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Integrated Continuous Plug-Flow Crystallization and Spray Drying of Pharmaceuticals for Dry Powder Inhalation Gabriela Daisy Hadiwinoto, Philip Chi Lip Kwok, Henry H.Y. Tong, Si Nga Wong, Shing Fung Chow, and Richard Lakerveld Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/acs.iecr.9b01730 • Publication Date (Web): 06 Aug 2019 Downloaded from pubs.acs.org on August 11, 2019

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Industrial & Engineering Chemistry Research

Integrated Continuous Plug-Flow Crystallization and Spray Drying of Pharmaceuticals for Dry Powder Inhalation Gabriela Daisy Hadiwinoto1, Philip C.L. Kwok2, Henry H.Y. Tong3, Si Nga Wong4, Shing Fung Chow4, Richard Lakerveld1* 1

Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong

2

Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, New South Wales 2006, Australia

3

4

School of Health Sciences, Macao Polytechnic Institute, R. de Luis Gonzaga Gomes, Macau Department of Pharmacology and Pharmacy, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong

KEYWORDS: Crystallization, Spray drying, Pharmaceuticals, Pulmonary drug delivery, Continuous pharmaceutical manufacturing

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ABSTRACT: The manufacture of dry powders for pulmonary drug delivery is complicated by stringent requirements for the aerodynamic size distribution and solid-state properties of the powder. Micronization is often needed after conventional batch crystallization to reduce the particle size, which lowers the process yield and may lead to particles with poor aerosolization behavior. A novel process combining continuous plug-flow crystallization and spray drying is presented to produce crystals with optimal properties for pulmonary drug delivery in a single step. Continuous flow enables fast nucleation with anti-solvent crystallization. Subsequently, the narrow and controllable residence time distribution of segmented-flow crystallization is exploited to grow the crystals uniformly into the optimal size range for pulmonary drug delivery. Finally, the solvent is evaporated rapidly using spray drying in continuous flow. Two case studies involving relevant drugs for pulmonary delivery are presented to demonstrate practical relevance and process flexibility. The process can be optimized for both cases such that a dry powder with excellent aerosolization behavior is produced. The novel process is simple and flexible due to the clear separation of process functions and the availability of sufficient process variables for optimization.

1. Introduction Direct delivery of active pharmaceutical ingredients (APIs) to the respiratory tract can offer numerous advantages compared to oral drug delivery for both the treatment of local and systemic diseases. The enormous surface area of the alveolar region in the lungs favors a fast absorption of APIs. Furthermore, APIs can be delivered directly to the site of action and avoid hepatic metabolism. Therefore, pulmonary drug delivery typically induces a rapid clinical response and minimizes side-effects.1 Dry powder inhalers are conveniently used to deliver pharmaceutical aerosols to the respiratory tract by inhalation. However, the manufacture of dry powders for pulmonary drug delivery is challenging due to a number of stringent product quality requirements.


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Particles deposit in the airways via different mechanisms.2 Large and heavy particles (aerodynamic diameter > 5 μm) deposit in the upper respiratory tract and throat by inertial impaction and are swallowed or may cause local side effects. Small and light particles (aerodynamic diameter < 1 μm) may be exhaled within the normal breathing cycle due to low inertia. Particles with an intermediate aerodynamic diameter (i.e., between 1-5 μm) can deposit in the lower airways by sedimentation and are in the optimal range for pulmonary drug delivery.3, 4 The manufacture of API particles with such a narrow size range is challenging. Consequently, various manufacturing methods, such as solution crystallization,5-11 spray drying from solution,12 spray freeze drying,13-15 and supercritical fluid technology16-22 have been investigated intensively (please see a recent review23 for a comprehensive overview). The advantages of crystallization include mild operating conditions, high product purity, and the inherent stability of a crystalline product. However, conventional batch crystallization may not yield crystals in the desired range. Therefore, particle micronization steps, such as jet milling, wet milling, or high pressure homogenization are typically needed to correct the particle size and improve product uniformity. Such micronization techniques are difficult to control and may cause chemical degradation of the API24 or amorphisation,25, 26 which compromises stability and may lead to agglomeration and poor aerosolization. Furthermore, adhesion of particles to the equipment lowers the yield. Finally, micronization typically leads to high-energy powders with poor flow properties due to their static, cohesive, and adhesive nature,27, 28 which also compromises product efficacy. Therefore, there is a need for crystallization processes that can reliably produce crystals within the optimal size range for pulmonary drug delivery in a single step followed by simplified downstream processing. The current practice in pharmaceutical manufacturing follows a batch-wise mode of operation. However, there is a strong drive within the pharmaceutical industry to adopt more efficient


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continuous processes.29, 30 Continuous manufacturing has inherent advantages related to process control, since steady-state conditions are generally easier to control compared to transient conditions, and footprint due to opportunities for tighter equipment integration and a higher level of automation.31-35 Furthermore, the transition offers opportunities to develop novel technologies that particularly work well in continuous flow. Continuous manufacturing offers opportunities to develop novel integrated crystallization processes for the manufacture of pulmonary drugs. In particular, a high nucleation rate followed by a short time for crystal growth is needed to produce crystals that are within the optimal size range for pulmonary drug delivery while maintaining a high process yield. Anti-solvent crystallization can create a highly supersaturated system that favors nucleation. However, anti-solvent crystallization also suffers from unpredictable scale-up behavior when conducted in the batch-mode of operation due to concentration gradients when approaching larger process volumes. The concentration gradients lead to variations in local supersaturation, which in turn lead to variations in crystallization kinetics and, thus, to variations in crystal quality attributes. This scale-up problem is inherently present in batch processes, as all material is processed at the same time. In contrast, when crystallization is conducted in continuous mode, anti-solvent can be mixed in a smaller process volume during the complete processing time. Therefore, it is expected that the product quality can be better controlled even at a very high supersaturation in a tubular crystallizer. Various types of tubular crystallizers have been studied. Plug-flow conditions are usually preferred to obtain a narrow residence time distribution, and thus, uniform product quality.36 Various radial mixing strategies and segmented flows have been explored to obtain plug-flow conditions in a tubular crystallizer at low fluid velocities.37, 38 Alvarez and Myerson created plug-flow conditions for crystallization by using a static mixer.39 Alternatively, oscillatory flow can be used to create plug-flow conditions when the fluid velocity


