Ind. Eng. Chem. Res. 2005, 44, 6233-6245
6233
A Visual Approach for Integrating Chemistry Research and Process Design: Separation Process with Crystallization Steps Sze W. Lin and Ka M. Ng* Department of Chemical Engineering, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong
Christianto Wibowo ClearWaterBay Technology, Inc., 20311 Valley Blvd., Suite C, Walnut, California 91789
This article presents a procedure for integrating chemistry research and process design for a crystallization based separation process starting from a chemist’s recipe. First, the recipe is represented on a composition space, providing a visual display of mass balances and phases encountered in the recipe. Second, the separation boundaries are identified and verified on a separation boundary map. This sets the stage for improving the process in view of the regions and boundaries limiting the degree of separation. Next, kinetic issues are considered to ensure product quality. Finally, possibilities of new recipes are explored, and the whole development cycle can be repeated if necessary. Examples are provided to demonstrate the approach. Introduction
Table 1. Perspective of Different Stakeholders on Process Developmenta
Speedy development of a scalable process for manufacturing a product with consistently high quality at a minimum cost is often the key to survival in today’s highly competitive environment. This is particularly true for the pharmaceutical industry, as the development of a successful drug from concept to finished product can take more than a decade and cost more than $800 million U.S., 1,2 partly due to lengthy preclinical trials with low success rates. Furthermore, since commercial production must use the same process used in producing the material for preclinical and clinical trials, it is crucial to develop a superior process at the early development stages.3 The success of a process development project depends to a large extent on effective communication among stakeholders, each of whom may have different working styles and emphases. For example, process chemists who carry out the chemistry research often focus on obtaining a high yield, leaving scale-up and operability issues to engineers responsible for process design.4 As a result, the recipe developed in the laboratory may not be applicable for the large scale plant, requiring significant modifications. This often calls for process revalidation, during which a new set of documented evidences must be generated to guarantee that the modified process will consistently produce a product with the given specifications. Such problems can be avoided if there are early and continuous interactions among different stakeholders. Table 1 summarizes some points suggested by practicing chemists and chemical engineers for a development team consisting of members of different backgrounds. As part of the overall goal to close the communication gap, this article proposes a visual approach for integrating chemistry research and process design. It outlines a workflow for transforming the chemist’s recipe into a conceptual design of the process, centered on the use of * To whom correspondence should be addressed. Tel.: (852)-2358-7238. Fax: (852)-2358-0054. E-mail: kekmng@ ust.hk.
• Reactions should be balanced. • The types of impurities present in the system and their amount should be recorded. • Same type of data under different operating conditions should be obtained. • Stability data over time should be taken into account. • Physical properties are important for process development. • In addition to improving the per-pass reaction yield, consider the use of reactant recovery and recycle to obtain high overall yield. • Insights for process scale-up can be obtained from bench scale experiments by taking the differences in heat and mass transfer effects at these two scales into account. • Engineers should pay more attention to the basic chemistry in the process. a “Chemists and Chemical Engineers: An Integrated Team for Process Development,” Fall 2000 Annual Meeting, Los Angeles, CA, AIChE, http://www.pd-aiche.com/conf/fall2000.html.
composition space as the basic platform. (It is increasingly common for chemical engineers to participate in chemistry research. The term “chemist’s recipe” refers to the chemistry content rather than the personnel performing the work. Alternatively, it can also be referred to as a “chemistry recipe”.) The workflow integrates synthesis, modeling, and experimental efforts by outlining the flow of information among stakeholders. In addition, it provides process understanding, which is expected to facilitate the implementation of good manufacturing practice initiatives such as the Process Analytical Technology.5 This article focuses on the use of phase diagrams and separation boundary maps in the development of separation processes, particularly those involving crystallization. Composition space representation is capable of clearly indicating the thermodynamic limitations posed by the phase behavior of the system as well as other constraints posed by various unit operations.6,7 Such physical insights allow rationalization of the observations recorded in a chemist’s recipe, so that the right directions for potential improvements can be systematically identified.
10.1021/ie049008y CCC: $30.25 © 2005 American Chemical Society Published on Web 04/02/2005
6234
Ind. Eng. Chem. Res., Vol. 44, No. 16, 2005
Figure 2. Examples illustrating solid-liquid separation using (a) isothermal cut and (b) polythermal projection.
Figure 1. Examples of separation boundary map (a) Polythermal SLE phase diagram, (b) Phase diagram with liquid-liquid immiscibility region, (c) Residue curve map.
Visual Approach. The basic idea in this approach is to visualize process operations such as cooling, heating, mixing, and splitting in a separation boundary map in addition to the traditional phase diagram. As the name suggests, a separation boundary map shows in composition space the extent to which a separation using a given driving force can achieve. Such maps, some of which are derived from phase diagrams, focus on separation objectives. Visualization allows different stakeholders to share a common understanding of the underlying physical phenomena behind the process, so that ideas can be communicated more easily within the development team. For example, Figure 1a shows a polythermal projection of a three-component isobaric solid-liquid equilibrium (SLE) phase diagram, featuring three compartments within each of which a different component (A, B, or S) can be crystallized in pure form. Here, AB, AS, and BS are binary eutectics. The compartment boundaries are the separation boundaries for crystallization.8 Figure 1b features the region in a three-component isobaric composition space where two liquid phases are observed at a given temperature. What can be achieved with liquid-liquid extraction can be visualized using a series of such isothermal phase diagrams.9 Figure 1c is a residue curve map for a ternary system, which is
widely used for designing distillation processes.10 Separation boundary maps that highlight the limitations caused by the interaction between the mixture to be separated and the separating agent (such as a membrane), instead of just the thermodynamic behavior of the mixture itself, have also been proposed.7 Any process can be represented as a series of basic movements on the composition space. There are only three types of basic movements: pressure, temperature, and composition swing. Pressure swing is equivalent to moving from one isobaric cut to another. Similarly, temperature swing (cooling or heating) is a movement from one isothermal cut to another. Composition swing (mixing or separation) is represented by tie-lines. The direction and extent of such a tie-line are determined by both the separation mechanism (SLE, LLE, VLE, or others) as well as equipment related parameters (number of stages in distillation and extraction, membrane pore size in membrane separation, throughput in chromatography, and so on). Separation can be represented on a phase diagram or on a separation boundary map. Figure 2a is an example showing the representation of a crystallization process on an SLE phase diagram. Stream 1, initially at temperature T1, is cooled to temperature T2. Since the isothermal phase diagram at this temperature indicates that point 1 lies in the two-phase region, it splits into a liquid phase (point 2) and solid A, as indicated by the SLE tie-line. Figure 2b shows a similar example, represented on a crystallization compartment map. Since the feed (point 3) lies inside compartment A, the solid product would be pure A and the liquid product (point 4) must lie on a straight line connecting A and point 3. The exact location of point 4 depends on the selected crystallization temperature; it would move further away from the feed as temperature decreases. Figure 3a illustrates a flash separation on a VLE phase diagram. At T2, as indicated by the isothermal diagram, point 1 phase-splits into vapor phase (point 2) and liquid phase (point 3) following a VLE tie-line. Figure 3b shows a separation process in a distillation column, represented on a residue curve map. The exact locations of points 5 (bottoms product) and 6 (distillate) depend on the number of stages in the column. Separation due to other separation mechanisms can be similarly represented on the composition space. However, the separation boundaries depend on the feed
Ind. Eng. Chem. Res., Vol. 44, No. 16, 2005 6235
Figure 3. Examples illustrating vapor-liquid separation using (a) isothermal VLE phase diagram and (b) residue curve map.
