Salting Effects on the Solubility and Transformation Kinetics of l

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Salting Effects on the Solubility and Transformation Kinetics of L‑Phenylalanine Anhydrate/Monohydrate in Aqueous Solutions Zhanzhong Wang, Yan Li, Wenzhi Fang, Qian Wang, Huazhi Xiao, and Leping Dang* School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, People’s Republic of China ABSTRACT: Understanding the salting effects on the solubility and transformation kinetics of amino acid solvates in aqueous solutions is important for a rational design of the industrial isolation and purification conditions of amino acid. We report measurements of L-phenylalanine anhydrate and monohydrate solubility as a function of temperature in aqueous NaCl, KCl, Na2SO4, and (NH4)2SO4 solutions with concentrations of 4 g/100 g of H2O in this work. It is found that salts play an important role in determining solubility reduction and solvated behavior, which had not been elucidated. This comparison has provided important insight into the dependence of L-phenylalanine solvates on temperature. The dependence of the L-phenylalanine anhydrate/monohydrate transformation kinetics on temperature in the presence of NaCl, as a typical salt, is discussed. It is noted that NaCl can markedly increase the rate of the transformation of L-phenylalanine between anhydrate and monohydrate compared with pure water. A simple model for the transformation kinetics based on the salt effect between anhydrate and monohydrate is established, which can quantitatively provide the observed experimental dependence of the transformation rate on time. This work can provide important instruction for optimum process control during industrial production of L-phenylalanine.

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INTRODUCTION Amino acids, important biochemical molecules, have been widely applied in the chemical, food, medical, and cosmetics industries. Amino acid separation and purification processes account for approximately 50% of the production cost.1 Therefore, choosing proper separation and purification operations is critical to improving the purity and yield of products as well as to reducing energy consumption. Crystallization is often considered as an effective means because of its efficient isolation and relatively mild thermal conditions.2 L-Phenylalanine, existing in two different crystalline forms, is an essential amino acid in food.3 The anhydrous form of L-phenylalanine is a white and platelike powdered crystal, while the monohydrate form is a needlelike powdered crystal. With regard to drugs, the difference in crystal forms can bring great impact on their dissolution and bioavailability. Therefore, the investigation of stability and transition behavior between different crystal forms is essential in solution. During the purification process of L-phenylalanine, salts are likely to be used to reduce solubility and thereby to enhance the recovery from aqueous solutions in which L-phenylalanine has been synthesized. NaCl, KCl, Na2SO4, and (NH4)2SO4, as possible salting-out additives, could be added to an aqueous solution of this product to enhance the recovery. Therefore, measurement of the solubility of L-phenylalanine anhydrate and monohydrate in pure water and aqueous solution in the presence of these salts is necessary. Mohan et al.3 reported the effect of a few additives, including electrolytes (NH4)2SO4, NaCl, KAl(SO4)2· 12H2O, and Al2(SO4)3 and nonelectrolytes dextrose (C6H12O6) and sucrose (C12H22O11), on the solubility of L-phenylalanine anhydrate. Furthermore, the effect of (NH4)2SO4 and dextrose (C6H12O6) on the transformation rate of L-phenylalanine in aqueous solution from anhydrate to monohydrate was investigated, while the transformation behavior and kinetics from the monohydrate to the anhydrate were ignored. Recently, Lu et al.4 © 2014 American Chemical Society

reported the solubility of L-phenylalanine anhydrate and monohydrate in acetone + water and ethanol + water mixtures. An experimental measurement and predictions were given. Kee et al.5 investigated the nucleation and growth kinetics for L-phenylalanine hydrate and anhydrate crystallization in propanol aqueous solution using in situ ATR-FTIR spectroscopy and a focused beam reflectance measurement (FBRM) probe. In this study, the solubility of L-phenylalanine anhydrate and monohydrate in pure water and in the presence of four electrolyte additives was experimentally determined from 293.00 to 328.00 K to demonstrate the transition point in thermodynamics. In addition, the transformation kinetics of L-phenylalanine anhydrate/monohydrate in pure water and in NaCl aqueous solution were also determined using powder X-ray diffractometry (PXRD) and microscopy at 10 and 50 °C, respectively. This work can provide important insight into the effect of electrolyte additives on the solubility and transformation kinetics of amino acid solvates. Especially, it can give some significant instruction for the control process and development during industrial manufacture of L-phenylalanine.