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in axial direction is low.36, 40 Eder et al.41 introduced a gas to produce a segmented-flow crystallizer to achieve a narrow residence time distribution, and hence a narrow particle size distribution. Kudo and Takiyama also produced fine crystals with a narrow crystal size distribution in a continuous sonocrystallization setup using a segmented gas-slurry flow.42 A segmented flow can be thermodynamically stable and enhances mixing within segments due to an internal circulation and minimizes the contact between the liquid and tube wall, which reduces fouling.43 In general, supersaturation and residence time can be manipulated in such devices to control the particle size distribution.44-48 Spray drying provides a fast technology for solvent removal from a slurry with small crystalline particles, which naturally operates in continuous flow and, thus, can be operated conveniently downstream of the continuous crystallization. Such integration minimizes work-up steps after the crystallization and offers the opportunity of a compact process that is well controllable due to the separation of particle formation and solvent removal. The integration of anti-solvent precipitation and spray drying has been used to produce nanoparticles,49-52 which can be agglomerated to produce particles in the micron range.53 The advantage of integration is an improved particle stability due to reduced Ostwald ripening and agglomeration leads to porous particles that are in the suitable size range for pulmonary drug delivery, which potentially eliminates the need for carriers. In the present work, we exploit the excellent control over the (narrow) residence time distribution in plug-flow crystallizers to grow the crystals uniformly into the desired size range for pulmonary drug delivery. The objective of this work is to characterize and optimize a continuous process for the manufacture of pulmonary drugs by integrating continuous plug-flow crystallization and spray drying. The process performance is characterized in terms of overall yield and total residence time.


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The product quality is characterized in terms of aerodynamic diameter distribution (within 1-5 μm), solid-state form (stable crystalline), and residual organic solvent content (below 5,000 ppm), which are optimized for the application of dry powder inhalation. The concept is illustrated for two relevant APIs for pulmonary drug delivery to demonstrate flexibility. The first API is rifapentine, which is an antibiotic used for the treatment of tuberculosis. The dosage form currently on the market is a tablet, but a potentially more effective dry powder form for pulmonary delivery has been reported in literature.54 The second API is beclomethasone dipropionate, which is a synthetic corticosteroid used for the treatment of various diseases and commercially available in different dosage forms including as a dry powder for inhalation for treatment of asthma and allergic rhinitis. For both APIs, the experimental work is divided into three parts: (1) stand-alone continuous crystallization, (2) stand-alone spray drying, and (3) integrated continuous crystallization and spray drying. Typical process variables of continuous anti-solvent crystallization such as initial supersaturation ratio, temperature, residence time, the application of ultrasound, and anti-solvent distribution, are used to optimize the yield and product quality. In case of spray drying, the inlet temperature of the drying gas and the atomization flow rate are optimized. Finally, the optimized conditions of the stand-alone processing steps are applied to the integrated process. 2. Experimental Section 2.1. Materials Rifapentine (99.5%) was purchased from Hangzhou ICH Biofarm Co., Ltd. Beclomethasone dipropionate (99.48%) was purchased from MedChem Express, USA. Acetone (99.5%) was purchased from Scharlau, Spain. Ethanol (96%) and methanol (HPLC grade) were purchased from VWR Chemicals, USA. All chemicals were used as received.


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2.2. Solubility The solubility of rifapentine in an acetone-water system was measured in triplicate at 50°C as a basis for the design of an anti-solvent crystallization process. Mixtures of acetone and water with a water mass fraction of up to 0.90 were prepared as solvent systems in 50-ml jacketed vessels. The temperature in the vessels was controlled with a thermostatic bath (Model DRC12, CPT Inc.). Subsequently, an excess amount of rifapentine was added to each solvent system and stirred for at least 24 hours to approach solid-liquid equilibrium. Finally, a sample of the upper portion of the solution was taken using a syringe filter to obtain a clear saturated solution. Each sample was diluted in a 25-mL volumetric flask between 250 and 417 times depending on the water fraction. The concentration of the samples was obtained using a calibrated ultra-violet visible (UV-Vis) spectrophotometry system at a wavelength of 474 nm. The solubility of beclomethasone dipropionate in an ethanol-water mixture with a water mass fraction of up to 0.66 was measured to provide a basis for the design of the anti-solvent crystallization process. A multiple reactor set-up with 1.5-ml vials and turbidity measurements (Crystal16, Technobis) was used for the solubility measurements. The instrument was connected to a recirculating cooler (F250, Julabo) for temperature control and nitrogen gas was used for purging water vapor. A certain amount of API and 1.0 ml of an ethanol-water mixture with a known composition were combined in the 1.5 ml closed glass vials. The vials were placed inside a reactor block and the mixture was stirred with a magnetic stirrer at 700 rpm. Slow cooling and heating ramps were implemented to determine the clear and cloud points in an automated fashion from which the solubility as a function of temperature was constructed at different solvent compositions. 2.3. Continuous crystallization and spray drying


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The experimental setup consisted of a tubular crystallizer and a spray dryer (see Figure 1). The tubular crystallizer was made out of rigid low-density polyethylene (LDPE) tubing with an inner diameter of 1/8 inch. Two 50-ml jacketed vessels were used to store the API solution and the antisolvent. The API solution was made by dissolving a certain amount of API with a concentration just below solubility. The temperature inside the vessels was controlled using a thermostatic bath (Model DRC12, CPT Inc.). Two calibrated peristaltic pumps (Masterflex L/S, Cole Parmer) with tygon tubing (Ø 1/16 inch) were used to transfer both solutions from the vessels to the crystallizer. A polyethylene T-mixer was used to combine the feed solution and the anti-solvent at the inlet of the crystallizer to create a supersaturated solution. The total liquid flow rate was chosen to match the requirements for downstream spray drying. The solution was mixed with nitrogen using a gasflow controller (EL-FLOW®, Bronkhorst) and another T-mixer to create a segmented flow. The crystallizer was immersed in an ultrasonic bath (Cole Parmer), which enabled the application of ultrasound at a frequency of 40 kHz and temperature control. All vessels were closed and mixed with a magnetic stirrer. The continuous crystallization was integrated with the spray drying by installing a buffer vessel at the outlet of the crystallizer to separate the crystal suspension and nitrogen before feeding the suspension into the spray dryer. Furthermore, the buffer vessel could be used to provide back mixing and possibly to recycle the suspension back to the inlet of the crystallizer for the case of rifapentine. A number of valves around the buffer vessel allowed for easy integration of this optional recycling system. The feed flow rate to the spray dryer was set lower compared to the slurry flow rate in the crystallizer to avoid draining the suspension vessel. The crystal slurry was fed from the buffer vessel to the spray dryer to evaporate the solvent and obtain a dry powder as the final product of the integrated process. The lab-scale spray dryer (Buchi, B-290) was operated in closed-loop blowing mode with application of an inert loop (Buchi, B-


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295) and dehumidifier (Buchi, B-296). The inlet temperature and atomizer gas flow rate could be varied to optimize the process.