Figure 4. Example illustrating chromatography and crystallization processes on crystallization compartment map.
Figure 5. Integrated procedure for process development starting from a recipe.
composition and equipment specifications. This is illustrated below with a batch separation process combining chromatography and crystallization (Figure 4). The separation into three fractions inside the chromatography column can be represented as a three-way split on a crystallization compartment map. The degree of separation depends on the packings and operating conditions. Also shown is the crystallization of pure A and pure B from two of the product streams (points 2 and 3, respectively). Note that the split due to chromatography is not restricted by the SLE separation boundaries. General Methodology. The workflow procedure consists of five stages, as depicted schematically in Figure 5. The experimental activities in chemistry research at each stage are shown on the left side, while modeling and synthesis activities in process design are featured on the right side. The arrows in between underscore the interconnection among synthesis, modeling and experiment, the three basic activities of process development that have to be properly coordinated to successfully integrate chemistry research and process design. The experimental plan must be driven by modeling needs, so that the right type and amount of data can be generated at the right time. On the other hand, the accuracy of the experimental data determines the level of details used in modeling, to ensure that the model is meaningful. Since such interconnection calls for close interaction and effective communication among team members, it is a good practice to always keep a
detailed record of the development process, such as experimental conditions, modeling assumptions, and so on to expedite information exchange. The starting point is a chemist’s recipe, which highlights a given production route along with the necessary operations to get the final desired product. Product form and specifications are assumed to have been defined. The objective is to transform this recipe into an efficient, operationally and economically feasible process for manufacturing a product that consistently meets the given specifications. First, the recipe is represented on composition space. Next, the separation boundaries are identified and verified, so that possible ways for improving the process can be identified. Beside thermodynamic driving forces, kinetic issues are also considered since they often control the product quality. Finally, possibilities of modifying the process, such as using a different separation technique, are explored. If necessary, the entire cycle is repeated for the modified process. Note that in reality, ideas for modifications can come up during the earlier stages; in that case several process alternatives can be simultaneously developed. Stage 1: Representation of Recipe in Composition Space. In this stage, each step of the recipe is translated into the corresponding basic movement and plotted on composition space, such that all team members understand the rationale behind the recipe. At the same time, the mass balance and details of experimental conditions in the recipe can be cross-checked.
6236
Ind. Eng. Chem. Res., Vol. 44, No. 16, 2005
Table 2. Determination of VLE, SLE and LLE Phase Diagrams phase diagram VLE
component
references
Required input information: • fugacity coefficient of vapor phase, φVi • pure-liquid fugacity, f Li • activity coefficients of liquid phase, γLi Models to predict the RCM: mass balance for species i:
Handbooks, databases and journal articles Widagdo and Seider16
dx ) xi - yi ) xi(1 - Ki) dL/L where
Ki )
yi γiL fiL ) xi φ V P i
Measurement technique to verify phase behavior: batch distillation experiment and analytical analysis, e.g., Gas chromatography (GC) & High performance liquid chromatography (HPLC) SLE
Required input information: • melting point, Tm • heat of fusion, ∆Hf • activity coefficients, γ i Models to predict crystallization compartment map: solubility equation:
xi )
[ (
∆Hf,i 1 1 1 exp R Tm,i T yi(x, T)
)]
Measurement technique to verify phase behavior: differential scanning calorimetry (DSC) LLE
Required input information: • activity coefficients, γi Models to predict liquid-liquid immiscibility region: phase equilibrium equation: γ1x1 ) γ2x2 Measurement technique to verify phase behavior: liquid-liquid extraction and analytical analysis, e.g., high performance liquid chromatography (HPLC), ion chromatography (IC)
Since operating conditions are normally specified in the recipe, representation on a phase diagram is a suitable starting point. Needless to say, the phases displayed on the phase diagram depend on the phases present in the system. The shape and dimensionality of the phase diagram depend on the number of components. It is always preferable to have as few components as possible, for example by neglecting the presence of minor constituents. Appropriate cuts and projections may be taken so that a two-dimensional diagram (or three-dimensional, if unavoidable) is obtained.11 Details on how to construct phase diagrams and take projections and cuts are available in the literature12-15 and will not be repeated here. Note that at this stage, only a sketch of the recipe on composition space is needed. This means the location of boundaries and process points on the phase diagram may not be exact. Nonetheless, based on available information from the recipe, effort must be made to correctly identify the overall phase behavior and the regions inside which the process points must lie. If there is not enough information to do so, the scientists creating the recipe should be asked to provide the missing of information. Stage 2: Identification of Separation Boundaries. After obtaining a sketch of the process on the phase diagram, the focus is now shifted to the separation objective. The location of separation boundaries, most of which are imposed by phase behavior, need to
Handbooks, journal databases and articles Walas17 and Reid et al.18
Ozawa and Matsuoka19
Handbooks, databases and journal articles Walas17
be identified. Therefore, corresponding separation boundary maps are constructed in this stage via an integrated effort combining modeling and experiment. Table 2 summarizes the models for calculating different phase diagrams and separation boundary maps along with required input information, some of which can either be found in the literature or estimated using physical property estimation methods such as those based on group contribution approach.20,21 Since pharmaceutical process development usually involves newly discovered chemical compounds, for which physical property data are nonexistent, experimental measurements are indispensable. Modeling of phase behavior is often complicated by the nonideal nature of the system, which translates to the need for an activity coefficient model. There is a limited amount of information in the literature on activity coefficient model parameters for specific systems, but they tend to be valid only for VLE and/or LLE. The regular solution model allows the calculation of SLE activity coefficients from solubility parameters,22 for which estimation methods are available. Unfortunately, existing methods do not provide reliable estimates of solubility parameters for molecules with very complex chemical structures. Activity coefficients can also be obtained indirectly by performing phase equilibrium experiments followed by regression to back out the parameters in the selected model.
