Relative Stabilities of the Five Polymorphs of Sulfathiazole - Crystal

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Relative Stabilities of the Five Polymorphs of Sulfathiazole Á ine Munroe, Åke C. Rasmuson, B. Kieran Hodnett, and Denise M. Croker* Solid State Pharmaceuticals Cluster, Materials and Surface Science Institute, Department of Chemical and Environmental Sciences, University of Limerick, Ireland ABSTRACT: The relative stabilities of the five polymorphs of sulfathiazole have been investigated using solution-based and solid-state methods. In the lower temperature range, the stability order is proposed to be FI < FV < FIV < FII < FIII. FI and FV were identified as the least stable polymorphs below 50 °C using a combination of solubility measurements and isothermal suspension equilibration, with FII, FIII, and FIV displaying very similar stabilities. Between 30 and 50 °C, the stability order was established as FIV < FII < FIII. At 10 °C, FII is still more stable than FIV, but it was not possible to place FIII in relation to these two forms. Above 100 °C, the results from DSC and high-temperature XRD measurements suggest that the stability order changes completely as a result of several enantiotropic transitions. In this upper temperature range, FII and FIII are the least stable forms, with FII being less stable than FIII. The stability order among the remaining three forms is FI < FV < FIV initially, but this reverses with increasing temperature, and as the transition into a melt is approached, a stability order of FII < FIII < FIV < FV < FI is suggested.

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INTRODUCTION Knowledge of the polymorphic stability of a drug substance is vital, so that conditions can be defined to control the isolation of the desired polymorph: If a metastable polymorph is required from a monotropic system, precautions must be taken during crystallization and storage to avoid transformation to the more stable form, whereas if the system is enantiotropic, detailed knowledge of the transition point is necessary to maintain the desired polymorph. Polymorph stability is determined by the free energies of different polymorphic forms. The lower the free energy of a given polymorph, the more stable the form is, and hence, a spontaneous change from one form to another is accompanied by a decrease in free energy. The solubility of different polymorphs of the same compound decreases with increasing stability, that is, with decreasing free energy. Therefore, comparing the solubilities of polymorphs is a reliable method for assessing their relative stabilities. It should be clear that the stability order between polymorphs is independent of the solvent; that is, it is entirely governed by the solid phases. However, the rate by which equilibrium is reached in the determination of solubility can depend significantly on the solvent. Another useful technique for assessing the order of stability of respective polymorphs is to perform so-called “suspension equilibration” experiments. In this method, a mixture of two polymorphs is added in solid form to a solvent and agitated, and sufficient time is allowed for the suspension to reach equilibrium. Polymorphic transformations are facilitated by the solvent, and thermodynamically, the more stable polymorph will prevail if the process is given sufficient time. It is also possible to recover an alternative polymorph that is more stable than either of the starting materials. Again, the solvent will not © XXXX American Chemical Society

influence on the equilibrium form remaining in the solvent but can substantially influence the time it takes to reach equilibrium. In the solid state, high-temperature powder X-ray diffraction (HTPXRD), differential scanning calorimetry (DSC), and hyperdifferential scanning calorimetry (HyperDSC) can give information on polymorph stability by investigating solid-state polymorphic transformations. Sulfathiazole (STZ) (Figure 1) is a well-known sulfonamide antibiotic agent whose crystallographic properties have been studied extensively throughout the past 40 years.1−6

Figure 1. Sulfathiazole molecule.

The five polymorphs of sulfathiazole are widely reported in the literature,7,8 but confusion arises over the naming of the polymorphs and their preparation methods. Recent work by Bakar et al.27 presents a comprehensive review of the reported preparation methods for the five polymorphs of sulfathiazole, along with an account of the preparation of each form in a pure state using a selected method. In this work the polymorphs are labeled FI−FV in accordance with CCDC reference codes as per the works of Blagden et al.,9 Davey et al.,10 and Chan et al.4 (Table 1), in good agreement with the aforementioned review. Received: December 12, 2011 Revised: April 24, 2012

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dx.doi.org/10.1021/cg201641g | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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Table 1. Lattice and Crystallographic Data for the Five Polymorphs of Sulfathiazole polymorph

FI

FII

FIII

FIV

FV

a (Å) b (Å) c (Å) β (deg) CCDC ref code

10.554 13.22 17.05 108.06 SUTHAZ01

8.235 8.55 15.58 93.67 SUTHAZ

17.57 8.57 15.583 112.93 SUTHAZ02

10.867 8.543 11.456 88.131063 SUTHAZ04

14.33 15.273 10.443 91.05 SUTHAZ06

For all of the preparation methods mentioned above, the polymorphs remained stable during storage in sealed containers in a desiccator for up to 2 months. Solubility Measurements. A thermostatic water bath (Grant GR150 with S38 stainless steel water bath; volume, 38 L; 690 × 300 × 200 mm; stability, ±0.005 °C; uniformity, ±0.02 at 37 °C) with a serial magnetic stirrer plate placed on the base was used. Twenty-five milliliter test tubes (150 × 25 mm) with a Teflon-coated magnetic stirrer were charged with solvent and monitored until the temperature of the solvent had reached the temperature of the water bath. Excess solid of the different pure polymorphs was added to each of the test tubes. The solutions were agitated at 500 rpm and allowed to equilibrate for 48 h in the temperature range of 5−50 °C in increments of 5 °C. The high stirring rate was required to maintain the solids in suspension. After equilibration, agitation was stopped, and the solids were allowed settle for 2 h. Samples of the clear saturated solution (approximately 4 mL) were transferred from each of the test tubes in triplicate to clean dry weighed vials (mass of dry vial = mempty) using preheated syringes. A 0.2-μm, 15-mm-membrane-diameter syringe filter was attached to the head of the syringe before the saturated solution was passed into the vials to further ensure that no suspended solid was present. The amount of liquid sample in each vial was determined by weighing the vial with liquid (mass = mliq) and subtracting the weight of the dry vial. Samples were then dried at room temperature, and the mass was monitored until no further change occurred. Finally, the vials were placed in an oven (Lenton Thermal Designs oven) at 45 °C to ensure complete dryness. The mass of dry solids was recorded (mass = mdry). All weighing was carried out using a Mettler Toledo AX054 balance with a weighing capacity of up to 520 g and a readability of 0.1 mg. The solubility of the polymorphs in the solution, Cs (g of solute/g of solution), was calculated as

