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Preparation and characterization of spray-dried submicron particles for pharmaceutical application
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Advanced Powder Technology journal homepage: www.elsevier.com/locate/apt
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Original Research Paper
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Preparation and characterization of spray-dried submicron particles for pharmaceutical application
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Ramona Strob, Adrian Dobrowolski, Damian Pieloth, Gerhard Schaldach, Helmut Wiggers, Peter Walzel, Markus Thommes ⇑ Chair of Solids Process Engineering, Department of Biochemical and Chemical Engineering, TU Dortmund University, Germany
a r t i c l e
i n f o
Article history: Received 2 May 2018 Received in revised form 10 September 2018 Accepted 11 September 2018 Available online xxxx Keywords: Spray drying Submicron particles Low water soluble drugs
a b s t r a c t The versatile use of submicron-sized particles (0.1–1 lm) requires new manufacturing methods. One possibility for the preparation of submicron-sized particles is spray drying. However, the generation of small droplets at a high production rate and the precipitation of submicron particles are quite challenging. In order to produce a sufficient amount of fine and uniform droplets, a two-fluid nozzle with internal mixing was combined with a cyclone droplet separator. The precipitation of particles was realized with an electrostatic precipitator. Considering the difficulty of electrostatic precipitation concerning explosion risks and to make it capable using organic solvents, the spray dryer was integrated in a pressure resistant vessel. Based on previous experiments, the now presented design is compact and the electrostatic precipitator is shortened. In addition, enhanced drying conditions ensured a controlled and reproducible preparation of submicron-sized particles. Thus, high separation efficiencies were shown. Spray-drying experiments were conducted with the model substance mannitol. With the cyclone droplet separator, a fine and uniform spray with a droplet size smaller 2 lm was produced. This robust atomizing technique is capable for high concentrations. For a 10 wt% mannitol solution, particles in the submicron range d50,3 = 0.7 lm were produced. Ó 2018 Published by Elsevier B.V. on behalf of The Society of Powder Technology Japan. All rights reserved.
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1. Introduction
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Spray drying is an established technique in the field of material, food and pharmaceutical science for producing particles with desired properties. It is a continuous, single-step process, wherein a liquid solution is atomized and dried to the final product [1–3]. The use of spray drying for submicron-sized particles (0.1–1 lm) is of common interest [4–7]. In pharmaceutics, submicron-sized particles can increase the dissolution rate and solubility of poorly water-soluble drugs. In drug discovery, more than 70% of newly identified drugs exhibit poor water solubility [8]. In traditional spray drying processes, the generation of small and uniform droplets and the efficient precipitation of submicron particles is challenging [9]. So far, different atomization techniques and spray drying concepts were introduced to overcome these challenges. For the production of droplets in the micrometer range (1–10 lm) many methods, such as ultrasonic atomization [10], de laval type
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⇑ Corresponding author at: Chair of Solids Process Engineering, TU Dortmund University, Emil-Figge-Str. 68, 44227 Dortmund, Germany. E-mail address: [email protected] (M. Thommes).
atomization in the supersonic spray dryer [11] and liquid atomization by electrospraying [12] were developed. These methods were applicable for small feed concentrations and low viscosities. In addition, the feed flow rate is low, resulting in high processing times and limited applications. Eggersdorfer et al. [11] introduced the principle of supersonic spray drying with a de laval type nozzle where the dried particles were collected with a glass fiber filter. Non-spherical particles in the submicron-sized range were produced and production rates of about 200 mg=h with scalability up to 1500 mg=h were possible. For spray dried particles in the submicron sized range from a solution, emulsion or suspension, the Nano Spray Dryer B-90 (BÜCHI Labortechnik AG, Flawil, Switzerland) was introduced for spray drying and encapsulation purpose with the focus on food and pharmaceutical applications and material science. Moreover, the Nano-Spray Dryer B-90 was applied and tested with numerous substances [3,6,7,10,13,14]. This spray drying device was designed for small quantities (minimum sample amount: 2 mL [10]) in the laboratory scale. Small droplets are generated with the vibrating mesh nozzle and after a gentle drying step, the particles are collected with the electrostatic precipitator [10]. This concept shows
https://doi.org/10.1016/j.apt.2018.09.016 0921-8831/Ó 2018 Published by Elsevier B.V. on behalf of The Society of Powder Technology Japan. All rights reserved.
Please cite this article in press as: R. Strob et al., Preparation and characterization of spray-dried submicron particles for pharmaceutical application, Advanced Powder Technology (2018), https://doi.org/10.1016/j.apt.2018.09.016
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R. Strob et al. / Advanced Powder Technology xxx (2018) xxx–xxx
certain limitations concerning the robustness, long-term stability and scale up possibility. The vibrating mesh nozzle with the piezoelectric actuator consists of different mesh hole sizes (4:0; 5:5; 7:0 lmÞ. The droplet size mainly depends on the mesh size and the fluid properties, thus the smallest mesh size is necessary for the finest droplets in the size range of 3–8 lm. The small mesh size leads to a high probability of crust formation, especially for higher concentrations or viscosities [7]. The liquid feed rate depends on several parameters like the liquid properties and mesh size. The maximum possible feed flow rate is about 150 mL=h. For the smallest droplet size with the 4:0 lm spray mesh, a feed flow rate of about 10–20 mL/h is possible. Due to the nozzle concept, solution concentrations are limited to about 0.1–1 wt% solids. The width of the droplet size distribution given by the span ¼ ðd90 d10 Þ=d50 ¼ 1:2 1:6, is comparable to common twofluid nozzles. Within the electrostatic precipitator, the particles deposit on the inner surface. The particle yield is high with 76– 96%, based on the initial solid mass in the feed flow [15]. Based on the described features, the robustness of the nozzle and the particle throughput is limited. Previously, a test spray-drying plant was designed for the generation and efficient precipitation of submicron-sized particles [16,17]. The aim of this concept, which is also applied here, was the robust production of fine droplets in the small micrometer range with a narrow droplet size distribution and the efficient precipitation of submicron-sized particles generated over a long process time. The atomization of the solution was performed with a two-fluid nozzle with internal mixing. A cyclone droplet separator was used for aerosol conditioning to separate large droplets from the primary aerosol. Droplets smaller than the cut-off size (2 lm) were entrained in the gas stream and exited the cyclone separator at the dip pipe. The droplet size distribution of the conditioned aerosol was independent of the liquid mass flow and the viscosity of the solution. In addition, the span of the distribution was about 0:2, indicating a narrow size distribution. However, the amount of droplets in the conditioned aerosol depends on the fine fraction in the primary aerosol, since no additional droplets have been generated in the aerosol conditioning step. Thus, optimal spraying conditions should be determined in order to increase the yield of fine droplets. Drying was realized in a cocurrent concept. Drying air was introduced through small holes at the top of the drying chamber. The holes at the top of the drying chamber were blocked due to a crust formation of mannitol. This may occur because of a high vacuum in the plant, leading to the entrainment of larger droplets into the conditioned aerosol. The separation of submicron-sized particles was performed with a two-stage electrostatic precipitator (ESP). An adapted ESP design was necessary to achieve high separation efficiency and a robust process. A separation efficiency higher than 99% for 3 h was shown. The length of the designed ESP can be optimized, with the same separation efficiency and process time. The electrostatic precipitator with its corona discharge is a constant source of ignition, which cannot be avoided. One main limitation of this prototype was the application of organic solvents for spray drying experiments with pharmaceuticals [16,17]. For the use of organic solvents, a pressure-resistant vessel in which the plant is integrated should be used. Based on this proof-of-concept, a newly designed spray dryer will be presented, which combines atomization, droplet separation and particle separation in a two-stage ESP, capable of using organic solvents. The spray dryer should fit into a pressure-resistant vessel. In addition, a new drying concept is presented to ensure reproducible spray drying experiments. The length of the precipitator should be reduced in order to fit into the pressure-resistant vessel, thus ensuring laminar conditions and efficient precipitation. For the characterization of the designed
spray dryer and the comparison to the previous test plant, the model substance mannitol was used, dissolved in water.
