Development of continuous spherical crystallization to prepare

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Development of continuous spherical crystallization to prepare fenofibrate agglomerates with impurity complexation using MSMPR crystallizer Kohei Tahara, Yuichi Kono, Allan S. Myerson, and Hirofumi Takeuchi Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b00426 • Publication Date (Web): 01 Oct 2018 Downloaded from http://pubs.acs.org on October 3, 2018

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Crystal Growth & Design

Development of continuous spherical crystallization to prepare fenofibrate agglomerates with impurity complexation using MSMPR crystallizer Kohei Tahara1,*, Yuichi Kono1, Allan S. Myerson2, Hirofumi Takeuchi1 1

Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, 1-25-4 Daigaku-

Nishi, Gifu 501-1196, Japan 2

Department of Chemical Engineering, Massachusetts Institute of Technology, 77

Massachusetts Avenue, 66-568, Cambridge, Massachusetts 02139, United States KEYWORDS. Continuous spherical crystallization, MSMPR, Complexing agent, Fenofibrate, Fenofibric acid

ACS Paragon Plus Environment

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ABSTRACT. Agglomeration during crystallization such as spherical crystallization, has the potential to integrate pharmaceutical downstream processes after compound synthesis. This process incorporates granulation and agglomeration during the crystallization process and to date has been performed in batch reactors. However, because it involves certain complicated phenomena, the batch process is difficult to scale up for commercial production. We demonstrate the feasibility of a continuous process of crystallization with agglomeration based on the spherical crystallization of fenofibrate (FF) as a model active pharmaceutical ingredient (API) by using a mixed-suspension, mixed-product removal (MSMPR) crystallizer. The characteristics of FF granules produced by the emulsion solvent diffusion method with MSMPR were compared with the characteristics of batch-prepared FF granules. The particle-size distribution of the FF agglomerates prepared by MSMPR crystallizer was not significantly different from that prepared by the equivalent batch-wise crystallizer. The effects of the operating parameters in MSMPR were examined based on the crystal properties of FF granules produced via continuous spherical crystallization. Conversely, pharmaceutical crystallization mainly is purification to generate pure solid APIs. However, impurity separation in spherical crystallization has not been demonstrated. Impurity inclusion in the crystal lattice is difficult to avoid, especially when the impurity and targeted API molecule structures are similar. Thus, we established effective purification during continuous spherical crystallization using a complexing agent (1,3-di-o-tolylguanidine, DOTG) with a representative impurity (fenofibric acid, FFA) to prevent impurity incorporation into the crystal lattice. Purification improvement using the FFA/DOTG complex was substantiated via continuous spherical crystallization with MSMPR.


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INTRODUCTION Pharmaceutical crystallization is a separation and purification technique used to produce a wide variety of active pharmaceutical ingredients (APIs), notably for low-molecular-weight drugs.1, 2 API crystals affect the performance of downstream operations such as filtration, drying, milling, powder mixing, and tableting. Furthermore, characterizing the final solid-dosage form, such as dissolution rate, also depends on the crystal properties of APIs. Spherical crystallization of APIs was established by Kawashima et al. as a downstreamprocess intensification for pharmaceuticals that can be integrated into crystallization and granulation.3 Ggranules obtained after crystallization may improve the efficiency of postcrystallization processes such as filtration and drying. Furthermore, the granules obtained from this process, which exhibit improved flowability, can subsequently be blended with excipients and compressed directly into tablets.4 However, many process parameters of spherical crystallization can influence the quality of granules. The phenomenon of spherical crystallization is complicated compared with conventional crystallization. Thus, scaling up spherical crystallization for use in large-scale commercial production might be difficult.5 Continuous manufacturing has been used for the production of various chemical products to achieve a cost-effective and flexible production. Recently, the pharmaceutical industry, which still largely uses batch processing, has paid greater attention to continuous manufacturing.6 When the operating principle of manufacturing equipment used in the development stage is the same as that used for commercial production, a design space and control strategies to ensure the product quality for commercial production can be rapidly established with a small amount of APIs.7 The operating conditions for continuous steady-state crystallization are constant. The key advantage