A number of solvates have also been reported for sulfathiazole11,12 but are not considered in this work. The solid-state transformation of sulfathiazole polymorphs has been reported. When the structures of FII and FIII were initially reported by Kruger and Gafner,1,2 it was noted that the melting point of FIII was 174−175 °C, but sometimes a transition occurred at 174−175 °C followed by melting at 200−202 °C. FII showed similar melting and transition points. The authors identified this as the transition to FI. Anwar et al.5 thoroughly characterized the four known polymorphs of sulfathiazole in 1989 and noted that DSC showed mixed behavior, with transformations occurring between 150 and 170 °C before melting at 201 °C. Lagas and Lerk13 reported the melting points of FI, FV, and FIII as 201, 196.5, and 173.6 °C, respectively. For the next 25 years, the solid-state transformation of sulfathiazole did not appear in literature until 2006, when Zeitler et al.14 characterized the transitions of the five polymorphic forms of sulfathiazole by terahertz pulsed spectroscopy and DSC. Zeitler et al. noted that FII, FIII, and FIV convert to FI at varying temperatures between 147 and 177 °C through solid-state transformations. They noted that FV melted at 196 °C. They also noted it was not possible to differentiate the forms based on DSC alone, and the work also included HyperDSC, which resulted in partial inhibition of the recrystallization of the lower melting form. Since the discovery of the fifth polymorph,7,14−25 the thermodynamic stability order of all five forms of sulfathiazole has not been determined. It has been suggested, based on the packing coefficients and the calculated densities, that the stabilities of the sulfathiazole polymorphs are in the order FI < FII < FIII < FIV (Blagden et al.9). In an earlier work based on solubility determinations, Khoshkhoo and Anwar26 reported that the stability order is FI < FV < FIV < FIII, whereas Lagas and Lerk13 reported that the order is FV < FI < FIII. It is clear that there are inconsistencies that need to be addressed, as sulfathiazole continues to be used extensively as a model compound for polymorphism studies. In the present study, the stabilities of all five polymorphs of sulfathiazole were assessed using a combination of solutionbased and solid-state analyses. A critical part of being able to perform this work was the reliable production of pure polymorphic forms.

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Cs =

mdry − mempty mliq − mempty

(1)

At all temperatures, a portion of the solid in contact with the solution prior to the removal of the fixed volume was also collected, filtered, and dried, and the polymorphic form verified by PXRD to ensure that the original phase had not transformed. Isothermal Suspension Equilibration Experiments. A mixture of two pure sulfathiazole polymorphs in powder form was dispersed in presaturated (with respect to FIII sulfathiazole) ethanol, 1-propanol, or water at 10, 30, or 50 °C for 3 or 7 days with agitation. The saturated solutions of sulfathiazole were prepared at each respective temperature by adding the amount of FIII sulfathiazole required for saturation to the pure solvent, heating to 5 °C above the saturation temperature for 1 h, cooling to the desired temperature, and holding for a further 30 min prior to addition of the solid forms, with agitation provided throughout. A saturated solution was used to prevent complete dissolution of either polymorph. Approximately 0.02 g of each pure polymorph was added to 5 mL of the prepared solution in an 8 mL glass vial pre-equilibrated at the appropriate temperature in a Grant GR150 thermostatic water bath. Agitation was provided by means of a 10-mm magnetic flea, and the agitation rate was held at 230 rpm. After 3 days, the excess solids were filtered using 25-mm poly(vinylidene difluoride) (PVDF) filter paper from Millipore and allowed to air-dry. PXRD analysis was undertaken on the recovered solids to determine the phases present. The procedure was repeated with a 7-day equilibration period to allow for transformations with very slow kinetics.

EXPERIMENTAL SECTION

Methods as described in Bakar et al.27 were used for the production of FII (Table 3, method 527), FIII (Table 4, method 227), FIV (Table 5, method 227), and FV (Table 6, method 127). FI was produced using the method described by Blagden et al.9 and Anwar et al.:5 Commercial sulfathiazole (a mixture of FIII and FIV) was placed on a dish and heated in an oven to 180 °C for 15 min. The crystals were removed from the oven and placed in a sealed container in a desiccator. The crystals were sometimes observed to have a pink tinge, but this did not affect the quality of the FI polymorph obtained. B



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X-ray Diffraction (XRD). Powder XRD was performed using a Philips X’Pert-MPD PRO diffractometer with nickel-filtered Cu Kα radiation (λ = 1.542 Å) as the X-ray source. The Cu Kα diffractometer anode was run under a tension of 40 kV and a current of 35 mA. An X’Celerator strip detector was used to collect the diffracted data. Dried ground samples were placed on a zero-background sample holder, and the samples were scanned over a range of 5−55° 2θ or 5−35° 2θ using a step size of 0.02° 2θ and a scan speed of 0.02° 2θ/s. High-temperature XRD was performed using an Anton Parr HTK1200 stage in conjunction with the above diffractometer. Before measurement, the chamber was calibrated with an indium standard to note the temperature lag between the chamber and the controller. The temperature difference was found to be 13 °C (i.e., the chamber was 13 °C higher than the temperature indicated on the controller), and this was taken into account in the analysis. Samples were measured under nitrogen at a heating rate of 20 °C/min from room temperature to 220 °C, using scan parameters similar to those listed above. Samples were placed on aluminum foil that had been pretreated with 1 M NaOH for 3 min to remove any coating, resulting in an aluminum oxide background with a peak at 25° 2θ. Differential Scanning Calorimetry (DSC). DSC was performed on a Perkin-Elmer Pyris 1 instrument, which was calibrated using indium (mp 156.6 °C; ΔH = 28.45 J/g). Calibration was performed for each heating rate and applied for each analysis to account for any changes in the thermal profiles and the thermal lag resulting from the increased heating rates. For each experiment, 2−5 mg of sample was accurately weighed into a hermetically sealed aluminum pan. An empty aluminum sample pan was placed in the reference holder, and both holders were covered with platinum lids. The sample and reference were heated to 240 °C at 20, 100, and 300 °C/min using nitrogen as a purge gas. The heat flow (milliwatts) was measured as a function of temperature. Raman Spectroscopy. Sulfathiazole samples were analyzed using a Renishaw Raman microscope system. The samples were placed, and areas of analysis located, on the stage of a Leica microscope, with 10×, 20×, and 50× objective lens. Measurements were made at room temperature using a 514-nm argon laser at 10% power, and the laser spot size was less than 5 μm. Samples were scanned from 150 to 3310 cm−1 with an exposure time of 50 s. Multiple (five) acquisitions were made to ensure that a representative spectrum was obtained.

