ARTICLE pubs.acs.org/crystal
Supersaturation Control in Cooling Polymorphic Co-Crystallization of Caffeine and Glutaric Acid Zai Qun Yu,*,† Pui Shan Chow,† Reginald B. H. Tan,†,‡ and Wei Han Ang† †
Institute of Chemical & Engineering Sciences Ltd., A*STAR (Agency for Science, Technology and Research), 1 Pesek Road, Jurong Island, Singapore 627833 ‡ Department of Chemical & Biomolecular Engineering, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260 ABSTRACT: A model polymorphic co-crystallization process for caffeineglutaric acid from acetonitrile was monitored and controlled using attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and particle vision measurement (PVM). A new method to calculate supersaturation for co-crystallization systems was proposed and used in this study. Results showed that feedback control of supersaturation was effective in eliminating the nucleation of the metastable Form I of co-crystal and also produced the largest particles with the lowest proportion of fines.
1. INTRODUCTION Co-crystals have advantages in physiochemical properties over their constituent components and are expected to find uses in product formulation such as enhanced active pharmaceutical ingredients, food components with improved absorbability, and specialty chemicals with better performance.15 Formation of co-crystals can also serve as a separation method to remove soluble components from fermentation solution because of lower solubility of co-crystal than that of constituent components.6 Recently, enantiomeric enrichment has been reported by formation of co-crystals which disrupts the symmetry in phase diagrams of racemic compounds,7 revealing the potential of co-crystallization in racemic resolution. To materialize and fully exploit these advantages, co-crystallization processes must be designed and controlled carefully to obtain the desired polymorphs, particle size distribution (PSD), purity, stoichiometry, etc.8 It is logical to draw on strategies and techniques developed for crystallization of single components, such as optimal cooling rate to minimize secondary nucleation,9,10 seeding to avoid secondary nucleation11 and appearance of metastable form,12 feedback control via attenuated total reflectance Fourier transform spectroscopy (ATR-FTIR),1317 and focused beam reflectance measurement (FBRM).18 These particle engineering strategies and techniques have not been applied systematically to co-crystallization up to now. In this study, effects of cooling rate and seed loading will be investigated using ATR-FTIR and PVM for monitoring and control. In particular, supersaturation control will be constructed based on concentration measurement by ATR-FTIR spectroscopy, and its effects will be evaluated in terms of polymorph occurrence and co-crystal PSD. At the same time, it is worthwhile to note the specificity of co-crystallization versus crystallization of single components. r 2011 American Chemical Society
First and foremost, pure co-crystal can only be obtained in a narrow region in the phase diagram and excursions outside this region will result in mixtures of co-crystal and crystal of single component.1921 This issue has been addressed in detail in a previous study with caffeine (CA)-glutaric acid (GA) in acetonitrile as a model system,22 and the phase diagram obtained therein will be referred to in the current study. Second, the determination of supersaturation in co-crystallizing systems needs to be re-examined. In crystallization of single components, supersaturation is defined as the ratio of actual to equilibrium activity of solute.23 For activity coefficients close to unity (ideal solutions), the solute activity can be replaced by solute concentration. More often supersaturation is defined as the concentration difference between actual and equilibrium state of liquid phase for engineering purposes. In co-crystallization of two components, the concentrations of both components change with time, and supersaturation has been defined by Rodríguez-Hornedo et al.24 as a ratio: C1 C2 1=2 ð1Þ σ ¼ KSP where KSP is the solubility product, and C1, C2 are the concentrations of each solute component. It is assumed in this definition that the equilibrium concentration curve of the co-crystal can be described by solubility product in the liquid phase. However, it is known that this ideal condition is not valid at relatively high temperatures. For example, the measured concentrations of CA and GA in equilibrium with CA-GA co-crystal in acetonitrile at 30 °C is shown in Figure 122 along with the least-squares fitting Received: June 14, 2011 Revised: August 31, 2011 Published: September 07, 2011 4525
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Figure 1. Equilibrium concentrations of caffeine and glutaric acid in acetonitrile at 30 °C.22 The least-squares fitting curve is based on solubility product.