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of continuous processing is that higher throughput can be treated with continuous manufacturing, which leads to significant savings of capital investment and operating expenses. Continuous processing of spherical crystallization is expected to offer several advantages over batch processing. The plug-flow crystallizer or mixed-suspension mixed-product removal (MSMPR) are the two major types of continuous crystallizers used in the industry.2,

8-10

The products of spherical

crystallization used to prepare the agglomerates in the crystallization process are generally larger than those of conventional crystallization. Therefore, using a plug-flow crystallizer for spherical crystallization would cause some concerns because agglomerates may clog the tube line. Recently, spherical crystallization, which is notably applied for continuous crystallization with MSMPR, was intensified by a few research groups.11-13 The MSMPR is more practical because it can handle higher suspension densities without clogging, which makes it suitable for spherical crystallization. Furthermore, the yield of MSMPR can be improved by increasing the number of stages and/or by recycling.14, 15 The main purpose for pharmaceutical crystallization is to purify targeted APIs to generate solid phases. The fusion of impurity separation, crystallization, and agglomeration processes in a single reactor and their continuous implementation by MSMPR would be ideal in terms of cost efficiency and labor and would allow a one-step pharmaceutical downstream process. However, the purification of APIs during spherical crystallization has yet to be demonstrated. When APIs and impurities have similar molecular weights and dimensions, the impurity often tends to be adsorbed on the API-crystal surface and/or to be incorporated into the crystal lattice. Such impurities may be by-products of the API synthesis or may be unconverted raw material or


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intermediate. A concern with conventional purification such as recrystallization or chromatography is that the yield is lowered after treatment, and a dilemma exists between API yield and purity. Impurity complexation can improve purity without compromising on yield and is therefore an effective solution to this problem.16 A complexing agent that can selectively bind with the impurity but not with the API is added to the solution prior to crystallization. Previous reports state that an impurity complex may reduce the tendency of impurities to be incorporated into the lattice, resulting in higher-purity crystals. This research focuses on combining “agglomeration during crystallization” and “impurity complexation” in continuous crystallization with MSMPR to obtain refined API granules suitable for post-crystallization processing and to obtain higher product purity. The applicability of this complexing-agent strategy under continuous spherical crystallization with MSMPR is demonstrated by using fenofibrate (FF), which decreases cholesterol levels in patients at risk of cardiovascular disease. FF is a model API and its major impurity is fenofibric acid (FFA). 1,3-dio-tolylguanidine (DOTG) was used as complexing agent with FFA to better eliminate impurities during spherical crystallization of FF.16, 17 The chemical structures are shown in Figure 1.


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Figure 1. Chemical structure of fenofibrate (MW 360.83), fenofibric acid (MW 318.75), and 1,3-di-o-tolylguanidine (MW 239.32). To prepare FF agglomerates during crystallization, we used quasi-emulsion solvent diffusion (ESD), which is a typical spherical-crystallization technique.18, 19 FF was previously prepared as spherical agglomerates by using a batch-wise crystallizer.18 Hydrophobic FF is dissolved in organic solvent (methanol + dichloromethane) and, when the solution is dispersed into water as an antisolvent, transient-emulsion (quasi-emulsion) droplets are produced, although they are miscible. Small amounts of dichloromethane are added into solvent to induce intense interactions between API and solvent. The transient emulsion is unstable due to increasing interfacial tensions between solvent and antisolvent. The methanol-dichloromethane solvent in which FF is gradually dissolved diffuses outside the emulsion droplets, and the water diffuses into the droplets, which reduces the solubility of FF inside the solvent droplets and eventually induces FF crystallization. The mechanism is illustrated in the supporting information.


