Mass Spectrometry as a Complementary Approach for Noncovalently Bound Complexes Based on Cyclodextrins

  • Mihaela SilionEmail author
  • Adrian Fifere
  • Ana Lacramioara Lungoci
  • Narcisa Laura Marangoci
  • Sorin Alexandru Ibanescu
  • Radu Zonda
  • Alexandru Rotaru
  • Mariana Pinteală
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1140)


An important and well-designed solution to overcome some of the problems associated with new drugs is provided by the molecular encapsulation of the drugs in the cyclodextrins (CDs) cavity, yielding corresponding inclusion complexes (ICs). These types of non-covalent complexes are of current interest to the pharmaceutical industry, as they improve the solubility, stability and bioavailability of the guest molecules. This review highlights several methods for cyclodextrin ICs preparation and characterization, focusing mostly on the mass spectrometry (MS) studies that have been used for the detection of noncovalent interactions of CDs inclusion complexes and binding selectivity of guest molecules with CDs. Furthermore, the MS investigations of several ICs of the CD with antifungal, antioxidants or fluorescent dyes are presented in greater details, pointing out the difficulties overcome in the analysis of this type of compounds.


Mass spectrometry Electrospray ionization Cyclodextrin Inclusion complex Noncovalent interactions 







Collision-induced dissociation






Electrospray ionization mass spectrometry


Fourier transform infrared spectrometry


Hydroxypropyl β-cyclodextrin


Inclusion complexes


Liquid chromatography mass spectrometry




Matrix-assisted laser desorption ionization mass spectrometry






Mass spectrometry


Methyl β-cyclodextrin


Nuclear magnetic resonance spectroscopy


Nuclear Overhauser enhancement spectroscopy


Rotating-frame Overhauser spectroscopy


Sulfobutyl ether β-cyclodextrin


β-cyclodextrin sulfate




X-ray diffraction



This publication is part of a project that has received funding from the H2020 WIDESPREAD 2-2014: ERA Chairs Project no. 667387: SupraChemLab–Laboratory of Supramolecular Chemistry for Adaptive Delivery Systems, ERA Chair initiative, and a grant of the Romanian National Authority for Scientific Research and Innovation, CNCS/CCCDI—UEFISCDI, project number PN-III-P3-3.6-H20202016-0011, within PNCDI III.