curve based on KSP. It can be seen that the fitting curve based on KSP deviates significantly from measured values. This error would lead to large errors in supersaturation calculation based on eq 1, and therefore a more accurate method to calculate supersaturation is needed for application of feedback control. Third, co-crystallization outcome may be influenced by extra factors such as the composition of the starting solution. Phase diagrams of co-crystals are usually incongruent and highly skewed due to drastic differences in solubility of different components. The ratio of two components in starting solution has been found to affect co-crystal purity25 and appearance of polymorphs.26 The effects of composition of starting solution will be studied in terms of nucleation temperature and polymorph formation. The model system used in this study is CA-GA in acetonitrile. As an active pharmaceutical ingredient, CA tends to transform to a hydrate when exposed to moisture in air. The moisture resistance of its co-crystals with various coformers can be greatly enhanced.27 It can form 1:1 co-crystal with GA in two polymorphs, Form I and Form II.28 Trask et al. have observed that Form I shows a tendency for conversion to Form II when exposed to moisture.27 It has been found that Form I (needlelike) transforms to Form II (prismatic) consistently in acetonitrile solution. The progress of polymorphic transformation can be effectively monitored by comparing the relative amounts of prismatic and needle-like crystals in PVM images. For systems with less drastic changes in crystal habit during polymorphic transformation, online Raman is a more reliable option than PVM in process monitoring and determination of end point.29,30
2. EXPERIMENTAL SECTION 2.1. Experimental Setup. The experimental setup is shown schematically in Figure 2. The flat-bottomed crystallizer has an inner diameter of 110 mm with a working volume of 1 L. There are four builtin baffles on the inner wall. An overhead stirrer with a marine type propeller rotates at 400 rpm to suspend crystals. Temperature is controlled by circulating water through the water jacket. The circulator (Julabo FP50-HL) has its own PID temperature controller. It can receive and execute set points sent forth from the computer. A PVM probe (Lasentec, V700S-5-C22-K) is inserted into the crystallizer to capture crystal images continuously during crystallization. FTIR spectra are also collected continuously via an ATR probe immersed in the suspension to monitor concentration change of CA and GA. FTIR spectrometer is of model Nicolet 4700 equipped with an ATR probe made by Axiom Analytical INC. A detailed calibration procedure and statistics can be found in our previous work.22
Figure 2. Experimental setup for cooling co-crystallization.
2.2. Chemicals and Experimental Procedures. Anhydrous CA of 99% purity was supplied by Fluka, GA of 99% purity by Alfa Aesar, HPLC grade acetonitrile from Fisher Chemical. The crystallizer was operated between 35 and 15 °C in batch mode (if not otherwise stated). In each batch, 400 g of acetonitrile were put into the crystallizer at room temperature, followed by addition of CA and GA solids. The crystallizer temperature was then raised to 40 °C to dissolve all solids. After that, the temperature was lowered to 35 °C at which the solution became saturated. Linear cooling or feedback control of supersaturation was then initiated to start co-crystallization. At the end of each batch, slurries were filtered and co-crystals were dried in open air overnight for PSD analysis. Co-crystals from unseeded co-crystallization were sifted and the cutoff size fraction < 150 μm was used as seeds for seeded crystallization. Dry seeds were introduced at a time when the solution was slightly supersaturated. PSD was analyzed with a Malvern Mastersizer 2000 equipped with a Scirocco dry dispersion unit. Dry samples were fed with an air pressure of 2 bar and a feed rate of 100%. Each PSD was an average of three replicas. 2.3. Co-Crystal Solubility and Calculation of Supersaturation in Co-Crystallization. Under the experimental conditions in this study, CA and GA always come out of solution simultaneously as a 1:1 co-crystal. The changes in CA and GA molality in liquid phase are stoichiometric. In order to align the calculation of supersaturation for co-crystallization with that for crystallization of single components, it can be imagined that molecular pairs of CA and GA exist in liquid phase, and it is this CA-GA pair that crystallizes out as co-crystal. The molecular weight of the CA-GA pair is the sum of molecular weights of CA and GA. The temperature dependence of CA-GA pair solubility can be deduced from the phase diagram. In Figure 3a, the x-axis stands for glutaric acid concentration and y-axis for caffeine concentration. The concentrations of GA and CA in equilibrium with co-crystal in acetonitrile have been obtained at different temperatures, and the fitting curves of GA and CA concentrations in molality (Form II) are duplicated from a previous study.22 Experimental data points of GA and CA concentrations are omitted for clarity of the graph. Eutectic points at different temperatures, where two solid phases coexist with the liquid phase, are joined together by two bold lines, and CA-GA co-crystal can be obtained in the region sandwiched between them. During co-crystallization, movement of composition in the phase diagram is along a straight line with a slope of 1:1. As an example, the composition of a starting solution is marked with a solid square on the equilibrium concentration curve at 35 °C. A straight line with a slope 4526
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Table 2. Effects of Starting Compositiona molality, mol/kg no.
