Continuous Crystallization with Impurity Complexation and

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Continuous Crystallization with Impurity Complexation and Nanofiltration Recycle Shankul Vartak, and Allan S. Myerson Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00438 • Publication Date (Web): 18 Jan 2017 Downloaded from http://pubs.acs.org on January 18, 2017

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Organic Process Research & Development

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

ACS Paragon Plus Environment

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Graphic for use in Table of Contents/Abstract


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ABSTRACT: For crystal-impurity systems with similar structures and molecular weights, the impurity has a strong tendency to incorporate into the crystal lattice, making it difficult to obtain high purity with a single crystallization or even multiple crystallizations. In such cases, complexation of the impurity with an additive can be used to sterically prevent impurity incorporation in the host lattice. A nanofiltration membrane can be used to preferentially reject the higher molecular weight impurity complex in solution, while allowing the lower molecular weight API to permeate through. This permeate stream can be concentrated and recycled to operate the crystallization in a continuous mode with the aim of enhancing both yield and crystal purity simultaneously. In the present work, this strategy was applied to the continuous cooling crystallization of two systems in a mixed-suspension mixed-product removal (MSMPR) crystallizer from their solutions in 50:50 (by volume) water-ethanol mixed solvent. The first system consists of benzamide with 3-nitrobenzoic acid added as an impurity, while the second one is the active pharmaceutical ingredient (API) ketoprofen containing two impurities, ibuprofen and α,4-dimethylphenylacetic acid. A working strategy for selecting the complexing agent and nanofiltration membrane was established. For both systems, the membrane-coupled continuous mode with recycle and complexation was found to have a better performance in terms of higher crystallization yield and lower impurity incorporation in crystals compared to both the batch process as well as the continuous process without recycle.

Keywords: Continuous crystallization, impurity complexation, organic solvent nanofiltration, membrane filtration


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INTRODUCTION Crystallization is a separation and purification technique involving a phase change in which a crystalline product is obtained from a solution 1. It is ubiquitous in the pharmaceutical industry, since about 90% of all active pharmaceutical ingredients (API) are crystalline small organic molecules 2. Traditionally, pharmaceutical crystallization is carried out in the batch mode either as antisolvent, cooling or reactive crystallization 3. While these batch processes are well characterized, there is an increasing desire to switch to continuous operation. This is apparent in the recent development of dedicated research facilities by a number of pharmaceutical companies. Continuous processes offer several advantages over the batch ones. The key one among these is that higher throughputs are more amenable with continuous processing, requiring significantly lower capital and operating expenditures than its batch counterpart. While higher yield is an obvious advantage of batch crystallization, appropriate recycle strategies in continuous mode allow the yield to match or even exceed the batch value. Mixedsuspension mixed-product removal (MSMPR) and plug flow are the two major types of continuous crystallizers employed in the pharmaceutical industry 4. The MSMPR is the more versatile of the two since it is able to handle higher suspension densities without risk of clogging. Furthermore, the yield of an MSMPR can be improved by increasing the number of stages and/or using recycle. Wong et. al. have demonstrated the application of recycle to a single stage MSMPR for the cyclosporine and deferasirox systems 4. In cases where the API and impurity have similar molecular weights and dimensions, the impurity often has a strong tendency to be adsorbed on the API crystal surface and/or be incorporated into the lattice 5, 6, 7, 8. Such impurities may be by-products of the API synthesis or may be unconverted raw material or intermediate. While the yield of an API can be increased by


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recycling a portion of the outlet stream, this inevitably leads to recycling the impurities too, leading to a higher impurity incorporation in the crystal compared to that obtained in the absence of recycle. Thus there is a trade-off between yield and crystal purity. This makes it difficult to purify the API crystals, and conventional purification methods viz. chromatography and recrystallization, can improve purity only at the cost of yield. Thus an acceptable yield necessitates multiple passes and higher energy consumption. Impurity complexation can improve purity without compromising on the yield

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and is

therefore an effective solution to this issue. In this process, a complexing agent which can selectively bind with the impurity but not with the API is added to the solution prior to crystallization. For successful separation of API and impurity, the impurity- complexing agent moiety must have a higher solubility than the impurity alone and must not be incorporated into the API lattice. Similarly, the complexing agent must have no affinity to be itself incorporated into the crystals. This ensures that the crystals are further enriched in the API 9. A synthon search for the impurity in the Cambridge Structural Database is a good starting point in the search for complexing agents. Urbanus et al were the first to employ this technique in 2010 to separate cinnamic acid from a fermentation broth 10. It has since been successfully demonstrated for a number of API/impurity systems including amoxicillin trihydrate/4-hydroxyphenylglycine 5, benzamide/benzoic acid and cinnamamide/cinnamic acid 9 and ketoprofen/ibuprofen 11. In addition to reducing the tendency of the impurity to incorporate into the API lattice, the larger dimensions of the impurity complex can also be exploited for its separation from the API solution. Separation processes account for about 40−70% of capital and operating costs in the chemical and pharmaceutical industries

