Application of Ionic Liquid to Polymorphic Design of Pharmaceutical

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DOI: 10.1021/cg1001489

Published as part of a virtual special issue of selected papers presented in celebration of the 40th Anniversary Conference of the British Association for Crystal Growth (BACG), which was held at Wills Hall, Bristol, UK, September 6-8, 2009.

2010, Vol. 10 3044–3050

Application of Ionic Liquid to Polymorphic Design of Pharmaceutical Ingredients Ji-Hun An,† Jong-Min Kim,‡ Sang-Mok Chang,‡ and Woo-Sik Kim*,† †

Department of Chemical Engineering, ILRI, Kyunghee University, Kyungki-do 449-701, Korea, and Department of Chemical Engineering, Dong-A University, Busan 602-714, Korea

‡

Received January 31, 2010; Revised Manuscript Received May 23, 2010

ABSTRACT: This study investigated the use of an ionic liquid for designing polymorphs of the active pharmaceutical ingredient adefovir dipivoxil (AD) in drowning-out crystallization. Because of the influence of 1-ally-3-ethylimidazolium tetrafluoroborate (AEImBF4) on the formation of the intermolecular interaction of AD in the solution, new anhydrous (N-II) and hemihydrate (N-I) crystals of AD were produced when varying the ionic liquid fraction and crystallization temperature. The polymorphic structure and number of hydrate crystals were determined using X-ray diffraction and thermogravimetric analysis, respectively. Also, AEImBF4 had a significant influence on the thermal stability of the AD molecules in the AEImBF4-water mixture, as there was no hydrolysis of the AD molecules up to a temperature of 90 °C. According to a differential scanning calorimetry thermal scan, the N-I and N-II crystals were uniquely transformed into other crystal phases in a solid state. That is, the N-I crystals underwent three polymorphic changes: N-I f amorphous f form-V f liquid, while the N-II crystals underwent two polymorphic changes: N-II f form-V f liquid. Introduction Polymorphs refer to different packing arrangements of the same molecules in a solid state based on different interactions between the molecules, resulting in significant differences in the physiochemical properties of the crystals, such as the solubility, structural stability, dissolution rate, density, and melting point. Consequently, the polymorphic design of active pharmaceutical ingredients has drawn a great deal of attention in terms of drug development, as it can determine the bioavailability of the drug and its shelf life, etc. The polymorphs of active pharmaceutical ingredients (APIs) essentially originate from the variety of hydrogen bonds between the molecules, which in turn depend on the crystallization conditions of the solvent, temperature, additives, and supersatuation. For example, in the cooling crystallization of the pharmaceutical ingredient diflunisal, the polymorphs are primarily determined by the polarity of the solvent.1 As such, form-III crystals are produced with polar solvents of methanol and ethanol, whereas form-I and -IV crystals are obtained with nonpolar solvents of toluene, chloroform, and carbon tetrachloride. Similarly, Pereira et al2 demonstrate to design three different polymorphs of dipyridodiazeoinone using three organic solvents of ethanol, N,N-dimethylformamide (DMF), respectively. Also, four distinct solvates of erythromycin are formed from four solvents of acetone, methylethylketone, ethanol, and isopropanol, respectively.3 Meanwhile, in the case of BPT ester *Corresponding author. Tel.: þ82-31-201-2576. Fax: þ82-31-273-2971. E-mail: [email protected]. pubs.acs.org/crystal

Published on Web 06/16/2010

(2-(3cyano-4-(2-methylpropoxy) phenyl)-4-methylthiazole-5carboxylate), the polymorph has been found to depend on the initial supersaturation of the crystallization.4,5 Here, when using solvents of ethanol and cyclohexane, metastable crystals are induced with a high supersaturation, whereas stable crystals are induced with a low supersaturation. Yet, a solvent of acetonitrile always generates stable crystals across the whole supersaturation range due to a conformational change of the BPT polyester in the solvent. A similar conformer of the peptide derivative taltirerin has also been observed during cooling crystallization in a water-methanol solution.6 Here, dihydromethylorotic acid and the prolinamido moiety of the taltirerin were rotated to change the molecular conformation while increasing the methanol fraction in the solution, resulting in two distinct R- and β-form crystal structures. The pseudopolymorphism of APIs along with the water composition in a water-organic mixture solvent has also been examined, as the water activity in a mixture varies with the composition and organic species of the solvent.7-10 In the case of hydrate crystals of APIs, the water activity in the mixture solvent increases when the water composition is increased and decreases when the miscibility of the organic solvent with water is enhanced. In addition, the water activity decreases when increasing the temperature. As a result, the number of hydrate crystals decreases when increasing the temperature and decreasing the water composition.11,12 As mentioned above, polymorphs are usually controlled using organic and/or water solvents, and attributed to the solvent-solute interactions in the solution.13-15 That is, a different interaction between the solvent and the solute molecules in the liquid phase induces a different packing arrangement r 2010 American Chemical Society