Ind. Eng. Chem. Res., Vol. 44, No. 16, 2005 6237 Table 3. Design Heuristics at Stages 3, 4, and 5 Stage 3. Improvement of the Recipe • Fractional crystallization allows complete recovery of a desirable product by separately crystallizing out the undesirable product. • Increase the crystallizer temperature to avoid precipitating out an unwanted component. • Select a recycle destination with a composition comparable to that of the recycle stream. If such destinations do not exist, direct the recycle stream to a destination in such a way that the feed location to each unit remains in the same region of the composition space.7 Stage 4. Consideration of Kinetic and Mass Transfer Effects23 • For a system showing solid-liquid-liquid equilibrium phase behavior, crystallization should be performed away from the liquid-liquid region. • Slow cooling and seeding can lead to large crystals with relatively narrow particle size distribution. • Fast cooling can lead to small crystals and significant impurity inclusion. • Rapid agitation can lead to small crystals, by dispersing nuclei during crystallization or shearing crystals. • Spray drying can produce small crystals or amorphous solids. • Impinging jet can produce small crystals with narrow range of particle size. Stage 5. Creation of New Recipe for the Same Product • If the melting point ratio for a binary pair is larger than 1.2, crystallization can separate them effectively.24 • The best solvent for a reaction may be the one from which the product can be crystallized directly.23 • For binary pair whose size and shape differences are not sufficiently large but having a large difference in dipole moment or polarization, molecular sieve adsorption is an alternative.24 • For azeotropic distillation or liquid-liquid extraction, large immiscibility regions would mean easier separation of the solvent from the solute.24 • If separation recovery by crystallization is low, chromatography before crystallization may be a good option.
To minimize experimental effort in constructing the separation boundary map, it is desirable to proceed with modeling first. With the availability of literature data for many systems and the availability of software tools such as SPLIT (Aspen Technology), VLE modeling for obtaining residue curve maps is straightforward. Experimental verification of a few residue curves is usually sufficient. In calculating crystallization compartment maps using SLE modeling, ideal mixture assumption or predicted activity coefficients from regular solution model normally provide a good starting point. Incorporation of a few experimental solubility data would significantly improve the accuracy of the results. However, obtaining LLE separation boundaries via modeling is a time-consuming task since it would require calculation of numerous tie-lines over a range of temperature and composition. In addition, activity coefficient data are seldom available and the ideal assumption is not applicable since it contradicts with the existence of liquid-liquid phase split. Therefore, it is often quicker to experimentally identify the boundaries of the liquidliquid region by finding the range of temperature in which mixtures of different compositions would phase split. Note that these boundaries are not meant to be exact, but to serve as a starting point for the next stage. Stage 3: Improvement of the Recipe. Once the separation boundaries have been identified, possible improvements of the original process suggested in the recipe can be evaluated. While this step depends largely on the accumulated experience and the individual inventiveness of the development team, typical actions include: (1) changing operating conditions, (2) switching from single-stage to multistage operation, (3) changing the sequence of operations, (4) changing feed composition, and (5) recycling of residues and solvent. Some heuristics to help decision making at this stage are summarized in Table 3. Changing the process operating conditions, such as temperature, pressure, and the amount of solvent being used, is the most common method to improve a recipe. With the help of a separation boundary map, one can readily see the possibility of improving the process within the limitations. For example, according to the crystallization compartment map in Figure 2b, a de-
crease in temperature would move point 4 further away from point 3, which by lever rule corresponds to an increase in the yield of pure A. However, the new location of point 4 should still be within compartment A in order to prevent cocrystallization of B. The selected operating conditions must also be feasible in full-scale process. For example, operation below room temperature is not favorable due to high refrigeration cost. Pushing the composition of a distillation product to the thermodynamic limit is also unwise because a very large reflux ratio would be necessary, leading to high energy consumption. Switching from single-stage to multistage process is often helpful to improve separation performance, since the product compositions from a multistage operation are not limited to lying on a single tie-line. For example, a multistage counter-current extractor can be used instead of a single decanter to obtain higher purity extract and/or raffinate. To assess the feasibility of this idea, a phase diagram showing the orientation of representative tie lines is needed. Modeling of LLE phase behavior can help reduce the experimental effort in determining the phase diagram, but a sufficient amount of data on extract and raffinate compositions for different temperature and feed compositions is required to allow for parameter regression. The sequence of operations in the process is another important issue to consider, especially for cases where more than one driving force is used in the overall process. It is convenient to superimpose different separation boundary maps, such that the potential outcome of various sequences can be easily identified. If the feed to the separation process is a reactor outlet, lowering conversion in the reactor may put the feed in a more desirable region with respect to the selected separation driving force. Finally, the possibility of recycling process streams that contain a significant amount of valuable materials should always be considered to minimize losses and waste generation. Since recycle changes the feed composition, the entire process must be reanalyzed to ensure that every process point lies within the correct separation region. Material balances must also be checked for convergence.
6238
Ind. Eng. Chem. Res., Vol. 44, No. 16, 2005
The separation boundary maps used in this stage are not highly accurate, since they are obtained from models and limited experimental data. Therefore, it is imperative that after all process points have been identified, the location of separation boundaries that are critical to the feasibility of the process are experimentally verified. For example, knowing the exact location of the boundary between compartment A and B is critical for achieving the objective of the crystallization operation illustrated in Figure 2b, because pure A can only be obtained if point 4 is indeed inside compartment A. For that reason, experimental verification should focus on this boundary instead of other compartment boundaries. At the end of this stage, suitable equipment units for performing the tasks represented by the basic movements are selected. In many cases, several subsequent movements can be accommodated in a single unit, especially in batch processes. For example, solvent addition, cooling, and crystallization can all be performed in a single multipurpose vessel. Stage 4: Consideration of Kinetic and Mass Transfer Effects. Since actual process do not operate under equilibrium conditions, kinetic and mass transfer effects must be taken into account. This is particularly important when solids are involved, since solids attributes such as particle size distribution (PSD), crystal shape or polymorphic form, and impurity content often strongly depend on kinetics and mass transfer effects. To ensure that the final product quality meets the desired specifications, these effects have to be properly taken into account in selecting operating conditions. For example, cooling rate or anti-solvent addition rate in a crystallization process has to be carefully adjusted to obtain the desired PSD. Crystallizers should be operated at least 5 °C away from compartment boundaries to avoid cocrystallization of impurities upon temperature fluctuations. Some other heuristics to be considered in this stage are summarized in Table 3. Kinetic and mass transfer effects may be the reason why the expected equilibrium conditions are not attained during bench-scale tests. For example, agitation during liquid-liquid extraction determines the rate of mass transfer from one liquid phase to the other, at the end controlling how close the extract and raffinate are to equilibrium compositions. Therefore, it is important to have access to information such as addition rate, cooling rate, agitation speed, and so on, which may help to provide explanation and suggestions for improving the process and ensuring a feasible and operable process at the commercial scale. In composition space representation, kinetic and mass transfer effects are signified by different process paths with the same starting and ending points. For example, a process path venturing deep into the metastable region of an SLE phase diagram reflects a high degree of supersaturation in a crystallization process. If the path penetrates beyond the metastable region into the unstable region, undesirable bursts of nucleation may occur, usually leading to problems such as undesirable PSD or significant impurity inclusion. Models for calculating the process paths under kinetic and mass transfer limitations have been developed,25,26 but most of the parameters have to be estimated or experimentally determined. For other important crystallizationrelated issues, such as metastable zone width, impurity inclusion kinetics, and washing performance, experimental determination is the only option since models
Table 4. Recipe for Example 1 step
procedure
1.