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. Membrane filtration is yet another purification

technique in addition to chromatography and recrystallization, which are conventionally used in


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pharmaceutical purification. It requires a lower energy input and can be carried out at lower temperatures, which makes it a cost-effective alternative 13. Other advantages of this technique include adaptability to a continuous mode and straightforward scale up. 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 portion of the feed stream which passes through the membrane is termed the permeate stream while the other stream, which is retained (or ‘rejected’) by the membrane is termed the retentate stream. The separation of a molecule by the membrane is quantified by its rejection ratio, which is defined as follows: 100 1

, ,

… Equation 1

Where Reji is the percentage rejection of solute i, Cp,i is the molar concentration of solute i in the permeate stream and Cf,i is the molar concentration of solute i in the feed (inlet) stream to the membrane, as depicted in Figure 1. Membrane rejection can be classified into reverse osmosis, nanofiltration, ultrafiltration and microfiltration in terms of membrane characteristics and applied pressure

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. Nanofiltration is

characterized by an applied pressure in the range of 5 to 40 bar, a pore size less than 2 nm and a molecular weight cut-off (MWCO) between 100-1000 Da. The nominal MWCO is the attribute used for selecting membranes, and is defined as the molecular weight of a compound, 90% of


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which is rejected by the membrane. The molecular weight and dimensions of small molecule pharmaceuticals fall in the operating range of nanofiltration. As a result, organic solvent nanofiltration (OSN) can be used to recover the API from its (typically organic) solvent. In the pharmaceutical industry, OSN membrane modules have been successfully applied in current good manufacturing practices (cGMP) 14. Outside the pharmaceutical sector, OSN is currently being investigated for diverse applications which include oil recovery, enrichment of aromatics and homogeneous catalyst recycle 15. Impurity complexation can be coupled with OSN to devise an effective strategy for obtaining high purity crystals at a high yield. The impurity complex has a higher apparent molecular weight and larger apparent molecular diameter than the impurity alone. This greatly reduces the tendency of the impurity for lattice incorporation, resulting in crystals of higher purity. Furthermore, the larger dimensions of the complex also translate into a higher rejection ratio and better separation. The permeate stream exiting the membrane unit, which now has less impurity, can be concentrated and recycled in a continuous mode to enhance the yield. This forms the basis of the application of complexation-assisted nanofiltration to continuous crystallization. Ferguson et al have demonstrated nanofiltration-mediated continuous crystallization with the deferasirox (API)/ 4-hydrazinobenzoic acid (impurity) system 16. Owing to the wide difference in the molecular weights of the API (MW 373 Da) and the impurity (MW 152 Da), no complexing agent was necessary for effective separation. Both the yield and purity of the API was enhanced using this process compared to the batch mode. In the present work, the efficacy of impurity complexation with nanofiltration for continuous crystallization with recycle is demonstrated for two systems employing cooling crystallization. The first system consisted of benzamide (BAM), containing 3-nitrobenzoic acid (NBA) as the


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impurity. It may be noted that benzamide is not an actual API, nor is it expected to contain 3nitrobenzoic acid as a synthetic impurity. However, in the course of the present study, NBA was observed to incorporate in the BAM crystal. In addition, complexation was able to mitigate the impurity incorporation in the crystals. Thus, this system served as a convenient basis to establish the methodology described herein. Note that benzamide is referred to here as an API for notational convenience. Selective complexation occurs at the site of the carboxyl group which is present in the impurity, but is lacking in BAM. The methodology established using the BAM-NBA system was tailored and employed for improving the yield and purity of an actual API in the second system. This system consisted of ketoprofen (KETO) with two added impurities, ibuprofen (IBU) and α,4-dimethylphenylacetic acid (DMPAA). Both these impurities incorporate into the KETO crystals, as the present study made clear. While all three molecules have a carboxyl group, the steric hindrance caused by the second phenyl ring in KETO can be exploited for selective complexation of the impurities but not the API 11. In the previous system, the complexing agent of choice, 1,3-di-o-tolylguanidine (DOTG), reduced the NBA incorporation to below detectable limits. Hence, this system afforded little flexibility to observe the trade-off of impurity incorporation with yield. However, there was a quantifiable presence of impurities in the KETO crystals even after complexation, and investigating the trade-off formed an additional aim for this system. The structures of the molecules in both systems are shown in Figure 2.

