Inclusion of Nonopiate Analgesic Drugs in Cyclodextrins. I. X-Ray Structure of a 1 : 1 β-Cyclodextrin-p-bromoacetanilide Complex

The preparation and X-ray crystal structure of a 1 : 1 complex between -cyclodextrin (-CD) and the analgesic p-bromoacetanilide are reported. Thermogravimetric and UV spectrophotometric analyses of single crystals grown from an aqueous solution containing host and guest in 1 : 1 molar ratio yielded the composition -CD p-bromoacetanilide $ 13.5H2O. Crystals of the complex are triclinic, space group P1, with a = 15.197(3), b = 15.613(2), c = 15.743(4) Å, = 87.16(2), = 98.29(2), = 103.39(1)° and Z = 2 crystallographically independent complex units per unit cell. The -CD molecules form head-to-head dimers which pack in the channel-mode. Each dimer contains two guest molecules whose acetylamino substituents are located at the dimer interface while the bromine atoms protrude from the -CD primary faces. The acetyl residues of both guest molecules were found to be disordered but the X-ray data permitted     

X-ray Structure and Thermal Properties of a 1:1 Inclusion Complex Between Permethylated β-Cyclodextrin and Psoralen

The phytoalexin psoralen (7H-furo[3,2-g][1]benzopyran-7-one) has been included in heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin (TRIMEB) to yield a solid crystalline complex of formula TRIMEB-psoralen-H₂O. Its X-ray structural elucidation provides an accurate model for cyclodextrin–furocoumarin interaction. Thermal analysis (hot stage microscopy, differential scanning calorimetry, thermogravimetry) indicated complex dehydration in the range 40–100°C followed by melting at 137.1°C. The X-ray analysis showed that the elongated guest molecule induces elliptical distortion in the host molecule, with which it interacts via C-H ?O hydrogen bonding and hydrophobic interactions. The host molecule adopts a very similar conformation to that in the isostructural complex with l-menthol as guest. Water molecules bridge symmetry-related TRIMEB molecules by hydrogen bonding.     

Stability of Ibuprofen in its Inclusion Complex with β-Cyclodextrin

The ibuprofen--cyclodextrin inclusion complex was prepared by theco-precipitation method. The identity of the obtained product was verified by X-ray and thermogravimetric techniques. The effect of -cyclodextrin on the stability of ibuprofen was analysed.     

Study of the Podophyllotoxin β-Cyclodextrin Inclusion Complex

The structure of the podophyllotoxin (P)/-cyclodextrin(-CD) inclusion complexhas been studied by infrared spectroscopy, UVspectroscopy, NMR spectroscopy and X-raydiffractometry. The association constant is 128 M^-1in water, calculated from thestraight portion of the phase-solubility diagram.     

Formation of an Inclusion Complex of a New Transition Metal Ligand in β-Cyclodextrin

The inclusion complex of a new transition metal ligand, 2,4,9-trithia-tricyclo[3.3.1.1^3,7]decane-7-carboxylic acid (2,4,9-trithia-adamantane-7-carboxylic acid, TPCOOH) in β-cyclodextrin was studied by ¹H NMR, 2D NOESY NMR spectroscopy, host-induced CD spectroscopy, and tandem mass spectrometry. ¹H NMR, MS–MS and NOESY data show that the TPCOOH guest forms a 1:1 inclusion complex with the host β-cyclodextrin. The NOESY experiments also show that TPCOOH is oriented in the complex with the thioketal end preferentially located at the larger opening of β-cyclodextrin. The orientation of the guest in the host molecule is also confirmed by the induced CD of the ligand, which shows a positive Cotton effect. An association constant of 660±20?M^?1 was determined by ¹H NMR titration for the complex at room temperature in D₂O.     

