Synthesis of Supercritical Crystallization Processes - Industrial

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PROCESS DESIGN AND CONTROL Synthesis of Supercritical Crystallization Processes 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

Supercritical crystallization using carbon dioxide has become a favorite alternative to conventional processes such as evaporative crystallization and antisolvent crystallization. Phase diagrams that show the regions where various phases are present can facilitate the design of such processes. Starting from a given process objective, a relevant phase diagram is generated to guide process synthesis and to determine feasible operating conditions. The approach is illustrated using two examples involving antisolvent and depressurization crystallization. Introduction There has been a growing interest in crystallization and extraction processes utilizing supercritical fluids. In particular, supercritical crystallization using carbon dioxide (CO2) has received considerable attention, especially in the pharmaceutical industry.1,2 It has become the favorite alternative to conventional processes such as evaporative crystallization and antisolvent crystallization. Carbon dioxide is attractive because it is readily available, is inexpensive, is environmentally friendly, is generally recognized as safe, and has a relatively low critical temperature allowing a mild operating temperature suitable for heat-sensitive materials. Due to a very high supersaturation created by rapid depressurization3 or rapid mass transfer between the solution and the supercritical fluid antisolvent,4,5 supercritical crystallization is capable of producing micro- and nanoparticles, which can be used in pharmaceutical applications. A relatively narrow size distribution and a different morphology can also be expected.6 Compared to the conventional process using liquid solvent, fewer processing steps are necessary and a potentially difficult and lengthy filtration step can be avoided. Also, the products can be free from organic solvent residues. At present, supercritical crystallization processes are often designed based on single solute solubility as a function of pressure data. This approach may not be reliable for multicomponent systems. For example, it is well-known that the solubility of an individual solute in a multicomponent system is generally greater than that observed in the single solute-solvent binary system.7 Also, single solute solubility does not reveal whether any other component is saturated under the reported conditions. This is important because crystallization of a pure solute is not possible if two or more components are saturated. Operating under different * To whom correspondence should be addressed. Tel.: +8522358-7238. Fax: +852-2358-0054. E-mail: [email protected].

phase equilibria can affect product properties such as size and morphology. For instance, crystallization under solid-vapor equilibrium may result in smaller spherical particles, while crystallization under solid-liquidvapor equilibrium may result in larger coalesced particles.8 Yet, single solute solubility does not normally specify the type of phase equilibrium. All these issues highlight the importance of understanding highpressure phase behavior in a comprehensive manner. This can be represented using a phase diagram that shows the regions where various phases are present. This article proposes a framework for the conceptual design of supercritical crystallization processes based on high-pressure solid-fluid equilibrium phase diagrams. The framework is akin to using solid-liquid equilibrium phase diagrams in the development of liquid crystallization processes.9 To meet a given process objective, a relevant phase diagram is generated by experiments and/or calculations. It can then be used to guide process synthesis, such as generating process alternatives, and determining feasible operating conditions, including temperature, pressure, and supercritical solvent-to-feed ratio. The proposed approach is expected to provide a more complete picture and deeper insights into the process. High-Pressure Phase Behavior Description of various types of high-pressure phase behavior is available,10,11 although solid-fluid equilibrium of a ternary or higher system has not been emphasized. To better understand their application in conceptual design, general trends and features of representative binary, ternary, and quaternary highpressure solid-fluid phase behaviors that are relevant to supercritical crystallization processes will be discussed next. A brief discussion will also be included for the determination of such high-pressure phase diagrams. Binary Phase Behavior. Figure 1a shows the schematic P-T-x phase diagram of a typical binary

10.1021/ie050791j CCC: $30.25 © 2005 American Chemical Society Published on Web 09/29/2005

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Figure 1. Schematic phase diagram of the binary system A-CO2. Diagram is not to scale. (a) P-T-x diagram; (b) P-T projection; (c) isothermal cut at T1; (d) isothermal cut at T3; (e) isothermal cut at T4; (f) isothermal cut at T6.

