Development of Amino Acid Crystallization Processes: l-Glutamic Acid

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Ind. Eng. Chem. Res. 2007, 46, 2814-2822

Development of Amino Acid Crystallization Processes:

L-Glutamic

Acid

Benny Harjo† and Ka Ming Ng* Department of Chemical Engineering, The Hong Kong UniVersity of Science and Technology, Clear Water Bay, Hong Kong

Christianto Wibowo ClearWaterBay Technology, Inc., 20311 Valley BouleVard, Suite C, Walnut, California 91789

Amino acids are widely used in food, chemical, agricultural, cosmetic, and pharmaceutical products. Crystallization is one of the key steps in their manufacturing processes. However, for a complex multicomponent system with solvates and compounds, it is not clear how to recover a specific amino acid or its salt. To address this issue, this article proposes a general framework for the conceptual design of amino acid crystallization processes. It is based on the representation and experimental determination of solid-liquid equilibrium (SLE) phase diagrams. Glutamic acid and its sodium salt, monosodium glutamate, are chosen as a model system to illustrate this framework. SLE experiments were performed to estimate the location of the boundaries between different crystallization compartments in each of which a single component can be recovered. Introduction Recent advances in biotechnology have intensified the need for the development of efficient separation and purification processes for biochemicals and natural products. Amino acids, which have numerous applications in the chemical, agricultural, food, cosmetic, and pharmaceutical industries, are among those of increasing research interest. They are used directly as an end product or serve as a key intermediate. For example, the wellknown flavor enhancer monosodium glutamate is the sodium salt of glutamic acid. Amino acids are generally produced by the fermentation process, protein hydrolysis, or chemical synthesis, although the major method in recent years has been the fermentation process.1 Regardless of the production methods, the presence of impurities is inevitable and must be removed by different separation and purification techniques. Crystallization is usually involved in the purification step to obtain amino acid crystals with high purity. A typical process for separation and purification of amino acids from the fermentation process has been discussed.2 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. Crystallization, usually by concentration, cooling, or neutralization, is then performed to obtain the amino acid crystals. The crystals may be further purified as required through recrystallization. In some cases, crystallization of the desired amino acid is performed after the fermentation step through neutralization, often done by adding acid to the broth.3 Process design of crystallization of amino acids customarily relies on the traditional solubility representation - the solubility of a solute in a solvent is expressed as a function of temperature. This approach is sufficient for simple binary or ternary systems. However, for complex multicomponent systems forming various * To whom correspondence should be addressed. Tel.: 852 2358 7238. Fax: 852 2358 0054. E-mail address: [email protected]. † Current address: Mitsubishi Chemical Group Science and Technology Research Center, Inc., 1-1 Shiroishi, Kurosaki, Yahatanishi-ku, Kitakyushu 806-0004, Japan.

hydrates or solvates, it is not clear how to recover a specific amino acid or its salt by crystallization. Two basic components are necessary to address this issue. First, we need a more complete and appropriate representation of solubility of amino acids, which are ampholytes, a special type of electrolytes that can donate or accept protons depending on the environment. This is possible by extending the work of Samant and Ng4 and Wibowo and Ng5 on the SLE phase diagrams of systems involving molecular and ionic species. Second, we need a framework for crystallization process synthesis. Fortunately, a general procedure for synthesizing crystallization-based separation processes based on visualization of a solid-liquid equilibrium (SLE) phase diagram has already been developed.6 This project combines these previous developments for amino acid systems. The objective is to develop a general framework for the representation of SLE phase diagrams of ampholytes and its application in crystallization process synthesis. To illustrate such a framework, glutamic acid and its sodium salt serve as a model system. Since SLE data for the glutamic acid system in the literature is incomplete, SLE experiments were performed to provide the phase behavior necessary for process synthesis. Representation of Phase Diagrams of Ampholytes Since electrolytes are reactive systems, ionic coordinates instead of mole fraction coordinates are used for plotting the phase diagram. We will briefly go over the procedure to come up with a suitable ionic coordinate system to represent the phase behavior, discuss the property of ampholytes, and explain some concepts based on such representation. Ionic Coordinate. Let us consider a mixture comprising ionic species (consisting of a simple cations, b simple anions, m complex cations, and n complex anions) and molecular species (consisting of s strong electrolytes, w weak electrolytes, and i nonelectrolytes). Simple cations and anions refer to ions that cannot undergo any further dissociation. From Gibbs phase rule, at fixed temperature and pressure, the degree of freedom is f ) C - P - R, where C is the number of components, P is the number of phases present, and R is the number of relationships

