Cyclodextrin-Induced Change in Crystal Habit of ... - ACS Publications

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Cyclodextrin-Induced Change in Crystal Habit of Acetylsalicylic Acid in Aqueous Solution Daisuke Iohara,†,∥ Kenshi Yoshida,§,∥ Kohki Yamaguchi,† Makoto Anraku,† Keiichi Motoyama,§ Hidetoshi Arima,§ Kaneto Uekama,‡ and Fumitoshi Hirayama*,† †

Faculty of Pharmaceutical Sciences and ‡DDS Research Institute, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan

§

S Supporting Information *

ABSTRACT: The present work refers to a method to selectively modify the crystal habit of acetylsalicylic acid (ASA) through the use of the cyclic oligosaccharide derivatives 2-hydroxybutyl-β-cyclodextrin (HB-β-CD) and 2,6-di-O-methyl-β-cyclodextrin (DM-β-CD) as a growth inhibitor. ASA crystallized in plate crystals in solutions containing only drug. On the other hand, the addition of HB-β-CD or DM-β-CD markedly changed the crystal habit of the drug to needle crystals that elongated along the crystallographic b-axis. The habit modification of these CDs was attributable to the suppression of the crystal growth of ASA toward the c-axis direction, which is perpendicular to the {001} surface and consisted of phenyl and methyl groups of ASA. These results suggested that HB- and DM-β-CDs inhibited the access of ASA to the {001} face due to the inclusion complex formation with the drug and/or due to the adsorption of the amphiphilic hosts on this face. These CDs can work as a tailor-made additive and may be useful for control of crystal habits of drugs.

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and indomethacin20 and was useful for selective isolation of metastable polymorphs that are difficult to isolate under usual conditions. For example, tolbutamide crystallized into metastable form IV polymorph in aqueous DM-β-CD solutions, but into stable form I in the absence of CDs. More recently, we have found out that a newly prepared β-CD derivative, 2hydroxybutyl-β-cyclodextrin (HB-β-CD),21 inhibited the transformation of chlorpropamide polymorph, from form II to form III step at higher CD concentrations but from form III to form A step at lower CD concentrations.22 These crystallizations into metastable forms were attributable to the ability of HB-β-CD to inhibit the solution-mediated polymorphic transition that proceeds according to “Ostwald’s Rule of Stages”,23 and this inhibition has been ascribed to the inclusion complex formation of the drug with the host molecule. In this study, we investigated the effect of CDs on the crystal growth of acetylsalicylic acid (ASA) in aqueous solution and report here that HB- and DM-β-CDs significantly modify the crystal habit of ASA.

INTRODUCTION Crystal morphology, or habit, significantly affects relevant properties of an active pharmaceutical ingredient (API), such as dissolution, physical and chemical stabilities, powder flow, bulk handling, ease of compression, and wettability.1−4 Therefore, in the development of high-quality drugs, it is important to select a proper crystal habit. The crystal habit modification can be induced by varying crystallizing environments such as solvent, temperature, agitating speed, and supersaturation.5,6 Recently, advanced approaches have been reported to selectively modify crystallization behavior by adding tailor-made additives such as structurally related compounds,7,8 surfactants,9−11 and polymers.12−14 However, solvents as crystallization media are limited in terms of their toxicity and the fact that they remain in final products.15 Furthermore, the use of tailor-made additives, particularly low-molecular weight compounds, often results in incorporation into the crystal lattice of API, because of their structural similarities. Surfactants and polymers are effective in modifying the crystal habit, but they sometimes need higher concentrations, leading to an undesirable increase in the viscosity of the crystallization solvent and to difficulties in the filtration step. Therefore, there is a strong need for new classes of additives in the crystal engineering field. Cyclodextrins (CDs), cyclic oligosaccharides usually consisting of six to eight D-glucose units, form inclusion complexes with various molecules in aqueous solution and in solid states and are successfully utilized for improvement of pharmaceutical properties of drugs.16−18 In previous studies, we found that 2,6di-O-methyl-β-cyclodextrin (DM-β-CD) significantly inhibited the solution-mediated polymorphic transitions of tolbutamide19 © 2012 American Chemical Society