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of the solutes, resulting in different polymorphs of the solute solid. Consequently, the use of ionic liquids as potential solvents for the design of new polymorphs of APIs is interesting to consider, as ionic liquids may induce unique molecular interactions. However, surprisingly few studies have explored the use of ionic liquids for polymorphic design. A study by Li et al.16 demonstrated a crystal structural change of the lysozyme protein when using an ionic liquid of BMImBF4. Because of the strong variability of the ionic shape of BMImBF4, the surface charge distribution of the protein differed from that induced by conventional salt ions. As a result, the dipole of the charged groups of proteins was differently enhanced, resulting in a distinct stacking of the proteins in a solid state. Meanwhile, according to the study of Pusey et al.,17 the application of ionic liquids to protein crystallization was quite successful with regard to the production of large single crystals of protein, which is otherwise impossible. Plus, when ionic liquids were used as additives to the crystallization, this resulted in a habitual change for the protein crystals. The influence of ionic liquids as crystallization additives on the morphology of protein crystals has also been broadly investigated by Judge et al.18 and Hekmat et al.19,20 However, their studies did not reveal any structural modifications of protein crystals by ionic liquids, although high quality protein crystals for X-ray diffraction resolution were obtained with the same crystal structure as the one formed without the ionic liquid.18 Various unique ways of crystallization using ionic liquids have already been introduced by Reichert et al.,21 including “thermal shift” and “solvothermal techniques”, which are effective for substances that are slightly soluble in ionic liquids. In other areas of material processing, ionic liquids have also been applied to produce nanoparticles of ZnS and Au.22,23 However, the present study uses an ionic liquid to design new polymorphs of the API adefovir dipivoxil (AD), 9-[2({bis[(pivalaoyloxy)methoxy]phosphinyl}methoxy)ethyl]adenia, which is an enzyme inhibitor of the human immunodeficiency virus24,25 (Figure 1). To date, six polymorphs of AD have been identified using organic and water solvents,26-28

Figure 1. Molecular structure of adefovir dipivoxil (AD).

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as summarized in Table 1. Since AD is a weak polar hydrophobic substance, the drowning-out method is applied to crystallize out the AD crystals. Here, an ionic liquid of 1-ally3-ethylimidazolium tetrafluoroborate (AEImBF4) is used as the solvent and water as the antisolvent. To control the polymorphism, the crystallization conditions of temperature and solvent composition (volume ratio of water to ionic liquid) are varied. Experimental Procedures Materials and Crystallization. The adefovir dipivoxil (AD; purity higher than 99.9%) was supplied from a pharmaceutical company (Daehe Chem. Co., Korea) and used without further purification. The 1-ally-3-ethylimidazolium tetrafluoroborate, AEImBF4, was purchased from Kanto Chem. Co. (Figure 2). The AD was dissolved in an ionic liquid at a concentration of 64 mg/mL, loaded into a small vial, and placed in a temperature bath to heat up to the set crystallization temperature. To induce the drowning-out crystallization of AD, water was then added to the ionic liquid and the vial was tightly capped. Here, the total volume of the water-ionic liquid mixture in the vial remained fixed at 3 mL, although the volume fraction of water to the ionic liquid was varied from 0.2 to 0.8. The crystallization temperature was also varied from 25 to 90 °C. After 24 h of crystallization, the AD crystals in the water-ionic liquid mixture were taken to analyze the polymorphs. Analysis. The concentration of AD in the ionic liquid was analyzed by high pressure liquid chromatography (Agilent 1100, Agilent Technology, U.S.A.) using a C18 column with a mobile phase of water/methanol/ACN (5:4:1 v/v/v). Meanwhile, the polymorphism of the AD crystals was analyzed using XRD (model), DSC (Q100, TA Instrument, U.S.A.), and FT-IR (Spectrum I, Perkin-Elmer, U.S.A.), the pseudopolymorphism of the AD crystals were examined using a TGA, and the thermal stability of the AD molecules in the ionic liquid were examined using a liquid chromatography-mass spectrometer (Agilent, U.S.A.).