  1. 1.
    Danikiewicz, W. (2006). Mass spectrometry of CyDs and their complexes. In H. Dodziuk (Ed.), Cyclodextrins and their complexes (pp. 257–276). Weinheim: WILEY-VCH Verlag GmbH & KGaA.Google Scholar
  2. 2.
    Astakhova, A. V., & Demina, N. B. (2004). Modern drug technologies: Synthesis, characterization, and use of inclusion complexes between drugs and cyclodextrins (a review). Pharmaceutical Chemistry Journal, 38(2), 105–108.Google Scholar
  3. 3.
    Buchanan, C. M., Buchanan, N. L., Edgar, K. J., & Ramsey, M. G. (2007). Solubilty and dissolution studies of antifungal drug: Hydroxybutenyl-beta-cyclodextrin complexes. Cellulose, 14(1), 35–47.Google Scholar
  4. 4.
    Ruggiero, A., Arena, R., Battista, A., Rizzo, D., Attina, G., & Riccardi, R. (2013). Azole interactions with multidrug therapy in pediatric oncology. European Journal of Clinical Pharmacology, 69(1), 1–10.PubMedGoogle Scholar
  5. 5.
    Loftsson, T., & Duchene, D. (2007). Cyclodextrins and their pharmaceutical applications. International Journal of Pharmaceutics, 329(1–2), 1–11.PubMedGoogle Scholar
  6. 6.
    Challa, R., Ahuja, A., Ali, J., & Khar, R. K. (2005). Cyclodextrins in drug delivery: An updated review. AAPS PharmSciTech, 6(2).Google Scholar
  7. 7.
    Kikuchi, M., Hirayama, F., & Uekama, K. (1987). Improvement of chemical instability of carmoful in beta-cyclodextrin solid complex by utilizing some organic acids. Chemical & Pharmaceutical Bulletin (Tokyo), 35(1), 315–319.Google Scholar
  8. 8.
    Loftsson, T., & Brewster, M. E. (1996). Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization. Journal of Pharmaceutical Sciences, 85(10), 1017–1025.PubMedGoogle Scholar
  9. 9.
    HIROSE, K. (2001). A practical guide for the determination of binding constants. Journal of Inclusion Phenomena and Macrocyclic Chemistry, 39, 193–209.Google Scholar
  10. 10.
    Bongiorno, D., Ceraulo, L., Mele, A., Panzeri, W., Selva, A., & Liveri, V. (2002). Structural and physicochemical characterization of the inclusion complexes of cyclomaltooligosaccharides (cyclodextrins) with melatonin. Carbohydrate Research, 337(8), 743–754.PubMedGoogle Scholar
  11. 11.
    Alexandrino, G. L., Calderini, A., Morgon, N. H., & Pessine, F. B. T. (2012). Spectroscopic (fluorescence, 1D-ROESY) and theoretical studies of the thiabendazole and β-cyclodextrin inclusion complex. Journal of Inclusion Phenomena and Macrocyclic Chemistry, 75(1–2), 93–99.Google Scholar
  12. 12.
    Loukas, Y. L. (1997). Multiple complex formation of fluorescent compounds with cyclodextrins: Efficient determination and evaluation of the binding constant with improved fluorometric studies. The Journal of Physical Chemistry. B, 101(24), 4863–4866.Google Scholar
  13. 13.
    Loukas, Y. L. (1997). Measurement of molecular association in drug: Cyclodextrin inclusion complexes with improved 'H NMR studies. The Journal of Pharmacy and Pharmacology, 49, 944–948.PubMedGoogle Scholar
  14. 14.
    Zhou, X., & Liang, J. F. (2017). A fluorescence spectroscopy approach for fast determination of β-cyclodextrin-guest binding constants. Journal of Photochemistry and Photobiology A: Chemistry, 349, 124–128.Google Scholar
  15. 15.
    Narayanan, G., Boy, R., Gupta, B. S., & Tonelli, A. E. (2017). Analytical techniques for characterizing cyclodextrins and their inclusion complexes with large and small molecular weight guest molecules. Polymer Testing, 62, 402–439.Google Scholar
  16. 16.
    Jürg, D. M., Friess, S. D., Rajagopalan, S., Wendt, S., & Zenobi, R. (2002). Quantitative determination of noncovalent binding interactions using soft ionization mass spectrometry. International Journal of Mass Spectrometry, 216, 1–27.Google Scholar
  17. 17.
    Gabelica, V., Galic, N., & De Pauw, E. (2002). On the specificity of cyclodextrin complexes detected by electrospray mass spectrometry. Journal of the American Society for Mass Spectrometry, 13(8), 946–953.PubMedGoogle Scholar
  18. 18.
    Dotsikas, Y., & Loukas, Y. L. (2003). Efficient determination and evaluation of model cyclodextrin complex binding constants by electrospray mass spectrometry. Journal of the American Society for Mass Spectrometry, 14(10), 1123–1129.PubMedGoogle Scholar
  19. 19.
    Guo, M., Zhang, S., Song, F., Wang, D., Liu, Z., & Liu, S. (2003). Studies on the non-covalent complexes between oleanolic acid and cyclodextrins using electrospray ionization tandem mass spectrometry. Journal of Mass Spectrometry, 38(7), 723–731.PubMedGoogle Scholar
  20. 20.
    Guo, M., Song, F., Liu, Z., & Liu, S. (2004). Characterization of non-covalent complexes of rutin with cyclodextrins by electrospray ionization tandem mass spectrometry. Journal of Mass Spectrometry, 39(6), 594–599.PubMedGoogle Scholar