10.1021/ie061148f CCC: $37.00 © 2007 American Chemical Society Published on Web 03/27/2007

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(independent reactions and an electroneutrality relationship). The total number of components in the system is given by C ) a + b + m + n + w + i. Note that strong electrolytes are not counted because they will completely dissociate into simple ions. There are m stabilization reactions for complex cations, n stabilization reactions for complex anions, w dissociation reactions for weak electrolytes, and an electroneutrality relationship. The total number of relationships in the system is thus given by R ) m + n + w + 1. Since there must be at least one phase present in the system, the number of independent coordinates is given by

C-R-1)a+b+i-2

(1)

Consequently, when no nonelectrolyte is present (i ) 0), the number of independent coordinates depends on only the number of simple cations and anions present in the system. One of the distinguishing features of ampholytes as compared to ordinary electrolyte systems is that they can donate or accept protons according to the environment. Amino acids (denoted as HA) undergo the following dissociation reactions in an aqueous solution:

HA S HA

(

KD

(2)

H2A + S HA( + H+ K1

(3)

HA( S A- + H+ K2

(4)

The value of KD is in general very large, which indicates that the amount of HA is negligible because they are practically always in the zwitterionic form (HA() in aqueous solutions at neutral pH. In the presence of an acid, reaction 3 occurs from right to left, while in the presence of a base, reaction 4 occurs from left to right. However, since the ionic coordinate is reaction-invariant, it is assumed that all species (including the ampholytes) dissociate into simple ions. Therefore, the same ionic coordinates used for other electrolyte systems can be used for the representation of ampholytic systems. The general expressions for the ionic coordinates are discussed elsewhere.5 One convenient choice of cationic and anionic coordinates are given by

R(Mi) )

zMi[Mi]

; i ) 1, 2, ..., a - 1

a

(5)

zM [Mj] ∑ j)1 j

R(Ni) )

zNi[Ni] b

; i ) 1, 2, ..., b - 1

(6)

zN [Nj] ∑ j)1 j

where Mi and Ni represent the simple cations and anions, respectively, and zMi and zNi represent their charge magnitude. Note that the square brackets indicate molalities (moles per gram of solvent) and the numerical values of all coordinates are between 0 and 1. The number of independent coordinates obeys eq 1 and the representation is reaction-invariant. Regardless of the actual situation, the set of coordinates describes the system as if all components completely dissociate into simple ions. This is because the number of dissociation reactions regarded as additional constraints on the system cancels out the number of extra complexes. The use of these coordinates also allows the

representation of any composition formed by mixing two points on the phase diagram using a linear material balance line. Phase Diagram Involving Ampholytes. This section discusses how systems involving ampholytes can be represented using the ionic coordinates. To facilitate the discussion, consider a mixture of an amino acid (HA), an acid (HCl), a base (NaOH), and water (H2O). There are two simple cations (H+ and Na+) and three simple anions (A-, Cl-, and OH-). Thus, there are one cationic and two anionic independent coordinates; the dimensionality of the phase diagram is three. If Na+, Cl-, and OH- are arbitrarily selected for the independent coordinates, the expressions of the coordinates according to eqs 5 and 6 are as follows:

R(Na+) ) R(Cl-) )

[Na+] [H+] + [Na+] [Cl-]

[A-] + [Cl-] + [OH-]

R(OH-) )

[OH-] [A-] + [Cl-] + [OH-]

(7)

(8)

(9)

