Investigation of the Polymorphic Transformation of the Active

Mar 7, 2016 - Since ionic liquids (ILs), salts with a melting point below 100 °C, have unique physicochemical properties, they have been spotlighted ...
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Investigation of the Polymorphic Transformation of the Active Pharmaceutical Ingredient Clopidogrel Bisulfate Using the Ionic Liquid AEImBF4 Ji-Hun An,†,# Feng Jin,‡,# Hak Sung Kim,‡ Hyung Chul Ryu,§ Jae Sun Kim,§ Hyuk Min Kim,§ Ki Hyun Kim,∥ Alice Nguvoko Kiyonga,† and Kiwon Jung*,† †

College of Pharmacy, CHA University, Pocheon 487-010, Republic of Korea College of Pharmacy, Wonkwang University, Iksan 570-749, Republic of Korea § R&D center, J2H biotech, Ansan 425-839, Republic of Korea ∥ School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea ‡

ABSTRACT: Since ionic liquids (ILs), salts with a melting point below 100 °C, have unique physicochemical properties, they have been spotlighted as novel alternatives to organic solvents. However, studies relating to polymorph control using IL as solvent have not yet been performed due to the numerous (1018) available IL types with unknown effects on the control of polymorphic transformation, and the extremely high unit price compared with conventional organic solvents. Presently, the pharmaceutical industry highly prefers the high soluble form-I polymorph among several polymorphs of the active pharmaceutical ingredients (APIs), clopidogrel bisulfate (CLP). However, as form-I polymorphs are metastable crystals, their phase transformation to stable form-II crystals occurs only within 5 min in the organic solvent. Therefore, the present study was performed in order to control the phenomenon that induces the rapid phase transformation from form-I to form-II. Ethanol was used as solvent, ILs including 1-allyl-3-ethylimidazolium tetrafluoroborate (AEImBF4), 1-butyl-2,3dimethylimidazolium tetrafluoroborate (BDMImBF4), and 1,3-diallylimidazolium tetrafluoroborate (AAImBF4) were used as antisolvents, and drowning-out crystallization was the method applied. Among three ILs used in this experiment, only AEImBF4 could induce crystals precipitation. Therefore, AEImBF4 was used as antisolvent for further studies. The thermodynamic factor, the temperature, was set in the range of 25 to 50 °C; then the phase transformation phenomenon from form-I to form-II under temperature variation was studied. In order to illustrate the quantitative analysis of the polymorphic transformation under the new IL solvent, the nucleation and mass transfer equations were used.

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INTRODUCTION Most of the market development of APIs is composed of the same molecules, but depending on different molecular arrangements or conformations, they have different polymorphs with different crystal structures. Since such polymorphs have different physicochemical properties, such as solubility, rate of dissolution, and crystal form, they bring great influence on bioavailability and stability, one of the concerning characteristics in the manufacture of medicine in the pharmaceutical field.1−3 Therefore, studies regarding polymorph control in order to obtain the desired polymorph are increasing. As a practical method to control the desired polymorph, the metastable crystal is dissolved, the stable crystal nucleation is formed, and the solvent-mediated phase transformation technique is used to form continuous stable crystal growth.4,5 The core driving force that affects the kinetics of the solventmediated phase transformation technique is the solubility difference between two crystals, or the energy difference between the metastable and the stable crystal. The factors © XXXX American Chemical Society

affecting the phase transformation rate of these two crystals can be categorized into thermodynamic factors and dynamic factors. The thermodynamic factors are the temperature of the solution that affects the solubility difference between two crystals,6,7 and the type and composition of the solvent.8,9 The dynamic factors are the rotation speed,10 the concentration of the suspension,11 seed addition,12 and viscosity.13 In the study by Sato et al.,6 the stable polymorph of steric acid has a different reversible relationship (enantiotropic polymorphs) under the transition temperature, and thus, as the temperature is increased, the solubility difference among the polymorphs is increased, while the solubility difference is decreased as the temperature gets closer to the transition temperature. In other words, if the temperature is lowered, supersaturation is increased to cause the stimulation of polymorphic transReceived: July 29, 2015 Revised: December 5, 2015