The Inclusion Complex of Ferrocene with a Dithiolene Functionalized β-Cyclodextrin

A new cyclodextrin derivative with the anion side-arm, mono[6-deoxy-6-(2-sodium thio-1,2-dicyane ethylenylthio)]-cyclodextrin (6-mnt-CD), and its inclusion complex with ferrocene (6-mnt-CD/Fc), have been prepared and characterized by elemental analysis, IR spectroscopy, UV spectroscopy, mass spectrometry, ¹³C-NMR spectroscopy, thermogravimetry, and cyclic voltammetry (CV). Thermogravimetry analysis of the compound shows that the thermal stabilities of both the host and the guest in the inclusion complex have been greatly improved due to an additional interaction between the side-arm of the host and the guest. The interplay between the guest and the host with side-arm in the complex resulted in smaller positive potential shifts in CV compared to that in the inclusion complex CD/Fc.     

Crystal Structure of β-Cyclodextrin-Felbinac Inclusion Complex

The crystal structure of the inclusion complex of β‐cyclodextrin (β‐CD) synthesized with felbinac (4‐biphenylacetic acid) was determined by single crystal X‐ray diffraction at 150 K. The complex contains two β‐CDs, two felbinac molecules, twenty‐two water molecules in the asymmetric unit, and could be formulated as (C₄₂H₇₀O₃₅)₂·(C₁₄H₁₂O₂)₂·22(H₂O). In the crystal lattice, the two β‐CD moieties form a head‐to‐head dimer jointed through hydrogen bonds, and the felbinacs that interact by face‐to‐face Π‐Π stacking are included in the β‐CD dimer cavity with their carboxyl groups protruding out from cavity opening. In crystals the dimer units of β‐CD are stacked in an intermediate type (IM) that consists of closely packed β‐CD dimer layers.     

Changes in the Solubility of β-Cyclodextrin on Complex Formation: Guest Enforced Solubility of β-Cyclodextrin Inclusion Complexes

The most common native host molecule, -cyclodextrin (cycloheptaamylose) is able toform inclusion complexes with a large variety of guestmolecules (or ions) of different size and shape. Theproperties of the included guest molecule are highlyinfluenced by the host-guest interaction, and thepractical usefulness of -cyclodextrin isdependent on these effects. These changes are mainlyinvestigated from the point of view of the guest andto a lesser extent from that of the host. In spite ofthis, the kind of guests and that of the host-guestinteractions during the formation of the inclusioncomplex seem to influence the properties of thehydrophilic domain of -cyclodextrin (i.e. thatof the supramolecule itself), too, and this effect canbe well demonstrated by the change of solubility ofdifferent -cyclodextrin inclusion complexes.This change can be best correlated with the solubilityof the guest as if the guest enforced its solubilityon the supramolecule.     

Study on the Structure of Supramolecular Inclusion Complex of β-Cyclodextrin with Retinoic Acid

The importance of Vitamin A for human health has been stressed in resent studies1, meanwhile its derivative so-called retinoic acid (RA) has been widely used as pharmaceutical to treat several types of skin disease and cancer2,3. However the application of retinoic acid is restrained for its poor water solubility, unstability and side effect on the human body.Cyclodextrins (CDs) are macrocyclic oligosaccharides built up from 6, 7, or 8 glucopyranose units called (, (, and (-CD, respectively…     

Structure of the β-Cyclodextrin·p-Hydroxybenzaldehyde Inclusion Complex in Aqueous Solution and in the Crystalline State