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EXPERIMENTAL SECTION Materials FF and FFA was purchased from Tokyo Kasei (Tokyo, Japan). DOTG was purchased from Sigma-Aldrich (St. Louis, MO, USA). Methanol and dichloromethane were purchased from Kishida Chemical Co., Ltd. (Osaka, Japan). All other chemicals were commercial products of reagent grade. Batch spherical crystallization of fenofibrate In conventional batch spherical crystallization, to prepare FF granules, a FF solution dissolved in a methanol-dichloromethane mixture is added to distilled water as an antisolvent while stirring.18 FF solution (4.7 mL, 0.11 g/mL) in methanol-dichloromethane (4/0.7) mixture was mixed into distilled water (100 mL), and the mixture was stirred at 500 rpm and 40 °C by using a magnetic stirrer. After mixing for 30 min, the precipitated agglomerates were collected via filtration. The solid particles after filtration were washed with water, dried in an oven at 30 °C for 24 h, and then stored in a desiccator. Continuous spherical crystallization of fenofibrate with MSMPR Figure 2 shows the schematic configuration of the MSMPR system for antisolvent spherical crystallization, and Table 1 lists the experimental parameters for all of the MSMPR studies. As a continuous crystallizer, the MSMPR crystallizer was used for continuous spherical crystallization. It comprises 125 mL five-necked and jacketed separable flasks (Asahi Glassplant Inc., Arao, Japan) as crystallizers, each with a magnetic stirrer (500 rpm) and independent temperature control, a filter unit with a glass-fritted disk, a separator flask, and three peristaltic


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pumps (Masterflex L/S, Cole Parmer, Vernon Hills, IL) fitted with Chem-Durance Bio tubing (Cole Parmer). During each MSMPR experiment, fresh FF solutions in the methanoldichloromethane mixture (0.25 g/mL) and water were continuously pumped into the crystallizer with a residence time of 30 min. In the experiment involving impurity separation, FFA as a model impurity and DOTG as complexing agent were dissolved in solvent. Once crystallized, the suspension of FF crystals was removed intermittently every 1.5 min (1/20th of the residence time). During the intermittent withdrawing, 5.2 mL suspension of FF (5% of the volume) in the crystallizer was removed rapidly at the maximum pump flow rate. After the solution level dropped below the level of the outlet dip tube, we pumped air into the tube, and removed the remaining suspension in the outlet tube. We separated the suspension discharged from the outlet tube by using the filter unit and collected the FF crystals from the filter unit. After filtration, the mother liquor was collected in the separator and the residual FF or FFA in the filtered mother liquor was measured by using high-performance liquid chromatography (HPLC). The details of HPLC method was shown in supporting information. The semidried cake of FF crystal entrapped in the filter unit was washed with pure water, further dried in an oven at 30 °C for 24 h, and then stored in a desiccator.


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Table 1. Experimental conditions for continuous spherical crystallization of fenofibrate using MSMPR. Given is the amount of each reagent and solvent per 100 mL of antisolvent (water)

API Impurity

Expt. 1 0.5

FF (g) FFA (g)

Complexing agent DOTG (g) Methanol (mL) Solvent Dichloromethane (mL) Antisolvent Water (mL) Reactor temperature (°C)

4 0.7 100 40

Expt. 2 0.5

4 0.37 100 40

Expt. 3 0.5

4 0.37 100 60

Expt. 4 0.5 0.03

Expt. 5 0.5 0.03

4 0.37 100 40

0.0225 4 0.37 100 40

Figure 2. Schematic diagram of single-stage MSMPR for continuous spherical crystallization of fenofibrate.


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Physicochemical properties of fenofibrate crystals The FF crystal particle sizes were measured by using a laser diffraction size analyzer (Microtrac MT-3000; Nikkiso Co., Ltd., Tokyo, Japan) and a FF suspension in water. The particle shape was imaged by scanning electron microscopy (SEM, JSM-6510LV, JEOL, Japan). Thermal analysis of FF crystals was done by using a differential scanning calorimeter (DSC; EXSTAR6000; Seiko Instruments Inc., Chiba, Japan). The sample powder was placed in an aluminum sample pan and measured as the temperature was increased at a rate of 3 °C/min. Powder x-ray diffraction (PXRD; D8 Advance X-ray diffractometer, Bruker, Karlsruhe, Germany, 40 kV, 40 mA) was used to investigate the crystalline state of the APIs over a 2θ range of 5° to 40° by using Cu Kα radiation (wavelength = 1.5406 Å). To measure the powder flow properties of FF crystals, the angle of repose, Hausner’s ratio, and the compressibility index were measured by powder tester (Hosokawa Micron, Ltd., Osaka, Japan).