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DOI: 10.1021/acs.cgd.5b01079 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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of IL, slow diffusion to form high quality crystals using the high viscosity of IL, and a cosolvent in the application of evaporation and to supplement the weakness of IL that does not dissolve the solute, showing that the crystallization was derived under conditions that other normal molecular solvents cannot be used. The study by Li et al.29 showed noteworthy results on the use of IL in protein crystallization. They used [BMIM][BF4] IL as an additive to lysozyme crystallization, and as a result, the amount of [BMIM][BF4] was increased to change the morphology of lysozyme. Furthermore, in solvent without IL, the lysozyme crystals ceased growing after 15 days, while in solvent with IL, the lysozyme crystal carried on growing even after 50 days. It was confirmed that the addition of [BMIM][BF4] to lysozyme crystallization changed the crystal structure of lysozyme. Therefore, they mentioned the electron polarization of lysozyme molecular groups due to a strong variability in the ionic shape of [BMIM][BF4], stating that it is caused by a change in the crystal packing change. Gao et al.30 attempted a study on the use of IL in the control of gold nanoparticles, and Zhao et al.31 studied the use of the imidazolium-based IL as a water solvent additive in the crystallization of calcium carbonate. In addition, An et al.32,33 used IL as a solvent and an antisolvent for the study of new polymorphs. According to this study, in an IL environment, three new polymorphs, which could not be found in other normal molecular solvent environments, were found, and it was stated that this was the result of new derivation of AD intermolecular interactions by the new solvent environment. Similarly, the study of the effect of IL in crystallization has been fruitful; however, studies of polymorphic transformation using IL as a solvent have not yet been performed. The reasons for this are because the desired IL could not be obtained commercially, the price is relatively higher than other normal molecular solvents, and there are no basic research data regarding the effect of IL on polymorphic transformation. Nevertheless, despite such disadvantages, since ILs can vary the thermodynamic and dynamic factors of solvent-mediated phase transformation under a wider range than other normal molecular solvents due to their unique characteristics, they are expected to be attractive solvents to control polymorphs. Clopidogrel bisulfate (CLP) has antiplatelet activity and is used as treatment for platelet-related vessel diseases such as angina, arrhythmia, peripheral arterial occlusive disease, stroke, cerebral arteriosclerosis, and cardiac infarction. It is expressed chemically as (+)-methyl-5-[4,5,6,7-tetrahydro-[3,2-c]thienopyridyl]-(2-chlorophenyl)acetate hydrogensulfate34 (Figure 1).