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EXPERIMENTAL SECTION Materials. A white platelike crystal of L-phenylalanine anhydrate was used, and its purity is higher than 99.0% mass fraction (supplied by the Tianjin Kewei Co. of China). L -Phenylalanine monohydrate was obtained by recrystallization from aqueous solution via a method described in the literature.3 The electrolyte additives used, including NaCl, KCl, Na2SO4, and (NH4)2SO4 (purchased from the Tianjin Kewei Co. of China), Received: Revised: Accepted: Published: 521

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two crystal forms was evaluated on the basis of the relationship between the peak intensities at the characteristic planes and then expressed as a percentage mass fraction of monohydrate and anhydrate, X, as described by the following equation:9

were of analytical reagent grade, and their purity was higher than 99.8% mass fraction. The amount of additives added was 4 g/100 g of H2O since the content of electrolyte salts in L-phenylalanine solution in industry production is approximately this level. Therefore, to provide more substantial instruction, the content of electrolyte salts was chosen to fix this value. The effect of different addition amounts of electrolyte salts on transformation will be checked in future work. Deionized water was used in all experiments. Measurement of Solubility. The solubility of L-phenylalanine anhydrate and monohydrate was measured by a method described in the literature,6−8 and some small experimental modifications were made. The relative uncertainty of the experimental solubility values is within 0.5%. To check if phase transformation occurs, suspension samples withdrawn from the crystallizer were analyzed by microscope and PXRD. TG Analysis. L-Phenylalanine anhydrate and monohydrate crystals were subjected to thermogravimetry−differential thermal analysis (TG−DTA; NETZSCH TG 209). Samples were tested in the range of 298−523 K at a heating rate of 0.17 K·s−1 and operated at a rate of 1.42 mL·s−1 under a dynamic atmosphere of dry nitrogen. The sample mass was between 4 and 6 mg. Transformation Kinetics Experiments. Transformation kinetics experiments were performed according to a method described in the literatures.3 The experiments were performed using the following procedure. A 100 mL glass cylindrical crystallizer with a jacket to circulate the thermostated water was used. The saturated solution of monohydrate/anhydrate was prepared by dissolving an excess amount of monohydrate or anhydrate in water at the desired temperature for 24 h in the crystallizer. Then the solid samples were filtered. A 40 g portion of the saturated solution of monohydrate/anhydrate with anhydrate/monohydrate powder (0.2 g) was used in each experiment. The transformation was carried out in pure water and with the addition of NaCl in the amount of 4 g/100 g of H2O with continuous stirring. Temperature was controlled at 10 °C in the experiments for transformation from anhydrate to monohydrate and at 50 °C for transformation from monohydrate to anhydrate. Samples were withdrawn and filtered at the desired time intervals. The solid phase was dried at 30 °C for 24 h. Using PXRD patterns, the crystal structure of the dried sample was analyzed to calculate the phase transformation degree. The effect of salts on the transformation rate was analyzed. Powder X-ray Diffractometry. PXRD data for L-phenylalanine samples at different times during transformation were collected using PXRD (D/MAX 2500 Japan) with Cu Kα radiation of 1.5406 Å wavelength at 200 mA and 40 kV. The sample was packed into a plastic holder and was scanned from 2θ = 5° to 2θ = 40° at a step size of 0.02° with a dwell time of 1 s. Divergence slits and receiving slits were 1° and 0.15 mm, respectively. Optical Microscopy. Crystal image analysis for L-phenylalanine at different times during transformation was performed using a Panasonic Lumix DMC-FZ20 system operating the Panasonic image analyzer connected to a 3CCD color vision camera mounted on an Olympus BH2 optical microscope. Calculation Curve and Fitting for Degree of Transformation. The progress of the transformation is also associated with mass changes. By measuring the rate of disappearance or appearance of a unique peak, the kinetics of the transformation between two crystal forms can be determined. The ratio of the

