Dataset Information

Structural diversity in the host-guest complexes of the antifolate pemetrexed with native cyclodextrins: gas phase, solution and solid state studies.

ABSTRACT: The complexation of the antifolate pemetrexed (PTX) with native cyclodextrins was studied. This process, along with the findings gathered for the structurally related folic acid was treated as a model for exploiting host-guest interactions of this class of guest molecules in the gas phase, in solution and in the solid state. Mass spectrometry was employed for the investigation of the architecture and relative gas-phase stabilities of these supramolecular complexes. The mode of complexation was further tracked by 1D and 2D NMR proving the formation of the exclusion-type complex with ?-CD and pseudorotaxane inclusion-type complexes with ?-, and ?-CDs. UV-vis titrations at pH 7.4 gave association constants for the obtained complexes. The stability of the complexes increases in the series: ?-CD/PTX < ?-CD/PTX << ?-CD/PTX. The association of PTX with a monomer cyclodextrin equivalent - methyl ?-D-glucopyranoside - was investigated for a deeper understanding of the type of host-guest interactions. Solid state studies of PTX/CDs were performed using FTIR-ATR and Raman spectroscopy techniques.

SUBMITTER: Ceborska M

PROVIDER: S-EPMC5669224 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Structural diversity in the host-guest complexes of the antifolate pemetrexed with native cyclodextrins: gas phase, solution and solid state studies.

Ceborska Magdalena M Zimnicka Magdalena M Kowalska Aneta Aniela AA Dąbrowa Kajetan K Repeć Barbara B

Beilstein journal of organic chemistry 20171025

The complexation of the antifolate pemetrexed (PTX) with native cyclodextrins was studied. This process, along with the findings gathered for the structurally related folic acid was treated as a model for exploiting host-guest interactions of this class of guest molecules in the gas phase, in solution and in the solid state. Mass spectrometry was employed for the investigation of the architecture and relative gas-phase stabilities of these supramolecular complexes. The mode of complexation was f ...[more]

PMID: 29114329

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Project description:Pterostilbene (3,5-dimethoxy-4'-hydroxystilbene, PTB) is a natural dietary stilbene, occurring primarily in blueberries and Pterocarpus marsupium heartwood. The interest in this compound is related to its different biological and pharmacological properties, such as its antioxidant, anti-inflammatory, and anticarcinogenic activities and its capacity to reduce and regulate cholesterol and blood sugar levels. Nevertheless, its use in therapy is hindered by its low aqueous solubility; to overcome this limitation we studied the feasibility of the use of cyclodextrins (CDs) as solubility-enhancing agents. CDs are natural macrocyclic oligomers composed of α-d-glucose units linked by α-1,4 glycosidic bonds to form torus-shaped molecules, responsible for inclusion complex formation with organic molecules. In particular, the aim of this study was to evaluate the feasibility of complexation between PTB and native CDs using various preparative methods. The isolated solid products were characterized using differential scanning calorimetry (DSC), simultaneous thermogravimetric/DSC analysis (TGA/DSC), Fourier transform infrared (FT-IR) spectroscopy, and X-ray diffraction (XRD) on powder and single crystals. The results indicated little or no evidence of the affinity of PTB to complex with α-CD using the kneading method. However, with β-CD and γ-CD thermal analysis revealed an interaction which was also corroborated by FT-IR and 1H-NMR spectroscopy. With β-CD, a hydrated complex of PTB was isolated and its characterization by single-crystal XRD revealed, for the first time, the mode of inclusion of the PTB molecule in the cavity of a CD. To complement the solid-state data, liquid-phase studies were carried out to establish the effect of CDs on the aqueous solubility of PTB and to determine the complex stoichiometries and the association constants for complex formation. Phase-solubility studies showed AL-type profiles for α- and β-CD and a BS profile for γ-CD, with K1:1 values of 1144, 4950, and 133 M-1 for α-CD·PTB, β-CD·PTB, and γ-CD·PTB, respectively. The stoichiometry of CD·PTB complexes, determined by Job's method, revealed for each system a 1:1 molar ratio. The dissolution rate of PTB was approximately doubled just by employing simple physical mixtures, but the best performance was achieved by products obtained via kneading and co-precipitation, which effected the complete dissolution of PTB in 40 and 20 min for β-CD and γ-CD, respectively.

Project description:A detailed comprehensive study on how the formation of soluble and insoluble carbamazepine/cyclodextrins (CBZ/CD) complexes (with consequent changes in the solid-phase composition) depends on the CD structure is not yet available. Moreover, the study of possible influence of this drug on the tendency of CDs and their complexes to self-aggregate is still lacking. Phase-solubility studies demonstrated that CDs and CBZ form a range of soluble (AL-type: αCD, βCD, and hydroxypropylated CDs) and insoluble (BS-type: γCD) complexes depending on CD used. HPβCD proved to be the best CD solubilizer for CBZ forming the most stable complex with highest apparent solubility, whereas γCD was shown to be the best native CD. For the native CDs, CBZ solubilization increases with increasing CD cavity diameter (αCD ≪ βCD < γCD). Solid phases collected from phase-solubility studies were characterized by Fourier-transformed infrared spectroscopy, differential scanning calorimetry, and X-ray powder diffraction to elucidate their composition and crystalline structure. They provided similar conclusions being overall supportive of phase-solubility, osmolality, and permeation studies results. Solid CBZ was the only detected component for AL-type profiles over the CD concentration range studied, whereas precipitation of poorly soluble CBZ/γCD complexes (BS-type) was observed (i.e., at and beyond plateau region). Osmometry and permeation studies were applied to evaluate the effect of CBZ on the aggregate formation and also to elucidate their influence on CD complex solubility and permeation profile. Permeation method was shown to be the most effective method to detect and evaluate aggregate formation in aqueous γCD and HPβCD solutions containing CBZ. CBZ did not affect the HPβCD tendency to self-aggregate but CBZ did modify the aggregation behavior of γCD decreasing the apparent critical aggregation concentration value from 4.2% (w/v) (in pure aqueous γCD solution) to 2.5% (w/v) (when CBZ was present).

Dataset Information

Structural diversity in the host-guest complexes of the antifolate pemetrexed with native cyclodextrins: gas phase, solution and solid state studies.

Publications

Structural diversity in the host-guest complexes of the antifolate pemetrexed with native cyclodextrins: gas phase, solution and solid state studies.

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