Results and Discussion Solubility of AD in Ionic Liquid. For the drowning-out crystallization of AD, the solubility of AD in the AEImBF4water mixture was measured along with its composition. While the AD was highly soluble in pure AEImBF4, as much as 64 mg/mL, its solubility was significantly reduced when increasing the water fraction in the mixture, and almost zero in pure water, as shown in Figure 3a. Meanwhile, as shown in Figure 3b, the solubility of the AD was slightly dependent on the temperature. With a fixed composition of AEImBF4water at 50:50 (vol %), the solubility of the AD only increased about 2 mg/mL when increasing the temperature

Figure 2. Molecular structure of ionic liquid of 1-allyl-3-ethylimidazolium tetrafluoroborate [AEImBF4].

Table 1. The Existing Polymorphs of Adefovir Dipivoxil (AD)

Form-I Form-II Form-III Form-IV Form-V Form-VI

polymorphs

crystallization method

solvent

remarks

anhydrate (C20H32N5O8P) dihydrate (C20H32N5O8P 3 2H2O) solvate (C20H32N5O8P 3 CH3OH) salt form (C20H32N5O8P 3 C4H4O4) anhydrate (C20H32N5O8P) monohydrate (C20H32N5O8P 3 H2O)

cooling drowning-out evaporation cooling spray drying evaporation

acetone þ di-n-butyl ether methanol/water methanol isopropanol þ fumaric acid ethanol methylene chloride þ methanol þ water vapor

Gilead Sciences (U.S.A) Gilead Sciences (U.S.A) Gilead Sciences (U.S.A) Gilead Sciences (U.S.A) Tianjin Kinsly Pharm. (China) Solmag S.P.A (Italy)

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Figure 3. Solubility of AD in AEImBF4-water mixtures depending on (a) water fraction of the AEImBF4-water mixture at fixed temperature of 25 °C, (b) temperature at fixed composition of AEImBF4-water (50:50 vol %).

Figure 5. Typical shapes of AD polymorphs obtained at a crystallization temperature of (a) 25 °C (form-II crystal), (b) 80 °C (N-I crystal), (c) 90 °C (N-II crystal). The composition of the AEImBF4water mixture was fixed at 50:50 (vol %).

Figure 4. Powder X-ray diffraction patterns of AD polymorphs obtained at various crystallization temperatures. The composition of AEImBF4-water mixture was fixed at 50:50 (vol %). The filled symbols indicate the characteristic peaks of each polymorph.

from 25 to 90 °C, which may have been due to the thermally stable physical property of the ionic liquid. Crystallization of AD in Ionic Liquid. With a fixed composition of the AEImBF4-water mixture for the drowning-out crystallization, the polymorphic change of the AD crystals according to the temperature was investigated using XRD, DSC, TGA, and FT-IR. As shown in Figure 4, the XRD patterns revealed an obvious change in the AD crystal

structure according to the temperature. The AD crystals produced at a low temperature below 70 °C showed XRD patterns identical to those for form-II of the dihydrate pseudopolymorph of AD. However, when increasing the temperature above 80 °C, two new XRD patterns were found for the AD crystals, implying new AD polymorphs. At a temperature of 80 °C, the characteristic peaks of the XRD pattern, appearing at 7.8°, 11.0°, 17.5°, and 25.1° (2θ), were clearly unique when compared with those of other known AD polymorphs (forms I-VI).26-28 Therefore, this polymorph was called a new form-I (N-I). Similarly, the AD crystals obtained at 90 °C also exhibited unique characteristic peaks in the XRD pattern (8.0°, 12.5°, 17.3°, 22.0°, 26.5°, 30.5°) and thus was called a new form-II (N-II). Furthermore, the polymorphic change of the AD according to the crystallization temperature was consistent with the morphological change, as shown in Figure 5. At a low temperature below 70 °C, long needle-shaped crystals were produced, which is the typical morphology for form-II. However, when increasing the temperature, the crystal shape

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Figure 6. The characterization of AD polymorphs obtained using an AEImBF4-water mixture at various crystallization temperatures. (a) DSC patterns of AD polymorphs obtained at various crystallization temperatures (heating rate 1 °C/min) and (b) powder X-ray diffraction patterns of polymorphs obtained during a thermal scan. The filled symbols indicate the characteristic peaks of each polymorph.