Figure 1. Integrated continuous crystallization and spray drying setup. A number of experiments have been conducted in which the crystallization part of the experimental setup was operated stand-alone to document the effect of supersaturation, ultrasound, flow rates, temperature, and residence time for both cases (see Table S1 for the range of investigated operating conditions). For those stand-alone crystallization experiments, instead of feeding the crystal suspension to the buffer vessel, a Buchner funnel with filter paper (Fisherbrand™ qualitative grade P4) and a flask under vacuum were used to separate the crystals exiting the crystallizer from the mother liquor. The filtered crystals were vacuum dried in a desiccator overnight. The yield was determined by measuring the weight increase of the filter paper after drying. A short residence time and no recycling was applied for the experiments with the beclomethasone dipropionate-ethanol-water system. In contrast, for the rifapentine-acetone-water system, longer residence times were needed, which were practically enabled via recycling. Crystallization experiments with rifapentine were conducted at 50°C, as preliminary experiments had shown restricted nucleation at room temperature. Finally, additional anti-solvent was added to


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the buffer vessel when recycling for some experiments with rifapentine to avoid amorphous particles while still obtaining a high yield. Similarly, a number of experiments have been conducted in which the spray dryer was operated stand-alone. For those experiments, the feed to the spray dryer was a suspension, which consisted of crystals obtained from stand-alone crystallization experiments suspended in saturated solution. The solid content of the slurry mimicked typical outlet conditions of the crystallizer during integrated processing. The effects of inlet temperature, atomized gas flow rate, and feed flow rate on the solid-state properties of the spray dried powder were characterized for both cases (see Table S2). The optimal conditions obtained from stand-alone experiments were applied in the integrated process (see Table S3) for the case of rifapentine to characterize the overall process performance. For the case of beclomethasone dipropionate, critical process variables of the integrated process were optimized once more using optimal conditions from stand-alone experiments as a starting point. The integrated production experiment with optimal process conditions was conducted two times for the case of rifapentine and three times for the case of beclomethasone dipropionate to assess reproducibility of the measured process and product performance characteristics. 2.4. Solid-state characterization The quality attributes of the particles obtained from the experiments were identified using a number of analytical techniques. The solid-state form of the dry powders was analyzed using powder X-ray Diffraction (X’Pert Pro, PANalytical). The spectra were obtained with diffraction angles (2θ) in the range from 5° to 50° at a scan rate of 0.05° using Cu Kα radiation. Scanning electron microscope (SEM, JSM-6390, JEOL, 20kV) was used to assess crystal morphology. Powders were dispersed onto carbon tape and sputter-coated with copper. The dimensions of the


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API crystals (mean length and width) were estimated from those SEM images. Thermal profiles of the API powders were analyzed using differential scanning calorimetry (DSC, Q1000, TA Instruments) from 25°C to 250°C at 5°C/min. Nitrogen gas was used as the purging gas at a rate of 50 ml/min. The thermographic profiles were scanned using thermal gravimetric analyzer (TGA Q5000, TA Instruments) from 25°C to 400°C at a rate of 5°C/min. Gas chromatography with a flame ionization detector (GC Agilent 6890 with FID and ECD, GenTech Scientific) and a polyethylene glycol column (AT™-Aquawax, Alltech) was used to analyze the residual solvent content of beclomethasone dipropionate dried powders. Standard solutions used for calibration contained either 50 ppm, 100 ppm, 250 ppm, or 500 ppm of ethanol dissolved in methanol, which was used as the mobile phase. The API samples were prepared by dissolving 0.030 g/ml of beclomethasone dipropionate crystals in methanol. The aerodynamic diameter is a critical quality attribute for dry API powders intended for inhalation. Therefore, particle deposition tests were conducted in a Next Generation ImpactorTM (NGI, see Figure S1) to provide a quantitative assessment of the deposition of the produced dry powders in the pulmonary tract. The NGI simulates the dispersion of dry powders from a dry powder inhaler into the lungs. The emitted fraction (EF) and fine particle fraction (FPF) are typical properties to characterize the aerodynamic diameter distribution of dry powders intended for inhalation. The EF is the mass fraction of the powder emitted from the inhaler device with respect to the dose loaded into the capsule, while the FPF is the mass fraction of the powder (with respect to the EF) that has an aerodynamic diameter smaller than 5μm. In other words, the FPF is the fraction of the powder that normally deposits at the intended site of action in the lungs. Furthermore, the mass median aerodynamic diameter (MMAD) was also determined together with the geometric standard deviation (GSD) as a measure of product uniformity. The air flow rate and


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deposition time in the NGI simulated the actuation conditions of an average adult. The NGI consisted of eight stages over which the dry powder was distributed to characterize the aerodynamic diameter distribution. In particular, a fraction of the powder deposited on eight removable impaction cups, which was measured to obtain the fraction of the dry powder within a specific aerodynamic diameter range. Before each test, the impaction cups were coated with silicon before use. Approximately 10 mg of API powder was loaded into a size 3 hydroxypropyl methylcellulose capsule (Capsugel, West Ryde), which was subsequently placed into a Breezhaler® inhaler device. The powders were discharged using a Milty Zerostat 3 anti-static gun for some cases to eliminate excessive particle charge before loading into the capsules. The NGI contained an L-shaped induction port that represented the throat above stage 1. The Breezhaler® was connected to this throat by using a mouthpiece adapter. The air flow was provided by a vacuum pump and the flow rate was calibrated before each test. The flow rate was chosen such that the pressure drop was approximately 4 kPa, which resulted in an air flow rate (Q) for the cases with rifapentine of approximately 99.5 ml/min for 2.4s and approximately 90 ml/min for 2.7s for the cases with beclomethasone dipropionate. The corresponding cut-off aerodynamic diameters are given in Table S4 (see also Supporting Information for the corresponding calculations). After each test, the inhaler device, capsule, adapter, tube, and each removable impaction cup were rinsed with 5 ml of methanol to dissolve dry powders deposited in each piece. The amount of API deposited in each component were determined by measuring the concentration of each sample using a UV spectrophotometer. 3. Results and Discussion 3.1. Solubility