(i)

(ii)

(iii)

(iv)

(v)


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Figure 2 Structures of (i) benzamide (ii) 3-nitrobenzoic acid (iii) ketoprofen (iv) ibuprofen and (v) α,4-dimethylphenylacetic acid EXPERIMENTAL SECTION Materials All compounds were used as received without any further purification. Benzamide (BAM), 3nitrobenzoic acid (NBA), ketoprofen (KETO), ibuprofen (IBU), α,4-dimethylphenylacetic acid (DMPAA), 4,4’-bipyridine (BPY), 1,3-di-o-tolylguanidine (DOTG), 1,3-diphenylguanidine (DPG), nicotinamide, isonicotinamide, N-phenylurea (NPU), 2-aminopyridine, potassium dihydrogen phosphate, HPLC-grade water, ethanol, methanol, acetonitrile, trifluoroacetic acid were all purchased from Sigma Aldrich. Organic solvent nanofiltration (OSN) membranes were supplied by the Livingston group at Imperial College London. Crystallization experiments For each system, batch crystallization was first performed to establish the benefits of complexation and to select the complexing agent before switching to full-fledged continuous mode experiments. The solvent was a 50:50 solution by volume of water and ethanol. The feed solution in the BAM-NBA system contained 0.5 g/g BAM and 0.025 g/g NBA. All concentrations stated here are in terms of mass of solute per mass of pure solvent, unless specifically stated otherwise. In experiments with DOTG as complexing agent, DOTG had equimolar concentration in the feed with respect to NBA (DOTG was established as the complexing agent of choice via separate experiments discussed later in the ‘selection of complexing agents’ section). Consequently, the DOTG concentration was 0.036 g/g.


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For the KETO-IBU-DMPAA system, the feed solution contained 0.25 g/g KETO and 0.0125 g/g each of IBU and DMPAA. Batch experiments with single impurities were performed prior to those with both impurities for purposes of comparison. The feed solution for such singleimpurity experiments contained 0.25 g/g KETO and 0.0125 g/g of the appropriate impurity. In experiments with BPY as complexing agent (this choice of complexing agent is discussed later in the ‘selection of complexing agents’ section), BPY had a feed concentration of 1:2 (BPY:impurity) by mole. This translates to a BPY concentration of 0.0047 g/g for experiments with IBU alone, 0.0059 g/g for those with DMPAA alone and 0.0106 g/g for those with both impurities together. Figure 3 depicts the schematic of a continuous crystallization setup with a nanofiltration membrane for separation prior to recycle; the same setup (without any recycle or membrane unit) was also employed for batch experiments. The crystallizer was a jacketed glass vessel with a working volume of 150 ml and was maintained at a temperature of 5°C (for the BAM-NBA system) and 10°C (for the KETO-IBUDMPAA system) by a water-ethylene glycol bath. A stirring speed of 350 rpm was employed for both systems. The fresh feed consisting of the API, impurities and complexing agents of desired concentration was fed to the crystallizer at a temperature of 55°C. In the batch mode, samples of the mother liquor and crystals (washed and dried) were taken for HPLC analysis. The yield and impurity incorporation of this first crystallization step was determined. Here, the yield was calculated as the ratio of the change in API concentrations between the feed stream and post-crystallization mother liquor to the API concentration in feed stream, expressed as a percentage. Impurity incorporation was expressed as the weight fraction of the impurity in the crystal. Based on the yield, the solids from the first step were re-dissolved


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in the appropriate volume of solvent and the crystallization was repeated. The yield and impurity incorporation in crystals from this step was also determined. The overall yield of the two steps equals the product of the individual step yields, while the overall impurity incorporation is simply that obtained at the end of the second step. These values serve as the benchmark for assessing the performance of the complexing agent. An agent is deemed effective if it is able to reduce the impurity incorporation to lower or comparable values at a higher yield in a single crystallization step compared to the two-step values without any complexation. In continuous experiments, the output from the crystallizer was first passed through a solid filter column where the crystals were separated from the mother liquor. Air saturated with the solvent was passed through this filter to reduce liquid entrainment in the crystals. The mother liquor was then subjected to nanofiltration, where the impurity-rich retentate was discarded. The stainless steel membrane cell had a working volume of 125 ml and was equipped with temperature control and a magnetic stirrer. The membrane pressure was adjusted by a regulator to have equal flow split between permeate and retentate. The stirring rate in the membrane cell was maintained at 250 rpm. The temperature in the cell was maintained at 45°C for the BAMNBA system and at 25°C for the KETO-IBU-DMPAA system. As a rough rule of thumb, a higher temperature (well within the membrane compatibility limits) is preferable to minimize issues with fouling and precipitation at the membrane. A higher temperature could be chosen for the first system since DOTG is a strong complexing agent, and the complex is stable even at the higher temperature. The permeate stream from the membrane has a lower impurity content, but must be concentrated prior to recycle. This can be achieved by evaporation in the concentrating unit. However, for a proof-of-concept demonstration, a simulated recycle process, described later, was


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used instead of actual solvent evaporation in the concentrating unit. This circumvented any issues involved with accurately maintaining solvent composition during evaporation.

