Study of tolbutamide-hydroxypropyl-gamma-cyclodextrin interaction in solution and solid state

Tolbutamide-hydroxypropyl-gamma-cyclodextrin (TBM-HPGCD) interaction has been investigated in an aqueous environment and in the solid state. The solubility of TBM was increased in accord with the amount of HPGCD added to the aqueous medium forming a soluble inclusion compound. The phase solubility diagram obtained was of A(L) type. Physical mixtures and kneaded systems of the drug and cyclodextrin derivative were prepared in 1:1 and 1:2 drug/cyclodextrin mol/mol ratio. All solid binary systems were characterised by hot-stage microscopy (HSM), differential scanning calorimetry (DSC), thermogravimetry (TG) and X-ray powder diffractometry (XRD). An inclusion complex was formed in both of the kneaded systems. In the 1:2 kneaded system, the entire drug was included in the cyclodextrin cavity, while, in the 1:1 kneaded system only a part of the drug formed an inclusion complex with the cyclodextrin. A significant improvement in the dissolution of the drug was obtained from the kneaded systems in comparison with that of the pure TBM and physical mixtures. However, there was no significant difference between the dissolution profiles of the two kneaded systems. The study suggests that an inclusion complex was obtained both in aqueous solution and in solid state.     

Comparative study of oxaprozin complexation with natural and chemically-modified cyclodextrins in solution and in the solid state

The complexing, solubilizing and amorphizing abilities toward oxaprozin (a poorly water-soluble anti-inflammatory agent) of some β-cyclodextrin derivatives (hydroxypropyl-βCd, heptakis-2,6-di-O-methyl-βCd (DIMEB) amorphous randomly substituted methyl-βCd (RAMEB) and semi-crystalline methyl-βCd (CRYSMEΒ)) were investigated and compared with those of natural (α-, β-, γ-) cyclodextrins. The role of both the cavity size, the amorphous or crystalline state and the presence and type of substituent on the ability of cyclodextrins in establishing effective interactions with the drug has been evaluated. Equimolar drug-cyclodextrin solid systems were prepared by blending, kneading, co-grinding, sealed-heating, coevaporation, and colyophilization. Drug-carrier interactions were studied in both the liquid and solid state by phase-solubility analysis, differential scanning calorimetry, X-ray powder diffractometry, FT-IR spectroscopy and scanning electron microscopy. βCd showed the best performance among the natural Cds, indicating that its cavity was the most suitable for accommodating the drug molecule. The presence of substituents on the rim of the βCd cavity significantly improved its complexing and solubilizing effectiveness towards the drug, and methylated derivatives were better than the hydroxy-propylated ones The amorphous nature of the partner was also important: among the examined methyl-derivatives, RAMEB proved to be the most effective in performing solid state interactions and in improving drug wettability and dissolution properties.     

Phase solubility analysis in studying the interaction of nifedipine with selected cyclodextrins in aqueous solution

The solubilizing potential and complexing tendencies of six cyclodextrins (CyD) with nifedipine in aqueous solution were evaluated using phase solubility methods. Solubility curves of nifedipine with -CyD, 2-hydroxypropyl--CyD (2HP--CyD) and 2-hydroxypropyl--cyclodextrin (2HP--CyD) were classified as type A_L, while for heptakis (2,6-dimethyl)--CyD (DIMEB), randomly methylated--CyD (RAMEB) and -CyD, A_p type phase behaviour was observed. Stability constants, calculated from phase solubility diagrams, decreased in the order: DIMEB > RAMEB > -CyD > 21HP--CyD > -CyD > 2HP--CyD.     

Diels-Alder reaction volumes in the solid state and solution

The densities of anthracene, tetracyanoethylene, maleic anhydride, N-phenylmaleineimide, trans, trans-1,4-diphenylbuta-1,3-diene, and their Diels-Alder adducts were measured in the solid state and in solution at 25 °C. The reaction volumes in the solid state were calculated from the difference in molar volumes. They turned out to be low, close to each other (–4 to –11 cm³ mol^–1), and slightly different from the reaction volumes (–8±1 cm³ mol^–1) calculated from the van der Waals radii. The reaction volumes in solutions (–15 to –32 cm³ mol^–1) were found from the difference in partial molar volumes of the reactants in dioxane, acetonitrile, and 1,2-dichloroethane, The experimental Diels-Alder reaction volumes in solution are determined not only by the formation of new bonds in an adduct: a considerably higher contribution (to 75%) is made by a change in the volume of intermolecular empty spaces in solution on going from reactants to adducts.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2386–2390, November, 2004.     

