Complexation-Assisted Continuous Crystallization ... - ACS Publications

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Complexation-Assisted Continuous Crystallization of Isomeric Systems with Nanofiltration Recycle Shankul Vartak and Allan S. Myerson* Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States S Supporting Information *

ABSTRACT: In API-impurity systems consisting of structural isomers, the impurity has a strong affinity to incorporate into the host crystal owing to their identical molecular weight and similar structure. Conventional successive recrystallization turns out to be an unattractive purification strategy in such cases, since it can improve crystal purity only at the cost of yield. As an alternative, selective complexation of the impurity can sterically prevent its incorporation into the host lattice by increasing the apparent molecular weight and dimensions of the impurity. The increase in size of the impurity post complexation can be further exploited using a nanofiltration membrane to preferentially reject the complex in solution, while allowing the smaller molecules of uncrystallized API to permeate through. The crystallization yield can be enhanced by concentrating the permeate stream and recycling it back to the crystallizer. Thus, complexation-assisted nanofiltration recycle presents a strategy to improve both yield and crystal purity simultaneously in a continuous mode. In the present work, the application of this strategy is described for the continuous cooling crystallization of two isomeric systems in a mixed-suspension mixed-product removal (MSMPR) crystallizer. The first system consists of 4-nitrophenol with 3-nitrophenol as an added impurity in an aqueous solvent, while the second one consists of the active pharmaceutical ingredient (API) acetaminophen with its isomer 3-acetamidophenol added as an impurity in a mixed solvent of 50:50 ethanol and water by volume. A working strategy for selecting the complexing agent and nanofiltration membrane is discussed. For both systems, the complexation-assisted continuous mode with nanofiltration recycle performed better than both the batch process as well as the unrecycled MSMPR process in terms of higher crystallization yield and lower impurity incorporation in crystals.

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host crystal surface and/or be incorporated into the lattice.13−16 In such cases, successive recrystallization is employed to improve crystal purity. However, the crystallization yield of any given step is never unity, so that the overall yield of multiple steps is lower than that of a single one. The yield may be increased by using appropriate concentration and recycle strategies in a continuous process. An undesired result of such recycling is the concentration of the impurities along with the uncrystallized API, which ultimately leads to a higher impurity incorporation in the crystal compared to unrecycled operation. This trade-off between yield and crystal purity encourages the search for novel techniques which would improve both these parameters simultaneously. Impurity complexation, coupled with nanofiltration recycle, is one such effective strategy. The concept of impurity complexation is based on finding a compound (termed the complexing agent) which can selectively bind with the impurity but not with the API. If such a compound is added to the feed solution prior to crystallization, it forms an impurity complex but does not incorporate

INTRODUCTION About 90% of all active pharmaceutical ingredients (API) are crystalline small organic molecules.1 This makes crystallization the preferred separation and purification technique in the pharmaceutical industry. Batch crystallization, in the form of cooling, antisolvent, or reactive crystallization, has been carried out for decades in this sector.2 However, in recent times, there has been an increasing preference for continuous operation, owing to the numerous advantages of this mode over its batch counterpart in terms of higher throughput and/or lower footprint. The estimated savings from continuous manufacturing can be as high as 40%.3 Mixed-suspension mixed-product removal (MSMPR) crystallizers and plug flow crystallizers are classes of continuous crystallizers currently being evaluated for use in pharmaceutical manufacturing.4−9 The former type is the more widely used since it can handle higher suspension densities without risk of clogging. By increasing the number of crystallization stages and/or using recycling, the yield of an MSMPR can be improved and made to exceed even the batch values.10−12 For an API containing one or more impurities having similar molecular weights and dimensions as the API molecule, the impurity often has a strong tendency to be adsorbed on the © XXXX American Chemical Society

Received: July 24, 2017 Revised: August 27, 2017 Published: August 30, 2017 A

DOI: 10.1021/acs.cgd.7b01030 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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complex (which stays predominantly in the retentate stream) from the uncrystallized API (predominantly in the permeate stream). The permeate stream can then be concentrated and recycled in a continuous mode. Thus, impurity complexation is able to reduce the incorporation of impurity in the target crystals, while nanofiltrationassisted recycle helps increase the crystallization yield. These two techniques can be coupled to design a continuous process for obtaining high-purity crystals at a high yield. This process is expected to be economically preferable to one involving recrystallization, in terms of smaller footprint and lower capital and operating costs. Furthermore, the filtration capacity (in terms of throughput) of the nanofiltration unit is directly proportional to the membrane area. This allows the process to be readily scalable. The resulting methodology of continuous crystallization with impurity complexation and nanofiltration recycle was successfully demonstrated by the present authors for two systems.10 The first system consisted of benzamide, containing 3-nitrobenzoic acid as an added impurity, for which 1,3-di-o-tolylguanidine was the complexing agent chosen. The second system had an actual API, ketoprofen, containing two added impurities, ibuprofen and α,4-dimethylphenylacetic acid. 4,4′-Bipyridine served as the complexing agent for both impurities. That work established a working methodology for selecting the complexing agent and OSN membrane, which has also been employed in the current work. Structural isomers represent an ideal avenue for application of this novel strategy. Since the impurity has the same molecular weight and functional groups as the target compound, it has a strong tendency for incorporating within the host lattice. A selective complexing agent must then be chosen taking advantage of the difference in the position of the functional groups between the target and impurity molecules. The present work demonstrates the efficacy of complexation-assisted nanofiltration recycle for the continuous cooling crystallization of two isomeric systems. The first system consists of 4-nitrophenol (4-NP) as the target compound containing an added impurity of 3-nitrophenol (3-NP) in an aqueous solvent. Note that while 4-NP is not an API, it has been referred to here as such for notational convenience. The purification of this system using impurity complexation in the batch mode has been described previously.21 3-Aminobenzoic acid (ABA) was established as the complexing agent for 3-NP. The structures of these two structural isomers and the complexing agent are shown in Figure 2.