Xα = Iiα /(Iiα + Ijβ(I °α /I ° β ))

(1)

In this equation, Xα is the mass fraction of monohydrate and Iiα and Ijβ represent the intensities of the diffraction peaks of the ith and jth diffraction lines of monohydrate and anhydrate, respectively. I°α and I°β stand for the intensity when Xα = 1 and Xβ = 1, respectively. Calculated data were fitted by the Avrami−Erofeev model.10 The model parameter values can be obtained. They can be used to predict the L-phenylalanine solvate crystal transformation rate: Xα = 1 − exp[−(kt )1/ n ]

(2)

where Xα is the mass fraction of the specific crystal form, t is time, and k and n are model parameters.

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RESULTS AND DISCUSSION Structure Characterization of L-Phenylalanine Anhydrate/Monohydrate. L-Phenylalanine anhydrate/monohydrate crystals obtained were subjected to TG analysis to check for the presence of water molecules in the compounds. Figure 1 shows

Figure 1. TG curves of L-phenylalanine anhydrate and monohydrate.

the TG curves of L-phenylalanine anhydrate/monohydrate. From Figure 1, it can be seen that there is no weight loss from 25 to 250 °C in the L-phenylalanine anhydrate TG curve, while losses of 9.1% (9.8% in theory) in total weight in the monohydrate TG curve correspond to one water molecule in one L-phenylalanine monohydrate molecule. The platelike L-phenylalanine crystals and needlelike crystals obtained were analyzed by PXRD. PXRD patterns of the two forms are shown in Figure 2, which are consistent with those reported in the literature.3 Hence, it was confirmed that the platelike L-phenylalanine crystals and the needlelike crystals used in the present study were indeed the anhydrate and monohydrate. Solubility of L-Phenylalanine Anhydrate/Monohydrate. The solubility of L-phenylalanine anhydrate and monohydrate in pure water and NaCl, KCl, Na2SO4, and (NH4)2SO4 solutions at different temperatures is graphically plotted in Figure 3, 522

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Figure 2. PXRD patterns of L-phenylalanine anhydrate and monohydrate. Figure 4. Solubility of anhydrous L-phenylalanine and monohydrate in the presence of salts: ◆, pure water; ▲, potassium chloride; ■, sodium sulfate; ●, ammonium sulfate; −, sodium chloride. Solid symbols represent data for the monohydrate form, while open symbols represent data for the anhydrous form. Lines are fits of eq 3.

Table 1. Thermodynamic Properties (J/mol) for Dissolution of L-Phenylalanine Anhydrate/Monohydrate in the Presence of Salts Determined by Fitting the Solubility Data with Eq 3 anhydrate

Figure 3. Mole fraction solubility of L-phenylalanine anhydrate from 293.00 to 308.00 K and monohydrate from 312.00 to 328.00 K in pure water and aqueous solution in the presence of four salts: ◆, pure water; ▲ , potassium chloride; ■ , sodium sulfate; ● , ammonium sulfate; −, sodium chloride.