Figure 3 Schematic of the nanofiltration-assisted continuous crystallization setup High Performance Liquid Chromatography (HPLC) Analysis HPLC was used to determine the composition of the mother liquor and crystals. Using calibration curves for each solute, the corresponding peak areas were used to calculate their concentrations in the mother liquor and crystal samples. These concentrations were used to calculate the yield and impurity incorporation in the crystals. The analysis was performed using an Agilent 1100 instrument equipped with a UV diode array detector for both systems. BAM-NBA 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. The samples were analyzed using an isocratic method with a 30:70 methanol/water mobile phase containing 0.3% trifluoroacetic acid. The detection wavelength was set at 230 nm, with the analysis time set at 30 minutes. KETO-IBU-DMPAA system: The column of choice was an Eclipse XDB-C18 column (Agilent Technologies) of dimensions 150 mm × 4.6 mm i.d. packed with 5 µm particles with 8 nm pore size. The samples were analyzed using an isocratic method with a 50:50 acetonitrile/50


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mM KH2PO4 mobile phase containing 0.1% trifluoroacetic acid. The detection wavelength was set at 230 nm, with the analysis time set at 7 minutes. Isothermal Titration Calorimetry (ITC) Analysis The binding constants of each impurity with the complexing agents and API were measured by ITC using a TA Instruments Nano ITC calorimeter. For the BAM-NBA system, four complexing agents were investigated in order to select the best one. For the other system, BPY was found to be a suitable complexing agent solely on the basis of batch experiments, and consequently was the only complexing agent in the ITC analysis. The reference cell was filled with pure solvent viz. 50:50 solution of water/ethanol. The sample cell was filled with the solution of the API or complexing agent with 10 µL aliquots of the impurity solution injected from the syringe stirrer every 300 s for a total of 25 injections at a stir speed of 250 rpm. The temperature set point was 5°C for the BAM-NBA system and 10°C for the KETO-IBU-BPY system. The resultant heat output was subtracted from a blank injection of the same impurity solution and the data were fitted to an independent binding model using NanoAnalyze software. Here a 1:1 stoichiometric binding was considered for data fitting in all cases except those involving BPY, where a 2:1 BPY:impurity binding was considered. At least three experiments were conducted for each complexing agent/API using at least two different concentrations in the sample cell. In all cases except those involving DOTG and DPG, the impurity solution concentration was ~100 mM while the sample cell solution concentration was ~10 mM. For DOTG and DPG, where a strong interaction was expected, these concentrations were reduced to ~10 mM for the impurity and ~1 mM for the complexing agent respectively. Organic Solvent Nanofiltration (OSN) membrane experiments


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OSN membranes provided by the Livingston group at Imperial College London were screened to evaluate their separation performance for the API, impurity and impurity complex. The membrane material was polybenzimidazole (PBI) dissolved in dibromoxylene (DBX) and cast on a non-woven polypropylene support. Since the purpose of the membrane is to allow a major proportion of the API to permeate while retaining most of the impurity complexes, the molecular weight cut-off (MWCO) of the membrane should be between the molecular weights of the API and the impurity complexes. Based on the molecular weights of BAM (121.14 Da) and the NBADOTG complex (406.44 Da), the following two membranes were screened for the first system: i. 22-PBI-DBX (MWCO ~300-400 Da) ii. 24-PBI-DBX (MWCO ~200-300 Da) In the second system, the molecular weight of KETO is 254.28 Da while those of the impurity complexes are 568.77 Da (for IBU-BPY complex) and 484.59 Da (for the DMPAA-BPY complex). Hence, only the 22-PBI-DBX membrane was tested to ensure its suitability for the separation. Here the 22 and 24 refer to the weight percentages of polymer in its casting solution. Broadly stating, a higher polymer concentration yields a ‘tighter’ membrane i.e. one with a lower MWCO. The stainless steel membrane cell had a working volume of 125 ml and was equipped with temperature control and a magnetic stirrer. For screening, the feed had the composition of the post-crystallization batch mother liquor. The feed flow rate through the HPLC pump was maintained at 2 ml/min and pressure was adjusted to have equal split between permeate and retentate. The stirring rate in the membrane cell was maintained at 250 rpm. The temperature in the cell was maintained at 45°C for the BAM-NBA system and at 25°C for the KETO-IBU-


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DMPAA system. The screening experiments were performed using solutions without and with complexing agent for comparison. RESULTS AND DISCUSSIONS Batch experiments The results for the two-step batch crystallization experiments for the BAM-NBA system are presented in Table 1. Crystallization step

Yield (%)

NBA incorporation in crystals (weight %)

First

71.52 ± 0.53

3.940 ± 0.027

Second

72.13 ± 0.26

1.606 ± 0.051

Table 1 BAM-NBA system: Yield and impurity incorporation for successive batch crystallizations The net yield of the two steps is 51.58 ± 0.57 %. The corresponding results for the second system can be seen in Table 2. For this system, experiments were performed with each impurity individually added, as well as both impurities together. Impurity

IBU alone

Crystallization Yield (%) step

IBU incorporation

DMPAA incorporation

in crystals (weight %) in crystals (weight %)

First

84.92 ± 0.06

3.532 ± 0.051

N/A

Second

84.19 ± 0.05

1.820 ± 0.047

N/A

First

86.31 ± 0.16

N/A

3.088 ± 0.121

Second

87.39 ± 0.14

N/A

1.626 ± 0.062

Both IBU and First DMPAA Second

85.49 ± 0.34

2.838 ± 0.077

2.324 ± 0.011

84.93 ± 0.16

1.659 ± 0.101

1.504 ± 0.023

DMPAA alone

Table 2 KETO-IBU-DMPAA system: Yield and impurity incorporation for successive batch crystallizations