into the crystals. Having an effective separation of the API and the impurity requires that the complex must neither precipitate out nor be incorporated into the API lattice. Such complexation has been shown to be an effective purification technique for a number of molecules including amoxicillin trihydrate,13 cinnamamide,17 benzamide,10,17 and ketoprofen.10,18 A beneficial effect of complexation is the increase in the apparent molecular weight and dimensions of the impurity. This can be exploited for separating the complex from the uncrystallized API by means of an Organic Solvent Nanofiltration (OSN) membrane. Here the membrane pore size is typically less than 2 nm and the molecular weight cutoff (MWCO; defined as the molecular weight of a compound, 90% of which is rejected by the membrane) lies in the range of 100−1000 Da.19 Thus, the molecular weights and dimensions of most small molecule APIs fall within the operating range of OSN. Compared to the traditional separation techniques of chromatography and recrystallization, membrane filtration consumes less energy and can be carried out at lower temperatures. Furthermore, this technique is adaptable to continuous operation and is easy to scale up. All these factors make OSN an attractive technique for the purification of APIs. It has been applied in a lab-scale continuous crystallization of deferasirox containing an impurity of 4-hydrazinobenzoic acid.5 OSN membrane modules have been employed within the pharmaceutical sector in current good manufacturing practices (cGMP).20 The membrane-mediated separation process is schematically depicted in Figure 1.

Figure 1. Schematic of membrane nanofiltration. Cf,i, Cp,i, and Cr,i are the molar concentrations of solute i in the feed, permeate, and retentate streams, respectively.

The inlet stream is split by the membrane into two streams, termed the permeate and the retentate streams. The permeate stream is the one which passes through the membrane and is enriched in the lower molecular weight solutes. On the other hand, the retentate stream is retained or “rejected” by the membrane, and has a major portion of the higher molecular weight solutes. This separation of a molecule by the membrane is quantified by its rejection ratio, given by ⎛ Cp,i ⎞ ⎟⎟ Rej = 100⎜⎜1 − Cf,i ⎠ ⎝

Figure 2. Structures of (i) 4-nitrophenol, (ii) 3-nitrophenol, and (iii) 3-aminobenzoic acid. (1)

Here Reji is the percentage rejection of component i, Cp,i is the molar concentration of component i in the permeate stream and Cf,i is the molar concentration of component i in the feed (inlet) stream to the membrane, as labeled in Figure 1. In the case of impurity complexation, the complex has a higher rejection ratio than the impurity alone owing to its larger apparent molecular weight and dimensions. Consequently, OSN can be effective in separating the impurity

The amino and carboxyl groups of ABA form hydrogen bonds with the nitro and hydroxyl groups, respectively, of 3-NP to yield a complex with a ring structure as shown in Figure 3. That previous study has been extended from the batch to the continuous mode in the present work. The second system in this work consists of an actual API, acetaminophen (AAP) containing an added impurity of its structural isomer, 3-acetamidophenol (3-AP) in a mixed solvent B



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Figure 3. Expected structure of the complex formed between 3-nitrophenol and 3-aminobenzoic acid. The intermolecular hydrogen bonds are depicted as arrows pointing toward the electron-withdrawing groups.

Figure 5. Expected structure of the complex formed between 3-acetamidophenol and 3-nitrobenzoic acid. The intermolecular hydrogen bonds are depicted as arrows pointing toward the electron-withdrawing groups.

of 50:50 ethanol and water by volume. The choice of this second system was obvious based on the similarities in the molecular structures of the two systems. Both 4-NP and AAP have two functional groups at the 1,4 positions on a benzene ring, while their impurities have the same groups at the 1,3 positions. This similarity leads to predicting that a complexing agent for this system should be able to form a ring structure complex with 3-AP by forming hydrogen bonds between the 1,3 functional groups of both molecules, just as ABA does with 3-NP. In the course of this study, 3-nitrobenzoic acid (NBA) was found to work as a suitable complexing agent for 3-AP, thereby validating this prediction. The structures of the API, impurity, and the complexing agent are shown in Figure 4. The expected structure of the complex formed between NBA and 3-AP is shown in Figure 5. Note the similarity in structure between this complex and the one in Figure 3.

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In batch experiments with complexing agent, NBA had equimolar concentration (equal to 27.64 mg/g) in the feed with respect to 3-AP. The crystallizer was a jacketed glass vessel with a working volume of 150 mL which was maintained at a temperature of 5 °C by a waterethylene glycol bath. It was equipped with an overhead stirrer maintained at a speed of 350 rpm. To begin with, batch experiments were conducted without any complexing agent, and were followed by those with the addition of complexing agent. HPLC analysis was performed on samples of the mother liquor and crystals (washed and dried) to calculate the crystallization yield and impurity incorporation. The yield was calculated as the ratio of the change in target compound concentrations between the feed stream and post-crystallization mother liquor to its feed concentration, expressed as a percentage. Impurity incorporation refers to the weight fraction of the impurity in the crystal. The crystals from this first step were weighed and redissolved in an appropriate volume of solvent and the crystallization was repeated under identical conditions. The yield and impurity incorporation values from this step were also determined using HPLC. The overall two-step yield is given by the product of the individual step yields, while the overall impurity incorporation is simply that obtained at the end of the second step. Such two-step crystallization was performed only for the case without any complexation, and was used to gauge the effectiveness of the complexing agent. In experiments with complexing agent, the crystallization was carried out for a single step. Continuous Crystallization Experiments. The schematic of the continuous crystallization setup is shown in Figure 6. The feed to the crystallizer consisted of the fresh feed at a flow rate of 2 mL/min and concentrated recycle stream through two distinct tubes. The temperature and stirring rate in the crystallizer had the same values as in the batch experiments. The crystallizer output was first passed through a solids filter column to recover the crystals. Air saturated with solvent was passed through this filter to reduce mother liquor entrainment in the crystals. The mother liquor emerging through the solids filter was then subjected to nanofiltration. The stainless steel membrane cell had a working volume of 125 mL and was equipped with temperature control, a magnetic stirrer, and a pressure regulator. The pressure was adjusted to have equal flow split between the permeate and retentate streams. The cell temperature and stirring rate were maintained at 50 °C and 400 rpm, respectively, for both systems. The retentate stream preferentially contained the impurity complex and was discarded, while the permeate stream, having the target compound, was recycled back to the crystallizer. Prior to recycle, it was concentrated by evaporating a portion of the solvent in a continuous evaporation setup. Continuous Evaporation Setup. Nitrophenol System. The evaporation of the solvent was carried out continuously under vacuum in the evaporation setup. The permeate stream was pumped into a jacketed glass vessel of 250 mL capacity. This vessel