Protonation of leucoemeraldine in the solid state and in solution

The protonation of leucoemeraldine in power form and in N-methylpyrrolidinone (NMP) solution by HCIO₄ and HBF₄ has been studied by x-ray photoelectron spectroscopy (XPS), infrared (IR), and ultraviolet (UV)-visible absorption spectroscopy. In powder form, less than 25% of the amine nitrogens can be protonated in the absence of oxygen. The effects of oxygen on the degree of protonation and the distribution of amine and imine units upon deprotonation of the salt are investigated. The degree of protonation in leuccemeraldine can be increased to about 50% with 3 M HCIO₄, similar to that achievable with emeraldine base in powder form. In NMP solution, leucoemeraldine is easily oxidized by dissolved oxygen. Protonation of both leucoemeraldine and emeraldine base in NMP solutions results in metastable species which gradually undergo deprotonation. The resulting products are affected by the O₂ content of the solutions. © 1993 John Wiley & Sons, Inc.     

Isomerization of cyclobutane ligands in the solid state and solution

Cyclobutane compounds are a class of compounds that can be conveniently synthesized in the solid state by employing crystal engineering principles. The rctt-isomer (or the syn-dimer) is the most common form of any cyclobutene compound that is obtained in the solid state by the photochemical [2 + 2] cycloaddition reactions. However, these rctt-isomers can be converted to other less accessible forms, under some special conditions. Isomerization of cyclobutane compounds thus plays an important role in synthetic chemistry. Such isomerization of cyclobutane compounds have been reported in organic salts, metal complexes, coordination polymers and metal-organic frameworks. In this review, these fascinating examples of isomerization that occur both in the solid state and solution phase have been discussed.     

Study of the 1,4-dihydroxyanthraquinone-yttrium(III) complex in solution and in the solid state

The photometric and fluorometric characteristics of the complex formed by 1,4-dihydroxyanthraquinone with Y(III) in 20–80% water-ethanol solution are described by the study of several variables. The stoichiometry and stability constant of the complex in the solution are 1:1 and log K = 4.57, respectively. The 1,4-dihydroxyanthraquinone-Y(III) solid complex has been prepared and studied by infrared spectroscopy and thermal analysis. The thermal behavior of this compound has been studied using thermogravimetry and differential scanning calorimetry techniques and the residue verified by X-ray diffraction.     

Spectroscopic investigation of the interaction of p-benzoquinone with casein in the solid state

The reaction between p-benzoquinone (PBQ) and casein (protein) in the solid state was studied. After reaction with protein, the FT-IR spectra showed a new band at 1215 cm^?1, with an intense sign attributed for casein/PBQ product. An optimum amount of PBQ for determination of the product when mixed with casein was 100 mg and a reaction time of 30 min. The product was stable for a period of 24 h after the reacting by heating. The interaction of PBQ with casein was investigated by FT-IR, reflectance, Raman and EPR spectroscopies. The reaction between PBQ and casein in the solid state yields a radical species (p-benzosemiquinone) that it is stabilized by the presence of p-biphenolate and p-benzoquinone species in the solid state.     

The structure of hydantoins in solution and in the solid state

The results of NMR spectroscopic and X-ray crystallographic studies are critically discussed with respect to the structure of hydantoins, their tautomerism, and their acidity. The imide NH proton of the preferred, nearly planar 2,4-imidazolidine-dione tautomer proved to be more acidic than the corresponding amide NH proton. Phenyl substituents at the ring nitrogen atoms and at C-5 are twisted from the plane of the hydantoin ring; in case ofortho substituents restricted rotation about the N-aryl bond was found and the barrier to rotation determined by dynamic NMR spectroscopy. For 5-benzyl substituents, afolded conformation of the two rings, due to intramolecular interactions, was found and for 5-exo-methylene substituted hydantoins the relevant E/Z isomerism at theexo-cyclic C, C double bond was studied. In addition, the¹H and¹³C chemical shifts of the hydantoins proved to excellently indicate the electronic distribution along the hydantoin ring moiety. Finally, the mass spectrometric fragmentation of the hydantoins is critically discussed.Dedicated to Prof. Rolf Borsdorf on the occasion of his 65th birthday.     

