Multistage Continuous Mixed-Suspension, Mixed-Product Removal

Article pubs.acs.org/OPRD

Multistage Continuous Mixed-Suspension, Mixed-Product Removal (MSMPR) Crystallization with Solids Recycle Jicong Li, Bernhardt L. Trout, and Allan S. Myerson* Novartis-MIT Center for Continuous Manufacturing and Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, E19-502, Cambridge, Massachusetts 02139, United States S Supporting Information *

ABSTRACT: Continuous crystallization process has potential advantages such as lower cost and improved flexibility in pharmaceutical production when compared to batch crystallization. A good continuous crystallization process should achieve a high product yield and purity comparable to current batch crystallization processes. For compounds that have low growth rates, a high yield is difficult to achieve without long residence times. Solids recycle is a potential solution for this problem as it can increase the surface area of crystals in the crystallizer thus increasing the mass deposition rate. In this study, solids recycle was used in a two-stage continuous mixed-suspension, mixed-product removal (MSMPR) cooling crystallization. Manual solids recycle and the use of a designed column for automatic slurry concentration were employed. The crystallization of cyclosporine, which has very low growth rate (about 0.1 μm/min) at low temperatures in acetone, showed only 65.0% yield in a two-stage MSMPR without solids recycle. With solids recycle to the second stage and both stages, 75.3% and 79.8% in yield were achieved, respectively. The product purity remained the same, while the yield was enhanced. A population balance model was developed to estimate the final yield of continuous process with solids recycle. The simulation results showed that optimization in stage number, stage temperatures, and solids recycle ratios could improve the yield to 83.9% in four-stage MSMPR crystallization with solids recycle. This yield was close to the batch yield at equilibrium, i.e., 86.0%. higher than the equilibrium batch yield.15 However, previous research showed that for multistage MSMPR cooling crystallization, the purity of cyclosporine crystal decreased from 96% to 94% with the increased yield using mother liquor recycle, and the mean crystal size decreased as well.16 Using a “growth-type” crystallizer17 will separate the slurry into a clear liquor and a heavier sludge. By removing the clear mother liquor at a higher rate and withdraw the sludge in a lower rate, the solids will have longer residence time in the crystallizer. Such a type of crystallizer provides a greater surface area for crystal growth and is widely used in precipitating the dissolved metals from wastewater.18−20 By recycling some portion of the precipitated sludge material, the sludge density was increased from 1 to 15% (w/w), and a better separation was obtained.18,19 However, such a separation device requires a large surface area, and the size can be impractical when the feed concentration is relatively high,18 e.g., in pharmaceutical crystallization. The goal of this work is to overcome the problems associated with the approaches mentioned above, i.e., to enhance the yield at low operating temperatures while keeping the residence time short and maintaining the desired crystal purity. To accomplish this goal, a two-stage MSMPR with solids recycle is employed for the cooling crystallization of cyclosporine from acetone solution. In addition, a population balance model in conjunction with experimentally determined crystallization

1. INTRODUCTION Continuous manufacturing has been well-developed in food and chemical industries; however, batch operation is still the most common method used in the pharmaceutical industry.1 For pharmaceutical manufacturing, the advantages of continuous processing can be enhanced reproducibility of results, reduced cost, improved process efficiency, and flexibility in production capacity.2 Due to these reasons, continuous crystallization has obtained great interest in both industry and academia in recent years.3−11 The major challenges associated with the transition from batch to continuous crystallization process are to obtain the desired yield, purity, and crystal size of active pharmaceutical ingredients (APIs).12−16 Batch process discharge at equilibrium, while continuous processes operate at a steady state in which the discharge is still supersaturated.14 One common approach of improving the yield of continuous crystallization is to lower the operating temperature and thus decrease the solubility of API. However, for some APIs, e.g., cyclosporine, whose growth kinetics are very sensitive to temperature, the growth rate is very low (about 0.1 μm/min) at low temperature. Thus, low operating temperature will cause low yield, or it is required a much longer process residence time. Another method to boost the yield of a continuous process is to separate the residence times of mother liquor and solids.17 Applying an appropriate mother liquor recycle stream to the system will make the residence time of mother liquor longer than that of solids. A study of cooling crystallization of cyclosporine showed 91.8% yield by using a single-stage mixedsuspension, mixed-product removal (MSMPR) crystallizer with concentrated mother liquor recycle system, which is 4.8% © XXXX American Chemical Society