  21. 21.
    Zhao, Y. F., Luo, X. P., Zhai, Z. D., Chen, L. R., & Li, Y. M. (2006). Simultaneous determination of andrographolide and dehydroandrographolide in Andrographis paniculata and Chinese medicinal preparations by microemulsion electrokinetic chromatography. Journal of Pharmaceutical and Biomedical Analysis, 40(1), 157–161.Google Scholar
  22. 22.
    Yu, Z., Cui, M., Yan, C., Song, F., Liu, Z., & Liu, S. (2007). Investigation of heptakis(2,6-di-O-methyl)-beta-cyclodextrin inclusion complexes with flavonoid glycosides by electrospray ionization mass spectrometry. Rapid Communications in Mass Spectrometry, 21(5), 683–690.PubMedGoogle Scholar
  23. 23.
    Biernacka, J., Betlejewska-Kielak, K., Witowska-Jarosz, J., Klosinska-Szmurlo, E., & Mazurek, A. P. (2014). Mass spectrometry and molecular modeling studies on the inclusion complexes between alendronate and beta-cyclodextrin. Journal of Inclusion Phenomena and Macrocyclic Chemistry, 78, 437–443.PubMedGoogle Scholar
  24. 24.
    Lee, S., Kwon, S., Shin, H.-J., Cho, E., Lee, K.-R., & Jung, S. (2009). Electrospray ionization mass spectrometric analysis of noncovalent complexes of hydroxypropyl-β-cyclodextrin and β-cyclodextrin with progesterone. Bulletin of the Korean Chemical Society, 30(8), 1864–1866.Google Scholar
  25. 25.
    Li, X. S., Liu, L., Mu, T. W., & Guo, Q. X. (2000). A systematic quantum chemistry study on cyclodextrins. Monatshefte Fur Chemie., 131(8), 849–855.Google Scholar
  26. 26.
    Harada, A. (2001). Cyclodextrin-based molecular machines. Accounts of Chemical Research, 34(6), 456–464.PubMedGoogle Scholar
  27. 27.
    Del Valle, E. M. M. (2004). Cyclodextrins and their uses: A review. Process Biochemistry, 39(9), 1033–1046.Google Scholar
  28. 28.
    Fifere, A., Marangoci, N., Maier, S., Coroaba, A., Maftei, D., & Pinteala, M. (2012). Theoretical study on beta-cyclodextrin inclusion complexes with propiconazole and protonated propiconazole. Beilstein Journal of Organic Chemistry, 8, 2191–2201.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Marangoci, N., Fifere, A., Farcas, A., Harabagiu, V., Pinteala, M., Simionescu, B. C., & Perichaud, A. (2008). Synthesis and characterization of polyrotaxanes based on cyclodextrins and viologen-modified polydimethylsiloxanes. High Performance Polymers, 20(6), 553–566.Google Scholar
  30. 30.
    Marangoci, N., Farcas, A., Pinteala, M., Harabagiu, V., Simionescu, B. C., Sukhanova, T., Perminova, M., Grigoryev, A., Gubanova, G., & Bronnikov, S. (2009). Synthesis, morphology, and thermal behavior of polyrotaxanes composed of gamma-cyclodextrin and polydimethylsiloxanes. Journal of Inclusion Phenomena and Macrocyclic Chemistry, 63(3–4), 355–364.Google Scholar
  31. 31.
    Marangoci, N., Ardeleanu, R., Ursu, L., Ibanescu, C., Danu, M., Pinteala, M., & Simionescu, B. C. (2012). Polysiloxane ionic liquids as good solvents for beta-cyclodextrin-polydimethylsiloxane polyrotaxane structures. Beilstein Journal of Organic Chemistry, 8, 1610–1618.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Farcas, A., Jarroux, N., Guegan, P., Fifere, A., Pinteala, M., & Harabagiu, V. (2008). Polyfluorene copolymer with a multiply blocked rotaxane architecture in the main chain: Synthesis and characterization. Journal of Applied Polymer Science, 110(4), 2384–2392.Google Scholar
  33. 33.
    Fifere, A., Budtova, T., ElenaTarabukina, P. M., Spulber, M., Peptu, C., Harabagiu, V., & Simionescu, B. C. (2009). Inclusion complexes of γ-cyclodextrin and carboxyl-modified γ-cyclodextrin with C60: Synthesis, characterization and controlled release application via microgels. Journal of Inclusion Phenomena and Macrocyclic Chemistry, 64(1–2), 83–94.Google Scholar
  34. 34.
    MM, A., KA, A., SA, M., & AR, I. (2010). Comparative evaluation of ketoconazole-β-cyclodextrin systems prepared by coprecipitation and kneading. Drug Discoveries & Therapeutics, 4(5), 380–387.Google Scholar
  35. 35.
    Abarca, R. L., Rodriguez, F. J., Guarda, A., Galotto, M. J., & Bruna, J. E. (2016). Characterization of beta-cyclodextrin inclusion complexes containing an essential oil component. Food Chemistry, 196, 968–975.PubMedGoogle Scholar
  36. 36.
    Mohammed, N. N., Pandey, P., Khan, N. S., Elokely, K. M., Liu, H., Doerksen, R. J., & Repka, M. A. (2016). Clotrimazole-cyclodextrin based approach for the management and treatment of Candidiasis—A formulation and chemistry-based evaluation. Pharmaceutical Development and Technology, 21(5), 619–629.PubMedGoogle Scholar
  37. 37.
    Spulber, M., Pinteala, M., Fifere, A., Harabagiu, V., & Simionescu, B. C. (2008). Inclusion complexes of 5-flucytosine with beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin: Characterization in aqueous solution and in solid state. Journal of Inclusion Phenomena and Macrocyclic Chemistry, 62(1–2), 117–125.Google Scholar