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RESULTS ANS DISCUSSIONS Characterization of fenofibrate agglomerates prepared by spherical crystallization: Batch vs continuous preparation with MSMPR In this paper, continuous crystallization by MSMPR was developed by focusing on the process intensification of ESD, which is one of spherical crystallization methods. The spherical crystallization method is classified into several techniques according to the mechanism; representative techniques are spherical agglomeration (SA) and ESD.5 SA consists of two steps: initially, the crystals are precipitated by crystallization using a miscible solvent and antisolvent, and then a third solvent called the bridging liquid is added to promote aggregation between the crystals.3 The third solvent should be not miscible with the solvent or antisolvent and interacts with the precipitated crystal (wetting between crystals) due to capillary negative pressure and interfacial tension at the solid-liquid interface. Crystal aggregates are then generated by collisions between particles under stirring. In the ESD method, which is based on antisolvent crystallization, it is necessary to produce transient emulsion under the condition that the solvent and the antisolvent for API are miscible. The solvent in the droplets gradually diffuse into the external phase. The antisolvent simultaneously diffuses into the droplets; therefore, the solubility of API in the droplet decreases, and then the API crystals precipitate. The particles prepared by ESD are generally smaller and more porous or hollow than those prepared by SA, which produces larger, dense, hard particles. For ESD, the solvent-antisolvent ratio is a critical parameter that controls spontaneous transit-emulsion formation, which, compared with SA,4 essentially requires a low concentration of APIs in the system.


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Conversely, for continuous production using MSMPR, multi-stage MSMSP or an additional vessel and pump would be required for SA with the two-step process of crystallization and agglomeration (addition of bridging liquid);12 thus, the setup and operation of the apparatus would be complicated. ESD, in which spherical crystallization is completed in a one-step operation, may be able to cope with single-stage MSMPR.11 Because advantages and disadvantages exist in both methods, an appropriate spherical crystallization method must be selected according to the targeted APIs, product quality, and yield. This section compares the characteristics of FF granules prepared by conventional batch-wise ESD with the same granules obtained in a continuous manner by using single-stage MSMPR. The spherical crystallization of FF was screened in a batch reactor, and the experimental parameters were determined before using the MSMPR crystallizer. To compare the batch preparation, spherical crystallization of FF was done by using the MSMPR crystallizer with a residence time of 30 min (see Expt. 1 in Table 1). The spherical agglomerates of FF made in continuous mode was prepared by operating the MSMPR for 5 h. During the MSMPR crystallization, the API concentration in the mother liquor was measured, and crystallization was hardly detected after 30 min. Fig.S.2. shows the crystal yields calculated from the monitored API concentration in the mother liquor. For the mother liquor concentration, a steady state was achieved after 30 min. The practical yield of spherical agglomerates prepared in the batch reactor or MSMPR both exceeded 98%. No significant difference in yield occurred between batch and MSMPR for ESD. A stable, continuous production of FF granules proceeded after steady-state operation was reached. Figure 3 shows the particle-size distribution of crystals recovered after drying (as determined by using a laser diffraction particle-size analyzer). The particle sizes (D10, D50, and D90) and


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the distributional characteristic (i.e., SD) have been shown as supporting information in Table S.1. The gray curve shows the distribution of the commercial FF. The mean particle size (D 50) of the commercial product is 13.0 µm. Larger agglomerates are prepared by the batch reactor (D50: 296.9 µm) with a narrow size distribution. The mean particle size of FF agglomerations prepared by MSMPR (D50: 310.6 µm) and the size distribution almost correspond with the batch results (Figure 3). Ferguson et al. demonstrated that MSMPR crystallization of benzoic acid could generate larger mean crystal sizes than the equivalent batch process.20 However, in ESD crystallization of fenofibrate, the particle-size distribution of granules would not be broader than that of batch configurations. In both cases of MSMPR and batch-wise crystallization, the API concentration in the mother liquor was almost undetectable after 30 min of feeding, as specified in the supporting information. Precipitation, growth, and crystal aggregation are completed relatively quickly in the system; therefore, the difference in crystal growth between MSMPR and batch configuration may not be reflected in the particle-size distribution. Figure 4 shows the particle morphologies of the original FF powder and of the agglomerates as imaged by SEM; agglomerate FF particles prepared by batch and continuous spherical crystallization are larger than the commercial FF, suggesting that the FF agglomerates are continuously produced during crystallization for 5 h in the MSMPR crystallizer.


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Figure 3. Particle-size distribution of fenofibrate commercial materials and crystals obtained by spherical crystallization in batch crystallizer or MSMPR.