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Rifapentine is soluble in acetone and has low solubility in water. Furthermore, it is known that crystallization of rifapentine from an acetone solution yields a nonsolvated solid-state form,54 which is beneficial due to low toxicity. Therefore, the acetone-water solvent is promising for antisolvent crystallization. The solubility of rifapentine at 50°C as a function of solvent composition exhibits two maxima (see Figure S2), which is referred to as the chameleonic effect and can be observed in the solubility behavior of some organic compounds in solvent mixtures of different polarities.55 The data demonstrate that rifapentine is soluble in acetone and sparingly soluble at least up to a water mass fraction of 25%, but is only slightly soluble at a water mass fraction higher than 56% according to the standards stated in British Pharmacopoeia 2019. The implication for the design of the anti-solvent crystallization process was that either the feed should be prepared as a binary mixture of rifapentine and acetone with a small amount of water to be added as antisolvent or as a ternary mixture with a water mass fraction of 25% to maximize the attainable yield (see Figure S3a for theoretical yield calculations). Beclomethasone dipropionate is sparingly soluble in ethanol at room temperature, but has a much lower solubility in water. The solubility of beclomethasone dipropionate increases when increasing the temperature and decreases sharply when increasing the water mass fraction in an ethanol-water solvent mixture (see Figure S4). In particular, beclomethasone dipropionate is at most only very slightly soluble at a water mass fraction larger than 46% at room temperature according to the standards stated in British Pharmacopoeia 2019. Therefore, a high API recovery can be obtained by using ethanol as the feed solution, potentially at elevated temperature, and by using water as the anti-solvent. In particular, a theoretical recovery of at least 90% can be achieved by adding water at a mass fraction of at least 46%. The theoretical API recovery decreases sharply


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as the water fraction approaches 100% (see Figure S3b), because of the dilution combined with a limited drop in solubility when adding water to mixtures with already a high water mass fraction. 3.2. Crystallization 3.2.1. Rifapentine Spherical amorphous particles and needle-like crystalline particles were obtained when crystallizing rifapentine in the continuous crystallizer (see Figure 2). Furthermore, the recovery and product crystallinity (see Figure S14) varied substantially depending on the experimental conditions (see Table 1). The product recovery was very low when ultrasound was not used (i.e., in case of Experiment A). Virtually no crystals were seen inside the crystallizer in the absence of ultrasound. The use of ultrasound increased the product recovery to some extent (see Experiment B) due to an increase in nucleation. The notion that ultrasound enhances nucleation has been reported extensively in literature including for cases with tubular crystallizers and cases with pulmonary APIs.7, 11, 41, 56, 57


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Figure 2. SEM images of the crystallized rifapentine from stand-alone continuous crystallization experiments (see Table 1).


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Table 1. Rifapentine crystallization process performance and product crystallinity A

B

C

D

E

F

Ultrasound

No

Yes

Yes

Yes

Yes

Yes

Initial supersaturation (S)

3.5

3.5

1.4a)

3.5

7.5

3.0

Flow rate API solution (ml/min)

2.0

1.5

0.5

2.0

2.0

2.2

Flow rate anti-solvent (ml/min)

1.2

0.90

0.50

1.2

2.6

2.2

Flow rate nitrogen (ml/min)

1.0

0.70

0.50

1.0

1.5

1.5

Residence time (min)

60

60

240

60

120

120

Recirculation

No

No

Yes

Yes

Yes

Yes

Anti-solvent distribution

1-stage

1-stage

1-stage

1-stage

1-stage

2-stage

Yield

2%

15%

93%

43%

25%

57%

Recovery

1%

11%

28%

30%

22%

48%

Degree of crystallinity b)

Low

Low

High

High

High

High

a)

The API solution did not contain water

b)

Qualitatively determined using pXRD (see Figure S14 for all XRD diagrams)

A substantial number of amorphous particles were produced in experiment B, which had a short residence time. Furthermore, preliminary experiments (not shown here) demonstrated that amorphous particles were also produced in cases with a very high supersaturation (up to S = 9.0). Therefore, it is likely that this amorphous form of rifapentine is the kinetically favored solid-state form and nucleates first at high supersaturation. Furthermore, Experiment E demonstrated that a high supersaturation favored agglomeration, which was difficult to control. Therefore, the supersaturation ratio should be chosen at an intermediate value for rifapentine when attempting to obtain sufficient nucleation of small particles while avoiding amorphous or agglomerated particles.


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For example, at the lower initial supersaturation of Experiment C (S = 1.4), small needle-like crystals were obtained (see Figure 2). Needle-like crystals have a high dynamic shape factor, which results in a smaller aerodynamic diameter,58 and are therefore preferred for pulmonary drug delivery. However, the recovery remained low at those conditions and a longer residence time was needed to obtain a yield that was close to the theoretical yield due to seemingly slow crystal growth. A low recovery is undesirable for the proposed integrated process, as the remaining rifapentine in solution may form (amorphous) particles in the spray dryer downstream upon integration and violates the principle of task separation between both unit operations. Furthermore, long residence times may pose practical problems for tubular crystallizers related to pressure drop and fouling. A distribution of anti-solvent distribution over the length of the crystallizer39 enabled a higher recovery while avoiding a high initial supersaturation (see Experiment F), which led to highly crystalline rifapentine particles of the desired shape and size for pulmonary drug delivery at an intermediate residence time. The experiments with a short residence time (i.e., Experiments A, B and D) showed a mixture of crystalline and amorphous particles. However, the fraction of crystalline material was significantly higher for the product from Experiment D compared to the product from Experiment B (see Figure 2 and Table 1). The only difference between those experiments was the application of recycling in Experiment D, which was used as a practical way to investigate the performance of the crystallizer at very long residence times, as an alternative to using a very long tubing. Although the mode of operation in such recirculation mode was batch-based, the tubular crystallizer still operated under flow conditions, which provided a practical way to mimic the crystallizer performance if very long tubing would be used. Rifapentine appeared to nucleate slowly under the tested conditions and it could be observed that some liquid segments in the tubular


