| dc.description.abstract | Three representative NSAID molecules, Ibuprofen, Diclofenac, and Indomethacin, have been included within the galleries of the anionic clay, Mg-Al LDH, by ion-exchange intercalation. These hybrid materials have been identified as potential candidates for pH-triggered drug release as well as drug storage [2]. In the present study, powder X-ray diffraction, IR and Raman vibrational spectroscopy, and 13C CPMAS NMR have been used to characterize the confined drug molecules in the Mg-Al LDH drug hybrids. Molecular dynamics simulations have been used to probe the interlayer structure, arrangement, orientation, and geometry of the intercalated species.
Spectroscopic measurements indicate that the structure of the intercalated Ibuprofen is identical to that outside the layers. This conclusion is also supported by MD simulations, which also show how a bilayer arrangement of the intercalated drug gives rise to the observed interlayer spacing. In the case of the intercalated Diclofenac and Indomethacin molecules, the presence of the electronegative chlorine atom gives rise to additional electrostatic interactions between the chlorine atoms and the positively charged Mg-Al LDH sheets. As a consequence, the bonds linking the chlorine-substituted phenyl ring with the rest of the molecule are affected, and the geometry of the intercalated drug is different from what it has outside. This observation is supported by spectroscopic measurements as well as by the simulations. The simulations also show how, as a consequence of the change in geometry, the experimentally observed interlayer spacing can be realized by a simple bilayer arrangement of the drug molecules without any interdigitation.
One of the longstanding paradigms in the host-guest chemistry of layered host lattices is that the interlayer spacing of the host is always so adjusted as to accommodate drug molecules without any change from the minimum energy geometry that they possess outside the layers. While the orientation and arrangement of the intercalated drug molecules in the galleries of different hosts could differ, depending on a number of factors including the charge on the layer and the extent of hydration, the geometries are usually the same and identical to that outside the layers. The Mg-Al LDH drug provides an exception to this rule; the geometry of the intercalated drug molecule is different. This is a consequence of electrostatic interactions between electronegative atoms on the drug molecule and the charge on the layer. The spectroscopic measurements and MD simulations complement each other in providing a better insight into the orientation and geometry of flexible drug molecules in layered host lattices. It has also been shown that the drug anions ion-exchange intercalated into the antacid, LDH, would offer an advantage of both bioavailability and better gastric tolerability.
The anionic clay, Mg-Al LDH, has been functionalized by anchoring the carboxymethyl derivative of ?-cyclodextrin to the gallery walls. Functionalization has the promise of greatly extending the host-guest chemistry of the anionic clay, from simple ion-exchange reactions to also include neutral and non-polar guest species. A key requirement for this is a detailed knowledge of the precise arrangement and geometry of the ?-cyclodextrin cavities in the interlayer space of the Mg-Al LDH. This chapter describes an analysis of the structure of the ?-cyclodextrin intercalated Mg-Al LDH using X-ray diffraction, 13C NMR spectroscopy, and infrared and Raman spectroscopy augmented with MD simulations.
Spectroscopic measurements indicate that the geometry of the anchored ?-cyclodextrin cavities is essentially unchanged from that of outside. This is also supported by MD simulations, which show that the structure of the gluco-pyranose units of the ?-cyclodextrin cavity is preserved on intercalation, but there are minor changes in the angles of the bonds that link these units. Snapshots of the MD simulations show how a bilayer arrangement, with the axis of the ?-cyclodextrin cavity perpendicular to the Mg-Al LDH sheets, allows for the experimentally observed interlayer lattice spacing to be realized.
The ?-cyclodextrin cavities in the intercalated bilayer are arranged with their wider opening facing away from the layer. This, in principle, can allow guest molecules to access the interior of the ?-cyclodextrin cavity. Using pyrene fluorescence as a probe, the similarities in the hydrophobicities of the microenvironment within the anchored ?-cyclodextrin and reported ?-cyclodextrin cavities have been established.