Raw materials weighing 50 g B undergoes an equilibrium reaction with a reaction product containing an equal amount by weight of A and B. After completely removing the reaction solvent, the solids are dissolved under agitation with 50 g of solvent S1 at 90 °C. Cool the solution mixture to 25 °C and filter out the solid formed. The solid weighing 24.72 g contains 69.8 wt % A and 30.2 wt % B. Recrystallize the solid by adding 25.3 g of solvent S1 to the system at 75 °C. Cool the solution to 25 °C and filter out the solid formed. It is found that the solid weighs 13.4 g and has a composition of 99% A and 1% B.
2. 3. 4.
are either inadequate or nonexistent. In such cases, the experiment should be designed to provide relevant information for the process conditions selected at the previous stage. For example, impurity inclusion tests should be performed using the feed composition and crystallization yield previously selected in stage 3. This is especially important when there are recycle streams involved, since the impurity concentration in the crystallizer feed would not be the same as if there were no recycle. Thus, material balance calculation results become the basis for designing the experiment. Stage 5: Creation of New Recipe for the Same Product. In this final stage, the possibilities of using other separation techniques are explored to generate a new recipe. New driving forces for achieving the separation objective are identified, and stages 2-4 are repeated for each alternative to determine the corresponding separation boundaries and construct the process flowsheets. These process alternatives are evaluated at the end to determine the best candidate for scale-up. Guidelines are available to synthesize a separation process based on the information on physical properties of the components involved.24,27-29 Some of these are cited in Table 3. While the selection of a new driving force is largely innovative, newly gained perspectives from composition space visualization of the current process can be helpful. For example, a different solvent may be chosen for a crystallization process, and the corresponding crystallization compartment map is constructed using the mathematical model shown in Table 2. Comparisons in term of the location of separation boundaries, temperatures, and so on can then be made to see which solvent is the best for achieving the separation objective. Chromatography-crystallization hybrid is another attractive alternative for separations of high-molecular weight compounds. Suitable packing can be synthesized to initiate separation and produce mixtures in the right crystallization regions, allowing further purification by crystallization. Visualization on phase diagrams helps to identify tradeoffs and optimize such a hybrid process.30 Examples. The general methodology is illustrated next using two examples. Despite the fact that they involve hypothetical components, these examples are designed to mimic routinely encountered scenarios in real-life process development projects. Emphasis is placed on the sequence of tasks to be performed and the goals to be achieved in each task, rather than the numerical results, which are included primarily for illustration purposes. Example 1: Recrystallization of desired product. An active ingredient A is produced in an equilib-
Ind. Eng. Chem. Res., Vol. 44, No. 16, 2005 6239 Table 5. Input Information for Example 1 physical property
A B S1 S2
MW (g/mol)
mp (°C)
heat of fusion (J/mol)
heat of evap. (J/mol)
180.16 206.28 88.11 100.12
135 104.76 -83.55 -72.15
25600 24610 10480 13330
/ / 3.22 × 107 3.39 × 107
binary solubility data
Figure 6. Block diagram for Example 1.
Figure 7. Stage 1 isothermal phase diagram: a sketch that captures the chemist’s recipe.
rium reaction that yields a mixture containing 50 wt % A. The rest mainly consists of reactant B plus a very small amount of inert impurities. Pure A is then isolated in a two-step batch crystallization process, with an overall yield of 26.8%. The recipe for the separation process is given in Table 4. The details of reaction step are not considered. It is desirable to explore alternatives for improving the yield and minimizing the number of process steps. Stage 1. As all operating temperatures, feed and product compositions are clearly stated in the recipe, no additional information needs to be requested at this stage. The recipe can be represented as a block flow diagram (Figure 6). Since the recipe indicates that solid and liquid phases are involved, an SLE phase diagram is constructed to represent the chemist’s process (Figure 7). Minor impurities that may exist in the mixture have been neglected, leaving a ternary system of A, B, and solvent S1. The process points shown on the phase diagram correspond to the stream labels in the block flow diagram. The feed (point F) containing 50 wt % A (∼53mole%) and 50 wt % B (∼47mole%) lies nearly of the middle of line AB in Figure 7a. With the addition of S1, the composition moves to point 1. Since complete dissolution occurs at 90 °C, point 1 should be located in the unsaturated liquid region of the isothermal SLE phase
T (°C)
A in S1 (mole)
T (°C)
A in S2 (mole)
25 37 47 57 67
0.03 0.05 0.08 0.11 0.15
25 35 45 55 65
0.06 0.09 0.11 0.16 0.21
T (°C)
B in S1 (mole)
T (°C)
B in S2 (mole)
25 36 48 59 73
0.13 0.19 0.24 0.32 0.48
25 36 45 54 62
0.13 0.18 0.24 0.31 0.38
diagram at 90 °C, that is, above the 90 °C isotherm. Since cooling to 25 °C gives solids containing both A and B, it is suspected that point 1 is located in the threephase region (A + B + liquid) at 25 °C, and the liquid composition is at the double saturation point, indicated by point 2. Based on the solid composition given in the recipe (69.8 wt % A and 30.2 wt % B), point 3 is marked approximately on the phase diagram. The second crystallization step is illustrated in Figure 7b. Addition of S1 to point 3 brings the overall composition to point 4, which should be located in the unsaturated liquid region at 75 °C (complete dissolution). From the fact that almost pure A was obtained at 25 °C, it is hypothesized that point 4 actually lies in the A saturation region at 25 °C, thus giving a liquid with the composition of point 5 after crystallization of pure A. The small amount of B in the product is assumed to be due to inclusion, which will be considered at stage 4. Stage 2. To evaluate the potential for process improvements, a crystallization compartment map showing the SLE separation boundaries is generated using the model listed in Table 2. The assumed input information is summarized in Table 5. The melting point and heat of fusion of A and B could have been obtained by performing DSC analysis, while those for S1 could be available in physical property databases. The solubility data could be determined experimentally using standard methods such as those proposed by Cohen-Adad and Cohen Adad.31 Figure 8 shows the calculated diagram, using NRTL model for the activity coefficients, with binary interaction parameters backed out from the assumed solubility data via regression with a software tool SLEEK (ClearWaterBay Technology). Thus, unlike the sketch in Stage 1, the process points and boundaries in Figure 8 represent the actual data. AB is the binary eutectic between A and B. The eutectic points between the solvent and solutes are indistinguishable from the vertex of S1 because of its very low melting point. Stage 3. With the separation boundary map on hand, actions for process improvements are identified next. Figure 8 indicates that point 1 is located within compartment A, so that A would actually crystallize out first upon cooling, and the liquid composition follows the path
6240
Ind. Eng. Chem. Res., Vol. 44, No. 16, 2005
Figure 8. Stage 2 polythermal phase diagram (in mole%).
