DOI: 10.1021/cg900573w
Incorporation of Salicylic Acid Molecules into the Intermolecular Spaces of γ-Cyclodextrin-Polypseudorotaxane
2009, Vol. 9 4243–4246
Kenjirou Higashi,* Saori Ideura, Haruka Waraya, Kunikazu Moribe, and Keiji Yamamoto Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan Received May 28, 2009; Revised Manuscript Received August 10, 2009
ABSTRACT: Sealed-heating of salicylic acid (SA) and polyethylene glycol (PEG)/γ-cyclodextrin (CD)-polypseudorotaxane induced a novel complex formation wherein SA was inhabited in the intermolecular spaces formed by the γ-CD/polypseudorotaxane columns. Incorporation of SA into the PEG/γ-CD-polypseudorotaxane structure was clarified by powder X-ray diffraction measurements and 13 C-solid-state NMR spectroscopy. Different water vapor adsorption and desorption behaviors between the novel complex and PEG/ γ-CD-polypseudorotaxane confirmed the incorporation of SA molecules into the intermolecular spaces in the complex.
*To whom correspondence should be addressed. Tel: þ81-43-290-2938. Fax: þ81-43-290-2939. E-mail:
[email protected].
The powder X-ray diffraction (PXRD) measurement showed evidence of a novel SA/(PEG/γ-CD-polypseudorotaxane) complex formation. It was reported that in all cases of the γ-CD inclusion complex, the columnar structure was arranged in such a way that the CD cavities stacked on top of each other to form long cylindrical channels.6 Figure 1 shows the changes in the PXRD patterns of PEG/γ-CD-polypseudorotaxane through the dehydration or the complex formation with SA. The diffraction patterns of PEG/γ-CD-polypseudorotaxane crystallized from water (Figure 1a) coincided with the diffraction pattern of the tetragonal columnar structure of γ-CD.3,6 The stoichiometry of the monomer unit of PEG and γ-CD was determined to be 4/1 by 1 H NMR measurement (see Supporting Information Figure S1). Harada et al. reported the double-stranded inclusion complexes of γ-CD threaded on end-modified PEGs.7 Therefore, the prepared PEG/γ-CD-polypseudorotaxane was considered to contain two side-by-side PEG chains in each γ-CD column. After drying the PEG/γ-CD-polypseudorotaxane at 100 °C, the diffraction pattern of the tetragonal columnar structure changed to that of a hexagonal columnar structure of γ-CD (Figure 1b).3,6,8 In the hexagonal columnar structure, PEG/γ-CD-polypseudorotaxane molecules were tightly packed compared to the tetragonal columnar structure due to the lack of water in the intermolecular spaces of the γ-CD columns. In the X-ray diffraction patterns of the PM (Figure 1c), the diffraction peaks of the SA crystals and the hexagonal columnar structure of γ-CD were observed. On the other hand, new diffraction peaks were observed in the X-ray diffraction pattern of the SA/(PEG/γ-CDpolypseudorotaxane) SH (SA/γ-CD=2/1) (Figure 1d), indicating a new complex formation. The diffraction peaks of hexagonal columnar structure was observed with the new peaks in the diffraction patterns of SH (SA/γ-CD=1/1) (Figure 1e). Meanwhile, the diffraction pattern of the SH (SA/γ-CD = 3/1) (Figure 1f) showed residual peaks of the SA crystals in addition to the new peaks. Hence, the stoichiometry of the SA/(PEG/γCD-polypseudorotaxane) complex was determined to be 2/1. To clarify the structure of the new complex, we compared the X-ray diffraction pattern with that of various γ-CD structures. Kawasaki et al. investigated an ambiguous γ-CD-polypseudorotaxane structure that was observed as an intermediate in the conversion from a tetragonal to a hexagonal columnar structure on drying. They determined the unknown structure as a monoclinic-columnar form by electron microscopy analysis and PXRD measurement.3,9 The low angle peaks (2θ=5.7° and 8.0°) in the X-ray diffraction pattern of PEG/γ-CD-polypseudorotaxane with the monoclinic-columnar structure (Figure 1f) corresponded to that of the newly obtained complex. From the comparison of
r 2009 American Chemical Society
Published on Web 08/20/2009
