extraction and high-performance liquid chromatography. J Chil Chem Soc. 61(3), 3090-3094.
16. Heydari R., Bastami F., Hosseini M., Alimoradi M., 2017. Simultaneous determination of Tropaeolin O and brilliant blue in food samples after cloud point extraction. Iran Chem Commun. 5, 242-251.
17. Heydari R., Lotfi Z., Ramezani M., 2018. Simultaneous determination of zidovudine and lamivudine in plasma samples using miniaturized homogenous liquid–liquid extraction and high-performance liquid chromatography. J Anal Chem. 73(11), 1105–1110.
18. Patel K.H., Luhar S.V., Narkhede S.B., 2016. Simultaneous estimation of sacubitril and valsartan in synthetic mixture by RP-HPLC method. J Pharm Sci Bioscientific Res. 6(3), 262-269.
19. Patel C.J., Mishra S., Patel M. M., 2017. Simultaneous estimation of sacubitril and valsartan in pharmaceutical dosage form by development and validation of stability indicating chromatographic method. WJPPS. 6(7), 1434-1448.
20. Mishra S., Patel C.J., Patel M.M., 2017. Development and validation of stability indicating chromatographic method for simultaneous estimation of sacubitril and valsartan in pharmaceutical dosage form. Int J App Pharm. 9(5), 1-8.
21. Moussa B.A., Hashem H.M.A., Mahrouse M.A., Mahmoud S.T., 2017. Experimental design approach in HPLC method development: Application for the simultaneous determination of sacubitril and valsartan in presence of their impurities and investigation of degradation kinetics. Chromatographia. 1-18.
22. Naazneen S., Sridevi A., 2017. Development of assay method and forced degradation study of valsartan and sacubitril by RP-HPLC in tablet formulation. Int J App Pharm. 9(1), 9-15.
23. Tabassum B., Rajeswar Dutt. K., Vasanthi R., Alagar Raja. M., VRao K. N., 2017. Simultaneous estimation of valsartan and sacubitril in pure and marketed formulation by using high performance liquid chromatography. IJMCA. 7(2), 93-99.
24. Ahmed M., Satishkumar Shetty A., Ahmed M., Aradhya V.K.C., Kumar S.M.A., Swamy M.S.S., 2017. Stability indicating RP-HPLC method for simultaneous estimation of sacubitril and valsartan in bulk and combined pharmaceutical dosage form. WJPPS. 6(4), 1714-1728.
25. Vaka S., Parthiban P., 2017. New method development and validation for the simultaneous estimation of sacubitril and valsartan in a bulk and pharmaceutical dosage forms. Int J Res. 4(1), 17-24.
26. Jyothi U., Umadevi P., 2018. Stability indicating RP-HPLC method for the simultaneous estimation of Sacubitril and Valsartan in drug product.  J Pharm Sci & Res. 10(9), 2201-2204.
27. Madana Gopal N., Sridhar C., 2017. RP-UPLC method for simultaneous estimation of sacubitril and valsartan in its bulk and tablet dosage form with force degadation studies.  Int J Chemtech Res. 10(4), 279-287.
28. Abou Al Alamein A. M., 2018. Validated eco-friendly chromatographic methods for simultaneous determination of sacubitril and valsartan in spiked human plasma and in pharmaceutical formulation. JAPS. 8(2), 011-017.
29. Attimarad M., Nagaraja S.H., Nair A.B., Aldhubaib B.E., Katharigatta V.N., 2018.   Development of validated RP HPLC method with fluorescence detection for simultaneous quantification of sacubitril and valsartan from rat plasma. J Liq Chromatogr Relat Technol., 1-7.
30. Gu J., Noe A., Chandra P., Al-Fayoumi S., Ligueros-Saylan M., Sarangapani R., Maahs S., Ksander G., Rigel D. F., Jeng A. Y., Lin T. H., Zheng W., Dole W. P., 2010. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-Acting Angiotensin Receptor−Neprilysin Inhibitor (ARNi). J Clin Pharmacol. 50, 401-14.
31. Chunduri R.H.B., Dannana G.S., 2016. Development and validation of a reliable and rapid LC-MS/MS method for simultaneous quantification of sacubitril and valsartan in rat plasma and its application to a pharmacokinetic study. Biomed. Chromatogr. 1-9.
32. Ragab M.A.A., Galal S.M., Korany M.A., Ahmed A.R., 2017. First derivative emission spectrofluorimetric method for the determination of LCZ696, a newly approved FDA supramolecular complex of valsartan and sacubitril in tablets. Luminescence. 1–9.
33. Ahmed M., Shetty A.S., Ahmed M., Aradhya V.K.C., 2017. Development and validation of UV spectrophotometric methods for the simultaneous estimation of sacubitril and valsartan in bulk and pharmaceutical formulations. IJUPBS. 6, 104-114.
34. Eissa M.S., Abou Al Alamein A.M., 2018. Innovative spectrophotometric methods for simultaneous estimation of the novel two-drug combination: sacubitril/valsartan through two manipulation approaches and a comparative statistical study. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 193, 365–374.
35. Attia K.A.M., Nassar M.W.I., El-Olemy A., Ramzy S., 2018. Simultaneous spectrophotometric determination of sacubitril and valsartan in their recently approved pharmaceutical preparation. JAPR. 2(2), 133-141.