from 1 to 1′. But if cooling is continued beyond 1′, which is at the eutectic trough between compartments A and B, both components would crystallize together and the liquid composition moves along the boundary to point 2. With this understanding, two ways of obtaining pure A can be proposed. The cooling can be stopped just before the liquid composition reaches point 1′, thus preventing B from crystallizing out (Figure 9a). Alternatively, more solvent can be added to the feed before cooling (Figure 9b), so that point 1 moves closer to S1 compared to the original recipe (shown as circles). Pure A can now be obtained even if the mixture is cooled to 25 °C. Both alternatives allow the separation objective to be achieved with only one crystallization step, thus significantly cutting down the overall processing time. The process can be further improved by considering the possibility of recycling the A and B in the mother liquor back to the reactor after completely evaporating the solvent. Note that to prevent accumulation of minor impurities, part of this recycle stream must be purged. With the same equilibrium constant as before, the composition of point F is represented by the same point on the phase diagram. However, the product loss would be much lower compared to the no-recycle case. Figure 10 shows the revised block flow diagram with recycle. Because the parameters used for calculating the crystallization compartment map at stage 2 were obtained from binary solubility experiments, it cannot be expected that the model would accurately predict the location of the boundary as well as the temperatures in the interior of the triangle. Preliminary calculation results show that the operating temperature of the crystallizer for the first and second alternative design is 37 °C and 25 °C, respectively. It is highly desirable that the AB boundary, especially in the temperature range of 25-40 °C should be experimentally verified. This can be done by analyzing the composition of a saturated solvent in equilibrium with solids A and B at a given temperature. Table 6 lists the assumed experimental results. The model parameters are then updated by repeating the regression with these new data taken into account. The recalculated polythermal projection is shown in Figure 11 along with isothermal cuts at 25 °C and 90 °C. Material balance calculations are then performed to obtain all flows in the process. Table 7 is a comparison of the alternatives. Here, the recovery of A is the mass of A recovered from the crystallizer (as the final product) over the mass of A fed to the crystallization train and the yield is the mass of A recovered from the crystallizer (as the final product) over the mass of B fed to the reactor. For the first design alternative, the minimum operating temperature of the crystallizer before B comes
Figure 9. Stage 3 polythermal phase diagram. (a) First alternative design: Raise crystallization temperature (b) Second alternative design: Increase the amount of solvent.
Figure 10. Block diagram of third alternative design. A and B in the mother liquor are recycled to the reactor after evaporating all the crystallization solvent.
out is calculated to be around 37 °C, corresponding to a recovery of 49.5%. The second design alternative uses 50% more solvent compared to the original recipe, but the recovery is higher. Clearly, the third design alternative with recycle is the most favorable with a recovery of 53.8% of A and a yield of 71%.
Ind. Eng. Chem. Res., Vol. 44, No. 16, 2005 6241
Figure 12. Polythermal phase diagram with the use of a new solvent S2. Table 8. Recipe for Example 2 Figure 11. Polythermal phase diagram along with isothermal cuts at 25 °C and 90 °C. Double saturation points are taken into account. Table 6. Double Saturation Point Data in Mole Fraction solubility data (A, B, S1)
29 °C
37 °C
45 °C
52 °C
59 °C
A B S1
0.07 0.13 0.80
0.09 0.19 0.72
0.11 0.23 0.66
0.15 0.27 0.58
0.17 0.34 0.49
solubility data (A, B, S2)
27 °C
35 °C
43 °C
52 °C
60 °C
A B S2
0.06 0.14 0.80
0.08 0.18 0.74
0.11 0.22 0.67
0.15 0.29 0.56
0.17 0.36 0.47
Table 7. Comparison of Different Process Alternatives in Example 1 1st design (higher 2nd design 3rd design new idea (more (with (solvent original crystallizer recipe temperature) solvent) recycle) switching) no. of crystallizer amount of solvent (kg/kg feed) recovery (%) yield (%) crystallization T (°C)
2
1
1
1
1
1
1
1.5
1.5
1.5
53.6 26.8 25
49.5 24.7 37
53.8 26.9 25
53.8 71.0 25
54.3 71.3 28
Stage 4. The product obtained during the development of the original recipe contains a small amount of B, which is most likely due to inclusion during crystallization process. The next step is to determine the cooling rate, which would yield a high purity product. No predictive tools exist and an experimental study needs to be conducted. If product specifications cannot be met at a cooling rate that is reasonably low, then recrystallization should be considered. Stage 5. New ideas are sought to further improve the process such as the use of another solvent. Solvent S2 with solute solubilities similar to that in S1, have not been considered during the development of the original recipe. It is decided to repeat stages 2 to 4 to evaluate a process alternative using S2. After taking some solubility data of A and B in S2, the crystallization compartment map for A-B-S2 system can be calculated (Figure 12). For comparison purposes, the AB compartment boundary for the system using solvent S1 (indicated by the dashed line) is drawn on the same figure. Clearly, with the same amount of solvent added to point F, more pure A can be obtained using solvent S2 compared to using solvent S1, since the boundary is
step
procedure
1.
Cut the roots into small pieces and then grind. Take 7 g of the resulting powder and mix with 9 g of solvent S1 in a beaker under agitation. Filter out the residue. About 12.8 g of extract containing A, B and S1 are obtained. Add 10 g of solvent S2. Mix well and let stand for an hour. The mixture separates into two liquid phases. Use a separating funnel to get the top layer, which contains about 15.86 wt % A and 6.26 wt %B. Evaporate 70% of the solvent in the mixture. Cool the remaining mixture to 25 °C. Filter the precipitate which contains both A and B. About 1.77 g is obtained where 73.7 wt % is A. Completely dry the solid and then dissolve it in 2.3 g of solvent S3 at 60 °C. Cool down the solution and filter out the precipitate. It contains 99.6% A.
