Microbubbles as Heterogeneous Nucleation Sites for Crystallization in

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Micro-bubbles as heterogeneous nucleation sites for crystallization in continuous microfluidic devices Naghmeh Fatemi, Zhengya Dong, Tom Van Gerven, and Simon Kuhn Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.8b03183 • Publication Date (Web): 10 Dec 2018 Downloaded from http://pubs.acs.org on December 16, 2018

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Micro-bubbles as heterogeneous nucleation sites for crystallization in continuous microfluidic devices Naghmeh Fatemi1, Zhengya Dong1, Tom Van Gerven1, Simon Kuhn1,* 1

KU Leuven, Department of Chemical Engineering, 3001 Leuven, Belgium

KEYWORDS: micro-bubbles, gas-liquid interface, crystallization ABSTRACT: Injecting a stream of micro-bubbles and thereby introducing a heterogeneous interface is proposed for enhancing nucleation and controlling particle formation in continuous microfluidic devices. Different gas and liquid flow rates were investigated to establish the two-phase flow regime map and to identify the optimum characteristics for micro-bubble flow. Subsequently, the effect

of

micro-bubbles

was

studied

for

the

cooling

crystallization

of

paracetamol. An enhanced nucleation rate compared to the operation without bubbles was observed, and the presence of micro-bubbles results in the formation of more crystals, which indicates that nucleation is faster than without bubbles, i.e. the metastable zone width is reduced. Determining the 1 ACS Paragon Plus Environment

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crystal yield confirmed that a larger mass of crystals is obtained in two-phase flow with micro-bubbles. Furthermore, results showed that the presence of micro-bubbles

allows

to

crystallize

continuously

without

important

separation

clogging

of

the

microreactor.

Introduction Crystallization

is

one

of

the

most

and

purification

processes in chemical and especially in pharmaceutical industries1–4. Currently most crystallization processes in industry are based on batch crystallization, however due to the variation of product quality per batch, efforts are done to move to continuous processes instead5. In this respect, microfluidics represents a promising technology due to their enhanced heat and mass transfer rates6–10, which, translated to particle generation, provide control of size, morphology and composition11–13. Furthermore, continuous production of crystals on the micro-scale also potentially enables to link micro-reactors with novel crystal characterization techniques, e.g. XFEL14. However, switching to microfluidics while solids are present in the system introduces the problem of clogging 2 ACS Paragon Plus Environment

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associated with small scale devices15–17. To overcome clogging, solid handling and controlled particle formation inside the microfluidic device are of utmost importance. Two-phase liquid-liquid segmented flow, has been successfully applied to prevent clogging of microchannels11,15,18,19, as encapsulating particles within

dispersed

droplets

limits

their

interaction

with

the

microchannel

surface17,20,21. Immiscible

liquid-liquid

flow

has

also

been

used

for

continuous

sonocrystallization of adipic acid in capillary devices (PFA capillary, ID=1mm, OD=1.5mm). The use of ultrasound and the associated cavitation effect eliminated the need for seeding to induce primary nucleation. However, the use of two phases (hexane and adipic acid/water solution) requires an additional

downstream

separation

process,

and

sonication

results

in

a

temperature rise in the medium due to the dissipated power22. Gas-liquid interfaces also provide lower surface free energy for the particles to accumulate. Subramaniam et al. showed that micron-sized particles accumulate at the immiscible gas-liquid interface due to the lower surface free energy23,24.

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Furthermore, an air-liquid interface was used by Wang et al. to achieve a size-based separation of particles in a microchannel by controlling the speed of the advancing interface25. Small particles (diameter below 100 µm), for which gravitational effects and buoyancy can be neglected, will bind to gasliquid interfaces if the contact angle is not zero26. Pieranski showed that the energy of detachment for spherical polystyrene particles with a diameter of 0.245 µm trapped at a water-air interface is 106 times the thermal energy kBT, and due to this energy well at the interface the particles cannot penetrate to the bulk27. For moving bubbles, particles captured at the interface will dominantly travel to the rear cap due to the fluid-dynamic conditions19. The use of gas bubbles in crystallization was first introduced in 1976 in a US patent from Henkel & Co. for removing tartar from a tartarous beverage. It was proposed that by introducing an inert gas, e.g. nitrogen, into a flow of a supersaturated solution, “there will be an increased boundary surface that increases the probability of the crystallization partners meeting and increases substantially the crystallization process”28.


