Journal of Thermal Analysis and Calorimetry

, Volume 136, Issue 4, pp 1701–1709 | Cite as

Thermodynamic study of complexation of Zn(II)/L (L = acetate, indomethacin and diclofenac anions) by isothermal titration calorimetry

  • Norma Rodríguez-Laguna
  • Luis Ignacio Reyes-García
  • Raúl Pacheco-Gómez
  • Raúl Flores
  • Alberto Rojas-Hernández
  • Rodolfo Gómez-BalderasEmail author


In this work, a thermodynamic study of the Zn(II)/L systems (L = acetate, AcO or indomethacin anion, Indo or diclofenac anion, Dic) in ethanolic solution was carried out by isothermal titration calorimetry (ITC). Thermodynamic properties such as enthalpy (∆H), entropy (ΔS), Gibbs energy (ΔG) and formation constant (reported as logβi) associated with the complexation reactions were determined; the stoichiometry of the formed species was also found. Zn(II)/AcO was used as a model system for the complexation of Zn(II) with indomethacin and diclofenac anions, because all of them coordinate through the carboxylate functional group. To determine the thermodynamic properties of each system under study, from the experimental results, a binding model has been devised to calculate the heat Qcalc that is released or absorbed in terms of the molar ratio \(r_{{{\text{L/Zn}}\left( {\text{II}} \right)}}\) in the complexation process between Zn(II) and L. Calculated data (Qcalc) are adjusted to the ITC experimental results (Qexp), by means of MicroCal PEAQ-ITC analysis software to determine the enthalpy and formation constants of the ML j (2−j) formed complexes. Distribution diagrams of the fractions of the M and L species were obtained as a function of the molar ratio to discuss the predominance of the species in the systems as the titration was carried out.


Zn(II)-NSAIDs Isothermal titration calorimetry Thermodynamic formation constants Zn(II)-indomethacin Zn(II)-diclofenac 



Norma Rodríguez-Laguna wants to acknowledge DGAPA-UNAM for the postdoctoral fellowship. Luis I. Reyes-García acknowledges to CONACyT for the PhD scholarship. This research was conducted under grants PAPIIT DGAPA-UNAM IN218118 and FESC-UNAM PIAPI 1846.

Compliance with ethical standards

Conflict of interests

The authors declare that there is no conflict of interests regarding the publication of this paper.