between the forms with this technique, identification of mixtures of polymorphic forms proved difficult. Each of the pure polymorphs exhibited a unique DSC profile at 20 °C min−1 heating rate (Figure 3). The DSC traces of

Figure 3. DSC profiles of FI, FII, FIII, FIV, and FV sulfathiazole measured at a heating rate of 20 °C min−1.

forms FII, FIII, and FIV showed a broad endotherm in the 130−170 °C region, indicative of a solid-state polymorphic transformation, and a second endotherm at 201 °C indicative of the melting point of FI. FV exhibited an initial endotherm at 195 °C followed directly by an exotherm that is indicative of a melt recrystallization. FII exhibited a small endotherm at 195 °C, which indicated that a portion of FII transformed to FV as well, or that there was a slight impurity of FV in the prepared FII. In general, the DSC traces were in good agreement with the findings of Bakar et al., with the exception of FII and FIII. In this work, FII was observed to transform to FI at a lower onset temperature than that at which FIII transformed, whereas Bakar et al. reported the opposite. This could be a function of the different heating rate employed: 20 °C/min was used here as opposed to 10 °C/min in the earlier study. The repeatability of the DSC data showed that onset times were within 1° when multiple samples of the same polymorph were analyzed. It was noted in a previous study14 that it is not possible to distinguish the different polymorphic forms by thermal analysis alone. However, under the conditions of this study (in the absence of diluents), the pure forms were distinguished from one another using DSC. When mixtures of polymorphs were present, the DSC endotherms could not be used to differentiate individual polymorphs present, as the mixtures caused the endotherms to shift and merge. Therefore, DSC alone could not be used to analyze the polymorphic purity of samples of sulfathiazole. PXRD patterns of each of the sulfathiazole polymorphs showed significant similarities, especially for FII, FIII, and FIV, but distinguishing peaks were identified for each form (Figure 4 and Table 2). It was difficult to obtain a pure sample of FIV without a trace of the FII XRD peak at 21.6° 2θ. Once the FII peak was less than 1% of the sample, the FIV material was considered to be as pure as possible. Theoretical diffraction patterns for each polymorph were generated using Mercury 2.2. There was good agreement between the experimental patterns and these theoretical patterns (Figure 4), indicating that the polymorph preparation methods were successful. There was some difference in the intensity profiles of the peaks compared to the theoretical patterns; this was due to preferred orientation effects, which persisted even when samples were ground prior to analysis.

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RESULTS Characterization of the Pure Polymorphs. Raman spectra were collected for polymorphs FII, FIII, FIV, and FV (Figure 2); a satisfactory spectrum of FI could not be collected

Figure 2. Raman spectra of the FII, FIII, FIV, and FV polymorphs of sulfathiazole using laser excitation of 532 nm.

because of its powder optical properties, which caused the sample to fluoresce. Although it was possible to differentiate C



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Figure 4. PXRD patterns for FI−FV sulfathiazole as labeled. The dashed traces represent the theoretical patterns calculated from CCDC files SUTHAZ01, SUTHAZ, SUTHAZ02, SUTHAZ04, and SUTHAZ06 for FI−FV, respectively, using Mercury 2.2. Prominent hkl planes are indicated. The solid traces represent the experimental patterns of sulfathiazole solids prepared as described above.

to a shift to lower 2θ value. Accordingly, we would expect the theoretical pattern to present the peaks at somewhat higher 2θ positions. Solubility Measurements. Solubilities were successfully determined for FIII in propanol, ethanol, and water; for FIV in ethanol and propanol; and for FII in ethanol only. The remaining measurements were not successful because of polymorphic transformation during the equilibration time or, in the case of water, because the differences in measured values between FII, FIII, and FIV were within experimental uncertainty. As illustrated in Figure 5, the solubility of sulfathiazole is quite low in all solvents, with the greatest solubility observed in ethanol, followed by propanol and then water. Commercial sulfathiazole (a mixture of FIII, FIV, and an amorphous phase) was reported by Bakar et al.27 to be soluble in acetonitrile, isopropanol, sec-butanol, and water, and good agreement was observed with our results for FIII in water and propanol. FI, FIII, and FIV sulfathiazole were described by Khoshkhoo and Anwar26 to be soluble in water, n-propanol, and acetone. In absolute terms, both our solubility values for FIII and FIV in water at 30 °C agree well with those reported by Khoshkhoo

Table 2. Distinguishing PXRD Peaks for the Five Polymorphs of Sulfathiazole polymorph FI FII FIII FIV FV

distinguishing PXRD peaks 2θ (deg), λ = 1.54 Å peaks at 17.7° 2θ and 20.9° 2θ major peak at 21.6° 2θ, peak at 25.18° 2θ, and triplet at 15° 2θ major peak triplet at 21.7° 2θ, peak at 22.9° 2θ, and doublet at 20−20.4° 2θ major peak at 22.22° 2θ and peak at 25.57° 2θ peak at 23.3° 2θ and doublet at 15.9−16.2° 2θ

The slight shift observed between the theoretical and experimental patterns is thought to be due to temperature differences between the original single-crystal data used for calculating the theoretical patterns and the powder obtained taken in the present work, especially with respect to the high-temperature PXRD data presented later. At higher temperature, the lattice spacing (d value) increases as a result of thermal expansion, and in the context of Bragg’s equation, an increase in d value corresponds D



