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Keywords:

  • molecular encapsulation;
  • inclusion complexes;
  • cyclodextrin;
  • thermodynamic parameters

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. REFERENCES

Molecular encapsulation on a molecular basis can be performed by cyclodextrins. The inclusion of organic molecules into the interior changes the properties of these molecules, which may be used for a broad variety of applications. The affinity of guest molecules for the cavities of various cyclodextrins depends on the stereochemistry and on the interaction forces of the molecules involved. Calculations of the thermodynamic parameters show that the reaction entropy is highly important for the inclusion reaction. Completely different reaction mechanisms are observed for various types of cyclodextrins as some of these reactions show enthalpy–entropy compensation. Others are supported by the reaction entropy or are even entropically controlled. Protonation and deprotonation reactions contribute significantly to the inclusion reaction, as first of all the solubility of the compounds in water is strongly influenced by the acidity of the solution, and, moreover, all tautomeric forms of the compounds show different affinities to various cyclodextrins. Copyright © 2006 Society of Chemical Industry


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. REFERENCES

Molecular encapsulation has attracted much attention in a broad area of science and technology, particularly in chemistry, biology and pharmacy. Natural as well as synthetic nanometre-sized supramolecular aggregations are widely used for host–guest complexation, influencing the properties of the mostly organic guest molecules.

In particular, cyclodextrins (CDs) have been used for a broad variety of applications, especially in pharmaceutical,1 environmental and technical chemistry2, 3 as well as in food chemistry,4 because these compounds are very convenient due to their wide spectrum of molecular properties. Stereospecific separations of diastereomers and optical isomers, extraction of natural products, protection of unstable compounds, e.g. light-, temperature- or oxidation-sensitive substances, may be effected by complexation with CDs.1 Moreover, emulsification of highly apolar compounds, modifications of catalytic activities and support in organic syntheses are factors which make CDs an indispensable excipient in many scientific disciplines. A property of most CDs which should not be underestimated should be mentioned here, i.e. the low toxicity to humans, which enables their application in a wide field of pharmacy and pharmaceutical technology,5 e.g. solubility enhancement of poorly-soluble drugs and increase in the bioavailability and efficiency of the active substance as well as the possibility of its controlled release.6

CDs are cyclic macromolecules obtained by the degradation of starch by α-1,4-glucan-glycosyltransferases. Depending on the respective transferase, different types of CDs result, consisting of six (α-CD), seven (β-CD) or eight (γ-CD) α(1 [RIGHTWARDS ARROW] 4) linked glucose units. The molecular shape of CDs resembles that of cones. They have a hydrophobic cavity with an average diameter of 5 Å (α-CD), 6.2 Å (β-CD) and 7.9 Å (γ-CD), respectively, and a thickness of 8 Å.7 Larger CDs also exist, e.g. δ-, ε- and ι-CDs with 9, 10, and 14 glucose residues. In these CDs, the macrocyclic rings are more distorted and do not form well-defined molecular cavities despite the formation of intramolecular hydrogen bonds. Native CDs are more or less rigid molecules. Modifications of these CDs lead to a variety of new derivatives with various properties. The strategy for modifications depends on the applicability of the final product.8 A large number of modified CDs have been synthesized to alter or improve their inclusion facilities and also to induce biomimetic functions.9

Structural determination of CDs

The molecular structure of CDs and some CD–guest complexes has been elucidated by X-ray diffraction.10 Hydrogen bond formation and the participation of water molecules have been investigated by neutron diffraction.11

Structural elucidation of various CDs and the related complexes is supported by molecular modelling studies. As a consequence of the size of these molecular systems, molecular mechanics studies on the conformations of CDs and the inclusion complexes have mainly been reported.12–14 Dynamic Monte Carlo simulations15, 16 including solvation led to host–guest geometries for which the calculated induced circular dichroism spectra are in good agreement with the experimentally measured ones. The application of quantum chemical methods on CDs is limited by the size of the molecules and molecular aggregates and the large number of local conformational minima. Nevertheless, some semi-empirical quantum-mechanical calculations have been performed on such systems,17 e.g. the geometries of some inclusion complexes were treated by semi-empirical methods.18, 19 A study based on results from density functional method calculations was published recently.20