monohydrate

solution

ΔHd

ΔSd

R

pure water KCl solution Na2SO4 solution (NH4SO4)2 solution NaCl solution

8452 7939 10158 8570 7277

19.13 22.07 16.91 20.61 25.35

0.998 0.993 0.999 0.992 0.998

2

ΔHd

ΔSd

R2

13435 20466 20109 18856 22064

2.858 18.46 15.54 12.39 22.57

0.999 0.998 0.988 0.995 0.982

the thermodynamic stability or the transition point of L-phenylalanine anhydrate and monohydrate. In this study, the transition temperatures between the two forms of L-phenylalanine in the presence of (NH4)2SO4 is nearly 37 °C from Figure 4 by extrapolations of the experimental data. Furthermore, the transition temperatures between the two forms of L-phenylalanine in the presence of the salt species studied are all nearly 37 °C. Solubility data are of great technical interest for their essential position in chemical engineering and chemistry research. The solubility is a prerequisite to determine the throughput, yield, and driving force of crystallization operations. Electrolyte additives strongly affect the solubility of L-phenylalanine monohydrate and anhydrate. The crystallization temperature controls the crystal form of the final product, while quality control for L-phenylalanine requires the control of the crystal structure to provide the desired product performance. Therefore, knowing the effect of electrolyte additives on the solubility and transition temperature is necessary to properly design the crystallization process of L-phenylalanine. The results in this work could provide some insight into the process development and control of L-phenylalanine crystallization from aqueous solution in the presence of electrolyte additives. To verify the salt effect on the transformation rate, transformation experiments between L-phenylalanine anhydrate and monohydrate were performed. As described in the literature,13 the transformation is induced by the difference in solubility. When it is farther away from the transition temperature, the differences in solubility of two solvates are greater in a general way. In this work, transformation experiments were performed

which clearly shows the influence of temperature and salt species on L-phenylalanine solubility. Using the van’t Hoff equation11 as indicated in eq 3, mole fraction solubility data of L-phenylalanine anhydrate and monohydrate were correlated as shown in Figure 4. ΔHd ΔSd + (3) RT R Thus, the dissolution enthalpy and entropy of L-phenylalanine were calculated from the slopes and intercepts of the linear fits to the experimental data from a plot of ln xi versus 1/T. The enthalpy and entropy of dissolution and correlation coefficient are listed in Table 1. Table 1 demonstrates that the dissolution enthalpy of L-phenylalanine monohydrate was higher than that of the anhydrate, while the dissolution entropy of L-phenylalanine anhydrate was higher than that of the monohydrate. The enantiomorphic behavior of L-phenylalanine anhydrate and monohydrate is illustrated is Figure 4. The intersections of the experimental data and regression can be used to determine the transition temperature. The transition point in Figure 4 between these two crystal forms in pure water is about 37 °C, which is in agreement with that reported in the literature.3 The monohydrate is stable below the transition point, and the anhydrous form is stable above the transition point. Sato12 reported that the additives affect only the transition rate but not ln xi = −

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Figure 5. Some snapshots taken during transformation by microscope at (a) 0 h, (b) 2 h, (c) 5 h, (d) 7 h, and (e) 9 h.

at two temperature points on both sides of the transition point, at which the absolute values of the solubility difference of the two crystal forms are equal. The transformation experiments were performed at 10 and 50 °C, respectively. Transformation Experiments from Anhydrate to Monohydrate. The transition point of L-phenylalanine monohydrate and anhydrate is about 37 °C from the solubility analysis. Our trial on transition temperature indicated that the transformation rate below 10 °C, for example, 5 °C, was very fast. The transformation process cannot be controlled and monitored well. On the contrary, the transformation time was very long when the transformation temperature was above 10 °C, for example, 15 or 20 °C. Therefore, the experiment was fixed at 10 °C in this work. Since the transformation from anhydrate to monohydrate was carried out in pure water at 10 °C, which is below the transition point, monohydrate is regarded as the stable form, while anhydrate is regarded as the metastable one. The differences in crystal morphology could also be used to identify the specific solvates that coexist with an equilibrated liquid phase and thereby determine the more stable of the two forms. Phase transformation between the monohydrate and anhydrate is recognized microscopically. The evolvement of crystal morphology during transformation in pure water at 10 °C is observed in Figure 5. The morphology of anhydrate crystals is platelike (Figure 5a) at the beginning of the measurement, whereas that of monohydrate is needlelike (Figure 5e). From Figure 5, at 0 h, there are only platelike crystals suspended in solution. After 2 h, needlelike crystals at the surface of platelike crystals are observed (Figure 5b). It can be clearly seen that needlelike crystals without platelike crystals are suspended in solution as shown in Figure 5e. This result also implies the mechanism of solvent-mediated transformation of L-phenylalanine anhydrate/monohydrate. To obtain insight into the transformation process, PXRD was performed and data were collected to analyze the transformation kinetics. The PXRD patterns of the samples from pure water at different times are shown in Figure 6. At t = 0 h, main characteristic peaks at 2θ = 16.8°, 17.7°, and 22.6° of anhydrate