became a rod (80 °C) and then changed to multidirectional needles from one point (90 °C), similar to a sea urchin. The AD polymorphs obtained using the AEImBF4-water mixture were identified and characterized using DSC and XRD. Because of the different intermolecular interaction strengths of the crystal structures, the thermal behavior of the polymorphs differed according to the temperature, as shown in Figure 6a. For example, the DSC thermal profile of the new AD N-II crystals included two endothermic peaks at 60 and 95 °C, respectively, where the first peak at 60 °C was due to the phase transformation in the solid state, and the second at 90 °C was due to the melting of the crystal. Meanwhile, the new AD N-I crystals showed a quite different thermal profile, including two endothermic peaks at around 50 and 95 °C, respectively, and an exothermic peak at 80 °C. Interestingly, an endothermic peak at around 50 °C appeared in all the thermal profiles of the AD crystals (formII) obtained using a crystallization temperature below 70 °C.

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However, in the case of the form-II crystals, further endoand exothermic peaks were found at 90 °C. The polymorphic shifts of the AD crystals during the thermal scan were also confirmed using an XRD analysis, as shown in Figure 6b. According to the powder pattern XRD, the phase transformation of N-II at 60 °C (endothermic peak) resulted in the crystal structure of formV (region a in Figure 6a), which was found by Wang et al.27 However, the phase transformation of N-I at around 50 °C produced an amorphous solid of AD (temperature region b in Figure 6a). A similar phase transformation to an amorphous solid at around 50 °C occurred in all the form-II crystals obtained using a crystallization temperature below 70 °C. Thus, when considering the dihydrated form-II crystals, it would appear that the endothermic peak of the N-I and form-II crystals at around 50 °C was due to the dissociation of the water molecules from the hydrate crystals. The AD crystals then became an anhydrous amorphous solid (temperature region b in Figure 6a) after the complete dissociation of the water molecules, and the amorphous solids recrystallized at 80 °C in a solid state. From the XRD patterns, it was interesting to find that the amorphous solid obtained from the N-I crystals was recrystallized into form-V crystals (temperature region c in Figure 6a). Meanwhile, the amorphous solid from the form-II crystals was transformed into N-II crystals (temperature region d in Figure 6a). These N-II crystals then melted and recrystallized at around 90 °C into form-V crystals. Therefore, the DSC profiles and XRD patterns confirmed that the N-II crystals underwent two polymorphic changes: N-IIf form-V f liquid, the N-I crystals underwent three polymorphic changes: N-Ifamorphousfform-Vfliquid, and the dihydrate form-II crystals underwent four polymorphic changes: form-IIfamorphousfN-IIfform-Vf liquid. In addition, the slow DSC temperature scan revealed that the N-II crystals underwent an enantiotropic change to form-V crystals at a transition temperature of 58 °C (Supporting Information S-1). The number of hydrate AD crystals was determined from the TGA thermal profile, as shown in Figure 7. In the case of the hydrate crystals, the water molecules were released from the lattices, resulting in a weight loss from 40 to 60 °C, as shown in Figure 7a. The weight loss of the form-II crystals was 6.57%, which was exactly equivalent to two water molecules per AD molecule, corresponding to a dihydrate form, whereas the weight loss of the N-I crystals was only 1.55%, indicating a hemihydrate form. As such, the weight losses of the form-II and N-I crystals in the TGA were exactly consistent with the endothermic peaks at around 50 °C for dissociating the water molecules from the crystal lattices in the DSC. However, the N-II crystals did not exhibit any weight loss, indicating an anhydrous form. The number of hydrate crystals was also estimated relative to the crystallization temperature, as shown in Figure 7b. Below a crystallization temperature of 70 °C, the AD crystals maintained a dihydrate form. However, the number of hydrate crystals decreased when increasing the crystallization temperature, and above a crystallization temperature of 85 °C the crystals all became anhydrous, which was due to the water activity relative to the temperature. When increasing the temperature, the water activity in the AEImBF4water mixture was reduced,10,29 as the water molecules preferred to interact with the AEImBF4 rather than the AD solute in the solution, resulting in a decrease in the

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Figure 7. TGA analysis of polymorphs obtained at various crystallization temperatures. The composition of the AEImBF4-water mixture was fixed at 50:50 (vol %). (a) Thermal profiles of AD polymorphs, (b) hydrate number of AD polymorphs.

