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Int. J. Mol. Sci. 2014, 15(9), 17077-17099; doi:10.3390/ijms150917077

Triethanolamine Stabilization of Methotrexate-β-Cyclodextrin Interactions in Ternary Complexes

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
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
Graduate Program on Development and Technologic Innovation in Pharmaceuticals, UFRN, Av. Salgado Filho, 3000-Lagoa Nova, 59072-970 Natal, Brazil
Graduate Program on Healthy Sciences, UFRN, Av. General Gustavo Cordeiro de Farias, Petrópolis, 59072-570 Natal, Brazil
Author to whom correspondence should be addressed.
Received: 17 July 2014 / Revised: 26 August 2014 / Accepted: 26 August 2014 / Published: 25 September 2014
(This article belongs to the Section Biomaterial Sciences)
View Full-Text   |   Download PDF [4526 KB, uploaded 25 September 2014]   |  


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. View Full-Text
Keywords: methotrexate; cyclodextrin; inclusion complexes; ternary complexes; drug delivery systems methotrexate; cyclodextrin; inclusion complexes; ternary complexes; drug delivery systems

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MDPI and ACS Style

Barbosa, J.A.A.; Zoppi, A.; Quevedo, M.A.; de Melo, P.N.; de Medeiros, A.S.A.; Streck, L.; de Oliveira, A.R.; Fernandes-Pedrosa, M.F.; Longhi, M.R.; da Silva-Júnior, A.A. Triethanolamine Stabilization of Methotrexate-β-Cyclodextrin Interactions in Ternary Complexes. Int. J. Mol. Sci. 2014, 15, 17077-17099.

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