formation. In the case of steric acid, when the phase transformation from the metastable crystal to the stable crystal occurs, instead of the nonpolar solvent hexane, the polar solvent methanol could accelerate stimulation of polymorphic transformation. This can be explained by the fact that the steric acid molecule stays as a dimer in the solution of a nonpolar solvent such as n-hexane, but is present as a monomer in the solution of a polar solvent such as methanol, and can be adsorbed on the crystal face (110) more quickly. Qu et al.14 considered the composition of the solvent, or one of the thermodynamic factors, as a parameter to study the phase transformation from the anhydrate to the dehydrate form of carbamazepine. From their study, it was confirmed that the phase transformation rate was stimulated as the amount of water was increased. Hence, they confirmed that under a solvent with a certain threshold value of water activity, the phase transformation rate was stimulated. This indicated that when the difference between the equilibrium water activity and the actual water activity is greater, the phase transformation rate is more greatly stimulated. In a study using dynamic factors, Ni et al.15 used the rotation speed as a parameter to observe the phase transformation of Lglutamic acid. They confirmed that as the rotation speed is increased, the nucleation is rapidly stimulated, and thus the phase transformation rate is stimulated. They also added the seed to observe the phase transformation, and as the amount or size of the seed was increased, the secondary nucleation was derived to stimulate the rate of phase transformation. Furthermore, depending on the properties of material, the phase transformation is extremely slow under the solution to cause high manufacturing cost and time. For example, aripiprazole, a material introduced from the study by Braun et al.,16 takes over 48 h for the phase transformation from form3 to Form-H1. In the case of Famotidine introduced by Lu et al.,17 10% of the phase transformation from metastable crystal to stable crystal takes over 96 h. In the case of sulfamerazine introduced by Gong et al.,18 Kawakami et al.,19 and Lee et al.,20 the phase transformation from metalstable form-I to stable form-II takes over 14 days, and to stimulate the phase transformation of sulfamerazine, the study used the stimulated phase transformation by using ultrasonic energy19 and Taylor Vortex,20 or unique fluid flow of Couette-Tayler continuous crystallizer. The study of IL, defined as a salt composed of separated cations and anions with a melting point below 100 °C, is carried out due to its possible use in various precision chemical fields as an alternative “green” solvent instead of conventional organic solvents. IL stays in liquid form under a range of temperatures, and in some cases it can stay in liquid form under temperatures over 400 °C. Moreover, along with its high polarity, negligible vapor pressure, stability of air and water, high ion conductivity, and thermal stability, it may be properly designed for the purpose of use, and as its solubility, hydrophobicity, and polarity may be changed freely, it is called a designer solvent.21−23 Recently, a study regarding the application of IL crystallization was strengthened from the beginning of use24−27 of IL under protein crystallization. Furthermore, Reichert et al.28 stated various methods of crystallization using the characteristics of IL. As well as the application of the general cooling crystallization technique, there are thermal shifts using a wide liquid range and high thermal stability of IL, the solvothermal technique to derive crystallization under high temperatures using the characteristics

Figure 1. Molecular structure of clopidogrel bisulfate.

As reported to date, there are six CLP polymorphs, with form-I and form-II among these being selectively used for medicine manufacturing.35 Song et al.,36 quantitatively analyzed the solubility of CLP form-I and form-II under alcohol and acetone. Kim et al.,37,38 studied the polymorphic transformation of form-I and form-II under parameters of ultrasonic waves, temperature, and composition of solvent in organic solvent, using the solvent-mediated phase transformation. As a result, B

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and the crystal of CLP form-I was precipitated (polymorph analyzed with FT-IR). By setting the transformation time to form-II as 20 min to 1 h, the suspension was sampled in order to be separated by vacuum filtering for the analysis of polymorphs. Analysis. To analyze the solubility under the temperature variation from 25 to 50 °C and the volume rate of Ethanol/AEImBF4 (v/v), high pressure liquid chromatography (Agilent 1100, Agilent Technology, USA) was used, with a C18 column, and a mobile phase of water/methanol/ACN (v/v/v 5:4:1). Quantitative analysis was carried out through the peak area under the concentration curve. To check the polymorphs of dried crystal after the phase transformation experiment, the PXRD (Cu−Kα ray (1.54056 Å), M18XHF-SRA, Mac Science, Japan) and DSC (Q100, TA Instrument, USA) was analyzed, and to determine the composition of polymorphs to be transformed, FT-IR (Spectrum I, PerkinElmer, USA) was used for the quantitative analysis through the vibration energy change in the characteristic peak of the CLP polymorphs form-I and form-II.

the induction time of phase transformation from form-I to form-II was at most 2 min, which was extremely fast, and the reconstruction time was less than 30 min. Through the results of this study, it was confirmed that the solvent-mediated phase transformation of CLP form-I to form-II under general organic solvent is very fast. However, the CLP polymorph preferred in current medicine manufacturing is form-I. In the case of form-II, although it is stable at the room temperature, since its solubility is much lower than that of form-I, domestic and foreign pharmaceutical companies mostly prefer form-I. However, as the polymorphic transformation from form-I to form-II is very fast, the crystallization method to obtain form-I is complicated. Therefore, studies on polymorphic transformation control of form-I are urgently required. Thus, we control the polymorphic transformation of CLP form-I to form-II, the active pharmaceutical ingredient, through a novel IL solvent environment. In order to propose the use of IL as a novel solvent to control polymorphic transformation, the temperature parameter as a thermodynamic factor, nucleation, and mass transfer equations are used for quantitative analysis.