The general outline of the isothermal-isobaric phase diagram of this system can be deduced using the coordinates. The sketch of this phase diagram showing various solubility surfaces is shown in Figure 1a. The existence of solvates and/or hydrates, as well as size and shape of various solubility surfaces on the phase diagram, is system-dependent. Three of the possible salts formed by the mixture (NaCl, NaA, and HA‚HCl) can also be seen in Figure 1a. To show how the coordinate expressions can be used to plot a data point on the phase diagram, let us consider a mixture of 1 mol of HA, 2 mol of NaOH, and 1 mol of water. It should be treated as a mixture of 2 mol of H+, 3 mol of OH-, 2 mol of Na+, and 1 mol of A-. Substituting these values into eqs 7-9 yields R(Na+) ) 0.5, R(Cl-) ) 0, and R(OH-) ) 0.75, which is located at point a (on the back face of the prism in Figure 1a). It should be pointed out that when there are H+ and OHions among the simple ions in the mixture, water should be considered as a weak electrolyte and not an inert. In this case, water can be represented using the ionic coordinate in the phase diagram. On the other hand, if either H+ or OH- is absent in the mixture, it is convenient to consider water as an inert, which does not dissociate. Therefore, in using the set of coordinates of eqs 7-9 for the four-component example above, water should be considered as a weak electrolyte. Some salient features of such a representation for ampholytes are discussed next. Relationship between Phase Diagram and Solubility Diagram. Figure 1b shows a common solubility diagram of an amino acid as a function of pH. It can be seen that HA has the lowest aqueous solubility at the isoelectric point (pI), which is the pH at which HA carries no net electrical charge (in the zwitterionic form). This feature has been utilized for crystallization of the amino acid. A typical solubility diagram as a function of acid (HCl) and base (NaOH) concentrations is shown in Figure 1c. This diagram is more complete than Figure 1b because the diagram shows the solubility over the wider scale of acid and base concentrations compared to the pH scale. It also shows possible salts that can be crystallized under certain concentrations of acid and base. Figure 1b is actually the small section around point p in Figure 1c, but of different scale. The solubility curve in Figure 1b is system-dependent. It corresponds to the solubility curve in Figure 1c only if the acid/base used

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Ind. Eng. Chem. Res., Vol. 46, No. 9, 2007

Figure 1. Amino acid in acid-base solution: (a) Isothermal-isobaric phase diagram showing various solubility surfaces (not to scale); (b) sketch of solubility diagram as a function of pH; (c) sketch of solubility diagram as a function of acid and base concentrations.

to lower/raise the pH is HCl and NaOH. Using different combinations of acid and base, one can come up with the same pH values, but the solubility values may be different.7 The conceptual phase diagram of an amino acid in the mixture of acid and base is depicted in Figure 1a. It can be seen that the phase diagram representation shows various solubility surfaces in which different possible components can be crystallized for the given system. The solubility of HA in H2O is at point p. Note that the diagram is not to scale. In reality, HA usually has low water solubility so that point p is very close to the H2O vertex. The curves pq and pr in Figure 1a correspond to the ones in Figure 1c, except that the scales and coordinates are different. From Figure 1c, it can be seen that when acid concentration is higher than point q, HA becomes HA‚HCl. This can be viewed as moving from the solubility surface of HA to the solubility surface of HA‚HCl in the phase diagram (Figure 1a), in which HA‚HCl, instead of HA, can be crystallized. Similarly, when the base concentration is higher than point r, HA becomes NaA. Points q and r are the double-