  38. 38.
    Spulber, M., Pinteala, M., Fifere, A., Moldoveanu, C., Mangalagiu, I., Harabagiu, V., & Simionescu, B. C. (2008). Water soluble complexes of methyl beta-cyclodextrin and sulconazole nitrate. Journal of Inclusion Phenomena and Macrocyclic Chemistry, 62(1–2), 135–142.Google Scholar
  39. 39.
    Spulber, M., Pinteala, M., Harbagiu, V., & Simionescu, B. C. (2008). Inclusion complexes of Sulconazole with beta-cyclodextrin and hydroxypropyl beta-cyclodextrin: Characterization in aqueous solution and in solid state. Journal of Inclusion Phenomena and Macrocyclic Chemistry, 61(1–2), 41–51.Google Scholar
  40. 40.
    Corciova, A., Ciobanu, C., Poiata, A., Mircea, C., Nicolescu, A., Drobota, M., Varganici, C. D., Pinteala, T., & Marangoci, N. (2015). Antibacterial and antioxidant properties of hesperidin: Beta-cyclodextrin complexes obtained by different techniques. Journal of Inclusion Phenomena and Macrocyclic Chemistry, 81(1–2), 71–84.Google Scholar
  41. 41.
    Ghiorghiasa, R., Petrovici, A. R., Rosca, I., & Miron, L. (2016). Inclusion complex of thiotriazinone with alpha-cyclodextrin-raman spectroscopy, DSC, preliminary antimicrobial and antifungal study. Digest Journal of Nanomaterials and Biostructures, 11(1), 235–241.Google Scholar
  42. 42.
    Zhao, D. Y., Yang, S. H., Hu, M., & Ma, X. Y. (2003). Structural study of inclusion complex of andrographolide with beta-cyclodextrin prepared under microwave irradiation. Chinese Chemical Letters, 14(2), 155–158.Google Scholar
  43. 43.
    Riela, S., Lazzara, G., Lo Meo, P., Guernelli, S., D’Anna, F., Milioto, S., & Noto, R. (2011). Microwave-assisted synthesis of novel cyclodextrin–cucurbituril complexes. Supramolecular Chemistry, 23(12), 819–828.Google Scholar
  44. 44.
    Fernandez-Ferreiro, A., Fernandez Bargiela, N., Varela, M. S., Martinez, M. G., Pardo, M., Pineiro Ces, A., Mendez, J. B., Barcia, M. G., Lamas, M. J., & Otero-Espinar, F. (2014). Cyclodextrin-polysaccharide-based, in situ-gelled system for ocular antifungal delivery. Beilstein Journal of Organic Chemistry, 10, 2903–2911.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Yurtdaş, G., Demirel, M., & Genç, L. (2010). Inclusion complexes of fluconazole with β-cyclodextrin: Physicochemical characterization and in vitro evaluation of its formulation. Journal of Inclusion Phenomena and Macrocyclic Chemistry, 70(3–4), 429–435.Google Scholar
  46. 46.
    Tenjarla, S., Puranajoti, P., Kasina, R., & Mandal, T. (1998). Preparation, characterization, and evaluation of miconazole-cyclodextrin complexes for improved oral and topical delivery. Journal of Pharmaceutical Sciences, 87(4), 425–429.PubMedGoogle Scholar
  47. 47.
    Alsarra, I. A., Alanazi, F. K., Ahmed, S. M., Bosela, A. A., Alhamed, S. S., Mowafy, H. A., & Neau, S. H. (2010). Comparative study of itraconazole-cyclodextrin inclusion complex and its commercial product. Archives of Pharmacal Research, 33(7), 1009–1017.PubMedGoogle Scholar
  48. 48.
    Loftsson, T., & Brewster, M. E. (2010). Pharmaceutical applications of cyclodextrins: Basic science and product development. The Journal of Pharmacy and Pharmacology, 62(11), 1607–1621.PubMedGoogle Scholar
  49. 49.
    Loftsson, T., Hreinsdottir, D., & Masson, M. (2005). Evaluation of cyclodextrin solubilization of drugs. International Journal of Pharmaceutics, 302(1–2), 18–28.PubMedGoogle Scholar
  50. 50.
    Mura, P. (2014). Analytical techniques for characterization of cyclodextrin complexes in aqueous solution: A review. Journal of Pharmaceutical and Biomedical Analysis, 101, 238–250.PubMedGoogle Scholar
  51. 51.
    Mura, P. (2015). Analytical techniques for characterization of cyclodextrin complexes in the solid state: A review. Journal of Pharmaceutical and Biomedical Analysis, 113, 226–238.PubMedGoogle Scholar
  52. 52.
    Singh, R., Bharti, N., Madan, J., & Hiremath, S. N. (2010). Characterization of cyclodextrin inclusion complexes—A review. Journal of Pharmaceutical Science and Technology, 2(3), 171–183.Google Scholar
  53. 53.
    Duchěne, D., Vaution, C., & Glomot, F. (1986). Cyclodextrins, their value in pharmaceutical technology. Drug Development and Industrial Pharmacy, 12(11–13), 2193–2215.Google Scholar
  54. 54.
    Fenn, J. B., Mann, M., Meng, C. K., Wong, S. F., & Whitehouse, C. M. (1989). Electrospray ionization for mass spectrometry of large biomolecules. Science, 246, 64–71.Google Scholar
  55. 55.
    Yamashita, M., & Fenn, J. B. (1984). Electrospray ion source. Another variation on the free-jet theme. The Journal of Physical Chemistry, 88(20), 4451–4459.Google Scholar