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Wohlgemuth et al. studied the effect of bubbles on batch cooling crystallization of dodecanedioic acid (DDDA) and adipic acid29,30. For DDDA synthetic air was used to gasify different solutions within the metastable zone via different gassing units: a stainless steel ring with 0.5 mm diameter orifices and a porous ceramic with pore diameters of 10 µm, which produces smaller bubbles at higher frequency29. For adipic acid the effect of ultrasonic irradiation and gassing was compared30. It was found that the gassing can reduce the metastable zone width (MZW) in case of DDDA, while for adipic acid no significant reduction in the MZW was observed. Furthermore, it was proposed that nucleation takes place due to the provided bubble surface resulting in heterogeneous nucleation. Different gassing units (different bubble surface areas) had no influence on the MZW and the induction time, however the gassing unit with larger bubble surface area (porous ceramic) increased the width of the crystal size distribution (CSD). Kleetz et al. observed for the cooling crystallization of succinic acid that gassing enlarges the median crystal diameter

from

70

µm

to

200

µm

while

at

the

same

time

reducing


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agglomeration31.

Lührmann

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et al. showed that gassing a single stage

continuous MSMPR crystallizer (V=50 ml) produces uniform L-alanine crystals with a narrow size distribution compared with the broad size range obtained for uncontrolled spontaneous nucleation32. Segmented gas-liquid flow can also be used for continuous crystallization processes in microfluidic devices. The produced crystals will have limited interactions with their surroundings and therefore prevent clogging inherent to the small scale. In a study carried out by Jiang et al. gas-liquid slug flow was used to design a continuous crystallizer containing three main parts: crystal nucleation, slug formation and crystal growth. The primary nucleation was induced either by mixing hot and cold solution in coaxial or radial geometries or feeding seeds obtained from batch crystallization. Following this nucleation step, air bubbles were added to the flow reactor to enhance mixing and to separate the fluids so no additional liquid-liquid separation step is necessary. Mixing within the slugs resulted in a narrow particle size distribution. With


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nucleation using a coaxial mixer the particle size distribution was narrower within each slug33. Here, we focus on the effects of micro-bubbles as heterogeneous nucleation sites for controlled particle formation in microfluidic devices. Furthermore, the gas phase is easily separated from the resulting suspension and a pure solid material is obtained.

Experimental Section Micro-bubble generation The microreactor used in this study is a horizontal glass capillary with an ID of 1 mm (OD 1.20 mm, tolerance ±10%, CM Scientific) with a total length of 10 cm. A microfluidic PEEK T- junction (IDEX) is used to bring the liquid and the gas in contact. As gas inlet, a silica infused capillary (ID 20 µm, L=5cm, Polymicro technologies) is inserted and sealed into the horizontal branch of the T-junction, so that it is centered in the glass capillary in which it slightly protrudes, effectively creating a co-flow geometry. Distilled water at room temperature is pumped via an HPLC pump (UHP-CP Legacy, Teledyne SSI)


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to the T-junction and the Nitrogen (99%, Air Liquide) flow rate was controlled by a mass flow controller (Bronkhorst, EL-Flow®, ±0.02- 2 ml/min N2).

A

schematic view of the setup is shown in Figure 1(a).

(a)

(b)

Figure 1. (a) Experimental setup to study the micro-bubble generation. The gas and liquid are introduced to the reactor via a T-junction. The reactor is a glass capillary with an inner diameter of 1 mm. Images are taken with a highspeed camera. (b) Experimental setup for crystallization: (1) feed solution, (2) water for cleaning the system and (3) sample collection; gas and liquid are 8 ACS Paragon Plus Environment

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introduced to the reactor via a T-junction. Samples are analyzed offline with a laser diffractometer.

To establish the flow regime map, the generated bubbles are recorded with a high-speed camera (Photron FASTCAM Mini UX100) equipped with a microlens (NAVITAR 1-50486). The reactor was placed in a rectangular glass box filled with glycerol to correct for the refractive index and to minimize image distortion. Images were recorded in the middle of the reactor capturing a total length of 2

cm (20 times the tube inner diameter) in the flow direction.

