Effect of Buffer Species on the Complexation of Basic Drug Terfenadine with β-Cyclodextrin

The complexation of terfenadine (Terf) with β-cyclodextrin (β-CD) in solution and solid state has been investigated by phase solubility diagram (PSD), differential scanning calorimetry (DSC), powder X-ray diffractometry (PXD) and proton nuclear magnetic resonance (¹H-NMR). The PSD results indicated that the salt saturation with the buffer counter ion (citrate⁻², H₂PO₄⁻¹ and Cl⁻¹ ions) of Terf (pK _a = 9.5) and the hydrophobic effect play in tandem to increase the value of the complex formation constant (K₁₁) measured at different conditions of pH, ionic strength, buffer type and buffer concentration. The correlation of the free energy of complex formation (ΔG₁₁) with the free energy of inherent solubility of Terf (ΔG_So) obtained by changing the pH, ionic strength and buffer concentration was used to measure the contribution of the hydrophobic effect (desolvation) to complex formation. The hydrophobic effect was found to constitute 57.8% of the driving force for complex stability, while other factors including specific interactions contribute −13.4 kJ/mol. ¹H-NMR spectra of Terf–citrate and Terf–HCl salts gave identical chemical shift displacements (ΔΔ) upon complexation, thus indicating that the counter anions are positioned somewhere outside of the β-CD cavity. DSC, XRPD and ¹H-NMR proved the formation of solid Terf/acid/β-CD ternary complexes.     

Inclusion complexation of diclofenac with natural and modified cyclodextrins explored through phase solubility, 1H-NMR and molecular modeling studies

Guest–host interactions were examined for neutral diclofenac (Diclo) and Diclofenac sodium (Diclo sodium) with each of the cyclodextrin (CD) derivatives: α-CD, β-CD, γ-CD and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), all in 0.05 M aqueous phosphate buffer solution adjusted to 0.2 M ionic strength with NaCl at 20 °C, and with β-CD at different pHs and temperatures. The pH solubility profiles were measured to obtain the acid–base ionization constants (pK _as) for Diclo in the presence and absence of β-CD. Phase solubility diagrams (PSDs) were also measured and analyzed through rigorous procedures to obtain estimates of the complex formation constants for Diclo/CD and Diclo sodium/CD complexation in aqueous solutions. The results indicate that both Diclo and Diclo sodium form soluble 1:1 complexes with α-, β-, and HP-β-CD. In contrast, Diclo forms soluble 1:1 Diclo/γ-CD complexes, while Diclo sodium forms 1:1 and 2:1 Diclo/γ-CD, but the 1:1 complex saturates at 5.8 mM γ-CD with a solubility product constant (pK _sp = 5.5). Therefore, though overall complex stabilities were found to follow the decreasing order: γ-CD > HP-β-CD > β-CD > α-CD, some complex precipitation problems may be faced with aqueous formulations of Diclo sodium with γ-CD, where the overall concentration of the latter exceeds 5.8 mM γ-CD. Both ¹H-NMR spectroscopic and molecular mechanical modeling (MM⁺) studies of Diclo/β-CD indicate the possible formation of soluble isomeric 1:1 complexes in water.     

Experimental Analysis of Complex Formation of Niflumic Acid with β-Cyclodextrins

Complex formation of niflumic acid with β-, hydroxypropyl-β- and methyl-β-cyclodextrins in aqueous solution (pH 7.4) were studied by calorimetry of solution, ¹H NMR spectroscopy and solubility method. The enhancement of niflumic acid solubility in the presence of hydroxypropyl-β-cyclodextrin was detected. This effect is explained on the basis of ¹H NMR data confirming the inclusion of hydrophobic trifluoromethylphenyl residue of niflumic acid molecule into the macrocyclic cavity. The thermodynamic parameters of 1:1 binding were derived from the data of␣calorimetry and solubility measurements. It was obtained, that complex formation of niflumic acid with β-cyclodextrin and both its derivatives is enthalpy driven. Substitutes surrounding the macrocyclic cavity slightly influence the thermodynamics of complex formation resulting in decrease of stability of the complexes formed.     