-Cyclodextrin (-CD) and p-hydroxybenzaldehyde (p-HB) were studied by ¹H-NMR in deuterated aqueous solution and the stoichiometry of the resulting complex (1:1) was determined by the continuous variation method. Inclusion of p-HB in -CD was confirmed by the observation of NMR shifts for the inside H5 protons of the -CD cavity. In the solid state X-ray analysis was carried out and revealed the detailed structure of the inclusion complex. Two -CDs cocrystallize with four p-HB and 9.45 water molecules[2(C₆H₁₀O₅)^7·4C₇H₆O_2·9.45H₂O] in the triclinic space group P1 with unit cell parameters: a = 15.262(2), b = 15.728(1), c = 16.350(1) Å, = 92.67(1)°, = 96.97(1)°, = 103.31(1)°. The anisotropic refinement of 1973 atomic parameters converged at an R-factor = 0.066 for 10157 data with F_o ² > 2 (F_o ²). The 2:4 stoichiometry for the -CD inclusion complex with p-HB in the crystalline state is different from that obtained in solution. -CD forms dimers stabilized by direct O2(m)₁O3(m)₁·O2(n)₂O3(n)₂ hydrogen bonds (intradimer) and by indirect O6(m)₁·O6(n)₂ hydrogen bonds with one or two bridging water molecules joined in between (interdimer). These dimers are stacked like coins in a roll constructing infinite channels where the p-HB molecules are included. The p-HB molecules direct their polar CHO and OH groups into the nonpolar -CD cavities and are hydrogen bonded to each other, yielding infinite, antiparallel chains. In addition, crystals of the complex were also investigated with thermogravimetry, vibrational spectroscopy (FTIR), and ¹³C CP-MAS NMR spectroscopy. The results obtained enabled us to structurally characterize the -CD inclusion complex with p-HB.     

Inclusion Complexes of Conjugated Nitroolefins in β-Cyclodextrin

Physical studies such as Powder X-ray,FT-IR, UV, ¹H and ¹³C NMR clearly identifya 1 : 1 inclusion complex formed between-cyclodextrin and nitroolefins such as-nitrostyrene, 1-nitrocyclohexene in thesolid state as well as in solution. The olefins lieshallow inside the cavity leaving the nitro groupoutside the torus. It has been found that the complexis capable of reacting with a-phenyl-N-p-methylphenyl nitrone ina 1,3-dipolar cycloaddition with excellent rateacceleration and regioselection. The NaBH₄reduction of the complex in the solid state leads tothe corresponding nitroalkane.     

The in vitro Pulmonary Deposition of a Budesonide γ-Cyclodextrin Inclusion Complex

The interest in dry powder inhalers (DPIs) has recently increasedbecause the problems associated with the propellants used in pressurized metered-dose inhalers (PMDIs) will be avoided. Cyclodextrins (CDs) may be used as excipients in inhalation powders;e.g., in order to increase the solubility, stability and absorption of an inhaled drug. In thepresent study, the effect of complexation of budesonide with -CD on its pulmonary deposition wasstudied in vitro. In the presence of -CD, the aqueous solubility of budesonidefollowed B_S-type phase-solubility behaviour. A precipitationcomplexation method was used to prepare the solid budenoside/-CD complexes. The pulmonary in vitrodeposition of budenoside was evaluated after inhalation of plain budesonide and budenoside/-CDcomplexes (lactose carrier used in both formulations) by using the ``Andersen' cascadeimpactor. The novel Taifun® was used as the DPI. The respirable fractionsof the emitted budesonide dose (initially and after the storage in 40 °C, RH 75%) werecomparable for both plain budesonide and budesonide/-CD complexes. The present studyindicates that a drug/CD-complex can be used in inhalation powderswithout lowering the pulmonary deposition of the drug.     

Theoretical Study on the Inclusion Complex of β-Cyclodextrin and Nitrobenzene

Quantum chemical calculations were carried out to investigate the structures and properties for the inclusion complexes of nitrobenzene (NB) into β-cyclodextrin. Two low-energy conformations of β-cyclodextrin (A and B) in the gas phase were initially investigated by the PM3 and B3LYP/6-31+G(d,p) calculations, respectively. Three different orientations were considered in the inclusion process of A and B with NB to form 1:1 complexes. Potential energy scan by PM3 calculations indicated that the phenyl orientation Ab for conformation A and the equator orientation Bc for conformation B are more favorable in energy, respectively. We also considered the 2:1 inclusion complexes of host A or B with guest NB in the gas phase. PM3 calculation indicated that the host-guest interaction energies to form 1:1 complexes are more negative than those to form 2:1 NB/B complexes. Finally, we studied the solvent effect of NB/CD complex, and PM3 results show that the influence of water molecules on the inclusion process is very important. The driving forces for the inclusion process and the geometries of complexes were discussed in detail.     

