Host–Guest Interactions of Risperidone with Natural and Modified Cyclodextrins: Phase Solubility, Thermodynamics and Molecular Modeling Studies

The solubility of risperidone (Risp) in aqueous buffered cyclodextrin (CD) solution was investigated for α-, β-, γ- and HP-β-CD. The effects of pH, ionic strength and temperature on complex stability were also explored. Neutral Risp tends to form higher order complexes (1:2) with both β- and HP-β-CD, but only 1:1 type complexes with α-, and γ-CD. The tendency of Risp to complex with cyclodextrins is in the order β-CD > HP-β-CD > γ-CD > α-CD. The 1:1 complex formation constant of Risp/HP-β-CD increases with increasing ionic strength in an opposite trend to the inherent solubility (S ₀) of Risp, thus indicating significant hydrophobic effect. The hydrophobic effect contributes to the extent of 72% towards neutral Risp/HP-β-CD complex stability, while specific interactions contribute only 4.7 kJ/mol. Thermodynamic studies showed that 1:1 Risp/HP-β-CD complex formation is driven by a favorable enthalpy change (ΔH ⁰=−31.2 kJ/mol, ΔS ⁰=−7 J/mol.K) while the 1:2 complex is largely driven by entropy changes (ΔH ⁰=−5.0 kJ/mol, ΔS ⁰=42 J/mol.K). Complex stability was found to vary with pH, with a higher formation constant for neutral Risp. Molecular mechanical computations using MM (atomic charges and bond dipole algorithms) and Amber force fields, which were carried out to explore possible sites of interactions between Risp and CDs and to rationalize complex stoichiometry, produced similar results concerning optimal inclusion complex geometries and stoichiometries.     

Effect of Buffer Species on the Inclusion Complexation of Acidic Drug Celecoxib with Cyclodextrin in Solution

The interaction of celecoxib (Celox) with cyclodextrins (CDs) has been investigated by phase solubility techniques. In this study, the influences of CD type, pH, buffer type, buffer concentration and temperature on the tendency of Celox to form inclusion complexes with CDs were examined. The tendency of Celox to complex with CDs is in the order HP-β-CD > β-CD > γ-CD > α-CD, where the complex formation constants (K ₁₁) were 1377, 693, 126 and 60 M⁻¹, respectively. Also ionization of the slightly acidic Celox (pK _a=9.7) was found to reduce its tendency to complex (i.e., The K ₁₁ values of Celox/β-CD in 0.05 M phosphate buffer were 976 and 210 M⁻¹ for neutral and ionized Celox, respectively). Increasing citrate and phosphate buffer concentration enhances the tendency of ionized Celox to complex with β-CD as a result of a corresponding decrease in the inherent solubility (S ₀) of the Celox anion. On the other hand, these two buffers interact differently with neutral Celox and β-CD, where increasing phosphate buffer concentration at low pH enhances the complexation of neutral Celox by lowering S ₀, while increasing citrate buffer concentration at low pH reduces complex formation as citrate buffer species, mainly citric acid, act as a solublizer and a competitor for Celox and β-CD. The contribution of Celox hydrophobicity for complex stability constitutes about 77% of the driving force for complex stability. The complex formation of neutral Celox with β-CD (ΔG ⁰=−28.6 kJ/mol) is driven by both enthalpy (ΔH ⁰=−21.7 kJ/mol) and entropy (ΔS ⁰=23.3 J/mol K) changes.     

A temperature study on critical micellization concentration (CMC), solubility, and degree of counterion binding of α-sulfonatomyristic acid methyl ester in water by electroconductivity measurements

 For a sodium salt of α-sulfonatomyristic acid methyl ester (14SFNa), one of the α-SFMe series surfactants, critical micellization concentration (CMC), solubility and degree of counterion binding (β) were determined by means of electrocon-ductivity measurements at different temperatures (at every 5 °C) ranging from 15 to 50 °C. The phase diagram of 14SFNa in pure water was constructed from the CMC- and solubility-temperature data, in which the Krafft temperature (critical solution temperature) was found around 0 °C. The changes in the Gibbs energy, ΔG ⁰ _m, enthalpy, ΔH ⁰ _m, and entropy, ΔS ⁰ _m, upon micelle formation as a function of temperature were evaluated taking βvalues into calculation. Received: 28 August 1996 Accepted: 5 November 1996     