Images are taken with a frame rate of 1000 frames/s at a resolution of 1280x480 pixels. During imaging the microchannel is illuminated with a white light source (SCHOTT KL 2500 LED).

Crystallization A schematic of the experimental setup for the crystallization study is shown in Figure 1(b). Instead of an HPLC pump, a centrifugal micropump (TCS Micropumps, M100S-180-V) was used. The tubing leading from the pump to


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the T-junction was insulated and heating elements (Omega, Kapton insulated flexible heater, 28 Volts) were added to ensure that the solution temperature at the T-junction did not drop below the saturation temperature34. In addition to the thermocouple (Omega, Type K, SC-GG-K-30-36) upstream of the liquid inlet, another thermocouple is installed at the microreactor outlet to record the reduction in temperature via a thermometer (HH374, Omega 4-channel data logger thermometer (accuracy ±0.1%)) and the corresponding supersaturation profile. The supersaturation ratio inside the reactor is defined as the ratio of the

solubility

at

the

local

temperature

to

the

solubility

at

the

outlet

temperature. However, the supersaturation ratio for the feed solution is defined as the ratio of the solubility at the specified feed temperature to the solubility at room temperature. Knowledge of the outlet temperature is also important as the outflowing solution is collected in 6 mL of saturated paracetamol solution at this outlet temperature, to prevent further nucleation and to allow crystals only to grow over a certain period of time. Furthermore, a microfluidic


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pressure sensor (PS1-1bar, Elveflow) was installed upstream of the liquid inlet to record the pressure drop and to detect clogging. The paracetamol starting solution was prepared by dissolving 4 g of 4acetamidophenol (98%, Acros Organics) in 200 mL ultra-pure water, which corresponds to a supersaturation of 1.86 at T=22 ºC (room temperature)34. The solution is heated to 80 ºC and stirred for at least half an hour and filtered afterwards (pore size 5-13 µm) to remove any particular substance. During the experiment, the starting solution is constantly stirred on a heating plate kept at 80 ºC. Samples are collected for 5 reactor volumes (3 ml), and the CSD is measured off-line using a laser diffractometer. For this, samples are subsequently injected into a particle size analyzer (Malvern Mastersizer 3000, small volume HYDRO SV). The first sample is inserted 1 min after 5 reactor volumes are collected, and additional samples are injected after 3 min and 6 min giving the crystals 4 and 7 minutes of growth time in total to characterize the particle growth. These growth times are dictated by the required time to prepare the


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sample injection into the laser diffractometer. After each experiment the setup is washed with warm water to empty the reactor and dissolve any remaining crystals. Results and Discussion Micro-bubble formation In a first step, the effect of the gas and liquid flow rates on the bubble generation was investigated. Figure 2 depicts snapshots of the formed bubbles for a fixed gas flow rate of G=0.05 from 0.02 to 10

ml/min and increasing liquid flow rates L

ml/min. It is observed that with increasing liquid flow rate the

formed bubbles become smaller, transitioning from slug flow to bubble flow. The obtained flow regime map is depicted in Fig S1 in the Supporting Information.


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Figure 2. Effect of the liquid flow rate L on the size of the generated bubbles. Images are obtained for a gas flow rate of G=0.05 ml/min and liquid flow rates L of (a) 0.02

ml/min, (b) 0.05 ml/min, (c) 0.1 ml/min, (d) 0.2 ml/min,

(e) 0.4 ml/min, (f) 0.5 ml/min, (g) 0.6 ml/min, (h) 0.8 ml/min, (i) 1 ml/min, (j) 2 ml/min, (k) 3 ml/min, (l) 5 ml/min, (m) 10 ml/min. The black indicator on the capillary denotes a distance of 5 cm from the inlet of the microreactor.

For crystallization, the microreactor will be operated within the bubble flow regime, and as the bubbles will introduce a heterogeneous interface for nucleation the effect of the gas and liquid flow rates on the gas-liquid interfacial area was investigated next.