Since the structure, too, is similar, this result suggests that the host-guest chemistry of ?-cyclodextrin should be reproduced by the intercalated ?-cyclodextrin cavities, and indeed this is found to be true. A range of non-polar guest molecules may be included in the cyclodextrin-functionalized Mg-Al LDH. Functionalization of the anionic clay has, therefore, resulted in the creation of hydrophobic nano-pockets within the hydrophilic interlamellar space of the layered metal hydroxide.
Poly-iodide anions, the I3– ion, are generally linear or nearly linear with an I–I–I angle of 180 ± 6°. Generally, the I3– shows Raman bands near 110 cm–1 and 75 cm–1 corresponding to outer and inner symmetric stretches, respectively. The bending mode, ?3, is active only in the infrared spectrum for linear undistorted I3– species and appears around 140 cm–1. The I5– outer and inner symmetric stretch modes appear around 155 and 113 cm–1, respectively, for the bent species, and 163 and 75 cm–1, respectively, for the linear species. Infrared spectral stretching frequencies are reported to appear in the far infrared and hence could not be compared in the present study.
It is shown that the cyclodextrin-functionalized Mg-Al LDH can adsorb neutral I2 molecules from vapor as well as polar and non-polar solutions to form stable inclusion compounds. Insertion occurs by the complexation of the iodine molecules by the anchored cyclodextrin cavities. UV-visible and Raman spectra provide conclusive evidence for the existence of linear, symmetric, triiodide (I3–) ions when iodine is included within cyclodextrin cavities anchored in a Mg-Al LDH. At higher iodine content, poly-iodide species like the linear I5– are formed.
The iodine inclusion chemistry of cyclodextrin confined in the galleries of the layered solid, Mg0.7Al0.3(OH)2 LDH, is similar to that of cyclodextrin in solution, where the presence of triiodide species has also been reported, following heterolytic dissociation of I2. The inclusion reaction may, therefore, be represented, as in the case of cyclodextrin in solution:
(LDH-cyclodextrin) + 2I2 ? (LDH-cyclodextrin–I+)…I3–
(LDH-cyclodextrin–I+)…I3– + I2 ? (LDH-cyclodextrin–I+)…I5–
Similar reactions of iodine are known to occur with amylase as well as oxygen- and nitrogen-containing macrocycles. The poly-iodide species, I3– and I5–, present in LDH-CMCD-I2 have no part to play in maintaining charge neutrality of the LDH, unlike, for example, the role of I– ions in [Mg1–xAlx(OH)2][I]I. The iodine content in the Mg-Al LDH-CMCD-I2 has, therefore, no relation to the negative charge deficit (the Mg/Al ratio) of the LDH layers. The poly-iodide anions formed by the heterolytic dissociation of neutral I2 in the anchored cyclodextrin cavities are weakly bound to the cyclodextrin cavities and are not ion-exchangeable, unlike the I– ions in Mg1–xAlx(OH)2(I)I.
The inclusion of iodine in the cyclodextrin-functionalized LDH highlights the changes in the host-guest chemistry of the LDH on functionalization. Unlike the iodide-exchanged Mg-Al LDH, the Mg-Al LDH-CMCD(I2) hybrid is stable even on thermal treatment and on exposure to air. Moreover, since the iodine plays no role in compensating for the charge deficit of the layer, in the Mg-Al LDH-CMCD(I2) compound, much larger amounts of iodine may be included as compared to the ion-exchange compounds. The cyclodextrin-functionalized LDH can, therefore, be used in storage and transport of iodine.