Figure 6. PXRD patterns of L-phenylalanine from anhydrate to monohydrate.

are observed. After 9 h, characteristic peaks at 2θ = 13.8°, 16.4°, and 20.7° of monohydrate are evident. The relative intensity of these two types of characteristic peaks changed as the transformation progressed. Furthermore, the progress of the transformation is also associated with mass changes. By measuring the rate of disappearance or appearance of a unique peak, the kinetics of the transformation between two crystal forms 524

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during the experimental determination. The evolvement of crystal morphology during transformation in NaCl aqueous solution at 10 °C is demonstrated in Figure 8. It can be observed from Figure 8 that there are only platelike crystals suspended in solution (Figure 8b) after transformation for 20 min, and after 40 min, needlelike crystals can be observed to be dominant (Figure 8c). After 60 min, there are nearly only needlelike crystals suspended in solution (Figure 8d).

Figure 7. Mass fractions of the two crystal forms versus time during transformation by quantitative PXRD analysis.

can be determined. The ratio of the two crystal forms was evaluated on the basis of eq 1. Using the strongest diffraction peaks for crystalline monohydrate and anhydrate, the mass fractions of monohydrate and anhydrate versus time of transformation were deduced and are plotted in Figure 7, which is in good agreement with microscopic observation. To investigate the salt effect on the crystal transformation kinetics, addition of NaCl (4/100 g of H2O), as a typical case, was chosen to investigate the salt effect on the transformation. As described above, phase transformation between L-phenylalanine anhydrate and monohydrate was characterized microscopically

Figure 9. PXRD patterns of L-phenylalanine from anhydrate to monohydrate in the presence of NaCl.

Figure 8. Some snapshots taken during transformation by microscope at (a) 0 min, (b) 20 min, (c) 40 min, (d) 60 min, and (e) 80 min in the presence of NaCl. 525

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Figure 10. Mass fractions of the two crystal forms versus time during transformation by quantitative PXRD analysis in the presence of NaCl.

Meanwhile, the PXRD patterns of the samples in this run are illustrated in Figure 9. After 20 min, characteristic peaks at 2θ = 16.8°, 17.7°, and 22.6° of anhydrate are clearly observed. After 60 min, characteristic peaks at 2θ = 13.8°, 16.4°, and 20.7° of monohydrate obviously occur. The mass fractions of monohydrate and anhydrate versus transformation time are displayed in Figure 10. Compared with the no salt case, the addition of NaCl obviously increased the rate of transformation of L-phenylalanine from anhydrate to monohydrate. Transformation Experiments from Monohydrate to Anhydrate. To clarify whether salts have the same effect on transformation from monohydrate to anhydrate as transformation from anhydrate to monohydrate, the transformation experiments were performed in pure water and in the presence

Figure 12. PXRD patterns of L-phenylalanine from monohydrate to anhydrate.

of NaCl at 50 °C. At this temperature, anhydrate is the stable form, while monohydrate is the metastable form. The evolvement of crystal morphology during transformation in pure water

Figure 11. Some snapshots taken during transformation by microscope at (a) 0 h, (b) 5 h, (c) 7.5 h, (d) 10 h, (e) 10.5 h, and (f) 11 h. 526