The inclusion of guests can be monitored by various spectroscopic methods. If the guest molecule absorbs in the UV range, its inclusion can be observed by titration with CD.21 In a similar way, the change of circular dichroism can be used, even if the guest is achiral, due to the fact that upon inclusion the complex shows an induced circular dichroism.22, 23 Thermal analysis can be used to investigate differences in the complexation capacity of guest molecules. Also, NMR spectroscopy offers excellent possibilities for the characterization of CD–guest complexes.24–27 NMR spectroscopy has also been used to study preferential inclusion of enantiomeric compounds.28

Self-assembly is nowadays recognized as a promising technique for building nanoscale structures. One aspect of biological and chemical self-assembly is the capture and organization of guest molecules. This property of self-aggregation can also be observed and investigated on natural CDs by photocorrelation spectroscopy.29 The self-aggregation capability depends on the CD being considered. Substituted CDs, for instance hydroxypropyl-β-CD (HP-β-CD), do not display significant aggregation, which also has been observed for natural CDs at high pH values, in the presence of salts or at high temperatures, which is explained by the fact that the aggregation occurs with the intervention of the hydrophilic rims.

As already mentioned, α-, β- and γ-CDs have cavities of increasing diameters. Modifications at the hydroxyl groups by substitution also changes the size of the cavity, but modifies additionally the properties of the CD derivative. Alkylation, for example, leads to a more hydrophobic interior but increases also the flexibility of the modified CD by breaking some of the intramolecular hydrogen bonds and, moreover, the intermolecular hydrogen bonds to encapsulated water molecules.

A broad variety of small- and medium-sized molecules can be included into the cavity of CDs and their derivatives and, consequently, their physicochemical properties are changed to a great extent by such a host–guest interaction. It is evident that the change of the microenvironment from the hydration shell in aqueous solution to the more hydrophobic interior of the host molecules is responsible for the modification of the molecular properties. The affinity of guest compounds to various CDs depends on several factors, including stereochemistry and polarity, but also on electrostatic potentials as well as on the ability to form hydrogen bonds.

The large number of experiments on CD host–guest complexes together with many physicochemical and theoretical investigations gives some insight into the nature of the forces which are responsible for the association of the CDs and guest molecules. Several driving forces have been proposed to be important for the specific affinity of ligand molecules.21, 30–32 Electrostatic interactions, van der Waals' interactions, hydrophobic interactions, hydrogen bonding abilities as well as the so-called induced fit (CDs undergo significant conformational changes upon complex formation to optimize opportunities for other modes of interactions).

The overall inclusion reaction consists of several elementary steps33 such as the desolvation of the guest and the internal desolvation of the host, conformational changes of host and guest molecules, host–guest binding, a reorganization of the solvent around and inside the cavity and structural relaxation of the complex. Moreover, for the overall complexation constants other parameters such as the solubility of the involved compounds and the respective reaction products have to be taken into account.

Thermodynamics of inclusion reaction

As the elementary steps cannot be determined easily the overall free energy of the association process has been investigated extensively. Several studies have investigated the influence of various molecular parameters on the complexation constants.

Guo et al.,34 for example, have correlated different experimentally determined quantities (molar refraction, hydrophobicity, Hammet constants, etc.) with the association constants.

Consequently, more general models for the prediction of the free energy of complexation between various CDs and guest molecules (mostly drugs) were developed, based on linear and nonlinear correlation analysis (multiple linear regression and partial least squares): experimentally determined free energies of complexation were correlated with molecular descriptors obtained from molecular calculations.35

Thermodynamic data are available for a large number of compounds with native α-, β- and γ-CDs,36 and for chiral guests with β-CD and dimethyl-β-cyclodextrin (DM-β-CD).37, 38 A linear correlation between reaction enthalpy and reaction entropy could be observed to some extent, showing enthalpy–entropy compensation for many substances. No pronounced dependence of thermodynamic parameters on other molecular properties could be recognized.

In the present paper, a few examples of cyclodextrin inclusion complexes are given, to compare thermodynamic parameters for selected compounds as guests and diverse β- and γ-CDs as host molecules. All of these selected substances are of low solubility in water. Spironolactone (SP) (Fig. 1) is a partial synthetic steroid-analogue of aldosterone, which works as a competitive aldosterone-antagonist. The affinity of this compound to β-CD and its derivatives is exceptionally high and therefore the thermodynamics of this process is of special interest.