2. 3. 4. 5. 6. 7. 8.
farther away from point 1. Similar to the previous case, a higher yield can be obtained by recycling the mother liquor after completely evaporating all the solvent. After verifying the boundary via double saturation point experiments and updating the model parameters, material balances and operating conditions for this new process alternative can be obtained and compared to the alternative using S1. The last column in Table 7 summarizes the calculation results. Although the overall recovery and yield of A is slightly higher with solvent S2, the evaporation load is also higher since the heat of vaporization of S2 is larger than that of S1. Therefore, the tradeoff between yield improvement and increased energy consumption for evaporation must be considered before selecting the best process. Example 2: Extraction and Isolation of a Natural Ingredient. A pharmaceutical company would like to develop a new process for producing a health care supplement. One of the active ingredients A can be recovered from the roots of a plant. Preliminary studies show that A can be isolated from this natural source via solvent extraction by using solvent S1. However, further purification is needed since impurity B is also extracted in a significant amount. The objective of the project is to develop an economical process which gives a solid product containing at least 99.5% A, with particle sizes in the range of 20-80 µm. The recipe is summarized in Table 8. Stage 1. A block flow diagram representing the recipe is shown in Figure 13. The representation on composition space begins from step 3. An isothermal LLE phase diagram is needed to represent the liquid-liquid extraction process. However, some key information for sketching the phase diagram, namely the extraction temperature and the concentration of A and B in the feed, is
6242
Ind. Eng. Chem. Res., Vol. 44, No. 16, 2005
Figure 13. Block diagram of the given recipe in Example 2. Table 9. Input Information for Example 2a LLE information mole fraction A B S1 S2
mixture of extract (1) and S2
raffinate (2)
extract (3)
mixture after evp. of solvent (5)
0.060 0.046 0.521 0.373
0.012 0.063 0.188 0.737
0.097 0.033 0.780 0.090
0.262 0.088 0.487 0.163
SLE information
A B S1 S2 S3
MW (g/mole)
Tm (°C)
∆Hfus (J/mol)
116.16 136.19 60.05 93.13 56.12
147 183 -21 -45 -19
19,554 21,611 13,133 10,014 12,133
a The numbers in parentheses are the stream numbers in the block flow diagram (Figure 13).
not clearly specified in the recipe. After consulting the chemists who developed the recipe, it is found that the extraction temperature was 25 °C, and the feed, extract, and raffinate compositions are as summarized in Table 9. The LLE phase diagram involving A, B, S1, and S2 would take the shape of a tetrahedron. To allow convenient visualization in two dimensions, a Cruickshank projection32 is taken by orthogonally projecting all points in the tetrahedron in the indicated direction (Figure 14ai). On Figure 14aii, mixing of stream 1 with solvent S2 gives an overall composition of point 1′. As the extract (point 3) is rich in A and S1 while the raffinate (point 2) is rich in B and S2, they are drawn near the A-S1 edge and B-S2 edge, respectively. The next step in the recipe is solvent evaporation from the extract. Since A and B are large chemical compounds, it is believed that only solvent S1 and S2 will exist in the vapor phase. Two questions arise at this point: first, what is the temperature at the end of evaporation, and second, what is the corresponding liquid composition. Again checking the experimental logbook, it is found that the final temperature was 70 °C and the liquid composition (point 5) is as given in the last column of Table 9. On the basis of this information, the cooling crystallization process in step 6 can now be represented on an SLE phase diagram. Note that the molar ratio of S1 to S2 at point 5 is about 3:1, a cut at constant S1 to S2 ratio (75:25) is selected for this purpose. Figure 14bi shows the corresponding sketch at this cutting plane. Since the recipe does not report the presence of solids after evaporation, point 5 is assumed to be unsaturated, thus lying above the
Figure 14. Stage 1 phase diagrams for Example 2: (ai) Reducing dimensionality by Cruickshank projection from AB, (aii) Cruickshank projection phase diagram, (bi) Constant composition cut (S1: S2 ) 3:1) of a quaternary diagram, (bii) Cutting plane of bi, (c) Isothermal phase diagram with solvent S3. Table 10. Liquid-Liquid Phase Split for A-B-S1-S2 at 25 °C and 40 °Ca 25 °C feed
raffinate
extract
xS1
xS2
xA
xB
xS1
xS2
xA
xB
xS1
xS2
0.13 0.14 0.18 0.24 0.32 0.40
0.75 0.74 0.70 0.64 0.56 0.48
0.050 0.047 0.038 0.028 0.021 0.017
0.070 0.070 0.072 0.075 0.080 0.085
0.130 0.132 0.141 0.155 0.175 0.195
0.750 0.751 0.749 0.741 0.724 0.703
0.226 0.219 0.193 0.161 0.130 0.106
0.046 0.045 0.043 0.042 0.043 0.045
0.562 0.578 0.628 0.678 0.721 0.746
0.166 0.158 0.136 0.118 0.106 0.102
40 °C feed
raffinate
extract
xS1
xS2
xA
xB
xS1
xS2
xA
xB
xS1
xS2
0.20 0.24 0.28 0.32 0.40
0.68 0.64 0.60 0.56 0.48
0.045 0.038 0.033 0.029 0.023
0.071 0.073 0.075 0.077 0.081
0.183 0.194 0.205 0.217 0.242
0.701 0.695 0.687 0.677 0.654
0.175 0.157 0.141 0.127 0.104
0.044 0.044 0.044 0.045 0.048
0.618 0.650 0.674 0.692 0.716
0.162 0.149 0.141 0.136 0.132
a The mole fraction of A and B in the feed is fixed at 0.05 and 0.07.
saturation curve at 70 °C. In contrast, point 5 should lie inside the three-phase region at 25 °C, because the solid product that comes out when the temperature is decreased to 25 °C contains both A and B. The mother liquor composition is represented by point 7 in Figure 14bii. To represent the dissolution and recyrstallization of the solid in solvent S3, an SLE phase diagram of the A-B-S3 system is used (Figure 14c). The solvent addition process gives point 8 in the liquid-phase region
Ind. Eng. Chem. Res., Vol. 44, No. 16, 2005 6243
Figure 16. Second design alternative of Example 2: Recycling of mother liquor and evaporated solvent. (a) Block diagram, (b) Phase diagram representing liquid-liquid extraction process.