EXPERIMENTAL SECTION

Materials. All compounds were used as received without any further purification. 4-Nitrophenol (4-NP), 3-nitrophenol (3-NP), 3-aminobenzoic acid (ABA), acetaminophen (AAP), 3-acetamidophenol (3-AP), 3-nitrobenzoic acid (NBA), isophthalic acid (IPhA), monobasic potassium phosphate, dibasic sodium phosphate (anhydrous), HPLC-grade water, methanol, and trifluoroacetic acid were all purchased from Sigma-Aldrich. Polybenzimidazole membranes for OSN were obtained from the Livingston group at Imperial College London. Batch Crystallization Experiments. Prior to continuous mode operation, batch crystallization experiments were performed for comparison of performance in terms of yield and impurity incorporation. In the nitrophenol system, water was chosen as the solvent. The solubility of 3-NP in water in the presence of 4-NP was previously established as 8 mg/g.21 The desired impurity level in the feed solution was 10% by weight of the target compound; consequently, the feed solution contained 80 mg/g 4-NP and 8 mg/g 3-NP. All concentrations stated here are in terms of mass of solute per mass of pure solvent, unless specifically stated otherwise. In batch experiments with ABA as the complexing agent, ABA had equimolar concentration (equal to 7.88 mg/g) in the feed with respect to 3-NP. The feed solution was prepared by dissolving the requisite amounts of solutes in water at 80 °C and was fed to the crystallizer. In the acetaminophen system, the solvent was a 50:50 solution of ethanol and water by volume. The feed solution contained 0.5 g/g AAP and 25 mg/g 3-AP (so that the impurity level was 5% by weight of the API), and was prepared by dissolving the required amounts of solutes in the solvent at 55 °C. NBA was chosen as the complexing agent (via separate experiments discussed later in the Batch Experiments: Acetaminophen system portion of the Results and Discussion section).

Figure 4. Structures of (i) acetaminophen, (ii) 3-acetamidophenol, and (iii) 3-nitrobenzoic acid. C



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Figure 6. Schematic of the continuous crystallization setup showing the nanofiltration cell and the evaporation setup.

Figure 7. Nitrophenol system: Schematic of the continuous evaporation setup. (labeled “reservoir” in Figure 7) had three ports, one for the inlet (the permeate stream), one for the outlet (the concentrated recycle stream), and the third for the solvent vapors. This reservoir contained 50 mL of a solution having the same concentration as the desired concentrated recycle, determined by a simple mass balance. Here all volumes and volumetric flow rates are stated at 25 °C, unless specifically stated otherwise. (The density changes over the temperature range of interest were within 3%, and were neglected.) Magnetic stirring at 200 rpm ensured that the contents of the reservoir were well mixed. The temperature of the reservoir was maintained by a water bath. Vacuum was applied to the setup via the vacuum line of the fume hood. This vacuum, along with the high temperature of the water bath, led to evaporation of the solvent. The solvent vapors first passed through a three-port vessel (labeled “condensation flask”) containing ice and placed in an ice bath, to condense out a part of the water, and then through a filter before finally entering the vacuum line. The vacuum valve served to pressurize the setup before opening it up when the vacuum line was shut off. The idea was to evaporate a part of the solvent from the permeate stream to give a solution having the composition of the concentrated recycle stream. The rate of evaporation was a function of temperature; thus prior to running the continuous experiments, the evaporation setup was calibrated in a standalone mode to determine this function. Here it was assumed that the thermal properties of the actual solution can be approximated by those of pure water, since the solution is sufficiently dilute (this approximation was found to hold in the experiments). The calibration process consisted of two steps. The first step determined how the actual flow rate of the outlet pump varied with the nominal flow rate, since the applied vacuum acted against the outlet pump and decreased its flow rate. The second step determined how the evaporation rate varied as a function of temperature. In this step, 10 mL water (from 50 to 40 mL) was first evaporated under