  56. 56.
    Heck, A. J., & Van Den Heuvel, R. H. (2004). Investigation of intact protein complexes by mass spectrometry. Mass Spectrometry Reviews, 23(5), 368–389.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Brodbelt, J. S. (2000). Probing molecular recognition by mass spectrometry. International Journal of Mass Spectrometry, 200(1–3), 57–69.Google Scholar
  58. 58.
    Grigorean, G., Cong, X., & Lebrilla, C. B. (2004). Chiral analyses of peptides by ion/molecule reactions. International Journal of Mass Spectrometry, 234(1–3), 71–77.Google Scholar
  59. 59.
    Lebrilla, C. B. (2001). The gas-phase chemistry of cyclodextrin inclusion complex. Accounts of Chemical Research, 34(8), 653–661.PubMedGoogle Scholar
  60. 60.
    Gabelica, V., Galic, N., Rosu, F., Houssier, C., & De Pauw, E. (2003). Influence of response factors on determining equilibrium association constants of non-covalent complexes by electrospray ionization mass spectrometry. Journal of Mass Spectrometry, 38(5), 491–501.PubMedGoogle Scholar
  61. 61.
    Ramanathan, R., & Prokai, L. (1995). Electrospray-ionization mass-spectrometric study of encapsulation of amino-acids by cyclodextrins. Journal of the American Society for Mass Spectrometry, 6(9), 866–871.PubMedGoogle Scholar
  62. 62.
    Camilleri, P., Haskins, N. J., New, A. P., & Saunders, M. R. (1993). Analyzing the complexation of amino-acids and peptides with beta-cyclodextrin using electrospray-ionization mass-spectrometry. Rapid Communications in Mass Spectrometry, 7(10), 949–952.Google Scholar
  63. 63.
    Selva, A., Redenti, E., Zanol, M., Ventura, P., & Casetta, B. (1993). A study of beta-cyclodextrin and its inclusion complexes with piroxicam and terfenadine by ionspray mass-spectrometry. Organic Mass Spectrometry, 28(9), 983–986.Google Scholar
  64. 64.
    Cunniff, J. B., & Vouros, P. (1995). False positives and the detection of cyclodextrin inclusion complexes by electrospray mass-spectrometry. Journal of the American Society for Mass Spectrometry, 6(5), 437–447.PubMedGoogle Scholar
  65. 65.
    Schalley, C. A. (2001). Molecular recognition and supramolecular chemistry in the gas phase. Mass Spectrometry Reviews, 20(5), 253–309.PubMedGoogle Scholar
  66. 66.
    Mele, A., & Selva, A. (1995). Detection of 1/1 adducts of piroxicam with beta-cyclodextrin or with maltohexaose by fast-atom-bombardment mass-spectrometry. Journal of Mass Spectrometry, 30(4), 645–647.Google Scholar
  67. 67.
    Vieira, A. C., Serra, A. C., Carvalho, R. A., Gonsalves, A., Figueiras, A., Veiga, F. J., Basit, A. W., & Rocha Gonsalves, A. M. (2013). Microwave synthesis and in vitro stability of diclofenac-beta-cyclodextrin conjugate for colon delivery. Carbohydrate Polymers, 93(2), 512–517.PubMedGoogle Scholar
  68. 68.
    Wen, X., Liu, Z., Zhu, T., Zhu, M., Jiang, K., & Huang, Q. (2004). Evidence for the 2:1 molecular recognition and inclusion behaviour between beta- and gamma-cyclodextrins and cinchonine. Bioorganic Chemistry, 32(4), 223–233.PubMedGoogle Scholar
  69. 69.
    Rabara, L., Aranyosiova, M., & Velic, D. (2006). Supramolecular host–guest complexes based on cyclodextrin–diphenylhexatriene. Applied Surface Science, 252(19), 7000–7002.Google Scholar
  70. 70.
    Short, L. C., & Syage, J. A. (2008). Electrospray photoionization (ESPI) liquid chromatography/mass spectrometry for the simultaneous analysis of cyclodextrin and pharmaceuticals and their binding interactions. Rapid Communications in Mass Spectrometry, 22(4), 541–548.PubMedGoogle Scholar
  71. 71.
    Greisch, J. F., Kyritsoglou, S., Leyh, B., & De Pauw, E. (2008). Mass spectrometric study of the ionized C60: (Gamma-Cyclodextrin)2 inclusion complex by collision induced dissociation. Journal of Mass Spectrometry, 43(2), 242–250.PubMedGoogle Scholar
  72. 72.
    Kwon, S., Lee, W., Shin, H.-J., S-i, Y., Y-t, K., Kim, Y.-J., Lee, K., & Lee, S. (2009). Characterization of cyclodextrin complexes of camostat mesylate by ESI mass spectrometry and NMR spectroscopy. Journal of Molecular Structure, 938(1–3), 192–197.Google Scholar
  73. 73.
    Sagiraju, S., Chen, K., Cole, R. B., & Jursic, B. S. (2009). Electrospray-ionization mass spectrometry study of cyclodextrin complexes with A007 prodrugs. Carbohydrate Research, 344(16), 2167–2172.PubMedGoogle Scholar
  74. 74.
    Uzqueda, M., González-Gaitano, G., Wouessidjewe, D., Zornoza, A., Sánchez, M., Martín, C., & Véla, I. (2009). Spectroscopic characterization of the inclusion complexes between the antifungal drugs Naftifine and Terbinafine and Cyclodextrins. Supramolecular Chemistry, 21(8), 759–769.Google Scholar
  75. 75.