Polyfunctional fluoroalkyl-containing carbonyl compounds in the synthesis of heterocycles

Efficient procedures for the regioselective synthesis of fluoroalkyl-containing threefive-, six-, and seven-membered heterocycles as well as of related fused compounds, namely, α,β-epoxyketones, α,β-aziridinylketones, pyrazoles, pyrazolines, isoxazolines, 1,2-dithiolenes, amino- and mercaptopyrimidines, Δ^3,5-2-thioxo-1,3,2-thiazaphosphorines, Δ^3,5-2-thioxo-1,3,2-oxazaphosphorines, 2,3-dihydro-1,4-diazepines, azirino[1,2-a]quinoxalines, benzo[b]-and naphtho[2,3-b]-1,4-diazepines, and triazolopyridazines, which have been developed by the authors and coworkers, are summarized. The α- and β-functionalized fluoroalkylcontaining carbonyl compounds (β-diketones, β-ketoesters, their salts, regioisomeric β-aminovinyl ketones, β-aminovinylthiones, β-hydroxyketones, α,β-enones, and their halogen derivatives) were used as synthons in the processes of formation of the above-mentioned heterocycles. Dedicated to the memory of Academician I. Ya. Postovskii on his 100th birthday. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1279–1286, July, 1998.     

Thermodynamic investigation of effect of salt concentrations on denatured α-Amylase adsorbed onto a moderately hydrophobic surface

The displacement adsorption enthalpies (ΔH) of denatured α-Amylase (by 1.8 mol L⁻¹ GuHCl) adsorbed onto a moderately hydrophobic surface (PEG-600, the end-group of polyethylene glycol) from solutions (x mol L⁻¹ (NH₄)₂SO₄, 0.05 mol L⁻¹ KH₂PO₄, pH 7.0) at 298 K are determined by microcalorimeter. Further, entropies (ΔS), Gibbs free energies (ΔG) and the fractions of ΔH, ΔS, and ΔG for net adsorption of protein and net desorption of water are calculated in combination with adsorption isotherms of α-Amylase based on the stoichiometric displacement theory for adsorption (SDT-A) and its thermodynamics. It is found that the displacement adsorptions of denatured α-Amylase onto PEG-600 surface are exothermic and enthalpy driven processes, and the processes of protein adsorption are accompanied with the hydration by which hydrogen bond form between the adsorbed protein molecules favor formation of β-sheet and β-turn structures. The Fourier transformation infrared spectroscopy (FTIR) analysis shows that the contents of ordered secondary structures of adsorbed α-Amylase increase with surface coverages and salt concentrations increment.     

Structural analysis of three novel trisaccharides isolated from the fermented beverage of plant extracts

Background  

A fermented beverage of plant extracts was prepared from about fifty kinds of vegetables and fruits. Natural fermentation was carried out mainly by lactic acid bacteria (Leuconostoc spp.) and yeast (Zygosaccharomyces spp. and Pichia spp.). We have previously examined the preparation of novel four trisaccharides from the beverage: O-β-D-fructopyranosyl-(2->6)-O-β-D-glucopyranosyl-(1->3)-D-glucopyranose, O-β-D-fructopyranosyl-(2->6)-O-[β-D-glucopyranosyl-(1->3)]-D-glucopyranose, O-β-D-glucopyranosyl-(1->1)-O-β-D-fructofuranosyl-(2<->1)-α-D-glucopyranoside and O-β-D-galactopyranosyl-(1->1)-O-β-D-fructofuranosyl-(2<->1)- α-D-glucopyranoside.     