vacuum at different temperatures to calculate the evaporation rate. No water was pumped in or out of the reservoir at this time. This gave the required function, which was validated via experiments with flow. For a fresh feed flow rate of 2 mL/min, a particular flow ratio (defined here as the ratio of outlet to inlet flow rates of the evaporation setup) gives unique values of the inlet and outlet flow rates. This also fixes the evaporation rate, which is simply the difference between the inlet and outlet flow rates. The calculations for the inlet and outlet flow rates for a given value of the flow ratio are discussed in the Supporting Information. Thus, the validity of the aforementioned function can be tested by observing if the water level in the reservoir is constant for the flow rates and temperature corresponding to a given flow ratio. Five equally spaced flow ratios from 0.5 to 0.9 were slated to be used in the continuous experiments, and were tested here. 50 mL water was filled in the reservoir to begin with. The corresponding flow rates were maintained using the pumps, and the water bath was maintained at the calculated temperature. Evaporation was carried out for a period of 3 h for each of the flow ratios. The level of water in the reservoir stayed constant, thus validating the function of evaporation rate against temperature. Acetaminophen System. Here the solvent is a 50:50 solution of ethanol and water by volume. The composition of this mixed solvent system changes on evaporation, and efforts must be made to restore it to the initial composition before the concentrated stream can be recycled back to the crystallizer. This was achieved by adding a “top-up” solvent of the appropriate composition (of ethanol and water) and flow rate to the outlet solution from the reservoir. The modified evaporation setup is shown in Figure 8. It was similar to the setup for the nitrophenol system, with the addition of an outlet flask where the outlet stream from the reservoir and top-up solution were mixed under magnetic stirring at 200 rpm. The outlet from this flask consisted of the actual concentrated recycle and was pumped to the crystallizer. D



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Figure 8. Acetaminophen system: Schematic of the continuous evaporation. A top-up solution is mixed with the outlet stream from the reservoir to maintain solvent composition in this mixed solvent system. While the construction of this setup is similar to that of the one for the nitrophenol system, the operation of the two setups differs in one key aspect. The nitrophenol system setup achieved varying outlet flow rates by varying the evaporation temperature (and consequently the evaporation rate). This was a useful strategy since no top-up solvent was necessary. However, in the present setup, the evaporation temperature was kept constant at 80 °C to ensure that the rate of evaporation was constant for all flow ratios. The variables here were the flow rate and composition of the top-up solvent stream. This constant evaporation rate was determined by measuring the time it took to evaporate 5 mL of pure solvent from 50 to 45 mL. The density of the unevaporated solvent was calculated, and the corresponding solvent composition was determined from the data at 25 °C in Table 3-110 of Perry’s Chemical Engineers’ Handbook, 6th ed.22 A simple mass balance on each component gave the average evaporation rate of both ethanol and water (in g/min) from the solvent. For a particular flow ratio, the inlet and required outlet flow rates (in g/min) were determined by simple mass balance on the solvent. The difference between the inlet flow rate and the evaporation rate for each component gave the actual outlet flow rate. Based on these values and those of the required outlet flow rates, the top-up solvent flow rate and composition was determined for each flow ratio. Sample calculations are presented in the Supporting Information. The validity of these calculations was tested in the final step before using the setup in the continuous crystallization experiments with recycle. 50 mL solvent was filled in the reservoir, and its temperature was maintained at 80 °C. For each of the five flow ratios, evaporation was carried out for 3 h, with the addition of top-up solvent of the appropriate composition and flow rate. In each case, the solvent level in the reservoir stayed constant, and the composition of the final outlet stream obtained by mixing the reservoir outlet and the top-up solvent corresponded to a 50:50 solution of ethanol and water by volume, thereby validating the evaporation setup. High Performance Liquid Chromatography (HPLC) Analysis. Samples of the mother liquor and crystals were analyzed using HPLC to determine their composition. The peak areas of each solute were converted into the concentration values using the corresponding calibration curves. These values were in turn used to calculate the yield and impurity incorporation within the crystals. An Agilent 1100 instrument equipped with a UV diode array detector was used for analysis. Nitrophenol System. The column of choice was a YMC-Pack ODS-A column (YMC America Inc.) of dimensions 150 mm × 4.6 mm i.d. packed with 3 μm particles with 12 nm pore size. An isocratic method with a 30:70 methanol/water mobile phase containing 0.3% trifluoroacetic acid was used with an analysis time of 18 min. The detection wavelength was 230 nm for 4-NP and ABA, and 275 nm for 3-NP. Acetaminophen System. The column of choice was a Zorbax SB-C8 column (Agilent) of dimensions 100 mm × 4.6 mm i.d. packed with 3.5 μm particles with 8 nm pore size. The gradient method

recommended for acetaminophen in its monograph in USP40-NF35 was employed. The mobile phase consisted of two solutions termed solution A and solution B. Solution A was an aqueous solution of 1.7 g/L of monobasic potassium phosphate and 1.8 g/L of dibasic sodium phosphate, anhydrous. Solution B was pure methanol. The time variation of the mobile phase composition in this gradient method is shown in Table 1. The detection wavelength was set at 254 nm and the analysis time at 10 min.

Table 1. Acetaminophen System: Time Variation of the HPLC Mobile Phase Composition time (min)

solution A (%)

solution B (%)

0.0 3.0 7.0 7.1 10.0

99 99 19 99 99

1 1 81 1 1

Organic Solvent Nanofiltration (OSN) Membrane Experiments. 24-PBI-DBX membranes provided by the Livingston group at Imperial College London were used for OSN for both systems. The membrane nomenclature refers to its preparation, viz., 24 weight % of polybenzimidazole (PBI) dissolved in dibromoxylene (DBX) and cast on a nonwoven polypropylene support, followed by cross-linking. Since the membrane must be able to permeate the target compound and retain the impurity complex, the molecular weight cutoff (MWCO) of the membrane should lie between the molecular weights of the target and the complex. Taking this into consideration, the 24-PBI-DBX membrane was chosen for both systems since it has a MWCO in the range to 200 to 300 Da. The membrane cell was fabricated in-house from stainless steel and had a working volume of 125 mL. It was equipped with temperature control and a magnetic stirrer. A feed solution having the composition of the post-crystallization batch mother liquor was fed through an HPLC pump at a flow rate of 2 mL/min for screening. The membrane pressure was adjusted via the pressure regulator to have equal flow split between permeate and retentate. The temperature and stirring rate in the cell were maintained at 25 °C and 200 rpm, respectively. The screening experiments were performed using solutions without and with complexing agent for comparison.

