Synthesis of ChromatographyCrystallization Hybrid Separation

910

Ind. Eng. Chem. Res. 2005, 44, 910-921

Synthesis of Chromatography-Crystallization Hybrid Separation Processes Ka Y. Fung and Ka M. Ng* Department of Chemical Engineering, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong

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

A systematic procedure is presented for the synthesis of chromatography-crystallization hybrid separation processes, which are widely used in the fine chemical and pharmaceutical industries for the recovery of high-purity products. The separation objectives and input information such as chromatograms and solid-liquid equilibrium phase diagrams are first identified. Second, the basic process structure is determined by specifying the order in which chromatography and crystallization units are used in the process. Third, the fractions of the chromatographic effluent and their destinations are specified to complete the process flowsheet. Finally, the generated process alternatives are evaluated to select the best one. Design heuristics are provided to assist decision making. The application of the procedure is illustrated using three examples. Introduction Chromatography and crystallization are routinely used in combination for separating and recovering highpurity products in the fine chemical and pharmaceutical industries. Chromatography is usually followed by crystallization to recover products in solid form. For example, in the industrial production of L-glutamine from fermentation broth, chromatography is used to concentrate the product immediately after centrifugation. Otherwise, crystals with adequate purity cannot be obtained in the subsequent crystallization step.1 Crystallization is also used to recover products such as antibiotics after chromatography.2 Despite the close interaction between chromatography and crystallization in such hybrid processes, they are often carried out separately in practice with little integration. Only Lim et al.3 and Lorenz et al.4 reported that an integration of these two processes leads to an improved recovery and productivity. A similar situation occurs in process design research. Design methods for crystallization and chromatographic processes are well established. Wibowo and Ng5 developed a unified procedure, which relies on the representation of basic crystallization operations as movements on the phase diagram, for synthesizing a crystallizationbased separation process. This procedure has been applied in the synthesis of separation processes for systems involving chiral compounds6 and polymorphs.7 The design of chromatographic processes can be based on methods such as the solute movement theory,8 in which different solutes move at different velocities due to the equilibrium between stationary and mobile phases, thus effecting separation. The triangle theory has been developed for the design of simulated moving bed (SMB) chromatographic processes, in which regions of complete separation can be graphically represented.9 * To whom correspondence should be addressed. Tel.: +8522358-7238. Fax: +852-2358-0054. E-mail: [email protected].

A design method for integrated hybrid process does not seem to exist. Chromatography and crystallization have their own advantages and disadvantages. For example, complete separation can in principle be achieved with a sufficiently long chromatographic column, but capital investment can often be reduced by using a shorter column and properly designing a crystallization process to recover the pure product. On the other hand, the crystallization process is always hindered by thermodynamic boundaries, which limit the amount of a component that can be recovered in pure form. The use of chromatography allows movements across such thermodynamic boundaries. This article discusses a general design procedure for such chromatography-crystallization hybrid systems. With bench-scale data on chromatographic separations and solid-liquid equilibrium as a starting point, flowsheet alternatives are generated to meet the separation objectives in a systematic manner. Systematic Procedure for Synthesizing Chromatography-Crystallization Hybrid Separation Processes The procedure consists of four steps: (1) identification of separation objectives, (2) determination of basic process structure, (3) synthesis of flowsheet alternatives, and (4) evaluation of alternatives. It focuses on batch processes using column chromatography. Chromatograms and solid-liquid equilibrium phase diagrams serve as the primary input data. Heuristics are provided in each step to aid the decision-making process. The procedure is illustrated alongside an example involving three solutes to be separated and a solvent (example 1). Additional examples are also discussed to highlight other points in the procedure. Typical input information necessary for synthesizing chromatography-crystallization hybrid separation processes is listed in Table 1. The chemical structure of

10.1021/ie0496075 CCC: $30.25 © 2005 American Chemical Society Published on Web 01/22/2005

Ind. Eng. Chem. Res., Vol. 44, No. 4, 2005 911 Table 1. Required Input Information for Synthesizing Chromatography-Crystallization Hybrid Processes Properties of Components to be Separated chemical structure molecular weight feed composition Separation Media stationary phase mobile phase (eluent) buffer crystallization solvent For Chromatogram Modeling column diameter and length porosity of stationary phase interstitial velocity effective longitudinal diffusivity mass transfer coefficient volumetric flow rate of eluent amount of feed per injection duration of feed injection distribution factor of components between the stationary phase and mobile phase For Phase Diagram Modeling melting point heat of fusion activity coefficient model parameters pKa values if ionic components are involved

Table 2. Input Information for Example 1 Components component

molecular weight (g/mol)

melting point (K)

heat of fusion (J/mol)