Special Issue: Continuous Processing, Microreactors and Flow Chemistry Received: September 28, 2015

A

DOI: 10.1021/acs.oprd.5b00306 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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maintained at 0 °C for 12 h. The liquid and solids phase samples were taken at the end of the process. 2.3.2. Two-Stage MSMPR Crystallization without Solids Recycle. During the experiment, the feed was continuously pumped into stage 1. The slurry in stage 1 was transferred intermittently into stage 2. The temperature of the first stage was set at 25, 15, and 0 °C, respectively, while that of second stage was set at 0 °C in order to test the effect of first-stage temperature on final results. Focused beam reflectance measurement (FBRM) was used to determine when the steady state chord length distribution was reached. The liquid and solids phase samples were taken after the process reached equilibrium. 2.3.3. Two-Stage MSMPR Crystallization with Manual Solids Recycle. In order to increase the yield of the process, cooling crystallization experiments with manual solids recycle were carried out, as shown in Figure 2. The feed concentration

kinetics and distribution coefficients is developed. The model can simulate n-stage MSMPR crystallizer with different number of slurry recycle or mother liquor recycle to any stage(s). Using this model, the optimal stage temperatures, residence time, feed concentration, and recycle ratios can be obtained.

2. MATERIALS AND METHODS 2.1. Materials. The compound chosen for this work is cyclosporine A (an immunosuppressant drug) which is supplied by Novartis in both crude and purified form with purity of 90.8% and 95.0%, respectively. The chemical structure of cyclosporine A is shown in Figure 1. There are about 38

Figure 1. Chemical structure of cyclosporine A (purity of commercial sample was 95%).

Figure 2. Schematic diagram of the two-stage MSMPR crystallizer with manual solids recycle to second stage.

and flow rate were the same as other MSMPR experiment. The temperature of stage 1 and 2 was set at 25 and 0 °C, respectively. The outlet stream of the second stage was filtered, and the crystals were collected on the filter paper. A certain amount of solids was weighted and manually added back to the second crystallizer every 18 min when the slurry of first stage was pumped into second stage so that the recycled solid and the ones from first stage would have the same residence time distribution in stage 2. Two different solids recycle ratio were used: 75% and 90%; i.e., 75% and 90% of solids collected on the filter each time were added back to stage 2. FBRM was used to determine when the steady state chord length distribution was reached. The liquid and solids phase samples were taken after the process reached equilibrium. 2.3.4. Two-Stage MSMPR Crystallization with Continuous Solids Recycle. In order to make the manual solids recycle to an automatic continuous recycle process without powder handling, a column separator was designed to accomplish this goal, as shown in Figure 3. Every 18 min, the slurry from stage 2 (F2) was pumped into the column instead of filter funnel. The length of the column was designed to allow the crystals to sediment to the bottom due to gravity within the time of each cycle. After all the crystals sediment, a certain amount of the clear liquor on the top would be removed as stream clear liquor (F4). The slurry exited from the bottom of the column was then concentrated. The suspension density of the concentrated slurry can be controlled by the clear liquor removal ratio x, defined as x = F2/F4. Then certain ratios of concentrated slurry were recycled to previous stages to alter the steady-state condition. The recycle ratio to stage i, noted as Ri can be determined by the flow splitting at the bottom of the column, i.e., Ri = F5,stage i/(F3 + F5,stage i + F5,stage j), where F5,stage i, F5,stage j are the flow rate recycle to stage i, and stage j, respectively. By