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crystallizer did not contain any solids. Furthermore, it was likely that in some segments only the kinetically favored amorphous particles were present while crystals were present in other segments, which was reflected by the product composition from Experiment B. In the recycling loop, a buffer vessel, with a much shorter residence time compared to the tubular crystallizer, was implemented, which provided some degree of back mixing and redistributed particles over a number of segments. Therefore, a higher number of liquid segments contained crystals after recycling. Consequently, a solvent-mediated solid-state transition occurred when both amorphous and crystalline particles were present within a single slurry segment, which resulted in a larger fraction of crystalline particles in the final product, as was observed in Experiment D. Finally, a better distribution of particles over the liquid segments increased the consumption of supersaturation in the segments, which resulted in a higher yield. Typically, back mixing is undesirable in tubular crystallizers due to a broadening of the residence time distribution, which compromises the uniformity of the final product, and is usually avoided. However, this work demonstrates that back mixing somewhere at an intermediate point within a segmented flow crystallizer can be beneficial for increasing yield and enhancing a solid-state transition towards a more stable form, which has not been reported in the literature yet to the best of our knowledge. 3.2.2. Beclomethasone dipropionate Needle-shaped crystals were obtained from the continuous anti-solvent crystallization process of beclomethasone dipropionate for all tested conditions (see Figure 3 and Figure S5), which is desirable for pulmonary drug delivery. Furthermore, recoveries in excess of 90% were achieved within 10 minutes of residence time (see Table 2). The effect of ultrasound was illustrated by the difference in product quality and recovery of the crystals obtained from Experiments #1 and #3, which had the same initial supersaturation and temperature but different residence times and


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ultrasound conditions. Despite the longer residence time of Experiment #3, smaller crystals (see Figure 3) and a higher yield were obtained (see Table 2). Just as was the case for continuous antisolvent crystallization of rifapentine, ultrasound lowered fouling, thus increasing the yield and nucleation, leading to smaller particles. The effect of initial supersaturation can be understood by comparing Experiments #3 to #8, which all had the same ultrasound conditions, residence time, and temperature, but had a different initial supersaturation. The product recovery showed a maximum at an intermediate supersaturation. Furthermore, the crystals at higher supersaturation tended to be smaller, as expected, but more agglomerated, which could be seen, for example, when comparing Experiments #3, #5, and #8 (note the different scale bars in Figure 3). A very high supersaturation led to some fouling, which reduced the number of crystals in the bulk of the suspension and, consequently, lowered the product recovery. Finally, increasing the temperature did not result in a substantially different product quality or yield when keeping all other operating conditions constant. The crystals produced with the continuous anti-solvent crystallization process had a different shape compared to the raw material used to prepare the feed solutions (see Figure 3). Furthermore, different peaks were observed when comparing the XRD diagrams of the raw material and product crystals (see Figure 4), which indicated that a different solid-state form had formed. A comparison with reference diagrams from the literature59 suggested that the raw material was the anhydrous form (characteristic peak at 9.6°) of beclomethasone dipropionate and the product crystals were of the monohydrate form (characteristic peaks at 8.3° and 12.5°). The DSC profile showed that both the raw material and the product crystals had a melting point around 212°C (Figure 5). Furthermore, a weak and broad endothermic peak just above 100°C was observed in the thermal profile of the product crystals, which was likely caused by the dehydration of the monohydrate


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form. Stability tests showed that the solid-state form of the product crystals was stable for at least one month at room temperature, but unstable after one month at an elevated temperature of 60oC and a relative humidity between 35% and 40% (see Figure S6).

Figure 3. Selected SEM images of the crystallized beclomethasone dipropionate from stand-alone continuous crystallization experiments (see Table 2) and raw material (“R”). Note that different scale bars are used. Additional SEM images and estimated dimensions of the particles are provided in Figure S5 and Table S5.


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Figure 4. XRD diagrams of beclomethasone dipropionate raw material and a typical product from a continuous experiment (see Figures S16-S17 for all XRD diagrams) and reference diagrams of the anhydrous and monohydrate form from the literature59.

Figure 5. DSC profiles of beclomethasone dipropionate raw material and a typical product from a continuous experiment.


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Table 2. Beclomethasone dipropionate crystallization process performance 1

2

3

4

5

6

7

8

9

10

Ultrasound

No

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Flow rate API solution (ml/min)

2.0

2.0

2.8

2.3

1.8

1.4

0.91

0.46

2.3

2.3

Flow rate antisolvent (ml/min)

1.3

1.3

1.8

2.3

2.7

3.2

3.7

4.1

2.3

2.3

Flow rate nitrogen (ml/min)

2.2

2.2

3.0

3.0

3.0

3.0

3.0

3.0

3.0

3.0

Residence time (min)

7

7

10

10

10

10

10

10

10

10

Temperature (oC)

25

25

25

25

25

25

25

25

30

35


16.0

16.0

16.0

23.0

42.3

83.0

127

147

21.7

22.0

Yield

46%

60%

79%

89%

95%

92%

89%

76%

91%

88%

Recovery

43%

56%

72%

85%

93%

91%

89%

76%

87%

84%

When comparing the crystallization performance of beclomethasone dipropionate to rifapentine, it can be concluded that both processes yielded particles with desirable characteristics for pulmonary drug delivery after optimization. However, the beclomethasone dipropionate system allowed for faster nucleation and growth of the crystalline form such that high recoveries could be achieved in a single pass with a much shorter residence time, which is beneficial for integrated continuous pharmaceutical manufacturing. 3.3. Spray drying 3.3.1. Rifapentine The spray-dried rifapentine crystals exhibited a similar needle-like shape (see Figure 6) compared to the particles obtained after vacuum drying of the suspension from stand-alone crystallization


22

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experiments (see Figure 2). However, the spray-dried product also contained a small fraction of irregular-shaped particles. Although solid-state form cannot be conclusively determined from SEM images alone, it is likely that those irregular-shaped particles were amorphous. Residual solute solidified rapidly during spray drying, which may have promoted the formation of amorphous particles. The yield of the spray drying step was 68%, which was mainly determined by the loss of fine particles in the filter bag or cyclone. In conclusion, spray drying did not significantly alter the quality attributes of the rifapentine crystals; however, product recovery had to be high in the crystallization step to avoid the formation of seemingly amorphous particles during spray drying.