A B C Eluent (S)

296 320 300 50

425 486 465 250

11 554 14 611 12 500 8 500

Activity Coefficient Model Parametersa A A B C S

B 0.2

0.3 0.4 0.8

0.2 -0.1

S 0.7 -0.1 0.1

0.8

Chromatogram Model Parameters fractional volume of mobile phase, FI 0.2 column diameter 5 cm column length 0.6 m effective longitudinal diffusivity, D 1× 10-6 m2/s volumetric flow rate 4.2 × 10-6 m3/s mass transfer coefficient, km 20 s-1 operating temperature 298 K feed per injection 500 g feed ratio of C to B, xC/xB 2 Operating Hours time

components undergoing separation is important, because components with similar structures are often difficult to separate using chromatography. Packings suitable for the chromatographic column need to be selected or synthesized, and a crystallization solvent and a chromatographic eluent for efficient separation need to be identified. Chromatograms and solid-liquid equilibrium (SLE) phase diagrams, which are the crucial data for synthesizing these processes, have to be modeled. The modeling parameters are also listed in Table 1. Step 1: Identification of Separation Objectives. Before process synthesis can be started, the separation objectives need to be identified, since whether a component is a desired or an undesired product can significantly affect the flowsheet structure. Depending on the use of the end product, the desired components can be recovered as a solid or a liquid. The undesired components or impurities can be purged as a liquid or recovered as a solid. The product purity is also specified in this step. Step 1 for Example 1. This example illustrates the separation of a mixture containing three desired products (A-C), which need to be recovered as solids with high purity. Solvent S serves as the crystallization solvent and the eluent in the chromatographic process and is recycled to minimize solvent cost. The input information is shown in Table 2. Step 2: Determination of Basic Process Structure. The basic process structure for the chromatography-crystallization hybrid separation process is shown in Figure 1. The process consists of three parts: precrystallization, chromatography, and crystallization. The feed to the chromatographic column is first dissolved in the eluent and mixed with the recycle(s) containing the solute(s). Additional eluent is then passed through the chromatographic column. The effluent is collected in several fractions, each containing a different amount of solutes. Further purification using crystallization may be needed to achieve the desired purity and/or recover the products in solid form. Frac-

C 0.5 0.5

a

14 h

γi ) Λ1x1 + Λ2x2 + Λ3x3.

Figure 1. Basic process structure of a chromatography-crystallization hybrid separation process.

tions referred to as solute-containing recycle or solventrich recycle streams are sent back to the feed stream and the eluent stream of the chromatographic column, respectively. Recycled solvent may also be sent back to crystallizers. Precrystallization can be used to minimize the load of subsequent processes. Heuristics based on SLE phase behavior, summarized in Table 3, can be used to assess its applicability. The phase behavior can be obtained from the literature, estimated, or experimentally measured. For convenience, the SLE phase behavior can be represented in the form of a phase diagram, which clearly shows regions of composition where certain product(s) can be obtained. A composition region where a pure component can be crystallized out is referred to as the compartment of that particular component.5 The compartments for different products are separated from each other by thermodynamic boundaries, which often limit the recovery of a pure product via crystallization. If the feed point is located well inside a desired product compartment, that is, it does not lie close to a thermodynamic boundary, precrystallization is preferred. In this case, a significant fraction of the component can be recovered, thus decreasing the load to the chromatographic column. In contrast, if the precrystallization recovery is low, it is better to crystallize the component after the chromatographic process instead.

912

Ind. Eng. Chem. Res., Vol. 44, No. 4, 2005

Figure 2. SLE phase behavior in the form of a Ja¨necke projection of a polythermal phase diagram for the three-solute system (example 1). Table 3. Heuristics for Step 2 rule 1: use precrystallization if the feed point is located in a desired product compartment and does not lie close to the thermodynamic boundary of a phase diagram rule 2: consider using precrystallization for a case in which the feed point is located close to the thermodynamic boundary of a phase diagram, if solvent removal leads to a high yield of the desired product using crystallization rule 3: consider using precrystallization for a case in which the feed point is located in an undesired product compartment, if stream combination with a recycle stream would allow the feed point to enter a desired product compartment and gives a high yield of the desired product using crystallization rule 4: use a series of precrystallization units if composition movements can be used to effect crystallization of another desired product rule 5: if a sufficiently high per-pass recovery of a pure component cannot be achieved in the precrystallization unit, consider cocrystallizing two or more components together followed by chromatographic separation, if necessary

