Molecular Modelling and 1H-NMR: Ultimate Tools for the Investigation of Tolbutamide: .BETA.-Cyclodextrin and Tolbutamide: Hydroxypropyl-.BETA.-Cyclodextrin Complexes.

Abstract

Cyclodextrins (CDs) are cyclic oligosaccharides composed of ␣-1,4-linked D-glucopyranose units. The most common of these ring-shaped molecules are the a-, b-, and g-CDs formed by six, seven, and eight glucose units, respectively. 1)CDs are toroidal molecules with a truncated cone structure where the secondary hydroxyl groups are located on the wider side of the ring, while the primary hydroxyl groups are positioned on the opposite, narrower side of the torus. The -CH groups carrying the H-1, H-2, and H-4 protons are located on the exterior of the molecule and the hydroxyl groups are oriented to the cone exterior, which makes the external faces of CDs decidedly hydrophilic. The interior of the torus, which offers an environment of much lower polarity than that present in water, is lined by two rings of -CH groups (H-3 and H-5) and by a ring of glycosidic "ether oxygens" (O-4), with H-6 located near the cavity.2) A great variety of "guest" molecules of suitable size and shape may be entirely or partially included in this hydrophobic cavity, resulting in a stable association without formation of covalent bonds. The complexation driving forces have been attributed to hydrophobic interactions, van der Waals-London dispersion forces, and hydrogen bonds. 3,4) In the pharmaceutical field this complexation phenomenon has been extensively applied to enhance the solubility, dissolution rate, and bioavailability of sparingly soluble drugs in gastrointestinal fluids.5-10) Because of the increasing interest in CDs and their inherent usefulness, several studies have been conducted to clarify the mechanism of complexation.In previous studies, the ability of b-CD and hydroxypropyl-b-cyclodextrin (HP-b-CD) to form inclusion complexes with tolbutamide (TBM), in order to increase its solubility, dissolution rate, 11) and oral bioavailability 12) was evaluated. Important information on the solid-phase structure of these complexes may be obtained via X-ray analysis when a suitable crystal of the product is available. However, X-ray diffractograms of the lyophilized TBM:CD complexes previously reported 11) have demonstrated the complete amorphousness of the product obtained, making it impossible to gain more detailed information from them. Although solubility studies indicated the existence of complexation between TBM and b-CD or HP-b-CD in solution, 11) the exact mechanism of complexation could not be deduced.The use of computer-aided molecular modelling and 1 H-NMR studies has proved to hold promise for such purposes, especially for systems or molecules of biological interest which "act" in aqueous medium. These techniques have been used as important tools for investigating the conformation of the most favored complexes and to obtain a better knowledge of the geometry of the system and the topology of the interactions between guest and CDs. [13][14][15][16][17] Therefore in the present study we coupled these techniques, which allowed us to compare and to integrate the theoretical findings obtained in a vacuum (molecular modelling) ...

A 5,7-Dimethoxyflavone/Hydroxypropyl-β-Cyclodextrin Inclusion Complex with Anti-Butyrylcholinesterase Activity

“…S3), where the Δδ of the protons H3 and (especially) H5 (inside the HPβ-CD structure) were indeed larger than the others (H1, H2, H4, H6 and Me) that are located on the outside of the structure. The larger changes are explained by the magnetic anisotropic effect in which the presence of the aromatic benzene moiety of 5,7-DMF caused a shielding effect towards the interior protons of HPβ-CD (26). Thus, these results strongly support the formation of a 5,7-DMF/HPβ-CD inclusion complex.…”

Study of inclusion complex of β-cyclodextrin and levofloxacin and its effect on the solution equilibria between gadolinium(III) ion and levofloxacin

“…In addition, piperazine protons 2 0 H and 6 0 H were shifted upfield (Dd = 0.080) as opposed to 3 0 H and 5 0 H (Dd = -0.026) and methyl group of piperazine (Dd = -0.028). The positive sign for LEV suggests that they are located near oxygen in the b-CD cavity, while the negative one indicates the position of this moiety outside the cavity [25].…”

Multicomponent complex formation between vinpocetine, cyclodextrins, tartaric acid and water-soluble polymers monitored by NMR and solubility studies

“…Previously, we have reported the preparation and physicochemical characterization of vinpocetine (VP) multicomponent complexes with ␤CD, SBE␤CD, tartaric acid (TA) and the water-soluble polymers hydroxypropylmethylcellulose (HPMC) and polyvinylpyrrolidone K30 (PVP), in solidstate, by scanning electron microscopy, differential scanning calorimetry, X-ray diffractometry and Fourier-transform infrared spectroscopy (Ribeiro et al, 2003a,b). However, these techniques can hardly suggest if guest molecules form a complex or not and cannot provide a clear answer about the type of complex formed (inclusion or adsorption) or the structural conformation of the molecules involved (Djedaini and Perly, 1991;Veiga et al, 2001). This information can only be provided by high resolution nuclear magnetic resonance spectroscopy (NMR) since this technique allows a clear distinction between inclusion and other possible external interaction processes by observing guest and host molecules simultaneously and is capable to differentiate the part of the guest molecule involved in the interaction with the CD cavity (Fernandes et al, 2003).…”