nucleation temperature, °C polymorph nucleating
GA
CA
1
1.491
0.3027
32.1 ( 0.1
Form I
2
1.105
0.2992
31.2 ( 0.3
Form I
3
0.7334
0.3332
30.4 ( 0.5
Form I
a
Note: the three compositions shown here fall on the equilibrium concentration curve at 35°C.
of co-crystal, at the corresponding temperature. The solubility of cocrystal in g/kg at different temperatures is listed in the last column in Table 1. It should be noted that the solubility of co-crystal depends on GA concentration of the starting solution which dictates the position of B1 on the x-axis. The solubility of co-crystal is plotted against temperature and fitted in Figure 3b. It can be seen that the solubility can be expressed as C/ ¼ a0 þ a1 T þ a2 T 2
Figure 3. (a) Changes of CA and GA molality during co-crystallization in phase diagram, (b) solubility of CA-GA co-crystal in acetonitrile at different temperatures.
Table 1. Composition at Crossing Points in Figure 2a and CA-GA Co-Crystal Solubilitya
where C* is solubility of co-crystal with a unit of g/kg, and T, temperature (°C). a0, a1, a2 are constants and their values depend on the composition of the starting solution. The transient molality of CA-GA pair during a co-crystallization run is the same as that of CA measured by ATR-FTIR, and the difference between transient concentration and solubility is defined to be the supersaturation in this study S ¼ C C/
ð3Þ
where C is the transient concentration of CA-GA co-crystal and S is the supersaturation, both with units of g/kg.
3. RESULTS AND DISCUSSION
molality at crossing points, mol/kg equilibrium concentration
ð2Þ
CA-GA co-crystal
curves crossed
GA
CA
solubility, g/kg
35 °C
0.7363
0.3364
109.768
30 °C 25 °C
0.6323 0.5594
0.2324 0.1595
75.83121 52.06011
20 °C
0.5088
0.1089
35.52141
15 °C
0.4764
0.07646
24.95037
10 °C
0.4422
0.04230
13.80143
B1
0.3999
0
0
a
Note: CA-GA co-crystal solubility is equal to its molality (equal to CA molality) times its molecular weight, i.e., the sum of molecular weight of CA and GA.