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EXPERIMENTAL SECTION

Materials. α-CD, β-CD, γ-CD, 2-hydroxypropyl-α-cyclodextrin [HP-α-CD, degree of substitution (DS) of 2-hydroxypropyl groups is 4.9], HP-β-CD (DS 4.6), HP-γ-CD (DS 5.5), and HB-β-CD (DS 5.5) were supplied by Nihon Shokuhin Kako Co. Glucuronylglucosyl-βcyclodextrin (GUG-β-CD) and maltosyl-β-cyclodextrin (G2-β-CD) Received: December 23, 2011 Revised: February 18, 2012 Published: March 8, 2012 1985

dx.doi.org/10.1021/cg201691c | Cryst. Growth Des. 2012, 12, 1985−1991

Crystal Growth & Design

Article

were supplied by Ensuikoseito Co. Sulfobutyl ether β-cyclodextrin (SBE7-β-CD) was supplied by Cydex Co. 2,6-Di-O-methyl-β-cyclodextrin (DM-β-CD) was purchased from Nacalai Tesque. ASA was purchased from Wako Pure Chemical Co. Other chemicals and solvents were of analytical reagent grade, and deionized water was used throughout the study. Crystallization. The crystallization of ASA from an aqueous solution was conducted as follows: ASA was dissolved at 40 mM in the absence and in the presence of CDs at various concentrations in pH 8.0 sodium phosphate buffer (10 mL, prepared with 0.1 M H3PO4/0.1 M NaOH, ionic strength 0.2) in a 50 mL beaker at room temperature. The solution was slowly titrated with aqueous 0.5 M HCl solution (about 1 mL) to pH 2.0, where ASA did not yet precipitate. The solution was paper-filtered and the filtrate was left standing for crystallization in a refrigerator (4 °C) for 1 day unless otherwise stated. The precipitated ASA crystals were collected by filtration and washed with small amounts of water. Large ASA single crystals were obtained from ethanol by slow evaporation of the solvent. Single crystals of ASA/DM-β-CD complex were obtained from water; i.e., ASA (30 mM) and DM-β-CD (30 mM) were dissolved in water at 4 °C and then stood at 40 °C, because DM-β-CD is freely soluble in water at lower temperature but less soluble at higher temperature.

CD solutions (5 mM) was measured by a CBC Materials VM-10A viscometer (Tokyo, Japan) at 25 °C. Solubility Study. The solubility method was conducted according to the method of Higuchi and Connors.25 An excess amount of ASA was added in a test tube containing CDs at various concentrations in pH 3.0 phosphate buffer and the mixture was shaken at 4 °C for 12 h. An aliquot was taken by a cotton-plugged pipet, diluted with water, and analyzed for ASA by UV spectroscopy at 274 nm.

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RESULTS Crystal Growth Behavior of ASA. Figure 2 shows photographs of crystals precipitated from an aqueous, buffered

Figure 2. Photographs of ASA crystals precipitated in the absence (A) and presence of 5.0 mM HB- (B) or DM-β-CD (C) in sodium phosphate/HCl solution (pH 2.0), stored for 1 day at 4 °C.

(pH 2.0) 40 mM ASA solution in the absence and presence of HB- and DM-β-CDs (5 mM) after 24 h. ASA crystals were grown to hexagonal plate crystals in the absence of CDs. The hexagonal plate crystals were also obtained from the solutions containing 5 mM parent α-, β- and γ-CDs; HP-α-, HP-β-, and HP-γ-CDs; GUG-β-CD; G2-β-CD; SBE7-β-CD; and 35 mM glucose (Figure S1 in Supporting Information). In contrast, in the presence of HB-β-CD or DM-β-CD, the ASA crystal morphology changed to needle crystals and this modification increased with CD concentrations (Figure S2 in Supporting Information). Figure 3 shows powder X-ray diffraction patterns