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Figure 1. Structure of spironolactone (SP), triflumizole (TF) and meloxicam (MEL).

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Triflumizole (TF) (Fig. 1) is used as systemic fungicide. As a consequence of the three side chains of this molecule, the flexibility of this compound is high and a complete inclusion of this compound into the β-CD's cavity should not be possible.

Meloxicam (MEL) (Fig. 1), a non-steroidal anti-inflammatory drug (NSAID), known as a cyclooxygenase-1 selective inhibitor, was selected, as for this type of compound protonation and deprotonation equilibria contribute considerably to both the solubility of the compound and to the inclusion reaction.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. REFERENCES

Materials

SP, 7α-(acetylthio)-17-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone (IUPAC), 4-pregnen-21-oic acid-17α-ol-3-one-7α-thiol-γ-lactone-7-acetate (C.A.), was provided by Kwizda Pharma (Vienna, Austria) (Ch. Nr.: A0846). TF, (E)-4-chloro-α, α, α-trifluoro-N-(1-imidazol-1-yl-2-propoxy-ethylidene)-o-toluidine (IUPAC), (E)-1-[1-[[4-chloro-2-(trifluoromethyl)phenyl]-imino]-2-propoxy-ethyl]-1H-imidazole (C.A.), was provided by Nippon Soda Co. Ltd (Tokyo, Japan) with a purity of >99%. MEL, (4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide) was provided by Böhringer Ingelheim Pharma GmbH (Vienna, Austria) and Kwizda Pharma (Vienna, Austria).

β-CD was obtained from Roquette Frères (Lestrem, France) as Kleptose® with a humidity of 14% (w/w). Dimethyl-β-CD (DM-β-CD) was obtained from PMCD Ringdex (Syntapharm, Mülheim, Germany), γ-CD, HP-β-CD and hydroxypropyl-γ-CD (HP-γ-CD) from Wacker Chemie (Munich, Germany). Water used in these studies was bidistilled. pH-values were adjusted with HCl (pH = 3.0) and 0.005 mol L−1 phosphate buffer (pH = 6.0). The mobile phase was filtered through a 0.45 µm pore membrane filter. The cosolvents used (ethanol, 2-propanol, 2-butanol and dioxane) were of analytical reagent grade.

Preparation of the complexes

Solubility measurements and the determination of the saturation concentrations were carried out by adding excess amounts of the drug to water and CD. The samples were stirred (300 rpm) in a temperature-controlled water bath until equilibrium was reached. After sedimentation of the excess drug, filtration was carried out and after 1:100 dilution with water (in the case of SP) the concentrations of the dissolved compounds were determined by electron absorption spectroscopy using a Perkin Elmer UV/VIS Spectrometer LAMBDA 16 (Perkin Elmer, Norwalk, CT, USA) at the corresponding wavelength (242 nm in the case of SP, TF at 294 nm and MEL at 362 nm). The saturation concentrations were estimated at different temperatures. Stock solutions of CDs were prepared and used for the solubility measurements as well as for the determination of the equilibrium constants. Due to the instability of the solutions, the spectra were recorded immediately after dilution and filtration.

The overall complexation constants (K) were estimated by the solubility method, assuming a one-step equilibrium, varying the CDs' concentration depending on the guest molecule, according to the method of Higuchi and Connors.39

In the case of SP and TF, bidistilled water was used for the determination of the solubility enhancement and the thermodynamic parameters, because the solubility was not pH-dependent. In contrast, for MEL, the pH-value40 has a strong influence on the solubility of the pure compound as well as on the inclusion complexes with CDs, therefore, complexes in solutions with different pH-values and buffered solutions have been investigated.

To obtain information about the influence of cosolvents on the complexation reaction of TF with β-CD, solutions of 4, 8 and 12% (w/w) of ethanol, 2-propanol, 2-butanol and dioxane have been investigated.