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RESULTS AND DISCUSSION Batch Experiments. Nitrophenol System. The results for the two-step batch crystallization experiments without any complexation are presented in Table 2. The net yield of the two steps is 77.80 ± 0.17%. With the addition of stoichiometric amount of ABA with respect to E



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carboxyl. NBA was found to be soluble in the solvent at the desired concentration and temperature. The yield of the single step batch crystallization in the presence of equimolar concentration of NBA with respect to 3-AP was found to be 90.32 ± 0.02%, which is appreciably higher than the overall two-step yield without complexation. The 3-AP level in the crystals was 0.942 ± 0.040%, which is lower than that obtained after two successive crystallization steps. As an added benefit, no NBA was detected in the crystals, implying that its levels were below the detection limit of the HPLC method of 10 ppm. These results establish the efficacy of NBA as a complexing agent for the acetaminophen system. Membrane Screening. The 24-PBI-DBX membrane was screened as described earlier and the rejection ratios of the target compound and the impurity were calculated using eq 1. These ratios are depicted in Figure 10 and Figure 11, for the nitrophenol system and the acetaminophen system, respectively.

Table 2. Nitrophenol System: Yield and Impurity Incorporation for Successive Batch Crystallization Steps without Complexation crystallization step

yield (%)

3-NP incorporation in crystals (weight %)

First Second

88.05 ± 0.03 88.36 ± 0.16

3.259 ± 0.019 0.422 ± 0.017

3-NP, the yield of the single step crystallization was found to be 87.50 ± 0.14%. The crystals showed an incorporation of 0.636 ± 0.011% of 3-NP and 330 ± 15 ppm of ABA. Although the addition of ABA gives higher 3-NP levels than the two-step experiments, the yield is higher by close to ten percentage points, implying that ABA is an effective complexing agent. The incorporation of ABA in the crystals is within the 500 ppm limit set previously.21 Acetaminophen System. The results for the two-step batch crystallization experiments without any complexation for this system are presented in Table 3. The net two-step crystallization yield is 82.76 ± 0.12%. Table 3. Acetaminophen System: Yield and Impurity Incorporation for Successive Batch Crystallization Steps without Complexation crystallization step

yield (%)

3-AP incorporation in crystals (weight %)

First Second

91.12 ± 0.11 90.83 ± 0.02

2.124 ± 0.082 1.182 ± 0.025

In selecting the complexing agent, the similarity between the structures of 3-NP and 3-AP was exploited. As a result, compounds having two acceptor groups at the 1,3 positions of a benzene ring were tested as complexing agents. Initially, isophthalic acid (IPhA), having two carboxyl groups at the 1,3 positions, was chosen owing to the strong electron withdrawing ability of the carboxyl groups. Its structure is depicted in Figure 9. An equimolar solution of IPhA with respect to

Figure 10. Nitrophenol system: Membrane rejection ratios for 4-NP and 3-NP without and with complexation.

Figure 9. Molecular structures of (i) isophthalic acid, and (ii) 3-nitrobenzoic acid. Both these structures have electron-withdrawing groups at the 1,3 positions, making them potential candidates for complexation with 3-acetamidophenol. Figure 11. Acetaminophen system: Membrane rejection ratios for AAP and 3-AP without and with complexation.

3-AP implies a concentration of 27.4 mg/g of IPhA in the 50:50 solution of ethanol and water by volume. The complexing agent must stay completely dissolved at this level at the crystallization temperature of 5 °C so as not to precipitate out and “adulterate” the target compound crystals. However, IPhA was found to be sparingly soluble in the solvent at this temperature. A high pH of about 13.7 was required to keep it dissolved. Since such a high pH is not recommended for membrane systems, IPhA was rejected as a feasible complexing agent and an attempt was made to look for another molecule. The next compound satisfying the structural and functional group conditions tested was 3-nitrobenzoic acid (NBA). Here one of the carboxyl groups of IPhA is replaced by a nitro group, which has a lower electron withdrawing tendency than the

In the absence of complexation, the rejection ratios of both the nitrophenol isomers are extremely close to each other, since they have the same molecular weight. The rejection of 3-NP increases by a factor of almost seven post complexation due to the high apparent molecular weight of the complex. On the other hand, since 4-NP is not complexed, there is no appreciable change in its rejection with the addition of complexing agent to the system. Similarly, the rejection ratio of AAP and its isomer 3-AP are very close to each other before complexation due to their identical molecular weights. However, after complexation with F



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NBA, the apparent molecular weight of 3-AP increases, leading to an almost 15-fold increase in its rejection ratio. Since AAP stays uncomplexed, there is no appreciable change in its rejection ratio. The high rejection ratios of the impurity complex validate the suitability of the 24-PBI-DBX membrane for separation in both systems. Continuous Evaporation Setup Calibration. Nitrophenol System. To calibrate the outlet pump with vacuum applied to the evaporation setup, the actual flow rate was measured at five equally spaced values of nominal flow rate from 5 mL/min to 7 mL/min. These limits were chosen since the measured flow rates lied within the interval of interest for the continuous experiments. The relation between the nominal and actual flow rates is depicted in Figure 12. It is a linear

Table 4. Flow Rates and Temperature Used to Validate the Calibration Function for the Continuous Evaporation Setup flow ratio (outlet:inlet)

inlet flow rate (mL/min)

outlet flow rate (mL/min)

nominal outlet flow rate (mL/min)

temperature (°C)