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Binary Mixture FI + FII. Mixtures of forms FII and FI normally underwent a transformation to FII. This indicates that FI is less stable than FII. In one instance (ethanol at 50 °C), a polymorph that was not originally presentFIIIwas identified. This illustrates that a new more stable polymorph, namely, FIII, nucleated and that the existing solids underwent a complete transformation to this form. This nucleation of FIII was seen only in ethanol at 50 °C, which can be considered a range more favorable to polymorphic transformations in the sulfathiazole system given the relatively larger differences in solubilites observed in this temperature range for polymorphs FII, FIII, and FIV of sulfathiazole. It can be summarized that, over the entire temperature range, FI is less stable than FII, and at 50 °C, the order of stability is F1 < FII < FIII. Binary Mixture FI + FIII. Pure FIII was recovered in all instances of this mixture, establishing that FI is less stable than FIII across the entire temperature range. Binary Mixture FI + FIV. Depending on the experimental conditions, this polymorphic mixture underwent transformations to FIV, FIII, a mixture of FIV and FIII, and a mixture of FII and FIV. However, at all three temperatures, there were cases in which only FIV remained, clearly showing that FIV is more stable than FI, and especially in ethanol, the conversion was promoted. The other forms that appeared under various conditions, namely, FII and FIII, are all similar in stability to FIV. Clearly, under the conditions used, FII and FIII can nucleate, and FI can transform into these forms through the intermediary of FIV or directly. At 50 °C in ethanol, only FIII was observed in the final solids; this indicates that, under these conditions, FIII is more stable than FIV and FI. Binary Mixture FI + FV. This polymorphic mixture underwent transformations to FII, FIII, and FIV. The most common new polymorph present at the end was FIV. FI and FV were never observed in the final solids obtained at the end of the experiment, and therefore, the stability order between FI and FV cannot be safely established from these experiments. However, given the facts that neither FI nor FV remained in the final mixture and that, in every case, at least one new polymorph nucleated, this experiment verifies that these forms are less stable than FII, FIII, and FIV. Binary Mixture FII + FIII. In most instances of this mixture, the slurry remained as a mixture of FII and FIII at the completion of the equilibration time. This was the case in all experiments at 10 °C. However, at 30 and 50 °C, several experiments resulted in pure FIII, and the fraction of such experiments clearly increased with increasing equilibration time. This establishes FIII as more stable than FII at 30 and 50 °C,

Figure 5. Solubilities of FII, FIII, and FIV sulfathiazole as determined gravimetrically after 2 days of equilibration in ethanol, propanol, and water as a function of temperature. The polymorph form was verified upon completion of the equilibration time using PXRD.

and Anwar, whereas our result in n-propanol is somewhat higher than theirs. The solubilities of the three polymorphs were very similar between 10 and 35 °C in ethanol. Above 35 °C, FIV appeared to have a slightly higher solubility than FII or FIII. The data on solubility in propanol indicate that FIII and FIV exhibit an enantiotropic relationship with a crossover in stability at 20−21 °C; FIII is more stable than FIV above this temperature, and vice versa below this temperature. Accurate solubilities could not be determined for FI and FV. FI transformed quickly upon contact with solvent, and it was not possible to generate the quantity of FV needed for the solubility study. Improvised experiments were attempted whereby known quantities of FI and FV were independently dissolved in pure ethanol. A greater amount of FI was observed to dissolve in these experiments, suggesting that FI is less stable than FV, but it was not possible to further confirm this finding experimentally. Solubility data were determined as accurately as possible. However, within the experimental error, the solubility curves for the polymorphs within each solvent system lie too close together to differentiate accurately, especially at lower temperatures. Isothermal Suspension Equilibration. The solid forms recovered following 3- and 7-day equilibration times were characterized with PXRD, and the results are summarized in Tables 3 and 4, respectively.

Table 3. Polymorphic Compositions of Solids Recovered after 3 Days of Equilibration of Binary Polymorphic Mixtures in Presaturated Solvents at 10, 30, and 50 °C as Identified by PXRD starting binary polymorph mixture solvent, temperature

FI + FII

FI + FIII

FI + FIV

FI + FV

ethanol, 10 °C propanol, 10 °C water, 10 °C ethanol, 30 °C propanol, 30 °C water, 30 °C ethanol, 50 °C propanol, 50 °C water, 50 °C

FII FII FII FII FII FII FIII FII FII

FIII FIII FIII FIII FIII FIII FIII FIII FIII

FIV FIV FIV + FII FIV FIV + FII FII + FIV FIV FIV FIV

FIV FIV FIII + FIV FII + FIV FII + FIV FIV FIII... FII

FII + FIII

FII + FIV

FII + FV

FIII + FIV

FIII + FV

FIV + FV

FII + FII + FII + FIII FIII FII + FIII FII + FII +

FII FII FII + FIV FII FII FII + FIV FIII FII FII + FIV

FII FII FII FII FII FII FII FII FII

FIII + FIV FIII + FIV FIII+ FIV FIII + FIV FIII + FIV FIII + FIV FIII FIII + FIV FIII + FIV


FII + FV FII + FIV FII + FIV FII + FV FIV FIII + FIV FIII FIII + FIV FIII + FIV

E

FIII FIII FIII

FIII FIII FIII



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Table 4. Polymorphic Compositions of Solids Recovered after 7 Days of Equilibration of Binary Polymorphic Mixtures in Presaturated Solvents at 10, 30, and 50 °C as Identified by PXRD starting binary polymorph mixture solvent, temperature ethanol, 10 °C propanol, 10 °C water, 10 °C ethanol, 30 °C propanol, 30 °C water, 30 °C ethanol, 50 °C propanol, 50 °C water, 50 °C