impurities in the crude which are detected by HPLC, however, are not fully identified. Acetone (99.5%) was purchased from Avantor Performance Materials and used as the solvent. 2.2. Experiment Setup. All continuous crystallization experiments were carried out with two-stage continuous MSMPR crystallizer with each stage being a 155 mL water jacketed reaction vessel with overhead mechanical stirring and independent temperature controlling (Thermo Scientific NESLAB RTE). In this system, peristaltic pumps (Masterflex, Cole-Parmer) with Chem-Durance Bio tubing (Cole-Parmer) were used for solution and slurry transfer. For all continuous experiments, feed solution, which is crude cyclosporine (27.3% w/w, API/solution, 90.8% purity) in acetone at 53 °C, was continuously pumped into the first crystallizer with flow rate of 0.86 mL/min, so that the residence time of the solvent in each stage was 3 h. In both stages, slurry was removed intermittently so that every 18 min, 15.5 mL slurry (10% of the vessel volume) was removed rapidly with max pump flow rate (170 mL/min). Once the solution level had dropped below the level of the outlet dip tube, air was pumped into the tube and removed the remaining slurry in the outlet tube. The pumps were set at “time distribution mode” to control the intermittent operation. 2.3. Procedure. 2.3.1. Batch Crystallization Experiment. A batch cooling crystallization experiment was carried out in the same 155 mL water jacketed reaction vessel with overhead mechanical stirring and independent temperature controlling (Thermo Scientific NESLAB RTE) in order to obtain a basis for comparison for the MSMPR with solids recycle. A solution with identical composition to the MSMPR feed of 27.3% (w/ w) of crude cyclosporine (90.8% purity) in acetone at 53 °C was cooled to 0 °C in 3 h with linear temperature decrease and B



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stage 2. The slurry from stage 2 was pumped into the column separator where the crystals are driven by gravity and sediment onto the bottom of the column. Clear liquor removal ratio x = 1/3.5 = 0.287 and recycle ratio R = 0.9 were used in this experiment. The temperature of the first stage was set at 25, 15, and 0 °C, respectively, while that of second stage was set at 0 °C in order to test the effect of first-stage temperature on final results. The experimental procedure for 2-stage MSMPR crystallizer with continuous solids recycle to both stages is shown in Figure 4b. Clear liquor removal ratio x = (1/3.5) = 0.287 and recycle ratio R1 = 0.45 and R2 = 0.45 were used in this experiment. The temperatures of both stages were set at 0 °C. 2.3.5. Experimental Conditions. In order to evaluate the performance of the solids recycle system, a total of nine continuous experiments were conducted. The experimental conditions are summarized in Table 1. For all the experiments, the feed concentration was 27.3% w/w of API with purity of 90.8%. The continuous processes reached steady state after 24 hours (i.e., mother liquor concentration and crystal size distribution of either stage were stable). 2.4. Liquid- and Solids-State Characterization. For liquid state, mother liquor was collected by filtrating the slurry with 0.45 μm PTFE filter and then diluted 40 times in 50% (v/ v) acetonitrile water solution. The concentration and purity of the mother liquor were measured using high-performance liquid chromatography (HPLC). For solids state, crystal size distribution (CSD) was measured online using focused beam reflectance measurement (FBRM). After filtrating, washing (with 0 °C acetone), and drying (in a 70 °C vacuum oven overnight), crystal samples were characterized by X-ray powder diffraction (XRPD). Crystals were dissolved in 50% v/v acetonitrile water solution for purity test by HPLC. The protocols for FBRM, HPLC, and XRPD are listed in the Supporting Information.

Figure 3. Schematic diagram of the column separator.

using this column separator, continuous solids recycle has been achieved successfully. This design avoids the power handling compared to dry crystal recycle, and each flow can be easily pumped by peristaltic pump without clogging. The experimental procedure for two-stage MSMPR crystallizer with continuous solids recycle to second stage is shown in Figure 4a. The feed solution was pumped into stage 1 and then

3. EXPERIMENTAL RESULTS 3.1. Batch Crystallization. The yield of the crystallization process is defined as Yield = (Mass of API in Solid Form/Mass of API in Feed Solution) The final yield and purity for the batch crystallization is 86.0% and 96.0%, respectively. The yield is equal to the theoretic batch yield at equilibrium calculated by solubility. The purity is slightly higher than that of commercial cyclosporine (95.0%). The XPRD patterns of the final crystals obtained from batch and continuous processes are consistent. The data are listed in Supporting Information. Starting with an amorphous crude material (90.8% purity), the multistage MSMPR crystallizer with solids recycle has successfully produced purified crystalline products.

Figure 4. Schematic diagram of the two-stage MSMPR crystallizer (a) with continuous solids recycle to second stage and (b) with continuous solids recycle to both stages.