0.5 0.6 0.7 0.8 0.9

1.34 1.43 1.54 1.67 1.82

0.68 0.86 1.08 1.34 1.64

5.29 5.53 5.81 6.15 6.55

74.2 71.3 67.0 60.4 48.3

from 0.5 to 0.9. The values of the relevant flow rates and temperatures are depicted in Table 4. The calculations for the inlet and outlet flow rates as a function of flow ratio are described in the Supporting Information. The nominal outlet flow rates and the temperature were calculated from the fitting equations in Figure 12 and Figure 13, respectively. The water level stayed constant even after 3 h, thereby validating the function of evaporation rate against temperature. Acetaminophen System. The evaporation rate was calculated by measuring the time it took to evaporate 5 mL of pure solvent from 50 to 45 mL at 80 °C under vacuum, and measuring the density of the unevaporated solution. From a simple mass balance on each component in the mixed solvent, the average evaporation rate was determined to be 0.36 g/min for ethanol and 0.38 g/min for water. The next step was to determine the flow rate and composition of the top-up solvent required at each flow ratio. A sample calculation for a flow ratio of 0.5, based on a simple mass balance, is shown in the Supporting Information. The composition and flow rate of the top-up solvent stream for each of the five flow rates from 0.5 to 0.9 were calculated in this manner, and are summarized in Table 5. As mentioned

Figure 12. Calibration curve for the outlet pump with vacuum applied, showing the relation between nominal and measured flow rates.

relation given by y = 0.776x − 3.374 where x and y are the nominal and measured flow rates respectively, in mL/min. The next step consisted of determining the variation of evaporation rate with temperature. The evaporation rate was measured as described earlier at six equally spaced temperatures from 50 to 75 °C. The relation between the evaporation rate and temperature is depicted in Figure 13. The fitting equation

Table 5. Acetaminophen System: Composition and Flow Rates of Top-Up Solvent as a Function of Flow Ratio flow ratio (outlet:inlet)

top-up solvent composition (weight % ethanol)

top-up solvent flow rate (mL/min)

0.5 0.6 0.7 0.8 0.9

70.09 59.14 54.30 51.50 49.67

0.15 0.24 0.35 0.48 0.63

earlier, the solvent level in the reservoir stayed constant, and the composition of the final outlet stream was 50:50 ethanol and water by volume, thereby validating the evaporation setup. Continuous Mode Experiments. Nitrophenol System. An MSMPR was first run without any recycle as a base case. The feed flow rate was 2 mL/min, corresponding to a residence time of 75 min. The crystallization conditions (feed solution composition, crystallizer temperature, and stirring rate) were the same as those used in the batch experiments. The yield in this base case was found to be 84.48 ± 0.04%. The corresponding impurity incorporation in the crystals was 0.592 ± 0.007% for 3-NP and 310 ± 10 ppm for ABA. The base case MSMPR experiments were followed by experiments with recycle. These were performed principally to demonstrate the efficacy of the membrane-coupled recycle process in reducing impurity incorporation in crystals and improving yield compared to a continuous process without recycle having the same residence time. Moreover, yield-impurity incorporation

Figure 13. Variation of evaporation rate with temperature with vacuum applied.

is y = 0.0159 exp(0.0502x) where x is the temperature in Celsius and y is the evaporation rate in mL/min. Note that the units of the evaporation rate stem from calculating evaporation as loss of liquid volume calculated at 25 °C. To test the validity of this function, evaporation experiments were carried out with flow at five equally spaced flow ratios G



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Table 6. Nitrophenol System: Yield and Impurity Incorporation Results as a Function of Flow Ratio in Continuous Experiments with Recycle flow ratio (outlet:inlet)

concentration ratio

0.5 0.6 0.7 0.8 0.9

2.00 1.67 1.43 1.25 1.11

yield (%) 90.33 89.34 88.19 86.65 84.76

± ± ± ± ±

3-NP incorporation in crystals (weight %)

0.08 0.03 0.07 0.11 0.07

0.430 0.363 0.310 0.275 0.241

± ± ± ± ±

3-ABA incorporation in crystals (ppm)

0.017 0.042 0.018 0.020 0.028

360 335 300 270 245

± ± ± ± ±

10 15 5 5 10

curves were also generated by varying the residence time in the crystallizer. This was achieved by choosing five equally spaced values of flow ratio from 0.5 to 0.9, and maintaining the flow rates and temperatures depicted in Table 4. The reciprocal of the flow ratio is defined here as the concentration ratio. It represents the factor by which the solutes are concentrated within the evaporation unit. The yield and impurity incorporation observed in this series of experiments are presented in Table 6. Figure 14 shows the variation of yield with concentration ratio. As expected, the yield increases with concentration of the

Figure 15. Nitrophenol system: Variation of 3-NP incorporation with yield.

Figure 14. Nitrophenol system: Variation of yield with concentration ratio. In the data labels, the first value is the concentration ratio and the second one is the percent yield.

recycle stream. Moreover, as the recycle stream gets more concentrated, the supersaturation of the target compound in the crystallizer progressively decreases, leading to the “flattening” of the curve at higher concentration ratios. While higher concentration ratios are beneficial to the yield, they also lead to increasing concentrations of the impurity and complexing agent (in addition to that of the target compound). Thus, higher yield can be expected to be associated with higher levels of impurity and complexing agent in the crystals. This can be seen in Figure 15 and Figure 16 which plot the incorporation of NP and ABA respectively against yield. The fitting curves, quadratic in this case, allow for the prediction of crystal incorporation of these two components at a desired value of yield. It can be observed that even at the highest value of impurity incorporation (corresponding to a flow ratio of 0.5), the ABA incorporation is just 360 ppm, which is below the maximum tolerated limit of 500 ppm. This occurs at an equimolar ratio of complexing agent to impurity. Higher values of this ratio can be expected to give lower impurity incorporation, while simultaneously leading to higher complexing agent incorporation. To test this theory, the molar ratio of ABA to 3-NP in the fresh feed was varied in steps of 0.1 at the same flow ratio of 0.5 until