FI + FII

FI + FIII

FI + FIV

FI + FV

FII FII FII FII FII FII FIII FII FII


FIV FII + FIV FIV + FII FIV FIV FIV + FII FIII FIV + FIII FIV

FIV FIV FIV FIV FIV FIII + FIV FIII FIV FII + FIII + FIV

but at 10 °C, the results do not establish the stability order. The data suggest that the transformation from FII to FIII is fastest in ethanol and slowest in water, as pure FIII is obtained in this medium only at the highest temperature, 50 °C, and the longest time, 7 days. This is due to the fact that the solubility is lower in water than in the alcohols. Binary Mixture FII -FIV. In most instances of these experiments, the remaining solid was identified as pure FII. A complete transformation to FII was observed at 10 and 30 °C in ethanol and at all three temperatures in propanol. This clearly establishes that FII is more stable than FIV at all three temperatures. However, at 50 °C in ethanol, the remaining solid phase was pure FIII, suggesting that FIII is more stable than FII and FIV, at least at 50 °C. In all water experiments, a mixture of FII and FIV remained at the end. The transformation is much slower in water, because of the overall lower solubility of sulfathiazole in water. Binary Mixture FII + FV. Pure FII was recovered in all instances of this mixture, establishing that FV is less stable than FII across the entire temperature range. In addition, the data suggest that the conversion from FV to FII is quite rapid. Binary Mixture FIII + FIV. This polymorphic mixture remained as FIII and FIV at the end of the equilibration time in almost all instances. However, at 50 °C, only FIII was detected at the end, indicating that FIV transformed into FIII in ethanol and water. This confirms that, at 50 °C, FIII is more stable than FIV, but at lower temperatures, the stability order is unclear. The data indicate that the transformation from FIV to FIII is most rapid in ethanol, followed by water and then propanol. Binary Mixture FIII + FV. Pure FIII was recovered in all instances of this mixture, establishing that FV is less stable than FIII across the entire temperature range. Binary Mixture FIV + FV. Results from this mixture were quite complex. At 10 °C, in all cases but one, the final material was a mixture of FII and FIV. This indicates that, at 10 °C, FV is less stable than FII, as the FV has disappeared, FIV remains, and FII has nucleated. However, after 3 days in ethanol at 10 °C, the final product was a mixture of FII and FV, suggesting that FIV has transformed into FII. The same situation was observed after 3 days at 30 °C in ethanol; however, FV was never found in any of the other experiments on this mixture. After 7 days in ethanol at 10 and 30 °C, FV was replaced by FIV. All experiments at 50 °C led to either pure FIII or a mixture of FIII and FIV. In addition to the ethanol experiment at 30 °C discussed in the preceding paragraph, the material at the end contained FIV, sometimes in pure form, sometimes together with FII, and sometimes together with FIII. These

FII + FIII

FII + FIV

FII + FII + FII + FIII FIII FII + FIII FIII FIII

FII FII + FII + FII FII FII + FIII FII FII +

FIII FIII FIII

FIII

FIII FIV

FIV

FIV

FII + FV FII FII FII FII FII FII FII FII FII

FIII + FIV FIII FIII FIII FIII FIII FIII FIII FIII FIII

+ + + + + +

FIV FIV FIV FIV FIV FIV

+ FIV

FIII + FV

FIV + FV


FII + FIV FII + FIV FII + FIV FII + FIV FIV FIII + FIV FIII FIII + FIV FIII + FIV

experiments suggest that FIV is more stable than FV. This was conclusively confirmed for 30 °C by the propanol experiments, and it is a reasonable interpretation of the results for the other temperatures. Solid-State Stability. PXRD patterns recorded during the heating of FII sulfathiazole from 20 to 202 °C demonstrate the solid-state transformation of FII to FI above 144 °C (Figure 6). At 163 °C, the transformation is complete, with all peaks present characteristic of FI sulfathiazole. The DSC trace for FII (Figure 3) showed a small endotherm at 195 °C, suggesting that a small amount of FV was present. Peaks associated with FV were not observed in any PXRD patterns recorded in this experiment, but the amount of FV generated could be below the detection limit of this method. The PXRD patterns exhibit a slight shift in the location of the peaks, but the sequence of peaks is correct. This is explained by the expansion of the crystal lattice at higher temperatures. DSC indicated that the melt of pure FI had an onset at 201 °C. PXRD patterns collected at 197 and 199 °C were characteristic of FI, whereas at 202 °C, no peaks were observed, indicating that the FI crystals had melted. This experiment was carried out also for FIII and FIV sulfathiazole, and in each case, a solid-state polymorphic transformation to FI was observed, in good correspondence with the recorded DSC data (Figure 6). For FV, no polymorphic transformation could be detected before the sample melted. The pure polymorphs of sulfathiazole were analyzed using HyperDSC conditions to investigate whether the solidstate transformation from FII, FIII, FIV, and FV to FI could be surpassed and a characteristic melting point for each of the pure polymorphs determined. In addition, HyperDSC provides increased capability to observe low-energy transitions, because the same amount of energy is released or absorbed over a shorter period of time (milliwatts), resulting in increased signal height (greater sensitivity). HyperDSC was performed at and 300 °C/min and is compared to the standard 20 °C/min trace in Figure 7. FI returned the same DSC profile at all heating rates (Figure 7). As the heating rate increased, the peak onset moved to lower temperatures, but only one characteristic peak was observed. The movement to a lower onset can be attributed to the heat transfer lag observed when using high heating rates. The thermal profiles of FII, FIII, and FIV obtained at higher heating rates showed an exaggeration of the initial transformation endotherm (Figure 7). The onset temperature of this endotherm increased with increasing heating rate. At 300 °C/ min, the transformation of FII, FIII, and FIV to FI was still F



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Figure 6. In situ PXRD patterns recorded at 25−202 °C during heating of the designated pure polymorphic forms at 20 °C/min under flowing nitrogen. Characteristic peaks for each of the forms are indicated with corresponding hkl values.

kinetically favorable and observed. Under the conditions used, it was not possible to surpass the transformation of these polymorphs to FI. However, when FV was heated at 100 and 300 °C/min, it showed a single endotherm, indicating the melting of FV (Figure 7). There is a possibility that the two endotherms observed at lower heating rates merged because of the lag associated with HyperDSC. This might be the case at 100 °C/ min, where a shoulder in the endotherm is observed, indicating the merger of two endotherms. At the higher heating rates, the initial endotherm corresponding to the melting of the polymorph is larger because of the increased sensitivity at higher heating rates.