It has been shown that the anionic species may be ion-exchange intercalated in the Mg-Al LDH from basic media. In the functionalized LDH, however, it is only from acidic solutions, where FCA exists as a neutral, hydrophobic species, that there is appreciable uptake (Figure 6.12). The difference in the equilibrium uptake with pH (Figure 6.12) is a consequence of the variation in the concentration of the neutral FCA species with the acidity of the medium. The equilibrium uptake isotherms are linear, indicating that the inclusion occurs by partitioning from aqueous solution, with the maximum uptake corresponding to an FCA/anchored ?-cyclodextrin molar ratio of ~1:1.
The functionalized Mg-Al LDH-CMCD has, therefore, the ability to separate hydrophobic and hydrophilic derivatives of ferrocene by preferential partitioning of the former. The Mg-Al LDH-NO3, on the other hand, selectively includes the ionic hydrophilic species by ion-exchange. Thus, Mg-Al LDH-CMCD can selectively include only hydrophobic species from a mixture of hydrophobic and hydrophilic species.
The present study provides the first example of the inclusion of neutral ferrocene species into an inorganic layered solid and promises a new route to generate organometallic–organic–inorganic nanohybrid materials held together by a combination of electrostatic and dispersive forces. Neutral ferrocene molecules are included in the cyclodextrin-functionalized Mg-Al LDH-CMCD by a partitioning process. The included ferrocene molecules retain D5h symmetry, with the Cp rings rotating about the fivefold axis. Vibrational and electronic spectra indicate an elongation of the Fe–Cp bond distance. The capability of the cyclodextrin-functionalized LDH to separate hydrophilic and hydrophobic derivatives of ferrocene is demonstrated.
The neutral hydrophobic ferrocenecarboxylic acid (FCA) is preferentially included in the Mg-Al LDH-CMCD from a mixture of neutral and ionic forms of FCA. In contrast, in the parent Mg-Al LDH-NO3, it is the ionized hydrophilic derivative that is included. This difference in behavior is because the mechanism of inclusion in the two hosts is different. In Mg-Al LDH-NO3, inclusion occurs by ion-exchange, whereas in the functionalized Mg-Al LDH-CMCD, it occurs by a partitioning process.
Naphthalene molecules have been included within a cyclodextrin-functionalized layered metal hydroxide. Within the functionalized solid, cyclodextrin cavities are anchored to the gallery walls, forming a bilayer with the wider openings of the cavity facing away from the layers, creating a random array of hydrophobic nanopockets. Naphthalene molecules are driven into these hydrophobic cavities by partitioning from a polar solvent. This system differs from its solution counterpart, naphthalene included in cyclodextrin cavities in aqueous solution, by the absence of translational mobility of the cavities.
Thus, only those naphthalene molecules that are included in ?-CMCD cavities with suitably oriented anchored cavities in the opposing layer are able to form excimers. In Mg-Al LDH-CMCD(naphthalene), the absence of translational mobility of the anchored ?-CMCD cavities manifests in an unusual concentration dependence of the excimer-to-monomer intensity ratio in the fluorescence spectra—the ratio decreases at higher concentrations of the included naphthalene. These results indicate that naphthalene molecules are preferentially included in those anchored cavities that allow for excimer formation, i.e., those that have their openings facing each other and in registry. Anchored cavities that have their openings facing each other randomly are occupied only at higher naphthalene/CMCD ratios.
Fluorescence decay measurements show an absence of a rise-time for the excimer, implying that they are formed from naphthalene monomers that require minimum or no displacement or rotation to adopt overlapping configurations suitable for excimer formation. The Mg-Al LDH-CMCD(naphthalene) contains two types of included naphthalene: a preformed excimer-like species and monomers that are incapable of forming excimers. A kinetic scheme that accounts for the presence of these two species has been used to analyze the temperature dependence of the fluorescence spectra and to extract the concentration of each species and the enthalpy of formation of the excimer.
The uniqueness of these hybrid materials is that they are thermally stable over a wide temperature range. The data in Figure 8.6b represent the harmonic mean of the lifetimes that describe the FAD and, therefore, cannot be associated with rotational diffusion around any particular axis.