mixture with a large difference in critical temperature, such as a relatively large organic molecule and CO2. The front and back faces of the rectangular prism show the P-T phase behavior of pure component A and pure CO2, respectively. The various surfaces inside the prism are the different phase boundaries. The SA-L surface (red) extends from the melting curve of pure A on the front face into the interior, where solid A (SA) is in equilibrium with the liquid phase (L). The SA-V surface (yellow), which signifies the phase boundary between solid A and the vapor phase (V), stretches from the sublimation curve of A inward. The V-L envelope (cyan) stems from the vaporization curve of A and is bounded by two surfaces representing vapor and liquid phases in equilibrium. The envelope ends at the locus of critical points, beyond which the vapor and liquid phases are indistinguishable. The intersection between the upper V-L surface and the SA-L surface is the L-intersection curve (blue dotted curve). The lower V-L surface intersects the SA-V surface at the V-intersection curve (orange dotted curve). These V- and L-intersection curves extend from the triple point of A (TPA) and end by intersecting the locus of critical points at the upper critical end point (UCEP). Similarly, such curves on the low-temperature side intersect the locus of critical points at the lower critical end point (LCEP). The V- and L-intersection curves represent the vapor and liquid phases that are in equilibrium with each other as well as with solid A (SA-L-V equilibrium). The locus of solid phase com-

positions (curve e, TPA) is on the front face of the prism because the solid phase is pure A. Therefore, SA-L-V equilibrium exists for any temperature between the UCEP and TPA. For example, at temperature T4, the solid, liquid, and vapor equilibrium composition is given by points s, l, and v, respectively. At the UCEP temperature, the solid phase is given by point e, while the vapor and liquid phases merge into a single fluid phase at point UCEP. The section of the SA-L surface between the LCEP and UCEP temperatures thus represents equilibrium between solid A and the fluid phase (also marked with yellow as the SA-V surface). Figure 1b is the P-T projection of the three-dimensional prism in Figure 1a, showing the pure component melting, sublimation, and vaporization curves as well as the locus of critical points. The SA-L-V region (eUCEP-TPA, Figure 1a) appears as the SA-L-V curve in the projection, because the liquid and vapor phases in equilibrium, while having different compositions, must have the same pressure and temperature. Also, for three-phase equilibrium in a binary system, the degree of freedom is unity. The P-T projection is especially useful for showing the regions of pressure and temperature in which various phase equilibria may exist.8,12 However, it does not show the compositions of the phases in equilibrium, which is an important piece of information for process design. Figure 1c-f shows the isothermal cuts of the binary phase diagram at different temperatures. At T1, which is below the critical temperature of pure CO2, the

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Figure 2. Schematic phase diagram of the ternary system A-B-CO2 (A and B are the solutes). Diagram is not to scale. (a) Isothermal cut at a temperature above the critical temperature of CO2; (b) isobaric cut at P1; (c) isobaric cut at P2; (d) isobaric cut at P3; (e) Isobaric cut at P4.

isothermal cut features the regions of SA-L, SA-V, and V-L equilibria (Figure 1c). The SA-L-V equilibrium (at P1) forms the boundary among the various regions. Such a boundary does not exist in the isothermal cut at T3, which is between the LCEP and UCEP temperatures (Figure 1d). The solid is always in equilibrium with a vapor-fluid phase. Notice that the phase boundary illustrates that solubility of a solute is generally higher at high pressures, with a significant change in the vicinity of the critical pressure of CO2. It is this portion of the phase diagram that is usually displayed as an isotherm curve in a solubility diagram. As the temperature is further increased to T4 (higher than the UCEP), the SA-L-V equilibrium (at P2) that forms the boundary among the various regions reappears (Figure 1e). Since the vapor and liquid phases are indistinguishable above P3, solid A is in equilibrium with the supercritical fluid phase (referred to as the SA-V

equilibrium). At a higher temperature T6 (Figure 1f), there is only a V-L region and a solid phase is not present. Ternary Phase Behavior. Two ternary systems of interest will be discussed. The first is a system involving two solutes and a supercritical solvent, which is relevant to the design of a depressurization crystallization process. The second one is a system consisting of a solute, an organic solvent, and a supercritical solvent, which is pertinent to an antisolvent and cosolvent (modifier) crystallization process. A cosolvent brings about certain chemical functionalities such as polar forces, hydrogen bonding, or other specific chemical forces that may lead to an increase in yield and/or selectivity, or reduction in operating pressure.13 For example, the solubility of a polar solute in CO2 could increase significantly with the addition of a small amount of polar cosolvent.