Table 1. Experimental Conditions for Continuous Crystallization Experiments with manual solids recycle

without solids recycle stage 1 temperature (°C) stage 2 temperature (°C) solids recycle ratio to stage 1 solids recycle ratio to stage 2 clear liquor removal ratio

with continuous solids recycle

expt 1

expt 2

expt 3

expt 4

expt 5

expt 6

expt 7

expt 8

expt 9

25 0 − − −

15 0 − − −

0 0 − − −

25 0 − 0.75 −

25 0 − 0.90 −

25 0 − 0.90 0.287

15 0 − 0.90 0.287

0 0 − 0.90 0.287

0 0 0.45 0.45 0.287

C



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3.2. Two-Stage MSMPR Crystallization with Manual Solids Recycle. In the experiment without solids recycle, the steady-state mother liquor concentration was significantly higher than the equilibrium concentration, which caused a low yield of 63%. In the experiment with solids recycle, the suspension density of stage 2 is increased from 0.17 to 0.59 g/ cm3, as shown in Figure 5. With larger surface area, the final

Figure 6. Effect of changing temperature at first stage and using solids recycle on final yield.

stage remains very low, the larger total crystal surface area entering the final stage will increase the final yield. When adding solids recycle streams to both stage, the final yield increased more as shown in Figure 7. The total solids

Figure 5. Results for manual solids recycle: (left) final yield; (right) suspension density in second stage.

yield of the process increased. Compared to the process without solid recycle, the yield increased 11% by using recycle ratio of 90%. Although there was still a 12% gap to the yield of batch at equilibrium, these three experiments proved that solids recycle method has the efficacy of enhancing yield. The purity of crystals is 96.0%, which is the same as that of the batch. In general, the impurity concentration at steady state is high, which may cause purity decrease. In this work, purity maintaining is observed due to the low linear growth rate. It is reported that lower growth rate contributed to less impurity incorporation.21 Thus, with solids recycle, the yield is improved while purity remains. 3.3. Two-Stage MSMPR Crystallization with Continuous Solids Recycle. The results of expt 5 and expt 6 can be used to compare the differences of the column separator and manual solids recycle, since they were conduct at same stage temperature and recycle ratio conditions. The final yield is 74.1% and 75.2% for expt 5 and expt 6, respectively. This indicates that the column separator has similar efficacy in improving the yield compared to manual solids recycle. This means the design of column separator is successful to apply solids recycle to the continuous crystallization process. With column separator, the final yield was slightly higher. This was because a portion of mother liquor was also recycled to the second stage with the slurry stream, which slightly increased the residence time of the liquid phase in second stage. The experiment data also showed that for expt 6, 7, 8, and 9, the final crystal purity remains the same at 96%. This is reasonable since impurities retaining in the solution were removed out of system with clear liquor removal. Figure 6 shows the combination effect of first-stage temperature and solids recycle to the second stage. At the same condition of stage temperature, using solids recycle can increase the yield. However, the effect of solids recycle is less significant when the first stage temperature is 15 °C. This is because faster crystallization kinetics was achieved at 15 °C in first stage due to the balance between the influence of supersaturation and temperature. Therefore, more crystal surfaces were generated in stage 1 and increase the crystal growth in stage 2 even though there was no solids recycle (final yield, 72.6%). This indicates that if the temperature of final

Figure 7. Effect of solids recycle to different stages on final yield.

recycle ratio remained the same at 90% in expt 9, but 45% to stage 1 and 45% to stage 2. It gave additional 4.5% increase in final yield. This was because the linear growth rate in first stage was higher and there were more crystal growths in first stage. Moreover, the 45% crystals recycle to first stage along with the additional growth in first stage would finally be pumped to stage 2. Thus, there would be more crystal surfaces in the second stage compared to the scenario of 90% recycle to second stage. A 79.8% yield is comparable to a four-stage MSMPR with a total 12 h residence time. The experiments proved that solids recycle with stage temperature optimization is an effective method to improve yield while maintaining product purity. In Figure 8, the crystal size distributions of three experiments which have the same temperature of stage 1 are compared. The data shows that, with either manual or automatic solids recycle, the mean size of the crystals obtained is larger and the size distribution is narrower, compared to those without solids recycle. Moreover, the results show the consistency between manual recycle and using column since the crystal size distributions are very similar. The result demonstrates that solids recycle is feasible and has its advantage of increasing the yield and at the same time control crystal purity and size. D



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The population balance equations are coupled by the mass balance of the API at each stage and the column. At steady state, there is no accumulation of the mass in each stage. Thus, the mass flowing into the stage equals the mass flowing out. Since the suspension density in this system is very high, the volume of the crystals in the solution is taken into consideration. For first stage, ⎛ M ⎞ F0C0 + FN + 1⎜⎜1 − N + 1 ⎟⎟CN + FN + 1MN + 1 ρc ⎠ ⎝

Figure 8. Cord length distribution of the crystals at steady state with and without solids recycle (data of expt 1, expt 5, and expt 6).