    Marangoci, N., Mares, M., Silion, M., Fifere, A., Varganici, C., Nicolescu, A., Deleanu, C., Coroaba, A., Pinteala, M., & Simionescu, B. C. (2011). Inclusion complex of a new propiconazole derivative with beta-cyclodextrin: NMR, ESI-MS and preliminary pharmacological studies. Results Pharma Sci., 1(1), 27–37.PubMedPubMedCentralGoogle Scholar
  76. 76.
    de Paula, W. X., Denadai, A. M., Santoro, M. M., Braga, A. N., Santos, R. A., & Sinisterra, R. D. (2011). Supramolecular interactions between losartan and hydroxypropyl-beta-CD: ESI mass-spectrometry, NMR techniques, phase solubility, isothermal titration calorimetry and anti-hypertensive studies. International Journal of Pharmaceutics, 404(1–2), 116–123.PubMedGoogle Scholar
  77. 77.
    Barylyuk, K., Balabin, R. M., Grünstein, D., Kikkeri, R., Frankevich, V., Seeberger, P. H., & Zenobi, R. (2011). What happens to hydrophobic interactions during transfer from the solution to the gas phase? The case of electrospray-based soft ionization methods. Journal of The American Society for Mass Spectrometry., 22(7), 1167–1177.PubMedGoogle Scholar
  78. 78.
    Garcia, A., Leonardi, D., Salazar, M. O., & Lamas, M. C. (2014). Modified b-cyclodextrin inclusion complex to improve the physicochemical properties of albendazole. Complete in vitro evaluation and characterization. PLoS One, 9(2), e88234.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Zhang, J. Q., Jiang, K. M., An, K., Ren, S. H., Xie, X. G., Jin, Y., & Lin, J. (2015). Novel water-soluble fisetin/cyclodextrins inclusion complexes: Preparation, characterization, molecular docking and bioavailability. Carbohydrate Research, 418, 20–28.PubMedGoogle Scholar
  80. 80.
    Kim, H., Yiluo, H., Park, S., Lee, J., Cho, E., & Jung, S. (2016). Characterization and enhanced antioxidant activity of the cysteinyl β-cyclodextrin-baicalein inclusion complex. Molecules, 21(6), 703.PubMedCentralGoogle Scholar
  81. 81.
    Jankowski, C. K., Lamouroux, C., Jimenez-Estrada, M., Arseneau, S., & Wagner, B. D. (2016). Factors affecting the formation of 2:1 host:guest inclusion complexes of 2-[(R-Phenyl)amine]-1,4-naphthalenediones (PAN) in beta- and gamma-cyclodextrins. Molecules, 21(11).Google Scholar
  82. 82.
    Zhang, J.-Q., Jiang, K.-M., Xie, X.-G., Jin, Y., & Lin, J. (2016). Water-soluble inclusion complexes of trans-polydatin by cyclodextrin complexation: Preparation, characterization and bioactivity evaluation. Journal of Molecular Liquids, 219, 592–598.Google Scholar
  83. 83.
    Roy, A., Saha, S., & Roy, M. N. (2017). Exploration of inclusion complexes of probenecid with α and β-cyclodextrins: Enhancing the utility of the drug. Journal of Molecular Structure, 1144, 103–111.Google Scholar
  84. 84.
    Al-Burtomani, S. K. S., & Suliman, F. O. (2017). Inclusion complexes of norepinephrine with b-cyclodextrin, 18-crown-6 and cucurbit[7]uril: Experimental and molecular dynamics study. RSC Advances, 7, 9888–9901.Google Scholar
  85. 85.
    Raza, A., Sun, H., Bano, S., Zhao, Y., Xu, X., & Tang, J. (2017). Preparation, characterization, and in vitro anti-inflammatory evaluation of novel water soluble kamebakaurin/hydroxypropyl-β-cyclodextrin inclusion complex. Journal of Molecular Structure, 1130, 319–326.Google Scholar
  86. 86.
    Mathiron, D., Iori, R., Pilard, S., Soundara Rajan, T., Landy, D., Mazzon, E., Rollin, P., & Djedaini-Pilard, F. (2018). A combined approach of nmr and mass spectrometry techniques applied to the alpha-cyclodextrin/moringin complex for a novel bioactive formulation (dagger). Molecules, 23(7).Google Scholar
  87. 87.
    Floresta, G., & Rescifina, A. (2018). Metyrapone-β-cyclodextrin supramolecular interactions inferred by complementary spectroscopic/spectrometric and computational studies. Journal of Molecular Structure, 1176, 815–824.Google Scholar
  88. 88.
    Pricope, G., Ursu, E. L., Sardaru, M., Cojocaru, C., Clima, L., Marangoci, N., Danac, R., Mangalagiu, I. I., Simionescu, B. C., Pinteala, M., & Rotaru, A. (2018). Novel cyclodextrin-based pH-sensitive supramolecular host-guest assembly for staining acidic cellular organelles. Polymer Chemistry, 9(8), 968–975.Google Scholar
  89. 89.
    Stražišar, M., Andrenšek, S., & Šmidovnik, A. (2008). Effect of β-cyclodextrin on antioxidant activity of coumaric acids. Food Chemistry, 110(3), 636–642.Google Scholar
  90. 90.
    Nouairi, M. A., Fergoug, T., Azayez, M., Boujoures, H., Zelmat, C., & Bouhadda, Y. (2017). Experimental and theoretical study of tetracaine-hydrochloride β-cyclodextrin complexation. Journal of Materials and Environmental Sciences, 8(5), 1589–1598.Google Scholar
  91. 91.
    Jankowska, A., Jankowski, C. K., & Chiasson, J. B. (2005). On chloralose-cyclodextrin complexes by ESI-mass spectrometry. Journal of Inclusion Phenomena and Macrocyclic Chemistry, 52(3–4), 213–221.Google Scholar