Comparative Study of the Inclusion Complexation of Pizotifen and Ketotifen with Native and Modified Cyclodextrins

The interaction of two benzocycloheptanes namely, pizotifen (Pizo) and ketotifen (Keto), with cyclodextrins (CDs: α-, β-, γ-, and HP-β-CDs) has been investigated by several techniques including phase solubility, X-ray powder diffractometry, ¹H-nuclear magnetic resonance and molecular mechanical modeling. The effects of CD type, pH, ionic strength and temperature on complex stability were also explored. The complex formation constant (K ₁₁) values for the Pizo/CD system follows the decreasing order β-CD > γ-CD > HP-β-CD > α-CD. However, for the Keto/CD system it follows the decreasing order γ-CD > β-CD > HP-β-CD > α-CD. The tendency of Pizo and Keto to complex with β-CD is driven to the extent of 70% by the hydrophobic effect. Complex formation of Keto and Pizo was substantially driven by entropy (>100 J⋅mol⁻¹⋅K⁻¹) but slightly retarded by enthalpy (3–8 kJ⋅mol⁻¹). ¹H-NMR and MM⁺ studies indicate multimodal inclusion of the methylpiperadine, thiophene and phenyl moieties into the β-CD cavity.     

A calorimetric study of the acid dissociation of the conjugate acids of poly(N-vinylimidazole) and polyallylamine

Thermodynamic parameters for acid dissociation of the conjugate acids of poly(N-vinylimidazole) and polyallylamine have been determined in the presence of sodium chloride and sodium nitrate. Even though the plots of ΔG ⁰ against the degree of dissociation, α, are highly dependent on the added salt concentration levels, the concentration effect has never been observed for the corresponding ΔH ⁰ versus α plots. The effect on the ΔG ⁰ versus α plots has been attributed to the entropy change of the counterions between a polyelectrolyte phase and a bulk solution phase. The α dependency of ΔH ⁰ is affected remarkably by the kinds of cationic polymers and counter-anions. Each ΔH ⁰ value at completely neutralized conditions is quite close to the corresponding ΔH ⁰ value of the monomer analog. The difference in the ΔH ⁰ values at fully charged conditions has been explained by the heats due to The ion-pair formation of chloride anion to the conjugate acids of poly(N-vinylimidazole) and polyallylamine has been supported by ³⁵Cl NMR measurement. It has also been suggested that chloride anions bind the basic polymer molecules even at fully neutralized conditions. Received: 2 June 1999/Accepted in revised form: 19 July 1999     

The Polymorphism of Glycine. Thermochemical and structural aspects

X-ray, DSC and solution calorimetric investigations were carried out for α-, β- and γ-modifications of glycine. Particular attention was paid to kinetic and thermochemical aspects of γ- → α-phase transition. The temperature of this phase transition turned out to be sensitive to a) conditions under which the crystals of the γ-modification were grown, b) tempering of crystals c) form (geometry) of crystals. Kinetics of this phase transition of single crystals of γ-phase in rhomboedric form can be described by the equation for two-dimension nuclei growth, whereas for crystals of triangle geometry the equation for three dimension growth is valid. On the basis of energy parameters describing growth of α-form in γ- →α-phase transition, the kind of structure defects, which are responsible for this phase transition, was estimated. Taking into account the Δ_sol H _m, the absolute values of the lattice energies of the investigated polymorphs indescending order are follows: γ->α->β-modification. The obtained results are discussed with respect to the peculiarity of the crystal lattice structures, particularly the network of hydrogen bonds. The β-modification of glycine is monotropically related to the other forms, whereas γ-and α-polymorphs are enantiotropically-related phases. This revised version was published online in July 2006 with corrections to the Cover Date.     

A comprehensive study on the inclusion mechanism of benzophenone into supramolecular nanoassemblies prepared using two water-soluble associative polymers

In this study, the entrapment of benzophenone (BZ) into supramolecular nanoassemblies prepared by mixing two water-soluble associative polymers (i.e. polymerized β-CD (pβ–CD) and dextran grafted with lauryl-side chains (MD)) has been investigated by using isothermal titration microcalorimetry (ITC) and molecular modeling. ITC experiments have been performed at various temperatures (4 °C (277 K), 25 °C (298 K), and 37 °C (310 K)) to evaluate the interaction of BZ with pβ–CD in comparison with β-CD. The inclusion complexation for both β-CD/BZ and pβ–CD/BZ interactions was entropy-driven (|ΔH| < |TΔS|) when the temperature of the experiment was low (4 °C) and enthalpy-driven (|ΔH| > |TΔS|) with minor entropic contribution when the temperature was increased (25 and 37 °C). Using all the thermodynamic data obtained for β-CD/BZ and pβ–CD/BZ interactions when the temperature of the experiment was varied, the \Updelta H   =   f(T\Updelta S ) \Updelta H\; = \;f(T\Updelta S ) plot was perfectly linear, which reflected an enthalpy–entropy compensation process. Finally, the combination of ITC data with molecular modeling provided consistent information in regard to the location of MD side chains and BZ inside the cyclodextrin cavity, as well as concerning the stability of the nanoassemblies loaded with BZ.     