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The total bubble surface area per unit volume of reactor, a [mm2/mm3], is related to the bubble diameter dB and the number of bubbles, n, present in the reactor volume, VR: 4𝑑2𝐵

𝐴

eq(1)

𝑎 = 𝑉𝑅𝑛 = 𝐷2𝐿𝑛

where A denotes the surface area per bubble, D the reactor diameter, and L its length. The number of bubbles present in the reactor volume depends on their frequency of generation, f, and their residence time 𝑡𝑏 eq(2)

𝑛 = 𝑓 𝑡𝑏 The

bubble

residence

time

can

be

calculated

from

the

experimentally

determined bubble velocity vB, according to 𝐿

eq(3)

𝑡𝑏 = 𝑣𝐵

Combining equations 1-3, the bubble surface area per unit volume of reactor can be calculated from variables accessible from high-speed imaging, namely the bubble diameter, dB, the bubble velocity, vB, and the bubble generation frequency, f:


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𝑎=

4𝑑2𝐵𝑓

eq(4)

𝑣𝐵𝐷2

These variables were extracted from the images captured by the high-speed camera using an in-house generated Matlab script35 and the PFA analysis software (Photron FASTCAM Analysis ver.1.3.2). The bubble diameter dB is depicted in Figure 3(a), and it is observed that the size of the bubbles is not strongly dependent on the gas flow rate but more on the liquid flow rate. The bubble break-up at the tip of the inserted capillary is influenced by the shear force exerted by the liquid phase, which explains this observation. However, with increasing gas flow rates also larger liquid flow rates are necessary to achieve bubble flow (see Figure 3). Increasing the gas flow rate will primarily affect the bubble generation frequency, f, which is depicted in Figure 3(b). At a constant liquid flow rate, increasing the gas flow rate will lead to the formation of more bubbles of the similar size. This interplay between bubble diameter and bubble generation frequency will result in different bubble velocities vB, which are plotted in Figure 3(c). Increasing either the gas or the liquid flow rate will result in increased bubble velocities. 15 ACS Paragon Plus Environment

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The experimental determination of these three variables allows to calculate the bubble surface area per reactor volume a, which is plotted in Figure 3(d). For the same gas flow rate, by increasing the liquid flow rate the surface area decreases. On the contrary for the same liquid flow rate, by increasing the gas flow rate, the surface area increases. Hence, a wide range of interfacial areas are accessible depending on the chosen gas and liquid flow rate. In Figure 3(a) the liquid flow rate is varied up to a maximum value of 10 ml/min to highlight that micro-bubbles as small as 0.4 mm can be generated at elevated liquid flow rates. However, in Figure 3(b)-(d) the liquid flow rate is limited at 2 ml/min to provide sufficient residence time in the reactor. For the crystallization experiments different gas flow rates between 0.05 and 0.2 ml/min were chosen to investigate the effect of different surface areas on nucleation, and the liquid flow rates were fixed at 0.5 and 1 ml/min to investigate the effect of residence time.


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(b)

Bubble diameter dB [mm]

1.2

G0.02 G0.05 G0.2

1 0.8 0.6 0.4 0.2 0 0.0

5.0 10.0 Liquid flow rate L [ml/min]

15.0

12

G0.02 G0.05 G0.2

10 8 6 4 2 0 0.0


3.0

(d) 70

G0.02 G0.05 G0.2

60 50 40 30 20 10 0 0.0


3.0

1.5 Bubble surface area per unit volume of reactor a [mm2/mm3]

(c)

Bubble generation frequency f [1/s]

(a)

Bubble velocity vB [mm/s]

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

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G0.02 G0.5 G0.2

1.0

0.5

0.0 0.0

1.0 2.0 Liquid flowrate L [ml/min]

3.0

Figure 3. Effect of gas and liquid flow rates on (a) size of the micro-bubbles, (b) frequency of micro-bubble generation, (c) micro-bubble velocity, (d) microbubble surface area per unit volume of the reactor for different liquid flow rates and at gas flow rates G of (

) 0.02 ml/min,

( ) 0.05 ml/min and ( ) 0.2 ml/min.