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and anhydrate versus time of transformation were deduced and are plotted in Figure 13. The transformation with addition of NaCl (4 g/100 g of H2O) was also performed to investigate the salt effect. The evolvement of crystal morphology during transformation in NaCl aqueous solution at 50 °C is demonstrated in Figure 14. There are only needlelike crystals suspended in solution (Figure 14a) at the beginning of the experiments, and after 70 min, platelike crystals can be observed to be dominant (Figure 14b). After 110 min, there are nearly only platelike crystals suspended in solution (Figure 14d). The PXRD patterns at different times are shown in Figure 15. After 70 min, characteristic peaks at 2θ = 13.8°, 16.4°, and 20.7° of monohydrate are clearly observed. After 110 min, characteristic peaks at 2θ = 16.8°, 17.7°, and 22.6° of anhydrate obviously occur. The mass fractions of monohydrate and anhydrate versus transformation time are displayed in Figure 16. The addition of NaCl obviously increased the transformation rate from monohydrate to anhydrate, which is similar to the case at 10 °C. Calculation of the Chemical Potential Difference and Modeling for Transformation. Kitamura14 reported that the transformation behavior for different crystal forms, including solvates, was explained by the chemical potential difference between the stable and metastable forms and the preferable nucleation and growth of the other metastable forms due to the specific solute−solvent interaction. Transformation occurs by the “solution-mediated” mechanism, and the metastable form dissolves and the stable form nucleates and grows in the transformation process. Then the driving force of the transformation from the metastable to the stable form is expressed by the difference in the chemical potential, Δμ(s), between each form:14

Figure 13. Mass fractions of the two crystal forms versus time during transformation by quantitative PXRD analysis.

at 50 °C is observed in Figure 11. At the beginning of the experiments, the morphology of monohydrate crystals is typically needlelike (Figure 11a), while that of the anhydrate is platelike (Figure 11e). From Figure 11, at 0 h, only needlelike crystals exist in solution. After 5 h, platelike crystals are observed (Figure 11b). Platelike crystals without the needlelike form are clearly seen in solution as shown in Figure 11e at 11 h. A dramatic transformation is observed, which is very different from the case at 10 °C. The PXRD patterns of the samples from pure water are shown in Figure 12. At t = 0 h, only characteristic peaks at 2θ = 13.8°, 16.4°, and 20.7° of monohydrate are observed. After 10.5 h, characteristic peaks at 2θ = 16.8°, 17.7°, and 22.6° of anhydrate are evident. The mass fractions of monohydrate

Δμ(s) = RT ln

X ms Xs

(4)

Figure 14. Some snapshots taken during transformation by microscope at (a) 0 min, (b) 70 min, (c) 100 min, (d)110 min, and (e) 150 min in the presence of NaCl. 527

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Figure 16. Mass fractions of the two crystal forms versus time during transformation by quantitative PXRD analysis in the presence of NaCl.

Table 2. Avrami−Erofeev Model Parameters for L-Phenylalanine Transformation anhydrate to monohydrate solution pure water NaCl solution

Figure 15. PXRD patterns of L-phenylalanine from monohydrate to anhydrate in the presence of NaCl.

where Xms and Xs are the solubilities of the metastable and stable forms (mole fraction), respectively. For L-phenylalanine, Δμ(s) for the transformation from anhydrate to monohydrate in pure water and in the presence of NaCl (4 g/100 g of H2O) is estimated by eq 4 at 10 °C to be 366 and 1500 J/mol, respectively. According to eq 4, with relatively large chemical potential differences, nucleation of the stable form tends to occur in a short time. Therefore, the transformation rate in theory from anhydrate to monohydrate in the presence of NaCl is greater than that in pure water, which is in agreement in PXRD analysis. Furthermore, Δμ(s) for the transformation from monohydrate to anhydrate in pure water and in the presence of NaCl is 173 and 399 J/mol, respectively. Therefore, this result also indicates that addition of NaCl is more profitable for the transformation from monohydrate to anhydrate and a greater transformation rate. The change of the calculated transformation degree with time was fitted by the Avrami−Erofeev model. The model parameter values are illustrated in Table 2. They can be used to predict the crystal transformation rate of L-phenylalanine solvates. The transformation between solvates is particularly interesting for drug molecules. The quality control for solvates requires the control of the crystal structure to provide the desired product performance. According to the recent report by Kee,5 a process model for the crystallization of L-phenylalanine from propanol aqueous solution was developed. The kinetic parameters for nucleation and growth for both the anhydrate and monohydrate forms were estimated. In our work, although a limited set, the salting effects on the solubility and transformation kinetics of L-phenylalanine anhydrate/monohydrate in aqueous solutions were demonstrated. Our experimental design for the transformation kinetics of L-phenylalanine anhydrate and monohydrate, combined with process modeling analysis for nucleation and growth of L-phenylalanine anhydrate and monohydrate from the literature,5 may facilitate process control and development

monohydrate to anhydrate

k

n

R2

k

n

R2

0.1444 1.2562

0.2908 0.4179

0.989 0.998

0.1177 0.6602

0.2961 0.1346

0.975 0.990

for L-phenylalanine production in industry and provide important instruction for other pharmaceutical compounds involving transformation between different solvates.

