ARTICLE pubs.acs.org/IECR
L-Glutamic
Acid Polymorph Control Using Amino Acid Additives
Yuxin Mo, Leping Dang, and Hongyuan Wei* School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, People’s Republic of China ABSTRACT: Additive is an effective factor in controlling crystallization of polymorph. L-Tryptophan, L-leucine, L-threonine, and L-valine, as additives during L-glutamic acid crystallization, were investigated for probing their effects on the polymorphic transformation. L-Tryptophan was then chosen as a representative case to evaluate the effect of addition concentration on the morphology, nucleation, and polymorphic transformation rate of L-glutamic acid. It is shown that all these additives have a certain influence on the polymorphic transformation and the presence of a bulky side chain (phenyl) in L-tryptophan and L-histidine is identified as an essential feature in achieving stabilization of the R-polymorph. When the concentration of Ltryptophan reaches above 0.008 M, the elongation of crystals occur. Increasing L-tryptophan concentration, the transformation time and nucleation rate of L-glutamic acid are retarded. The inclusion behavior of additive molecules in L-Glu crystals was investigated, and the results show that the effect of additive molecule on the polymorphic transformation may be through incorporating into crystal structures by adsorption.
L-histidine, L-alanine,
1. INTRODUCTION L-Glutamic acid (L-Glu) is one of the naturally occurring L-amino acids, which form important building blocks for protein assembly as well as are used as food additives for taste in the food industry, particularly in the form of the monosodium salt. It is produced using Corynebacterium or Brevibacterium strains by means of aerobic processes requiring the ultimate electron acceptor oxygen, throughout the fermentations.13 Generally, L-Glu was produced at 30 °C, and the pH value was about 7 during the fermentation process. Regardless of the production methods for L-Glu, the presence of impurities is inevitable and must be removed by different separation and purification techniques. Usually, microbial cells and other insoluble impurities are first removed by centrifugal separation or filtration. The remaining impurities such as soluble proteins and other amino acids are usually eliminated using ultrafiltration and the ion-exchange process, and the typical concentration of some amino acid impurities is about 0.00010.001 mol 3 L1 in different fermentation conditions.4 Crystallization including evaporation, cooling, or precipitation, which is an efficient purification technique, is then performed to obtain the L-Glu crystals with high purity.5 The two L-Glu polymorphs were crystallized from aqueous solutions with different characteristic crystal habits, which are the metastable, more soluble, prismatic R-form and the stable, less soluble, needle like β-form. The crystal habits of both forms are present in Figure 1. For the production of monosodium glutamate, the R-form is preferred as it is more robust and has much better separability from the mother liquor, while the β-form tends to break during downstream handling and therefore processes less well. However, the solution-mediated transformation of R-form to β-form can occur spontaneously, the polymorphic transformation rate proceeds rapidly at temperatures higher than 40 °C.6 Thus, the control of the polymorphs to ensure that material with the required polymorphic specification is a significantly important issue in industry. Selective crystallization of polymorphs requires design of the nucleation and growth processes and may be achieved using additives. Additive molecules with similar structure or r 2011 American Chemical Society
conformation to that of the bulk crystal can selectively inhibit the crystallization of the stable polymorph by molecular mimicry.7 LAmino acid is an effective additive because of the similar molecule conformation with L-Glu; all of them have an amino group and a carboxyl group, and the intermolecular relationships between the additives and polymorphs should be more stronger. Sano et al.8 elucidated the mechanism of polymorph-selective crystallization of L-Glu by the additives. The effects of various L-amino acids, carboxylic acids, and a dipeptide on the three dominant faces of the β-form of L-Glu have been investigated. Kitamura9 examined the kinetic effect of L-phenylalanine on the growth process of LGlu polymorphs. Most of that research focused on the influence of additives on the entire polymorphic transformation process, but for each step in the transformation process, it was not well addressed. In the present study, the polymorphic transformation of L-Glu in the presence of L-amino acid and the interaction mechanism of the additives were investigated. A series of L-amino acid including L-tryptophan (L-Trp), L-leucine (L-Leu), L-threonine (L-Thr), L-histidine (L-His), L-alanine (L-Ala), and L-valine (L-Val) was chosen in turn as additives (Table 1) to investigate the influences on the morphological change, the nucleation induction time, and the polymorphic transformation rate of L-Glu. At last, the inclusion behavior of additive molecules in L-Glu crystals was discussed.