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RESULTS AND DISCUSSION Characterization of CLP polymorphs. Figure 3(a) shows PXRD patterns of form-I and form-II; this matches with a 2θ angle and with the form-I and form-II PXRD patterns of Koradla et al.35 And the analysis of the DSC of form-I and form-II by Koradla et al.35 demonstrated that form-I had an endothermic peak at 181 °C to 186 °C, with an enthalpy of 31−35 kJ mol−1, and form-II had an endothermic peak at 179 °C to 182 °C, with the enthalpy of 34−35 kJ mol−1. The relationship between form-I and form-II was enantiotropic polymorphs. In our analysis of FT-IR, the C−O vibration peak of form-I was shown at 1175 cm−1 and that of form-II was shown at 1187 and 1155 cm−1. The characteristic vibration peak to distinguish form-I was observed at 841 cm−1 and that of form-II was shown at 864 cm−1. Figure 3(b) shows the result of the DSC analysis of CLP form-I and form-II, and (c) shows the analytical result of FT-IR. These results are in accordance with the results obtained by Koradia et al.35 Calibration of the polymorphic fraction. To observe the phase transformation steps of the CLP polymorphs, FT-IR was used for quantitative analysis. Koradila et al.35 performed quantitative analysis through the characteristic peaks of form-I at 841 cm−1 and form-II at 864 cm−1. Based on the above results, pure form-I and form-II were mixed under a certain mass ratio to obtain the FT-IR spectrum (Figure 4(a)), and the area ratio of each characteristic peak was calculated to obtain the quantitative curve under the polymorph fractions (Figure 4(b)). These calibrations based on the characteristic peaks of the FT-IR spectra accurately matched the standard polymorphic fractions of the binary crystal mixtures (R2 > 0.993), and thus could be applied to the kinetics of polymorphic transformation during crystallization. Solubility of the CLP polymorphs. The solubility difference between two polymorphs is the driving force to initiate phase transformation, or a very significant factor in the rate of phase transformation. In this study, high pressure liquid chromatography was used to measure the solubility. First, CLP was dissolved in an Ethanol/AEImBF4 volume rate [5:5] at room temperature (25 °C), and the quantitative curve was obtained using the area value of the peak. Thereafter, to obtain the solubility curve under the temperature change, with a fixed volume rate of 5:5 Ethanol/AEImBF4, enough CLP form-I and form-II was inserted until the suspension liquid was obtained at a temperature from 25 to 50 °C. It was then agitated for roughly 30 min and after kept still for 30 min. After keeping the solution still for 30 min (form-I was sampled and analyzed in

EXPERIMENTAL PROCEDURES

Materials. Clopidogrel bisulfate (purity higher than 99.9%, formII) was provided by the raw material medicine company J2H biotech. Co., Ltd. Korea, and the ionic liquids 1-allyl-3-ethylimidazolium tetrafluoroborate (AEImBF4), 1-butyl-2,3dimethylimidazolium tetrafluoroborate (BDMimBF4), and 1,3-diallylimidazolium tetrafluoroborate (AAImBF4) (Figure 2) were purchased from Kanto Chem Co., Ltd.