Figure 1. A homemade quartz cell used for observation of crystal growth of ASA. Observation of Crystal Growth of ASA. A homemade quartz cell (2 × 2 × 3.5 cm in width, length and height, Figure 1) was used for observation of the crystal growth of ASA. The cell was filled with 0.3% w/v (17 mM) ASA solution with and without HB-β-CD in 7.0 mL of phosphate buffer (pH 2.0, ionic strength 0.2). The hexagonal ASA crystal (0.3−0.6, 1−1.2, and 1−1.2 mm in the a-, b-, and cdirections; see Figure 7) as a seed crystal was mounted on a capillary glass by epoxy−resin and soaked in the buffered solution at 4 °C. The crystal sizes were periodically measured from the three directions using a microscope (Keyence VH-7000). Apparatus. Powder X-ray diffraction patterns were measured with a powder X-ray diffractometer (Rigaku Ultima+) under the following conditions: Ni-filtered Cu Kα radiation (1.542 Å), 40 kV, 40 mA, divergent slit of 1.74 mm (1°), scanning slit of 0.94 mm (1°), receiving slit of 0.15 mm, and goniometer angular increment of 1°/min. Crystals were ground in a mortar and sieved through 100 mesh screen. The powder sample (15 mg) was mixed with an internal standard, silica (5 mg), and subjected to the diffraction study. The peak area of ASA was compared with that of silca (2θ = 28.4°). Oscillation photographs of single ASA crystals were measured by a Rigaku RAXIS RAPID II diffractometer with Mo Kα radiation (0.710 75 Å) operating at 50 kV, 20 mA. The single crystal was mounted on a glass fiber, set on a goniometer head along the crystal axes reported by AubreyMedendorp et al.,24 and rotated about the axes after fine alignments to give horizontal straight diffraction lines. 1H NMR spectra were taken on a JEOL JNM-A500 spectrometer operating at 500 MHz for 5 mM ASA/D2O solutions without or with CDs (5−25 mM) at 25 °C. The sessile contact angle of crystal surfaces was measured by a Kyowa CA-D apparatus (Tokyo, Japan); i.e., a droplet of water (diameter about 20 μm) was deposited onto crystal surfaces, and at least 10 contact angles were measured on each crystal facet. The viscosity of

Figure 3. Powder X-ray diffraction patterns of ASA crystals precipitated in the absence and presence of CDs (5 mM) or glucose (35 mM) in sodium phosphate/HCl solution (pH 2.0), stored for 1 day at 4 °C.

of ASA crystals precipitated from buffered (pH 2.0) 40 mM ASA solutions. In all cases, ASA crystallized into stable form I crystals, giving the diffraction peaks typical for form I crystal,26 e.g. 2θ = 7.8° and 15.6°, and no change in the melting point (140 °C), demonstrating no polymorphism. However, the peak intensity at 2θ = 15.6° of the HB-β-CD or DM-β-CD system significantly increased, suggesting changes in the crystal habit. 1986



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Figure 4 shows the effects of CD concentration on the peak area of 2θ = 15.6° relative to the peak area of an internal

Figure 4. Effects of β-CD concentration on peaks areas at 2θ = 15.6° of ASA crystals obtained in sodium phosphate/HCl solution (pH 2.0), stored for 1 day at 4 °C: (□) HP-β-CD, (○) HB-β-CD, (Δ) DM-βCD. Each point represents the mean ± SE of 3−6 experiments.