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2. Materials and methods
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2.1. Materials
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Atomization and spray-drying experiments were performed with mannitol (160C RoquetteÒ Pharma, Lestrem, France) as a model substance. The liquid solutions were prepared with deionized water as the solvent.
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2.2. Method
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2.2.1. Aerosol characterization 2.2.1.1. Droplet size distribution. The droplet size was measured using laser diffraction (Spraytec, Malvern Instruments, Worcestershire, United Kingdom). Mie theory was used for evaluation, where particles between 0.1 and 900 lm can be measured. The droplet size distribution was measured 15 mm above the dip pipe. The volumetric droplet size distribution of the conditioned aerosol was evaluated and the mass median, d50,3, was computed for the distribution. The mass median is the 50% quantile of the volumetric distribution and is equal to the cut-off size of the cyclone separator. The droplet size distribution was evaluated for three atomizing gas mass flows (1:5; 2:0; 2:5 kg=h) and a liquid-to-gas _ L =m _ G in the range of 0.5–4.2, where m _ L is mass flow ratio l ¼ m the feed mass flow of the atomized liquid.
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2.2.1.2. Yield of conditioned aerosol. The yield of the conditioned aerosol was measured gravimetrically. Therefore, the feed reservoir was positioned on a weighing device (MSA20201S-000-D0, Sartorius, Göttingen, Germany) in order to weigh the mass loss during time (see Fig. 1). The conditioned aerosol was exhausted 10 cm above the cyclone, not affecting the aerosol. Each experiment was conducted three times for 15 min. The first 5 min was used for system equilibration. Given the mass m of the reservoir at the times t1 and t2, the yield of the conditioned aerosol Y CA is defined as:
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Y CA
m2 m1 Dmt ¼ ¼ t2 t1 Dt
ð1Þ
The yield was measured for a 10 wt% mannitol solution for two gas mass flows (1:5; 2:5 kg=h). The liquid mass flow was varied in the range of 1.2–18 kg/h. For the statistical analysis of the droplet
Fig. 1. Schematic of the experimental setup for determining the yield of the conditioned aerosol.
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size distributions, the yield of the aerosol, the droplet size analysis or for the evaluation of the separation efficiency, all experiments were made in triplicate or some representative results were presented. The mean value of the triplicate was analyzed and plotted with the standard deviation. In addition, for the droplet size measurement, the distribution was recorded every second. Afterwards, the average was calculated for a minimum of two minute measurement time. This was done in triplicate. Thus, even for one point, high amount of measurement variables are included.
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2.2.2. Spray-drying experiments 2.2.2.1. Experimental setup. Spray-drying experiments were conducted without the pressure resistant container. The watersoluble substance mannitol was used for the characterization of the plant. The experimental setup for spray-drying experiments is presented in Fig. 2. Drying air was adjusted to the desired mass flow rate, and the drying temperature was fixed using the heating unit. The liquid feed was supplied by a gear pump (D2D40-KOMPAKT, Gather Industrie, Wülfrath, Deutschland). Pressurized air flow was controlled with a rotameter and a manometer. The exhaust gas was filtered with a pleated paper filter. When the operating point was reached, the particle size distribution in the raw gas with disabled ESP was measured between the spray dryer and the pleated paper exhaust filter with a GRIMM Aerosol optical particle counter 1.109 (GRIMM AEROSOL Technik GmbH & Co. KG, Ainring, Germany) by isokinetic sampling. Afterwards, the separation of the produced submicron particles was performed with the ESP. For this operation, the negative high voltage power supply (HPS Compact 350 W, iseg Spezialeletronik GmbH, Radeberg, Deutschland) was switched on. The exhaust gas was observed online with the optical particle counter. Spray drying experiments were conducted for at least three hours. The spray dryer was disassembled to collect the particles. Particles were removed from the inner wall of the precipitator with a rubber spatula. The experiments were performed with a 10wt% mannitol solution and with drying tempera^ C, analyzing particle size as well as the tures of 50, 80 and 110 A
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precipitation behavior.
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2.2.2.2. Product characterization. The morphology of separated and collected particles was analyzed by a scanning electron microscope (Hitachi H-S4500 FEG, Krefeld, Germany). The particle size was analyzed by laser diffraction (Mastersizer 3000, Malvern Instruments, Worcestershire, United Kingdom) with a measurement
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Fig. 2. Schematic of the experimental setup for spray drying experiments.
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range of 0.001–3500 lm in a wet dispersion. It is based on the Mie theory, which considers absorption and reflection of the particles. The stability of the dispersion is crucial since agglomeration and dissolution have an effect on the measured particle-size distribution. Therefore, the selection of the right dispersion medium is necessary. Here, a prefiltered, saturated solution was used [18], produced by cooling crystallization. To do this, mannitol particles were dispersed in water at a higher temperature. The solution was cooled down to room temperature and nucleation and crystal growth occurred. The saturated solution was filtered to remove the produced crystals. The particle size was measured online with the optical particle counter. The separation efficiency of the particles according to a specific particle class was calculated as follows:
c 100% separation efficiency ¼ 1 c0
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ð2Þ
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where c0 and c represent the inlet and outlet particle concentrations, respectively.
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3. Experimental results and discussion
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For spray drying of poorly water-soluble pharmaceuticals, the use of organic solvents is essential. One limitation of the previous design was the lack of explosion protection. The electrostatic precipitator is an inherent source of ignition, thus an explosionpressure-resistant vessel in which the plant is integrated should be used. The vessel was limited to a height of 650 mm and a width of 300 mm in order to keep the system mobile and connect it to an
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Fig. 3. Dimensions of the pressure resistant vessel.
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existing ventilation system. The container (see Fig. 3) was designed in accordance with a guideline for the design of unfired pressure vessels [19]. Furthermore, all cable glands and material flow fittings were designed to withstand pressure. During an explosion, the vessel shall serve as protection against the environment even though an explosion under normal operating conditions is unlikely. The dimension limitations of the vessel additionally constrained the geometry of the designed spray-drying device.