In addition to extracting the bubble velocity, a slip analysis was carried out to determine the relative velocity between the dispersed gas phase and the


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continuous liquid phase. In case of no slip, the two phases would travel at the same velocity within the reactor, and consequently both phases have the same residence time. However, our experiments show that the bubbles slip and possess slightly higher velocities than the bulk liquid velocity, with an estimated slip ratio of 1.25 (see section S1 in the Supporting Information).

Micro-bubbles as heterogeneous nucleation sites Crystallization under stagnant conditions

To identify the location of crystal formation preliminary experiments were performed in stagnant conditions. For this, the reactor was filled with a supersaturated solution (with a supersaturation ratio of S=2.14 at room temperature) and a different number of bubbles was injected. The reactor was then sealed and observed under the microscope (SZ25 Nikon). It was found that crystallization indeed occurs at the gas-liquid interface, see the snapshots in Figure 4 (a)-(d) and (e)-(h). Some crystals are also observed in the bulk solution, however, over time they will also attach at the gas-liquid interphase due to its lower free energy, see Figure 4(i) to (l). As such, these preliminary


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experiments support that the presence of the gas-liquid interface affects the crystallization. Therefore, the continuous crystallization of paracetamol in single phase and two-phase bubble flow was investigated next.

Figure 4. Crystallization of paracetamol under stagnant conditions with supersaturation degree of S=2.14 at T=22°C. Crystal growth in the bulk and at the interface for one bubble after (a) 20 min, (b) 24 min, (c) 35 min and (d) 46 min; Crystal growth in the bulk and at the interface for another bubble after (e) 6 min, (f) 12 min, (g) 18 min and (h) 25 min; crystal forming in the bulk solution and afterwards attaching to the gas-liquid interface due to its lower free energy, snapshots after (i) 8 min, (j) 16 min, (k) 25 min and (l) 35 min.


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Continuous crystallization at a constant gas flow rate and varying liquid flow rates

The effect of bubbles on the continuous crystallization of paracetamol was investigated by comparing the obtained crystal size distributions (CSD) for liquid flow rates of 0.5 and 1 ml/min with and without formed micro-bubbles for a supersaturated solution with supersaturation ratio of S=1.81. For the cases with bubbles, the gas flow rate was fixed to 0.05 ml/min. Figure 5 depicts the CSD for a liquid flow rate of 0.5 ml/min with and without microbubbles present. The number density distribution is calculated from the measured volume distribution using a shape factor of 0.8, which represents plate-like crystals commonly observed for

36–38.

Adding the micro-bubbles

results in larger crystals at identical residence and growth times, which indicates that nucleation is induced earlier (reduced induction time) and that the gas-bubble interface acts as a heterogeneous nucleation site. This finding is independent of the applied liquid flow rate, as shown in Figure 6, which depicts the volume and number density distributions for a liquid flow rate of 1 ml/min. Increasing the liquid flow rate results in smaller crystal sizes as the


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residence time (and therefore the time for nucleation) is reduced. Furthermore, the total bubble surface area per reactor volume is decreasing with higher liquid flow rates (see Figure 3(d)). SEM images confirm that the presence of the bubbles does not affect the crystal morphology, thus it can be concluded that they solely promote heterogeneous nucleation, see Figure 7. The crystals have a plate-like shape which is expected for higher supersaturations36. From the SEM images the only polymorph formed is the monoclinic form I39. Furthermore, the temperature profile and the supersaturation profile along the reactor for these continuous crystallization experiments are provided in section S2 in the Supporting Information.


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(a) 18

with bubble no bubble

Volume Density [%]

16 14 12 10 8 6 4 2 0 0

100

200 300 Crytal size [µm]

400

500

(b) 18


16 Number Density [%]

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

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14 12 10 8 6 4 2 0 0

20

40 Crystal size [µm]

60

80

Figure 5. Effect of micro-bubbles on the crystal size distribution for a growth time of 1 minute and a supersaturation of S=1.81: (a) volume density, (b) number density. The liquid flow rate was L=0.5 ml/min, and the gas flow rate

G=0.05 ml/min. The dashed line shows the resulting size distributions without any micro-bubbles and the continuous line with micro-bubbles.