2. EXPERIMENTAL PROCEDURES 2.1. Materials. L-Glu (99% in mass fraction) was purchased from Tianjin Yi fang Technology Co. Ltd. (China). L-Trp, L-Leu, L-Thr, L-His, L-Ala, and L-Val for the experiments were obtained from Sigma-Aldrich, and their mass fraction purities are more Received: October 24, 2010 Accepted: August 8, 2011 Revised: August 8, 2011 Published: August 09, 2011 10385
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Figure 1. Crystal habit of R- and β-form.
Table 1. Molecular Structure of the Additives
than 99%. The distilled deionized water was used in all the experiments. 2.2. Solubility Analysis of L-Glu in the Presence of Additives. The solubility was measured by a gravimetric method.11 First, an excess amount of R- or β-form L-Glu was suspended in a certain amount of solution containing a known concentration of an additive at a certain temperature under stirring. The temperature was kept constant for enough time to establish equilibrium. Then, approximately 3 mL of clear solution was filtered from the slurry using a membrane filter (pore size = 0.2 μm). The solubility was determined from the weight before and after the evaporation of the water from the sample. When determining of R-form solubility, the solid phase was sampled and analyzed by PXRD to ensure that no polymorphic transformation occurred. The R- or β-form L-Glu used for solubility determination was recrystallized from aqueous solution, and the purity was analyzed by FT-IR and PXRD. 2.3. Recrystallization of L-Glu with Additives. Recrystallization of L-Glu was performed in the presence of L-Trp, L-Leu, L-Thr, L-His, L-Ala, and L-Val with the concentration being 0.004 M. The selected amino acids were added to solutions of L-Glu at 80 °C and brought to supersaturation by cooling to 45 °C. The supersaturation ratio, defined as S = C/C*, (C is the solute concentration/g 3 100 gH2O1; C* is the equilibrium concentration/g 3 100 gH2O1) was 2.6. Samples were used to
analyzed the content of R-form in the mixtures using FT-IR every 2.5 h. 2.4. Quantitative Analysis of L-Glu Polymorph using FT-IR. Methods for the measurement of the polymorphic content have been proposed in a lot of literature.1215 In this work, the content of R-form in the mixtures was obtained by ex situ calibration using prepared polymorph mixtures. FT-IR spectra were recorded from 4000 to 400 cm1, using the Bruker TENSOR 27 FT-IR spectrophotometer with a DTGS detector. Samples were scanned as KBr disks; the spectral resolution is 4 cm1. OPD velocity is 0.3 cm 3 s1; operation in auto mode and the number of scans per spectrum was 16. 2.5. Polarizing Microscope. The crystals were observed with a polarizing microscope (Olympus BX51) with an attached CCD video camera, and images were taken to analyze effect of additives on crystal morphology. 2.6. Analysis of the Residue of Additives in L-Glu Crystals. HPLC was used to quantify analysis of the residue of additives in L-Glu crystals. Standards were prepared for the additives in the concentration range of 10300 ppm. The solvent used was deionized water, and solutions were filtered using a 0.2 μm membrane filter. The stationary phase was C18 column, with dimensions of 250 4.6 mm. The mobile phases were as follows: 50 mmol/L KH2PO4, 94%; acetonitrile (HPLC grade), 6% (adjust pH value of mobile phases to 2.4 using phosphoric acid); the 10386
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Figure 2. Apparatus for induction time and polymorphic transformation time measurement: 1, thermometer; 2, equilibrium vessel; 3, laser receiver;4, recording display; 5, magnetic stirrer; 6, laser generator; 7, thermostatic bath. Figure 4. Effect of pH value on solubility of L-glutamic acid.
3. RESULTS AND DISCUSSION 3.1. Solubility Analysis of L-Glu in the Presenceof L-Amino Acid. First, the solubilities of both forms in pure water were
Figure 3. Solubility of R- and β-form L-Glu (the solubility was measured in this study by a gravimetric method, and the mass fraction purity of both forms for solubility measurement are more than 99%).
injection volume was 20 mL, and UV detection at 220 nm was employed. All calibration graphs yielded R2 values of >0.99. 2.7. Induction Time and Polymorphic Transformation Time Measurement. The experiments were performed in a 50 mL crystallizer, and the laser monitoring technique was used to measure the induction time of R-form.16,17 The apparatus is shown in Figure 2. Initially, the crystallizer was filled with saturated solution containing a known concentration of the additive and heated 5 °C above the saturation temperature under agitation for at least 20 min. The solution was then quickly cooled toward the experiment temperature, 50 °C. The supersaturation (S = C/C*) of the solution was 2.2. The induction time of R-form was then measured by the change of the laser intensity. When the solid phase appeared, the intensity of the laser beam penetrating the vessel dramatically decreased. Then, a portion of the suspension was withdrawn and filtered at designated times, and the polymorphic composition of the solid phase was determined by FT-IR. The induction time of β-form and the polymorphic transformation time were determined on the basis of the polymorphic composition in the solid phase, when β-form was detected in the solid phase meant that the induction time of β-form had finished and when there was no R-form present meant that the polymorphic transformation had finished.