of 1:1 is drawn through this point, and the crossing points with various equilibrium concentration curves are marked with open circles and the crossing point with the x-axis is marked with a solid diamond (point B1 on x-axis). The compositions at these points are listed in Table 1 for reference. They are obtained by solving equations describing the straight line and respective equilibrium concentration curves.31 It is worthwhile to note that the position of B1 on x-axis depends on the composition of starting solution. At B1, CA molality is zero and the molality of CA-GA pair is also zero. Using the reference point B1, the molality of the CA-GA pair is equal to CA molality along the straight line. The difference in concentration between each circle and B1 is the solubility of CA-GA pair, i.e., solubility
3.1. Effects of Starting Solution Composition on Metastable Zone Width and Polymorph. It can be seen in Figure 3a
that the region sandwiched between two bold lines where pure co-crystal can be obtained covers a relatively wide range of composition. The starting composition may influence the cocrystallization process. Therefore, the effects of starting composition were assessed in terms of nucleation temperature and polymorph formation with a series of experiments. Ramp cooling of 0.2 °C/min was started at 35 °C and ended at 25 °C to keep the solution within the operating region. The concentration of starting solutions and results are shown in Table 2. All starting solutions were saturated at 35 °C. Nucleation temperature is the average of three replicate runs. It can be seen in Table 2 that CA-GA cocrystals of Form I were obtained from all three starting solutions with different compositions. Form I was metastable and transformed to Form II in acetonitrile after some time. This process is similar to polymorphic crystallization of single components.32 The nucleation temperature, decreased with decreasing GA concentration, but only slightly. The composition of starting solution has no significant effects on the co-crystallization process. 3.2. Unseeded Co-Crystallization: Nucleation and Polymorphic Transformation. The effect of cooling rate on polymorph formation was investigated in the range of 0.10.4 °C/min. It was found that Form I always nucleated out first and then transformed to the stable Form II. A representative trajectory of supersaturation at a cooling rate of 0.2 °C/min is plotted in Figure 4. 4527
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Figure 4. Supersaturation profile in unseeded crystallization at a cooling rate of 0.2 °C/min.
Figure 5. (af) PVM images captured at different moments in unseeded crystallization with a cooling rate of 0.2 °C/min.
Figure 4 shows that at the beginning of cooling, supersaturation increased monotonously until the value of 32 g/kg 1560 s after cooling had started. After that, supersaturation decreased sharply to around 5 g/kg. The supersaturation of 5 g/kg lasted for around 720 s (supersaturation plateau) and dropped abruptly to around zero for the rest of the batch. PVM images captured in situ revealed clearly what happened in the crystallizer. Figure 5af are representative images taken at different times. Immediately after supersaturation reached its peak value of 31.0 g/kg, acicular co-crystals (Form I) nucleated out in a burst as shown in Figure 5a. Co-crystals of Form I grew in width as supersaturation declined as the image in Figure 5b demonstrates. Co-crystals of Form II appeared in Figure 5c taken
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Figure 6. Supersaturation profiles in seeded crystallization with seed loadings of 0.25 and 0.5 g respectively at a cooling rate of 0.2 °C/min. Seeds were introduced at the point indicated by arrows.
at t = 3150 s, indicating that polymorphic transformation had already started. Form I was still dominating at this time. 350 s later, however, co-crystal of Form I became the minority. It took only another 10 s before Form I disappeared completely from the crystallizer as shown in Figure 5e. Disappearance of Form I was accompanied by the step change in supersaturation in Figure 4 when solute concentration was close to the solubility of Form II. Co-crystals of Form II continued to grow and became larger at the end of the batch as shown in Figure 5f. Polymorphic transformation involves dissolution of the metastable form and growth of the stable one.33 The existence of a plateau in the middle of the supersaturation profile results from the relative rates of these two processes,34 and it indicates that dissolution of the metastable form is not the limiting step. Plateaus also appeared in supersaturation profiles of polymorphic transformation processes of glutamic acid29 and flufenamic acid.30 3.3. Seeded Co-Crystallization: Suppressing Form I. Unseeded co-crystallization resulted in nucleation of metastable Form I and subsequent polymorphic transformation. Although polymorphic transformation of the model co-crystal is relatively fast, it is desirable in many cases to circumvent polymorphic transformation because it simplifies manufacture and enhances robustness. Seeding with the stable form is one effective way for polymorphic control in crystallization of single components.10,32,35 Seed loading, seed size, and cooling rate are three vital factors for successful application.36 In this study, the effects of seed loading and cooling rate are investigated for polymorphic control in cocrystallization. In the first two experiments, seed loadings of 0.25 and 0.5 g were used respectively with the same cooling rate of 0.2 °C/min. The supersaturation trajectories are plotted in Figure 6. The peak supersaturation with a seed loading of 0.25 g was slightly higher than that with a seed loading of 0.5 g. Nevertheless, the evolvement of supersaturation profiles after the peak diverged markedly. Supersaturation dropped faster after the peak with a seed loading of 0.25 g than with a seed loading of 0.5 g. With a seed loading of 0.25 g, moreover, there is a short plateau after the peak followed by a second abrupt drop. Meanwhile, supersaturation steadily declined after the peak with a seed loading of 0.5 g. The plateau in supersaturation profile with a seed loading of 0.25 g points to the possibility of polymorphic transformation, which is verified by online PVM images in Figure 7. The image in Figure 7a was taken at t = 1170 s when supersaturation reached its peak value of 16.2 g/kg, which was much lower than the peak value (31.0 g/kg) in unseeded co-crystallization at the same 4528
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Figure 7. (ad) Images taken at different moments during seeded co-crystallization with a seed loading of 0.25 g and a cooling rate of 0.2 °C/min.