⎛ M⎞ − F1⎜⎜1 − 1 ⎟⎟C1 − FM 1 1 = 0 ρc ⎠ ⎝

4. STEADY STATE SIMULATION 4.1. Governing Equations and Analytic Solution. The flowchart for an n-stage MSMPR with multiple recycle streams is shown in Figure 9. In this schematic diagram, the

(5)

Here, the first term is the API (weight) from feed solution. The second term is the API from the liquid phase of the recycle stream. The third term is the API from the solid phase of the recycle stream. The fourth and fifth terms are the API pumped out from stage 1 in liquid and solid phase, respectively. For the following stages, ⎛ ⎛ M ⎞ M ⎞ Fi − 1⎜⎜1 − i − 1 ⎟⎟Ci − 1 + Fi − 1Mi − 1 + FN + i⎜⎜1 − N + 1 ⎟⎟CN ρc ⎠ ρc ⎠ ⎝ ⎝ ⎛ M⎞ + FN + iMN + 1 − Fi ⎜⎜1 − i ⎟⎟Ci − FM i i = 0 ρc ⎠ ⎝

Figure 9. Schematic diagram of the multistage MSMPR with different number of recycle streams to any stages. F is volume flow rate. T, V, τ, and M are the temperature, volume, residence time, and solid suspension density of the stage, respectively).

i = 2, 3, ..., N

And the mass balance for the column separator is FN MN − (1 − x)FN MN + 1 = 0

concentrated slurry can be recycled to any stage(s) at any recycle ratio. One dimension population balance model was introduced to describe the crystallization of crystallization in each stage. The governing equations at steady state for stage i is G1V1 GiVi

dn1 = FN + 1nN + 1 − Fn 1 1 dL

(1)

(2)

(3)

where n is the matrix of crystal number density distribution, e.g., column 1 of n is the crystal number density distribution of stage 1. A is the coefficient matrix describing eqs 1 and 2; e.g., the first element is coefficient for n1 in eq 1: A1,1 = −(F1/ (G1V1)). The homogeneous solution for eq 3 is n = ∑Ni=1civi exp(λiL), where λi is the eigenvalues of matrix A, vi is the corresponding eigenvectors, and ci is constant that satisfy the boundary condition: ni(L = 0) = Bi /Gi

⎞g ⎛ Ea, g ⎞⎛ Ci ⎜ ⎟⎟ − 1 Gi = kg ,0 exp⎜ − ⎟⎜ ⎝ RT ⎠⎝ Csat, i ⎠

(8)

⎞b ⎛ E b,g ⎞⎛ Ci − 1⎟⎟ Mimωs Bi = k b,0 exp⎜ − ⎟⎜⎜ ⎝ RT ⎠⎝ Csat, i ⎠

(9)

where kg,0 and kb,0 are the pre-exponential factors, Ea,g and Eb,g are the energy barrier for growth and nucleation, Csat,i is the solubility at the stage temperature, M is the suspension density, and ω is the stir rate. The effect of the impurities on the parameters had been taken into consideration since crude cyclosporine was used in the experiments. The impurity incorporation is determined by the distribution coefficient: DCi,j, where i is the i-th stage, j is the j-th impurity. The definition and calculation of distribution coefficient are expressed as eqs 10 and 11:

where G is the growth rate, n is crystal number density distribution, L is crystal length, and i is the i-th stage. Equations 1 and 2 form a homogeneous ordinary differential equation system: dn = An dL

(7)

The crystallization kinetics is

dni = Fi − 1ni − 1 + FN + inN + 1 − Fn i i dL

i = 2, 3, ..., N

(6)

DCi , j = (Mi , j /Mi)/(Ci , j/Ci) DCi , j =

aCi , j Ci , j + Ci

(10)

+b (11)

At steady state, the mass balance equations for the impurity are similar to those for the API. For each stage, the mass balance of impurity can be expressed as follows:

(4)

where B is the nucleation rate. E



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⎛ M ⎞ F0C0, j + FN + 1⎜⎜1 − N + 1 ⎟⎟CN , j + FN + 1MN + 1, j ρc ⎠ ⎝ ⎛ M⎞ − F1⎜⎜1 − 1 ⎟⎟C1, j − FM 1 1, j = 0 ρc ⎠ ⎝