Figure 2. Molecular structures of the ionic liquids used as antisolvents. Crystallization and phase transformation. Following addition of 5 mL solvent ethanol into the double-jacket stirred crystallizer (50 mL working volume flask), 450 mg CLP form-II was inserted and dissolved at room temperature. Thereafter, 5 mL of ILs (AEImBF4, BDMimBF4, and AAImBF4) was added as an antisolvent to observe whether a crystal was precipitated through drowning-out crystallization. Among these, a crystal was precipitated in approximately 10 min from AEImBF4, the rest did not produce a crystal even after 1 day (concentration of 45 mg/mL and solvent composition of ethanol/IL [v/v 5:5]). Subsequently, the antisolvent was fixed as AEImBF4, and the crystallization was carried out using the same method above (fixing the concentration and solvent composition), however, the temperature was varied from 25 to 50 °C, the rotation speed was fixed to 300 rpm, C

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Figure 4. CLP polymorphic fraction analysis using FT-IR spectroscopy: (a) characteristic peak intensities variation of polymorphs with polymorphs fraction weight; (b) characteristic peak calibration by polymorphs’ fraction weight.

Figure 5. Solubility of CLP in the AEImBF4−EtOH mixtures (temperature at fixed composition of AEImBF4−ethanol (50:50 vol %)).

Figure 3. PXRD, DSC, and FT-IR analysis of the CLP polymorphs (Form-I and Form-II): (a) The PXRD patterns, (b) the DSC thermal data, (c) the FT-IR spectrum.

data we can observe that the solubility curves of form-I and form-II at 35 °C were overlapped. This result is different from the solubility curve of form-I and form-II in general organic solvent. Effect of composition and temperature using ionic liquid. Among the polymorphic transformation phenomenon, the solvent-mediated phase transformation rate relies upon the solubility difference between two polymorphs. Therefore, based on the solubility curve change between two polymorphs under the temperature change at ethanol/AEImBF4 [v/v 5:5], the

different time interval through FT-IR to confirm whether the crystal present in the suspension solution was transformed into form-II. It was confirmed that the crystal was transformed into form-II after 1h 30 min) the saturated solution and crystal were separated from the suspension solution using a 25 μm syringe filter and then quickly diluted 100 times in the mobile phase; and after the solubility analysis was performed. Figure 5 shows the solubility curve of the CLP form-I and form-II in ethanol/ AEImBF4 [v/v 5:5] under the temperature change. From this D

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Figure 6. Profiles of the polymorphic fractions during phase transformation at (a) 25 °C, (b) 30 °C, (c) 40 °C, and (d) 50 °C.

nucleation rate, and the reliance on supersaturation is Volmer’s Model39,40 and is expressed as follows:

solvent-mediated phase transformation between the two CLP polymorphs was observed. Figure 6(a) shows the phase transformation profile of CLP form-I → form-II at 25 °C. As shown, the induction time of form-II was increased to 2 h, and the reconstruction time was increased to 1h, indicating a significant decrease in the phase transformation rate compared to the rate seen in normal organic solvent. Thus, the maintenance time of form-I was increased to 2 h. Figure 6(b) shows the phase transformation profile at 30 °C. The induction time of form-II was 2.5 h, and the reconstruction time was 1.5 h. The phase transformation profile at 40 °C shown in Figure 6(c) indicates that the induction time of form-II was 4.5 h, and the reconstruction time was 3 h. The phase transformation profile at 50 °C shown in Figure 6(d) indicates that the induction time was 5 h, and the reconstruction time was 3.5 h, showing a decrease in the phase transformation rate of form-II. These results demonstrate that as the temperature was increased, form-I was maintained longer within the solvent, and the phase transformation rate into form-II was slow. Figure 7(a) and (b) show graphs of the induction time and reconstruction time of Figure 6. This result appears to be from the solubility curve variation between the two CLP polymorphs seen in Figure 5 by the ethanol/IL solvent environment. The verifying equation of the CLP polymorphic transformation rate by the temperature change under the ethanol/IL solvent environment is shown below. The formula to indicate the relationship between the induction time and nucleation rate, the temperature of the

J∼

⎡ −16πσ 3 V2 ⎤ 1 M ⎥ ∼ A exp⎢ 3 3 tI ⎣ 3k T (ln S)2 ⎦

(1)