saturation points, at which two components can be simultaneously crystallized. The use of a different acid or base could result in different solubility values. This is not surprising because a different mixture will have different phase behavior and hence the solubility is not expected to be the same. This shows that solubility is not a unique function of pH. Such an understanding can be made easier if the phase diagram is available or can be conveniently visualized. It can be noticed that the diagrams in Figures 1b and 1c provide no information about the interior of the prism diagram in Figure 1a, which is important for crystallization process synthesis. For example, it could guide us to the appropriate compartment in the phase diagram so that crystallization of a desired salt can be obtained. This illustration shows that phase diagram representation provides a complete picture, while the solubility diagram only reveals a portion of what is shown in the phase diagram. As will be discussed next, the phase diagram representation is very useful in process synthesis. Application in Process Synthesis. The conceptual phase diagram in Figure 2a features solubility curves and surfaces, double saturation points, and troughs, similar to those of molecular SLE phase diagrams. To reduce dimensionality and to make the representation more practical for process synthesis, projections and cuts can be used. The purpose is to see in which region the final process point is located or how the addition of acid/base will affect the process point. Figure 2b shows a triangular cut which is a pseudo-ternary system consisting of HA, HCl, and a mixture of NaOH-H2O with a fixed composition. Point d1 is the double saturation point for HA and HA‚ HCl, at which both components cocrystallize. The cut is usually selected based on the feed composition, which can be visualized on the phase diagram. For example, for the feed with composition given by point F1, this cut can be useful to see how the addition of HCl would affect the process point. The possible location of the resulting mixture should lie on the tie-line connecting F1 and HCl (dashed line). On the other hand, the rectangular cut shown in Figure 2c is chosen based on the final mixture composition. For example, starting from a feed mixture with composition given by point F2 (on the left face of the prism diagram in Figure 2a), a cut can be selected depending on how much aqueous NaOH (point b) is added. If F2 and point b are mixed to give a mixture with composition of point c, the rectangular cut can be selected such that it passes through point c. It can be seen in Figure 2c that point c is inside the HA saturation region, in which crystallization of HA will take place. Points d2 and d3 are the double-saturation points. In process synthesis, it is important to be able to determine which component can be crystallized out upon removal of solvent such as water. One convenient way to look at it is by using Ja¨necke projection with respect to water (Figure 2d). Since there is no intention to crystallize NaOH, HCl, or NaCl, only the HA and NaA solubility surfaces are projected to the base of the prism diagram. Consider a mixture with a composition of point F1 (Figure 2a). From the projection, crystallization of HA is possible by evaporation of water because it appears to be inside the HA region (point F1′ in Figure 2d). The crystallization has to stop before reaching the double-saturation trough or otherwise NaCl will start to cocrystallize. In this case, the crystallization should stop at point y′. Points t1 and t2 are the triple-saturation points in which three components cocrystallize. As illustrated, one cut and/or projection may be more useful than others under different circumstances. The cut/projection


diagram for process synthesis. Also, a region or part of the phase diagram that is not involved in the crystallization process of the target component can be ignored. In any case, process movements, such as addition of acid/base and temperature swing, should be visible in the chosen cut or projection. Determination of SLE Phase Diagrams Electrolyte phase diagrams can be calculated from thermodynamics using solubility product (Ksp) equations and appropriate activity coefficient models, such as Debye-Hu¨ckel and Pitzer ion interaction. Consider an electrolyte which dissociates according to the following dissociation reaction

MmNn(s) S mMn+(aq) + nNm-(aq)

(10)

The solubility product equation can be written as follows,

Ksp ) aMm‚aNn

(11)

where ai is the chemical activity of species i. The solubility product equation determines the maximum amount of an electrolyte that can dissolve as ions in aqueous solution at a given temperature. Several modeling attempts for systems involving amino acids have been made.8-10 However, results in the low or high pH regions are generally unsatisfactory. One possible reason is the highly nonideal behavior at high electrolyte concentrations. In addition, multicomponent systems and phase behavior involving hydrates and/or solvates greatly increase the complexity. Therefore, experimental determination of SLE data is often inevitable in practice. To illustrate the applicability of our approach, crystallization of glutamic acid and its sodium salt will be considered. The goal is to have a better idea on the phase behavior, especially the phase boundaries among different crystallization regions and use of the diagram for glutamic acid crystallization process synthesis. These SLE data for the glutamic acid system are not available in the literature, but can be obtained using the isothermal-dissolution method.11 This method involves the determination of dissolution point by adding solvent under the isothermal condition. L-Glutamic acid with purity higher than 98.5% (International Laboratory, USA), monoammonium glutamate monohydrate with minimum purity of 99% (Sigma Aldrich, USA), ammonium chloride (NH4Cl) with minimum purity of 99.5% (Riedel-de Hae¨n, Germany), and 37% hydrochloric acid (Fisher Scientific, U.K.) were used. Water was supplied by a Milli-Q water purifier system (Millipore, USA). All commercially available chemicals were used without any further purification. In the next section, crystallization process synthesis will be demonstrated based on the SLE phase diagram representation. Process Synthesis

Figure 2. Application of phase diagram representation in process synthesis: (a) Isothermal-isobaric phase diagram (not to scale); (b) triangular cut; (c) rectangular cut; (d) Ja¨necke projection of the lower pyramid (waterless projection).

should not be randomly taken, but with particular intention for process synthesis. In general, it is advisable to choose a cut that shows the target component such as the desired amino acid and lump together other components to simplify the phase