Figure 6. SEM image of rifapentine powder obtained from spray drying a suspension. 3.3.2. Beclomethasone dipropionate The yield of the spray drying step was characterized as a function of the atomizer gas flow rate and inlet temperature and particle properties for beclomethasone dipropionate (see Table 3). The


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particle size and shape (see Figure 7) were essentially identical as those obtained from continuous crystallization experiments (e.g., compare Experiment a and b in Figure 7 to Experiment 5 in Figure 3) with a few exceptions. In particular, the particles obtained from experiments f and g were smaller compared to the particle size of the vacuum dried crystals. The particles obtained from the corresponding stand-alone crystallization experiments were agglomerated crystals (see Figure 3) due to the high supersaturation. It appeared that those agglomerates broke during atomization at the start of the spray drying process, which was supported by the low yield for those cases. Although in general the maximum yield obtained was larger than 70% for optimal conditions, the yield could drop to only a few percent for those cases in which the primary particles in the feed were small. The spray dryer was designed to collect particles generally in the size range of 1 – 25μm. Therefore, smaller particles could have been retained in the filter bag or trapped in the cyclone, which lowered the yield. The low yield for those agglomerated particles in the spray dryer was another reason why the supersaturation in the continuous crystallizer should be chosen at an intermediate value for optimal performance of the integrated system. Increasing the inlet temperature from 75°C to 90°C improved the yield when keeping all other process variables constant (see Experiments a and b). However, the yield decreased when further increasing the inlet temperature to either 120°C (see Experiments c and d) or 105°C (see Experiments h and j). Therefore, the inlet temperature was optimal at an intermediate value of around 90°C when the objective was to maximize the yield. The dried powder remained in the monohydrate solid-state form (see Figure S18-S19). The residence time of drying in the spray dryer was most likely not sufficiently long to facilitate a solid-state transition to the anhydrous form despite the high temperature. Thermographic profiles of both vacuum-dried and spray dried powders showed a weight loss in the beginning of the heating (see Figure S7). The weight loss


24

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could in principle be caused by the release of solvent. However, it was more likely that dehydration occurred, as was observed from the DSC profiles for the vacuum dried material. The weight loss was approximately 3% for both powders, which was consistent with a solid-state transition from a monohydrate to an anhydrous form. Furthermore, the ethanol concentration in the dried powder was below 2,500 ppm for all tested gas chromatography samples, which corresponded to the detection limit. Therefore, the weight loss in the thermographic profile should be caused by the release of water. Residual organic solvent content is a key quality attribute of the dried powders. For example, a concentration limit of 5,000 ppm has been recommended by the Food and Drug Administration for solvents with low toxic potential such as ethanol.60 Therefore, optimal conditions for spray drying can be chosen to maximize the yield within the tested range without compromising industry standards for residual solvent content. The aerosolization tests (see Table 3) showed that the beclomethasone dipropionate crystals produced by the continuous anti-solvent crystallization at an intermediate level of initial supersaturation (i.e., Experiments 5 and 6) exhibited an MMAD within or just outside the optimal range for pulmonary drug delivery. The FPF varied between 12% and 35% and the EF between 64% and 84% for those experiments, which provided a good starting point for optimization of the integrated process.


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Figure 7. Selected SEM images of the dried beclomethasone dipropionate from stand-alone spray drying experiments using crystals obtained from continuous crystallization experiments (see Table 3) as feed material. Note that different scale bars are used. Additional SEM images and estimated dimensions of the particles are provided in Figure S8 and Table S6, respectively.


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Table 3. Yield and characteristics of aerodynamic size distribution of the crystals produced with stand-alone spray-drying experiments of beclomethasone dipropionate a

b

c

d

e

f

g

h

i

j

Source of crystals 5 (see Table 2)

5

5

5

6

7

8

6

6

6

Inlet temperature 75 (°C)

90

90

120

95

95

95

95

105

105

Atomizer flow rate (L/h)

601

601

742

742

742

742

742

357

742

357

Outlet temperature (°C)

40

50

50

68

53

55

52

56

57

62

Yield

65%

70%

72%

53%

66%

3.0%

7.8%

66%

53%

64%

EF

81%

76%

84%

68%

68%

―

56%

64%

76%

83%

FPF

22%

12%

22%

15%

35%

―

24%

16%

31%

21%

MMAD (µm)

6.9

12.2

7.6

8.4

4.9

―

10.4

7.1

4.0

6.2

GSD (µm)

3.3

4.0

5.1

3.1

2.7

―

3.8

3.1

2.7

2.9

3.4. Integrated process 3.4.1. Rifapentine The rifapentine particles obtained from the integrated process exhibited a similar size and needlelike shape compared to the particles obtained from the stand-alone crystallization experiments under optimal conditions (see Figure 8a). The morphology of the particles suggested that the majority of the produced material was crystalline, which was confirmed by powder XRD (see Figure S9) and the DSC profile (see Figure S10). The former showed distinct peaks corresponding to a crystalline form of rifapentine and the latter exhibited a sharp endothermic peak at around 170°C. However, some small amorphous particles with a hollow shape could also be observed (see


27


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Figure 8b), which were characteristic for particle formation from spray drying solutions.54 The overall yield of the integrated process was 62%, which was the average of a duplicate run with virtually identical yields. The fouling during the continuous crystallization and adhesion of the powder to the spray drying chamber or filter bag were likely the main causes of the yield loss, as was the case for stand-alone experiments. The total moisture/solvent content of the vacuum dried and spray dried particles were both around 6%, which were estimated from the TGA profiles (see Figure S11). The vacuum dried rifapentine showed a higher weight loss just before 50°C compared to the spray dried sample obtained from the integrated process, which most likely corresponded to the evaporation of a solvent with low boiling point (i.e., acetone with a normal boiling temperature of 56°C). Therefore, the vacuum dried rifapentine likely contained more residual organic solvent than the spray dried rifapentine powders. The aerodynamic size distribution of the produced rifapentine powder (see Figure 9) had the desirable characteristics for pulmonary drug delivery. In particular, the EF and FPF obtained from a triplicate measurement of dried powder from a single run were 91.1 ± 4.1% and 60.2 ± 5.8%, respectively. The MMAD was 3.3 ± 0.3 µm, which was well within the optimal range for pulmonary drug delivery. Note that the excellent aerosolization performance was not only the result of the small particle size, but also of the favorable needle-like particle shape. Finally, the fact that no excipients were used in the tested formulation showed the potential of the integrated process to not only simplify the manufacture of the API powder, but also of the downstream formulation steps.