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The net yield of the two steps is 71.49 ± 0.09 % for the case with only IBU impurity, 75.43 ± 0.26 % for the case with only DMPAA impurity, and 72.61 ± 0.42 % for the case with both impurities. In each case, the final impurity level is more than 1%, well above the typical industry standard of below 100 ppm, suggesting a potential to use complexation for further purification. Selection of complexing agents BAM-NBA system: The reported synthon partners of NBA were found from the Cambridge Structural Database. Of the search results, hydrazide and benzotriazole were rejected for concerns of stability and toxicity, while isonicotinamide and 4,4’-bipyridine were selected to be tested further. Owing to the strong affinity of the guanidine and carboxyl groups, two other compounds viz. 1,3-diphenylguanidine (DPG) and 1,3-Di-o-tolylguanidine (DOTG) were also tested. The K-values i.e. binding constants were measured using ITC. The results from Table 3 compare with a value of 16.08 ± 1.95 for the API-impurity pair. Complexing agent

K-value

Isonicotinamide

33.92 ± 2.06

4,4’-bipyridine (BPY)

85.53 ± 1.93

1,3-diphenylguanidine (DPG)

15026.64 ± 870.77

1,3-di-o-tolylguanidine (DOTG)

23235.28 ± 1524.73

Table 3 BAM-NBA system: K-values for binding of impurity and complexing agents The results demonstrate that solely relying on synthon partners may not always be able to identify an effective complexing agent. The guanidine-containing agents bind to NBA three orders of magnitude stronger than does BAM. The batch crystallization experiment was repeated for a single step with the addition of DOTG such that DOTG and NBA had equimolar concentrations. The yield after one step was 73.32 ± 0.26 %, which is higher than the net yield


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(51.58 ± 0.57 %) of two steps without complexation. No impurity and complexing agent were detected in the crystals by HPLC, implying that their levels were below 1 ppm each, based on the resolution of the HPLC method. The absence of any DOTG or impurity complex in the API crystal can be expected since the molecular weights of DOTG (MW 239.32 Da) and complex (MW 406.44 Da) are significantly higher than that of the API (MW 121.14 Da), leading to steric exclusion from the crystal. Thus DOTG proves to be an effective complexing agent for the isolation of NBA from BAM. The molecular structure of DOTG is shown in Figure 4.

Figure 4 Molecular structure of 1,3-di-o-tolylguanidine (DOTG) KETO-IBU-DMPAA system: In the previous system, BAM lacks the carboxyl group which is exploited in selective complexation with DOTG. This made the selection of complexing agent fairly straightforward on the basis of ITC analysis. However, in the current system, the API and the two impurities all possess a carboxyl group. Consequently, the factor to be exploited for selective impurity complexation is not the carboxyl group, but rather the second phenyl group present solely in the API molecule. So long as the complexing agent is not too strong, this group sterically hinders complexation with the API. However, a strong complexing agent may be able to overcome the steric hindrance and bind to the API, rendering it unsuitable for purification. This was experimentally observed with DOTG and N-phenylurea. Simple vial-scale cooling crystallization of 10g solutions containing 0.25 g/g KETO and 0.0125 g/g of either of these two compounds yielded crystals incorporating the complexing agents, suggesting against the use of such strong complexing agents.


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A search of the Cambridge Structural Database returned 4,4’-bipyridine (BPY) and nicotinamide as the synthon partners for IBU, while DMPAA had no reported synthon partners. Hence the binding performance of BPY and nicotinamide with DMPAA was investigated via batch experiments. In addition to these two compounds, 2-aminopyridine was also considered on account of its ability to bind to the carboxyl group. Batch crystallization of KETO solutions containing DMPAA as the sole impurity were repeated with the addition of stoichiometric amounts of each of the three complexing agents. The incorporation of DMPAA in the crystals is shown in Table 4. Complexing agent

DMPAA incorporation in crystals (weight %)

4,4’-bipyridine (BPY)

1.692 ± 0.026

Nicotinamide

2.826 ± 0.048

2-aminopyridine

2.708 ± 0.023

Table 4 DMPAA incorporation in crystal in the presence of complexing agents The complexing agent of choice was BPY for yielding crystals with the least impurity incorporation. The molecular structure of BPY is shown in Figure 5. After selecting the complexing agent, its performance in reducing the impurity incorporation was tested via batch experiments with IBU as the sole impurity, as well as with both impurities simultaneously (the experiment with DMPAA as the sole impurity was already performed while selecting the complexing agent). The yield and incorporation values are presented in Table 5. There was no detectable incorporation of BPY in the crystals, implying that its concentration was below 1 ppm, based on the resolution of the HPLC method.