Phase Diagram of Glutamic Acid System. There are mainly two processes to be considered in the recovery and separation processes of glutamic acid. The first step is the crystallization of glutamic acid from the fermentation broth. The second step is the crystallization of monosodium glutamate (MSG) monohydrate from the glutamic acid crystals. The feed to the crystallization of glutamic acid process is from fermentation broth, which is assumed to contain mainly glutamic acid (H2Glu), ammonium hydroxide (NH4OH), and water (H2O). Since hydrochloric acid (HCl) will also be involved in the crystallization process, it should be taken into account. All other

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components from the broth, such as bacterial cells and other debris, are assumed to be inert and will be ignored. It is necessary to hypothesize how the actual phase diagram may look like prior to the SLE measurement because it will be helpful in designing the experiment and conceptualizing the process. A proper way to represent the phase diagram for this system will be considered next. There are two simple cations (H+ and NH4+) and three simple anions (Glu2-, Cl-, and OH-) in the system. Note that Glu2- represents the glutamate ion. Therefore, according to eq 1 the dimensionality of the phase diagram or the number of independent coordinates is three, with one cationic and two anionic independent coordinates. If NH4+, Cl-, and OH- are chosen, the expressions of the coordinates are given by

R(NH4+) )

R(Cl -) )

R(OH-) )

[NH4+] [H+] + [NH4+] [Cl-]

2[Glu2-] + [Cl-] + [OH-] [OH-] 2[Glu2-] + [Cl-] + [OH-]

(12)

(13)

(14)

The conceptual phase diagram is shown in Figure 3a. It shows the two possible salts formed by the mixture, namely, diammonium glutamate ((NH4)2Glu) and ammonium chloride (NH4Cl). In addition to these salts, glutamic acid hydrochloride (H2Glu‚HCl) and monoammonium glutamate monohydrate (NH4HGlu‚H2O) are also known to exist based on the information from various sources.1,3 The saturation regions on the back face of the lower pyramid diagram (Figure 3a) are depicted in Figure 3b for clarity. The NH4HGlu‚H2O point lies halfway between the NH4HGlu point and H2O vertex. The fact that monoammonium glutamate is crystallized as monohydrate is reflected in this diagram because there is no region for NH4HGlu. Strategy of SLE Measurements. The following practical strategy is proposed to conduct the measurement of the phase diagram of the glutamic acid system. A similar approach was used to obtain the phase diagram of the ibuprofen chiral system.12 When the upper half of the conceptual prism diagram depicted in Figure 3a is ignored, the phase diagram can be viewed as a pyramid diagram shown in Figure 3c. The base of the pyramid diagram is divided into grids of different concentrations of NH4+ and Cl-. A mixture consisting of H2Glu, NH4HGlu‚H2O, NH4Cl, and HCl with appropriate proportions is prepared. Using the isothermal-dissolution method, water is added until a clear homogeneous solution is obtained. The advantage of this approach is that it does not involve the addition of ammonium hydroxide and only pure water is added. The concentration of ammonium hydroxide in aqueous solution is difficult to maintain because ammonia easily vaporizes from the mixture. The objective of these measurements is to locate approximately the phase boundaries, particularly those between the saturation regions of H2Glu and H2Glu‚HCl and of H2Glu and NH4Cl. The base of the pyramid diagram (Figure 3c) is divided into grids, in which it involves R′(NH4+) of 0, 0.1, 0.2, 0.3, 0.4, and 0.5 in the NH4+ direction and R′(Cl-) of 0, 0.2, 0.3, 0.4, and 0.5 in the Cl- direction. In addition, additional data points within the grids can be obtained to refine the search and ascertain the existence of double-saturation points.

Figure 3. Strategy for the SLE measurements for the glutamic acid system: (a) Sketch of the isothermal-isobaric phase diagram (unconfirmed phase behavior); (b) back face of the lower pyramid diagram in Figure 3a; (c) lower pyramid diagram showing planned experimental points; (d) sketch of Ja¨necke projection of the lower pyramid (waterless projection).


Figure 5. Process synthesis for the glutamic acid system: (a) Ja¨necke projection; (b) process alternative involving crystallization of H2Glu‚HCl; (c) process alternative without crystallization of H2Glu‚HCl. Figure 4. Experimental results for the glutamic acid system at 50 and 10 °C: (a) Contour map describing the experimental results; (b) cut at R′(Cl-) ) 0.5.