Even if the feed point lies close to the thermodynamic boundary, precrystallization should be considered if solvent removal moves the feed point away from the boundary. In case the feed point is not located in a desired product compartment, precrystallization is still an option if stream combination with the recycle stream places the feed point in a suitable location of the phase diagram.5 Subsequent precrystallization of another product is possible if solvent addition or removal can be used to cross a boundary to get to the appropriate compartment. If a sufficiently high per-pass recovery of a single pure component cannot be achieved, cocrystallization of several components as determined by the phase behavior may be a viable option. The solid mixture can then be separated using a chromatographic process. Also, undesired byproducts should always be cocrystallized in the precrystallizer or purged in the mother liquor stream without further separation, if possible. Step 2 for Example 1. The SLE phase diagram (Figure 2) is estimated using the solubility equation10 with input data shown in Table 2. The feed point is located in the desired product compartment C (a threedimensional region bounded by C-AC-ABC-BC-BCS-

Figure 3. Experimental and modeled chromatograms.

ABCS-ACS, the projection of which is indicated by the shaded region in Figure 2). However, it lies close to the thermodynamic boundary and only 12% recovery of component C is achieved if precrystallization is carried out. Since solvent movement could not significantly increase the recovery of the desired product, precrystallization is not used in this example (rule 2). Step 3: Synthesis of Flowsheet Alternatives. After determining the basic structure, we define the fractions of the chromatographic effluent and select their destinations. The fractionation of the chromatographic effluent begins by representing the chromatogram using a mathematical model. Di Marco and Bombi11 summarized various models available for this purpose. If an experimental chromatogram depicts the total concentration of the solutes (Figure 3), the composite chromatogram has to be resolved into its component peaks using deconvolution methods or other curvefitting methods.12,13 The experimental chromatogram is matched by adjusting the parameters in the model. Heuristics to guide the fractionation of the chromatographic effluent are summarized in Table 4. Depending on the extent of peak overlapping, a fraction can contain one or more solutes. The degree of peak overlapping can be quantified by defining resolution, which is commonly used in analytical chemistry, as

tr,i+1 - tr,i wi+1 + wi

Ri,i+1 ) 2

(1)

where tr,i and wi are the retention time and peak width for component i, respectively. Here, i+1 represents a component with a longer retention time. A large resolu-

Ind. Eng. Chem. Res., Vol. 44, No. 4, 2005 913 Table 4. Heuristics for Step 3 Fractionation of Chromatographic Effluent rule 6: collect component i separately as one fraction if its resolution with respect to adjacent components is higher than 1.25 rule 7: Collect component i together with an adjacent component as one fraction if the resolution is lower than 0.5 rule 8: keep both options for further evaluation if the resolution is between 0.5 and 1.25 rule 9: collect a region containing components of both fractions (overlapping region) separately as a fraction and recycle it rule 10: if two consecutive fractions contain only undesired products, collect them together as one fraction rule 11: whenever possible, do not collect desired products and undesired products together in one fraction Flowsheet Synthesis rule 12: for each fraction that contains product for recovery, use a crystallizer or a series of crystallizers to recover the components in solid form rule 13: consider using another chromatographic column to resolve a fraction of the chromatographic effluent that cannot be separated by crystallization rule 14: if a fraction contains only undesired products, consider using a crystallizer to cocrystallize all the solutes rule 15: if a series of crystallizers is needed, use solvent removal or addition to move across the SLE compartment boundaries rule 16: use solvent switching if the same solvent cannot be used in two consecutive operations rule 17: use solvent removal to concentrate the chromatographic effluent if it is too dilute rule 18: if the final product is to be obtained in liquid form, use a dissolver or melting tank to dissolve or melt the solids recovered from the crystallizer Recycle Destination rule 19: send the recycle stream to a stream with the most similar composition rule 20: if solvent switching is required, send the recycle stream to a point located after the solvent switching rule 21: if the recycle is sent back to a chromatographic column, send the recycle containing solute and solvent-rich recycle separately to the feed and eluent of the chromatographic column, respectively

tion indicates widely separated peaks. On the basis of typical values from analytical chemistry,14 component i is considered to be separated from its adjacent components and should be collected as a separate fraction if

Ri-1,i > 1.25 and Ri,i+1 > 1.25

i ) 2, ..., n - 1 (2)

For the first and last solutes in the chromatogram, only the second half or the first half of eq 2, respectively, is necessary. In contrast, a small resolution means two adjacent peaks are highly overlapped and may need to be collected together in one fraction. When R < 0.5, the component peaks do not appear separated in an unresolved chromatogram. Therefore, component i is collected together with component i+1 if

Ri,i+1 < 0.5

i ) 1, 2, ..., n - 1

(3)