number of hydrate crystals. These experimental results were consistent with the previous reports by Variankaval et al7 and Ticehurst et al,30 where a higher water activity was required to produce a higher number of hydrate crystals at a higher crystallization temperature in the pseudopolymorphism of active pharmaceutical ingredients. Meanwhile, the water activity generally increased with the water fraction in the mixture.29 Thus, when the crystallization temperature was fixed at 90 °C, the water content in the crystals increased when increasing the water fraction in the AEImBF4-water mixture, as shown in Figure 8. With a water fraction of up to 60% of the mixture, anhydrous crystals were obtained from the crystallization. However, a 70% water fraction produced crystals that included a 1.68 wt % water content, and this water content increased to 6.53 wt % in the case of an 80% water fraction in the mixture. However, it should be noted that in this experiment the crystals obtained with a water fraction above 70% were not pure AD due to thermal decomposition, which is investigated in the next section. Thus, the hydrate number could not be determined based on the weight loss of water. Thermostability of AD in Ionic Liquid. It is already known the AD molecules are hydrolyzed in a water mixture at a high temperature due to their weak phosphate bonds. As such, AD molecules in a methanol-water mixture (50/50 vol %) are completely decomposed at a temperature above 50 °C (Supporting Information S-2). However, in the AEImBF4water mixture (50/50 vol %), the AD molecules in the

An et al.

Figure 8. TGA analysis of polymorphs obtained at various compositions of AEImBF4-water mixture. The crystallization temperature was fixed at 90 °C. (a) Thermal profiles of AD polymorphs, (b) weight loss of AD polymorphs.

crystals did not decompose, even at a high temperature of 90 °C, as the ionic liquid likely stabilized the AD molecules, thereby avoiding thermal decomposition. As a result, the AD crystals obtained in the AEImBF4-water mixture remained pure, as shown in Figure 9a. Nonetheless, at a fixed temperature of 90 °C, the stability of the AD molecules varied according to the water fraction in the AEImBF4-water mixture, as shown Figure 9b. When the water fraction in the mixture was 90%, the AD molecules were almost completely decomposed, yet this was dramatically reduced when reducing the water fraction, and pure AD crystals were always obtained with a water fraction below 50%. A similar stabilizing effect of ionic liquids was also previously observed with proteins.31-34 According to Fujita et al.,32 ionic liquids stabilize proteins by protecting against degradation by hydrolysis, meaning that the protein activity in an ionic liquid-water mixture lasted more than 6 months in contrast to a week in pure water. Also, ionic liquids provide proteins with thermostability, which allowed proteins in an ionic liquid-water mixture to unfold up to 100 °C. Therefore, in the present study, it would appear that the ionic liquid protected the weak phosphor bonds in the AD molecules from hydrolysis, thereby stabilizing the AD, even at a high temperature. Polymorphic Preorientation of AD in Ionic Liquid. Finally, the influence of the ionic liquid on the polymorphic design of the AD was investigated using FTIR-ATR. According to Davey et al,14,15 the polymorphs of pharmaceutical

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Figure 10. ATR-FT-IR spectra of AD molecule in saturated solution of AEImBF4-water mixture at 50:50 (vol %). The solution temperature was varied from 25 to 90 °C.

Figure 9. Thermal stability test of AD molecules in an AEImBF4water mixture (a) with various temperatures at a fixed composition of AEImBF4-water at 50:50 (vol %), (b) with various compositions of AEImBF4-water mixture at a fixed crystallization temperature of 90 °C.

ingredients are primarily predetermined in a solution, as the intermolecular interaction of a pharmaceutical ingredient in a solution is oriented by the solvent polarity. That is, different solvent polarities induce different hydrogen interactions between pharmaceutical molecules, resulting in a different molecular stacking during crystallization for different polymorphs of a crystal. Therefore, in the present study, the intermolecular interaction of the AD in the AEImBF4-water mixture was monitored according to the temperature and ionic liquid fraction, as shown in Figure 10. Here, each solution was prepared to create an equilibrium of AD in a given AEImBF4-water mixture. When the fraction of the AEImBF4-water mixture was fixed at 50/50 in vol %, one stretching vibration peak representing the diester (two CdO’s) group in the AD molecule appeared at 1745 cm-1 due to the identical hydrogen interaction of both CdO’s with water at a low temperature below 70 °C. This hydrogen interaction of the diester group with two water molecules in the solution agreed well with the formation of dihydrate AD crystals at the same crystallization temperature. However, when increasing the temperature above 90 °C, two stretching vibration peaks of the diester group appeared at 1717 and 1750 cm-1. When considering the formation of anhydrous crystals at the same crystallization temperature, the absorption peak at the low frequency (1717 cm-1) was apparently due to the intermolecular interaction of one ester (CdO)