Cyclodextrins (CDs), which are host molecules, are known to include various kinds of guest molecules in their cavities.1 Inclusion complex formations with active pharmaceutical ingredients (APIs) have been widely studied because inclusion complex formations improve physicochemical properties such as solubility, dissolution rate, bioavailability, and stability of APIs. Guest molecules were reported to be able to exist both in the cavities of CDs and in the intermolecular spaces formed by CDs.2 Indeed, Harata et al. described that in the evaporated sample of p-nitrophenol/dimethyl-β-CD, p-nitrophenol existed in the interstitial sites of the molecular arrangement of dimethyl-β-CD molecules.2 In the case of m-nitrophenol or m-bromophenol, the guest molecules were located not only in the cavity of R-CD but also in the intermolecular spaces of R-CD columns.2 However, there have been few publications that have discussed the existence of guest molecules outside the CD cavities. Recently, a large number of studies on the inclusion complexes of CDs with polymers, named CD-polypseudorotaxanes, have been published.3,4 CD-polypseudorotaxanes have received a great deal of interest because of their unique structural, electrical, and mechanical properties. Their applications in the pharmaceutical field, however, have been extremely limited because the CD cavities are filled with polymers and no more space in the cavity remains for the inclusion of drugs. Herein we report a novel complex prepared by utilizing the sealed-heating technique, in which both the guest and host molecules are only heated in an enclosed space.5 In this novel complex, it was found that salicylic acid (SA) molecules were inhabited in the intermolecular spaces formed by polyethylene glycol 2000 (PEG)/γ-CD-polypseudorotaxane columns. A novel inclusion complex was prepared in two steps. In step 1, conventional PEG/γ-CD-polypseudorotaxane was prepared by the coprecipitation method.3 PEG and γ-CD were suspended in distilled water. The suspension was stirred at 25 °C for 2 days and then stored for 1 day at 25 °C. The precipitate was filtrated and dried for 1 day at 25 °C to obtain PEG/γ-CD-polypseudorotaxane. In step 2, SA and the polypseudorotaxane were sealedheated in order to incorporate SA molecules into the intermolecular spaces of the γ-CD molecules. PEG/γ-CD-polypseudorotaxane, which was dried at 100 °C for 3 h, was mixed with SA at various molar ratios to prepare the physical mixture (PM). The prepared PM (200 mg) was sealed in a glass ampule with a capacity of 2 mL and heated at 150 °C for 3 h to obtain a sealed-heated sample (SH).
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Figure 2. Schematic representation of the structural changes of PEG/γ-CD-polypseudorotaxane by sealed-heating with SA. (a) PEG/γ-CD-polypseudorotaxane with hexagonal columnar structure and (b) SA/(PEG/γ-CD-polypseudorotaxane) complex with monoclinic columnar structure. Top views of the γ-CD columns are given. The “O” and “b” indicate PEGs included in the cavity and SA molecules between the intermolecular spaces of γ-CD columns, respectively.
Figure 1. Changes in PXRD patterns through the SA/(PEG/γ-CD polypseudorotaxane) complex formation. (a) PEG/γ-CD-polypseudorotaxane crystallized from water, (b) the PEG/γ-CD-polypseudorotaxane complex after drying at 100 °C for 3 h, (c) SA/(PEG/γ-CD-polypseudorotaxane) PM (SA/γ-CD = 2/1), (d) SA/(PEG/γ-CD-polypseudorotaxane) SH (SA/γ-CD = 2/1), (e) SA/(PEG/γ-CD-polypseudorotaxane) SH (SA/γ-CD = 1/1), (f) SA/(PEG/γ-CD-polypseudorotaxane) SH (SA/γ-CD = 3/1), and (g) PEG/γ-CD-polypseudorotaxane after drying at 40 °C for 12 h. 0 Tetragonal columnar structure, ) hexagonal columnar structure, O monoclinic columnar structure, and 9 SA.
various PXRD patterns, it was concluded that the structure of the new SA/(PEG/γ-CD-polypseudorotaxane) complex was of the monoclinic columnar form. Kawasaki et al. have also stated that the monoclinic columnar structure of PEG/γ-CD-polypseudorotaxane observed during the drying process coexisted with the remaining tetragonal columnar structure. Therefore, it should be noted that this is the first report detailing the preparation of γ-CD-polypseudorotaxane with a single phase monoclinic columnar structure. The structural change in the molecular arrangement of the columnar structure from a hexagonal to a monoclinic columnar form results in an expansion of the space formed by columnar γ-CD crystal stacking (Figure 2). It was reported that the minimum cross-section diameter of the SA molecule was estimated to be 6.4 A˚.5 Taking the size of the SA molecule into consideration, the monoclinic columnar structure provided enough space that two SA molecules could be inserted. Hence, it is suggested that SA molecules exist in the intermolecular spaces between γ-CD columns in the novel complex. Figure 3 shows the 13C-cross-polarization and magic angle spinning (CP/MAS) solid-state NMR spectra of the SA crystal and the SA/(PEG/γ-CD-polypseudorotaxane) complex (SA/γCD = 2/1) in the range of 100-180 ppm, where the carbon peaks of SA were observed. Chemical shift and shape of some
Figure 3. 13C-CP/MAS NMR spectra of (a) SA and (b) the SA/(PEG/γ-CD-polypseudorotaxane) complex (SA/γ-CD = 2/1) in the range of 100-180 ppm. O spinning sideband.