Figure 4. SEM images of (a) starting commercial material of fenofibrate, (b) agglomerates of fenofibrate produced using batch crystallizer or (c) MSMPR. The crystal properties of FF were evaluated by using PXRD and DSC. The PXRD patterns of untreated FF and crystallized agglomerates irrespective of preparation process are similar and show intense crystalline peaks (see Figure 5a). In the DSC studies, untreated original FF powder shows a sharp endotherm at 80.04 °C, which corresponds to its melting point (Figure 5b). No


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appreciable change occurs in the melting temperature of agglomerates with respect to the pure drug. The DSC results may also indicate a slight decrease in crystallinity of FF when prepared in the form of agglomerates, which is attributed to a reduced change in enthalpy upon crystallization of FF compared with commercial FF. To summarize this evaluation of FF crystal properties, the properties of FF crystals produced by MSMPR are similar to those of crystals prepared using the batch process. However, the SEM image of batch-prepared crystals (Figure 4b) shows small crystals that are not observed much in the SEM image of MSMPR-prepared crystals (Figure 4c). This is attributed to the influence of the speed of the solvent drop into the antisolvent (water). In batch preparation, because solvent and antisolvent were all mixed at the same time, many crystal nuclei may have been generated, resulting in insufficient crystal growth.

Figure 5. Crystallinity of FF crystal agglomerates: (a) x-ray powder diffraction pattern and (b) differential scanning calorimetry for commercial FF and granules prepared by batch or MSMPR crystallization. The flow properties of API powder are important in determining the ease with which pharmaceutical powders can be stored, handled, and processed in solid-dosage forms. Table 2


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lists the parameters of powder flowability of FF granules: angle of repose, compressibility index, and Hausner ratio as measured by the Hosokawa powder tester. These factors are related to the rheology of the powder. The angle of repose is a measure of the internal angle made by a pile of powder with the plane surface when the powder flows through a specific funnel. The qualitative characteristics of powder fluidity indicated by the angle of repose are generally evaluated by the classification shown in Table S.2. The compressibility index and the Hausner ratio, which could also predict the powder flow, were calculated by using the bulk volume and tapped volume of the powder. The scale generally used for flowability is shown in Table S.3. Powder with “good” flow properties is suitable for manufacturing solid dosage forms. Original FF powders have poor flowability due to the adhesive properties of the small, irregular-shaped primary crystals. Each parameter of FF agglomerated crystals prepared by MSMPR continuous spherical crystallization is smaller than the corresponding parameter of the original commercial FF powders, irrespective of flowability factors, which indicates better flowability and packing for the FF agglomerated crystals. The Hausner ratio of the agglomerate is less than 1.25, which also indicates an improved flowability of the agglomerated crystals. The reason for the excellent flowability of the agglomerates is the significant reduction in interparticle friction, which results from the larger size of the crystal agglomerates. Table 2. Comparison of powder rheology attributes of initial material with that of product made by ESD. Data are presented as mean ± standard deviation (n = 3)

Commercial material MSMPR

Angle of repose (degrees) 59.9 ± 0.8 50.0 ± 0.7

Compressibility index (%) 46.3 ± 1.4 12.2 ± 2.1

Hausner ratio 1.86 ± 0.05 1.14 ± 0.03


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Effect of MSMPR conditions on continuous spherical crystallization of fenofibrate Changing the experimental parameters for continuous spherical crystallization allows us to control the properties of the FF granules. For example, the solvent, antisolvent, and the reactor temperature all affect the particle-size distribution of the FF granules. Figure 6 shows how the amount of dichloromethane and the reactor temperature affects particle-size distribution of FF agglomerates obtained by MSMPR continuous crystallization. All experimental parameters for MSMPR are listed in Table 1. Experiment 2 uses less dichloromethane than Expt. 1. In this system, dichloromethane acts as a “bridging liquid” and might induce interactions between individual crystals. In a typical spherical crystallization process, a general rule states that decreasing the quantity of bridging liquid reduces the agglomerate particle size.21 This study obtains the same results as previous reports, which shows that the quantity of dichloromethane controls the particle-size distribution of the final product.