Interactions of cholesterol with cyclodextrins in aqueous solution

The interaction of cholesterol with several cyclodextrins (CDs) was investigated in water using solubility method. It was found that heptakis (2,6-di-O-methyl)-beta-CD (DOM-beta-CD) forms two types of soluble complex, with molar ratios of 1 : 1 and 1 : 2 (cholesterol : DOM-beta-CD), and neither a soluble nor insoluble complex is formed between cholesterol and alpha-CD, beta-CD, and gamma-CD, although a minor soluble complex formation was observed between cholesterol and 2-hydroxylpropyl-beta-CD. The thermodynamic parameters for 1 : 1 and 1 : 2 complex formation of cholesterol with DOM-beta-CD obtained from the changes in K with temperature are as follows: DeltaG degrees (1 : 1)=-11.6 kJ/mol at 25 degrees C (K(1 : 1)=1.09x10(2) M(-1)); DeltaH degrees (1 : 1)=-3.38 kJ/mol; TDeltaS degrees (1 : 1)=8.25 kJ/mol; DeltaG degrees (1 : 2)=-27.1 kJ/mol at 25 degrees C (K(1 : 2)=5.68x10(4) M(-1)); DeltaH degrees (1 : 2)=-3.96 kJ/mol; and TDeltaS degrees (1 : 2)=23.2 kJ/mol. The formation of the 1 : 2 complex occurred much more easily than that of the 1 : 1 complex. The driving force for 1 : 1 and 1 : 2 complex formation was considered to be mainly hydrophobic interaction. Also, based on the measurements of proton nuclear magnetic resonance spectra and studies with Corey-Pauling-Koltun atomic models, the probable structutures of the 1 : 2 complex were estimated.     

Physicochemical characterization of terbinafine-cyclodextrin complexes in solution and in the solid state

Terbinafine (TB) is an allylamine derivative used as oral and topical antifungal agent. The physicochemical properties of the complexes between TB and different cyclodextrins (CDs): α-CD, β-CD, hydroxypropylβ-CD, methylβ-CD and γ-CD, have been studied in pH 12 aqueous solutions at 25 °C and in the solid state. Different phase solubility profiles of TB in the presence of CDs have been obtained: A_L type for TB with hydroxypropylβ-CD and γ-CD, A_P type for the complexes with methylβ-CD and α-CD, while a B_S profile was found for TB-β-CD. The apparent stability constants of the complexes were calculated at 25 °C from the phase solubility diagrams. The higher increase of TB solubility, up to 200-fold, together with the higher value of the stability constant were found for the complex with methylβ-CD. Solid systems of 1:1 drug:CD molar ratio were prepared and characterised using X-ray diffraction patterns, thermal analysis and FTIR spectroscopy. The coevaporation method can be considered the best method in preparing these solid complexes. The complexes of TB with natural CDs, except with α-CD, were crystalline, whereas the methyl and hydroxypropyl derivatives gave rise to amorphous phases. Dissolution rate studies have been performed with TB-β-CD and TB-HPβ-CD complexes, showing a positive influence of complexation on the drug dissolution.     

The interaction of solvatochromic pyridiniophenolates with cyclodextrins

The interactions of six solvatochromic pyridiniophenolate dyes with α- and β-cyclodextrins were investigated with the aid of UV-vis and ¹H NMR spectroscopies, and molecular dynamics simulations. The deduced mode of encapsulation of these dyes within the hydrophobic host cavity was employed as a measure of the relative contributions of the donor and acceptor moieties to their solvatochromic properties.     

Structure formation of sulfonated polyphenylquinoxalines in solution and in the solid state

Sulfonated polyphenylquinoxalines with different content of sulfo groups have been synthesized by polymer analogous reactions under different conditions. The rheological properties of these polymers in Nmethylpyrrolidone have been studied. The mechanical properties of films based on sulfonated polyphenylquinoxalines under uniaxial tension have been measured. The structures of the polymers have been examined by AFM.     

Electronic transitions of vanadyl phthalocyanine in solution and in the solid state

The electronic absorption and luminescence of vanadyl phthalocyanine (Pc) in dilute solution. and solids at 300 K were measured and analyzed qualitatively with the Ake and Gouterman(AG) mode [1] and the exciton in molecular crystal model [2]. Good agreement between the group theoretical predictions and the observed spectra was found. The presence of trace aggregates in VOPc dilute solutions was clearly illustrated by their characteristic O-O fluoreseences. The dimer fluoresces on the high energy side of the monomer, whereas the signal from the heavier aggregates appears on the low energy side. The presence of an unpaired electron in the monomer results in a much smaller fluorescence yield as compared to the dimeric form in which the odd electrons are paired. The absorption and fluorescence vibronic progressions suggest that the monomer is quite stable upon optical excitation to the first excited singlet. Our spectra show that there are at least two crystal forms in the phase I solid in agreement with Griffiths et al.`s calorimetric observation [3]. One of the two forms is dimeric as proposed by Griffiths et al. and confirmed by us. The extremely low radiative yield of the dimeric form is attributed to ultrafast exciton migration and to the intrinsic low yield of the molecules. In the phase II crystal, two prominent electronic absorptions were predicted and assigned. The low luminescence yield of this phase is ascribed to the rapid ²Q ? ²T₁ relaxation which also leads to the greatly red shifted luminescence (i.e. ²T₁ → ²T) relative to the absorption, ²T → ²Q. Molecules in this phase are treated as monomeric rather than dimeric as in one of the phase I forms. Thus, the characteristics of the unpaired electron of the single molecule are preserved in the phase II crystal.     