standard, silicon. The peak area of the HP-β-CD system, which exhibited no habit change, did not change at these concentrations, whereas that of the HB-β-CD and DM-β-CD systems increased. In particular, the peak area of needle crystals obtained from HB-β-CD solutions markedly increased, and that at 5 mM HB-β-CD was about 6 times larger than that of plate crystals obtained from ASA alone solutions. These results indicate that HB-β-CD and DM-β-CD modify the crystal morphology of ASA and that HB-β-CD is superior in this respect compared with other CDs. The diffraction peak of 2θ = 15.6° is assigned to those from the (200) and (002) planes,24 suggesting an increase in the relative area of the {100} and/or {001} facets in the needle crystal. No contamination or cocrystallization of other compounds, such as CDs and salicylic acid, in ASA crystals was confirmed by 1H NMR spectroscopy, thin-layer chromatography, and elementary analysis (data not shown). To gain insight into the elongated direction, oscillation photographs of the needle ASA crystal obtained from HB-β-CD and DM-β-CD solutions were taken and compared with those of a large ASA crystal grown in ethanol, as shown in Figure 5. The needle crystal mounted on a goniometer along the elongated direction gave diffractions corresponding to 6.6 Å (Figure 5A,B). This value coincided with the length of the baxis of the reference crystal (Figure 5D) and with the reported length of the b-axis (the monoclinic space group P21/c with a = 11.242 Å, b = 6.539 Å, c = 11.245 Å, and β = 95.9°).26 The lengths of the other directions coincided with those of a- and caxes. These results indicated that the needle crystal obtained from HB- and DM-β-CD solutions elongated along the b-axis of ASA crystals. We observed macroscopically the crystal growing behavior of ASA in the absence and presence of HB-β-CD solutions. The hexagonal plate crystal of ASA grew, keeping a constant morphology in the absence of CDs (Figure 6A), whereas it changed to the longer shape in the presence of HB-β-CD (Figure 6B). On the other hand, the needle ASA crystal grew, changing its shape to the plate-like crystal in the absence of CDs (Figure 6C), whereas it kept the same needle morphology in the presence of HB-β-CD (Figure 6D). Next, we measured

Figure 5. Schematic shapes (left) and oscillation photographs (right) of ASA crystals obtained in the presence of HB-β-CD (A) or DM-βCD (B) in sodium phosphate/HCl solution (pH 2.0) and from ethanol (C−E).

the growth rate of the hexagonal ASA single crystal along the a-, b-, and c-directions, using the crystallization cell (Figure 7). The face with the largest area of the ASA crystal was assigned to the {100} face, because this face gave no systemic absences of (h00) diffractions, 2θ = 7.8° (100), 15.6° (200), 23.5° (300), and 31.5 (400), whereas the secondary large face {001} gave only a (002) peak at 2θ = 15.6° due to the systemic absences of (00l) diffractions for the space group P21/c (Figure S3 in Supporting Information). Further, this assignment of the crystal faces was supported by measurements of contact angles; i.e., the contact angle (60.2° ± 0.7°) of the {100} face with the widest area was larger than that (53.3° ± 1.0°) of the secondary wide {001} face. These results were consistent with the reports of Aubrey−Medendorp et al.24 and Li et al.27 Figure 8 shows changes in crystal sizes of ASA along the a-, b-, and c-axis directions in the absence and presence of HB-β-CD, as a function of time. Without HB-β-CD (Figure 8A), the ASA crystal grew mainly along the b- and c-directions while slowly along the a-direction, exhibiting the larger surface of the {100} face. The lengths grown along the a-, b-, and c-directions were 716, 1352, and 1473 μm, respectively, in 7 days. In the presence of HB-β-CD (Figure 8B), the growth rate of these directions 1987



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Figure 6. Changes in crystal habit of ASA during storage at 4 °C. (A) Plate crystal in the absence of HB-β-CD. (B) Plate crystal in the presence of HB-β-CD (5 mM). (C) Needle crystal in the absence of HB-β-CD (5 mM). (D) Needle crystal in the presence of HB-β-CD.