  92. 92.
    MaubonOdds, F. C., Brown, A. J. P., & Gow, N. A. R. (2003). Antifungal agents: Mechanisms of action. Trends in Microbiology, 11(6), 272–279.Google Scholar
  93. 93.
    Maubon, D., Garnaud, C., Calandra, T., Sanglard, D., & Cornet, M. (2014). Resistance of Candida spp. to antifungal drugs in the ICU: Where are we now? Intensive Care Medicine, 40(9), 1241–1255.PubMedGoogle Scholar
  94. 94.
    Iman, M., & Davood, A. (2014). Homology modeling of lanosterol 14 alpha-demethylase of Candida albicans and insights into azole binding. Medicinal Chemistry Research, 23(6), 2890–2899.Google Scholar
  95. 95.
    Koontz, J. L., & Marcy, J. E. (2003). Formation of natamycin: Cyclodextrin inclusion complexes and their characterization. Journal of Agricultural and Food Chemistry, 51(24), 7106–7110.PubMedGoogle Scholar
  96. 96.
    Koontz, J. L., Marcy, J. E., Barbeau, W. E., & Duncan, S. E. (2003). Stability of natamycin and its cyclodextrin inclusion complexes in aqueous solution. Journal of Agricultural and Food Chemistry, 51(24), 7111–7114.PubMedGoogle Scholar
  97. 97.
    Chakraborty, K. K., & Naik, S. R. (2003). Therapeutic and hemolytic evaluation of in-situ liposomal preparation containing amphotericin-beta complexed with different chemically modified beta-cyclodextrins. Journal of Pharmacy and Pharmaceutical Sciences, 6(2), 231–237.PubMedGoogle Scholar
  98. 98.
    Hv, D., & Bosch, E. H. (1991). Stability and in vitro activity of nystatin and its y-cyclodextrin complex against Candida albicans. International Journal of Pharmaceutics, 73(1), 43–49.Google Scholar
  99. 99.
    Davis, M. E., & Brewster, M. E. (2004). Cyclodextrin-based pharmaceutics: Past, present and future. Nature Reviews. Drug Discovery, 3(12), 1023–1035.PubMedGoogle Scholar
  100. 100.
    Pedersen, M., Edelsten, M., Nielsen, V. F., Scarpellini, A., Skytte, S., & Slot, C. (1993). Formation and antimycotic effect of cyclodextrin inclusion complexes of econazole and miconazole. International Journal of Pharmaceutics, 90(3), 247–254.Google Scholar
  101. 101.
    Pedersen, M., Bjerregaard, S., Jacobsen, J., Larsen, A. R., & Sorensen, A. M. (1998). An econazole beta-cyclodextrin inclusion complex: An unusual dissolution rate, supersaturation, and biological efficacy example. International Journal of Pharmaceutics, 165(1), 57–68.Google Scholar
  102. 102.
    Pedersen, M., Jacobsen, J., & Sorensen, A. M. (1999). Cyclodextrin inclusion complexes of miconazole and econazole—Isolation, toxicity on human cells, and confirmation of a new interpretation of the drug supersaturation phenomenon. Drug Development and Industrial Pharmacy, 25(4), 463–470.PubMedGoogle Scholar
  103. 103.
    Pedersen, M. (1993). Effect of hydrotropic substances on the complexation of clotrimazole with beta-cyclodextrin. Drug Development and Industrial Pharmacy, 19(4), 439–448.Google Scholar
  104. 104.
    Pedersen, M., Bjerregaard, S., Jacobsen, J., & Sorensen, A. M. (1998). A genuine clotrimazole gamma-cyclodextrin inclusion complex-isolation, antimycotic activity, toxicity and an unusual dissolution rate. International Journal of Pharmaceutics, 176(1), 121–131.Google Scholar
  105. 105.
    Minea, B., Marangoci, N., Peptanariu, D., Rosca, I., Nastasa, V., Corciova, A., Varganici, C., Nicolescu, A., Fifere, A., Neamtu, A., Mares, M., Barboiu, M., & Pinteala, M. (2016). Inclusion complexes of propiconazole nitrate with substituted beta-cyclodextrins: The synthesis and in silico and in vitro assessment of their antifungal properties. New Journal of Chemistry, 40(2), 1765–1776.Google Scholar
  106. 106.
    Neamtu, A., Marangoci, N., & Harabagiu, V. (2013). Beta-cyclodextrin/propiconazole complexes probed by constraint free and biased molecular dynamics simulations. Revista De Chimie., 64(5), 502–508.Google Scholar
  107. 107.
    Alvarez-Parrilla, E., Rosa, L. A. D. L., Torres-Rivas, F., Rodrigo-Garcia, J., & González-Aguilar, G. A. (2005). Complexation of apple antioxidants: Chlorogenic acid, quercetin and rutin by β-cyclodextrin (β-CD). Journal of Inclusion Phenomena and Macrocyclic Chemistry, 53(1–2), 121–129.Google Scholar
  108. 108.
    Calabro, M. L., Tommasini, S., Donato, P., Stancanelli, R., Raneri, D., Catania, S., Costa, C., Villari, V., Ficarra, P., & Ficarra, R. (2005). The rutin/beta-cyclodextrin interactions in fully aqueous solution: Spectroscopic studies and biological assays. Journal of Pharmaceutical and Biomedical Analysis, 36(5), 1019–1027.PubMedGoogle Scholar
  109. 109.