tainer. In order to ensure a laminar flow in the drying and precipitation step, the diameter of the dryer and the ESP was fixed (see Section 3.3). Therefore, the inner diameter of the cyclone was fixed to 90 mm: The radius of the dip pipe was fixed to 16 mm in order to avoid a direct spraying of the primary aerosol. In addition, a moderate outlet velocity of 3 m=s can be realized. The heights H and Hi of the cyclone were selected by choosing an optimized cyclone from the literature [22,23]. Optimal cyclones were defined according to cut off size and pressure loss. With
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3.1. Atomization and conditioning
H ri
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For the aerosol generation step, an appropriate atomization method must be selected. The atomizer should be robust enough to handle high concentrations and viscosities. In addition, a small droplet size with a narrow droplet-size distribution under moderate conditions should be produced. Prior to this, different atomization techniques for producing fine droplets have been introduced including ultrasonic nebulizers, electrospraying and laval atomizers [11–13]. However, these techniques are only applicable for low concentrations, viscosities and feed flow rates. Here, a twofluid nozzle with internal mixing was selected [20]. Larger orifices can be applied, and fine droplets (< 10 lm) are produced under moderate pressure conditions. This technique is sufficiently robust for high concentrations and viscosities. The aerosol produced directly influences the particle size. Therefore, the cut off for the primary aerosol must be set to the desired diameter. In addition, recycling separated large droplets is crucial in order to avoid losses of valuable feed ingredients. One possibility is the separation with inertial separator. For a cut off size in the micrometer range, a sharp redirection with small dimensions is necessary but blockage with high solution concentrations may occur. To avoid this, cyclonic separation was used, in which large droplets are separated out of a vortex. Droplets larger than the cut off diameter d50;3 are separated by impaction with the inner wall and then flow down the inner wall to return to the liquid feed. Small droplets are entrained in the gas flow and leave the separator with the carrier gas at the dip pipe. The cut off diameter can be adjusted by altering the dimensions of the cyclone and the flow characteristics of the primary aerosol.
¼ 20 and
Hi ri
¼ 18, the heights H and Hi were determined to be
160 mm and 144 mm, respectively. With the separation height, the length of the dip pipe in the cyclone is fixed to 16 mm. With the given relationships and assumptions, the calculation of the velocity of the inner vortex v i was realized iteratively. Assuming an initial condition for v i ¼ 2 ms, in 100 iteration steps with a maximum change of 1 103 , the velocity v i was calculated to be 6.88 m/s [21]. According to Eq. (3), the cut off size diameter was defined for a mannitol solution (qL qG ¼ 1032:6 mkg3 ) to 3.13 µm. All dimensions are summarized in Fig. 4. 3.1.2. Droplet size distribution A compact cyclone was designed in order to produce a fine aerosol and to fit into the pressure resistant vessel. The mass median droplet size was measured for different conditions and is presented depending on the liquid-to-gas-mass flow ratio in Fig. 5. The mass median droplet size d50;3 is about 1:7 lm and constant over this loading range. Hence, it is smaller compared to the previously designed cyclone. In addition, the change in air mass flow leads to a small change in droplet size. For a mass flow higher than 2:5 kg=h, large droplets were entrained within the air flow to the outlet of the dip pipe. It is obvious that the experimental dro-
3.1.1. Cyclone droplet separator The previous cyclone separator [16] was designed based on calculations of the inner tangential velocity according to the potential theory. A sharp cut off at the desired droplet size was possible. For the new design, the cyclone had to fit in the pressure resistant vessel, so it had to be smaller in length and diameter than the previous design. In addition, the cut off diameter had to be small to ensure the generation of submicron-sized particles for high solution concentrations. The characteristic value for cyclonic separation is the cut off size diameter d50;3 . The separation of droplets can be described similar to the separation of particles [21]. The design of the droplet separator was realized according to Muschelknautz and Trefz [21]. The cut off diameter is a function of the forces acting on a particle, including the inward acting drag force and the centrifugal force acting outward:
d50;3 ¼ dcutoff
sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi 18gG 0:9V_ ¼ 2pðqL qG Þv 2i Hi
ð3Þ
The cut off diameter depends on the tangential velocity v i the separation height Hi and the properties of the liquid and gas phase with the density qL of the liquid phase and qG the density of the gas phase and the viscosity of the gas phase gG . According to the used atomizer, orifice and spray angle, the minimum radius for the inlet is about 28 mm. The diameter of the cyclone is defined by the con-
Fig. 4. Schematic of the designed cyclone droplet separator. All dimensions in mm.
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Fig. 5. Mass median droplet size of the conditioned aerosol as a function of the liquid-to-gas mass flow ratio for different air mass flows. (av ± s, n = 3). The grey colored star represents the results with the previously designed separator.
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plet size is much smaller than the theoretical. One reason may be the underestimated air inlet velocity in the cyclone separator.
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3.1.3. Yield of the conditioned aerosol During aerosol conditioning, the primary aerosol is separated at the cut off diameter. As no new droplets were generated, the mass of fine droplets in the primary aerosol depends exclusively on the number of small droplets in the primary aerosol. The total mass of droplets in the conditioned aerosol was measured gravimetrically for different inlet mass flows (see Fig. 6). The yield increases for both air mass flows until a liquid mass flow of 6 kg=h is reached. A higher liquid mass flow leads to larger droplets in the primary aerosol, so the amount of fine droplets decreases. With an air mass flow of 2:5 kg=h, a maximum yield of 0:5 gAerosol =min was obtained.
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3.2. Spray drying
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The conditioned aerosol was conveyed together with the drying air into the drying chamber in a co-current manner. Reproducible drying conditions, a constant drying temperature and a laminar flow were preferred [7]. Laminar flow (Re < 2300) was ensured for a wide range of drying-air mass flows (1–12 kg/h) by setting the inner diameter of the drying stage to about 199 mm. The minimum residence time to completely dry the fine droplets was calculated to be 0:38 s [24]. The available length in the container (486:8 mm) was used for the length of the drying chamber. In
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Fig. 6. Yield of the conditioned aerosol as a function of the feed liquid mass flow for different air mass flows. (av ± s, n = 3).
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the previous plant, the holes for the drying air distribution became blocked. Here, a perforated plate with twelve holes of 5 mm diameter in a circular arrangement was used and placed above the dip pipe of the cyclone. By placing an insulating material between air distributor and dip pipe, no drying of layers within the dip pipe occur (see Fig. 7).
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3.2.1. Particle size distribution In case of drying operation, the conditioned aerosol is conveyed together with the drying gas though the drying chamber and the ESP. The mass flow of drying air was fixed to 4:5 kg=h for optimal drying conditions. A minimum mass flow was necessary to prevent the heating cartridge from overheating, but too high mass flow would increase the vacuum in the plant and lead to entrainment of large droplets in the drying chamber. Previous experiments showed that this could cause a blockage of the air distributor. The dried particles were recovered by removing them from the inner wall of the electrostatic precipitator, and the particle size distribution was evaluated for three different drying temperatures by laser diffraction in advance. The cumulative mass distributions show particles in the submicron size range (see Fig. 8). A bimodal distribution for all drying temperatures was observed. Laser diffraction measurements indicated a local maximum in the submicron range, and a second maximum around 2 lm. The GRIMM particle counter was used to measure particle size directly in the flow operating with isokinetic sampling. A high number of particles in the submicron range were observed. Nevertheless, a few large droplets were also traced, possibly due to particle agglomeration. Scanning electron microscopy images of dried mannitol particles were also analyzed (see Fig. 9). In accordance to the particle size measurements, the SEM images show particles in the submicron sized range. In addition, the particles are spherical and indicate a smooth surface for small drying air temperatures. The redispersion of primary particles at low drying temperatures was possible. At high drying temperatures, however, a molten surface likely formed on the particles (see Fig. 9, right), resulting in surface stickiness and irreversible agglomeration [25–27]. The drying behavior and morphology of the dried particles depends on the type of material [28], which cannot be generalized and described in this work. However, this model substance can adequate characterize the new spray drying setup and demonstrate the possibility and limitations.