Figure 16. Nitrophenol system: Variation of ABA incorporation with yield.

the observed ABA incorporation exceeded 500 ppm. This limit was crossed at a ratio of 1.3. The yield and crystal incorporation values in this series of experiments is shown in Table 7. Table 7. Nitrophenol System: Yield and Impurity Incorporation Results as a Function of Molar Ratio of Complexing Agent to Impurity in Fresh Feed at a Flow Ratio of 0.5 ABA:3-NP molar ratio in fresh feed 1.0 1.1 1.2 1.3

yield (%) 90.33 90.40 90.12 90.53

± ± ± ±

0.08 0.09 0.14 0.23

3-NP incorporation in crystals (weight %) 0.430 0.352 0.284 0.253

± ± ± ±

0.017 0.043 0.013 0.022

ABA incorporation in crystals (ppm) 360 415 480 565

± ± ± ±

10 10 15 5

An increase in the amount of complexing agent added to the feed leads to a decrease in the impurity incorporation and an increase in the level of complexing agent in the crystals, without H



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any significant variations in the yield. The variation of the levels of 3-NP and ABA with the ABA:3-NP ratio are depicted in Figure 17 and Figure 18, respectively. Since the ABA level at a

Table 8. Acetaminophen System: Yield and Impurity Incorporation Results as a Function of Flow Ratio in Continuous Experiments with Recycle flow ratio (outlet:inlet)

concentration ratio

0.5 0.6 0.7 0.8 0.9

2.00 1.67 1.43 1.25 1.11

yield (%)

3-AP incorporation in crystals (weight %)

± ± ± ± ±

0.672 ± 0.009 0.611 ± 0.004 0.59 ± 0.026 0.525 ± 0.008 0.491 ± 0.04

93.06 92.45 91.67 90.66 89.32

0.04 0.03 0.06 0.01 0.08

Figure 17. Nitrophenol system: Variation of 3-NP incorporation with complexing agent-to-impurity ratio.

Figure 19. Acetaminophen system: Variation of yield with concentration ratio. In the data labels, the first value is the concentration ratio and the second one is the percent yield. Figure 18. Nitrophenol system: Variation of ABA incorporation with complexing agent-to-impurity ratio.

ratio of 1.3 exceeds 500 ppm, a ratio of 1.2 was deemed the most optimal ratio for reducing the 3-NP incorporation. In summary, a flow ratio of 0.5 and a complexing agent-toimpurity ratio of 1.2 give a yield of 90.12 ± 0.14% and a 3-NP level of 0.284 ± 0.013%. These are an improvement over the base case values of 84.48 ± 0.04% yield and 0.592 ± 0.007% 3-NP. For purposes of validation, a mass balance was performed on the optimal case for each of the solutes based on composition and flow rates of all streams. The net out-flows and in-flows of the components agreed within the following limits: 4-NP: 0.69%, 3-NP: 0.41%, ABA: 0.38%. Acetaminophen System. The sequence of continuous experiments performed for this system was similar to that in the nitrophenol system. The yield in the base case of unrecycled MSMPR with a residence time of 75 min was found to be 86.43 ± 0.01%, and the 3-AP incorporation in the crystals was 0.925 ± 0.051%. The next step consisted of running the MSMPR with concentrated recycle at five equally spaced values of flow ratio from 0.5 to 0.9, and maintaining the flow rates and temperatures depicted in Table 4. The corresponding yield and impurity incorporation values are presented in Table 8. The “flattening” of yield with increasing concentration ratio is seen in Figure 19. As in the previous system, higher yields are associated with higher impurity incorporation, as depicted in Figure 20. The fitting curve, quadratic in this case, allows for the prediction of 3-AP incorporation at the desired value of yield. In this system, no complexing agent was observed in the crystals at an equimolar ratio of complexing agent to impurity.

Figure 20. Acetaminophen system: Variation of 3-AP incorporation with yield.

Hence we decided to investigate if higher relative amounts of complexing agent would be able to further reduce the impurity incorporation. It was expected that at a sufficiently high concentration, the solubility of NBA under the prevailing conditions would be exceeded and it would precipitate out, thereby being detected in the crystals. The molar ratio of NBA to 3-AP in the fresh feed was varied in steps of 1 at the same flow ratio (0.5) until NBA was detected within the crystals by HPLC. This detection occurred at a molar ratio of 5, where the yield was 93.24 ± 0.06%, and the levels of 3-AP and the precipitated NBA were 0.121 ± 0.005% and 3.157 ± 0.025%, respectively. This was followed by a similar experiment with a NBA:3-AP ratio of 4.5 to check if this too would lead to precipitation of 3-NBA. No complexing agent was detected in the crystals in this case; consequently 4.5 was deemed the most optimal ratio. The yield and 3-AP incorporation values for ratios up to 4.5 are shown in Table 9. As expected, higher relative amounts of complexing agent were able to reduce the impurity incorporation in the crystals, as seen in Figure 21. Based on the fitting equation in this graph, the 3-AP incorporation I



Article

A study of the behavior of yield and impurity incorporation with varying concentration ratios in the evaporator and complexing agent-to-impurity ratios in the fresh feed solution led to finding the optimal values of these ratios. In each system, the complexation-assisted continuous crystallization process with nanofiltration recycle was found to exceed the performance of both the batch process and the unrecycled MSMPR in terms of higher yield and lower impurity incorporation.