System Involving Two Solutes and a Supercritical Solvent (CO2). One of the possible phase behaviors for such a ternary system is shown as an isothermal cut in Figure 2a. The three sides of the prism are the P-x diagram for each binary pair. To illustrate the presence of various phase behaviors, it is assumed that, at this temperature (above the critical temperature of pure CO2), the A-CO2 pair takes the behavior described in Figure 1d, while the B-CO2 pair takes the behavior described in Figure 1e. Such a phase behavior may be possible when the UCEP of A-CO2 is significantly different from that of B-CO2. For easier visualization, it is preferable to examine isobaric cuts at different pressures (Figure 2b-e). An isobaric cut at a low pressure (P1) features two S-V regions extending from both edges into the interior of the triangle (Figure 2b). The two S-V saturation curves intersect at the double-saturation point (point D). The triangular region ABD is a three-phase region, in which solid A and solid B are in equilibrium with the vapor phase with a composition given by point D. Note that the shape of the S-V saturation curves in general shows that solubility of a solute in a ternary mixture is enhanced compared to that in its binary subsystems. For example, solubility of A at point D (ternary) is higher than that at point b (binary). Increasing the pressure to P2 will result in the phase behavior shown in Figure 2c. Such an isobaric cut features an S-V region extending from the A-CO2 edge and both V-L and S-L regions from the B-CO2 edge. The SA-V region will intersect with the V-L region inside the triangle, resulting in the SA-L-V threephase region. Next to this region is the SA-L region, which intersects the SB-L region to form the SA-SB-L three-phase region. Note that the solubility of A in the vapor is higher due to the increased pressure. Further increasing the pressure to P3 (above the critical point of the B-CO2 pair) will result in the phase behavior shown in Figure 2d. The phase behavior is similar to that at P2 (Figure 2c) except that the V-L region shrinks such that it no longer extends to the B-CO2 edge. The region marked as SB-L/V means that in a part of it solid B is in equilibrium with the liquid (SBL) and in the other part solid B is in equilibrium with the supercritical fluid (SB-V). When the pressure is further increased to P4, the liquid region disappears and the fluid phase is now supercritical in all proportions (Figure 2e). System Involving a Solute, a Liquid Solvent, and a Supercritical Solvent (CO2). One of the possible phase behaviors for such a system is shown in Figure 3a. It is assumed that the A-CO2 pair takes the behavior described in Figure 1d. The V-L region on the C-CO2 pair is similar to that described in Figure 1f, but only the upper portion is drawn. An isobaric cut at low pressure (P1) features SA-V, SA-L, and V-L regions extending from the three edges into the interior of the triangle (Figure 3b). The intersection among these three regions results in the SA-L-V three-phase region. The phase diagram shows that the solubility of the solute in CO2 is in general much lower compared to that in the liquid solvent, signifying the role of CO2 as an antisolvent. From the diagram, it is also evident that the solubility of A in the mixture of C and CO2 (point 2) is significantly higher than that in pure CO2 (point 1). Therefore, C can act as a cosolvent that increases the solubility of A. Increasing the pressure to P2 will result

Figure 3. Schematic phase diagram of the ternary system A-CCO2 (A is the solid solute and C is the liquid solvent). Diagram is not to scale. (a) Isothermal cut at a temperature above the critical temperature of CO2; (b) isobaric cut at P1; (c) isobaric cut at P2; (d) isobaric cut at P3.

Figure 4. Schematic phase diagram of the quaternary system A-B-C-CO2 at fixed P and T (A and B are the solid solutes; C is the liquid solvent). Diagram is not to scale. (a) Isothermal-isobaric cut at a pressure and temperature above the critical pressure and temperature of CO2; (b) cut at constant C to CO2 ratio of the quaternary system.

in the phase behavior shown in Figure 3c. The V-L region has shrunk and no longer touches the C-CO2 edge, because at this pressure the mixture of C and CO2 has become supercritical. At P3, A is in equilibrium with a supercritical fluid phase, and all the liquid regions disappear (Figure 3d). Quaternary Phase Behavior. Quaternary systems are common in supercritical crystallization. Let us

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Table 1. Common Models Used in the Calculations of Various Phase Equilibria in High-Pressure Phase Diagrams type sat

S-V

yi )

Pi

V

φi P

exp

phase equilibrium model

[

]

S

Vi (P - Pisat) RT

typical required information

(1)

EOS, mixing rule molar volume and sublimation pressure of the solute critical properties of solutes and binary interaction parameters

i ) 1, 2, ..., m m ) number of solute(s)

V-L

yi )

φiL φiV

xi

(2)

EOS, mixing rule critical properties of solutes and binary interaction parameters

i ) 1, 2, ..., n n ) number of components

S-L

xi )

[

(

)

]