Figure 7. Photographs of ASA plate crystal grown in the absence (A) and presence (B) of HB-β-CD (5 mM). Upper images show crystal growth in the a-axis direction and lower images show crystal growth in the b- and c-axis directions from a seed crystal.

was suppressed, probably because of a decrease in the supersaturation level of ASA in solutions due to an increase in its apparent solubility by the complex formation with the host molecule. However, of these directions, the growth rate along the c-direction was markedly suppressed by HB-β-CD, the lengths grown along the a-, b-, and c-directions being 195, 624, and 60 μm, respectively, in 7 days and thus the inhibition ratios being about 3.7-, 2.2-, and 25-fold, respectively, when compared with the lengths obtained without CDs. These results indicate that the growing rate of ASA crystals is in the order of b- ≫ a- > c-directions, exhibiting elongated needle crystals along the b-axis. This result was consistent with the

powder X-ray diffraction data (Figures 3 and 4) that the peak intensity of the (002) face at 2θ = 15.6° significantly increased in the presence of HB-β-CD. Therefore, these results indicate that HB-β-CD selectively suppresses the crystal growth of aspirin, especially along the c-direction. Interaction of ASA with HB- and DM-β-CDs. The interaction of ASA with HB- and DM-β-CDs in aqueous solution was studied by the solubility method25 and 1H NMR spectroscopy (Figures S4 and S5 in the Supporting Information). In all CDs, the solubility of ASA increased linearly with CD concentrations, showing AL type diagrams, and the stability constants of the ASA/HB-β-CD complex (K = 1988



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Information). However, these surfactant solutions did not give needle crystals of ASA but much thinner hexagonal crystals similar to those obtained from aspirin alone solution. Therefore, the crystallization behavior of ASA may differ slightly between the surfactants and HB- and DM-β-CDs, and the guest−host inclusion takes part in the crystallization of needle crystals. To gain insight into the morphology change of ASA crystal with the addition of HB- and DM-β-CDs, we inspected the packing feature of ASA molecules in the crystal. Figure 10 shows the molecular packing ASA viewed from the a- or c-axis and the schematic shape of the hexagonal plate crystal of ASA obtained from water. The a- and c-axes of the hexagonal shape are not perpendicular to one another but are at β = ca. 96°, and the b-axis is perpendicular to both of the a- and b-axes. In ASA crystals, the intermolecular hydrogen-bonding networks run roughly along the b-axis, although it is not exactly parallel to this axis, and there are no truncations in the b-axis direction. On the other hand, two truncations of void space exist along the aand c-axes, which are defined as (200) and (004) planes, as shown in Figure 10. The acetyloxy groups of ASA face each other in the (200) plane, while the phenyl and methyl groups face each other in the (004) plane, and they interact weakly through van der Waals force. Li et al.27 reported that this (200) plane consisting of the acetyloxy group appears as the {100} surface of the ASA crystal with the largest area, while the (004) plane consisting of the phenyl and methyl groups is exposed as the {001} surface with the secondary large area. In the absence of CDs, the growth rate of ASA crystal along the a-axis direction was the slowest of the three directions, probably due to the weak interaction in the (200) plane, thus developing the large {100} surface. As demonstrated by NMR spectroscopic and X-ray crystallographic studies, the phenyl group of ASA was preferably included in the HB- and DM-β-CD cavities in aqueous solution and shallowly around the primary hydroxyl group of DM-β-CD in the solid state. As described above, the {001} surface of ASA crystals consists of the (004) plane of the phenyl and methyl groups. Therefore, these results suggest that the access of ASA molecules to the {001} surface is significantly inhibited by the inclusion complex formation in solution and/ or by the adsorption of the amphihilic host molecules21 on the {001} surface, as shown in Figure 11. As a result of the inhibition, the crystal was elongated along the b-axis, resulting in the needle crystals. In conclusion, the present study indicates that HB-β-CD and DM-β-CD are effective in modifying the crystal habit of ASA.

Figure 8. Changes in crystal size of ASA in the absence (A) and presence (B) of HB-β-CD in sodium phosphate/HCl solution (pH 2.0) at 4 °C: (□) a-axis, (Δ) b-axis, (●) c-axis.