(12)

⎛ ⎛ M ⎞ M ⎞ Fi − 1⎜⎜1 − i − 1 ⎟⎟Ci − 1, j + Fi − 1Mi − 1, j + FN + i⎜⎜1 − N + 1 ⎟⎟ ρc ⎠ ρc ⎠ ⎝ ⎝ ⎛ M⎞ CN , j + FN + iMN + 1, j − Fi ⎜⎜1 − i ⎟⎟Ci , j − FM i i,j = 0 ρc ⎠ ⎝ i = 2, 3, ..., N

Figure 10. Simulation results for two-stage MSMPR with solids recycle. Yield of batch at equilibrium is 86.0%.

(13)

FN MN , j − (1 − x)FN MN + 1, j = 0

(14)

The homogeneous ordinary equation system coupled with mass balance and kinetics were solved numerically. We can solve the steady-state conditions for each stage. In the model, we incorporate the purity estimation module and use the literature value10 for the kinetic parameters and distribution coefficient as listed in Table 2. And m is considered as the effect Table 2. Kinetic Parameters for Nucleation and Growth parameter

value

units

kg,0 Ea,g/R kb,0 Eb,g/R g b m s a b

1.13 × 10 9.06 × 103 4.80 × 1020 7.03 × 103 1.33 1.50 2/3 0 3.49 −0.104 7

m/min K #/(m3 min) K dimensionless dimensionless dimensionless dimensionless dimensionless dimensionless

Figure 11. Simulation results for four-stage MSMPR with solids recycle. Yield of batch at equilibrium is 86.0%.

5. CONCLUSION In continuous steady state processes, it can be difficult to obtain the same yield-purity relationship as in a well-designed batch process. In this work, a lab scale multistage MSMPR crystallizer with continuous solids recycle was built and successfully run at steady state. With solids recycle stream, the yield is significantly increased while the product purity remains the same. This design also shows the possibility to control the crystal size distribution. The methodology outlined in this work can also be applied to other systems to achieve acceptable yield, purity and crystal size in a continuous process. A population balance model was built to optimize the yield and by adjusting stage number, stage temperature, recycle ratio, and clear liquor removal ratio. The simulation results indicate that MSMPR crystallizer with solids recycle can boost the yield close to the theoretical maximum. Currently, experiments with different conditions were being conducted to valid the model. With the development of continuous crystallization processes in pharmaceutical industry, the significant difference between equilibrium in batch process and steady state in continuous process is noticed. The methodology developed in this work demonstrates a way to benefit the performance at steady state and will help the industry in moving from batch to continuous manufacturing.

of secondary nucleation so that it is set as 2/3 representing the surface area of the crystals. Since the stir rate in the experiment is always set at 250 rpm as a constant for both stages, parameter s is set as 0. We treated all the impurities as one “dummy” impurity for simplicity. The parameters for the distribution coefficient of such impurity was a and b listed below. Further investigation is needed for distribution coefficient of the actual individual impurities. 4.2. Steady State Simulation. Simulation results for twostage MSMPR with solids recycle are shown in Figure 10. Column 1 and 2 show the effect of only changing the solids recycle ratios. The yield can be increased be 14%. The simulation results are comparable with the experiment results. Column 3 shows the further improvement in yield by changing the first stage temperature and solids recycle ratios. Additional 5.2% increase in yield is achieved. In Figure 11, the stage number increases to four. If no solids recycle is used, the yield is even lower than that of the two-stage MSMPR with solids recycle. This indicates that simply increasing the stage numbers is not able to provide more crystal surface area in the last stage, thus leads to failure in yield improvement. After optimizing the stage temperatures and solids recycle ratios, the yield is only 2.1% less than value of the batch at equilibrium. F



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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.5b00306. FBRM, HPLC, and XRPD protocol, XRPD data, HPLC calibration and impurity content of crude and purified cyclosporine (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Phone: 617-452-3790. Fax: 617-253-2072. E-mail: Myerson@ mit.edu. Notes

The authors declare no competing financial interest.

■ ■

ACKNOWLEDGMENTS We acknowledge the Novartis-MIT Center for Continuous Manufacturing for funding and technical guidance. REFERENCES

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Multistage Continuous Mixed-Suspension, Mixed-Product Removal

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