The advantage of dividing the base of the pyramid diagram into such regular grids is that the same set of data can be utilized by taking cuts in the NH4+ and Cl- directions. For example, at R′(Cl-) ) 0.2, the cut is shown as a red dashed triangle, and at R′(NH4+) ) 0.1, the cut is shown as a blue dashed triangle (Figure 3c). To obtain data for the boundary between the H2Glu and NH4Cl regions, additional experiments based on the diagonal of the base of the prism can be performed. The purpose of plotting in different directions is to trace the existence of double-saturation points, which will appear as a point on the phase boundary in the Ja¨necke projection. For example, consider the SLE experimental data points at R′(NH4+) ) 0 (left face of the pyramid diagram in Figure 3c). The estimated doublesaturation point (between H2Glu and H2Glu‚HCl region) is at point d. This point appears as point d′ in the Ja¨necke projection or waterless projection (Figure 3d). Crystallization of Glutamic Acid. The experimental results for the glutamic acid system at 50 and 10 °C are summarized in a contour map shown in Figure 4a. The squares on the map

indicate experimental data points and the numbers next to them signify the corresponding R(OH-) values. Contour lines representing the saturation surfaces of H2Glu, H2Glu‚HCl, and NH4Cl are sketched in red, blue, and green, respectively. The presence of a double-saturation point, which marks the boundary between two different saturation surfaces, can be identified by examining an appropriate cross section. For example, a cross section at R′(Cl-) ) 0.5 (Figure 4b) reveals two segments of the solubility curve, marked by an initial decrease followed by a sharp increase in solubility with increasing R′(NH4+). Such a trend indicates the presence of a double-saturation point (marked with a yellow square for 50 °C and a yellow triangle for 10 °C), the location of which is estimated based on the intersection of the saturation curves that best fit the data points. From the contour map, various saturation regions inside which various components would crystallize can be identified, as shown in the Ja¨necke projection in Figure 5a. Note that even though the regions of NH4HGlu‚H2O and (NH4)2Glu are marked on the projection, the location of their boundaries are only approximate. Since no double-saturation point is found within the range of available experimental data, it is expected that the boundary between the H2Glu and NH4HGlu‚H2O regions is

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located beyond the R′(NH4+) ) 0.5 line. No attempt was made to locate the boundary because, without the crystallization of ammonium glutamate salts, this boundary is not expected to affect the process flow sheet. The boundary between the H2Glu and H2Glu‚HCl region, the location of which is important to process synthesis, can be identified from the contour map. The boundary at 50 °C is sketched in red and the one at 10 °C is shown in blue. It can be seen that the location is rather insensitive to temperature. The phase boundary between the H2Glu‚HCl and NH4Cl regions is also important because it determines the end point of NH4Cl crystallization and the amount of HCl to be added such that H2Glu‚HCl can be crystallized. This boundary is also marked in red (for 50 °C). Note that it branches out at the bottom end due to the presence of an additional region at the lower left corner of the diagram, within which the mixture is unsaturated even when no water is present (at R(OH-) ) 0). One of the proposed process alternatives is shown in Figure 5b. Based on the phase diagram in Figure 5a, one way to crystallize glutamic acid from the feed (point F) is to mix it with a mixture of HCl and H2Glu‚HCl (mixture composition of point 7) to give a mixture that is inside the H2Glu region (point 1). Note that in practice HCl is added as an aqueous solution. Due to the very low solubility of H2Glu in water (as indicated by the R(OH-) value that is close to 1), the H2Glu saturation surface is much higher than other saturation surfaces, although this information is not shown in the projection (Figure 5a). However, this information is obvious from the contour map in Figure 4, which shows that the H2Glu saturation region has high R(OH-) values. The consequence is that when we add HCl to the feed to give point 1, the mixture is already below the H2Glu saturation surface and inside the H2Glu region, in which H2Glu is crystallized. Further crystallization can be effected by evaporating water. The crystallization of H2Glu in the first crystallizer (C1) should stop when the mother liquor composition is at point 2, beyond which NH4Cl starts to cocrystallize. A way to recover glutamic acid from the mother liquor and thus to improve the overall yield is through crystallization of H2Glu‚HCl, which can then be recycled to the feed stream. However, the mother liquor of point 2 cannot move directly to the H2Glu‚HCl region. As shown in the phase diagram (Figure 5a), the process path has to cross the NH4Cl region first. Since the NH4+ from the feed and Cl- from the added HCl have to be removed, it is beneficial to crystallize out NH4Cl. This can be done by mixing stream 2 with HCl to create a mixture of point 3, which is inside the NH4Cl region, followed by water evaporation in the second crystallizer (C2). The mother liquor composition is given by point 4. It should be noted that although the phase boundaries at 10 and 50 °C do not significantly shift from each other, our experimental results show that the solubility values at 10 °C are much lower. This suggests that the crystallization from point 3 to point 4 (Figure 5b) is preferably performed at 10 °C because less water evaporation is necessary. To get into the H2Glu‚HCl compartment, HCl is added to stream 4, resulting in a mixture of point 5. Crystallization of H2Glu‚HCl is then performed from point 5 to point 6 in the third crystallizer (C3). The mother liquor of point 6 has much less glutamic acid compared to the previous mother liquor (point 2) upstream and can be purged to avoid accumulation of impurities from the broth. The H2Glu‚HCl is recycled back to the feed stream to create an HClrich stream and the process is repeated. This process alternative agrees with the process described in the literature.3 As they