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3.3. Electrostatic precipitator
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An electrostatic precipitator (ESP) was selected because of its compact design and high separation efficiency in the submicron range. Based on previous tests, an existing two-stage electrostatic precipitator according to the Penney concept could be adapted [17]. The first stage, which also represents the ionization zone, consisted of a tungsten wire (d ¼ 0:5 mm; l ¼ 50 mmÞ attached to a tube, which formed the separation zone (d ¼ 30 mm; l ¼ 315 mm). The discharge electrode was installed in a wider pipe (d ¼ 83 mm; l ¼ 400 mm) as a precipitation electrode. A hard fabric seal insulated the discharge from the precipitation electrode and enabled the build-up of a potential difference. This design is modular and enables laminar flow control minimizing turbulence. Submicron particles especially tend to follow the air flow, and would thus be subject to redispersion by turbulence during a separation process [29]. The separation of the particles is a key factor in the profitability of the system. The yield of recovered product increases with increasing efficiency of the separation performance. Thus, the operating parameters of electrostatic precipitation such
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Fig. 7. Left: schematic drawing of the conditioning and the drying step; all dimensions in mm. Right: CAD-drawing of the air distribution (1) with the perforated plate (2).
Fig. 8. Cumulative mass particle size distribution for a 10 wt% mannitol solution, measured by laser diffraction (left) and with the GRIMM particle counter (right).
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as current density and operating voltage have been optimized for the material used in previous work [16,17]. The separation efficiency in the two-stage electrostatic precipitator has already been investigated and optimised in previous tests [16,17]. A discharge electrode with a length of 50 mm at a current density of j ¼ 6:5 mA=m2 and a voltage of about 20 kV delivered a constant deposition rate of higher than 99% in the submicron range for 3 h. The influence of the drying temperature on deposition was investigated for the production of submicron particles as a continuous process. Fig. 10 (left) shows an example of the separation performance in the first three hours for 300 nm mannitol
particles. The drying temperature not only influences the morphology of the resulting particles, but can also determine the degree of separation. In order to maintain the overview, two temperatures ^ C are shown. Higher drying temperatures exhibit a 50 and 110 A
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reduction in separation efficiency of up to 1.5%. This tendency was also confirmed in tests with a drying temperature of 80 °C. The literature distinguishes between two conductivity mechanisms in particle layers: surface and bulk conductivity [30]. Particles generally have a layer of adsorbed water molecules, which form a wet layer on the surface of the particle. If such a particle is charged with electrons, they can move via the surface. This hap-
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Fig. 9. Scanning electron microscopy images of spray dried submicron particles for three drying temperatures. 50 °C (left), 80 °C (middle), 110 °C (right).
Fig. 10. Time dependent separation efficiencies for mannitol particles at various temperatures (left) (av ± s, n = 3). Time dependent separation efficiencies for mannitol particles at a current density of 6.5 mA/m2 negative corona (right) (av, s < 5%, n = 3).
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pens when the resistance of the water is lower than that of the particle. As the temperature increases, the water desorbs, and the surface conductivity decreases. The increase in resistance leads to changes in the charging conditions, and in the worst case can lead to the so-called back corona. In the presence of back corona, the charge in a particle layer can no longer flow down to the electrode for discharge, which creates a potential and leads to microexplosions in the layer, whereby already deposited material can be returned to the air flow. In this case the diminishing effect of surface conductivity occurs. Thus, moderate drying temperatures not only help with the formation of round particles, but also with the separation. In order to compare the new design with previous work, a longterm test was carried out with the model material mannitol in order to determine the maximum deposition time (see Fig. 10, right). Compared to preliminary tests, the separation time in the new design has been increased to approximately 15 h. After 15.5 h the separation for fractions smaller than 1 lm breaks down and a complete recovery of the sprayed material is no longer guaranteed.
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4. Conclusion
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Spray-drying processes for the preparation of submicron-sized particles show limitations regarding small droplets and efficient precipitation. In this work, a previously developed spray-drying concept was used and redesigned. The new design is compact and fits in a pressure resistant vessel. Hence, spray-drying experiments with pharmaceuticals that were dissolved in organic solvents are possible. Here, the spray dryer was characterized with the model substance mannitol in aqueous solution for simplicity of the operation. Compared to the previous design, slightly smaller droplets (d50;3 < 1:7 lm) in the conditioned aerosol were pro-
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duced. Nevertheless, a yield loss was recorded. A maximum atomizing air flow of 2:5 kg=h was determined to prevent droplet entrainment. Reproducible drying conditions were realized with the new drying air distributor. Spray-drying experiments with mannitol were performed and submicron-sized particles were generated.
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Declaration of interest
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None.
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Acknowledgement
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The authors thank Roquette Pharma for providing mannitol, and Monika Meuris (TU Dortmund University) for taking the SEM images. We thank Elizabeth Ely for editing the manuscript. We also want to thank our students Philip da Igreja and Jan Frederik Herzog for their help in the design and characterization of the spray drying device.
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References
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[1] J. Vicente, J. Pinto, J. Menezes, F. Gaspar, Fundamental analysis of particle formation in spray drying, Powder Technol. 247 (2013) 1–7. [2] K. Masters, Spray Drying Handbook, Longman Scientific & Technical, Harlow, 1991. [3] Y.A. Haggag, A.M. Faheem, Evaluation of nano spray drying as a method for drying and formulation of therapeutic peptides and proteins, Front. Pharmacol. 6 (2015). [4] J. Broadhead, S.K.E. Rouan, C.T. Rhodes, The spray drying of pharmaceuticals, Drug Dev. Ind. Pharm. 18 (1992) 1169–1206. [5] H.K. Chan, P.C.L. Kwok, Production methods for nanodrug particles using the bottom-up approach, Adv. Drug Deliver Rev. 63 (2011) 406–416. [6] X.A. Li, N. Anton, C. Arpagaus, F. Belleteix, T.F. Vandanune, Nanoparticles by spray drying using innovative new technology: The Buchi Nano Spray Dryer B90, J. Control. Release 147 (2010) 304–310.
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[7] K. Schmid, C. Arpagaus, W. Friess, Evaluation of the nano spray dryer B-90 for pharmaceutical applications, Pharm. Dev. Technol. 16 (2011) 287–294. [8] Y. Kawabata, K. Wada, M. Nakatani, S. Yamada, S. Onoue, Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: Basic approaches and practical applications, Int. J. Pharm. 420 (2011) 1–10. [9] A. Sosnik, K.P. Seremeta, Advantages and challenges of the spray-drying technology for the production of pure drug particles and drug-loaded polymeric carriers, Adv. Colloid Interfac. 223 (2015) 40–54. [10] C. Arpagaus, A. Collenberg, D. Rutti, E. Assadpour, S.M. Jafari, Nano spray drying for encapsulation of pharmaceuticals, Int. J. Pharm. 546 (2018) 194– 214. [11] M.L. Eggersdorfer, V. Koren, E. Stolovicki, E. Amstad, D.A. Weitz, Rapid production of submicron drug substance particles by supersonic spray drying, Cryst. Growth Des. 17 (2017) 2046–2053. [12] A. Jaworek, A.T. Sobczyk, Electrospraying route to nanotechnology: An overview, J. Electrostat. 66 (2008) 197–219. [13] M. Beck-Broichsitter, I.E. Paulus, A. Greiner, T. Kissel, Modified vibrating-mesh nozzles for advanced spray-drying applications, Eur. J. Pharm. Biopharm. 92 (2015) 96–101. [14] N. Schafroth, C. Arpagaus, U.Y. Jadhav, S. Makne, D. Douroumis, Nano and microparticle engineering of water insoluble drugs using a novel spray-drying process, Colloid. Surface B 90 (2012) 8–15. [15] C. Arpagaus, P. John, A. Collenberg, D. Rütti, 10 – Nanocapsules formation by nano spray drying, Nanoencapsulation Technologies for the Food and Nutraceutical Industries, Academic Press, New York, 2017. [16] R. Strob, A. Dobrowolski, G. Schaldach, P. Walzel, M. Thommes, Preparation of spray dried submicron partilces: Part A- Particle generation by aerosol conditioning, Int. J. Pharm. 548 (2018) 423–430.