For anthracene included in the Mg-Al LDH-CMCD, since the cyclodextrin cavities are anchored to the gallery walls, tumbling of the cyclodextrins is not possible. The inner diameter of the bucket-like ?-CMCD cavity is ~7.8 Å at its widest and ~6 Å at the narrow end, while the kinetic diameter of the anthracene molecule is 5.8 Å along its short axis. The anthracene molecule sits in the cavity with its long axis coincident with the molecular axis of the cyclodextrin cavity, as shown in Figure 8.1. The only allowed motion, therefore, is a spinning diffusion of the anthracene molecule about its long axis. Motion about a single axis is insufficient to depolarize the fluorescence completely, and hence the observed residual anisotropy. The observed lifetime, 110 ps, is the rotational correlation for the spinning diffusion of an isolated anthracene molecule in a cyclodextrin cavity in an environment free of solvent molecules.
In conclusion, it has been shown that when anthracene molecules are included within the anchored cyclodextrin cavities of the functionalized Mg-Al LDH-CMCD, the system may be effectively modeled as an ensemble of isolated single anthracene molecules. This was inferred from the total absence of Stokes shift in the excitation-emission spectra. The orientational dynamics of the included anthracene was probed using fluorescence anisotropy decay measurements. Within the restricted geometries of the anchored cyclodextrin, the only motion that the included anthracene can perform is spinning about its long axis, and consequently, the fluorescence anisotropy decays to a finite value with a lifetime of 110 ps. In contrast, when anthracene is included in cyclodextrin in aqueous solutions, the whole complex can tumble, and the fluorescence is fully depolarized.
The present studies show that the cyclodextrin-functionalized layered solid offers a unique environment to study molecules in isolation and restricted geometries. The environment is less polar but comes at the cost of loss of mobility (Figure 9.29). The loss of mobility is reflected in the absence of excimer formation in the fluorescence spectra. The presence of pyrene in the interior of the bilayer probably causes the alkyl chains to splay, allowing for large free space for the chain termini and hence end-chain disorder. The increased end-chain disorder is seen as the absence of the end-chain tt conformers in the methyl rocking modes in the Raman spectra.
The anionic clay, Mg-Al LDH, has been functionalized by anchoring surfactant dodecyl sulfate (DDS) ions to the gallery walls. Dodecyl sulfate ions are confined within the galleries of layered double hydroxide by a simple ion-exchange intercalation reaction to give Mg0.37Al0.37(OH)2(DDS)0.37. Intercalation occurs with an expansion of 21.4 Å, which indicates that within the galleries of the LDH the methylene chains are arranged as a normal bilayer with a tilt angle of 58°. 13C NMR spectroscopy and vibrational spectroscopy indicate that the intercalated methylene chains adopt an almost all-trans conformation. Functionalization extends the host-guest chemistry of the anionic clay, from simple ion-exchange reactions to also include neutral and non-polar guest species.
Pyrene molecules have been solubilized in the intercalated bilayer phase Mg-Al LDH-DDS by partitioning from a polar solvent. Pyrene molecules induce conformational disorder in the intercalated alkyl chains and, more importantly, reduce the rotational disordering motion of the -SO3? head group of the surfactant. The fluorescence spectra of pyrene indicate formation of excimers, whose intensity increases at higher concentrations of the solubilized pyrene, indicating that they are mobile. The pyrene-solubilized Mg-Al LDH-DDS(pyrene) exhibits an unusual phenomenon: on evacuation, the excimer band disappears but reappears on releasing the vacuum. It is shown that this behavior arises due to the loss of water of hydration of the head group on evacuation, and as a consequence, the pyrene moves into the less polar interior of the bilayer, where it is immobile and can no longer diffuse and form excimers.
The motion of pyrene into the interior of the bilayer creates free space near the surfactant chain termini, which manifests in the disappearance of ordered end-chain (-tt) modes in the Raman spectra. | |