Here, J indicates the nucleation rate, tI indicates the induction time, A indicates the intrinsic constant, VM indicates the volume of unit molecule, S indicates supersaturation, k indicates a Boltzmann constant, T indicates the absolute temperature, and σ indicates the surface tension. Through the above equation, it is known that the nucleation rate and induction time are inversely related, and the temperature and supersaturation level are directly proportional. The supersaturation level of the CLP polymorphs under the temperature change is expressed as follows: S = C*meta /C*stable

(2)

Here, C* is the concentration of the metastable and stable forms. Equation 1 includes physical properties such as the size distribution of the metastable crystal, crystalline, and the specific surface area. Therefore, under fixed physical properties, if temperature and reliance on supersaturation are concerned, the nucleation rate is expressed as follows:39,40 FTS = T3(ln S)2 E

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polymorphs’ solubilities decreases when the temperature increases. According to eq 1, the induction time (tI) is inversely proportional to the nucleation rate (J) and the nucleation rate is proportional to the supersaturation. Hence, in Figure 7, the increasing of form-II’s induction time when temperature increases results from the fact that form-II’s nucleation rate decreases depending on the decreasing of supersaturation when the temperature increases. Thus, we can deduce that the increasing of the form-I holding time results also from the supersaturation decreasing due to temperature increasing. In addition, the values of the eq 4 (1/[T3 ln2 S]) model equation in Table 1 were predictions of the increasing of form-II’s induction time; and these values match with the experimental values of the form-II crystal. The total amount of transformed crystals (m) is represented by the relation m ∼r·tR ; where (r) is the mass transfer rate and (tR) the reconstruction time. And when the total amount of crystals (m) is constant, the reconstruction time (tR) is inversely proportional to the mass transfer rate (r). The mass transfer rate can be written as r ∼ kΔC; thus, when the mass transfer rate increases due to the mass transfer coefficient (k) and the difference of concentration (ΔC), the reconstruction time decreases. During the phase transformation process, ΔC can be calculated as the solubility difference between metastable and stable phases (ΔC = C*meta − C*stable). Based on film theory, the mass transfer coefficient (k) can be expressed as to be in proportional relation with the diffusivity (DAB); K = DAB/ δ, where δ is the mass transfer layer thickness. Also in the Stokes−Einstein equation, the diffusivity DAB = KT/6πγ0μ is expressed as a function of temperature. 41 Thus, the reconstruction time can be explained in the perspective of temperature and the solubility difference between metastable and stable phases. 1 tR ∼ ∼ 1/[TΔC] (5) r As indicated in Table 2, we used two polymorphs’ solubility data present in Figure 5 and predicted the dependence of

Figure 7. Influence of temperature on the phase transformation: (a) induction time and (b) reconstruction time as functions of temperature. The fixed composition of AEImBF4/ethanol (50:50 vol %).

Here, FTS is temperature−supersaturation combined effects variable, or the variation of nucleation rate under the temperature and supersaturation level.39,40 Therefore, the relationship between eq 3 and the induction time is expressed as follows:

ln tI = 1/[T3 ln 2 S]

Table 2. Correlation of Reconstruction Time in Terms of Parameters of Mass Transfer Rate Form-I to Form-II

(4)

Through eq 3 and 4, the reliance on temperature and supersaturation level by the nucleation rate and induction time can be observed.39 According to eq 4 both, temperature and supersaturation accelerate the induction time. Therefore, the result of the quantitative effect of temperature and supersaturation on the induction time is illustrated in Table 1. Figure 5 shows that as temperature increases, the solubility of the two polymorphs also increases, but refer to Table 1, which shows, upon supersaturation (S = C*form‑I/C*form‑II), the ratio of

Form-II S

[T3 ln2 S]−1 × 10−7

tI [hr]

25 30 40 50

2.30 1.70 1.13 1.06

0.23 0.34 1.33 2.54

2.0 2.3 4.3 5.0

ΔC

[T·ΔC]−1 × 10−4

tR [hr]