Self-association and self-assembly of molecular clips in solution and in the solid state

Clip molecules based on diphenylglycoluril form well-defined dimeric structures in chloroform solution and in the solid state. In solution the dimerization process is based on favourable π-π interactions and cavity filling effects. A combination of favourable π-π interactions and crystal packing forces determine the self-assembly of clips in the solid state. The geometry that the clip molecules adopt in solution and in a series of X-ray crystal structures is compared with favourable geometries predicted by molecular modelling calculations.     

Unprecedented synthesis of 1,3-dimethylcyclobutadiene in the solid state and aqueous solution

Cyclobutadiene ( CBD ), the smallest cyclic hydrocarbon bearing conjugated double bonds, has long intrigued chemists because of its chemical characteristics. The question of whether the molecule could be prepared at all has been answered, but the parent compound and its unperturbed derivatives have eluded crystallographic characterization or synthesis “in water”. Different approaches have been used to generate and to trap cyclobutadiene in a variety of confined environments: a) an Ar matrix at cryogenic temperatures, b) a hemicarcerand cage enabling the characterization by NMR spectroscopy in solution, and c) a crystalline guanidinium–sulfonate–calixarene G₄C matrix that is stable enough to allow photoreactions in the solid state. In the latter case, the 4,6‐dimethyl‐α‐pyrone precursor, Me₂1 , has been immobilized in a guanidinium–sulfonate–calixarene G₄C crystalline network through a combination of non‐covalent interactions. UV irradiation of the crystals transforms the entrapped Me₂1 into a 4,6‐dimethyl‐Dewar‐β‐lactone intermediate, Me₂2 , and rectangular‐bent 1,3‐dimethylcyclobutadiene, Me₂CBD^R , which are sufficiently stable under the confined conditions at 175 K to allow a conventional structure determination by X‐ray diffraction. Further irradiation drives the reaction towards Me₂3&Me₂CBD^S /CO₂ (63.7 %) and Me₂CBD^R (37.3 %) superposed crystalline architectures and the amplification of Me₂CBD^R . The crystallographic models are supported by additional FTIR and Raman experiments in the solid state and by ¹H NMR spectroscopy and ESI mass spectrometry experiments in aqueous solution. Amazingly, the 4,6‐dimethyl‐Dewar‐β‐lactone, Me₂2 , the cyclobutadiene‐carboxyl zwitterion, Me₂3 , and 1,3‐dimethylcyclobutadiene, Me₂CBD , were obtained by ultraviolet irradiation of an aqueous solution of G₄C{Me₂1} . 1,3‐Dimethylcyclobutadiene is stable in water at room temperature for several weeks and even up to 50 °C as demonstrated by ¹H NMR spectroscopy.     

The interaction of caffeine with substituted cyclodextrins in water

The interaction of caffeine with hydroxypropyl-and methylcyclodextrins in water was studied by the calorimetry, spectroscopy, and solubility methods at 298.15 K. The interaction of caffeine with these cyclodextrins did not result in the formation of stable inclusion complexes and was mostly accompanied by predominantly endothermic effects of particle dehydration. The introduction of substituents and changes in the size of cyclodextrin molecular cavity did not influence the ability of cyclodextrins to form complexes with caffeine. The conclusion was drawn that substituted cyclodextrins could not be used for increasing the solubility of caffeine in water.     

Inclusion complex of cinnarizine withβ-cyclodextrin in aqueous solution and in solid state

Inclusion complex formation of cinnarizine (CN) with -cyclodextrin (-CD) in aqueous solution and in solid state was confirmed by the solubility method, powder X-ray diffractometry, differential scanning calorimetry (DSC) and proton nuclear magnetic resonance (¹H-NMR) spectroscopy. The apparent stability constant, K, of the complex in water at 20°C was estimated as 6.2×10³M^–1. The stoichiometry of the complex was given as the ratio 12 of CN to -CD. The dissolution rate of CN/-CD complex which could be prepared three different methods, coprecipitation method, neutralization method and spray-drying method, was much more rapid than intact CN, i.e., about 30 times or more. The degradation of CN in acidic solution was found to be of pseudo first-order reaction. The pseudo first-order rate constant with -CD decrease with an increase in concentration of -CD at pH 1.20. The inclusion complex prepared by spray-drying method was very stable under heating conditions and under high humid conditions. There was no difference in the bioavailability of CN between oral administration of -CD complex and that of CN alone. The absorption of CN decreased significantly when CN administered with NaHCO₃. However, there was observed no decrease in the case of CN/-CD inclusion complex.