Figure 6. Process synthesis for the MSG system: (a) Sketch of the isothermal-isobaric phase diagram (unconfirmed phase behavior); (b) plot of data at 35 °C showing the glutamic acid and sodium glutamate region; (c) proposed MSG process flow sheet.

suggested, NH4Cl and the purged mother liquor can be used in fertilizer application. Alternatively, the feed can be mixed with the recycled mother liquor stream in order to get into the H2Glu region. This proposed process alternative is shown in Figure 5c. Point F is mixed with a recycle stream of point 4 to create a mixture of point 1′, which is inside the H2Glu region (Figure 5a). The crystallization of H2Glu is then performed from point 1′ to point 2 in C1. To cross into the NH4Cl compartment, HCl is added to stream 2 to create stream 3. Crystallization of NH4Cl is performed from point 3 to point 4 in C2. The mother liquor of point 4 is still rich in H2Glu and therefore will be recycled to the feed stream and the process is repeated. A portion of stream 4 should be purged to avoid the accumulation of impurities.


Assuming the purge is 40%, material balance calculations on the two process alternatives show that the process alternative in Figure 5c consumes approximately 36% less HCl than the process shown in Figure 5b. However, since the mother liquor stream of point 4, which has a higher H2Glu concentration compared to that of point 6, has to be purged, the recovery of H2Glu is lower for the second process alternative. After conceptual design, more experiments are needed to pinpoint the location of the double-saturation curves in Figure 5a, which is beyond the scope of this project. Crystallization of Monosodium Glutamate (MSG). Once the glutamic acid is obtained, the next step is to convert it to the desired monosodium salt. Since the objective is to obtain the sodium salt, a sodium base such as sodium hydroxide (NaOH) should be used. To synthesize this process, the applicable phase diagram consisting of H2Glu, NaOH, and H2O needs to be constructed. There are two simple cations (H+ and Na+) and two simple anions (OH- and Glu2-); therefore, the dimensionality of the phase diagram is 2. The conceptual phase diagram for this system, with R(Na+) and R(OH-) arbitrarily chosen as the independent coordinates, is illustrated in Figure 6a. This conceptual diagram shows possible crystallization regions of various components, including the monosodium glutamate monohydrate (NaHGlu‚H2O) region. Again, to synthesize a more realistic process, SLE data for this system are required. Fortunately, the necessary solubility data are available from the literature.3 They are plotted using the phase diagram representation (Figure 6b). The data show only the glutamic acid and the desired monosodium glutamate regions for the crystallization of the monosodium salt. A possible process flow sheet to crystallize NaHGlu‚H2O (MSG) is shown in Figure 6c. The H2Glu feed is mixed with a recycle stream (point 5) to give a mixture with composition of point 1. Water is added to dilute this mixture to give a mixture of point 2. Aqueous NaOH solution (point 4) is then added to this mixture, leading to the mixture with composition of point 3. This point is inside the unsaturated liquid region at 35 °C and is fed to the crystallizer (C). Crystallization of MSG is possible upon the evaporation of water at this temperature because the process point moves into the NaHGlu‚H2O region (point 3′). The mother liquor from C has the composition of point 5 and is recycled. The process is then repeated. In principle, one can mix aqueous NaOH solution with the glutamic acid to get into the NaHGlu‚ H2O region directly. However, in practice, the glutamic acid solid has to be dissolved first. Therefore, the route described in Figure 6c is preferable. Conclusions Amino acids are an important class of natural products. We have developed an approach based on phase diagram representation for the conceptual design of amino acid crystallization processes. The development discussed in this article builds upon our previous work on representation of phase diagrams of ionic systems,4 crystallization process synthesis,5 and experimental strategy for determining SLE phase diagrams.11 In this approach, the design engineer first sketches the phase behavior based on all the information on hand. Then, an experimental plan is designed to determine the minimum amount of data necessary for process synthesis. The processes for the production of glutamic acid and monosodium glutamate were considered. Interestingly, despite its commercial significance, the SLE phase behavior of the glutamic acid-diammonium glutamate-HCl-ammonium system is not well-known. Among other features, we found that