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Figure 5 Molecular structure of 4,4'-bipyridine (BPY) Impurity

Yield (%)

IBU incorporation

DMPAA incorporation

in crystals (weight %)

in crystals (weight %)

IBU alone

83.98 ± 0.19

1.929 ± 0.014

N/A

DMPAA alone

87.49 ± 0.47

N/A

1.692 ± 0.026

Both IBU and DMPAA

87.41 ± 0.33

1.633 ± 0.019

1.305 ± 0.134

Table 5 Yield and impurity incorporation in batch crystallization with BPY as the complexing agent Batch experiments rather than ITC analysis were employed for selecting the complexing agent in the KETO-IBU-DMPAA system. However, ITC experiments were performed to quantify the binding constants of each impurity to KETO and to BPY, for possible future reference. The results are presented in Table 6. The preference of the impurities for the complexing agent over the API is reflected in the higher K-values for each impurity with BPY compared to those with KETO. Interacting Pair

K-Value

IBU-BPY

327.39 ± 12.54

IBU-KETO

55.45 ± 3.19

DMPAA-BPY

284.23 ± 9.63

DMPAA-KETO

32.83 ± 5.04

Table 6 KETO-IBU-DMPAA system: K-values for binding of impurity with KETO and BPY Selection of OSN membrane BAM-NBA system: Two OSN membranes were screened as described earlier. The separation of the target molecule (BAM) and the impurity complex is schematically shown in Figure 6.


19


Figure 6 Schematic of membrane separation of target molecule (BAM) from the impurity complex (NBA-DOTG complex) The rejection ratios were calculated using Equation 1 where the concentrations were in units of g/g. The rejection ratios of the API and impurity before and after complexation were the determining factor in the selection of the right membrane, and are depicted in Figure 7.

Membrane Rejection

% Rejection

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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100.00 90.00 80.00 70.00 60.00 50.00 40.00 30.00 20.00 10.00 0.00

90.44 82.58

22.64 18.65

13.44

12.84 6.01 3.83

BAM, 24-PBI-DBX NBAC, 24-PBI-DBX BAM, 22-PBI-DBX NBAC, 22-PBI-DBX No complexation

With complexation

Figure 7 BAM-NBA system: Comparison of rejection ratios for BAM and NBA without and with complexation for the two membranes


20

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Owing to the widely differing molecular weights of the impurity alone and the impurity complex, the rejection ratio of the impurity increased drastically after complexation. Since the impurity level was already below 1 ppm after complexation, the focus of further efforts was to improve yield. This required the selection of a membrane with the lower rejection factor for the API, and hence the 22-PBI-DBX membrane was chosen for nanofiltration. KETO-IBU-DMPAA system: Of the available membranes, only the 22-PBI-DBX membrane was found to be suitable in theory based on its MWCO and the molecular weights of the API and the impurity complexes. It was screened to gauge if it was able to separate the complex from the API in practice, and the rejection ratios are depicted in Figure 8. The high rejection ratios of the impurity-complex confirm the suitability of the membrane for separation.

Membrane Rejection 85.20

90.00

76.73

80.00 70.00

% Rejection

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


60.00 50.00 40.00 30.00 20.00 10.00

3.72

6.61

2.00

2.50

0.00 KETO

IBU

No complexation

DMPAA

With complexation

Figure 8 KETO-IBU-DMPAA system: Comparison of rejection ratios for KETO, IBU and DMPAA without and with complexation Continuous mode experiments BAM-NBA system: The concentration of the impurity post complexation was below detectable limits. As a result, continuous mode experiments were restricted to demonstrate that a


21


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membrane-coupled recycle process can increase yield over the batch value. The latter system allowed for deeper investigation using continuous experiments. The membrane screening for this system was performed at a feed flow rate of 2 ml/min through the membrane; hence it was decided to use the same flow rate for the continuous mode experiments. This translated into a residence time of 75 minutes in the crystallizer. The feed solution composition, crystallizer temperature and stirring rate were the same as those used for the batch experiments. The corresponding yield in an MSMPR without recycle was found to be 65.74 ± 0.04 %. This yield can be increased by using a membrane assembly to separate the impurities and recycling permeate back to the crystallizer. However, the permeate stream must first be concentrated. A simulated recycle, instead of actually concentrating the stream by evaporation prior to recycle, was employed to demonstrate the effect of recycle. In the simulated recycle method, the crystallizer has a single feed stream (stream B in Figure 9). This stream has the net flow rate and the net composition of the combination (stream A) of the fresh feed stream and the concentrated recycle stream. As a result, the yield and impurity incorporation observed in this simpler process are the same as those which can be observed in the process involving recycle. The permeate stream from the membrane, which would be concentrated and recycled in an actual process, can be discarded.