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Figure 8. SEM images of the rifapentine powder obtained from the integrated process.


29


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Figure 9. Aerodynamic diameter distribution of the rifapentine particles obtained from the integrated process. The error bars represent the standard deviation of a triplicate measurement from the product of a single integrated run at optimal conditions. 3.4.2. Beclomethasone dipropionate The integrated process generally produced small beclomethasone dipropionate crystals of the monohydrate form (See Figure S20-S21) with a needle-like shape (see Figure 10) and an overall yield that depended strongly on operating conditions (see Table 4). The conditions of experiments I to VI led to the formation of small particles due to the high initial supersaturation. Therefore, generally, a lower yield was obtained for those experiments, which was likely caused by the adhesion of the particles on the chamber of the spray dryer and possibly by a low efficiency of the


30

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cyclone to collect the small particles, as was observed for stand-alone spray drying experiments. The duplicate experiments V and VI showed that the low yield at high supersaturation was reproducible when all operating conditions were kept constant. Nevertheless, a substantial variability in the yield was seen among the experiments conducted at high supersaturation when varying other operating conditions. This variability was to some extent caused by the particles that initially adhered to the internals of the spray dryer but later fell into the powder collector during the experiment (see Figure S13 for illustrative photos). This process was difficult to predict or control and could be sensitive to small variations in operating conditions, which might explain the high variability in the yield among the experiments with high supersaturation. The yields obtained from experiments at a lower initial supersaturation were more consistent and generally higher due to the reduced adhesion of the bigger particles and, consequently, improved collection efficiency of the cyclone. Finally, note that the optimal yield of the integrated process was consistent with the yields obtained from stand-alone experiments and showed good reproducibility. The EF and FPF of the powders produced from the integrated process (see Table 4) were good for pulmonary drug delivery. Just as was the case for rifapentine, the small particle size with a favorable needle-like particle shape yielded good aerosolization performance without the use of carriers. In contrast, the vacuum dried powder from a crystallization experiment under optimal conditions only had an EF of 51% and FPF of 11%. The conventional filtration followed by vacuum drying easily led to particle agglomeration and consequently to poor aerosolization. The superior performance of the powder from the integrated process demonstrated the benefit of continuous manufacturing in this application area. In the continuous process, no work-up steps are needed after crystallization and the transfer time between unit operations is minimal, leading to not only more compact equipment and a simpler process, but also to superior product quality due


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to reduced agglomeration when growing the crystals to the desired size range in a plug-flow crystallizer. Electrostatic charging of powders caused particles to stick to the surface of the capsule, which lowered the emitted dose from the device. The spray-dried powder might have obtained a high electrostatic charge as a result of the drying process. Several powders were discharged before conducting deposition tests, which showed enhanced EF. For example, the EF and FPF of the powder from experiment X were 30% and 18%, respectively, when the powders were not discharged. Such low EF and FPF values were caused by the adhesion of the powder in the capsule and early particle deposition in the throat. However, the EF and FPF increased to 80% and 34%, respectively, for a single measurement when the powders were discharged before aerosolization. The EF varied strongly for the experiments with a high supersaturation within the tested range, which might have been caused by particle adhesion or static charges. The EF was generally more consistent when the initial supersaturation was at a low or intermediate level. Furthermore, when not considering the experiments with a very low yield (i.e., Experiments I, V, and VI), a dry powder with an FPF in the range of 16% to 33% was obtained. This optimal FPF is acceptable for the delivery of corticosteroid from dry powder inhalers and substantially higher than those reported in the literature for beclomethasone mixtures based on conventional micronized particles.61, 62 The characterization of process performance showed that optimal process conditions required a tradeoff between yield and product quality characteristics (e.g., EF and FPF). Experiment X was considered to be optimal when the aim was to maximize EF and FPF, while avoiding low process yields. Note that a higher initial supersaturation would be attractive when the design of the cyclone would be tailored for capturing smaller particles. Currently, the aerodynamic size distribution of the particles produced under optimal conditions (see Figure 11) was within the upper range for


32

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pulmonary drug delivery. However, the data showed that only under those conditions a satisfactory yield could be obtained from the spray dryer. Therefore, modifying the design of the cyclone could potentially enlarge the window of operation and is of interest for future research. Finally, the process and product performance showed at least under optimal conditions excellent reproducibility. Table 4. Yield and characteristics of the aerodynamic size distribution of the crystals produced with the integrated process for the case of beclomethasone dipropionate. I

II

III

IV

V

VI

VIIa

VIII

IXa

Xa,b

Water mass fraction

0.75

0.75

0.75 0.75 0.75

0.75

0.66

0.66

0.66

0.71


83.0

83.0

83.0 83.0 83.0

83.0

48.0

48.0

48.0

63.5

Inlet 95 temperature (°C)

95

80

95

105

105

75

95

105

105

Atomizer rate (L/h)

357

742

742

742

742

742

742

742

742

Outlet 61 temperature (°C)

58

44

54

60

60

41

54

59

60

Feed flow rate (ml/min)

3.3

4.0

4.0

4.0

4.0

4.0

4.0

4.0

4.0

4.0

Yield

7%

49% 64% 49% 13%

15%

62%

68%

63% 65±3%

EF

60%

77% 43% 41% 35%

58%

80%

68%

83% 75±5%

FPF

50%

27% 32% 21% 20%

54%

25%

16%

23% 33±1%

MMAD (µm)

3.9

5.8

6.1

8.7

8.7

4.2

5.3

11.5

7.2

5.2±0.3

GSD (µm)

2.5

3.1

3.1

2.9

3.5

2.4

2.9

3.9

2.8

2.6±0.1

742

a

Powders were discharged using an anti-static gun before the particle deposition test.

b

Experiment has been conducted in triplicate (standard deviation reported)


33


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Figure 10. Selected SEM images of the beclomethasone dipropionate crystals produced with the integrated process (see Table 4 for operating conditions). Additional SEM images are provided in Figure S12 of the Supporting Information.