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Figure 6. Effect of MSMPR experimental parameters on continuous spherical crystallization of FNB in MSMPR. Particle-size distributions of each sample was measured by laser diffraction analyzer. The temperature in the MSMPR reactor also affects the physicochemical properties of the agglomerations. Thus, finding the optimum temperature is essential to optimize the agglomeration. At higher temperatures (60 °C; Expt. 3; Table 1), the agglomerates formed are bigger than those formed at 40 °C. The usual theory of antisolvent crystallization suggests that the rate of nucleation is inversely proportional to temperature.22 Thus, the temperature in the reactor is an important parameter for controlling the final particle size and the particle-size distribution of crystals. When crystallization occurs at higher temperatures, general observations indicate that larger crystals are produced. At low temperature, the solubility of the drug in the solvent-antisolvent mixture decreases, which leads to higher supersaturation conditions. Therefore, low temperatures decrease the diffusion and growth kinetics at the crystal–boundarylayer interface. As a result, smaller drug particles are obtained at low temperature.22 These data demonstrate that the characteristics of FF crystals can be manipulated by tuning the experimental parameters to achieve the desired product quality. Further investigations are planned to optimize the experimental conditions of continuous FF spherical crystallization; for instance, creating design space to satisfy critical product quality.

Separation of impurity using complexing agent in continuous spherical crystallization by MSMPR


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Impurity removal is of particular importance for the pharmaceutical industries, where the presence of even low levels of certain compounds can have significant consequences for the safety, efficacy, and regulatory approval of the product. This section demonstrates the simultaneous reduction of impurity levels and crystal agglomeration in the crystallization process in the MSMPR continuous crystallizer. For Figure 7, FFA is used as a model impurity within FF (Expts. 4 and 5) to investigate the possibility of impurity separation in continuous ESD. FFA is a typical by-product (Fenofibrate EP Impurity B; Fenofibrate USP Related Compound B) of FF synthesis. FF is the isopropyl ester of FFA. The difference between FF and FFA is the presence of the carboxylic acid moiety in FFA versus the ester in FF (Figure 1). The hydroxyl group in carboxylic acid in FFA may form strong hydrogen bonds with other materials. One guanidine derivative, DOTG, was used as complexing agent with FFA. Guanidine compounds strongly interact with carboxylic acids.23 FFA interacts preferentially with DOTG via hydrogen bonds instead of FF; this prevents the incorporation of FFA into the crystal lattice of FF primarily because of steric effects. DOTG leads to a significant improvement in the purity of FF by complexing FFA/DOTG in conventional antisolvent or cooling crystallization (which were not spherical crystallizations), as compared with crystallization without the complexing agent.16, 17 Improved efficiency of impurity removal was expected upon using a complexation technique with DOTG under continuous spherical crystallization using MSMPR. To examine the impact of DOTG on the crystallization, impure FF containing 5.7 wt% FFA was crystallized from methanol-dichloromethane by using water as an antisolvent both in the absence (Expt. 4) and


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presence (Expt. 5) of DOTG. The molar ratio FFA/DOTG in the system was set to unity to allow interactions between all molecules. The results of these experiments are summarized in Figure 7. As shown in Figure 7a, a 98.5% improvement in purification of FF occurs upon using DOTG as complexing agent, whereas lower purity (95.1%) is the result in the absence of DOTG. Under batch spherical crystallization with the equivalent experiments, FF purity in spherical crystallization was 94.6%, whereas it increased to 96.5% when DOTG was added. Even in the case of spherical crystallization regardless of batch/continuous preparation, DOTG functioned as a complexing agent with FFA and efficiently removes impurities. Although the crystal purity was significantly increased by the addition of DOTG, both FFA and DOTG were detected in the small amount of impurity remaining in the FF granules. The molar ratio of FFA/DOTG in the impurities was approximately 0.9. By controlling the growth rate, it is possible to prevent FFA or DOTG from incorporation into the crystal lattice. Figure 7b compares the particle-size distribution of agglomerates prepared by MSMPR in the FF/FFA system. In the absence of DOTG (Expt. 4), the mean particle size of granules is smaller (D50: 78.0 µm) than that of granules prepared in Expts. 1–3 (no impurity in the system in Figure 4) and in Expt. 5 (addition of DOTG, D50: 389.4 µm). These particle-size distributions demonstrate that the incorporation of impurities (FFA) into the crystals affects crystal growth during crystallization.24 The complexing agent with the impurity significantly enhanced the purification and applicability of spherical crystallization via MSMPR.