[17] A. Dobrowolski, R. Strob, J. Nietfeld, D. Pieloth, H. Wiggers, M. Thommes, Preparation of spray dried submicron particles: Part B- Particle recovery by electrostatic precipitation, Int. J. Pharm. 548 (2018) 237–243. [18] U.S.P. Convention, Light Diffraction Measurement of Particle Size USP 429, in, http://www.pharmacopeia.cn/v29240/usp29nf24s0_c429.html. [19] DIN EN 13445-3:2017-12, Unfired pressure vessels – Part 3: Design. [20] B. Schlinge, A. Mescher, P. Walzel, Pneumatic nozzle with modified internal mixing geometry, 12th Triennial International Conference on Liquid Atomization and Spray Systems, September 2.-6, Heidelberg, Germany, 2012. [21] A.C. Hoffmann, L.E. Stein, Gas Cyclones and Swirl Tubes, Springer Verlag, Berlin, 2008. [22] M. Bohnet, Cyclone separators for separation of gas solids flow systems, Chem.-Ing.-Tech. 54 (1982) 621–630. [23] E. Muschelknautz, Design of cyclone separators for gases, Chem.-Ing.-Tech. 44 (1972) 63. [24] A.A. Bandyopadhyay, A.A. Pawar, C. Venkataraman, A. Mehra, Modelling size and structure of nanoparticles formed from drying of submicron solution aerosols, J. Nanopart. Res. 17 (2015). [25] C. Turchiuli, A. Gianfrancesco, S. Palzer, E. Dumoulin, Evolution of particle properties during spray drying in relation with stickiness and agglomeration control, Powder Technol. 208 (2011) 433–440. [26] E. Amstad, F. Spaepen, D.A. Weitz, Stabilization of the amorphous structure of spray-dried drug nanoparticles, J. Phys. Chem. B 120 (2016) 9161–9165. [27] B.R. Bhandari, N. Datta, T. Howes, Problems associated with spray drying of sugar-rich foods, Dry Technol. 15 (1997) 671–684. [28] D.E. Walton, The morphology of spray-dried particles a qualitative view, Dry Technol. 18 (2000) 1943–1986. [29] A. Bürkholz, Droplet Separation, Wiley-VCH, Weinheim, 1989. [30] H.J. White, Industrial Electrostatic Precipitation, Addison-Wesley, New York, 1963.
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Contents lists available at ScienceDirect
Advanced Powder Technology journal homepage: www.elsevier.com/locate/apt
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Original Research Paper
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Preparation and characterization of spray-dried submicron particles for pharmaceutical application
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Ramona Strob, Adrian Dobrowolski, Damian Pieloth, Gerhard Schaldach, Helmut Wiggers, Peter Walzel, Markus Thommes ⇑ Chair of Solids Process Engineering, Department of Biochemical and Chemical Engineering, TU Dortmund University, Germany
a r t i c l e
i n f o
Article history: Received 2 May 2018 Received in revised form 10 September 2018 Accepted 11 September 2018 Available online xxxx Keywords: Spray drying Submicron particles Low water soluble drugs
a b s t r a c t The versatile use of submicron-sized particles (0.1–1 lm) requires new manufacturing methods. One possibility for the preparation of submicron-sized particles is spray drying. However, the generation of small droplets at a high production rate and the precipitation of submicron particles are quite challenging. In order to produce a sufficient amount of fine and uniform droplets, a two-fluid nozzle with internal mixing was combined with a cyclone droplet separator. The precipitation of particles was realized with an electrostatic precipitator. Considering the difficulty of electrostatic precipitation concerning explosion risks and to make it capable using organic solvents, the spray dryer was integrated in a pressure resistant vessel. Based on previous experiments, the now presented design is compact and the electrostatic precipitator is shortened. In addition, enhanced drying conditions ensured a controlled and reproducible preparation of submicron-sized particles. Thus, high separation efficiencies were shown. Spray-drying experiments were conducted with the model substance mannitol. With the cyclone droplet separator, a fine and uniform spray with a droplet size smaller 2 lm was produced. This robust atomizing technique is capable for high concentrations. For a 10 wt% mannitol solution, particles in the submicron range d50,3 = 0.7 lm were produced. Ó 2018 Published by Elsevier B.V. on behalf of The Society of Powder Technology Japan. All rights reserved.
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1. Introduction
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Spray drying is an established technique in the field of material, food and pharmaceutical science for producing particles with desired properties. It is a continuous, single-step process, wherein a liquid solution is atomized and dried to the final product [1–3]. The use of spray drying for submicron-sized particles (0.1–1 lm) is of common interest [4–7]. In pharmaceutics, submicron-sized particles can increase the dissolution rate and solubility of poorly water-soluble drugs. In drug discovery, more than 70% of newly identified drugs exhibit poor water solubility [8]. In traditional spray drying processes, the generation of small and uniform droplets and the efficient precipitation of submicron particles is challenging [9]. So far, different atomization techniques and spray drying concepts were introduced to overcome these challenges. For the production of droplets in the micrometer range (1–10 lm) many methods, such as ultrasonic atomization [10], de laval type
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⇑ Corresponding author at: Chair of Solids Process Engineering, TU Dortmund University, Emil-Figge-Str. 68, 44227 Dortmund, Germany. E-mail address: [email protected] (M. Thommes).
atomization in the supersonic spray dryer [11] and liquid atomization by electrospraying [12] were developed. These methods were applicable for small feed concentrations and low viscosities. In addition, the feed flow rate is low, resulting in high processing times and limited applications. Eggersdorfer et al. [11] introduced the principle of supersonic spray drying with a de laval type nozzle where the dried particles were collected with a glass fiber filter. Non-spherical particles in the submicron-sized range were produced and production rates of about 200 mg=h with scalability up to 1500 mg=h were possible. For spray dried particles in the submicron sized range from a solution, emulsion or suspension, the Nano Spray Dryer B-90 (BÜCHI Labortechnik AG, Flawil, Switzerland) was introduced for spray drying and encapsulation purpose with the focus on food and pharmaceutical applications and material science. Moreover, the Nano-Spray Dryer B-90 was applied and tested with numerous substances [3,6,7,10,13,14]. This spray drying device was designed for small quantities (minimum sample amount: 2 mL [10]) in the laboratory scale. Small droplets are generated with the vibrating mesh nozzle and after a gentle drying step, the particles are collected with the electrostatic precipitator [10]. This concept shows
https://doi.org/10.1016/j.apt.2018.09.016 0921-8831/Ó 2018 Published by Elsevier B.V. on behalf of The Society of Powder Technology Japan. All rights reserved.