36. Leung A.K.M, Chau F.T., Gao J.B., 1998. A review on applications of wavelet transform techniques in chemical analysis: 1989–1997. Chemom Intell Lab Syst. 43, 165–184.
37. Dinc E., Baleanu D., 2003. A zero-crossing technique for the multidetermination of thiamine HCl and pyridoxine HCl in their mixture by using one-dimensional wavelet transform. J Pharm Biomed Anal. 31, 969-978.
38. Dinc E., Özdemir A., Baleanu D., 2005. An application of derivative and continuous wavelet transforms to the overlapping ratio spectra for the quantitative multiresolution of a ternary mixture of paracetamol, acetylsalicylic acid and caffeine in tablets. Talanta. 65, 36–47.
39. Dinc E., Baleanu D., 2007. Continuous wavelet transform and chemometric methods for quantitative resolution of a binary mixture of quinapril and hydrochlorothiazide in tablets. J Braz Chem Soc. 18(5), 962-968.
40. Afkhami A., Madrakian T., Abbasi-Tarighat M., 2008. Simultaneous determination of calcium, magnesium and zinc in different foodstuffs and pharmaceutical samples with continuous wavelet transforms. Food Chem. 109, 660–669.
41. Pektas G., Dinc E., 2009. Combined application of continuous wavelet transform-zero crossing technique in the simultaneous spectrophotometric determination of perindopril and indapamid in tablets. Quim Nova. 32(6), 1416-1421.
42. Sohrabi M.R., Abdolmaleki P., Abdollahzade Esmaeili E., 2010. Simultaneous spectrophotometric determination of cyproterone acetate and ethinyl estradiol in tablets using continuous wavelet and derivative transform. Spectrochim Acta A. 77, 107–111.
43. Mohammadpour K., Sohrabi M. R., Jourabchi A., 2010. Continuous wavelet and derivative transform applied to the overlapping spectra for the quantitative spectrophotometric multi-resolution of triamterene and hydrochlorothiazide in triamterene-H tablets. Talanta. 81, 1821–1825.
44. Sohrabi M.R., Kamali N., Khakpour M., 2011. Simultaneous spectrophotometric determination of metformin hydrochloride and glibenclamide in binary mixtures using combined discrete and continuous wavelet transforms. Anal Sci. 27, 1037-1041.
45. Dinç E., Baleanu D., 2012. Fractional-continuous wavelet transforms and ultra-performance liquid chromatography for the multicomponent analysis of a ternary mixture containing thiamine, pyridoxine, and lidocaine in ampules. J AOAC Int. 95(3), 903-912.
46. Dinç E., Büker E., 2012. A new application of continuous wavelet transform to overlapping chromatograms for the quantitative analysis of amiloride hydrochloride and hydrochlorothiazide in tablets by ultra-performance liquid chromatography.  J AOAC Int. 95(3), 751-756.
47. Shariati-Rad M., Irandoust M., Amini T., Ahmadi F., 2012. Partial least squares and continuous wavelet transformation in simultaneous spectrophotometric determination of amlodipin and atorvastatine. Pharmaceut Anal Acta. 3(8), 1-7.
48. Hoang V.D., Ly D.T.H., Tho N.H., Nguyen H.M.T., 2014, UV Spectrophotometric simultaneous determination of paracetamol and ibuprofen in combined tablets by derivative and wavelet transforms. Sci World J. 1-13.
49. Sohrabi M.R., Tayefeh Zarkesh M., 2014, Spectra resolution for simultaneous spectrophotometric determination of lamivudine and zidovudine components in pharmaceutical formulation of human immunodeficiency virus drug based on using continuous wavelet transform and derivative transform techniques. Talanta. 122, 223–228.
50. Devrim B., Dinc E., Bozkir A., 2014. Fast determination of diphenhydramine hydrochloride in reconstitutable syrups by CWT, PLS and PCR methods. Acta Poloniae Pharmaceutica - Drug Research. 71(5), 721-729.
51. Ashour A., Hegazy M.A., Abdel-Kawy M., Elzeiny M.B., 2015. Simultaneous spectrophotometric determination of overlapping spectra of paracetamol and caffeine in laboratory prepared mixtures and pharmaceutical preparations using continuous wavelet and derivative transform. J Saudi Chem Soc. 19(2), 186–192.
52. Sohrabi M.R., Darabi G., 2016. The application of continuous wavelet transform and least squares support vector machine for the simultaneous quantitative spectrophotometric determination of myricetin, kaempferol and quercetin as flavonoids in pharmaceutical plants. Spectro chim Acta A. 152, 443–52.
53. Dinç E., Üstünda─č Ö., Yüksel Tilkan G., Türkmen B., Özdemir N., 2017. Continuous wavelet transforms methods for the simultaneous determinations and dissolution profiles of valsartan and hydrochlorothiazide in tablets. Braz J Pharm Sci. 53(1), 1-11.
54. Daubechies I., 1992. Ten Lectures on Wavelets Society for Industrial and Applied Mathematics, First ed., Philadelphia.
Volume 9, Issue 4
December 2019
Pages 331-344
  • Receive Date: 29 June 2019
  • Revise Date: 04 December 2019
  • Accept Date: 16 September 2019
  • First Publish Date: 01 December 2019