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Figure 7. Complexing agent (DOTG) with impurity affects continuous spherical crystallization of fenofibrate via MSMPR. (a) Purification results for fenofibrate in methanoldichloromethane with 5.66% initial impurity (Expts. 4 and 5). Data are presented as mean ± standard deviation (n = 5). (b) Particle-size distribution of fenofibrate agglomerates prepared by MSMPR. Recycling the mother liquor in steady-state MSMPR crystallizations have possible to improve yield. Incorporating an additional nanofiltration-membrane unit into continuous MSMPR crystallization and recycling the mother liquor could dramatically increase the crystallization yield without decreasing purity.25 Thus, nanofiltration would be also a promising tool for continuous spherical crystallization with MSMPR to achieve high yield and API-crystal purity though the complexing agent with the FFA impurity.


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CONCLUSIONS We implemented continuous ESD of FF by using a single-stage MSMPR crystallizer. The particle-size distribution of the FF granules prepared by MSMPR was almost the same as the particle-size distribution of the granules for the batch-wise reactor. (The D50 values of MSMPR crystallizer and the batch-wise reactor were 310.6 and 296.9 µm, respectively.) The physical properties of the FF granules produced by MSMPR were controlled by tuning the experimental conditions, such as the amount of solvent and the temperature of the reactor. The MSMPR parameters play an important role in determining the characteristics of crystals with desirable powder properties for pharmaceutical manufacturing. In addition, we demonstrated that impurity complexation with DOTG could be purified during continuous spherical crystallization. The incorporation of the impurity (i.e., FFA) into the crystal lattice could be prevented by using DOTG as the complexing agent. We were able to improve the purity level of the FF granules from 95.1% to 98.5%. These findings demonstrate the consolidation of purification and granulation during continuous crystallization with MSMPR without extra pharmaceutical operations.


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ASSOCIATED CONTENT Supporting Information. HPLC conditions to measure FF, FFA, and DOTG. Figure S.1. Quasi-emulsion solvent diffusion method to prepare fenofibrate agglomerates. Figure S.2. Yield profile for fenofibrate spherical crystallization with MSMPR. At each time step, the FF concentration in the mother liquor (after filtration) at the crystallizer outlet was determined by using HPLC. Table S.1. Particle size (D10, D50, and D90) and the distribution of fenofibrate commercial materials and crystals obtained by spherical crystallization in the batch or MSMPR crystallizer with expt.1–5. Table S.2. Flow properties and corresponding angles of repose (adapted from Japanese Pharmacopoeia XVII) Table S.3. Scale of flowability for compressibility index and Hausner ratio (adapted from Japanese Pharmacopoeia XVII)

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT


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The authors are grateful for the financial support provided by Open Partnership Joint Projects of JSPS Bilateral Joint Research Projects, the Hosokawa Powder Technology Foundation (research grant), the Information Center of Particle Technology (research grant) and a special grant in 2016 from Gifu Pharmaceutical University.

ABBREVIATIONS APIs, active pharmaceutical ingredients; FF, fenofibrate; FFA, fenofibric acid, DOTG, 1,3-di-otolylguanidine; MeOH, methanol; DCM, dichloromethane; MSMPR, mixed-suspension, mixedproduct removal; XRPD, powder x-ray diffraction; DSC, differential scanning calorimeter; SEM, electron scanning microscopy; HPLC, high-performance liquid chromatography; SA, spherical agglomeration; ESD, emulsion solvent diffusion.

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For Table of Contents Use Only Manuscript title: Development of continuous spherical crystallization to prepare fenofibrate agglomerates with impurity complexation using MSMPR crystallizer Author list: Kohei Tahara*, Yuichi Kono, Allan S. Myerson, Hirofumi Takeuchi TOC graphic:

Synopsis: We demonstrate the continuous process of spherical crystallization of fenofibrate (FF) as a model drug using a mixed-suspension, mixed-product removal (MSMPR) crystallizer. The roles played by the operating parameters in MSMPR are examined based on the crystal properties of FF granules. The feasibility of impurity separation when using a complexing agent is also investigated for continuous spherical crystallization with MSMPR.


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Development of continuous spherical crystallization to prepare

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