  1. 1.
    Dimiza F, Perdih F, Tangoulis V, Turel I, Kessissoglou DP, Psomas G. Interaction of copper(II) with the non-steroidal anti-inflammatory drugs naproxen and diclofenac: synthesis, structure, DNA- and albumin-binding. J Inorg Biochem. 2011;105:476–89.CrossRefGoogle Scholar
  2. 2.
    Gouda AA, El-Sayed MIK, Amin AS, El Sheikh R. Spectrophotometrci and spectrofluorometric methods for the determination of non-steroidal anti-inflammatory drugs: a review. Arab J Chem. 2013;6:145–63.CrossRefGoogle Scholar
  3. 3.
    Williams PAM, Molinuevo MS, Okulik N, Jubert AH, Etcheverry S. Synthesis, characterization and biological properties of vanadyl(IV) complexes of diclofenac and Indomethacin: an experimental and theoretical study. Appl Organomet Chem. 2005;19:711–8.CrossRefGoogle Scholar
  4. 4.
    Puranik R, Bao S, Bonin AM, Kaur R, Weder JE, Casbolt L, Hambley TW, Lay PA, Barter PJ, Rye K-A. Novel class of copper(II)- and zinc(II)-bound non-steroidal anti-inflammatory drugs that inhibits acute inflammation in vivo. Cell Biosci. 2016;6:1–7.CrossRefGoogle Scholar
  5. 5.
    Agotegaray M, Gumilar F, Boeris M, Toso R, Minetti A. Enhanced analgesic properties and reduced ulcerogenic effect of a mononuclear copper(II) complex with fenoprofen in comparison to the parent drug: promising insights in the treatment of chronic inflammatory diseases. Biomed Res Int. 2014;2014:505987.Google Scholar
  6. 6.
    Fountoulaki S, Perdih F, Turel I, Kessissoglou DP, Psomas G. Non-steroidal anti-inflammatory drug diflunisal interacting with Cu(II). Structure and biological features. J Inorg Biochem. 2011;105:1645–55.CrossRefGoogle Scholar
  7. 7.
    Chang-Ying Y, Yi L, Jun-Cheng Z, Dan Z. Inhibitory effect of copper complex of indomethacin on bacteria studied by microcalorimetry. Biol Trace Elem Res. 2008;122:82–8.CrossRefGoogle Scholar
  8. 8.
    Fernández-Madrid F. Copper and zinc in inflammatory and degenerative diseases. In: Rainsford KD, Milanino R, Sorenson JRJ, Velo GP, editors. Chapter: Zinc and copper in the treatment of rheumatic diseases. Berlin: Springer; 1998. p. 125–37.Google Scholar
  9. 9.
    Al-Masoudi NA, Jafar NNA, Abbas LJ, Baqir SJ, Pannecouque C. Synthesis and anti-HIV activity of new benzimidazole, benzothiazole and carbohydrazide derivatives of the anti-inflammatory drug indomethacin. Z Naturforsch. 2011;66:953–60.CrossRefGoogle Scholar
  10. 10.
    Banti CN, Hadjikakou SK. Non-steroidal anti-inflammatory drugs (NSAIDs) in metal complexes and their effect at the cellular level. Eur J Inorg Chem. 2016;3048–3071:2016.Google Scholar
  11. 11.
    Moya-Hernandez R, Gómez-Balderas R, Mederos A, Domínguez S, Ramírez-Silva T, Rojas-Hernández A. Complex formation of the anti-inflamatory drugs tenoxicam and piroxicam with Fe(III) in methanol and acetone. J Coord Chem. 2009;62:40–51.CrossRefGoogle Scholar
  12. 12.
    Rodríguez-Laguna N, Reyes-García LI, Moya-Hernández R, Rojas-Hernández A, Gómez-Balderas R. Chemical speciation of the system Cu(II)-indomethacin in ethanol and water by UV–Vis spectrophotometry. J Chem. 2016;2016:1–12.CrossRefGoogle Scholar
  13. 13.
    Ramírez-Silva MT, Guzmán-Hernández DS, Galano A, Rojas-Hernández A, Corona-Avendaño S, Romero-Romo M, Palomar-Pardavé M. Spectro-electrochemical and DFT study of tenoxicam metabolites formed by electrochemical oxidation. Electrochim Acta. 2013;111:314–23.CrossRefGoogle Scholar
  14. 14.