Thermodynamics of Nicotinic Acid Interactions with Some Saccharides

The interactions of nicotinic acid with α-D-glucose and maltose, and with α-, β-, hydroxypropyl-α- and hydroxypropyl-β-cyclodextrins were studied by using solution calorimetry at T = 298.15 K and pH = 3.4. The thermodynamic parameters (log₁₀ K, Δ G∘_c, Δ H∘_c and Δ S∘_c) were calculated for the systems in which complex formation was observed. Systems with weak interparticle interactions lacking complex formation were characterized by enthalpic virial coefficients calculated on the basis of the McMillan–Mayer theory. It was found that the complexation affinity of α-cyclodextrin to nicotinic acid is stronger in comparison to β-cyclodextrin and the mono- and disaccharides. The influence of different factors, such as the availability of the macrocyclic hydrophobic cavity, the relationship of the sizes of guest molecule to the host cavity, the presence of bulky hydroxypropyl substitutes and their structure, and the solvation of guest molecules on the stability of complexes and their thermodynamic parameters of interaction is discussed.     

Prednisone/Cyclodextrin Inclusion Complexation: Phase Solubility,Thermodynamic, Physicochemical and Computational Analysis

Guest–host interaction of prednisone (PN) with cyclodextrins (CDs) have been investigated using phase solubility diagrams (PSD), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), scanning electron microscopy (SEM) and molecular mechanical modeling (MM). Estimates of the complex formation constant (K ₁₁) show that the tendency of PN to complex with CDs follows the order: β-CD>γ-CD>HP-β-CD>α-CD. At the same pH of 7.0, β-CD forms soluble 1:1 and insoluble 1:2 PN/CD complexes (B_S-type PSDs). The thermodynamic functions for 1:1 PN/β-CD estimated at pH = 7.0 (ΔG ₁₁^o=−20.8 kJ⋅mol⁻¹) show that complexation is driven by enthalpy (−30.7 kJ⋅mol⁻¹) but retarded by entropy (ΔS ₁₁^o=−33.1 J⋅mol⁻¹⋅K⁻¹) changes. The MM modeling study indicates the formation of different isomeric 1:1 complexes with CDs. PSD, DSC, XRPD, SEM and MM studies established the formation of inclusion complexes in solution and the solid state.     

Stereochemical effects during [M-H]− dissociations of epimeric 11-OH-17β-estradiols and distant electronic effects of substituents at C(11) position on gas phase acidity

The affinity of estradiol derivatives for the estrogen receptor (ER) depends strongly on nature and stereochemistry of substituents in C₍₁₁₎ position of the 17β-estradiol (I). In this work, the stereochemistry effects of the 11α-OH-17β-estradiol (III_α) and 11β-OH-17β-estradiol (III_β) were investigated using CID experiments and gas-phase acidity (ΔH_acid^∘) determination. The CID experiments showed that the steroids decompose via different pathways involving competitive dissociations with rate constants depending upon the α/β C₍₁₁₎ stereochemistry. It was shown that the fragmentations of both deprotonated [III_α-H]⁻ and [III_β-H]⁻ epimers were initiated by the deprotonation of the most acidic site, i.e. the phenolic hydroxyl at C₍₃₎. This view was confirmed by H/D exchange and double resonance experiments. Furthermore, the ΔH_acid^∘ of both epimers (III_α and III_β), 17β-estradiol (I), and 17-desoxyestradiol (II) was determined using the extended Cooks’ kinetic method. The resulting values allowed us to classify steroids as a function of their gas-phase acidity as follows: (III_β)≫(II)>(I)>(III_α). Interestingly, the α/β C₍₁₁₎ stereochemistry appeared to influence strongly the gas-phase acidity. This phenomenon could be explained through stereospecific proton interaction with π-orbital cloud of A ring, which was confirmed by theoretical calculation.     