measured; the results are present in Figure 3. It can be seen that the solubility increases with an increase in temperature and that R-form has a higher solubility than β-form, which is consistent with the fact that β-form is the thermodynamically stable form and R-form is the metastable form. The data in this work are consistent with the literature data. The effect of pH value on the solubilities of L-Glu were also determined. Figure 4 presents the solubility of β-form L-Glu in pure water with different pHs at 25 and 35 °C; the results show that pH value has no effect on the solubility in the range of 2 to 12. All of the following experiments were operated in this pH range, so the effect of pH can be ignored. The solubilities of R- and β-form L-Glu in water containing additives at 45 and 50 °C were measured; the concentration range of the additives was from 0.0025 to 0.03 M. Figure 5 presents the solubility of R- and β-form L-Glu in the presence of L-Trp and L-His. Relative error (RE) was defined as eq 1 and was used to describe the change in the solubility after adding additives. The measurement results are present in Table 2. C C 100 % ð1Þ RE % ¼ C where C* is the solubility of L-glutamic acid in the absence of additives and C is the solubility of L-glutamic acid in the presence of additives. From the results, it can be seen that the influence of these additives on solubility of both forms was not obvious, so the change of solubility can be ignored in the following research. The calculation of supersaturation still is according to the solubility of 18 L-glutamic acid in pure water. Jin and Chao found the solubility of L-Glu will double when the concentration of L-serine and glycine reached 1.46 and 1.68 M, but it has no obvious effect within such a lower range, as studied in this paper. 3.2. Effect of Different L-Amino Acid on Polymorphic Transformation. Many references have been reported on the application of additives to stabilize metastable crystal forms.19,20 Currently, it is believed that additives operate by adsorption onto crystal facets, which consequently changes the surface free energy and may block sites which are necessary for incorporation 10387
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Figure 5. Effect of L-Trp and L-His on the solubility of R- and β-form L-Glu in water.
Table 2. RE Value of L-Trp and L-His Additive β-form
R-form
concentration of additive/mol 3 L1
45 °C
0.0021 0.0041
6.6% 4.9%
6.6% 4.9%
0.0071
5.1%
0.0100
4.5%
0.0129
concentration of additive/mol 3 L1
50 °C
45 °C
50 °C
0.0020 0.0100
3.9% 2.5%
0.1% 0.3%
5.1%
0.0020
2.4%
1.1%
4.5%
0.0036
4.7%
0.5%
5.9%
5.9%
0.0065
5.2%
1.1%
0.0160
2.8%
2.7%
0.0080
4.3%
1.0%
0.0201
4.8%
4.8%
0.0020 0.0071
1.4% 1.0%
0.0020 0.0070
3.7% 4.2%
0.6% 0.2%
0.0130
0.2%
8.3%
0.0131
3.7%
1.3%
0.0163
1.6%
4.9%
0.0161
5.0%
1.8%
0.0201
1.1%
7.7%
0.0202
4.4%
0.7%
0.0241
2.1%
3.4%
0.0240
4.3%
1.1%
0.0282
2.7%
4.7%
0.0281
4.7%
1.8%
RE Value of L-Trp Additive
RE Value of L-His Additive 2.7% 8.8%
of solute into the crystal lattice. This may ultimately result in kinetic and morphological changes. Figure 6 presents a general overview of the effect of all the L-amino acids used in this study for the stabilization of the R-form of L-Glu. The mass fraction of R-form in the crystals, which are sampled at 2.5 h and 25 h, are shown in the figure. The result demonstrates that L-Trp and L-His can suppress notably the polymorphic transformation. Almost 100% R-form is observed when L-Trp is added. The effect of L-Leu, L-Thr, L-Ala, and L-Val is much less than L-Trp and L-His; the polymorphic transformations have been finished in 25 h. The rank order of the inhibitory effect is L-Trp > L-His . L-Thr > L-Val > L-Leu > L-Ala. The molecular structures of the additives were shown in Table 1. L-Trp, which differs in structure from L-His by a phenyl group, is found to be extremely effective, at low concentrations for the selective crystallization of R-form L-Glu. Both L-Trp and L-His stabilize R-form L-Glu at lower concentrations more effectly than the other additives due to the bulky side chain in their molecular structure, which is in agreement with the result proposed by Kitamura and Funahara.21
Figure 6. Mass fraction of R-form in the crystals when sampled at 2.5 and 25 h. L-Glu molecule is connected to each other with hydrogen bonds in the crystals. These hydrogen bonds are participated
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Figure 7. Effect of L-Trp concentration on the nucleation of R- and β-form L-Glu.