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certain limitations concerning the robustness, long-term stability and scale up possibility. The vibrating mesh nozzle with the piezoelectric actuator consists of different mesh hole sizes (4:0; 5:5; 7:0 lmÞ. The droplet size mainly depends on the mesh size and the fluid properties, thus the smallest mesh size is necessary for the finest droplets in the size range of 3–8 lm. The small mesh size leads to a high probability of crust formation, especially for higher concentrations or viscosities [7]. The liquid feed rate depends on several parameters like the liquid properties and mesh size. The maximum possible feed flow rate is about 150 mL=h. For the smallest droplet size with the 4:0 lm spray mesh, a feed flow rate of about 10–20 mL/h is possible. Due to the nozzle concept, solution concentrations are limited to about 0.1–1 wt% solids. The width of the droplet size distribution given by the span ¼ ðd90 d10 Þ=d50 ¼ 1:2 1:6, is comparable to common twofluid nozzles. Within the electrostatic precipitator, the particles deposit on the inner surface. The particle yield is high with 76– 96%, based on the initial solid mass in the feed flow [15]. Based on the described features, the robustness of the nozzle and the particle throughput is limited. Previously, a test spray-drying plant was designed for the generation and efficient precipitation of submicron-sized particles [16,17]. The aim of this concept, which is also applied here, was the robust production of fine droplets in the small micrometer range with a narrow droplet size distribution and the efficient precipitation of submicron-sized particles generated over a long process time. The atomization of the solution was performed with a two-fluid nozzle with internal mixing. A cyclone droplet separator was used for aerosol conditioning to separate large droplets from the primary aerosol. Droplets smaller than the cut-off size (2 lm) were entrained in the gas stream and exited the cyclone separator at the dip pipe. The droplet size distribution of the conditioned aerosol was independent of the liquid mass flow and the viscosity of the solution. In addition, the span of the distribution was about 0:2, indicating a narrow size distribution. However, the amount of droplets in the conditioned aerosol depends on the fine fraction in the primary aerosol, since no additional droplets have been generated in the aerosol conditioning step. Thus, optimal spraying conditions should be determined in order to increase the yield of fine droplets. Drying was realized in a cocurrent concept. Drying air was introduced through small holes at the top of the drying chamber. The holes at the top of the drying chamber were blocked due to a crust formation of mannitol. This may occur because of a high vacuum in the plant, leading to the entrainment of larger droplets into the conditioned aerosol. The separation of submicron-sized particles was performed with a two-stage electrostatic precipitator (ESP). An adapted ESP design was necessary to achieve high separation efficiency and a robust process. A separation efficiency higher than 99% for 3 h was shown. The length of the designed ESP can be optimized, with the same separation efficiency and process time. The electrostatic precipitator with its corona discharge is a constant source of ignition, which cannot be avoided. One main limitation of this prototype was the application of organic solvents for spray drying experiments with pharmaceuticals [16,17]. For the use of organic solvents, a pressure-resistant vessel in which the plant is integrated should be used. Based on this proof-of-concept, a newly designed spray dryer will be presented, which combines atomization, droplet separation and particle separation in a two-stage ESP, capable of using organic solvents. The spray dryer should fit into a pressure-resistant vessel. In addition, a new drying concept is presented to ensure reproducible spray drying experiments. The length of the precipitator should be reduced in order to fit into the pressure-resistant vessel, thus ensuring laminar conditions and efficient precipitation. For the characterization of the designed
spray dryer and the comparison to the previous test plant, the model substance mannitol was used, dissolved in water.
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2. Materials and methods
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2.1. Materials
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Atomization and spray-drying experiments were performed with mannitol (160C RoquetteÒ Pharma, Lestrem, France) as a model substance. The liquid solutions were prepared with deionized water as the solvent.
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2.2. Method
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2.2.1. Aerosol characterization 2.2.1.1. Droplet size distribution. The droplet size was measured using laser diffraction (Spraytec, Malvern Instruments, Worcestershire, United Kingdom). Mie theory was used for evaluation, where particles between 0.1 and 900 lm can be measured. The droplet size distribution was measured 15 mm above the dip pipe. The volumetric droplet size distribution of the conditioned aerosol was evaluated and the mass median, d50,3, was computed for the distribution. The mass median is the 50% quantile of the volumetric distribution and is equal to the cut-off size of the cyclone separator. The droplet size distribution was evaluated for three atomizing gas mass flows (1:5; 2:0; 2:5 kg=h) and a liquid-to-gas _ L =m _ G in the range of 0.5–4.2, where m _ L is mass flow ratio l ¼ m the feed mass flow of the atomized liquid.
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2.2.1.2. Yield of conditioned aerosol. The yield of the conditioned aerosol was measured gravimetrically. Therefore, the feed reservoir was positioned on a weighing device (MSA20201S-000-D0, Sartorius, Göttingen, Germany) in order to weigh the mass loss during time (see Fig. 1). The conditioned aerosol was exhausted 10 cm above the cyclone, not affecting the aerosol. Each experiment was conducted three times for 15 min. The first 5 min was used for system equilibration. Given the mass m of the reservoir at the times t1 and t2, the yield of the conditioned aerosol Y CA is defined as:
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Y CA
m2 m1 Dmt ¼ ¼ t2 t1 Dt
ð1Þ
The yield was measured for a 10 wt% mannitol solution for two gas mass flows (1:5; 2:5 kg=h). The liquid mass flow was varied in the range of 1.2–18 kg/h. For the statistical analysis of the droplet
Fig. 1. Schematic of the experimental setup for determining the yield of the conditioned aerosol.
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size distributions, the yield of the aerosol, the droplet size analysis or for the evaluation of the separation efficiency, all experiments were made in triplicate or some representative results were presented. The mean value of the triplicate was analyzed and plotted with the standard deviation. In addition, for the droplet size measurement, the distribution was recorded every second. Afterwards, the average was calculated for a minimum of two minute measurement time. This was done in triplicate. Thus, even for one point, high amount of measurement variables are included.
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2.2.2. Spray-drying experiments 2.2.2.1. Experimental setup. Spray-drying experiments were conducted without the pressure resistant container. The watersoluble substance mannitol was used for the characterization of the plant. The experimental setup for spray-drying experiments is presented in Fig. 2. Drying air was adjusted to the desired mass flow rate, and the drying temperature was fixed using the heating unit. The liquid feed was supplied by a gear pump (D2D40-KOMPAKT, Gather Industrie, Wülfrath, Deutschland). Pressurized air flow was controlled with a rotameter and a manometer. The exhaust gas was filtered with a pleated paper filter. When the operating point was reached, the particle size distribution in the raw gas with disabled ESP was measured between the spray dryer and the pleated paper exhaust filter with a GRIMM Aerosol optical particle counter 1.109 (GRIMM AEROSOL Technik GmbH & Co. KG, Ainring, Germany) by isokinetic sampling. Afterwards, the separation of the produced submicron particles was performed with the ESP. For this operation, the negative high voltage power supply (HPS Compact 350 W, iseg Spezialeletronik GmbH, Radeberg, Deutschland) was switched on. The exhaust gas was observed online with the optical particle counter. Spray drying experiments were conducted for at least three hours. The spray dryer was disassembled to collect the particles. Particles were removed from the inner wall of the precipitator with a rubber spatula. The experiments were performed with a 10wt% mannitol solution and with drying tempera^ C, analyzing particle size as well as the tures of 50, 80 and 110 A
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precipitation behavior.