ViS - ViL ∆Hf,i 1 1 1 exp + (P - Pm,i) R Tm,i T RT γiL

i ) 1, 2, ..., m m ) number of solute(s)

(3)

excess Gibbs free energy (Gex) to calculate γi heat of fusion, melting pressure and temperature, and molar volume of the solute binary interaction parameters

Table 2. Selected Constitutive Models Used in High-Pressure Phase Equilibrium Calculations constitutive model

remarks

Peng-Robinson EOS with classical van der Waals mixing rule17

is simple and common can represent S-L-V equilibrium is generally good for nonpolar components requires critical properties of solutes and binary interaction parameters is suitable for dilute supercritical solutions can predict crossover pressures requires critical properties of solutes and binary interaction parameters in general is superior to the van der Waals mixing rule, but with the expense of additional parameters requires critical properties of solutes and binary interaction parameters can represent systems involving biological compounds does not require critical properties of solutes requires fewer parameters compare to other models

Peng-Robinson EOS with modified covolume-dependent mixing rule18 cubic EOS with Gex mixing rule19

regular solution and Flory-Huggins model20

consider the special case of two solid solutes, a liquid cosolvent, and CO2. One of the possible isothermal and isobaric phase behaviors for such a quaternary system is shown as a tetrahedron diagram in Figure 4a. It is assumed that, at this pressure and temperature, the phase behaviors of A-C-CO2 and B-C-CO2 ternary subsystems are similar to that described in Figure 3b, A-B-CO2 ternary subsystem is similar to that described in Figure 2b, and the A-B-C ternary subsystem is a simple eutectic S-L equilibrium. The interior of the tetrahedron is not drawn. Figure 4b is a cut at a constant ratio of C to CO2 (at a low concentration of C). The cut shows the same regions as in the A-B-CO2 ternary subsystem, but the location of the saturation curves indicates a higher solubility of both solutes in the presence of C. This illustrates the cosolvent effect in the quaternary mixture. Note that if the cut is taken at a higher ratio of C to CO2, a liquid phase will appear. By comparing such cuts for systems containing different cosolvents, the effect of the cosolvents in increasing or decreasing the solubility of the solutes can be evaluated, thus allowing the selection of an appropriate cosolvent. Determination of High-Pressure Phase Diagrams. The phase diagram of the system under consideration can be generated using literature data,12,14 thermodynamic models,15 empirical solubility models,16 and/or experimental measurements. Table 1 shows some common thermodynamic models, and Table 2 lists a number of constitutive models. Various calculation

procedures are available.21 To improve the accuracy of thermodynamic estimations, different models on different regions of the phase diagram can be used, for example, by using one model for S-V equilibrium and another model for S-L-V equilibrium. However, since the database is often not available, particularly for new compounds, predictions may not be very successful. For these reasons, experiments are often necessary and will be discussed next. General descriptions of various experimental setups and procedures are available.11 Dynamic method (continuously flowing the supercritical solvent through a bed of solute and then analyzing the vapor phase composition) is commonly used to obtain solubility data. To make sure the correct phase equilibrium is measured within the range of experimental conditions, it is important to examine the type of phases involved, such as by allowing visualization during an experiment so that any phase transitions could be observed.22 However, relying on such a visualization method alone is often not enough in practice. For example, it is challenging to visually distinguish between S-L-V and S-V equilibria. In this case, knowledge of possible phase behavior that the system may possess can be used to cross-check the experimental results. For illustration, assume the phase behavior as shown in Figure 5. To obtain solubility data in the SA-V region, experiments at constant pressure and temperature could be performed by varying the composition of C in CO2. For example, point 1 is obtained when the overall mixture


Figure 5. Schematic phase diagram of the ternary system A-CCO2 (not to scale), illustrating how the knowledge of phase behavior is used in the measurement of high-pressure phase diagram.