and partly because the solubilities of FII, FIII, and FIV are quite similar. However, the results do establish that FII, FIII, and FIV are very close from a stability point of view in the temperature range from 10 to 50 °C and that FI and FV are clearly less stable in that temperature range. Solubility data further indicate that FIII is more stable than FIV at 50 °C and that this order is possibly altered at lower temperature (i.e., that the pair is enantiotropically related). Finally, solubility data demonstrate that the solubilities of FII, FIII, and FIV of sulfathiazole are greatest in ethanol, followed by propanol and then water, but overall, sulfathiazole is poorly soluble in all solvents. Earlier solubility measurements reported by Khoshkhoo and Anwar26 demonstrated the solubilities of FIII and FIV to be similar in n-propanol, water, and acetone and indicated an enantiotropic relationship between FIII and FIV in n-propanol, albeit in the reverse order from that which we propose. This work clearly establishes that FII, FIII, and FIV are close in terms of stability, and we note that it has been shown that FII and FIV have significant structural similarities.28 The results presented here provide a foundation for investigating possible polymorphic transformations in the sulfathiazole system.

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DISCUSSION In this work, solubility measurements could not conclusively establish the stability order among the five forms of sulfathiazole, partly because the solubilities in the three solvents used were quite low, which impacts the accuracy of the measurements; partly because metastable forms have a tendency to convert into more stable forms during the equilibration period; G



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Figure 7. HyperDSC of the pure polymorphs of sulfathiazole, as designated, at 20, 100, and 300 °C/min under flowing nitrogen.

(FI < FII < FIII < FIV) gives a reasonably correct trend in that FI is placed as the least stable form, but it is not able to resolve the small differences in stability among FII, FIII, and FIV. The results of the equilibration at 30 °C for FII + FIV and FIII + FIV suggest that the transformation of FIV to FII is more kinetically favorable than that of FIV to FIII, because the conversion to FII goes to completion whereas a mixture remains for FIII + FIV. This could be due to FII and FIV having mutually identical structural features, which might facilitate the transformation.28 The influence of the solvent on the rate of conversion was observed in several ways. Complete conversion to one pure polymorph was most common in ethanol and rarely observed in water, in good agreement with the solubility order observed from the solubility measurements. A higher rate of transformation is expected in a solvent in which the compound has a high solubility. The solvent can also interact with solute molecules, and this molecular interaction might have some influence on stabilizing a metastable form and slowing, or preventing, the onward transformation to a more stable form. In this work, this is evident in propanol at 50 °C, where a mixture of FIII and FIV persists after an equilibration time of 7 days. The equivalent experiment in ethanol and water resulted in complete conversion to FIII within 3 and 7 days, respectively. This suggests an interaction between FIV and propanol that slows the onward transformation to FIII. Complete conversion was also most likely at 50 °C, illustrating the effect of temperature on the rate of transformation. Experiments at 10 °C tended to remain as a mixture after 7 days of equilibration. This is most likely due to a combination of a reduced driving force and slower conversion kinetics at lower temperature. In the solid state, all of the polymorphs transformed to FI before melting, suggesting that FI is, in fact, the most thermodynamically stable form at temperatures above 130 °C. At a 20 °C/min heating rate, FII, FIII, and FIV showed one initial

The isothermal suspension equilibration experiments confirmed the highly metastable nature of FI and FV and provided further information with respect to the relative stabilities of FII, FIII, and FIV. However, complete clarity with respect to the stability order could not be reached. There are several reasons for this. The first reason is that FI and FV were never found at the end of a suspension experiment where these two forms were added simultaneously from the beginning. The second reason is that the rate of conversion is very low when the driving force is very low, that is, when the forms are very close in stability, or at low temperatures. The isothermal suspension equilibration experiments do reveal that FII is more stable than FIV in the temperature range of 10−50 °C, that FIII is more stable than FIV at 50 °C, and that FIII is more stable than FII at 30 and 50 °C. Combined, these results imply a stability order of FIV < FII < FIII in the range 30−50 °C. At 10 °C, FII is more stable than FIV, but in all solvents, a mixture of FIII and FIV and a mixture of FIII and FII persisted after 3 and 7 days of equilibration, which provides no information on where FIII is placed at 10 °C (other than that FIII is clearly more stable than FI and FV). This could be due to a lower “solubility-difference” driving force for conversion at 10 °C, coupled with a lower rate of conversion at the lower temperature. Hence, the stability order at 10 °C remains somewhat unclear, and the possible enantiotropic transition temperature between FIII and FIV at 21−23 °C, as indicated by the solubility measurements, cannot be verified. Overall, a stability order of FI < FV < FIV < FII < FIII is proposed from the isothermal suspension equilibration experiments at 30−50 °C, whereas at 10 °C, the position of FIII is unclear. The result is in good agreement with the stability order reported by Khoshkhoo and Anwar,26 namely, FI < FV < FIV < FIII, and supplements the relative stability of FII to that finding. The stability order proposed by Lagas and Lerk13 (FV < FI < FIII) is also in general agreement with our findings, but with FV and FI interchanged. The stability order predicted by Blagden et al.9 from density measurements H



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Figure 8. Mercury 2.2 representations of the unit cells of (left) FII, FIII, and FIV and (right) FI.

based on a unique dimer growth unit packed into chains, referred to as α, consisting of two molecules that are hydrogenbonded through two imine nitrogen and amino hydrogen contacts N2−H3. These dimers are linked in eight-membered chains through H1−O2 hydrogen bonding. FII, FIII, and FIV all are based on a dimer growth unit referred to as β, constructed from sulfato oxygen to aniline hydrogen (O2−H1) and aniline nitrogen to amino hydrogen (N1−H3) contacts, that is assembled into sheets, and the variation of assembly gives rise to the difference between the forms. FV is also unique and based on a tetrameric growth unit with a dimer chain structure assembled into sheets. The transformations of FII, FIII, and FIV can be considered in terms of the β sheets rearranging themselves into α chains, which are energetically more stable at higher temperatures (Figure 8). The stabilities of the five polymorphs inferred from the above experimental measurements are represented in Figure 9, illustrating a relative stability order at specific temperatures. The solubility determinations in conjunction with the outcome of the isothermal suspension equilibration were used to determine the stability order below 50 °C. At higher temperatures, the onset temperature of the transformation endotherms observed for each polymorph with DSC was used to propose the order of stability. One polymorph was considered less stable than another polymorph if it transformed to FI at a lower temperature than that polymorph; however, we are aware that this approach can be used only as an indication of the order. Post-transformation, the polymorph is represented by a