Figure 8. Nucleation of β-form on the surface of R-form.
with the two carboxyl and one amino groups. All of the additives have one carboxyl and one amino group, which can also form hydrogen bonds with L-Glu molecule. The major difference is the structure of the side chain. The side chain of L-Glu containing a carboxyl group can form hydrogen bonds, while the other L-amino acid additive can not, so the side chain of additives act as a repellent to influence the normal growth of L-Glu molecule. However, the bulkier side chain may occupy more space on the growth surface to hinder the next solute molecule to be adsorbed. The other additives behave similarly on the inhibition of polymorphic transformation. L-Ala is the poorest additive; it has hardly an effect on the polymorphic transformation of R-form to β-form of L-Glu at a concentration of 0.004 M. 3.3. Effect of Additive Concentration on Nucleation and Grow of Polymorph. The crystallization and solvent-mediated transformation of L-Glu consists of the following steps: nucleation and growth of metastable R-form, dissolution of R-form, nucleation of the stable β-form, and crystal growth of β-form.22 Additives may affect any or all of these steps. The classic model of Cabrera and Vermilyea23 proposes that some additives may adsorb onto terraces or steps of growing crystals and become almost immobile. Additives which have adsorbed onto a terrace cannot be passed by a straight growing step because additives act as local pinning points. Therefore, these additives serve as a “fence” to growing steps. Consequently, growing steps must bend in order to squeeze through the additive “fence”, and the
velocity of the steps is reduced compared with that of straight steps growing in the absence of additives. In order to confirm the effect of additives, the nucleation of R- and β-form and polymorphic transformation time of L-Glu were determined under different addition levels of L-Trp at 50 °C. The induction time is the time period between the attainment of the initial supersaturation and the detection of the onset of particle formation. The effect of additives on the nucleation of R- and β-form is determined on the basis of induction time, and the concentration of additive is expressed as mole ratio of L-Trp/ L-Glu. The results are presented in Figure 7. It can be seen that the induction time of both forms increase sharply with an increase in L-Trp concentration. The increasing trend for both forms is also different. For R-form, when the L-Trp concentration is below 0.004 M, the effect of additives on induction time is not obvious, while for β-form, there is almost a linear increase for the induction time. Compared with R-form, the induction time of β-form is longer. Moreover, the effect of L-Trp on the induction time of β-form is also greater. The cross-nucleation of β-form on the surface of R-form is reported.2426 In order to investigate whether the additive has an impact on the nucleation mechanism of β-form sampling, the slurry was performed after β-form nucleate. The micrograph of the crystals was shown in Figure 8. β needles forming on the surface of R crystals could clearly be observed, which means that additives have no effect on the nucleation mechanism of β-form. The polymorphic transformation time as a function of the addition concentration of L-Trp is presented in Figure 9. It can be seen that the transformation time increases with an increase in LTrp concentration. When the additive concentration reaches 0.02 M, the polymorphic transformation will reach about 200 h, which is more than 100 times as compared with that in the absence of additives. Comparing the induction time and the polymorphic transformation time of β-form at the same additive concentration, it can be deduced that the growth of β-form can also be inhibited by L-Trp. 3.4. Effect of Additive Concentration on the Morphology. Additives used to control polymorphism can also induce morphological changes which cannot be avoided.27 During the crystal growth process, additives can adsorb onto the crystal surfaces, change the relative surface free energies of the faces, and block the active growth sites. Some additives may suppress growth 10389
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Figure 9. Effect of L-Trp concentration on polymorphic transformation time of L-Glu.
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Figure 11. Relationship between R value on the washing time.
Figure 12. Mole ratio (additive to L-Glu) in harvested R- and β-form crystals.