If the resolution is between these two values, no determination can be made at this stage. All the possible fraction distributions are kept at this stage and will be compared to select the best fraction distribution in flowsheet synthesis. When two peaks overlap in a chromatogram, the overlapping region is often collected as a separate fraction, such that the fraction before and/or after the overlapping region consists of mainly one component (Figure 3). The starting point of the overlapping region is defined as the time at which the relative concentration (Ci/C0,i) of the most adsorbed component at the

leading edge of the peak reaches an arbitrarily small value, chosen to be 10-3 in this study. The overlapping region ends when Ci/C0,i of the least adsorbed component at the trailing edge of the peak reaches 10-3. Here, C0,i is the concentration of component i at the entrance of the chromatographic column. A similar idea could be extended to two groups of peaks overlapping in a chromatogram. Having defined the fractions of the chromatographic effluent, the process flowsheet can be synthesized by defining the destination of each fraction using the heuristics in Table 4. If a fraction contains only one desired product, crystallization is used to recover the product in solid form. If a fraction contains more than one desired product, a series of crystallizers are needed to recover all the products. Solvent addition or removal is used to move the composition from one compartment to another in the phase diagram. If a fraction cannot be separated using crystallization (for example, a racemic mixture of chiral compounds), it can be sent to another chromatographic column, which may have different packings and operating conditions compared to the earlier one. This is the last resort, because crystallization is generally cheaper than chromatography. Solvent switching, which involves a solvent removal and a solvent addition step, is required if the same solvent cannot be used in two consecutive operations. For example, the eluent used for chromatography may not be a good solvent for crystallization. The fraction containing the overlapping region is usually recycled back to a stream with the closest composition. Clearly, if solvent switching between chromatography and crystallization is required, the recycle streams can only be sent back to a point after the solvent-switching step. Solute-containing recycle and solvent-rich recycle streams to be sent back to the chromatographic column inlet should be kept separate. Solute-containing recycle goes to the feed stream, while solvent-rich recycle is combined with the eluent stream. Various recycle schemes such as mixed recycle, segmented recycle, and backflush chromatography are available.15 In this study, only mixed recycle chromatography, in which the recycle stream is mixed with the fresh feed, is considered. Step 3 for Example 1. The first task in this step is to model the chromatogram. We chose the van Deemter equation16 for this purpose

Ci ) C0,i

βt0

x2π(σ12 + σ22)

(

exp -

(z/u - βt)2 2(σ12 + σ22)

where

FII 1 )1+ β FIK Dz u3

σ12 ) 2

FII2z σ22 ) 2β2 kmFIK2u K)

Ci Cs

)

(4)

914


Figure 4. Chromatogram for the three-solute system (KA ) 0.36, KB ) 0.265, KC ) 0.25) in example 1.

and where Ci is the concentration of component i in the mobile phase or eluent, Cs is the concentration in the stationary phase, C0,i is the concentration of component i in the feed, t0 is the feed duration, t is the time, z is the column length, u is the interstitial velocity, FI and FII are the fractional volumes of the mobile and stationary phases, respectively, K is the distribution factor, D is the effective longitudinal diffusivity, km is the mass transfer coefficient per unit volume of packings, and σ1 and σ2 are the standard deviations of the peaks. The parameter values used in this example are shown in Table 2. Figure 4 shows the chromatogram for a case where KA ) 0.36, KB ) 0.265, and KC ) 0.25. In this case, RAB ) 2.84 and RBC ) 0.55 (eq 1). The value of RAB indicates that A should be collected separately as a fraction (rule 6). However, no conclusion can be drawn at this point as to whether B and C should be collected separately or together as one fraction, since RBC is between 0.5 and 1.25. Therefore, both fraction distributions are kept for further evaluation (rule 8). If B and C are collected separately, six fractions are obtained after fractionation (alternative I, Figure 5a). Fractions 1 and 3 contain eluent only, since A is completely separated from the other components. Fraction 5 is the overlapping region containing both B and C and should be recycled (rule 9). If B and C are collected together as one fraction, there is no overlapping region and four fractions are obtained (alternative II, Figure 6a). The flowsheet (Figures 5b and 6b) synthesized in this step is shown alongside the chromatogram and phase diagram (Figures 5c and 6c). If B and C are collected separately, a crystallizer is used to recover the product in each fraction (rule 12) (Figure 5b). Solvent removal is carried out in an evaporator or a distillation column (S) to concentrate the chromatographic effluent before crystallization (rule 17). All the recycle streams are sent back to the inlet of the chromatographic column because of a similar composition (rule 19). The solute-containing recycle and the solvent-rich recycle are sent back to the feed and eluent streams, respectively (rule 21). A similar flowsheet for the case where B and C were collected together in one fraction is shown in Figure 6b; two crystallizers in series are used to recover the products.