characteristic endotherm, indicative of a solid-state transformation, before melting as FI. According to Burger’s heat of transition rule, an endothermic enthalpy of transition is indicative of an enantiotropic polymorph pair, with the thermodynamic transition point lying somewhere below the onset of that endothermic peak.29 Thus, FII, FIII, and FIV are all enantiotropically related to FI, with thermodynamic transition points lying below 139, 153, and 156 °C, respectively. The thermodynamic transition point of FIII to FI has been experimentally determined as 94.530 and 95.5 °C31 in the published literature. The delay in observation of the endothermic transition peak is most likely due to the relatively high heating rate used in this study. The relative stabilities of these three forms in the temperature range of 130−200 °C are not as clear. It might be reasonable to assume that the polymorph that transforms at the lowest temperature is least stable at higher temperatures, as it requires the least amount of energy to transform to FI. FV displays a melt recrystallization to FI at 198 °C before melting as FI at 201 °C. This behavior does not distinguish whether FV is enantiotropically or monotropically related to FI,31 but it does show that FV is less stable than FI at 200 °C. Combined, these data propose a stability order of FII < FIII < FIV < FV < FI in the upper end of the range 130−201 °C. The molecular packing of the molecules in FI sulfathiazole is different from the packing in the other forms.20 Blagden and Davey20 used graph set analysis to investigate the intermolecular interactions in FI, FII, FIII, and FIV polymorphs, all of which are monoclinic. This showed that the FI structure is I



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FV in the low temperature range, as FI dissolves much more rapidly than FV. Polymorph behavior above 50 °C is indicated in a qualitative fashion only with the melting point (m.p.) of FI presented at 201 °C.

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CONCLUSIONS As is evident in the numerous published works dedicated to it, the sulfathiazole system is challenging. In this work, the five polymorphs of sulfathiazole were prepared, and the purity of each polymorph was assessed using DSC, Raman spectroscopy, and PXRD. Based on a combination of solubility measurements and isothermal suspension equilibration experiments, it is clearly shown that, in the temperature range of 10−50 °C, FI and FV are less stable than FII, FIII, and FIV and there are only small differences in stability among the latter three forms. However, it is established that, in the range of 30−50 °C, FIII is more stable than FII, which, in turn, is more stable than FIV. At 10 °C, we cannot experimentally clarify where FIII is positioned in relation to FIV and FII, only that FII is more stable than FIV. Based on the various experimental results, it is proposed that, in the lower temperature range of 10−50 °C, the stability order is FI < FV < FIV < FII < FIII. At temperatures above 100 °C, the order of stability between the polymorphs changes completely, as deduced from the transformation behavior suggested by DSC and HTPXRD. FII appears to be the least stable phase, followed by FIII. At first, the stability order among the three more stable forms is FI < FV < FIV, but with increasing temperature, this alters into the complete opposite. Accordingly, when approaching the final melting temperature, the stability order appears to be FII < FIII < FIV < FV < FI. In the lower temperature range, slurry experiments demonstrated that the choice of solvent can have an impact on the rate of conversion from a metastable to a more stable polymorph. The transformation will be fastest in a solvent in which the compound has a high solubility, but specific molecular interactions between the solvent and the molecule can also have an effect.

Figure 9. Relative stabilities of the five polymorphs of sulfathiazole at specific temperatures, based on solubility, slurry conversion, DSC, and HTPXRD data. A dashed line is used to represent the inconclusive stability of FIII relative to FII and FIV at 10 °C.

transparent colored block. The stability of polymorphs prior to transformation to FI was approximated as the order observed at lower temperatures. FI itself is represented with a transparent color block post-melting. From the stability information, a schematic free energy diagram for the system was constructed across the entire temperature range (Figure 10). Here, polymorph stability is correlated

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Figure 10. Schematic representation of the free energy phase diagram for the five polymorphs of sulfathiazole.

Notes

with free energy, with the most stable polymorph at any given temperature having the lowest free energy. A schematic liquidus curve is included. In the lower temperature range, we excluded an enantiotropic transition between FIII and FIV, a transition that was indicated in the solubility data. As shown in Figure 10, the DSC data combined with suspension equilibration data at 30 and 50 °C suggest that there is an enantiotropic transition point between these two forms in the upper temperature range (or at least above 50 °C). If FIV is more stable than FIII at 10 °C, it would suggest that there are two enantiotropic transitions between FIII and FIV, which should be a violation of the phase rule. The relation between FII and FIII at 10 °C is not clear, but for simplicity, we have kept FIII as the most stable phase at 10 °C because we do not have any results pointing to an enantiotropic transition between these two forms. Even though not fully proved, we believe that FI is less stable than

ACKNOWLEDGMENTS The authors gratefully acknowledge the generous support of this research under the Embark Initiative of the Irish Research Council for Science, Engineering and Technology (IRCSET). This material is based on works supported by the Solid State Pharmaceutical Cluster and by Science Foundation Ireland under Grant 07/SRC/B1158

The authors declare no competing financial interest.