Figure 15. Stage 2 phase diagrams for Example 2: (a) Comparison of the isothermal LLE phase diagram between 25 °C and 40 °C, (b) Phase diagram of constant composition cut with S1:S2 equal to 3:1, (c) Comparison between original recipe (shown as circles) and the first design alternative (shown as triangles) on a polythermal phase diagram of A-B-S3.
at 60 °C. Since cooling crystallization (step 8) gives almost pure A (99.6% purity), it is expected that point 8 lies in the two phase (A + liquid) region at 25 °C, thus giving solid A and liquid stream 10. Discussion with the chemists revealed that the hot liquid mixture was cooled with melting ice, and crystals came out within a minute or so. As cooling is not being controlled, it is suspected that the 0.4% impurity actually comes from inclusion. Stage 2. To identify potential improvements for the extraction part, an LLE phase diagram is needed. As the ratio of A to B in the feed is fixed, it is decided to perform experiments to determine a few tie-lines at the extraction temperature (25 °C), by varying the relative amount of S1 to S2 in the feed. The same set of experiments is then repeated at a higher temperature (40 °C) to get an indication of the temperature effect. The analysis results of the extracts and raffinates, summarized in Table 10, are plotted in Figure 15a to outline the location and size of the liquid-liquid region at the two temperatures. Comparison of the two figures indicates that the liquid-liquid region at 25°C is larger than that at 40°C, with extract compositions closer to the A-S1 edge. Crystallization compartment maps for the A-B-S1-S2 system (cut at S1:S2 ) 75:25) (Figure 15b) and A-B-S3 system (Figure 15c) are prepared through modeling and experimental verification in a manner as discussed in Example 1. Under the constant composition cut of S1:S2 at 3:1, the binary eutectics between A and B with S1/S2 are indistinguishable from
the vertex of S1S2 because of its low melting point. In Figure 15c, since solvent S3 has a higher melting point (closer to that of A and B), all the binary eutectic points are clearly shown. Stage 3. Potential process improvements are considered at this stage. An alternative to improve the recipe without making too many changes is to modify the last step only, namely by reducing the amount of solvent S3 being used. As shown in Figure 15c, the composition after dissolution would be at point 8′ instead of point 8 (shown as triangles). After cooling to 25 °C, the liquid composition would be at point 10′ (shown as triangles). By lever rule, it is clear that more A can be recovered compared to the original recipe. Note that the dissolution temperature would now be higher than 60 °C. We can also reduce the number of processing steps. As in Example 1, it may be possible to obtain pure A directly in one crystallization step, by increasing the crystallization temperature. Using the SLE model, it is found that cooling to 55 °C, instead of 25 °C, should give pure A, with a recovery of 30.1%, compared to 39.6% for the original recipe. The third design alternative eliminates solvent S3 and the mother liquor (stream 7) is recycled back to the extractor (Figure 16a). Some of the evaporated solvent is also returned to the extractor. Since the overall composition of the feed to the extractor changes as a result of the recycle, it is convenient to model the LLE behavior such that the extract and raffinate compositions can be readily determined for any given feed. In practice, the parameters of the model should be obtained from experimental data via regression. For illustration purposes, however, the LLE behavior in this example was obtained by prediction using the ICAS software (CAPEC, Technical University of Denmark). The phase diagram indicating several tielines at 25 °C is shown in Figure 16b. The bold dashed line indicates the phase split (shown as diamonds) for the original feed composition, while the bold solid line is the phase split (shown as triangles) for the new
6244
Ind. Eng. Chem. Res., Vol. 44, No. 16, 2005
Table 11. Comparison of Different Process Alternatives in Example 2 2nd design (higher 3rd design original 1st design crystallizer recipe (less S3) temperature) (with recycle) no. of crystallizer recovery (%) yield (%) crystallization T (°C)
2 39.6 5.6 25
2 49.8 7.1 25
1 30.1 4.3 55
1 4.3 4.6 39
composition when 90% of stream 7 is recycled. The composition of the new feed, extract, and raffinate is represented by points 9, 3, and 2, respectively. With the crystallizer operating at 39 °C, 4.6% yield of pure A is obtained. Table 11 is a comparison of the original recipe and the three new alternatives. Here, the percentage recovery of A equals to the mass of A recovered at the crystallizer (as the final product) over the mass of A fed to the crystallization train and the yield equals to the mass of A recovered at the crystallizer (as the final product) over the mass of extract (A + B + S1) fed to the separation plant. As the third alternative provides a lower but reasonably good yield and involves less processing steps compared to the original recipe, it is decided to pursue it further. Experimental verification of the liquid-liquid phase split and crystallization process would be necessary to ensure process operability. Stage 4. There are two kinetic-related issues to be considered: impurity inclusion and PSD. A suitable cooling profile must be obtained such that inclusion can be minimized and the target crystal size of 20-80 µm can be met. Modeling nucleation and growth kinetics coupled with population balance equations can help in the effort of choosing the best cooling profile.33 Stage 5. In place of liquid-liquid extraction, chromatography can be considered as an alternative. If a suitable stationary phase can be found, a simulated moving bed (SMB) process is a good alternative for obtaining A-rich and B-rich fractions. This process can be coupled with crystallization to obtain pure A as a product, as shown by the block diagram in Figure 17a. With the same feed as before (stream 1), the SMB process gives a raffinate (stream 2) and extract (stream 3). As chromatography usually gives solvent rich extract (A-rich stream), some solvent should be removed first prior to crystallization. Evaporation gives stream 5, which has to lie in compartment A and crystallization of A gives the mother liquor of stream 7. To prevent the loss of valuable substances, stream 7 is recycled back to the SMB after a purge. In addition, to prevent saturation of substances in the column, some of the evaporated solvent is being recycled too. The crystallization compartment map of the A-B-S1 system (Figure 17b) shows all the processing points of this hybrid process. Conclusions This article proposes a workflow procedure that integrates chemistry research and process design through visualization in composition space. Process recipe is captured on phase diagrams and separation boundary maps by representing each operation as a movement in composition space. Although the examples only focus on systems involving three and four components to main-
Figure 17. New design for example 2. (a) Block diagram of hybrid of chromatography and crystallization process. (b) Ja¨necke projection SLE phase diagram (A-B-S1).