    Paczkowska, M., Mizera, M., Piotrowska, H., Szymanowska-Powalowska, D., Lewandowska, K., Goscianska, J., Pietrzak, R., Bednarski, W., Majka, Z., & Cielecka-Piontek, J. (2015). Complex of rutin with beta-cyclodextrin as potential delivery system. PLoS One, 10(3), e0120858.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Jullian, C., Moyano, L., Yanez, C., & Olea-Azar, C. (2007). Complexation of quercetin with three kinds of cyclodextrins: An antioxidant study. Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy, 67(1), 230–234.PubMedGoogle Scholar
  111. 111.
    Lucas-Abellan, C., Fortea, I., Gabaldon, J. A., & Nunez-Delicado, E. (2008). Encapsulation of quercetin and myricetin in cyclodextrins at acidic pH. Journal of Agricultural and Food Chemistry, 56(1), 255–259.Google Scholar
  112. 112.
    Jullian, C., Orosteguis, T., Perez-Cruz, F., Sanchez, P., Mendizabal, F., & Olea-Azar, C. (2008). Complexation of morin with three kinds of cyclodextrin—A thermodynamic and reactivity study. Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy., 71(1), 269–275.PubMedGoogle Scholar
  113. 113.
    Celik, S. E., Ozyurek, M., Tufan, A. N., Guclu, K., & Apak, R. (2011). Spectroscopic study and antioxidant properties of the inclusion complexes of rosmarinic acid with natural and derivative cyclodextrins. Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy, 78(5), 1615–1624.PubMedGoogle Scholar
  114. 114.
    Aksamija, A., Polidori, A., Plasson, R., Dangles, O., & Tomao, V. (2016). The inclusion complex of rosmarinic acid into beta-cyclodextrin: A thermodynamic and structural analysis by NMR and capillary electrophoresis. Food Chemistry, 208, 258–263.PubMedGoogle Scholar
  115. 115.
    Zhang, M., Li, J., Zhang, L., & Chao, J. (2009). Preparation and spectral investigation of inclusion complex of caffeic acid with hydroxypropyl-beta-cyclodextrin. Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy, 71(5), 1891–1895.PubMedGoogle Scholar
  116. 116.
    Gornas, P., Neunert, G., Baczynski, K., & Polewski, K. (2009). Beta-cyclodextrin complexes with chlorogenic and caffeic acids from coffee brew: Spectroscopic, thermodynamic and molecular modelling study. Food Chemistry, 114(1), 190–196.Google Scholar
  117. 117.
    Zhao, M., Wang, H., Yang, B., & Tao, H. (2010). Identification of cyclodextrin inclusion complex of chlorogenic acid and its antimicrobial activity. Food Chemistry, 120(4), 1138–1142.Google Scholar
  118. 118.
    López-García, M. Á., López, Ó., Maya, I., & Fernández-Bolaños, J. G. (2010). Complexation of hydroxytyrosol with β-cyclodextrins. An efficient photoprotection. Tetrahedron, 66(40), 8006–8011.Google Scholar
  119. 119.
    Lu, Z., Cheng, B., Hu, Y., Zhang, Y., & Zou, G. (2009). Complexation of resveratrol with cyclodextrins: Solubility and antioxidant activity. Food Chemistry, 113(1), 17–20.Google Scholar
  120. 120.
    Wang, Y. L., Qiao, X. N., Li, W. C., Zhou, Y. H., Jiao, Y., Yang, C., Dong, C. A., Inou, Y., & Shuang, S. M. (2009). Study on the complexation of isoquercitrin with beta-cyclodextrin and its derivatives by spectroscopy. Analytica Chimica Acta, 650(1), 124–130.PubMedGoogle Scholar
  121. 121.
    Bergonzi, M. C., Bilia, A. R., Di Bari, L., Mazzi, G., & Vincieri, F. F. (2007). Studies on the interactions between some flavonols and cyclodextrins. Bioorganic & Medicinal Chemistry Letters, 17(21), 5744–5748.Google Scholar
  122. 122.
    Lungoci, A.-L., Turin-Moleavin, I.-A., Corciova, A., Mircea, C., Arvinte, A., Fifere, A., Marangoci, N. L., & Pinteala, M. (2019). Multifunctional magnetic cargo-complexes with radical scavenging properties. Materials Science and Engineering: C, 94, 608–618.Google Scholar
  123. 123.
    Akal, Z. Ü., Alpsoy, L., & Baykal, A. (2016). Superparamagnetic iron oxide conjugated with folic acid and carboxylated quercetin for chemotherapy applications. Ceramics International, 42(7), 9065–9072.Google Scholar
  124. 124.
    Dsouza, R. N., Pischel, U., & Nau, W. M. (2011). Fluorescent dyes and their supramolecular host/guest complexes with macrocycles in aqueous solution. Chemical Reviews, 111(12), 7941–7980.PubMedGoogle Scholar
  125. 125.
    Wagner, B. D., Stojanovic, N., Leclair, G., & Jankowski, C. K. (2003). A spectroscopic and molecular modelling study of the nature of the association complexes of Nile Red with cyclodextrins. Journal of Inclusion Phenomena and Macrocyclic Chemistry, 45(3–4), 275–283.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Mihaela Silion
    • 1
    Email author
  • Adrian Fifere
    • 1
  • Ana Lacramioara Lungoci
    • 1
  • Narcisa Laura Marangoci
    • 1
  • Sorin Alexandru Ibanescu
    • 1
  • Radu Zonda
    • 1
  • Alexandru Rotaru
    • 1
  • Mariana Pinteală
    • 1
  1. 1.Advanced Research Centre for Bionanoconjugates and Biopolymers“Petru Poni” Institute of Macromolecular Chemistry of Romanian AcademyIasiRomania

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