Figure 5. Fractionated chromatogram (a), flowsheet (b), and phase diagram (c) for alternative I in example 1.

Ind. Eng. Chem. Res., Vol. 44, No. 4, 2005 915

Figure 7. Productivity as a function of separation factor in example 1.

Figure 6. Fractionated chromatogram (a), flowsheet (b), and phase diagram (c) for alternative II in example 1.

Step 4: Evaluation of Flowsheet Alternatives. If two or more fractionation policies are possible in step 3, the flowsheet alternatives need to be compared to determine whether partially overlapping peaks should be collected separately or together as one fraction. One measure to quantify the performance of each alternative

is the productivity. For high-value-added products such as pharmaceuticals, a larger productivity at the expense of a slightly higher operating cost is often preferred. Productivity mainly depends on resolution, which is in turn a function of the separation factor, RAB ) KA/KB.17 For a system with low resolution (separation factor close to 1), there would be a large overlapping region and a large recycle flow rate. If the column dimensions and eluent flow rate are fixed, a large flow rate in the solutecontaining recycle means more eluent is required and a longer batch time is necessary for processing the given amount of feed. Consequently, the productivity of the system expressed as number of batches produced per day would decrease. Step 4 for Example 1. To determine whether partially overlapped peaks should be collected as one fraction or not, material balance calculations are performed. As mentioned in step 3, B and C can be collected either separately as two fractions or together as one fraction. For illustrative purposes, KA and KC are fixed while KB is varied to show the effect of RBC on the number of batches produced per day (Figure 7). If they are collected separately as two fractions (alternative I), a large recycle, which translates to a small number of batches per day, is required for small values of RBC. However, if they are collected as one fraction (alternative II), RBC has no effect on the productivity. As shown in Figure 7, alternative II is preferred for this case (KB ) 0.265, RBC ) 1.06). Alternative I would be favored if RBC > 1.083. It is interesting to note that, depending on the values of KA, KB, and KC, the most favorable alternative can be different. By performing similar analyses for different values of K, a map showing the favorable fraction distribution for different values of separation factors can be produced (Figure 8). For low values of RAC and RBC, satisfactory separation cannot be obtained using chromatography, and crystallization is a more promising option. Note that this map is system specific, since it depends on the component properties and the chromatographic column characteristics. A similar map can be produced for a different system, but the boundaries would shift. Besides the separation factor, other factors such as column length can also affect the resolution and the number of batches produced per day. As shown in Figure 9, for fixed values of separation factors, a longer column leads to a larger resolution and better separa-

916


Figure 8. Map of the preferred fractionation method for different values of separation factors.

Figure 9. Effect of column length on productivity and resolution (example 1).

tion. However, a longer column leads to a decrease in the total number of batches produced per day due to longer process cycle time, in addition to higher capital and operating costs. If the column is too short, although capital and operating costs are lower, poor separation would lead to a large recycle flow rate and low productivity. The chosen column length of 0.6 m is already an optimum value. The use of hybrid separation process is not limited to simple eutectic systems. In fact, the merit is more substantial for systems with complex phase behaviors such as racemic compound (e.g. mandelic acid4) or solid solution (e.g. carvoxime18). For racemic compound phase behavior, the racemic mixture M lies in the compound compartment such that crystallization would produce the compound instead of a pure enantiomer (Figure 10a). Chromatographic separation gives two fractions (streams 2 and 4) located in (R)-A and (S)-A compartments, respectively, such that pure enantiomers can be subsequently crystallized out. The flowsheet is shown in Figure 10b. For a chiral system exhibiting a solid solution phase behavior, the hybrid process is particularly advantageous compared to crystallization alone. If the phase diagram is symmetric (Figure 11a), the tie lines are oriented in such a way that dissolution and recrystallization of a racemic mixture does not result in a change of the relative enantiomeric composition. Chromatography can be used to produce nearly pure enantiomers,

Figure 10. Polythermal phase diagram (a) and flowsheet (b) for racemic compound phase behavior.

which can be further purified using crystallization. The flowsheet is given in Figure 11b. If the phase diagram is not symmetric, as is often observed for a pair of enantiomers with multiple chiral centers, separations of enantiomers using crystallization alone would require a series of crystallizers.3 With the hybrid process shown in Figure 11b, nearly pure enantiomers are produced by chromatography, and two crystallizers may be sufficient to recover highly pure products. Example 2: A Multicomponent System This example illustrates the application of the procedure in synthesizing a hybrid process with six solutes. The flowsheet is synthesized to meet the separation objectives in a systematic manner. A different scenario is discussed at the end of this example to illustrate the effect of separation objectives on the flowsheet synthesized. Step 1. The separation objectives and relevant input information are summarized in Table 5. Among the six components, only B and C are undesired products. S is used as the eluent in the chromatography process.