Figure 10. Effect of L-Trp concentration on morphology of R-form L-Glu (a) no additive, (b) =0.002 M, (c) =0.008 M, and (d) =0.02 M.
entirely; the others may produce a selective effect to act to varying degrees on each crystallographic surface and consequently modify the crystal habit.28 L-Trp was chosen as the additive to investigate the effect on the morphology of L-Glu. The morphology of R-form crystals obtained under different addition levels of L-Trp is shown in Figure 10. The crystallization condition is similar to that mentioned in section 3.2. All of the crystals are sampled after the same crystallization time. It can be seen that crystals are block prism under no additives. The morphological variations are not obvious when L-Trp concentration is low. However, when additive concentration reaches above 0.008 M, elongation of crystals will occur. The crystals became column-like. A similar phenomenon is also observed when L-His is used as additive. 3.5. Incorporation of Additive in L-Glu Crystals. Generally, it is believed that the incorporation of additive molecules in crystals was the primary factor for controlling the polymorph. Additive incorporation may be classified as primary (formed during growth) or secondary (formed later). Primary incorporation constitutes samples of fluid in which the crystals grew. Secondary
incorporation gives evidence of later environments and are often formed as a result of crystals cracking due to internal stresses created during growth, incorporating mother liquor by capillary attraction, and resealing later.28 As for the cause of additive incorporation in crystals, mainly three cases can be considered, (1) incorporation in crystal structure by adsorption, (2) inclusion with mother liquor as an adhesive on the crystal surface due to insufficient solidliquid separation, and (3) inclusion with liquid droplet in an irregular growth process, e.g., step bunching. In order to examine the inclusion behavior of additive molecules in L-Glu crystals, the following tests were performed. In these tests, the residual additives in the crystals were analyzed using HPLC after washing the crystals with distilled deionized water for a certain time. The amount of additives in L-Glu crystal is expressed with the molar ratio, R, in the following equation: R ¼
additive ðmolÞ L-Glu ðmolÞ
Figure 11 presented the results of the tests in the case when concentration is 0.006 M. The R value seems initially to decrease slightly and attain a constant value. From this result, it is considered that the effect of additive molecule on the polymorphic transformation may be included in crystal structures by adsorption. L-Trp
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Industrial & Engineering Chemistry Research The resident additives in L-Glu crystals are shown in Figure 12. It is clarified that the amount of additives in crystals increases with additive concentration in solutions for both forms. When the concentration of L-Trp is above 0.006 M, the increase of the R value is not obvious. It may indicate that the maximum number of sites on the crystal surface is occupied at high L-Trp concentrations. Furthermore, it is observed that the R value of β-form is larger than R-form, which may suppose that the L-Trp molecules may pack more tightly on the surfaces of the β-form crystals than the R-form crystals. Thus, recrystallization is an effective process to remove these impurities from the crystals.
4. CONCLUSION The objective of the current work was to demonstrate the polymorphic transformation process of L-glutamic acid in the presence of additives. First, the influence of a range of L-amino acid additives on the solubility of L-glutamic acid has been investigated. The results showed that there was no obvious change in the solubility of both forms after adding L-amino acid, so additives on the polymorphic transformation of L-glutamic acid and the change of solubility could be ignored. The calculation of supersaturation is based on the solubility of L-glutamic acid in pure solvent. The structure of additive molecules can be main factors for impeding the polymorphic transformation through the sterical hindrances by its bulky phenyl side chain. The rank order of the inhibitory effect is L-Trp > L-His . L-Thr > L-Val > L-Leu > L-Ala. L-Trp, as a typical case, was used to study the effect of addition concentration on nucleation and growth of R- and β-form in the polymorphic transformation process. The result showed that polymorphic transformations, including nucleation and growth, are retarded by additives. The morphology of the crystals also varied with additive concentrations. When the quantity of additives was above 0.008 M, elongation of crystals occurred. In addition, the residual additives in L-glutamic acid crystals were determined to discuss the interaction mechanism. It indicated that the additives can affect the polymorphic transformation through incorporation into the crystal lattice of L-glutamic acid. The results of this work could provide essential data and potential methods for selective crystallization of polymorphs in industry. ’ AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected].
’ ACKNOWLEDGMENT We thank National Nature and Science Foundation of China (NSFC, No. 20776098), Tianjin Municipal Natural Science Foundation (11JCYBJC 04600), and the Seed Foundation of Tianjin University for their financial assistance in this project. We are grateful to Dr. Simon Black (AstraZeneca UK) for the valuable technical discussions. ’ REFERENCES (1) Kinoshita, S. Glutamic acid bacteria. In Biology of industrial microorganism; Demain, A.L., Slomon, N.A., Eds.; Benjamin/Cummings: Menlo Park, CA, 1985. (2) Takac, S.; Calık, G.; Mavituna, F.; Dervakos, G. Metabolic flux distribution for the optimized production of L-glutamate. Enzyme Microbiol. Technol. 1998, 23, 286.
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