Application of scanning calorimetry to estimate soil organic matter loss after fires

The severe heating of soil during wildfires and prescribed burns may result in adverse effects on soil fertility due to organic matter loss. No rapid and reliable procedure exists to evaluate soil organic matter (SOM) losses due to heating. Enthalpy of SOM combustion correlates with organic matter content. Quartz is a ubiquitous mineral in soils and has a remarkably constant composition and reversible α–β phase transition at 575 °C. We suggest that SOM content in heated and unheated soils can be compared using the ratio of SOM combustion enthalpy on heating to the β–α quartz transition enthalpy measured on cooling of the same sample. This eliminates the need to dry and weigh the samples, making possible field applications of the proposed method. The feasibility of using the (ΔH _{comb SOM})/(ΔH _β–α Qz) ratio was established with experiments on soil samples heated in the laboratory and the method was then used for evaluation of SOM loss on two pile burn sites at UC Berkeley’s Blodgett Forest Research Station in Georgetown, California.     

Rationalizing some experimental facts on the complexation of 2-methyl naphthalenecarboxylate and hydroxypropyled cyclodextrins by molecular mechanics and molecular dynamics

Molecular mechanics (MM) and Molecular dynamics (MD) calculations were applied to study the complexation of 2-Methyl naphthalenecarboxylate (2MN) and 2-hydroxypropyl -α-, -β-, and γ-cyclodextrins (HPCDs) in the presence of water. Results showed that 1:1 complexes of 2MN with modified cyclodextrins are stable and that the non-bonded van der Waals interactions are mainly responsible for the complexation. Theoretical results are in good agreement with fluoresence results and they permit us to explain the signs and quantitative differences of ΔH ⁰ and ΔS ⁰ on the basis of the different cavity sizes and the movement of the guest inside the HPCD cavity. Results also reveal a more favorable complexation when 2MN approaches on its polar side.     

Amino acids in aqueous solution. Effect of molecular structure and temperature on thermodynamics of dissolution

The enthalpies of dissolution of glycine (Gly) and L-α-alanine (Ala) in water at 288.15–318.15 K were measured. The results were compared with the earlier obtained data for L-α-phenylalanine (Phe) and L-α-histidine (His). The standard enthalpies of dissolution (Δ_soln H ₀) and differences (ΔC _p ⁰ ) between the limiting partial molar heat capacity of the amino acids in solution and the heat capacity of the amino acids in the crystalline state were calculated in the temperature interval 273–373 K. Changes in the entropy of dissolution (ΔΔ_soln S ₀) and reduced Gibbs energy [Δ (Δ_soln G ₀/T)] in the temperature interval from 273 to 373 K were determined from the known thermodynamic relationships. The ΔC _p ⁰ value is negative for hydrophilic glycine and positive for other amino acids. The ΔΔ_soln S ⁰ values increase with an increase in the hydrophobicity of the amino acids. The Δ(Δ_soln G ₀/T) values become more negative in the order Ala, Phe, Gly, His. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 711–714, April, 2007.     

Thermal coefficients and internal pressure of aqueous urea. Concentration,temperature, and isotopy effects

The thermal expansion α, isothermal compressibility β, and internal pressure coefficients of H₂O-(NH₂)₂CO and D₂O-(ND₂)₂CO fy systems at 278 K, 298 K, and 318 K and aquamolality m ≤ 1.5 were calculated. The changes in the isotope differences Δα, Δβ_T, and Δfy at different solute concentrations and temperature are discussed. In contrast to Δα and Δfy, Δβ_T is almost independent of the urea concentration already at 298 K and independent of m at 318 K. The derivative δfy/δT increased in dilute solution, at lower temperatures, and on passing from protium to deuterium system, which corresponded to increased structuring. The isotope difference for the Grüneisen constant at given temperatures and concentrations is shown to be independent of the urea content.     