the glutamic acid region is much larger than other regions. With this better understanding, improvement of existing processes is now a possibility. This study is limited to pure amino acid crystals. However, it is well-known that a mixture of certain amino acids tends to form solid solutions. The phase behavior and the corresponding separation process would be very different from what has been discussed here. Work on such systems is currently underway. Acknowledgment Research support of the Research Grants Council (Grant HKUST602704) is gratefully acknowledged. Notation a ) number of simple cations ai ) chemical activity of component i b ) number of simple anions C ) number of components i ) number of nonelectrolytes K ) dissociation constant Ksp ) solubility product constant L ) liquid phase m ) number of complex cations or stoichiometric coefficient of cation M ) simple cation n ) number of complex anions or stoichiometric coefficient of anion N ) simple anion P ) number of phases present R ) number of relationships (independent reactions and an electroneutrality relationship) s ) solid phase w ) number of weak electrolytes zi ) magnitude of ionic charge Literature Cited (1) Yu, X. Wei Jing Gong Ye Shou Ce (Handbook of MSG Industry); Zhongguo Qing Gong Ye Chu Ban She: Beijing, 1995. (2) Mori, S.; Iitani, K.; Yamamoto, M.; Miyazawa, M.; Kaneko, T.; Kaneko, T.; Yarita, K. Process for Recovering L-Amino Acid from Fermentation Liquors. U.S. Patent No. 5017480, 1991. (3) Kawakita, T. Amino Acids, Glutamate. In Encyclopedia of Bioprocess Technology: Fermentation, Biocatalysis, and Bioseparation; Flickinger, M. C., Drew, S. W., Eds.; Wiley: New York, 1999. (4) Samant, K. D.; Ng, K. M. Representation of High-Dimensional SolidLiquid Phase Diagrams of Ionic Systems. AIChE J. 2001, 47, 861. (5) Wibowo, C.; Ng, K. M. Visualization of High-Dimensional Phase Diagrams of Molecular and Ionic Mixtures. AIChE J. 2002, 48, 991. (6) Wibowo, C.; Ng, K. M. Unified Approach for Synthesizing Crystallization-Based Separation Processes. AIChE J. 2000, 46, 1400. (7) Pradhan, A. A.; Vera, J. H. Effect of Acids and Bases on the Solubility of Amino Acids. Fluid Phase Equilib. 1998, 152, 121. (8) Nass, K. K. Representation of the Solubility Behavior of Amino Acids in Water. AIChE J. 1988, 34, 1257. (9) Gupta, R. B.; Heidemann, R. A. Solubility Models for Amino Acids and Antibiotics. AIChE J. 1990, 36, 333. (10) Kuramochi, H.; Noritomi, H.; Hoshino, D.; Nagahama, K. Measurements of Solubilities of Two Amino Acids in Water and Prediction by the UNIFAC Model. Biotechnol. Prog. 1996, 12, 371. (11) Kwok, K. S.; Chan, H. C.; Chan, C. K.; Ng, K. M. Experimental Determination of Solid-Liquid Equilibrium Phase Diagrams for Crystallization-Based Process Synthesis. Ind. Eng. Chem. Res. 2005, 44, 3788.

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(12) Lam, W. H. Chiral Resolution by Diastereomeric Salt Crystallization; M.Phil. Thesis, The Hong Kong University of Science and Technology, Hong Kong, 2005.

ReceiVed for reView August 31, 2006 Accepted February 19, 2007 IE061148F

Development of Amino Acid Crystallization Processes: l-Glutamic Acid

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