composition is at point p. One of the possible situations that may be encountered after reaching a certain concentration of C in CO2 (point q) is that the saturated vapor composition becomes independent of such variations (point 2). From the phase diagram, this is clear that S-L-V equilibrium, instead of S-V equilibrium, is measured. Process Synthesis With the desired phase diagram on hand, it can be used to guide process synthesis and determine suitable operating conditions. This is discussed below. Depressurization Crystallization. When the solubility of solutes in supercritical fluid is higher than 1000 ppm, it is preferable to dissolve them and then crystallize them out.23 The conditions suitable for dissolution and crystallization can be determined using the phase diagram. While crystallization is usually performed by depressurization, there could be different ways to do

dissolution depending on the phase behavior to be exploited. This will be discussed next. Dissolution Using Vapor Phase. One way to do dissolution is to make use of S-V equilibrium at high pressures, such as at P2 and T2, as illustrated in Figure 6a. Note that the solubility curves are greatly exaggerated for clarity because in reality they are usually close to the CO2 vertex due to the relatively low solubility of solids in CO2. The feed (point F) consists of solid A and solid B, and the tie line representing any possible CO2to-feed ratio is shown as the dotted line. If crystallization of pure A is desired, the CO2-to-feed ratio should be chosen such that the overall mixture (point q) during the dissolution process at P2 and T2 would result in a saturated vapor (point 1) that is inside the A saturation region (SA-V) under the crystallization condition at P1 and T1, so that crystallization of A takes place. The composition of the saturated vapor in the crystallizer is given by point 2. The process schematic is shown in Figure 6b. Such a process is generally known as the rapid expansion of supercritical solutions (RESS).24 Alternatively, if the cocrystallization of both solids is desired such as the production of microcapsules for controlled-release dosage forms,25 the CO2-to-feed ratio should be chosen such that the vapor composition (point 3, Figure 6a) resulting from the dissolution process at P2 and T2 (point r) is inside the double-saturation region (SA-SB-V) under the crystallization condition at P1 and T1. The composition of the saturated vapor in the crystallizer is given by point 4, the double-saturation point. Therefore, the crucial region on the phase dia-

Figure 6. Process representation and schematic of depressurization crystallization: (a) example of both dissolution and crystallization in the S-V region (not to scale); (b) schematic of the RESS process; (c) example of crossover behavior (not to scale); (d) example of dissolution in the V-L region (not to scale); (e) crystallization in the S-V region (not to scale); (f) schematic of the PGSS process.

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gram is determined by the process objective. If it is desired to crystallize pure A, we focus on the A saturation region (SA-V). If cocrystallization of A and B is desired, AB double-saturation region (SA-SB-V) is the region of interest. The phase behavior depicted in Figure 6a shows that pure A can be obtained from an A-rich feed. However, to obtain both pure A and pure B is not possible by pressure and temperature swings between the two sets of conditions, unless there is a retrograde or crossover behavior. In general, this behavior is due to the relative influence of the supercritical solvent density on the solubility, which predominates at lower pressures (solubility decreases with temperature), and the solute vapor pressure, which predominates at higher pressures (solubility increases with temperature).26 The potential application of such behavior for separations has been discussed elsewhere.26,27 This idea can be illustrated using phase diagrams. For example, Figure 6c illustrates a phase diagram with crossover behavior, and a complete separation of A and B is possible. Suppose that the CO2-to-feed ratio is chosen such that the saturated vapor at P2 and T1 is given by point 1. Then, an isobaric increase to T2 will crystallize pure B, with the saturated vapor composition given by point 2. To crystallize pure A, the condition should change to P1 and T1 because point 2 is in the A saturation region (SA-V) and the saturated vapor is given by point 3. Note that there could be a case where a complete separation is difficult or not possible, for example, if the two saturation curves at different operating conditions only slightly cross each other. Parallel to the ideas developed in the conventional crystallization, one of the ways to solve the problem is to alter the phase behavior by using a cosolvent.28 Alternatively, a hybrid separation process can be considered.29 Dissolution Using Liquid Phase. Another way to do dissolution is to make use of the phase behavior involving liquid phase such as V-L equilibrium, as illustrated in Figure 6d. If a high temperature is required to achieve such a phase behavior, it is not preferable for heat-sensitive solutes. To completely dissolve the solute at P2, the CO2-to-feed ratio should be chosen such that the overall mixture is inside the V-L region. If pure B is desired, the overall mixture (point r) should be selected in such a way that the composition of the saturated liquid (point 2) is inside the B saturation region (SB-V) under the crystallization condition at P1 (Figure 6e). The process schematic is shown in Figure 6f. Such a process is usually referred to as the particles from gas-saturated solutions (PGSS).30 Note that additional heating is often necessary to maintain the isothermal process in the crystallizer due to depressurization and vaporization. Compared to RESS, PGSS processes a relatively more concentrated solute without a cosolvent and thus a higher yield is possible. However, unlike RESS, which is normally operated at a relatively low temperature, PGSS may be operated at a relatively high temperature (higher than the critical end point of the mixture so that liquid phase appears). It is possible to lower the operating temperature, hence reducing the thermal degradation of the solute in the PGSS process, by adding another solute. For example, addition of the polymer PEG 4000 facilitated a substantial