Quantum chemical study of the host-guest inclusion complexes of the local anaesthetic drugs, procaine hydrochloride and butacaine hydrochloride, with α- and β-cyclodextrins

Quantum mechanical (QM) calculations were carried out in order to study the host-guest inclusion complexes of procaine hydrochloride (Pro-H) and butacaine hydrochloride (But-H) with α- and β-cyclodextrins (α- and β-CDs) by PM3 and AM1 methods. The systems were studied by a 1:1 (α-CD/Pro-H, α-CD/But-H, β-CD/Pro-H, and β-CD/But-H) stoichiometric ratio. In this work we calculated the energy of complex formation in vacuo, and this investigation was carried out on the basis of the host-guest approach. The stabilization energy results for the 1:1 host-guest inclusion complexes indicate that the β-CD/Pro-H complex is more stable than the α-CD/Pro-H complex. Furthermore, stabilization energy for the 1:1 inclusion complex of α-CD with But-H is lower than that for the 1:1 inclusion complex of β-CD with But-H. The calculation results show that all complexation processes for the four complexes are exothermic. Enthalpy changes for the α-CD/But-H and β-CD/Pro-H host-guest inclusion complexes are more negative than those for the other ones. ΔG ^o values for both the β-CD/Pro-H and α-CD/But-H complexes are negative. Correspondence: S. M. Hashemianzadeh, Department of Physical Chemistry, College of Chemistry, Iran University of Science and Technology, Tehran, Iran.     

Thermodynamic evaluation of antibacterial activity for inclusion complexes of amoxicillin with cyclodextrins

The antibacterial action of amoxicillin (AMPC) and the inclusion complexes of AMPC with α-, β- and γ-cyclodextrins (α-CD, β-CD and γ-CD, respectively) to Escherichia coli B (E. coli) was evaluated by isothermal titration microcalorimetry and by petri-dish bioassay method. The effects of the compounds on produced heat during the exponential phase of the E. coli growing were measured and the growing rate constants of the cells was calculated from the power-time (p-t) curve before and after the treatment with AMPC. Results from the both methods showed that the antibacterial activity became stronger in the following order: AMPC-βCD > AMPC-γCD ≈ AMPC-αCD > AMPC only.     

Cisapride/β-cyclodextrin complexation: stability constants, thermodynamics, and guest–host interactions probed by 1H-NMR and molecular modeling studies

Phase solubility techniques were used to obtain the complexation parameters of cisapride (Cisp) with β-cyclodextrin (β-CD) in aqueous 0.05 M citrate buffer solutions. From the UV absorption spectra and the pH solubility profile, two basic pK _as were estimated: pK _a(1+) = 8.7 and pK _a(2+) < 2. The inherent solubility (S _o) of Cisp was found to increase as pH decreases, but is limited by the solubility product of the CispH⁺·citrate¹⁻ salt at low pH (pK _sp = 3.0). Cisp forms soluble 1:1 and 1:2 Cisp/β-CD complexes. A quantitative measure of the hydrophobic effect (desolvation) contribution to 1:1 complex formation was obtained from the linear variation of free energy of 1:1 Cisp/β-CD complex formation (ΔG ₁₁ = −RT ln K ₁₁ < 0) with that of the inherent solubility of Cisp . The results show that the hydrophobic character of Cisp contributes about 35% of the total driving force to 1:1 complex formation (slope = −0.35), while other factors, including specific interactions, contribute −10.6 kJ/mol (intercept). Protonated 1:1 Cisp/β-CD complex formation at pH 6.0 is driven by favorable enthalpy (ΔH° = −9 kJ/mol) and entropy (ΔS° = 51 J/mol K) changes. In contrast, inherent Cisp solubility is impeded by unfavorable enthalpy (ΔH° = 12 kJ/mol) and entropy (ΔS° = 90 J/mol K) changes. ¹H-NMR spectra in D₂O and molecular mechanical studies indicate the formation of inclusion complexes. The dominant driving force for neutral Cisp/β-CD complexation in vacuo was predominantly van der Waals with very little electrostatic contribution.