Interactions of tetrakis(4-N-methylpyridyl)porphyrin with cyclodextrins and disodium phthalate in aqueous solution

In pH 7.3 buffers, the interactions of a cationic porphyrin, tetrakis(4-N-methylpyridyl)porphyrin (TMPyP), with cyclodextrins (CDs) and disodium phthalate (DSP) have been examined by means of absorption, fluorescence, and induced circular dichroism spectroscopy. α-CD, β-CD, and γ-CD form a 1:1 inclusion complex with a TMPyP monomer, which dimerizes in solution without CD. TMPyP also forms a 1:1 organic cation–organic anion complex with DSP. The 1:1 TMPyP–DSP complex forms a ternary CD–TMPyP–DSP inclusion complex with α-, β-, and γ-CD, in which a DSP molecule is not incorporated into the CD cavity. From the fluorescence intensity change, the␣equilibrium constants have been evaluated for the formation of the inclusion complexes and the organic cation–anion complexes.     

Selective Binding Thermodynamics of Bile Acids by Oligo (ethylenediamino)-β-Cyclodextrins and Their Copper (II) Complexes

Complex stability constants (K _S), standard molar enthalpy changes (ΔH°) and entropy changes (TΔS°) for the inclusion complexation of native β-cyclodextrin (β-CD) (1) and some modified β-CDs, i.e., mono(6-ethylenediamino-6-deoxy)-β-CD (3), mono[6-diethylenetriamino-6-deoxy]-β-CD (4) and their corresponding copper complexes 5 and 6, with four representative bile acid guests, i.e., cholate (CA), deoxycholate (DCA), glycocholate (GCA) and taurocholate (TCA), were determined at 25 °C in aqueous phosphate buffer solution (pH 7.20) by means of isothermal titration microcalorimetry (ITC). The stoichiometry of resulting inclusion complexes between CDs and bile acids was demonstrated by UV and conductivity as well as ITC experiments, showing 1:1 binding model upon all inclusion complexation except for metal-mediated dimer 5. The complex stability constants for modified β-CD 2–4 are dramatically magnified with the extended length of amino tether. As compared with 3 and 4, copper(II) complexes 5 and 6 significantly enhance not only binding ability but also molecular selectivity toward bile guest molecule CA through multipoint recognition, but decreased complexes stability toward TCA could be attributed to the decreased hydrophobic microenvironment of CDs cavity due to the introduction of copper(II) coordination center. Thermodynamically, the resulting complexes between hosts and bile guests are driven absolutely by enthalpy, accompanied by entropy gain or loss. Using the present data and those previously reported for mono(6-amino-6-deoxy)-β-CD (2), thermodynamic behavior and enhanced molecular selectivity could be discussed from the viewpoint of hydrophobic interactions, electrostatic cooperation and van der Waals between the hosts and guests.     

Crystal structure of <Emphasis Type="Italic">N</Emphasis>-(3-hydroxypropyl)-β-alanine and Bis(<Emphasis Type="Italic">N</Emphasis>-(3-hydroxypropyl)-β-alaninato)dicopper(II) [Cu<Subscript>2</Subscript> (Pro-ala)<Subscript>2</Subscript>]

N-(3-Hydroxypropyl)-β-alanine was synthesized by the reacti on of 3-aminopropanol with acrylic acid. From this ligand and basic copper carbonate, bis(N-(3-hydroxypropyl)-β-alaninato)dicopper(II) [Cu₂ (C₆H₁₁NO₃)₂] was obtained. The structures of the chelating agent and the copper complex were studied by X-ray diffraction. The Cu(II) coordination polyhedron is a distorted square pyramid. Each ligand forms six-membered β-alaninate and propanolamine chelate rings. The propoxy group functions as a bridge. In the crystal structure, the molecules form intermolecular coordination bonds C=O→Cu, which are perpendicular to the layers. The EPR signal typical of dimeric copper complexes is not observed due to low occupancy of the excited paramagnetic triplet state. The weak paramagnetic signal from monomeric copper complex allowed recording of the ¹H NMR spectrum of [Cu₂ (Pro-ala) ₂] with characteristic line broadening and contact shift. It follows from the obtained data that on dissolution, the complex dissociates by 40% to give monomeric copper complexes.     

The modes of complexation of benzimidazole with aqueous β-cyclodextrin explored by phase solubility, potentiometric titration, 1H-NMR and molecular modeling studies

The results of rigorous modeling of phase solubility diagrams, pH solubility profiles and potentiometric titrations revealed the following for benzimidazole (BZ) and BZ/β-CD complexation in aqueous solution: (a) the pK _a value of BZ estimated at 5.66 ± 0.08 was reduced to 5.33 ± 0.06 in the presence of 15 mM β-CD at 25 °C, thus indicating inclusion complex formation; (b) BZ forms soluble 1:1 and 2:1 BZ/β-CD complexes with complex formation constants K ₁₁ = 104 ± 8 M⁻¹ and K ₂₁ = 16 ± 6 M⁻¹; (c) protonated BZ forms only 1:1 complex with K ₁₁ = 42 ± 12 M⁻¹; (d) ¹H-NMR studies in D₂O showed significant upfield chemical shift displacements for inner cavity β-CD protons indicating inclusion complex formation, while (e) Molecular modeling of BZ-β-CD interactions in water clearly indicated complete inclusion of one BZ molecule into the β-CD cavity.     