Figure 7. Process representation and schematic of antisolvent crystallization: (a) example of the process representation (not to scale); (b) schematic of the GAS process; (c) schematic of the PCA process.

decrease in the melting of the cardiovascular drug nifedipine.30 Antisolvent Crystallization. When the solute is insoluble or only slightly soluble in the supercritical solvent, it is preferably dissolved first in an organic solvent. The supercritical solvent, which functions as an antisolvent, is then added to induce crystallization. For illustration, consider a typical ternary phase behavior shown in Figure 7a. The position of the overall composition point along the tie line (shown as a dotted line) depends on how much the feed solution is loaded with CO2. For example, the tie line connecting CO2 and feed F1 passes through the SA-L, SA-L-V, and SA-V regions. Depending on the CO2-to-feed ratio, solid particles can be collected when the overall mixture is inside one of these regions. There are different ways to mix the antisolvent and the solution. One way is to begin with the solution (point F1) in the crystallizer, and then CO2 is introduced into the liquid solution at P and T (a batch process). This operation tends to have a lower CO2-to-feed ratio, such as point q inside the SA-L-V region. While the compositions of the saturated liquid (point 1) and vapor (point 2) are constant in this region, their relative amounts would depend on the CO2-to-feed ratio. After crystallization, the remaining liquid solvent in the solid can be removed by flushing with a larger amount of CO2 (the mixture moves into the SA-V region). The process schematic is shown in Figure 7b.


Figure 8. Ternary phase diagram of SA-EtOH-CO2 for example 1 with part of the S-V region enlarged to show various operating points (M1-M6) representing different feed concentrations (M1 and M4, 0.05 g/mL; M2 and M5, 0.2 g/mL; M3 and M6, 0.35 g/mL) and CO2-to-feed ratios (M1-M3, 33.9; M4-M6, 67.8).

Such a process is generally referred to as the gas antisolvent (GAS) process.31 Consider a relatively dilute feed solution (point F2). There will be a single liquid phase, V-L equilibrium, or a single vapor phase, depending on the CO2 loading. No solid can be collected regardless of the CO2-to-feed ratio for this feed. Therefore, the concentration of feed solution is an important parameter to consider in antisolvent crystallization. It is apparent from the phase diagram (Figure 7a) that the use of a higher CO2-to-feed ratio that directly puts the operating point in the S-V region is desirable because it could eliminate the drying step in the GAS process. One way to achieve this is to spray the feed solution (point F1) into a crystallizer where CO2 passes through at constant pressure, temperature, and flow rate (semibatch). Since the liquid droplets formed inside the crystallizer are in contact with a large excess of CO2, a much higher CO2-to-feed ratio is possible. For an operating point inside the SA-V region, such as point r, solid particles can be obtained in a single step. The organic solvent and CO2 in the saturated vapor, which would have a composition along the S-V saturation curve such as point 3, can be separated in a low-pressure tank and recycled. This process is commonly known as the precipitation with compressed antisolvent (PCA) process (Figure 7c).32

Examples Two examples are provided to illustrate how this approach can be used for the conceptual design of supercritical crystallization processes. Example 1: Process Representation of Antisolvent Crystallization (PCA Process). Let us consider the design of a PCA process for a ternary mixture of salicylic acid (SA), ethanol (EtOH), and CO2. The objective is to identify feasible operating conditions, particularly the CO2-to-feed ratio and feed concentration, to crystallize SA. Normally, such conditions are determined by performing a series of bench-scale experiments in a trial-and-error manner. We performed a bench-scale PCA experiment at 96 bar and 45 °C, with a feed concentration of 0.05 g/mL and a CO2 (g/min) to feed (mL/min) ratio of 33.9. No solid particles were collected. The details of the experimental setup and procedure in this bench-scale experiment are discussed elsewhere.33 Instead of attempting to obtain solid particles by trial and error, the applicable phase diagram at 45 °C and at two different pressures (96 and 157 bar) was constructed (Figure 8) with solubility data from Ke et al.34 Referring to the phase diagram, the operating conditions of the unsuccessful

