Monatshefte für Chemie - Chemical Monthly

, Volume 146, Issue 1, pp 99–109 | Cite as

Cocrystals of quercetin: synthesis, characterization, and screening of biological activity

  • Miroslav Veverka
  • Tibor Dubaj
  • Ján Gallovič
  • Vladimír Jorík
  • Eva Veverková
  • Martina Danihelová
  • Peter Šimon
Original Paper


Cocrystallization of quercetin with 22 cocrystal formers, i.e. phenolic acids, proline, urea, N-acetylcytosine, carnitine, dacarbazine, diflunisal, kojic acid, lactamide, baclofen, pyrazole, edaravone, salicylamide, O-acetylsalicylamide, 2-imidazolidinone, allopurinol, dipyridamole, 5-sulfosalicylic acid, and 4-sulfobenzoic acid resulted in cocrystals with various stoichiometric ratios. The cocrystals were characterized by FT-IR, DSC, and XRPD. Some of them were non-hygroscopic and stable to thermal stress. The cocrystals quercetin:pyrazole (1:1), quercetin:imidazolidinone (1:1), and quercetin:baclofen (1:2) were found to be stable at various relative humidity conditions at 20–40 °C for up to 3 months. The in vitro antioxidant activity, cytotoxicity, and serine protease inhibitory activity were tested. The best inhibitory activity to pathophysiological proteases was observed for cocrystals with N-acetylcytosine, carnitine, and kojic acid; these cocrystals were the most potent inhibitors of thrombin. About two times better cytotoxic activity to human cervical cancer cells (HeLa) and human colon cancer cells (Caco-2) in comparison with quercetin itself was observed for quercetin:kojic acid (2:1).

Graphical abstract


Solid phase synthesis Drug research Nutraceutical Cytotoxicity Serine protease inhibitory activity Antioxidant activity 



This investigation was supported by the Slovak Research and Development Agency, Grant No. APVV-121-2009 and The Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic for the Structural Funds of EU ITMS 26240220040 (M. Veverka, J. Gallovič, E. Švajdlenka).

Supplementary material

706_2014_1314_MOESM1_ESM.doc (1.4 mb)
Supplementary material 1 (DOC 1412 kb)


