title: Triethanolamine stabilization of methotrexate-β-cyclodextrin interactions in ternary complexes.
abstract: The interaction of methotrexate (MTX) with beta-cyclodextrin (β-CD) in the presence of triethanolamine (TEA) was investigated with the aim to elucidate the mechanism whereby self-assembly cyclodextrin systems work in association with this third component. Solubility diagram studies showed synergic increment of the MTX solubility to be about thirty-fold. Experiments using 2D ROESY and molecular modeling studies revealed the inclusion of aromatic ring III of the drug into β-CD cavity, in which TEA contributes by intensifying MTX interaction with β-CD and stabilizes MTX:β-CD:TEA ternary complex by electrostatic interaction. The maintenance of these interactions in solid phase was also studied in ternary MTX:β-CD:TEA and comparisons were made with freeze dried binary MTX:β-CD and physical mixtures. FTIR studies evidenced that MTX-β-CD interaction remained in solid ternary complexes, which was also supported by thermal (differential scanning calorimetry (DSC), thermogravimetric analysis (TG)/first derivative of TG analysis (DTG) and C,N,H elementary analysis) and structural (X-ray diffraction analysis, (XRD)) studies, mainly regarding the increment of drug stability. The efficient in vitro drug dissolution studies successfully demonstrated the contribution of ternary complexes, which highlights the importance of this possible new raw material for further applications in drug delivery systems.
authors.affiliation: Graduate Program on Pharmaceutical Sciences, Department of Pharmacy, Federal University of Rio Grande do Norte (UFRN), Av. General Gustavo Cordeiro de Farias, Petrópolis, 59072-570 Natal, Brazil. jamunauepb@gmail.com.
authors.forename: Jahamunna A A
authors.initials: JA
authors.lastname: Barbosa
authors.affiliation: Research and Pharmaceutical Technology Development Unit (UNITEFA, CONICET-UNC) and Department of Pharmacy, Faculty of Chemical Sciences, National University of Córdoba, Ciudad Universitaria, X5000HUA Córdoba, Argentina. ariana@fcq.unc.edu.ar.
authors.forename: Ariana
authors.initials: A
authors.lastname: Zoppi
authors.affiliation: Research and Pharmaceutical Technology Development Unit (UNITEFA, CONICET-UNC) and Department of Pharmacy, Faculty of Chemical Sciences, National University of Córdoba, Ciudad Universitaria, X5000HUA Córdoba, Argentina. alfredoq@fcq.unc.edu.ar.
authors.forename: Mario A
authors.initials: MA
authors.lastname: Quevedo
authors.affiliation: Graduate Program on Development and Technologic Innovation in Pharmaceuticals, UFRN, Av. Salgado Filho, 3000-Lagoa Nova, 59072-970 Natal, Brazil. polyanne_melo86@yahoo.com.br.
authors.forename: Polyanne N
authors.initials: PN
authors.lastname: de Melo
authors.affiliation: Graduate Program on Pharmaceutical Sciences, Department of Pharmacy, Federal University of Rio Grande do Norte (UFRN), Av. General Gustavo Cordeiro de Farias, Petrópolis, 59072-570 Natal, Brazil. arthurmedeiros@ymail.com.
authors.forename: Arthur S A
authors.initials: AS
authors.lastname: de Medeiros
authors.affiliation: Graduate Program on Development and Technologic Innovation in Pharmaceuticals, UFRN, Av. Salgado Filho, 3000-Lagoa Nova, 59072-970 Natal, Brazil. leticiastreck@gmail.com.
authors.forename: Letícia
authors.initials: L
authors.lastname: Streck
authors.affiliation: Graduate Program on Healthy Sciences, UFRN, Av. General Gustavo Cordeiro de Farias, Petrópolis, 59072-570 Natal, Brazil. farmalix@yahoo.com.br.
authors.forename: Alice R
authors.initials: AR
authors.lastname: de Oliveira
authors.affiliation: Graduate Program on Pharmaceutical Sciences, Department of Pharmacy, Federal University of Rio Grande do Norte (UFRN), Av. General Gustavo Cordeiro de Farias, Petrópolis, 59072-570 Natal, Brazil. mpedrosa@ufrnet.br.
authors.forename: Matheus F
authors.initials: MF
authors.lastname: Fernandes-Pedrosa
authors.affiliation: Research and Pharmaceutical Technology Development Unit (UNITEFA, CONICET-UNC) and Department of Pharmacy, Faculty of Chemical Sciences, National University of Córdoba, Ciudad Universitaria, X5000HUA Córdoba, Argentina. mrlcor@fcq.unc.edu.ar.
authors.forename: Marcela R
authors.initials: MR
authors.lastname: Longhi
authors.affiliation: Graduate Program on Pharmaceutical Sciences, Department of Pharmacy, Federal University of Rio Grande do Norte (UFRN), Av. General Gustavo Cordeiro de Farias, Petrópolis, 59072-570 Natal, Brazil. arnobiosilva@ufrnet.br.
authors.forename: Arnóbio A
authors.initials: AA
authors.lastname: da Silva-Júnior
mesh_terms: D002152:Calorimetry, Differential Scanning; D018360:Crystallography, X-Ray; D004337:Drug Carriers; D004983:Ethanolamines / Q000494:pharmacology*; D005079:Excipients / Q000737:chemistry*; D005612:Freeze Drying; D057927:Hydrophobic and Hydrophilic Interactions; D008727:Methotrexate / Q000008:administration & dosage / Q000737:chemistry*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D055672:Static Electricity; D013818:Thermogravimetry; D014867:Water; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D004337:Drug Carriers; D004983:Ethanolamines; D005079:Excipients; D047392:beta-Cyclodextrins; D014867:Water; C009546:triethanolamine; C031215:betadex; D008727:Methotrexate