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Figure 9. PVM images taken at different moments in seeded cocrystallization with a seed loading of 0.5 g and cooling rate of 0.1 °C/ min. Only Form II is visible from (a) to (d) and particle size is increasing from (a) to (d).
Figure 8. Supersaturation profile in seeded crystallization with a seed loading of 0.5 g at a cooling rate of 0.1 °C/min. Seeds were introduced at the point indicated by the arrow.
cooling rate. Co-crystals of metastable Form I were found on the seed surface. 480 s later, crystals of Form I became the dominant polymorph as shown in Figure 7b. Polymorphic transformation was going on at the same time. Figure 7c shows that Form I was still discernible until at t = 2290 s when supersaturation started depleting. At the end of the batch, co-crystals of various sizes were obtained as shown in Figure 7d. The shape of the supersaturation profile with a seed loading of 0.5 g at a cooling rate of 0.2 °C/min does not suggest the occurrence of polymorphic transformation. PVM images (not shown), nevertheless, confirmed that metastable form nucleated out as well. However, there were far fewer Form I crystals observed compared to when the seed loading was 0.25 g. In the third experiment, a cooling rate of 0.1 °C/min and a seed loading of 0.5 g were employed. The supersaturation trajectory is graphed in Figure 8 and images captured at four different times are shown in Figure 9. The peak value of supersaturation in this experiment is around 10 g/kg, lower than in the previous two experiments. Metastable co-crystals were not observed in all PVM images throughout the batch. Images in Figure 9 demonstrate a continual increase in particle size with time.
Figure 10. Structure of feedback control system.
3.4. Feedback Control of Seeded Crystallization. Control Structure. Supersaturation can be more effectively controlled by
adjusting crystallizer temperature in a real-time manner based on in situ concentration measurement. It has been successfully applied in crystallization of single components.13,14,3739 This study demonstrates its application to co-crystallization. Shown in Figure 10 is the two-level feedback control structure used in this study. In the first level, an interface programmed in VB. net language on the control computer is responsible for supersaturation calculation based on spectral data from ATR-FTIR and transient temperature from the crystallizer. It compares actual supersaturation with its set point and decides the new set point for crystallizer temperature to keep supersaturation constant. The second level is actually the PID controller integrated in the circulator. It receives and executes commands from the first level. Control Algorithm. In the first level, the transient supersaturation S is compared with its set point Sp. Then decisions are made depending on two scenarios: If S < Sp, a new temperature set point Tp is calculated to bring supersaturation back to its set point by solving the following 4529
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Figure 11. Supersaturation and temperature trajectories in feedback control. The bold dashed line is the set point for supersaturation. Seeds were introduced at the point indicated by the arrow.