    Verastegui B, Palomar-Pardavé M, Rojas-Hernández A, Corona Avendaño S, Romero-Romo M, Ramírez-Silva MT. Spectrophotometric quantification of the thermodynamic constants of the complexes formed by dopamine and Cu(II) in aqueous media. Spectrochim Acta Part A Mol Biomol Spectrosc. 2015;143:187–91.CrossRefGoogle Scholar
  15. 15.
    Dillon CT, Hambley TW, Kennedy BJ, Lay PA, Weder JE, Zhou Q. Copper and zinc complexes as antiinflammatory drugs. Sydney: Centre for Heavy Metals Research, School of Chemistry, University of Sydney; 2006.Google Scholar
  16. 16.
    Castro MA, Rusjan M, Vega D, Peña O, Weyhermüller T, Cukiernik FD, Slep LD. An unexpected carboxylato-bridged- only hexanuclear copper compound. Innorganica Chimica Acta. 2011;374:499–505.CrossRefGoogle Scholar
  17. 17.
    Weder JE, Dillon CT, Hambley TW, Kennedy BJ, Lay PA, Biffin JR, Regtop HL, Davies NM. Copper complexes of non-steroidal anti-inflammatory drugs: an opportunity yet to be realized. Coord Chem Rev. 2002;232:95–126.CrossRefGoogle Scholar
  18. 18.
    Moya-Hernandez MR, Mederos A, Domínguez S, Orlamdini A, Ghilardi CA, Cecconi F, González-Vergara E, Rojas-Hernández A. Speciation study of the anti-inflammatory drugs tenoxicam (Htenox) with Cu(II): X-ray crystal structure of [Cu(Tenox)2(Py)2]EtOH. J Inorg Biochem. 2003;95:131–40.CrossRefGoogle Scholar
  19. 19.
    Ràfols C, Rosés M, Bosch E. A comparison between different approaches to estimate the aqueous pKa values of several non-steroidal anti-inflammatory drugs. Anal Chim Acta. 1997;338:127–34.CrossRefGoogle Scholar
  20. 20.
    Aguilar-Lira GY, Álvarez Romero GA, Rojas-Hernández A, Páez-Hernández ME, Rodríguez-Ávila JA, Romero-Romo MA. New insights on naproxen quantification using voltammetry and graphite electrodes: development of an optimized and competitive methodology. ECS Trans. 2015;19:79–89.CrossRefGoogle Scholar
  21. 21.
    Guzmán-Hernández DS, Ramírez-Silva MT, Palomar-Pardavé M, Corona-Avendaño S, Annia Galano A, Rojas-Hernández M Romero-Romo. Electrochemical characterization of tenoxicam using a bare carbon paste electrode under stagnant and forced convection conditions. Electrochim Acta. 2012;59:150–5.CrossRefGoogle Scholar
  22. 22.
    Rodríguez-Barrientos D, Rojas-Hernández A, Gutiérrez A, Moya-Hernández R, Gómez-Balderas R, Ramírez-Silva MT. Determination of pKa values of tenoxicam from 1H NMR chemical shifts and of oxicams from electrophoretic mobilities (CZE) with the aid of programs SQUAD and HYPNMR. Talanta. 2009;80:754–62.CrossRefGoogle Scholar
  23. 23.
    Mamett LJ, Kalgutkar AS. Cyclooxygenase 2 inhibitors: discovery, selectivity and the future. Trends Pharmacol Sci. 1999;20:465–9.CrossRefGoogle Scholar
  24. 24.
    Barnett J, Chow J, Ives D, Chiou M, Mackenzie R, Osen E, Nguyen B, Tsing S, Bach C, Freire J, Chan H, Sigal E. Purification, characterization and selective inhibition of human prostaglandin G/H synthase 1 and 2 expressed in the baculovirus system. Biochem Biophys Acta. 1994;1209:130–9.Google Scholar
  25. 25.
    Jain AK. Solubilization of indomethacin using hydrotropes for aqueous injection. Eur J Pharm Biopharm. 2008;68:701–14.CrossRefGoogle Scholar
  26. 26.
    Kovala-Demertzi D. Transition metal complexes of diclofenac with potentially interesting anti-inflammatory activity. J Inorg Biochem. 2000;79:153–7.CrossRefGoogle Scholar
  27. 27.
    Moser P, Sallmann A, Wiesenberg I. Synthesis and quantitative structure-activity relationships of diclofenac analogs. J Med Chem. 1990;33:2358–68.CrossRefGoogle Scholar
  28. 28.