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(a) 18


Volume Density [%]

16 14 12 10 8 6 4 2 0 0

100

200 300 Crystal size [µm]

400

500

(b) 18


16 Number Density [%]

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

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14 12 10 8 6 4 2 0 0

20 Crystal size [µm] 40

60

Figure 6. Effect of micro-bubbles on the crystal size distribution for a growth time of 1 minute and a supersaturation of S=1.81: (a) volume density, (b) number density. The liquid flow rate was L=1 ml/min, and the gas flow rate

G=0.05 ml/min. The dashed line shows the resulting size distributions without any micro-bubbles and the continuous line with micro-bubbles.


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Figure 7. SEM images of paracetamol crystals after 1 minute growth time. (a), (b), (c): with micro-bubbles (G=0.05 ml/min; L=1 ml/min); (d), (e), (f): without micro-bubbles (L=1 ml/min).

To quantify the obtained crystal sizes, Table 1 shows the mean crystal size based on volume, Dv(50), together with the Dv(10) and Dv(90) values, denoting that 10, respectively 90 percent of the crystals are below a certain size. Furthermore, the span of the CSD is calculated as

𝑆𝑝𝑎𝑛 =

𝐷𝑣(90) ― 𝐷𝑣(10) 𝐷𝑣(50)

eq( 5)


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For a liquid flow rate of 0.5 ml/min, the mean crystal size after 1 min of growth is 113 µm when the micro-bubbles are added, and 25 µm without, representing a decrease in the mean size by a factor of 4.5. This decrease is less pronounced for the higher liquid flow rate of 1 ml/min, where the Dv(50) reduces from 48 µm with micro-bubbles to 14 µm without. While the presence of bubbles increases the obtainable crystal size, it also broadens the CSD as quantified by the value of the span. While there is only a small increase in the span upon addition of micro-bubbles for the liquid flow rate of 0.5 ml/min, increasing the liquid flow rate to 1 ml/min increases the span by 50%. As mentioned above, the crystals flowing out of the reactor are collected in a saturated solution, which stops nucleation but still allows for crystal growth. A potential explanation for this observed increase in the span is therefore that at larger residence times (lower liquid flow rates) the formed initial crystals have more time to aggregate and grow in the reactor (and collection vessel), and therefore the CSD is skewed towards smaller sizes when increasing the liquid


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flow rate. To address this, we determined the CSD for different growth times of 1, 4, and 7 min, respectively.

Table 1. Effect of micro-bubbles and varying liquid flow rates on the Dv() values of the crystal size distribution for a gas flow rate G=0.05

ml/min and

a growth time of 1 min.

with bubble no bubble with bubble no bubble

Liquid flow rate

Dv(10)

Dv(50)

Dv(90)

[ml/min]

(µm)

(µm)

(µm)

0.5 0.5 1 1

28.26 11.35 14.42 7.30

112.81 25.23 48.07 13.96

270.06 58.38 162.34 35.69

Span

2.14 1.86 3.07 2.03

Figure 8 depicts the CSD for these different growth times for the liquid flow rate of 1 ml/min and a gas flow rate of 0.05 ml/min when the micro-bubbles are added. After 4 minutes of growth the mean crystal sizes increase to 171 µm with micro-bubbles and to 59 µm without. These mean sizes increase further for 7 minute growth time to 191 µm with micro-bubbles and to 115 µm without. Consequently, nucleation in the presence of micro-bubbles results in larger crystal sizes also during growth, but the relative difference in size becomes smaller, which indicates that the growth rate is larger compared to the nucleation rate. Furthermore, with increasing growth time the CSD


Page 27 of 63

becomes more symmetric, reducing the tail towards larger crystal sizes especially

for

the

crystallization

with

micro-bubbles.

This

indicates

size

dependent growth rates and agglomeration of smaller crystals during growth. As a consequence, the span of the CSD with and without added microbubbles are approaching each other.