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Figure 11. Aerodynamic diameter distribution of the beclomethasone dipropionate particles obtained from continuous crystallization followed by vacuum drying and from the integrated process including spray drying (Experiment X). The error bars indicate the standard deviation determined from triplicate experiments of the optimized integrated process.

4. Conclusion Continuous anti-solvent crystallization in a plug-flow crystallizer was effectively integrated with spray drying to produce pharmaceuticals with favorable properties for dry powder inhalation without the need for particle size modification or the addition of excipients. Anti-solvent crystallization in continuous flow allowed efficient mixing of an API feed solution and an anti-


35


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solvent such that a high supersaturation and high nucleation rate were obtained. Subsequently, plug-flow crystallization was used to grow crystals uniformly in the optimal size range for pulmonary drug delivery. The final crystal size and process yield were controlled by optimizing the initial supersaturation, temperature, and residence time. Spray drying did not substantially alter the quality attributes of the product from the crystallizer and reduced the residual organic solvent content below industry standards for all tested cases. A high recovery was needed in the crystallizer to avoid the potential formation of amorphous particles during spray drying. The integrated process was optimized for the manufacture of a dried powder of rifapentine and beclomethasone dipropionate for pulmonary drug delivery. For both APIs, a product with excellent aerosolization behavior was obtained after optimization. This was due to a high degree of freedom for optimization and clear separation of process functions, which aligned with general strategies to achieve process intensification for crystallization processes.63 The optimal conditions for both cases were different, which indicated that although the process concept was generally applicable, optimization should be conducted on a case-by-case basis. The predictable conditions obtained by mixing in continuous flow and the separation of process functions allowed for predictable optimization. Future work may focus on scale-up by running the process longer, increasing the flow rate, or increasing the equipment dimensions. The design of customized equipment to improve powder collection efficiency in the spray dryer is also of interest for future research. Furthermore, an extension of the process concept towards other types of APIs, such as biopharmaceuticals, is also of interest to be explored due to their growing importance in the pharmaceutical industry and general incompatibility with oral delivery. A more detailed investigation on product efficacy involving characterization of the produced dry powder with in vivo and in vitro studies is also of


36

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interest for future research.64, 65 Finally, further alignment with recent quality considerations for continuous manufacturing that have been published by regulatory authorities will be important for successful commercialization.66 The presented process has a narrow residence time distribution, which should facilitate easy product traceability. A control strategy should be developed such that operation within a state of control is guaranteed even when operating the process for a long time or when disturbances are acting on the system. Fouling may limit the maximum run time, which can possibly be extended with ultrasound and active controls. Advanced process analytical technologies installed with help of the transparent tubing or flow cell can be implemented together with a model, which are considered of crucial importance to support active process control strategies, accurate material diversion, and real-time release testing.

ASSOCIATED CONTENT Supporting Information.     

Calculations and values of the NGI cut-off diameters. Illustrative photos of experimental setup. Additional experimental data (solubility, SEM images, XRD diagrams, TGA and DSC profiles of produced powders). Tables with ranges of experimental conditions investigated. Estimated particle dimensions of beclomethasone dipropionate powders obtained from stand-alone crystallization and spray-drying experiments.

AUTHOR INFORMATION Corresponding Author * Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong


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Phone: (852) 3469 2217 / Fax: (852) 2358 0054 [email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Funding Sources This research is funded by the Hong Kong Innovation and Technology Commission, under ITSP Tier 3 Scheme (Project No. ITS/137/16). ACKNOWLEDGMENT This research is funded by the Hong Kong Innovation and Technology Commission, under ITSP Tier 3 Scheme (Project No. ITS/137/16). ABBREVIATIONS API, Active Pharmaceutical Ingredient; NGI, Next Generation Impactor; EF, Emitted Fraction; FPF, Fine Particle Fraction; MMAD, Mass Median Aerodynamic Diameter; GSD, Geometric Standard Deviation. REFERENCES 1.

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Figure 1. Integrated continuous crystallization and spray drying setup. 304x113mm (96 x 96 DPI)



Figure 2. SEM images of the crystallized rifapentine from stand-alone continuous crystallization experiments (see Table 1). 165x184mm (96 x 96 DPI)


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Figure 3. Selected SEM images of the crystallized beclomethasone dipropionate from stand-alone continuous crystallization experiments (see Table 2) and raw material (“R”). Note that different scale bars are used. Additional SEM images and estimated dimensions of the particles are provided in Figure S5 and Table S5. 165x184mm (96 x 96 DPI)



Figure 4. XRD diagrams of beclomethasone dipropionate raw material and a typical product from a continuous experiment (see Figures S16-S17 for all XRD diagrams) and reference diagrams of the anhydrous and monohydrate form from the literature59. 189x189mm (96 x 96 DPI)


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Figure 5. DSC profiles of beclomethasone dipropionate raw material and a typical product from a continuous experiment. 189x189mm (96 x 96 DPI)



Figure 6. SEM image of rifapentine powder obtained from spray drying a suspension. 104x78mm (96 x 96 DPI)


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Figure 7. Selected SEM images of the dried beclomethasone dipropionate from stand-alone spray drying experiments using crystals obtained from continuous crystallization experiments (see Table 3) as feed material. Note that different scale bars are used. Additional SEM images and estimated dimensions of the particles are provided in Figure S8 and Table S6, respectively. 165x184mm (96 x 96 DPI)



Figure 8. SEM images of the rifapentine powder obtained from the integrated process. 108x165mm (96 x 96 DPI)


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Figure 9. Aerodynamic diameter distribution of the rifapentine particles obtained from the integrated process. The error bars represent the standard deviation of a triplicate measurement from the product of a single integrated run at optimal conditions. 189x189mm (96 x 96 DPI)



Figure 10. Selected SEM images of the beclomethasone dipropionate crystals produced with the integrated process (see Table 4 for operating conditions). Additional SEM images are provided in Figure S12 of the Supporting Information. 165x184mm (96 x 96 DPI)


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Figure 11. Aerodynamic diameter distribution of the beclomethasone dipropionate particles obtained from continuous crystallization followed by vacuum drying and from the integrated process including spray drying (Experiment X). The error bars indicate the standard deviation determined from triplicate experiments of the optimized integrated process. 189x189mm (96 x 96 DPI)


Integrated Continuous Plug-Flow Crystallization ... - ACS Publications

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