  1. 1.
    Boots AW, Haenen GRMM, Bast A (2008) Eur J Pharmacol 585:325CrossRefGoogle Scholar
  2. 2.
    Kleemann R, Verschuren L, Morrison M, Zadelaar S, van Erk MJ, Wielinga PY, Kooistra T (2011) Atherosclerosis 218:44CrossRefGoogle Scholar
  3. 3.
    Russo GL, Russo M, Spagnuolo C, Tedesco I, Bilotto S, Iannitti R, Palumbo R (2014) Quercetin: a pleiotropic kinase inhibitor against cancer. In: Zappia V, Panico S, Russo GL, Budillon A, Della Ragione F (eds) Advances in nutrition and cancer, vol 159. Springer, BerlinCrossRefGoogle Scholar
  4. 4.
    Zandi K, Teoh BT, Sam SS, Wong PF, Mustafa MR, AbuBakar S (2011) Virol J 8:560CrossRefGoogle Scholar
  5. 5.
    Moon H, Choi HH, Lee JY, Moon HJ, Sim SS, Kim CJ (2008) Arch Pharm Res 31:771CrossRefGoogle Scholar
  6. 6.
    Wright B, Spencer JPE, Lovegrove JA, Gibbins JM (2013) Cardiovasc Res 97:13CrossRefGoogle Scholar
  7. 7.
    Wang Y, Zhang ZZ, Wu Y, Ke JJ, He XH, Wang YL (2013) Braz J Med Biol Res 46:861CrossRefGoogle Scholar
  8. 8.
    Harborne JB, Williams CA (2000) Phytochemistry 55:481CrossRefGoogle Scholar
  9. 9.
    Materska M (2008) Pol J Food Nutr Sci 58:407Google Scholar
  10. 10.
    Graefe EU, Wittig J, Mueller S, Riethling AK, Uehleke B, Drewelow B, Pforte H, Jacobasch G, Derendorf H, Veit M (2001) J Clin Pharmacol 41:492CrossRefGoogle Scholar
  11. 11.
    Williamson G, Manach C (2005) Am J Clin Nutr 81:243SGoogle Scholar
  12. 12.
    Biasutto E, Marotta E, Garbisa S, Zoratti M, Paradisi C (2010) Molecules 15:6570CrossRefGoogle Scholar
  13. 13.
    Razmara SR, Daneshfar A, Sahraei R (2010) J Chem Eng Data 55:3934CrossRefGoogle Scholar
  14. 14.
    Srinivas K, King JW, Howard LR, Monrad JK (2010) J Food Eng 100:208CrossRefGoogle Scholar
  15. 15.
    Harborne JB (1994) The flavonoids—advances in research since 1986. Chapman & Hall/CRC, LondonGoogle Scholar
  16. 16.
    Perrier E, Mariotte AM, Boumendjel A, Bresson-Rival D (2001) Flavonoide esters and their use notably in cosmetics. US Patent No. 6,235,294, May 22, 2001; (1999) Chem Abstr 131:355899Google Scholar
  17. 17.
    Veverka M, Gallovič J, Švajdlenka E, Veverková E, Prónayová N, Miláčková I, Štefek M (2013) Chem Pap 67:76CrossRefGoogle Scholar
  18. 18.
    Kruzlicova D, Danihelova M, Veverka M (2012) Nova Biotechnol Chim 11:37Google Scholar
  19. 19.
    Trask AV (2007) Mol Pharm 4:301CrossRefGoogle Scholar
  20. 20.
    Brittain HG (2010) Cocrystal systems of pharmaceutical interest. In: Brittain HG (ed), Profiles of drug substances, excipients, and related methodology, vol. 35. Academic Press & Elsevier, AmsterdamGoogle Scholar
  21. 21.
    Childs LS, Chyall JL, Dunlap TJ, Smolenskaya NV, Stahly CB, Stahly PG (2004) J Am Chem Soc 126:13335CrossRefGoogle Scholar
  22. 22.
    Shan N, Toda F, Jones W (2002) Chem Comm 20:2372CrossRefGoogle Scholar
  23. 23.
    Li Z, Yang B-S, Jiang M, Eriksson M, Spinelli E, Yee N, Senanayake C (2009) Org Process Res Dev 13:1307CrossRefGoogle Scholar
  24. 24.
    Basavoju S, Boström D, Velaga PS (2007) Pharm Res 25:530CrossRefGoogle Scholar
  25. 25.
    Veverka M, Šimon P, Gallovič J, Jorík V, Veverková E, Dubaj T (2012) Monatsh Chem 143:1405CrossRefGoogle Scholar
  26. 26.
    Veverka M, Dubaj T, Gallovič J, Švajdlenka E, Meľuchová B, Jorík V, Šimon P (2013) Monatsh Chem 144:1335CrossRefGoogle Scholar
  27. 27.
    Sekhon BS (2012) RGUHS J Pharm Sci 2:16Google Scholar
  28. 28.
    Kruthiventi KA, Javed I, Jaggavaruppu RS, Nagalapali RK, Vishwananda SG, Anand KS (2012) Pharmaceutical co-crystals of quercetin. US Patent Application US20120258170A1, Oct 11, 2012Google Scholar
  29. 29.
    Sowa M, Slepokura K, Matczak-Jon E (2012) Acta Cryst C 68:262CrossRefGoogle Scholar
  30. 30.
    Jullian C, Moyano L, Yanez C, Olea-Azar C (2007) Spectrochim Acta A 67:230CrossRefGoogle Scholar
  31. 31.
    Smith AJ, Kavuru P, Wojtas L, Zaworotko MJ, Shytle RD (2011) Mol Pharmaceut 8:1867CrossRefGoogle Scholar
  32. 32.
    Zaworotko MJ, Clarke H, Kapildev A, Kavuru P, Shytle RD, Pujari T, Marshall L, Ong TT (2010) Nutraceutical co-crystal compositions. US Patent Application 2010/0204204A1, Aug 12, 2010Google Scholar
  33. 33.
    Kavuru P, Aboarayes D, Arora KK, Clarke DH, Kennedy A, Marshall L, Ong TT, Perman J, Pujari T, Wojtas L, Zaworotko MJ (2010) Cryst Growth Des 10:3568CrossRefGoogle Scholar
  34. 34.
    Veverka M, Veverková E, Ratkovská Ľ, Gallovič J (2011) Flavonoids co-crystals, method for the preparation thereof and their use. Slovak Patent Application 29-2011A3, Dec 3, 2012Google Scholar
  35. 35.
    Nordström FL, Rasmuson AC (2006) Eur J Pharm Sci 28:377CrossRefGoogle Scholar
  36. 36.
    Descamps M, Willart JF, Dudognon E, Caron V (2007) J Pharm Sci 96:1398CrossRefGoogle Scholar
  37. 37.
    Sing KSW, Everett DH, Haul RAW, Moscou L, Pierotti PA, Rouquerol J, Siemieniewska T (1985) Pure Appl Chem 57:603CrossRefGoogle Scholar
  38. 38.
    Jayasankar A, Good DJ, Rodriguez-Hornedo N (2007) Mol Pharm 4:360CrossRefGoogle Scholar
  39. 39.
    Karki S, Friščić T, Jones W, Motherwell WDS (2007) Mol Pharm 4:348CrossRefGoogle Scholar
  40. 40.
    Walker B, Lynas JF (2001) Cell Mol Life Sci 58:596CrossRefGoogle Scholar
  41. 41.
    Yen GC, Chen HY (1995) J Agric Food Chem 43:27CrossRefGoogle Scholar
  42. 42.
    Benzie IF, Strain JJ (1996) Anal Biochem 239:70CrossRefGoogle Scholar
  43. 43.
    Jedinák A, Maliar T, Grančai D, Nagy M (2006) Phytother Res 20:214CrossRefGoogle Scholar
  44. 44.
    Theiszová M, Jantová S, Dragúňová J, Grznárová P, Palou M (2005) Biomed Pap 149:393CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2014

Authors and Affiliations

  • Miroslav Veverka
    • 1
  • Tibor Dubaj
    • 2
  • Ján Gallovič
    • 1
  • Vladimír Jorík
    • 2
  • Eva Veverková
    • 3
  • Martina Danihelová
    • 2
  • Peter Šimon
    • 2
  1. 1.EUROFINS BEL/NOVAMANN Ltd.Nové ZámkySlovakia
  2. 2.Faculty of Chemical and Food TechnologySlovak University of TechnologyBratislavaSlovakia
  3. 3.Faculty of Natural SciencesComenius UniversityBratislavaSlovakia

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