peaks derived from SA in the complex changed compared to that of SA crystal. This indicated that the molecular mobility of the incorporated SA and the chemical environment in which it existed changed due to complex formation through a newly occurring intermolecular interaction. In particular, peak “a”, derived from the carbonyl group of SA, shifted significantly (from 176 to 172 ppm). SA molecules were reported to have the dimer structure in the crystal structure due to intermolecular hydrogen bonding.10 The NMR peak shift of the SA molecules resulted from the breakage of the intermolecular hydrogen bonding between SA molecules. Subsequently, hydrogen bonding of the SA monomer and PEG/γ-CD-polypseudorotaxane took place. In the infrared (IR) spectrum of the SA/(PEG/γ-CD-polypseudorotaxane) complex (SA/γ-CD = 2/1), the carbonyl stretching band of SA was observed at a higher frequency (1673 cm-1) than that of the SA crystals (1673 cm-1) (see Supporting Information Figure S2). Nakai et al. have reported on the IR peak shift of the carbonyl stretching band to a higher frequency (around 20 cm-1) in the IR spectrum of a ground mixture of drugs (SA, benzoic acid, and aspirin) and additives (microcrystalline cellulose or β-CD).11 They attributed the peak shifts to the breakage of the intermolecular hydrogen bonding between drug dimers and the formation of intermolecular hydrogen bonding between the drug and the additive. The changes observed in the IR spectra during the complex formation of SA with PEG/γ-CDpolypseudorotaxane might be consistent with the solid-state NMR results. NMR and IR measurements suggested that the
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in the Japanese Pharmacopeia first medium (pH 1.2) was significantly higher than that of the intact and PM. On the basis of the results of the dissolution test, it was assumed that an increase in the wettability of the complex resulted in the improvement of the dissolution rate. In conclusion, we have succeeded in preparing a novel complex compound composed of SA and PEG/γ-CD-polypseudorotaxane. Two SA molecules for every γ-CD molecule could inhabit in the intermolecular spaces between the γ-CD-polypseudorotaxane columns. Efforts are currently underway to extend the application of this novel complex for another drug and polymer system. Novel CD complexes composed of CD-polypseudorotaxane may be potentially used in new drug formulations and the preparation of functional materials.
Figure 4. Schematic representation of the structural changes in (a) PEG/γ-CD-polypseudorotaxane and (b) the SA(PEG/γ-CDpolypseudorotaxane) complex as a result of water vapor adsorption and desorption. Small dots indicate water molecules which were absorbed into the intermolecular spaces between the PEG/γ-CDpolypseudorotaxane columns.
SA molecules were embedded in the crystal structure of PEG/ γ-CD-polypseudorotaxane through intermolecular interaction. The effects of water vapor adsorption and desorption on the structure of the novel complex were evaluated to clarify the spatial molecular arrangements of SA molecules in the novel complex. On water vapor adsorption, the X-ray diffraction pattern of the complex changed from a monoclinic to a tetragonal columnar form, while the formed tetragonal columnar structure remained unchanged after water vapor desorption (see Supporting Information Figure S3). It was found that structural changes in the novel complex due to water vapor adsorption and desorption were irreversible (Figure 4). On the other hand, PEG/γ-CD-polypseudorotaxane changed from a monoclinic to a tetragonal columnar structure and vice versa due to the water adsorption and desorption cycle.3 The different water vapor adsorption and desorption behaviors of the novel complex and PEG/γ-CD-polypseudorotaxane were attributed to the incorporation of SA molecules into the intermolecular spaces in the complex. The trapped SA molecules appeared to inhibit the shrinkage of the formed tetragonal columnar crystal lattice and maintain the structure stably, even after the removal of water molecules from the intermolecular spaces of the γ-CD columns. The complex was reprepared and PXRD measurements were carried out to confirm the novel complex formation between SA and PEG/γ-CD-polypseudorotaxane. The results showed that the SA/(PEG/γ-CD-polypseudorotaxane) complex was reproducible. Other drug/(PEG/γ-CD-polypseudorotaxane) complexes were prepared to elucidate the generality of the novel complex formation. Novel complexes with PEG/γ-CD-polypseudorotaxane were obtained when benzoic acid, salicylamide, and p-aminobenzoic acid were used as the guest molecules (see Supporting Information Figure S4). The structural changes of each complex due to water vapor adsorption and desorption were similar to those of the SA/(PEG/γ-CD-polypseudorotaxane) complex. These results indicated that the novel complex formation with CD-polypseudorotaxane could have wider applications by the use of this unique two-step sample preparation method. Dissolution tests were performed in order to evaluate the effect of the complex formation on the pharmaceutical property of the incorporated guest molecules (see Supporting Information Figure S5).8,12 The dissolution rate of SA from the complex
Acknowledgment. This research was supported by a Grant-inAid from the Ministry of Education, Culture, Sports, Sciences and Technology (Monbukagakusho) of Japan, Mochida Memorial Foundation for Medical and Pharmaceutical Research, Japan. Supporting Information Available: Experimental procedures; 1H NMR spectrum of PEG/γ-CD-polypseudorotaxane (Figure S1); changes in PXRD pattern of SA (PEG/γ-CD-polypseudorotaxane) complex on water vapor adsorption and desorption (Figure S2); changes in IR spectra due to novel SA/(PEG/γ-CD polypseudorotaxane) complex formation (Figure S3) and due to novel drug/ (PEG/γ-CD polypseudorotaxane) complex formation (Figure S4); dissolution profiles of SA (Figure S5). This information is available free of charge via the Internet at http://pubs.acs.org/.
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