Table 9. Acetaminophen System: Yield and Impurity Incorporation Results as a Function of Molar Ratio of Complexing Agent to Impurity in Fresh Feed at a Flow Ratio of 0.5 NBA:3-AP molar ratio in fresh feed 1 2 3 4 4.5

yield (%) 93.06 93.09 93.04 93.00 93.01

± ± ± ± ±

0.04 0.02 0.01 0.02 0.07

3-AP incorporation in crystals (weight %) 0.672 0.443 0.299 0.203 0.127

± ± ± ± ±

0.009 0.005 0.004 0.002 0.010

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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.cgd.7b01030. Components of the membrane cell, calculation of flow rates in the continuous evaporation setup, sample calculations for the flow rates and composition of the top-up solvent stream for the acetaminophen system, crystal purity results (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Shankul Vartak: 0000-0001-5125-1051 Allan S. Myerson: 0000-0002-7468-8093

Figure 21. Acetaminophen system: Variation of 3-NP incorporation with complexing agent-to-impurity ratio.

Notes

The authors declare no competing financial interest.

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expected for a ratio of 5 is 0.113%. However, the observed incorporation, 0.121%, is higher since not all of the NBA is available for complexation due to its partial precipitation. Thus, the limit to the impurity level reduction is set by the solubility of the complexing agent. In summary, a flow ratio of 0.5 and a complexing agent-to-impurity ratio of 4.5 give a yield of 93.01 ± 0.14% and a 3-AP level of 0.127 ± 0.010%. These values were an improvement over the base case values of 86.43 ± 0.01% yield and 0.925 ± 0.051% 3-AP. For purposes of validation, a mass balance was performed on the optimal case for each of the solutes based on composition and flow rates of all streams. The net out-flows and in-flows of the components agreed within the following limits: AAP: 0.28%, 3-AP: 0.53%, NBA: 1.06%.

ACKNOWLEDGMENTS The authors acknowledge the Novartis-MIT Center for Continuous Manufacturing for financial support for this project. The authors are grateful to the Livingston group at Imperial College London for supplying the nanofiltration membranes.

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REFERENCES

(1) Alvarez, A.; Myerson, A. Cryst. Growth Des. 2010, 10, 2219−2228. (2) Chen, J.; Sarma, B.; Evans, J.; Myerson, A. Cryst. Growth Des. 2011, 11, 887−895. (3) Schaber, S.; Gerogiorgis, D.; Ramachandran, R.; Evans, J.; Barton, P.; Trout, B. Ind. Eng. Chem. Res. 2011, 50 (17), 10083−10092. (4) Wong, S.; Tatusko, A.; Trout, B.; Myerson, A. Cryst. Growth Des. 2012, 12, 5701−5707. (5) Ferguson, S.; Ortner, F.; Quon, J.; Peeva, L.; Livingston, A.; Trout, B.; Myerson, M. Cryst. Growth Des. 2014, 14, 617−627. (6) Su, Q.; Nagy, Z.; Rielly, C. Chem. Eng. Process. 2015, 89, 41−53. (7) Majumder, A.; Nagy, Z. AIChE J. 2013, 59 (12), 4582−4594. (8) Neugebauer, P. Cryst. Growth Des. 2015, 15 (3), 1089−1095. (9) Kwon, J.; Nayhouse, M.; Orkoulas, G.; Christofides, P. Chem. Eng. Sci. 2014, 119, 30−39. (10) Vartak, S.; Myerson, A. Org. Process Res. Dev. 2017, 21 (2), 253− 261. (11) Griffin, D.; Mellichamp, D.; Doherty, M. Chem. Eng. Sci. 2010, 65 (21), 5770−5780. (12) Power, G.; Hou, G.; Kamaraju, V.; Morris, G.; Zhao, Y.; Glennon, B. Chem. Eng. Sci. 2015, 133, 125−139. (13) Hsi, K.; Concepcion, A.; Kenny, M.; Magzoub, A.; Myerson, A. CrystEngComm 2013, 15, 6776−6781. (14) Givand, J.; Chang, B.; Teja, A.; Rousseau, R. Ind. Eng. Chem. Res. 2002, 41, 1873−1876. (15) Givand, J.; Teja, A.; Rousseau, R. AIChE J. 2001, 47, 2705− 2712. (16) Teja, A.; Givand, J.; Rousseau, R. AIChE J. 2002, 48, 2629− 2634.

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CONCLUSIONS Impurity complexation coupled with nanofiltration recycle was previously established as an effective strategy to reduce the crystal impurity incorporation and improve yield of a continuous crystallization process. This strategy is especially beneficial to systems comprising a target compound and impurity having a strong affinity owing to similar structures and molecular weights, which can be purified by conventional recrystallization only at the cost of yield. In the current work, this crystallization methodology was successfully extended to structural isomers. Two systemsthe nitrophenol system consisting of a 3-nitrophenol impurity in 4-nitrophenol, and the acetaminophen system consisting of a 3-acetamidophenol impurity in acetaminophenwere tested to demonstrate the efficacy of the process. An effective complexing agent for the former system was chosen elsewhere based on structural considerations of the complex formed. Based on similarities between the two systems, similar structural arguments were successfully used to search for a complexing agent for the latter system. J



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(17) Hsi, K.; Kenny, M.; Simi, A.; Myerson, A. Cryst. Growth Des. 2013, 13, 1577−1582. (18) Hsi, K.; Chadwick, K.; Fried, A.; Kenny, M.; Myerson, A. CrystEngComm 2012, 14, 2386−2388. (19) Marchetti, P.; Jimenez Solomon, M.; Szekely, G.; Livingston, A. Chem. Rev. 2014, 114, 10735. (20) Pink, C.; Rundquist, E. Network Young Membrains, 2012. (21) Pons-Siepermann, C.; Huang, S.; Myerson, A. CrystEngComm 2016, 18, 7487−7493. (22) Perry’s Chemical Engineers’ Handbook, 6th ed., Green, D.; Perry, R., Eds.; McGraw-Hill, 1984

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