266 M−1) and/DM-β-CD complex (K = 333 M−1) were higher than those of β-CD (K = 112 M−1) and HP-β-CD (K = 188 M−1). In 1H NMR spectroscopic studies, relatively large chemical shift changes were observed in the phenyl protons of ASA in the presence of HB- and DM-β-CDs. The continuous variation plot of the ASA/HB-β-CD and/DM-βCD systems gave the maximum at a 1:1 host:guest molar ratio, indicating the 1:1 complex formation (Figures S6 in Supporting Information). These results indicated that ASA formed the 1:1 complex with HB- and DM-β-CDs and that the phenyl group of ASA was preferably included in these CD cavities in aqueous solution. Figure 9 shows the results of X-ray structure analysis of the ASA/DM-β-CD complex.28 Four ASA and DM-β-CD molecules were packed in a unit cell forming the 1:1 complex in the solid state. The ASA molecule was not deeply included in the cavity of DM-β-CD but was deposited shallowly around the primary hydroxyl side of the host molecule.

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DISCUSSION ASA crystallized into hexagonal plate crystals of the stable form I in aqueous solutions of the drug alone. On the other hand, ASA crystallized into needle crystals of the form I in the presence of HB-β-CD or DM-β-CD, where the crystals grew preferably toward the b-axis direction and the growth toward the c-axis direction was markedly suppressed by HB-β-CD and DM-β-CD. It has been reported that the viscosity of solvents and the surface activity of additives affect crystal morphology.29 However, CDs used in this study did not change the viscosity (about 1.5 mPa·s) at these concentrations (0−5 mM). We studied the crystallization of ASA in the presence of surfactants such as lauryltrimethylammonium chloride (LAC), sodium laurylsulfate (SLS), and Tween 80 (Figure S7 in Supporting

Figure 9. Crystal structure of ASA/DM-β-CD complex viewed from the b-axis (A) and the inclusion mode of the complex (B). 1989



Article

Figure 10. Structure of ASA viewed from the c-axis (A) and the a-axis (B) directions and a schematic figure of the hexagonal plate crystal of ASA (C).

Figure 11. Proposed mechanism of inhibition of ASA crystal growth along c-axis direction (A) and a schematic figure of the needle crystal of ASA (B).

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CDs are known to include stereospecifically some part of molecules within the cavity and to form inclusion complexes.

Corresponding Author

* Tel: +81-96-326-4098. Fax: +81-96-326-5048. E-mail: fhira@ ph.sojo-u.ac.jp. Web address: http://www.ph.sojo-u.ac.jp/ ∼dio/.

This suppresses the access of drug molecules onto specific crystal surfaces, leading to morphological changes of crystals. Therefore, CDs can work as a tailor-made additive and may be

Author Contributions ∥

useful for control of crystal habits of drugs.

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AUTHOR INFORMATION

These authors contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ASSOCIATED CONTENT

S Supporting Information *

REFERENCES

(1) Prestidge, C. A.; Tsatouhas, G. Int. J. Pharm. 2000, 198, 201−212. (2) Heng, J. Y. Y.; Bismarck, A.; Lee, A. F.; Wilson, K.; Williams, D. R. Langmuir 2006, 22, 2760−2769. (3) Heng, J. Y. Y.; Williams, D. R. Langmuir 2006, 22, 6905−6909. (4) Riebel, U.; Kofler, V.; Loeffler, F. Part. Part. Syst. Charact. 1991, 8, 48−54.

The photographs of ASA crystals, powder X-ray diffractograms, the solubility diagrams, the 1H NMR chemical shift displacements, and the continuous variation plots. This material is available free of charge via the Internet at http://pubs.acs.org. 1990