A Study of Haloperidol Inclusion Complexes with <Emphasis Type="Italic">β</Emphasis>-Cyclodextrin Using Phase Solubility,NMR Spectroscopy and Molecular Modeling Techniques

Guest-host interactions of haloperidol (Halo) with β-cyclodextrin (β-CD) have been investigated using several techniques including phase solubility diagrams (PSD), proton nuclear magnetic resonance (¹H-NMR), X-ray powder diffractometry (XRPD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and molecular mechanical modeling (MM⁺). From an analysis of the PSDs, both protonated and neutral Halo (pK _a=8.5) form soluble 1:1 and 1:2 Halo/β-CD complexes, while the insoluble complex has 1:2 (Halo:β-CD) stoichiometry (B_S-type PSD). Ionization of Halo reduces its tendency to complex with β-CD, where the protonated species at pH=4.6 and 6.0 have K ₁₁ values of 100 L⋅mol⁻¹ and 298 L⋅mol⁻¹, respectively, compared with 2000 L⋅mol⁻¹ for neutral species at pH=10.6. The hydrophobic character of Halo was found to provide 32% of the driving force for complex stability, whereas other factors including specific interactions contribute −15 kJ⋅mol⁻¹. ¹H-NMR and MM⁺ studies indicate the formation of isomeric 1:1 and 1:2 complexes, where the chlorophenyl, flurophenyl, piperidine and butanone moieties become included into separate β-CD cavities. The dominant driving force for complexation is evidently van der Waals with very little electrostatic contribution. PSD, ¹H-NMR, XRPD, DSC and SEM studies indicate the formation of inclusion complexes in solution and in the solid state.     

Thermodynamics of the effects of substituent,degree of substitution,and pH on complex formation of hydroxypropyl-α- and hydroxypropyl-β-cyclodextrins with ascorbic acid

The interaction of ascorbic acid with hydroxypropyl-α- and hydroxypropyl-β-cyclodextrins of different degree of substitution was studied at 298.15 K and different pH using solution calorimetry. In an aqueous solution, only hydroxypropyl-β-cyclodextrins form weak molecular complexes with the nonionized form of ascorbic acid. The thermodynamic functions of complex formation and stability constants of the complexes were calculated. The systems with weak intermolecular interaction without complex formation were characterized by enthalpic virial coefficients. On the basis of the obtained thermodynamic characteristics it was shown that the selectivity of complex formation of hydroxypropyl-α- and hydroxypropyl-β-cyclodextrins with ascorbic acid is determined by the size of the macrocyclic cavity, the presence of the hydroxypropyl substituent, and the medium acidity. The degree of substitution of hydroxypropyl-β-cyclodextrins exerts no substantial effect on the thermodynamic parameters of interaction with ascorbic acid. __________ Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1828–1831, August, 2005.     

Experimental and Molecular Mechanical Studies of Complexation of Some 2H- and 3H- Indole Derivatives with Aqueous β-Cyclodextrin

Phase solubility diagrams (PSDs) at 25 ^∘C and molecular mechanical (MM) modeling were used to study the aqueous complexation of some 2H- and 3H-indole derivatives with β-cyclodextrin (β-CD). Among the 3H-indole derivatives investigated in this work, indole-3H-butyric acid forms the most stable 1:1 complex of the B _s -type PSD, whereas shorter chain derivatives form soluble 1:1 complexes (A _L -type PSDs) with their stability increasing as the chain length increases. Indole-2 carboxylic acid forms highly stable 1:1 and 1:2 complexes, with the lower-order complex reaching saturation first (B _s -type PSD). MM modeling indicates that the stability of the complex is highly correlated with the flexibility of the 3H-indole hydrocarbon chain, which yields a better geometrical fit within the β-CD cavity resulting from different hydrophilic interactions. These interactions are represented in the H-bonding of the carboxyl group with the primary hydroxyl group network that is situated at the narrow rim of the cavity, and also by a favorable interaction of the aromatic ring with the hydroxyl group network at the other rim.