it is possible to crystallize pure D from the feed, only less than 1% recovery can be achieved before other products begin to cocrystallize. Therefore, precrystallization is not considered (rule 1). Step 3. The chromatogram calculated using the van Deemter equation is shown in Figure 12a. The values of RAB, RBC, and RCD are 1.1, 1.27, and 2.04, respectively, suggesting that C should be collected separately as a single fraction (rule 6), and there are two possibilities for collecting A and B (rule 8). However, since B is an undesired product and RAB is larger than 0.5, it is better to collect A and B separately as two fractions (rule 11). Meanwhile, B and C could be lumped together as a single fraction, since both are undesired products (rule 10). The overlapping region between A and B is collected as a fraction and recycled (rule 9). For the second group of peaks containing components D-F, it can be calculated that RDE and REF are 1.41 and 0.28, respectively. Therefore, D should be collected separately (rule 6), while E and F are collected together as one fraction (rule 7). The flowsheet is also shown in Figure 12b. Crystallization is carried out to recover A and D from fractions 2 and 6, respectively, while two crystallizers in series are needed to crystallize E and F from fraction 8 (rule 12) (Figure 12c). A single crystallizer is used to recover B and C together from fraction 4, since they are byproducts (rule 14). No melting is required after crystallization, since all products should be in solid form (rule 18). A Different Scenario for Example 2. Consider a scenario involving the same system at 360 K, but only D is the desired product. SLE calculations reveal that, if crystallization is carried out at 325 K, D can be obtained with 70% recovery with cocrystallization of A and B. If crystallization is continued below 325 K, component E would also cocrystallize. On the basis of these results, precrystallization can be used to recover A, B, and D together, so as to reduce the load of the chromatographic section (rule 5). The process flowsheet is shown in Figure 13. Note that it is unfavorable to also crystallize E, since the peaks of D and E overlap. The mother liquor containing C, E, and F can be sent to another crystallizer to recover these undesired products together (rule 14). Chromatography is used to separate the mixture of A, B, and D into four fractions (rules 6 and 8). A crystallizer is used to recover D (rule 12). Since A and B are both undesired products, a single

Figure 11. Isothermal phase diagram (a) and hybrid separation process flowsheet (b) for solid solution phase behavior with symmetric tie lines.

Step 2. Since it is impossible to plot the phase diagram of the multicomponent system, SLE calculations assuming ideal behavior are performed to assess the potential of using precrystallization. The calculation was done using the SLEEK software package (ClearWaterBay Technology, Inc.). It is found that, although Table 5. Components and Input Information for Example 2

Separation Objectives separation objective desired form melting point (K) heat of fusion (J/mol) distribution factor molecular weight (g/mol) mole fraction in feed

A

B

C

D

E

F

S

desired product solid 430.15 29 290 0.265 228.3 0.105

byproduct

byproduct solid 346.3 21 450 0.21 212.3 0.031



recycle

solid 440.65 27 700 0.238 151.2 0.142


Chromatogram Model Parameters fractional volume of mobile phase, FI column diameter column length effective longitudinal diffusivity, D volumetric flow rate mass transfer coefficient, km operating temperature

0.2 5 cm 0.8 m 1× 10-6 m2/s 2.5× 10-6 m3/s 20 s-1 298 K

liquid 159.05 4931 46.1 0.136

918


Figure 13. Flowsheet for the second scenario in example 2. Table 6. Input Information for Example 3 pKa Values for Buffer 1 and the Corresponding Components buffer 1 (PQ) 4.8 AH 9.4 CH 9.2 PA 3.15 HQ 5.3 pKa Values for Buffer 2 and the Corresponding Components buffer 2 (P′Q′) 5.8 AH 9.4 CH 9.2 PA 4 HQ 4.7 Chromatography Model Parameters fractional volume of mobile phase, FI 0.2 column diameter 5 cm column length 0.6 m effective longitudinal diffusivity, D 1 × 10-6 m2/s volumetric flow rate 4.2 × 10-6 m3/s mass transfer coefficient, km 20 s-1 operating temperature 298 K feed per injection 283 g mass fraction of AH in feed, xAH 0.53 Operating Hours time

14 h

Example 3: Buffer in a ChromatographyCrystallization Hybrid Process

Figure 12. Fractionated chromatogram (a), flowsheet (b), and phase diagram (c) for example 2.

crystallizer can be used to recover them together (rule 14).

Buffer is often used in chromatography to allow a better separation of the components. While organic buffer can be easily vaporized before crystallization is carried out, inorganic buffer is difficult to separate and can significantly affect the solubility of the components. This can lead to the formation of undesired products during crystallization if the process is not designed properly. This example illustrates how to balance the effects of buffer on chromatography and crystallization and how to ensure that the desired products can be obtained using crystallization.