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2.2.2.2. Product characterization. The morphology of separated and collected particles was analyzed by a scanning electron microscope (Hitachi H-S4500 FEG, Krefeld, Germany). The particle size was analyzed by laser diffraction (Mastersizer 3000, Malvern Instruments, Worcestershire, United Kingdom) with a measurement
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Fig. 2. Schematic of the experimental setup for spray drying experiments.
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range of 0.001–3500 lm in a wet dispersion. It is based on the Mie theory, which considers absorption and reflection of the particles. The stability of the dispersion is crucial since agglomeration and dissolution have an effect on the measured particle-size distribution. Therefore, the selection of the right dispersion medium is necessary. Here, a prefiltered, saturated solution was used [18], produced by cooling crystallization. To do this, mannitol particles were dispersed in water at a higher temperature. The solution was cooled down to room temperature and nucleation and crystal growth occurred. The saturated solution was filtered to remove the produced crystals. The particle size was measured online with the optical particle counter. The separation efficiency of the particles according to a specific particle class was calculated as follows:
c 100% separation efficiency ¼ 1 c0
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ð2Þ
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where c0 and c represent the inlet and outlet particle concentrations, respectively.
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3. Experimental results and discussion
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For spray drying of poorly water-soluble pharmaceuticals, the use of organic solvents is essential. One limitation of the previous design was the lack of explosion protection. The electrostatic precipitator is an inherent source of ignition, thus an explosionpressure-resistant vessel in which the plant is integrated should be used. The vessel was limited to a height of 650 mm and a width of 300 mm in order to keep the system mobile and connect it to an
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Fig. 3. Dimensions of the pressure resistant vessel.
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existing ventilation system. The container (see Fig. 3) was designed in accordance with a guideline for the design of unfired pressure vessels [19]. Furthermore, all cable glands and material flow fittings were designed to withstand pressure. During an explosion, the vessel shall serve as protection against the environment even though an explosion under normal operating conditions is unlikely. The dimension limitations of the vessel additionally constrained the geometry of the designed spray-drying device.
tainer. In order to ensure a laminar flow in the drying and precipitation step, the diameter of the dryer and the ESP was fixed (see Section 3.3). Therefore, the inner diameter of the cyclone was fixed to 90 mm: The radius of the dip pipe was fixed to 16 mm in order to avoid a direct spraying of the primary aerosol. In addition, a moderate outlet velocity of 3 m=s can be realized. The heights H and Hi of the cyclone were selected by choosing an optimized cyclone from the literature [22,23]. Optimal cyclones were defined according to cut off size and pressure loss. With
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3.1. Atomization and conditioning
H ri
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For the aerosol generation step, an appropriate atomization method must be selected. The atomizer should be robust enough to handle high concentrations and viscosities. In addition, a small droplet size with a narrow droplet-size distribution under moderate conditions should be produced. Prior to this, different atomization techniques for producing fine droplets have been introduced including ultrasonic nebulizers, electrospraying and laval atomizers [11–13]. However, these techniques are only applicable for low concentrations, viscosities and feed flow rates. Here, a twofluid nozzle with internal mixing was selected [20]. Larger orifices can be applied, and fine droplets (< 10 lm) are produced under moderate pressure conditions. This technique is sufficiently robust for high concentrations and viscosities. The aerosol produced directly influences the particle size. Therefore, the cut off for the primary aerosol must be set to the desired diameter. In addition, recycling separated large droplets is crucial in order to avoid losses of valuable feed ingredients. One possibility is the separation with inertial separator. For a cut off size in the micrometer range, a sharp redirection with small dimensions is necessary but blockage with high solution concentrations may occur. To avoid this, cyclonic separation was used, in which large droplets are separated out of a vortex. Droplets larger than the cut off diameter d50;3 are separated by impaction with the inner wall and then flow down the inner wall to return to the liquid feed. Small droplets are entrained in the gas flow and leave the separator with the carrier gas at the dip pipe. The cut off diameter can be adjusted by altering the dimensions of the cyclone and the flow characteristics of the primary aerosol.
¼ 20 and
Hi ri
¼ 18, the heights H and Hi were determined to be
160 mm and 144 mm, respectively. With the separation height, the length of the dip pipe in the cyclone is fixed to 16 mm. With the given relationships and assumptions, the calculation of the velocity of the inner vortex v i was realized iteratively. Assuming an initial condition for v i ¼ 2 ms, in 100 iteration steps with a maximum change of 1 103 , the velocity v i was calculated to be 6.88 m/s [21]. According to Eq. (3), the cut off size diameter was defined for a mannitol solution (qL qG ¼ 1032:6 mkg3 ) to 3.13 µm. All dimensions are summarized in Fig. 4. 3.1.2. Droplet size distribution A compact cyclone was designed in order to produce a fine aerosol and to fit into the pressure resistant vessel. The mass median droplet size was measured for different conditions and is presented depending on the liquid-to-gas-mass flow ratio in Fig. 5. The mass median droplet size d50;3 is about 1:7 lm and constant over this loading range. Hence, it is smaller compared to the previously designed cyclone. In addition, the change in air mass flow leads to a small change in droplet size. For a mass flow higher than 2:5 kg=h, large droplets were entrained within the air flow to the outlet of the dip pipe. It is obvious that the experimental dro-
3.1.1. Cyclone droplet separator The previous cyclone separator [16] was designed based on calculations of the inner tangential velocity according to the potential theory. A sharp cut off at the desired droplet size was possible. For the new design, the cyclone had to fit in the pressure resistant vessel, so it had to be smaller in length and diameter than the previous design. In addition, the cut off diameter had to be small to ensure the generation of submicron-sized particles for high solution concentrations. The characteristic value for cyclonic separation is the cut off size diameter d50;3 . The separation of droplets can be described similar to the separation of particles [21]. The design of the droplet separator was realized according to Muschelknautz and Trefz [21]. The cut off diameter is a function of the forces acting on a particle, including the inward acting drag force and the centrifugal force acting outward:
d50;3 ¼ dcutoff
sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi 18gG 0:9V_ ¼ 2pðqL qG Þv 2i Hi
ð3Þ
The cut off diameter depends on the tangential velocity v i the separation height Hi and the properties of the liquid and gas phase with the density qL of the liquid phase and qG the density of the gas phase and the viscosity of the gas phase gG . According to the used atomizer, orifice and spray angle, the minimum radius for the inlet is about 28 mm. The diameter of the cyclone is defined by the con-
Fig. 4. Schematic of the designed cyclone droplet separator. All dimensions in mm.
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Fig. 5. Mass median droplet size of the conditioned aerosol as a function of the liquid-to-gas mass flow ratio for different air mass flows. (av ± s, n = 3). The grey colored star represents the results with the previously designed separator.
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plet size is much smaller than the theoretical. One reason may be the underestimated air inlet velocity in the cyclone separator.
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3.1.3. Yield of the conditioned aerosol During aerosol conditioning, the primary aerosol is separated at the cut off diameter. As no new droplets were generated, the mass of fine droplets in the primary aerosol depends exclusively on the number of small droplets in the primary aerosol. The total mass of droplets in the conditioned aerosol was measured gravimetrically for different inlet mass flows (see Fig. 6). The yield increases for both air mass flows until a liquid mass flow of 6 kg=h is reached. A higher liquid mass flow leads to larger droplets in the primary aerosol, so the amount of fine droplets decreases. With an air mass flow of 2:5 kg=h, a maximum yield of 0:5 gAerosol =min was obtained.