10

Volume Density [%]

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

Langmuir

with bubble, 1 min growth no bubble, 1 min growth with bubble, 4 min growth no bubble, 4 min growth with bubble, 7 min growth no bubble, 7 min growth

8 6 4 2 0 0

200


600

Figure 8. Effect of the growth time on the CSD for crystallization with (G=0.05 ml/min; L=1 ml/min) and without (L=1

ml/min) micro-bubbles at a

supersaturation ratio of S=1.81. Continuous crystallization at a constant liquid flow rate and varying gas flow rates

The effect of different gas flow rates was investigated next by keeping the liquid flow rate constant at 1 ml/min for a supersaturated solution at S=1.81 at room temperature. The two additional gas flow rates investigated are 0.1 and 27 ACS Paragon Plus Environment

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0.2 ml/min, which results in a higher frequency of bubble generation and a larger bubble surface area (see Figure 3). However, at these elevated gas flow rates not enough crystals were detected by the laser diffractometer for a growth time of 1 min, hence the CSD was evaluated for growth times of 4 and 7 min, respectively (see Figure 9). As it is observed in Figure 9(a), for a growth time of 4 minutes the mean crystal size decreases when increasing the gas flow rate. For a gas flow rate of 0.2 ml/min, the measured CSD is very similar to the case without bubbles, resulting in a slightly larger mean crystal size Dv(50) of 68 µm with micro-bubbles compared to 60 µm without. This observation is explained via the interplay of the increase in interfacial area and the decrease in bubble residence time. The bubble surface area per reactor volume, a, increases with increasing gas flow rate (Figure 3(d)), creating more surface for nucleation to occur, potentially resulting in an increased number of formed nuclei. These nuclei will stay a shorter time inside the tubular reactor, as with increasing gas flow rate the slip of the bubbles increases as well to a value of 1.31, resulting in an even further


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reduced bubble residence time. The combination of these 2 effects will result in smaller crystals leaving the reactor, which will be initially not detectable with the laser diffractometer used in this study. This explanation is in line with the afore mentioned observation that after a growth time of 1 min no crystals could be detected in the laser diffractometer, but when increasing the growth time further to 7 min, Figure 9b) clearly indicates larger crystal sizes for all crystallization cases in the presence of micro-bubbles.


Langmuir

(a)

Volume Density [%]

10

with bubble-G0.05 with bubble-G0.1 with bubble-G0.2 no bubble

8 6

4 min growth

4 2 0 0

200


600

800

(b) 10 Volume Density [%]

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

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with bubble-G0.05 with bubble-G0.1 with bubble-G0.2 no bubble 7 min growth

5

0 0

200


600

800

Figure 9. Effect of varying gas flow rates on the CSD at a liquid flow rate of

L=1 ml/min and at a supersaturation ratio of S=1.81 for a growth time of (a) 4 min and (b) 7 min. To

quantify

this

observation,

the

produced

crystals

were

collected

and

weighted to determine the crystal yield. For this, the samples were collected in a saturated solution at the outlet temperature and afterwards filtered (pore size 0.45µm) using a vacuum pump. The filter was dried overnight in an oven at 30 ACS Paragon Plus Environment

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50ºC and subsequently weighed (see Table 2). The results show that for both considered liquid flow rates adding micro-bubbles at a gas flow rate of 0.05 ml/min more than doubles the crystal yield compared to the single phase crystallization. However, at a liquid flow rate of 1

ml/min, increasing the gas

flow rate even further to 0.2 ml/min results in a decrease in the crystal yield even below the single phase crystallization values. Despite the fact that by increasing the gas flow rate the surface area for nucleation increases, it also drastically reduces the residence time in the reactor, as well as the available liquid volume for nucleation to occur.

Table 2. Crystal weight and yield for different liquid and gas flow rates. Liquid flow rate

Gas flow rate

Weight

Yield

[ml/min]

[ml/min]

[mg/ml]

[%]

0.5 0.5 1 1 1

0.05 No bubble 0.05 0.2 No bubble

0.45±0.05 0.20±0.06 0.33±0.07 0.02±0.01 0.15±0.01

4.67±0.55 2.04±0.64 3.42±0.78 0.29±0.12 1.56±0.16

Using micro-bubbles to prevent clogging


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Using micro-bubbles to prevent clogging was investigated for a liquid flow rate of 1 ml/min and a gas flow rate of 0.05 ml/min. The crystallization was run continuously at a supersaturation ratio of S=1.81 while recording the pressure in the liquid line upstream of the T-junction over time. It is worth noting that the working principle of the used micro-pumps is to establish a certain pressure level, thus if the pressure drop over the reactor exceeds this value the flow will stop resulting in a sharp decrease of measured pressure. Figure 10(a) depicts this recorded pressure over time for the crystallization with (black line) and without (grey line) micro-bubbles. Without bubbles, the system will clog after almost 30 minutes of continuous operation, while in the presence of micro-bubbles continuous crystallization was possible without any clogging for the entire duration of 70 min. For the system without bubbles the surface of the capillary was covered with crystals restricting its cross-sectional area and increasing the pressure drop above the pump specification (see Figure 10(b)). These experiments prove that the bubbles induce nucleation (resulting in a