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CONCLUSIONS The measurement of the solubility of L-phenylalanine anhydrate and monohydrate in pure water and NaCl, KCl, Na2SO4, and (NH4)2SO aqueous solutions has allowed us to estimate the enthalpies and entropies of dissolution in aqueous solution and has led to the prediction of transition temperatures between L-phenylalanine anhydrate and monohydrate. The solvated behavior and transformation kinetics were also determined by transformation experiments of L-phenylalanine between anhydrate and monohydrate. The addition of NaCl markedly increased the transformation rate whether from anhydrate to monohydrate or monohydrate to anhydrate, which is in good agreement with the result of chemical potential calculation. This work can provide some important insight into the process design and industrial control of L-phenylalanine crystallization. The content of electrolyte additives and the effects of additives on the nucleation and growth mechanism of L-phenylalanine solvates will be investigated in later work.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel.: 86 (0)22 27400291. Notes

The authors declare no competing financial interest.

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REFERENCES

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(3) Rajeev, M.; Kee-Kahb, K.; Christine, S.; Allan, S. M. Effect of additives on the transformation behavior of L-phenylalanine in aqueous solution. Ind. Eng. Chem. Res. 2001, 40, 6111. (4) Lu, J.; Lin, Q.; Li, Z.; Rohani, S. Solubility of L-phenylalanine anhydrous and monohydrate forms: experimental measurements and predictions. J. Chem. Eng. Data 2012, 57, 1492. (5) Kee, N. C. S.; Arendt, P. D.; Goh, L. M.; Tan, R. B. H.; Braatz, R. D. Nucleation and growth kinetics estimation for L-phenylalanine hydrate and anhydrate crystallization. CrystEngComm 2011, 13, 1197. (6) Roberts, K. L.; Rousseau, R. W.; Teja, A. S. Solubility of longchain n-alkanes in heptane between 280 and 350 K. J. Chem. Eng. Data 1994, 39, 793. (7) Nie, Q.; Wang, J. K.; Wang, Y. L.; Wang, S. Solubility of 11αhydroxy-16α,17α-epoxyprogesterone in different solvents between 283 and 323 K. J. Chem. Eng. Data 2005, 50, 989. (8) Wang, Z. Z.; Wang, J. K.; Zhang, M. J.; Dang, L. P. Solubility of erythromycin A dihydrate in different pure solvents and acetone + water binary mixtures between 293 and 323 K. J. Chem. Eng. Data 2006, 51, 1062. (9) Zhu, H. J.; Xu, J.; Varlashkin, P.; Long, S.; Kidd, C. Dehydration, hydration behavior, and structural analysis of fenoprofen calcium. J. Pharm. Sci. 2001, 90, 845. (10) Bechtloff, B.; Nordhoff, S.; Ulrich, J. Pseudopolymorphs in industrial use. Cryst. Res. Technol. 2001, 12, 1315. (11) Waid, O.; Joachim, U. Solid liquid equilibrium, metastable zone and nucleation parameters of the oxalic acid−water system. Cryst. Growth Des. 2006, 6, 1927. (12) Sato, T.; Sano, C. European Patent 0703214A2, 1995. (13) Maruyama, S.; Oshima, H.; Kato, J. Crystal structures and solvent-mediated transformation of taltireline polymorphs. Chem. Eng. J. 1999, 75, 193. (14) Kitamura, M. Controlling factors and mechanism of polymorphic crystallization. Cryst. Growth Des. 2004, 4, 1153.

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