tain clarity in visualization, this approach is applicable to systems involving any number of components, provided that a convenient projection or cut is chosen for visualization. This approach promotes mutual understanding of driving forces and separation boundaries among all members of the process development team, thus facilitating the achievement of the overall process objectives through an integrated network of synthesis, modeling, and experimental activities. Rather than individually trying to deliver the best solutions on separate subproblems, stakeholders closely interact with each other in finding the best overall solution. With a clear view of the entire development process, potential problems at later stages can be anticipated and prevented at the earlier stages. Such a working style can lead to a significant reduction in the time, effort, and money for process development. The application of this concept of integrating chemistry research and process design by combining synthesis, modeling, and experimental activities in a coherent workflow is not limited to separation processes, but can be extended to chemical process development in general. For example, a better reactor design can be expected if experimental activities such as catalyst selection and reaction mechanism studies are performed in coordination with synthesis and modeling activities in designing the reactor, rather than sticking to a fixed reaction
Ind. Eng. Chem. Res., Vol. 44, No. 16, 2005 6245
condition which has been found to give the best yield in the laboratory. Efforts in this direction are now underway. Acknowledgment We thank Prof. R. Gani of CAPEC-TU Demark for providing the ICAS (Integrated Computer Aided System) software for property predictions. Financial support from the Research Grant Council HIA02/03.EG02 is gratefully acknowledged. Nomenclature f Li ) pure-liquid fugacity, Nm-2 ∆Hf,i ) heat of fusion of component i, J‚mol-1 Ki ) equilibrium constant for species i L ) no. of moles of liquid P ) total pressure, Nm-2 R ) universal gas constant, 8.314 J‚mol-1‚K-1 T ) temperature, °C or K Tm,i ) melting point of component i, °C or K xi ) mole fraction of component i yi ) mole fraction of component i in vapor phase Greek Letters γi ) activity coefficient of component i γLi ) activity coefficient of component i for the liquid phase φVi ) fugacity coefficient of component i for the vapor phase
Literature Cited (1) Mehta, A. Birth of a Drug: For Chemists, There’s Many a Role to Play in the Long Process of Drug Development. C&EN March 22, 2004, 51. (2) Pharmaceutical Research and Manufacturers of America, 2004 Industry Profile, URL http://www.phrma.org/publications/ publications//2004-03-31.937.pdf. (3) Pisano, G. P. The Development Factory; Harvard Business School Press: Boston, MA 1997. (4) Basu, P. K. Pharmaceutical Process Development is Different. Chem. Eng. Prog. 1998, 94, 75. (5) Yu, L. X.; Lionberger, R. A.; Raw, A. S.; D’Costa, R.; Wu, H.; Hussain, A. S. Applications of Process Analytical Technology to Crystallization Processes. Adv. Drug Delivery Rev. 2004, 56, 349. (6) O’Young, L.; Natori, Y.; Pressly, T. G.; Ng, K. M. A Physical Limitation Based Framework for Separations Synthesis. Comput. Chem. Eng. 1997, 21, S223. (7) Pressly, T. G.; Ng, K. M. Process Boundary Approach to Separations Synthesis. AIChE J. 1999, 45, 1939. (8) Wibowo, C.; Ng, K. M. Unified Approach for Synthesizing Crystallization-Based Separation Processes. AIChE J. 2000, 46, 1400. (9) Harjo, B.; Wibowo, C.; Ng, K. M. Visualization of HighDimensional Liquid-Liquid Equilibrium Phase Diagrams. Ind. Eng. Chem. Res. 2004, 43, 3566. (10) Doherty, M. F.; Malone, M. F. Conceptual Design of Distillation Systems; McGraw-Hill: New York, 2001. (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. Manuscript submitted to IECR. 2005.
(12) Samant, K. D.; Berry, D. A.; Ng, K. M. Representation of High-Dimensional Solid-Liquid Phase Diagrams. AIChE J. 2000, 46, 2435. (13) Samant, K. D.; Ng, K. M. Representation of HighDimensional Solid-Liquid Phase Diagrams for Ionic Systems. AIChE J. 2001, 47, 861. (14) Wibowo, C.; Samant, K. D.; Ng, K. M. High-Dimensional Solid-Liquid Phase Diagrams Involving Compounds and Polymorphs. AIChE J. 2002, 48, 2179. (15) Wibowo, C.; Ng, K. M. Visualization of High-Dimensional Systems via Geometric Modeling with Homogeneous Coordinates. Ind. Eng. Chem. Res. 2002, 41, 2213. (16) Widagdo, S.; Seider, W. D. Azeotropic Distillation. AIChE J. 1996, 42, 96. (17) Walas, S. M. Phase Equilibria in Chemical Enigneering; Butterworth: Boston, MA, 1985. (18) Reid, R. C.; Prausnitz, J. M.; Poling, B. E. The Properties of Gases and Liquids, 5th ed.; McGraw-Hill: New York, 1993. (19) Ozawa, R.; Matsuoka M. Determination of Solid-Liuqid Phase Equilibrium of Orgainc Ternary Eutectic Mixtures by Differenctial Scanning Calorimeter-The o-, m-, and p-Nitroaniline System. J. Cryst. Growth 1989, 98, 411. (20) Constantinou, L.; Gani, R. New group contribution method for estimating properties of pure compounds. AIChE J. 1994, 40, 1697. (21) Marrero, J.; Gani, R. Group-contribution Based Estimation of Pure Component Properties. Fluid Phase Equilibria 2001, 183184, 183. (22) Myerson, A. S. Handbook of Industrial Crystallization, 2nd ed.; Butterworth-Heinemann: Boston, MA, 2002. (23) Anderson, N. G. Tools for Purifying the Product: Column Chromatography Crystallizaiton and Reslurrying. Practical Process Research & Development; Academic Press: San Diego, 2000. (24) Jaksland, C. A.; Gani, R.; Lien, K. M. Separation Process Design and Synthesis Based on Thermodynamic Insights. Chem. Eng. Sci. 1995, 50, 511. (25) Kelkar, V. V.; Ng, K. M. Design of Reactive Crystallization Systems Incorporating Kinetics and Mass-Transfer Effects. AIChE J. 1999, 45, 69. (26) Schroer, J. W.; Ng, K. M. Process Paths of Kinetically Controlled Crystallization: Enantiomers and Polymorphs. Ind. Eng. Chem. Res. 2003, 42, 2230. (27) Barnicki, S. D.; Fair, J. R. Separation System Synthesis: A Knowledge-Based Approach. 1. Liquid Mixture Separations. Ind. Eng. Chem. Res. 1990, 29, 421. (28) Barnicki, S. D.; Fair, J. R. Separation System Synthesis: A Knowledge-Based Approach. 2. Gas/Vapor Mixtures. Ind. Eng. Chem. Res. 1992, 31, 1679. (29) Humphery J. L.; Keller II G. E. Process Selection. Separation Process Technology; McGraw-Hill: New York, 1997. (30) Fung, K. Y.; Ng, K. M.; Wibowo C. Synthesis of Chromatography-Crystallization Hybrid Separation Processes. Ind. Eng. Chem. Res. 2005, 44, 310. (31) Cohen-Adad, R.; Cohen Adad, M. T. Solubility of Solids in Liquids. In The Experimental Determination of Solubilities; Hefter, G. T., Tomkins, R. P. T., Eds.; Wiley: New York, 2003. (32) Cruickshank, A. J. B.; Haertsch, N.; Hunter, T. G. LiquidLiquid Equilibrium of Four-Component Systems. Ind. Eng. Chem. 1950, 42, 2154. (33) Wibowo, C.; Chang, W. C.; Ng, K. M. Design of Integrated Crystallization Systems. AIChE J. 2001, 47, 2474.
Received for review October 13, 2004 Revised manuscript received February 15, 2005 Accepted February 18, 2005 IE049008Y