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REFERENCES

(1) Kruger, G. J.; Gafner, G. The Crystal Structures of Polymorphs I and III of Sulphathiazole. Acta Crystallogr. 1971, 28, 272−283. (2) Kruger, G. J.; Gafner, G. The Crystal Structure of Sulphathiazole Polymorph II. Acta Crystallogr. 1971, 27, 306−333. (3) Babilev, F. V. Polymorphism of norsulfazole. Khim.-Farm. Zh. 1987, 1275−80. (4) Chan, F. C.; Anwar, J.; Cernik, R.; Barnes, P.; Wilson, R. M. Ab initio structure determination of sulfathiazole polymorph V from

J



Article

synchrotron X-ray powder diffraction data. J. Appl. Crystallogr. 1999, 32 (3), 436−441. (5) Anwar, J.; Tarlin, S. E.; Barnes, P. Polymorphism of sulfathiazole. J. Pharm. Sci. 1989, 78 (4), 337−342. (6) Blagden, N.; Davey, R. J.; Rowe, R.; Roberts, R. Disappearing polymorphs and the role of reaction by-products: The case of sulphathiazole. Int. J. Pharm. 1998, 172 (1−2), 169−177. (7) Parmar, M. M.; Khan, O.; Seton, L.; Ford, J. L. Polymorph Selection with Morphology Control Using Solvents. Cryst. Growth Des. 2007, 7 (9), 1635−1642. (8) Lee, I.; Lee, A.; Myerson, A. Concomitant Polymorphism in Confined Environment. Pharm. Res. 2008, 25 (4), 960−968. (9) Blagden, N.; Davey, R. J.; Lieberman, H. F.; Williams, L.; Payne, R.; Roberts, R.; Rowe, R.; Docherty, R. Crystal chemistry and solvent effects in polymorphic systems: Sulfathiazole. J. Chem. Soc., Faraday Trans. 1998, 94 (13), 1919 [Erratum to document cited in CA129:10804]. (10) Davey, R. J.; Allen, K.; Blagden, N.; Cross, W. I.; Lieberman, H. F.; Quayle, M. J.; Righini, S.; Seton, L.; Tiddy, G. J. T. Crystal engineeringNucleation, the key step. CrystEngComm 2002, 4 (47), 257−264. (11) Bingham, A. L.; Hughes, D. S.; Hursthouse, M. B.; Lancaster, R. W.; Stewart, T.; Threlfall, T. Over one hundred solvates of sulfathiazole. Chem. Commun. 2001, 603−604. (12) Threlfall, T. Crystallization of polymorphs: Thermodynamic insight into the role of the solvent. Org. Process Res. Dev. 2000, 4, 384− 390. (13) Lagas, M.; Lerk, C. F. The polymorphism of sulphathiazole. Int. J. Pharm. 1981, 8, 11−24. (14) Zeitler, J. A.; Newnham, D. A.; Taday, P. F.; Threlfall, T. L.; Lancaster, R. W.; Berg, R. W.; Strachan, C. J.; Pepper, M.; Gordon, K. C.; Rades, T. Characterization of temperature-induced phase transitions in five polymorphic forms of sulfathiazole by terahertz pulsed spectroscopy and differential scanning calorimetry. J. Pharm. Sci. 2006, 95 (11), 2486−2498. (15) Roberts, R. J.; Payne, R. S.; Rowe, R. C. Mechanical property predictions for polymorphs of sulphathiazole and carbamazepine. Eur. J. Pharm. Sci. 2000, 9 (3), 277−283. (16) Blagden, N. Crystal engineering of polymorph appearance: The case of sulfathiazole. Powder Technol. 2001, 121 (1), 46−52. (17) Kordikowski, A.; Shekunov, T.; York, P. Polymorph Control of Sulfathiazole in Supercritical CO2. Pharm. Res. 2001, V18 (5), 682− 688. (18) Aaltonen, J. Polymorph screening of sulfathiazole. Ph.D. Thesis, University of Helsinki, Helsinki, Finland, 2002. (19) Aaltonen, J.; Rantanen, J.; Siiria, S.; Karjalainen, M.; Jorgensen, A.; Laitinen, N.; Savolainen, M.; Seitavuopio, P.; Louhi-Kultanen, M.; Yliruusi, J. Polymorph Screening Using Near-Infrared Spectroscopy. Anal. Chem. 2003, 75 (19), 5267−5273. (20) Blagden, N.; Davey, R. J. Polymorph Selection: Challenges for the Future? Cryst. Growth Des. 2003, 3 (6), 873−885. (21) Pollanen, K.; Hakkinen, A.; Huhtanen, M.; Reinikainen, S.-P.; Karjalainen, M.; Rantanen, J.; Louhi-Kultanen, M.; Nystrom, L. DRIFT-IR for quantitative characterization of polymorphic composition of sulfathiazole. Anal. Chim. Acta 2005, 544 (1−2), 108−117. (22) Pollanen, K.; Hakkinen, A.; Reinikainen, S.-P.; Rantanen, J.; Karjalainen, M.; Louhi-Kultanen, M.; Nystrom, L. IR spectroscopy together with multivariate data analysis as a process analytical tool for in-line monitoring of crystallization process and solid-state analysis of crystalline product. J. Pharm. Biomed. Anal. 2005, 38 (2), 275−284. (23) Drebushchak, T.; Boldyreva, E.; Mikhailenko, M. Crystal structures of sulfathiazole polymorphs in the temperature range 100− 295 K: A comparative analysis. J. Struct. Chem. 2008, 49 (1), 84−94. (24) Gelbrich, T.; Hughes, D. S.; Hursthouse, M. B.; Threlfall, T. L. Packing similarity in polymorphs of sulfathiazole. CrystEngComm 2008, 10 (10), 1328−1334. (25) Hughes, D. A new polymorph for sulphathiazole. Acta Crystallogr. 1999, 55, 1831−1833.

(26) Khoshkhoo, S.; Anwar, J. Crystallization of polymorphs: The effect of solvent. J. Phys. D: Appl. Phys. 1993, 26, B90−B93. (27) Bakar, M. R. A.; Nagy, Z. K.; Rielly, C. D.; Dann, S. E. Investigation of the riddle of sulfathiazole polymorphism. Int. J. Pharm. 2011, 414, 86−103. (28) Munroe, A.; Croker, D.; Hodnett, B. K.; Seaton, C. C. Epitaxial growth of polymorphic systems: The case of sulfathiazole. CrystEngComm 2011, 13 (19), 5903−5907. (29) Bernstein, J. Polymorphism in Molecular Crystals; Oxford University Press: New York, 2002. (30) Milosovich, G. J. Pharm. Sci. 1964, 53, 484−487. (31) Threlfall, T. Turning DSC charts of polymorphs into phase diagrams: A tuitorial paper. Org. Process Res. Dev. 2009, 13, 1224− 1230.

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Relative Stabilities of the Five Polymorphs of Sulfathiazole - Crystal

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