    Ali HA, Omar SN, Darawsheh MD, Fares H. Synthesis, characterization and antimicrobial activity of zinc(II) ibuprofen complexes with nitrogen-based ligands. J Coord Chem. 2016;69:1110–22.CrossRefGoogle Scholar
  29. 29.
    Morgant G, Viossat B, Daran J-C, Roch-Arveiller M, Giroud J-P, Dung N-H, Sorenson JRJ. Crystal structure at 180 °K of bis-3,5-diisopropylsalicylatobisdimethylsulfoxidozinc(II) and the inhibition of seizures and polymorphonuclear leukocyte chemiluminescence. J Inorg Biochem. 1998;70:137–43.CrossRefGoogle Scholar
  30. 30.
    Ramadan S, Hambley TW, Kennedy BJ, Lay PA. NMR spectroscopic characterization of copper(II) and zinc(II) complexes of indomethacin. Inorg Chem. 2004;43:2943–6.CrossRefGoogle Scholar
  31. 31.
    Zhou Q, Hambley TW, Kennedy BJ, Lay PA. XAFS studies of anti-inflammatory dinuclear and mononuclear Zn(II) complexes of indomethacin. Inorg Chem. 2003;42:8557–66.CrossRefGoogle Scholar
  32. 32.
    Bucci R, Magrì AD, Magrì AL, Napoli A. Spectroscopic characteristics and thermal properties of divalent metal complexes of diclofenac. Polyhedron. 2000;19:2515–20.CrossRefGoogle Scholar
  33. 33.
    Reiss A, Cioatera N, Chifiriuc MC, et al. New biologically active mixed-ligand Co(II) and Ni(II) complexes of enrofloxacin. Synthesis, spectral study and thermal behavior. J Therm Anal Calorim. 2018. Scholar
  34. 34.
    Fuliaş A, Vlase G, Ledeţi I, et al. Ketoprofen–cysteine equimolar salt synthesis, thermal analysis, PXRD and FTIR spectroscopy investigation. J Therm Anal Calorim. 2015;121:1087. Scholar
  35. 35.
    Kobelnik M, Cassimiro DL, Ribeiro CA, et al. Preparation of the Ca–diclofenac complex in solid state. Study of the thermal behavior of the dehydration, transition phase and decomposition. J Therm Anal Calorim. 2010;102:1167. Scholar
  36. 36.
    Rojas-Hernández A, Rodríguez-Laguna N, Ramírez-Silva MT, Moya-Hernández R. Chapter 13: Distribution diagrams and graphical methods to determine or to use the stoichiometric coefficients of acid-base and complexation reactions. In: Innocenti A, editor. Stoichiometry and research: the importance of quantity in biomedicine. Rijeka: InTech; 2012. p. 287–310.Google Scholar
  37. 37.
    Velázquez-Campoy A, Ohtaka H, Nezami A, Muzammil S, Freire E. Isothermal titration calorimetry. Curr Protoc Cell Biol. 2004;17.8:17.8.1–8.24.Google Scholar
  38. 38.
    Kulkarni S, Prakash S, Upmanyu N, Tonpay SD. Solubility enhancement of water insoluble drug for ophthalmic formulation. Int J Drug Deliv. 2011;3:141–8.CrossRefGoogle Scholar
  39. 39.
    Microcal PEAQ-ITC Analysis Software, 2014 Malvern Instruments Ltd. Enigma Business Park, Grovewood Road, Malvern, Worcestershire WR14 1XZ, United Kingdom. MAN0576-01-EN-00, 2015.Google Scholar
  40. 40.
    Giordano TH, Drummond SE. The potentiometric determination of stability constants for zinc acetate complexes in aqueous solution to 295 °C. Geochim Cosmochim Acta. 1991;55:2401–15.CrossRefGoogle Scholar

Copyright information

© Akadémiai Kiadó, Budapest, Hungary 2018

Authors and Affiliations

  1. 1.Laboratorio de Fisicoquímica Analítica, Unidad de Investigación Multidisciplinaria, Facultad de Estudios Superiores-CuautitlánUniversidad Nacional Autónoma de MéxicoCuautitlán IzcalliMexico
  2. 2.Malvern Panalytical LtdMalvernUK
  3. 3.Laboratorio R-105/R-107, Área de Química Analítica, División de Ciencias Básicas e Ingeniería, Departamento de QuímicaUniversidad Autónoma Metropolitana-IztapalapaMexicoMexico

Personalised recommendations