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3.2. Spray drying
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The conditioned aerosol was conveyed together with the drying air into the drying chamber in a co-current manner. Reproducible drying conditions, a constant drying temperature and a laminar flow were preferred [7]. Laminar flow (Re < 2300) was ensured for a wide range of drying-air mass flows (1–12 kg/h) by setting the inner diameter of the drying stage to about 199 mm. The minimum residence time to completely dry the fine droplets was calculated to be 0:38 s [24]. The available length in the container (486:8 mm) was used for the length of the drying chamber. In
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Fig. 6. Yield of the conditioned aerosol as a function of the feed liquid mass flow for different air mass flows. (av ± s, n = 3).
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the previous plant, the holes for the drying air distribution became blocked. Here, a perforated plate with twelve holes of 5 mm diameter in a circular arrangement was used and placed above the dip pipe of the cyclone. By placing an insulating material between air distributor and dip pipe, no drying of layers within the dip pipe occur (see Fig. 7).
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3.2.1. Particle size distribution In case of drying operation, the conditioned aerosol is conveyed together with the drying gas though the drying chamber and the ESP. The mass flow of drying air was fixed to 4:5 kg=h for optimal drying conditions. A minimum mass flow was necessary to prevent the heating cartridge from overheating, but too high mass flow would increase the vacuum in the plant and lead to entrainment of large droplets in the drying chamber. Previous experiments showed that this could cause a blockage of the air distributor. The dried particles were recovered by removing them from the inner wall of the electrostatic precipitator, and the particle size distribution was evaluated for three different drying temperatures by laser diffraction in advance. The cumulative mass distributions show particles in the submicron size range (see Fig. 8). A bimodal distribution for all drying temperatures was observed. Laser diffraction measurements indicated a local maximum in the submicron range, and a second maximum around 2 lm. The GRIMM particle counter was used to measure particle size directly in the flow operating with isokinetic sampling. A high number of particles in the submicron range were observed. Nevertheless, a few large droplets were also traced, possibly due to particle agglomeration. Scanning electron microscopy images of dried mannitol particles were also analyzed (see Fig. 9). In accordance to the particle size measurements, the SEM images show particles in the submicron sized range. In addition, the particles are spherical and indicate a smooth surface for small drying air temperatures. The redispersion of primary particles at low drying temperatures was possible. At high drying temperatures, however, a molten surface likely formed on the particles (see Fig. 9, right), resulting in surface stickiness and irreversible agglomeration [25–27]. The drying behavior and morphology of the dried particles depends on the type of material [28], which cannot be generalized and described in this work. However, this model substance can adequate characterize the new spray drying setup and demonstrate the possibility and limitations.
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3.3. Electrostatic precipitator
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An electrostatic precipitator (ESP) was selected because of its compact design and high separation efficiency in the submicron range. Based on previous tests, an existing two-stage electrostatic precipitator according to the Penney concept could be adapted [17]. The first stage, which also represents the ionization zone, consisted of a tungsten wire (d ¼ 0:5 mm; l ¼ 50 mmÞ attached to a tube, which formed the separation zone (d ¼ 30 mm; l ¼ 315 mm). The discharge electrode was installed in a wider pipe (d ¼ 83 mm; l ¼ 400 mm) as a precipitation electrode. A hard fabric seal insulated the discharge from the precipitation electrode and enabled the build-up of a potential difference. This design is modular and enables laminar flow control minimizing turbulence. Submicron particles especially tend to follow the air flow, and would thus be subject to redispersion by turbulence during a separation process [29]. The separation of the particles is a key factor in the profitability of the system. The yield of recovered product increases with increasing efficiency of the separation performance. Thus, the operating parameters of electrostatic precipitation such
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Fig. 7. Left: schematic drawing of the conditioning and the drying step; all dimensions in mm. Right: CAD-drawing of the air distribution (1) with the perforated plate (2).
Fig. 8. Cumulative mass particle size distribution for a 10 wt% mannitol solution, measured by laser diffraction (left) and with the GRIMM particle counter (right).
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as current density and operating voltage have been optimized for the material used in previous work [16,17]. The separation efficiency in the two-stage electrostatic precipitator has already been investigated and optimised in previous tests [16,17]. A discharge electrode with a length of 50 mm at a current density of j ¼ 6:5 mA=m2 and a voltage of about 20 kV delivered a constant deposition rate of higher than 99% in the submicron range for 3 h. The influence of the drying temperature on deposition was investigated for the production of submicron particles as a continuous process. Fig. 10 (left) shows an example of the separation performance in the first three hours for 300 nm mannitol
particles. The drying temperature not only influences the morphology of the resulting particles, but can also determine the degree of separation. In order to maintain the overview, two temperatures ^ C are shown. Higher drying temperatures exhibit a 50 and 110 A
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reduction in separation efficiency of up to 1.5%. This tendency was also confirmed in tests with a drying temperature of 80 °C. The literature distinguishes between two conductivity mechanisms in particle layers: surface and bulk conductivity [30]. Particles generally have a layer of adsorbed water molecules, which form a wet layer on the surface of the particle. If such a particle is charged with electrons, they can move via the surface. This hap-
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Fig. 9. Scanning electron microscopy images of spray dried submicron particles for three drying temperatures. 50 °C (left), 80 °C (middle), 110 °C (right).
Fig. 10. Time dependent separation efficiencies for mannitol particles at various temperatures (left) (av ± s, n = 3). Time dependent separation efficiencies for mannitol particles at a current density of 6.5 mA/m2 negative corona (right) (av, s < 5%, n = 3).
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pens when the resistance of the water is lower than that of the particle. As the temperature increases, the water desorbs, and the surface conductivity decreases. The increase in resistance leads to changes in the charging conditions, and in the worst case can lead to the so-called back corona. In the presence of back corona, the charge in a particle layer can no longer flow down to the electrode for discharge, which creates a potential and leads to microexplosions in the layer, whereby already deposited material can be returned to the air flow. In this case the diminishing effect of surface conductivity occurs. Thus, moderate drying temperatures not only help with the formation of round particles, but also with the separation. In order to compare the new design with previous work, a longterm test was carried out with the model material mannitol in order to determine the maximum deposition time (see Fig. 10, right). Compared to preliminary tests, the separation time in the new design has been increased to approximately 15 h. After 15.5 h the separation for fractions smaller than 1 lm breaks down and a complete recovery of the sprayed material is no longer guaranteed.
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4. Conclusion
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Spray-drying processes for the preparation of submicron-sized particles show limitations regarding small droplets and efficient precipitation. In this work, a previously developed spray-drying concept was used and redesigned. The new design is compact and fits in a pressure resistant vessel. Hence, spray-drying experiments with pharmaceuticals that were dissolved in organic solvents are possible. Here, the spray dryer was characterized with the model substance mannitol in aqueous solution for simplicity of the operation. Compared to the previous design, slightly smaller droplets (d50;3 < 1:7 lm) in the conditioned aerosol were pro-
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duced. Nevertheless, a yield loss was recorded. A maximum atomizing air flow of 2:5 kg=h was determined to prevent droplet entrainment. Reproducible drying conditions were realized with the new drying air distributor. Spray-drying experiments with mannitol were performed and submicron-sized particles were generated.
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Declaration of interest
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None.
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Acknowledgement
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The authors thank Roquette Pharma for providing mannitol, and Monika Meuris (TU Dortmund University) for taking the SEM images. We thank Elizabeth Ely for editing the manuscript. We also want to thank our students Philip da Igreja and Jan Frederik Herzog for their help in the design and characterization of the spray drying device.
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References
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