Study on the Supramolecular Inclusion Complex of β-Cyclodextrin/Lappaconitine

Lappaconitine (Lap) is a diterpenoid akaliamide, naturally occurring in roots and rhizomes of Aconitum and delphinium. Lap reveals bradycardic, hypotensive, antinocieptive activity. However, its application is restrained owing to its poor water solubility, toxicity and side effects on humans. In a number of pharmaceutical studies,CDs have been reported to interact with many drug molecules to form inclusion complexes. These inclusion complexes have been extensively used to improve water solubility of poorly soluble drugs, to reduce their toxicity, and to increase the dissolution rate [1]. In the present work, the β-CD/Lap complex was prepared by kneading method. The products have been characterized by the solubility measurement as well as UV, FTIR, NMR spectroscopy and X-ray powder diffractometry.     

Short Communication: Crystal Structure of a Molecular Complex from Native β-Cyclodextrin and Copper(II) Chloride

Reaction of β-cyclodextrin (β-CD) with CuCl₂ in neutral aqueous solutions gave a stable molecular complex without any side-arm support. The X-ray crystallographic analysis clarified that the copper ion was located at the bottom of the primary-hydroxy side as a CuCl₂(H₂O)₂ form. Hydrogen bonds were found between the Cl and H₂O ligands and β-CD hydroxy and ether groups. The copper ion is axially coordinated with a hydroxy group of a neighboring β-CD molecule, giving a one-dimensional β-CD/CuCl₂ array.     

Inclusion of Polyphenol Oxidase Substrates in β-Cyclodextrin: A 1 H-NMR Study

A ¹H-NMR study of the interactionsbetween -cyclodextrin (-CD) and included phenolic molecules (chloragenic acid and caffeic acid ) in aqueous medium is reported. The results confirm that inclusion occurs. Data analysis by the continuous variation method shows that all the complexes have 1 : 1 stoichiometries. Values for the apparent association constants of the inclusion compounds are estimated and compared with previously reported values.     

Stability of Mefenamic Acid in the Inclusion Complex with β-Cyclodextrin in the Solid Phase

The inclusion complex of mefenamic acid with -cyclodextrin was obtained by the method of coprecipitation from diethyl ether. The product was identified by the thermogravimetric and X-ray methods. The complex stability constants were determined by the potentiometric method. The effect of -CD on the solubility and stability of mefenamic acid was analysed.     

Inclusion of Enantiomeric Carvones in β-Cyclodextrin: a Variable Temperature 1H NMR Study in Aqueous Solution

In aqueous solution, the apparent association constant at room temperature for the 1 : 1 inclusion of S-(+)-carvone in - cyclodextrin is double of that for R-(-)-carvone, whereas, at 45 °C, both enantiomers have association constants two orders of magnitude smaller, with the S-(+) inclusion being then slightly weaker than the R-(-) encapsulation. Calculations carried out at the molecular mechanics, AM1 and STO-3G levels confirm the preferential inclusion of the S-enantiomer and provide important clues for understanding chiral discrimination by -cyclodextrin.     

X-Ray Diffraction and NMR Study of Inclusion Complex of Podophyllotoxin with β-Cyclodextrin

Podophyllotoxin(Figurel)isalignan,naturallyoccurringinrootsandrhizomesofPodophyllumemodiWall.var.ChineseSprague'.Thiscompoundisclinicallyusedtotreatseveraltypesofcancer2.However,asadrug,itisrestraintedduetoitshightoxicityandsideeffecttohumanbody.Wehavepreparedtheinclusioncomplexofpodophyllotoxinwith0-cyclodextrin(Figure2)inordertodecreasetoxicityandincreasesolubilityofpodophyllotoxin.ThestrUctureoftheinclusioncomplexofthepodophyllotoxinwith0-cyclodextrinhavebeenstudiedbythemethodsofX-raydi…