Figure 14. Fractionated chromatogram (a), flowsheet (b), and phase diagram (c) for the separation of two organic acids using buffer 1 (example 3).

Figure 15. Fractionated chromatogram (a), flowsheet (b), and phase diagram (c) for the separation of two organic acids using buffer 2 (example 3).

920


Consider the separation of two chiral compounds, (R)AH and (S)-AH, using chromatography followed by crystallization. Separation in the chromatographic column can be improved by the addition of a buffer, which maintains a slightly acidic condition that suppresses the ionization of the acid groups, thus enhancing hydrogen bonding with the stationary phase.19 Since the resolution is often a strong function of pH, the use of different buffers may lead to different separation performances. The situation resembles the separation of (R)- and (S)propranolol in a β-cyclodextrin column using triethylammonium acetate (TEAA) as a buffer.20 In this example, it is assumed that two electrolytes, PQ and P′Q′, can be used as a buffer. The resolutions (RR-S) are 2.4 and 0.89 when using buffer 1 (PQ) and buffer 2 (P′Q′), respectively. Other required input information is shown in Table 6. pKa values have been assumed to provide a clear illustration. Figure 14a shows the chromatogram for separation using buffer 1, along with the process flowsheet (Figure 14b). Because of the high resolution, (R)-AH and (S)AH are collected separately as two fractions (rule 6). Each fraction is sent to a crystallizer (rule 12), after removing some solvent by evaporation (rule 17). Since the (R)-AH fraction also contains the buffer (PQ), the electrolyte phase diagram as shown in Figure 14c has to be used for process synthesis. Readers unfamiliar with this type of phase diagram are referred to Berry and Ng21 for details. The existence of a compartment boundary between (R)-AH and PQ regions limits the maximum per-pass recovery of pure (R)-AH to 52%, above which PQ starts to cocrystallize. A similar diagram can be plotted for the (S)-AH fraction, but it will not be discussed here. The chromatogram and flowsheet for separation using buffer 2 are shown in parts a and b, respectively, of Figure 15. Since the resolution is between 0.5 and 1.25, (R)-AH and (S)-AH can be collected either together or separately (rule 8). In this example, the discussion will be focused on the alternative in which they are collected separately. The overlapping region is collected as a separate fraction and recycled (rule 9). Figure 15c also shows the phase diagram for the system involving (R)AH and buffer 2 (P′Q′). Comparison between Figures 14c and 15c reveals that the sizes of the (R)-AH compartments are very different in the two cases. When the compositions of streams 2-1 and 2-2 are compared, it can be calculated that the maximum per-pass recovery in the second alternative (using buffer 2) is 95%, which is much higher compared to the alternative using buffer 1. Consequently, the alternative using buffer 2 has a smaller recycle stream and higher productivity at fixed feed flow rate and column length. From material balance calculations, it can be found that the productivity is 9 batches per day for buffer 2, compared to 7 batches per day for buffer 1. Therefore, the alternative using buffer 2 is superior. Note that the conclusion would have been different if chromatography were considered in isolation, since buffer 1 gives a higher resolution in the chromatographic column. Conclusions With recent advances in chemistry and biochemistry, the chemical processing industries are faced with new challenges of producing high-molecular-weight chemicals, which often include separation and recovery of

high-purity products using chromatography and crystallization. Separation of a multicomponent mixture using chromatography alone tends to be expensive, while the use of crystallization is limited by the existence of thermodynamic boundaries. Therefore, a systematic procedure for synthesizing an integrated chromatography-crystallization hybrid separation process is proposed. On the basis of the separation objectives, flowsheet alternatives are systematically generated by positioning the chromatography and crystallization units in such a way that the composition movement caused by one unit would overcome the limitations of the other unit. Material balances, combined with chromatogram and SLE phase behavior modeling, are performed to evaluate and compare the alternatives. This article has focused on the use of column chromatography. However, this systematic procedure can easily be extended to SMBs, which have been gaining popularity in industrial operations, with minor modifications of the heuristics. Efforts in these directions are now underway. Acknowledgment Financial support from the Research Grant Council HIA02/03.EG02 is gratefully acknowledged. Notation C ) concentration in mobile phase or eluent, kg/m3 C0 ) concentration in the feed, kg/m3 Cs ) concentration in stationary phase, kg/m3 D ) effective longitudinal diffusivity, m2s-1 FI ) fractional volume of the mobile phase, dimensionless FII ) fractional volume of the stationary phase, dimensionless K ) distribution factor, dimensionless km ) mass transfer coefficient per unit volume of packings, s-1 R ) resolution, dimensionless t0 ) feed duration, s t ) time, s tr ) retention time, s u ) interstitial velocity, ms-1 w ) peak width, s z ) column length, m Greek Letters R ) separation factor, dimensionless σ1, σ2 ) standard deviation of the peaks, s Subscripts A-F ) component indices i ) component index R ) R enantiomer S ) S enantiomer