Figure 11. ATR-FT-IR spectra of AD polymorphs obtained at various crystallization temperatures. The composition of the AEImBF4-water mixture was fixed at 50:50 (vol %).

group with the -NH2 of AD, while the other ester group remained free from intermolecular interaction, resulting in the other absorption peak at the high frequency (1750 cm-1). Similarly, two vibration peaks (1717 and 1747 cm-1) of the diester (two CdO’s) group in AD were found at 80 °C, which were due to the intermolecular interaction with NH2 and water, respectively, resulting in the formation of hemihydrate AD crystals at the same crystallization temperature. In this case, the slight frequency shift of the CdO vibration seemed to be due to the partial interaction of CdO and water. When comparing the frequency shift of the ester groups, it might appear that the intermolecular interaction of CdO with NH2 was stronger than that with water. At a fixed temperature of 25 °C, the influence of the AEImBF4 fraction in the AEImBF4-water mixture on the intermolecular interaction of the AD appeared consistent with the above modification of the intermolecular interaction (Supporting Information S-3). When the mixture was 50/ 50 vol %, the two CdO’s from the diester group in an AD molecule interacted with water, resulting in one stretching vibration peak at 1743 cm-1. However, when increasing the AEImBF4 fraction in the mixture to above 80%, two absorption peaks appeared for the diester group due to the intermolecular interactions of the two CdO’s with NH2 and water, respectively.35-37 The solid-state spectroscopic spectra of the AD crystals were also matched with the liquid-state spectroscopic spectra, as shown in Figure 11. In the case of the N-II

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crystals, the new anhydrous form, two absorption peaks of the diester group appeared at 1705 and 1750 cm-1 due to the unsymmetric intermolecular interaction of the two CdO’s. Similar dual absorption peaks (1736 and 1755 cm-1) were also observed for the diester group with the anhydrous formI crystals. However, for the form-II crystals obtained at a crystallization temperature below 70 °C, there was only a single absorption peak at 1747 cm-1, due to the intermolecular interaction of both CdO’s from the diester group with water. Thus, the experimental results confirmed that the ionic liquid induced a unique intermolecular interaction of AD in the solution, resulting in the new polymorphs N-I and N-II. Conclusion An ionic liquid solvent was shown to be capable of producing new polymorphs of AD, which are not achievable with conventional organic solvents. The specific intermolecular interaction of AD, resulting in the formation of new polymorphic crystals, was modified based on the ionic liquid fraction in the solution and crystallization temperature. As a result, a high ionic liquid fraction (above 50 vol %) in the AEImBF4-water mixture and a high crystallization temperature (above 85 °C) produced a new anhydrous polymorph of AD (N-II), whereas a crystallization temperature of 80 °C produced a new hemihydrate crystal (N-I). Meanwhile, the conventional form-II polymorph was produced at a crystallization temperature below 70 °C, even in the AEImBF4-water mixture (50/50 vol %). Using FTIRATR, it was also confirmed that the formation of the new polymorphic crystals directly originated from the intermolecular interactions of the AD induced in the AEImBF4water solution. Interestingly, a DSC temperature scan revealed that the new N-I and N-II crystals displayed different pathways of polymorphic change in a solid state when compared with conventional form-II crystals. Furthermore, the ionic liquid provided the AD with thermostablility in the solution. Thus, the AD in the AEImBF4-water mixture (50/50 vol%) remained perfectly stabilized up to 90 °C, whereas it was easily hydrolyzed in a methanol-water mixture, even at a low temperature of 50 °C. Acknowledgment. This work was supported by Mid-career Researcher Program through NRF grant funded by the MEST (No. 2010-0017993). Supporting Information Available: DSC thermal scan to prove the enantiotropic polymorphs between N-II and form-V crystals of AD and estimate the transition temperature; thermal stability test of AD molecules in methanol-water mixture at various temperatures; ATR-FT-IR spectra of AD molecules in saturated solution of various AEImBF4-water mixtures. This material is available free of charge via the Internet at http://pubs.acs.org.

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