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(5) Berkovitch-Yellin, Z.; Van Mil, J.; Addadi, L.; Idelson, M.; Lahav, M.; Leiserowitz, L. J. Am. Chem. Soc. 1985, 107, 3111−22. (6) Carstensen, J. T.; Ertell, C.; Geoffroy, J. M. Drug Dev. Ind. Pharm. 1993, 19, 195−219. (7) Edgar, R.; Schultz, T. M.; Rasmussen, F. B.; Feidenhans’l, R.; Leiserowitz, L. J. Am. Chem. Soc. 1999, 121, 632−637. (8) Weissbuch, I.; Addadi, L.; Berkovitch-Yellin, Z.; Gati, E.; Weinstein, S.; Lahav, M.; Leiserowitz, L. J. Am. Chem. Soc. 1983, 105, 6615−21. (9) Chan, H. K.; Gonda, I. J. Cryst. Growth 1989, 94, 488−98. (10) Luhtala, S. Acta Pharm. Nord. 1992, 4, 85−90. (11) Rodriguez-Hornedo, N.; Murphy, D. J. Pharm. Sci. 2004, 93, 449−460. (12) Nokhodchi, A.; Bolourtchian, N.; Dinarvand, R. J. Cryst. Growth 2005, 274, 573−584. (13) Rasenack, N.; Muller, B. W. Int. J. Pharm. 2002, 245, 9−24. (14) Raghavan, S. L.; Trividic, A.; Davis, A. F.; Hadgraft, J. Int. J. Pharm. 2001, 212, 213−221. (15) Kuldipkumar, A.; Tan, Y. T. F.; Goldstein, M.; Nagasaki, Y.; Zhang, G. G. Z.; Kwon, G. S. Cryst. Growth Des. 2005, 5, 1781−1785. (16) Uekama, K.; Hirayama, F.; Irie, T. 1998, 98, 2045-2076. (17) Loftsson, T.; Brewster, M. E. J. Pharm. Sci. 1996, 85, 1017− 1025. (18) Rajewski, R. A.; Stella, V. J. J. Pharm. Sci. 1996, 85, 1142−1169. (19) Sonoda, Y.; Hirayama, F.; Arima, H.; Yamaguchi, Y.; Saenger, W.; Uekama, K. Cryst. Growth Des. 2006, 6, 1181−1185. (20) Iohara, D.; Hirayama, F.; Ishiguro, T.; Arima, H.; Uekama, K. Int. J. Pharm. 2008, 354, 70−76. (21) Ishiguro, T.; Morishita, E.; Iohara, D.; Hirayama, F.; Wada, K.; Motoyama, K.; Arima, H.; Uekama, K. Int. J. Pharm. 2011, 419, 161− 169. (22) Ishiguro, T.; Hirayama, F.; Iohara, D.; Arima, H.; Uekama, K. Eur. J. Pharm. Sci. 2010, 39, 248−255. (23) Ostwald, W. Z. Phys. Chem. 1897, 22, 289−330. (24) Aubrey-Medendorp, C.; Parkin, S.; Li, T. J. Pharm. Sci. 2008, 97, 1361−1367. (25) Higuchi, T.; Connors, K. A. Adv. Anal. Chem. Instr. 1965, 4, 117−212. (26) Kim, Y.; Machida, K.; Taga, T.; Osaki, K. Chem. Pharm. Bull. 1985, 33, 2641−7. (27) Li, T.; Liu, S.; Feng, S.; Aubrey, C. E. J. Am. Chem. Soc. 2005, 127, 1364−1365. (28) Crystal data of 1:1 ASA/DM-β-CD complex: C9H9O4/ C56H98O35, M = 1511.53, orthorhombic, space group P212121, a = 14.305(3) Å, b = 19.256(3) Å, c = 28.634(4) Å, V = 7887.5(1) Å3, Z = 4, Dc = 1.273 g/cm3, R = 0.146, Rw = 0.215. The structure was solved by the Patterson orientation/translation search using data for the piodophenol/DM-β-CD complex.30 All calculations were performed using the crystallographic software package Crystal Structure.31 The detailed crystal structure of ASA/DM-β-CD complex will be reported elsewhere. (29) Michaels, A. S.; Tausch, F. W. Jr. J. Phys. Chem. 1961, 65, 1730−7. (30) Harata, K. Bull. Chem. Soc. Jpn. 1988, 61, 1939−44. (31) CrystalStructure 3.6.0: Crystal Structure Analysis Package; Rigaku and Rigaku/MSC, 9009 New Trials Dr., The Woodlands, TX 77381, USA (2000−2004).

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