Literature Cited (1) Kusumoto, I. Industrial Production of L-Glutamine. J. Nutr. 2001, 131, 2552S. (2) Oka, M.; Tomita, K.; Tenmyo, O.; Naruse, N. Antiviral Antibiotic BU-4344V, U.S. Patent No. 5,256,548, 1993. (3) Lim, B. G.; Ching, C. B.; Tan, R. B. H.; Ng, S. C. Recovery of (-)-Praziquantel from Racemic Mixtures by Continuous Chromatography and Crystallization. Chem. Eng. Sci. 1995, 50, 2289. (4) Lorenz, H.; Sheehan, P.; Seidel-Morgenstern, A. Coupling of Simulated Moving Bed Chromatography and Fractional Crystallization for Efficient Enantioseparation. J. Chromatogr., A 2001, 908, 201.

Ind. Eng. Chem. Res., Vol. 44, No. 4, 2005 921 (5) Wibowo, C.; Ng, K. M. Unified Approach for Synthesizing Crystallization-Based Separation Processes. AIChE J. 2000, 46, 1400. (6) Schroer, J. W.; Wibowo, C.; Ng, K. M. Synthesis of Chiral Crystallization Processes. AIChE J. 2001, 47, 369. (7) Schroer, J. W.; Ng, K. M. Process Paths of Kinetically Controlled Crystallization: Enantiomers and Polymorphs. Ind. Eng. Chem. Res. 2003, 42, 2230. (8) Wankat, P. C. Physical Picture and Simple Theories for Adsorption and Chromatography. Large-scale Adsorption and Chromatography; CRC Press: Boca Raton, FL, 1986. (9) Storti, G.; Mazzotti, M.; Morbidelli, M.; Carra, S. Robust Design of Binary Countercurrent Adsorption Separation Processes. AIChE J. 1993, 39, 471. (10) Walas, S. M. Phase Equilibria in Chemical Engineering; Butterworth: Boston, 1985. (11) Di Marco, V. B.; Bombi, G. G. Mathematical Functions for the Representation of Chromatographic Peaks. J. Chromatogr., A 2001, 931, 1. (12) Youn, D. Y.; Yun, S. J.; Jung, K. H. Improved Algorithm for Resolution of Overlapped Asymmetric Chromatographic Peaks. J. Chromatogr. 1992, 591, 19. (13) Papai, Z.; Pap, T. L. Determination of Chromatographic Peak Parameters by Nonlinear Curve Fitting Using Statistical Moments. Analyst 2002, 127, 494. (14) Meyer, V. R. Theoretical Principles. Practical HighPerformance Liquid Chromatography; Wiley: New York, 1988.

(15) Tondeur, D.; Bailly, M. Recycle and Flow-Reversal Schemes in Nonlinear Production-Scale Chromatography. In Preparative and Production Scale Chromatography; Ganetsos, G., Barker, P. E., Eds.; Marcel Dekker: New York, 1993. (16) van Deemter, J. J.; Zuiderweg, F. J.; Klinkenberg, A. Longitudinal Diffusion and Resistance to Mass Transfer as Causes of Nonideality in Chromatography. Chem. Eng. Sci. 1956, 5, 271. (17) Sofer, G.; Hagel, L. Handbook of Process Chromatography: A Guide to Optimization, Scale-Up and Validation; Academic Press: San Diego, CA, 1997. (18) Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates, and Resolutions; Wiley: New York, 1994. (19) Earll, M. Online Guide to Chiral HPLC. www. raell.demon.co.uk/chem/CHIbook/Chiral.htm, 1999. (20) Ching, C. B.; Fu, P.; Ng, S. C.; Xu, Y. K. Effect of Mobile Phase Composition on the Separation of Propranolol Enantiomers Using A Perphenylcarbamate Beta-Cyclodextrin Bonded Chiral Stationary Phase. J. Chromatogr., A 2000, 898, 53. (21) Berry, D. A.; Ng, K. M. Separation of Quaternary Conjugate Salt Systems by Fractional Crystallization. AIChE J. 1996, 42, 2162.

Received for review May 11, 2004 Revised manuscript received November 9, 2004 Accepted November 22, 2004 IE0496075

Synthesis of ChromatographyCrystallization Hybrid Separation

Recommend Documents