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run correspond to point M1, which is still in the vapor region. This explains why no solid particles were recovered. To obtain solid particles, M1 has to move to the right to get inside the S-V region. This can be achieved by using a more concentrated feed solution. For example, two operating points (M2 and M3) using the same but more concentrated feed solutions (0.2 and 0.35 g/mL, respectively) are plotted on the diagram. Notice that M1-M2-M3 is not a horizontal line because the CO2to-feed ratio used is not a molar ratio; instead it is the ratio of CO2 mass flow (g/min) to feed volumetric flow rate (mL/min). Since M2 and M3 are inside the S-V region at 96 bar, the crystallization of SA is possible. Note that the solubility of SA in EtOH, which was reported to be 0.37 g/mL at 25 °C,35 will limit the choice of feed concentration. The selected bench-scale experiment (M3) was performed and verified that solid particles could indeed be recovered. Alternatively, a different CO2-to-feed ratio can be used to get inside the S-V region. Increasing this ratio of M1 to 67.8 leads to point M4, which is closer to the saturation curve at 96 bar (red curve). However, M4 is still in the vapor region. Following the same idea as previously discussed, more concentrated feed solutions have to be used. Increasing the feed concentration of M4 to 0.2 g/mL and then 0.35 g/mL results in M5 and M6, respectively. These points are now inside the S-V region, and the bench-scale experiment for M6 verified that solid particles could be recovered. Assuming equilibrium and no loss, the maximum solid recovery is almost 100% for M6 because the saturated vapor mixture has a very low solute concentration (Figure 8). On the other hand, the maximum solid recovery for M3 is only around 77%, but more solid can be produced per pass because a smaller CO2-to-feed ratio means a higher feed flow rate. Also, the supersaturation at M3 is higher than that at M6 as is apparent from the comparison of lengths of the two arrows, which are connected to the SA vertex. The solids collected from both conditions are expected to have different attributes such as size and size distribution. Besides trying different operating points by varying the feed concentration and CO2-to-feed ratio, different operating pressures can also be investigated. Increasing the operating pressure to 157 bar results in the S-V region that is slightly smaller compared to that at 96 bar (Figure 8). At higher pressure, a more concentrated feed solution is necessary to crystallize the solute for a given CO2-to-feed ratio. For example, points M2 and M5 (same feed concentration), which are in the S-V region at 96 bar, are still in the vapor region at 157 bar (blue curve). It has been demonstrated that the phase diagram serves as a map that guides crystallization experimental effort and process synthesis. If the data are plotted, for example, as solubility versus ethanol concentration, we do not know whether we are in the correct region for crystallization or not. Also, it does not suggest a solution to a problem, for example, of what can be done when solid is not recovered. In this regard, a phase diagram serves as a meaningful representation and provides insights into the process. If the CO2-to-feed ratio is too low, the operating point could be inside the S-L-V region (such as point q in Figure 7a) and undesired solid products would be collected. In such a case, the problem could be solved by increasing the CO2-to-feed ratio or

reducing the operating pressure. Clearly, this information can only be envisioned from the phase diagram. If the point is already in the S-V region, increasing the feed concentration generally increases the yield of solid because the point would move further into the interior of the S-V region. The yield is defined as the amount of solute collected as solid divided by the amount of solute initially dissolved. Instead of performing benchscale experiments on a trial-and-error basis, various ideas can be first screened using the phase diagram. Example 2: Conceptual Design of Depressurization Crystallization (RESS Process). This example illustrates the application of phase diagram representation in the conceptual design of a separation process using RESS. The model system is a ternary system of palmitic acid (PA), tripalmitin (TP), and CO2. The objective is to obtain both solids in substantially pure form. The solubility data for both the binary and ternary mixtures at two temperatures (35 and 50 °C) and two pressures (110 and 130 bar) were calculated by Mukhopadhyay and Rao.18 The data at these operating conditions are superimposed and plotted in the ternary phase diagram (Figure 9a). Four different regions can be identified in the diagram: the vapor region, the PA saturation region (SPA-V), the TP saturation region (STP-V), and the PA-TP doublesaturation region (SPA-STP-V). It can be seen from the phase diagram that the two saturation curves at 130 bar have crossover behavior; that is, in increasing the temperature from 35 to 50 °C at this pressure, the solubility of PA in CO2 will increase, while that of TP in CO2 will decrease. Another example of crossover behavior is the benzoic acid-1,10decanediol-CO2 system.26 To describe how the phase diagram (Figure 9a) can be used to synthesize the separation process, a feed containing an equal amount of PA and TP (not shown) is assumed. The dotted line shows the possible ratios of CO2 to feed. The process flowsheet is shown in Figure 9b. Since a high solute concentration in the dissolution vessel (D) is desired, an operating condition of 35 °C and 130 bar is selected. Note that the saturated vapor composition (point 1) is at the double-saturation point because both PA and TP solids are always present in D (both solids are in excess). Based on the available saturation regions in Figure 9a, TP is first crystallized out by isobarically increasing the temperature to 50 °C in the first crystallizer (C1) and the saturated vapor will have the composition given by point 2. To crystallize PA, the operating condition has to change such that point 2 would be in the PA saturation region. From the diagram, PA can be crystallized by reducing both the temperature and pressure to 35 °C and 110 bar in the second crystallizer (C2). The saturated vapor in C2 (point 3) is recycled (with a portion of it being purged in case impurity purge is required) by recompression to 130 bar and diluted with pure CO2 to create a CO2rich stream (point 4). If no purge is necessary, the fresh CO2 is not required as point 4 coincides with point 3. It should be pointed out that there are two possible ways to do the crystallization by changing the condition from point 2 to point 3 (Figure 9a). One way is to reduce the pressure first, followed by reducing the temperature. Because of the location of the four saturation curves, such a route would face the risk of getting into the double-saturation region at 50 °C and 110 bar, resulting in cocrystallization. Although it finally will end up in