25 30 40 50

5.40 5.16 1.87 1.30

6.20 6.40 17.07 23.80

1.0 1.3 3.0 3.3

reconstruction time on the temperature variation. As can be seen in Table 2, the reconstruction time from form-I crystals to form-II crystals increases with the increasing of temperature. Therefore, when the temperature increases, the reconstruction time increasing derives from the decreasing of the two polymorphs solubility difference. According to eq 2, the mass transfer rate is proportional to the mass transfer coefficient and the two polymorphs’ solubility difference. Therefore, as shown in Table 2, the decreasing of the two polymorphs solubility difference reduces the mass transfer rate; thereby, we conclude that it can be the major factor that induced the increasing of reconstruction time from form-I crystals to form-II crystals. As presented in Figure 8, the kinetics of the phase transformation are plotted as induction and reconstruction times and with T3

Table 1. Correlation of Induction Time in Terms of Parameters of Volmer’s Nucleation Model

T (°C)

T (°C)

F

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AEImBF4 solvent environment under different temperatures. The induction time and reconstruction time of form-II at 25 °C were 2 and 1 h, respectively; the induction time and reconstruction time of form-II at 30 °C were 2.5 and 1.5 h, respectively; the induction time and reconstruction time of form-II at 40 °C were 4.5 and 3 h, respectively; and the induction time and reconstruction time of form-II at 50 °C were 5 and 3.5 h. These data indicated that the induction and reconstruction time increased and that the phase transformation rate of form-II decreased; they indicated also that the holding time of form-I increased. This is due to the fact that the new solvent environment (ethanol/IL) and the variation of temperature affect the solubility of the two CLP polymorphs and thus influence the induction and reconstruction time to increase. Thus, the decreasing of both supersaturation, expressed as the ratio of form-I and form-II polymorphs’ solubility (S = C*form‑I/C*form‑II), and the solubility difference (ΔC = C*meta − C*stable) brings the effect of the nucleation rate and mass transfer rate of form-II to decrease and consequently contributes to the increase of form-I holding time. From this result, the efficiency of the IL called AEImBF4 as a new solvent to control the polymorphic transformation was studied and confirmed.

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AUTHOR INFORMATION

Corresponding Author

*Tel.: +82-31-881-7173. E-mail: [email protected]. Author Contributions #

J.-H.A. and F.J. equally contributed to this work.

Notes

The authors declare no competing financial interest.

Figure 8. Kinetic correlation of (a) the induction time of the polymorphs in phase transformation based on Volmer’s nucleation model, (b) reconstruction time of the polymorphs in phase transformation based on the film theory mass transfer rate.

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REFERENCES

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ln2 S and TΔC. In Figure 8(a) we can see the result of the plotting of 1/[T3 ln2 S] values with the induction time present in Table 1, which matches linearly; in Figure 8(b) also we can see the result of the plotting of the 1/[TΔC] values and the reconstruction time present in Table 2, which matches linearly. This conformity of kinetic variation of the phase transformation with temperature depends on nucleation and mass transfer rates.

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CONCLUSION In the pharmaceutical industry, the CLP polymorphs form-I is preferred; however, because of the speedy phase transformation of CLP polymorph form-I to form-II, pharmaceutical companies undergo great hardships to produce the CLP polymorphs form-I. Therefore, in order to control the phenomenon leading to the fast phase transformation of CLP polymorphs form-I to form-II, the ionic liquids AEImBF4, BDMImBF4, and AAImBF4 were used as antisolvent and ethanol was used as solvent. The temperature, the thermodynamic factor, was set as parameter, and through the drowningout crystallization method we aimed to propose the utility of ILs as new polymorph control solvents. As a result, when two ILs (BDMImBF4 and AAImBF4) were used as antisolvent, crystallization could not be derived, but when AEImBF4 was used as antisolvent, crystallization could be induced and form-I could be precipitated. Afterward, we observed the CLP form-I → form-II solvent-mediated phase transformation in ethanol/ G

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Crystal Growth & Design

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DOI: 10.1021/acs.cgd.5b01079 Cryst. Growth Des. XXXX, XXX, XXX−XXX