RESULTS AND DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. REFERENCES

The solubility of SP was determined using increasing amounts of β-CD and DM-β-CD, varying from 0 up to 9 × 10−3 mol L−1 in a temperature range from 20 °C to 40 °C. For TF the amount of β-CD and DM-β-CD was varied from 0 up to 6 × 10−3 mol L−1 in a temperature range from 25 °C to 38 °C. An increase in the solubility of the guest compounds with rising CD concentration and ascending temperature was observed. As the next step, the equilibrium constants (K) of the inclusion reaction were determined. In the case of SP an exceptionally large association constant was observed, for both CDs under investigation, namely β-CD and DM-β-CD. The value of K with DM-β-CD is slightly higher. The reason for this large association constant is the good steric agreement between the molecular surface and the complementary surface of the CDs' interior. The results for the equilibrium constants of SP and TF with two different CDs, namely β-CD and DM-β-CD, are given in Table 1.

Table 1. Thermodynamic parameters of the overall complexation between β-CD and DM-β-CD with TF and SP
 K (mol L−1)ΔG (kJ mol−1)ΔH (kJ mol−1)TΔS (kJ mol−1)
β-CD-SP34000−24.8−46.0−21.2
β-CD-TF476−15.3−23.0−7.7
DM-β-CD-SP47400−26.7−20.4+6.3
DM-β-CD-TF623−16.0−4.2+11.8

From a first glance, these differences can be explained by the higher rigidity of SP compared with that of TF and by a much better fit of SP into the CDs' cavities. Moreover, for TF, only one of the three side chains can be included into the CDs' cavities. K values of both compounds with β-CD and DM-β-CD are similar but their temperature dependence is completely diverse, resulting in different reaction enthalpies and reaction entropies. The dependencies of lnK on the reciprocal temperatures (according to the Van't Hoff equation) are given in Fig. 2, the corresponding thermodynamic values are depicted also in Table 1.

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Figure 2. Van't Hoff plot of the logarithm of the overall equilibrium constant K of the inclusion complex of TF in the presence of β-CD and DM-β-CD and of SP in the presence of β-CD and DM-β-CD.

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The complexation of SP with β-CD shows an overall reaction enthalpy of −46 kJ mol−1 and the related reaction entropy is negative, which leads to a pronounced enthalpy–entropy compensation. In contrast, the enthalpy of the reaction with the more hydrophobic DM-β-CD is much smaller, even the association constant is larger. The resulting reaction entropy is therefore positive, which means that the entropy contributes to the increase in the free reaction enthalpy and the equilibrium constant.

The association constants of TF are three orders of magnitude lower than for SP, probably a consequence of the higher flexibility of the molecule and the fact that only one side chain of the molecule can be included in the CDs' cavities. Again, the complexation constants with both CDs are of the same order of magnitude—the equilibrium constant with DM-β-CD is somewhat higher—and again their temperature dependencies differ markedly. In particular for the TF–DM-β-CD complex, the temperature dependence of the equilibrium constant is rather low (ΔH = −4.2 kJ mol−1, see Table 1). The reaction is, therefore, mainly entropy driven.

Investigations on the influence of cosolvents on the inclusion mechanism were done with TF and CD in solutions of 4, 8 and 12% (w/w) of ethanol,41 2-propanol, 2-butanol and dioxane. Generally, the solubility of the compound decreases in the presence of small amounts of cosolvent, although the pure cosolvent shows high solubility potency. This is due to competition of the cosolvent molecule for inclusion into the CDs' cavity, which destabilizes the complex, indicated by a significant decrease in the equilibrium constant. Interestingly, the temperature dependence of the equilibrium is more pronounced at higher cosolvent concentration, which means that there is an increase in the absolute value of the overall ΔH. A diagram of the changes of lnK with increasing concentration of 2-propanol as cosolvent, together with the increase in the reaction enthalpy, is given in Fig. 3.

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Figure 3. Influence of 2-propanol on the complexation mechanism between TF and β-CD.

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The reaction entropies increase for rising concentration of cosolvents in the measured range from 0 to 12% (w/w). The data were determined using the phase solubility method in a temperature range from 25 °C to 38 °C. Enthalpy–entropy compensation occurs for almost all cosolvents and concentrations. The correlation between ΔH and TΔS is given in Fig. 4.

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Figure 4. Thermodynamic parameters of the inclusion complexes of TF and β-CD under influence of diverse cosolvents.

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Remarkably, also, in the case of the addition of different cosolvents, a rather good linear correlation between both thermodynamic parameters can be recognized. Only in the case of the non-protic solvent dioxane can small deviations from linearity be seen.