Figure 9 Schematic of replacing the actual system with a simulated recycle system


22

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It was decided to simulate a case where the API concentration in the recycle stream was same as that in the fresh feed stream, viz. 0.25 g/g. For comparing the performance with the unrecycled MSMPR, the residence time was kept the same viz. 75 minutes. From the yield in the MSMPR without recycle and the membrane rejection, the fresh feed flow rate was determined to be 1.67 ml/min. Consequently, the steady state concentration of impurity in the feed stream was calculated to be 0.0114 g/g solvent. Thus for the simulated recycle case, the feed solution had the composition of 0.25 g/g of BAM, 0.0114 g/g of NBA and 0.0163 g/g of DOTG (equimolar with NBA). This solution was pumped to the crystallizer at a flow rate of 2 ml/min. The yield in this case was 80.68 ± 0.04%, which is higher than the 65.74 ± 0.04% obtained without recycle. The level of both impurity and complexing agent in each experiment remained below 1 ppm. The concentration of the impurity in the retentate served to validate the choice of composition and flow rate of the feed stream. From this value, the impurity concentration in the actual feed solution was back-calculated to be 0.0126 g/g solvent, which is within 0.8% of the desired value of 0.0125g/g solvent. Thus it was experimentally demonstrated that it is possible to exceed the batch yield using a continuous mode with recycle, while still maintaining impurity levels within acceptable limits. For purposes of validation, a mass balance was performed 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- BAM: 0.31%, NBA: 0.59%, DOTG: 1.58%. KETO-IBU-DMPAA system: Unlike the previous system, here there was detectable incorporation of both impurities post complexation. This allowed for investigating the trade-off of crystal purity and yield, which itself can be varied by changing the overall feed flow rate to the crystallizer.


23


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As a base case, a simple MSMPR without recycle was operated at a residence time of 75 minutes (i.e. feed flow rate of 2 ml/min) with a same feed composition, crystallizer temperature and stirring rate as the batch process. The yield was 81.45 ± 0.07% with impurity incorporation of 1.442 ± 0.098% of IBU and 1.161 ± 0.117% of DMPAA. The simulated recycle process described earlier was employed to observe the effect of recycle. The principal goal was to demonstrate the efficacy of the membrane-coupled recycle process in terms of reducing impurity incorporation and improving yield compared to a continuous process without recycle having the same residence time. Additionally, yield-impurity incorporation curves were also obtained by varying the residence time in the crystallizer. For this, five equally spaced values of residence time between 37.5 minutes and 75 minutes were chosen. In practice, these residence times were implemented by choosing the appropriate flow rate of stream B in Figure 9 varying from 2 ml/min to 4 ml/min. A theoretical mass balance was performed to determine the compositions of the feed stream corresponding to each residence time, which are presented in Table 7. The validity of choosing these theoretical values was tested by checking if the mass flow rate of each solute in the feed stream matched that which would be obtained by mixing the fresh feed with the concentrated recycle. Note here that the concentrated recycle has the same solute mass flow rate as the experimentally obtained permeate. In each case, the two values matched within 2% for each component. Residence Flow time rate

Concentration KETO

IBU

DMPAA

BPY

(min)

(ml/min) (g/g)

(mg/g)

(mg/g)

(mg/g)

37.5

4

0.146

6.746

7.101

6.431

46.875

3.2

0.176

8.524

8.682

7.885

56.25

2.67

0.206

9.906

10.563

9.505


24

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65.625

2.29

0.234

11.795

12.233

11.23

75

2

0.266

13.628

13.921

12.884

Table 7 Composition of feed stream for various residence times The observed yield and impurity incorporation for these values of residence time are reported in Table 8. The yield-impurity incorporation curves shown in Figure 10 and Figure 11 match the theoretical expectations of incorporation increasing with yield. The fitted equation (quadratic in this case) allows for determining the incorporations at any desired value of yield and vice versa. Residence (min)

time Yield (%)

IBU incorporation DMPAA incorporation in crystals (weight %) in crystals (weight %)