equation: C ða0 þ a1 Tp þ a2 Tp2 Þ ¼ Sp Tp ¼
a1 þ
pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi a21 4a2 ða0 C þ Sp Þ 2a2
ð4Þ ð5Þ
If S g Sp, the current temperature is maintained (cooling rate is zero). C stands for the actual relative concentration of co-crystal measured by ATR-FTIR. Sp was set at 8 g/kg, slightly lower than the peak value in seeded co-crystallization with a seed loading of 0.5 g and a cooling rate of 0.1 °C/min. In addition, the algorithm includes two constraints: (1) final temperature is 15 °C, (2) the highest allowable cooling rate is 0.4 °C/min. Outcome of Feedback Control. The feedback control loop was activated when supersaturation was about 6 g/kg (crystallizer temperature was 34 °C). 0.5 g of seeds were applied at the same time. The resulting supersaturation and temperature profiles are plotted in Figure 11. It can be seen that supersaturation decreased a little at the beginning because seeds started growing and incorporating solute molecules. Cooling was started because supersaturation was below its set point. In a few minutes, temperature decreased from 34 to 32.6 °C and supersaturation overshot to 10 g/kg. Subsequently, cooling was suspended for a short while, and supersaturation decreased slowly to its set point due to co-crystal growth. During this period, temperature changed little. When supersaturation dropped under its set point, cooling was sped up and the temperature profile became steeper. Supersaturation stayed slightly below its set point until the temperature reached 15 °C, at which time it was kept constant at 15 °C and supersaturation was consumed along the way by crystal growth. PSD of co-crystals obtained in feedback control is plotted in Figure 12 along with those from unseeded and seeded cocrystallization at different seed loadings and cooling rates for comparison. It can be seen that PSD differed remarkably when operating factors changed. Seeded operation produced co-crystal products with a much larger average size than unseeded operations, and the largest average size resulted from feedback control. Burst nucleation occurring in unseeded crystallization resulted in smaller particle size, while nucleation was suppressed to various degrees in seeded co-crystallization which led to fewer particles and a bigger average size. Among the runs with linear cooling, slower cooling rate with the same seed loading or higher seed loading with the same cooling rate led to the larger average
Figure 12. Particle size distribution from different operating conditions.
particle size. As evidenced in Figures 5 and 7, slower cooling rate or higher seed loading brought about a lower peak value of supersaturation, reducing secondary nucleation. The PSD from unseeded co-crystallization is less skewed. Most particles have similar development history in unseeded cocrystallization, that is, nucleating out as metastable form followed by polymorphic transformation and growth. As a result, the resulting PSD of co-crystal product was relatively symmetrical. In seeded co-crystallization, secondary nucleation was not totally suppressed throughout the run, which resulted in a persistence of fine particles in the distribution. It can be noted that the run with supersaturation control produced the lowest proportion of fines. PVM images show that Form I co-crystals did not appear throughout the experiment with feedback control. This is clearly an advantage of the feedback control since it is desirable to completely eliminate the appearance of metastable form during crystallization. Even though in our case, Form I can easily and rather quickly transform to Form II under our experimental conditions, in a real crystallization system, polymorphic transformation may be hampered by the presence of impurities or small differences in lattice energy from the stable form, resulting in mixed polymorphs in the final crystallization products. Without feedback control, Form I also did not appear in the batch with a cooling rate of 0.1 °C/min and a seed loading of 0.5 g (openloop control). However, the batch time was halved when feedback control was applied. This shows that our feedback control method is able to prevent the appearance of metastable form as well as improving productivity by reducing batch time. Metastable polymorphs have a higher solubility than the stable one, and relatively low supersaturation will keep the stable form growing and avoid nucleation of the metastable forms. Therefore, it is believed that feedback control developed here to suppress the appearance of metastable polymorphs can also be extended to other co-crystallization systems and more work will be done in the future.
4. CONCLUSION A polymorphic co-crystallization process was monitored and controlled using ATR-FTIR and PVM with CA-GA in acetonitrile. A new calculation method of supersaturation was proposed and adopted for co-crystallization systems. It was found that the composition of the starting solution had little effect on nucleation temperature. The metastable form crystallized out first in unseeded crystallization and then transformed to a stable form. This was due to the relatively high peak value of 4530
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Crystal Growth & Design supersaturation attained when primary nucleation started. The end point of polymorphic transformation could be clearly monitored by a sharp decrease in supersaturation, coinciding with the disappearance of the metastable form in PVM images. Seeding with the stable form could avoid nucleation of the metastable form when the cooling rate was commensurate, eliminating the often problematic polymorphic transformation process. Feedback control of co-crystallization was implemented and supersaturation could be maintained close to its set point. With the same seed loading, it resulted in a larger average particle size than batches with linear cooling rates. Unseeded co-crystallization produced a much smaller average particle size than seeded crystallization.
’ AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected].
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