For substances which undergo protonation and deprotonation the influence of the inclusion reaction is more complex. MEL, for example, is a twobasic acid and, therefore, several different tautomeric forms are competing with each other in the inclusion process with CDs. The structure of MEL obtained by crystallization from non-polar organic solvents such as tetrahydrofuran is characterized by a tautomeric arrangement (enol–zwitterion). Under physiological conditions (pH = 7.4), the anionic form is the predominant structure. In aqueous solution the existence of the zwitterionic form has been suggested. Under acidic conditions the cationic form is present.40, 42, 43

The solubility of MEL in water was determined at different pH values, and a very low solubility for the neutral forms around pH 3 was measured. At pH 6 the solubility is considerably higher as the solvation of the anionic tautomers is energetically more favourable. The dependence of the concentration of dissolved MEL at pH 6 on the concentration of different CDs is shown in Fig. 5.

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Figure 5. Phase solubility diagram of the MEL-CDs inclusion complexes at pH = 6 and 25 °C.

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The enhancement in solubility by complexation with β-CD and HP-β-CD is somewhat higher than by γ-CD and HP-γ-CD, as a consequence of the greater affinities of MEL with β-CDs. Linear relationships are observed within the given concentration ranges, indicating 1:1 stoichiometric ratios.

The temperature dependence of the solubility enhancement for γ-CD is depicted in Fig. 6—for pH 3 in Fig. 6(a), for pH 6 in Fig. 6(b). Evidently, the solubility of MEL in pure water (and also at various pH values) is also concentration dependent, which leads to the fact that both diagrams show different concentration ranges for MEL.

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Figure 6. Comparison of the phase solubility of γ-CD-MEL inclusion complexes at pH 3 (a) and pH 6 (b) at different temperatures.

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Linear correlations are observed for all temperatures and from the temperature dependence of the equilibrium constants the thermodynamic parameters can be estimated. The results are given in Table 2 for β- and γ-CD.

Table 2. Thermodynamic parameters of the overall complexation between β-CD and γ-CD with MEL at different pH values
 K (mol L−1)ΔG (kJ mol−1)ΔH (kJ mol−1)TΔS (kJ mol−1)
β-CD, pH 3488−15.3−41.8−26.4
γ-CD, pH 3539−15.8−10.6+5.2
β-CD, pH 6198−13.1−24.0−10.9
γ-CD, pH 6113−11.5−20.8−9.3

Although the solubility of MEL at various CD concentrations is much lower at pH 3 than at higher pH values, the equilibrium constants are larger for the neutral forms of MEL. For β-CD ΔH as well as ΔS are more negative at pH 3, indicating enthalpy–entropy compensation, whereas in the case of γ-CD ΔH is smaller and a positive contribution of the reaction entropy is observed. At pH 6 both CDs show larger contributions of the reaction enthalpy than for the corresponding (negative) reaction entropies.

CONCLUSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. REFERENCES

The complexation of organic compounds with CDs leads to a significant enhancement of the solubility with increasing amounts of CDs. The resulting equilibrium constants depend on the interaction between host and guest molecules. Different constants are observed for the native CDs and, moreover, some correlation between the reaction enthalpy and the reaction entropy has been found for these host molecules. Interestingly, modifications at β-CD have some consequences for the association constant, because of the slightly changed size of the cavity and the modified abilities for hydrogen bonding and so on. But there is a drastic change in the reaction mechanism as the temperature dependence of the overall association constant differs significantly for β-CD and DM-β-CD.

Generally, association constants are influenced or even controlled by the reaction entropy. For the two compounds investigated—one with a very high affinity to the CDs' cavity–the association with β-CD shows enthalpy–entropy compensation, whereas the reaction with DM-β-CD is supported by the reaction entropy.

For compounds which might undergo protonation and deprotonation reactions the protonation state contributes significantly to the inclusion reaction, as first of all the solubility of the compounds in water is strongly influenced and all tautomeric forms of the compounds show different equilibrium constants.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. REFERENCES

This investigation was supported by the Austrian ‘Fonds zur Förderung der wissenschaftlichen Forschung’ (P15431) and by the ‘Hochschuljubiläumsstiftung der Stadt Wien’ (H1142/2002). The technical assistance of Mrs E Liedl is gratefully acknowledged

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS AND DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. REFERENCES
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