Figure 9. Phase diagram and process flowsheet for example 2: (a) ternary phase diagram of PA-TP-CO2 (zoom near the vertex of CO2); (b) proposed process flowsheet.

the single-saturation region (which means TP would redissolve), there is a chance that TP is trapped inside the crystals of PA, thus reducing the purity. Consequently, reducing temperature first is a better idea because no double-saturation region is encountered along the process path. This illustrates the fact that phase diagrams also provide insights on operational issues. If we wish to improve yield, the saturated vapor mixture after the dissolution should have a higher solute content. One possibility is to explore the behavior at higher pressure, in which higher solute solubility is expected. Another possibility is to use a cosolvent to increase the solubility. Concluding Remarks Supercritical crystallization processes are gaining popularity because of their environmental friendliness and capability of producing particles with size, size

distribution, or morphology that cannot be achieved by conventional processes. Despite the relatively high cost of pressurization, they are still an attractive alternative to conventional processes using liquid solvents, particularly for manufacturing high-value-added products. Thus, the design of supercritical crystallization processes based on a proper representation of high-pressure solid-fluid equilibrium has been presented. Starting from a given process objective, a relevant phase diagram is generated to guide process synthesis. The proposed approach serves as a key component in an integrated workflow consisting of modeling, experimental, and synthesis activities to speed up process development of supercritical processes. The discussion on phase behavior is not exhaustive in order to maintain focus on process design. In reality, the phase behavior can be more complex, such as the presence of liquid-liquid phase split.36,37 While thermodynamics provides a good starting point for designing

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supercritical crystallization processes by identifying the feasible range of operating conditions, kinetic and mass transfer effects also need to be considered.38 For example, controlling supersaturation level during crystallization, such as by adjusting the rate of depressurization, is often the key to obtaining the desired particle size and morphology. Therefore, it is desirable to couple the thermodynamics-based approach outlined in this article with consideration of crystallization kinetics and mass transfer effects such as mixing and diffusion. Further work in this direction is under way. Acknowledgment We thank Ms. Candy Lin for performing the supercritical crystallization experiments. Financial support of the Research Grant Council (Grant HIA02/03EG02) is gratefully acknowledged. Notation CP ) critical point L ) liquid LCEP ) lower critical end point P ) pressure, bar Pisat ) sublimation pressure of component i, bar R ) gas constant; R ) 8.314 J mol-1 K-1 S ) solid T ) temperature, K TPi ) triple point of component i UCEP ) upper critical end point V ) vapor Vi ) molar volume of component i, m3 mol-1 xi ) mole fraction or solubility of component i in liquid phase yi ) mole fraction or solubility of component i in vapor phase Greek Letters γi ) activity coefficient of component i ∆Hf,i ) heat of fusion of component i, kJ mol-1 φi ) fugacity coefficient of component i Superscripts V ) vapor L ) liquid S ) solid Subscript m ) melting c ) critical

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Received for review July 5, 2005 Revised manuscript received August 23, 2005 Accepted August 30, 2005 IE050791J

Synthesis of Supercritical Crystallization Processes - Industrial

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