37.5

83.78 ± 0.71

0.334 ± 0.002

0.343 ± 0.033

46.875

88.76 ± 0.30

0.453 ± 0.040

0.471 ± 0.043

56.25

91.77 ± 0.11

0.548 ± 0.003

0.555 ± 0.007

65.625

93.04 ± 0.43

0.619 ± 0.009

0.632 ± 0.010

75

94.68 ± 0.05

0.670 ± 0.013

0.679 ± 0.003

Table 8 Yield and impurity incorporation for simulated recycle experiments

Yield against IBU incorporation 0.8 0.67

0.7

Ibu incorporation %

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


0.619 0.548

0.6 0.453

0.5 0.334

0.4 0.3

y = 0.0012x2 - 0.186x + 7.3655

0.2 0.1 0 82

84

86

88

90

92

94

96

Yield %


25


Figure 10 Yield-impurity incorporation curve for IBU

Yield against DMPAA incorporation 0.8 0.679

DMPAA incorporation %

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 29

0.632

0.7 0.555

0.6 0.471

0.5 0.343

0.4 0.3 0.2

y = 0.001x2 - 0.1529x + 5.9104

0.1 0 82

84

86

88

90

92

94

96

Yield %

Figure 11 Yield-impurity incorporation curve for DMPAA As mentioned earlier, the yield of the base case (MSMPR without recycle, residence time 75 minutes) was 81.45 ± 0.07% with impurity incorporation of 1.442 ± 0.098% of IBU and 1.161 ± 0.117% of DMPAA. The performance for the same residence time can be enhanced by using membrane-coupled recycle, as seen by the higher yield (94.68 ± 0.05%), as well as lower impurity incorporations (0.670 ± 0.013% of IBU and 0.679 ± 0.003% of DMPAA). For purposes of validation, a mass balance was performed for each solutes for the simulated recycle case with residence time 75 minutes, and the net in-flows and out-flows agreed within the following limitsKETO: 0.91%, IBU: 1.08%, DMPAA: 1.45%, and BPY: 1.31%. As a final step, to demonstrate that similar benefits cannot be reaped simply with recycle in the absence of complexation, the simulated recycle experiment at a residence time of 75 minutes was repeated without any complexing agent. The feed stream in this case contained 0.265 g/g KETO, 16.156 mg/g IBU and 16.640 mg/g DMPAA. The yield in this case was 93.18 ± 0.04%, which is


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comparable to that with complexation. However, the impurity incorporations were significantly higher- 3.536 ± 0.012% of IBU and 2.902 ± 0.011%, owing to recycling the impurities along with the API. This re-emphasizes the necessity and benefits of complexation in the process. CONCLUSIONS Impurity complexation is an effective strategy to reduce the lattice incorporation of an impurity having similar structure and molecular weight as the API. This was previously demonstrated elsewhere for batch crystallization. In the current work, this strategy was successfully extended to the continuous mode. Membrane nanofiltration was employed in rejecting the impurity complex and yielding a more ‘pure’ permeate stream for recycle. A working methodology for selecting the complexing agent and membrane was also developed. The efficacy of the process was demonstrated by the cooling crystallization of two systemsthe

benzamide/3-nitrobenzoic

acid

system

and

the

ketoprofen/ibuprofen/α,4-

dimethylphenylacetic acid system. The first system served as a starting point to gauge the effectiveness of the technique, while the second one, involving two impurities, allowed for greater investigation in terms of observing the behavior of impurity complexation with yield in a continuous crystallization setup with recycle. In each system, the continuous membrane-coupled recycle process was observed to have a better performance than the batch process as well as the simple MSMPR without recycle in terms of higher yield and lower impurity incorporation. ASSOCIATED CONTENT Supporting information The supporting information is available free of charge.


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Components of the membrane cell, details regarding determining feed stream composition in the simulated recycle process for both systems, mass balance calculations on simulated recycle process for both systems, crystal purity results for the KETO-IBU-DMPAA system (PDF). AUTHOR INFORMATION Corresponding Author *Email: [email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGEMENTS 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. REFERENCES 1. Myerson, A. Handbook of Industrial Crystallization 2002. 2. Alvarez, A.; Myerson, A. Cryst. Growth Des. 2010, 5, 2219-2228. 3. Chen, J.; Sarma, B.; Evans, J.; Myerson, A. Cryst. Growth Des. 2011, 11, 887-895. 4. Wong, S.; Tatusko, A.; Trout, B.; Myerson, A. Cryst. Growth Des. 2012, 12, 5701-5707. 5. Hsi, K.; Concepcion, A.; Kenny, M.; Magzoub, A.; Myerson, A. Cryst. Eng. Comm. 2013, 15, 67766781. 6. Givand, J.; Teja, A.; Rousseau, R. AIChE Journal 2001, 47, 2705–2712. 7. Givand, J.; Chang, B.; Teja, A.; Rousseau, R. Ind. Eng. Chem. Res. 2002, 41, 1873–1876.


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8. Teja, A.; Givand, J.; Rousseau, R. AIChE Journal 2002, 48, 2629–2634. 9. Hsi, K.; Kenny, M.; Simi, A.; Myerson, A. Cryst. Growth Des. 2013, 13, 1577-1582. 10. Urbanus, J.; Roelands, M.; Verdoes, D.; Jansens, P.; ter Horst, J. Cryst. Growth Des. 2010, 10, 1171−1179. 11. Hsi, K.; Chadwick, K.; Fried, A.; Kenny, M.; Myerson, A. Cryst. Eng. Comm. 2012, 14, 2386-2388. 12. Adler, S.; Beaver, E.; Bryan, P.; Robinson, S.; Watson, J. Centre for Waste Reduction Technologies of the AIChE and Dept. of Energy 2000. 13. Marchetti, P.; Jimenez Solomon, M.; Szekely, G.; Livingston, A. Chemical Reviews 2014, 21, 1073510799. 14. Pink, C.; Rundquist, E. Network Young Membrains 2012. 15. Peeva, L.; Malladi, S.; Livingston, A. Comprehensive Membrane Science and Engineering 2010. 16. Ferguson, S.; Ortner, F.; Quon, J.; Peeva, L.; Livingston, A.; Trout, B.; Myerson, A. Crys. Growth Des. 2014, 14, 617-627.


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Continuous Crystallization with Impurity Complexation and

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