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higher crystal yield) and at the same time act as transport vehicle for the formed crystals, effectively preventing wall attachment (clogging prevention).

(a) 16 14 Gauge pressure[mbar]

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

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With

12

bubble

10 8 6 4

no bubble

2 0 0

10

20

30 40 Operational time[min]

50

60

70

(b)

Figure 10. (a) Reactor inlet pressure for the continuous crystallization with (G=0.05 ml/min; L=1 ml/min) and without (L=1 ml/min) micro-bubbles at a supersaturation ratio of S=1.81. (b) Images of wall-attached crystals inside the


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reactor for the continuous crystallization without micro-bubbles at a liquid flow rate of L=1 ml/min and a supersaturation ratio of S=1.81.

Conclusions The effect of micro-bubbles on the cooling crystallization of paracetamol in a tubular microreactor was investigated. The effect of the applied gas and liquid flow rates on the resulting bubble diameter, bubble generation frequency, and the bubble surface area was investigated. This allowed to identify the optimum operating conditions for the continuous crystallization experiments to ensure sufficient residence time in the nucleation section and providing a large bubble surface area. The smallest micro-bubbles were observed at large liquid flow rates, however at these conditions the supersaturated solution will not spend enough time in the reactor for nucleation to occur. The continuous crystallization experiments provided proof that the microbubbles act as a heterogeneous nucleation site. In the presence of microbubbles, the measured crystal size distributions revealed the formation of


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larger crystals compared to the single phase crystallization. Furthermore, quantifying the crystal yield showed an increase by more than a factor of 2 in the presence of micro-bubbles. These results allow the conclusion that the low-energy heterogeneous surface introduced by the bubbles promotes crystal nucleation. Furthermore, SEM images revealed that the gas phase does not alter the crystal shape or morphology. However, increasing the gas flow rate to introduce an even larger surface area for nucleation is counteracted by the adverse effects of decreasing the residence time in the nucleation zone and reducing the liquid volume for nucleation. Our results reveal an optimum operation range at gas to liquid flow rate ratios of 0.05-0.1. In addition, adding micro-bubbles enables the continuous crystallization for long operating times, as the bubbles act as carriers for the formed crystals and effectively prevent wall deposition and thus clogging. The presented methodology for the continuous crystallization of paracetamol as a model API compound can be extended to additional systems, e.g. the crystallization of other organic (macro)molecules and precipitation reactions.


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Acknowledgments We acknowledge funding from the European Research Council under the ERC Starting Grant Agreement n.677169– Micro Particle Control. We thank Senne Fransen for providing the Matlab source code for analyzing the high-speed camera images.

Supporting Information Flow regime map and details for the calculation of the temperature and supersaturation profiles along the reactor

Nomenclature Abbreviations

L

Liquid flowrate [ml/min]

CSD

Crystal Size Distribution

ID

Inside diameter

𝑚 n

OD

Outside Diameter

R0

Reactor Diameter

S

Supersaturation ratio

Roman symbols a

Surface

area

per

volume[mm2/mm3] A

Surface area per bubble[mm2]

Cp

Heat capacity

dB

Bubble diameter

unit tb TB F

U

Mass flowrate [kg/s] Number of bubbles

Bubble residence time Temperature of the bulk flow [K] Overall

heat

transfer

coefficient vB

Bubble velocity [mm/s] 36

ACS Paragon Plus Environment

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D

Reactor diameter

Dv(x

x

)

below a certain size

f

Frequency [1/s]

Greek symbols

L

Gas flowrate [ml/min]

ρ

percent

of

the

crystals

VR

are vZ

Reactor volume Fluid

velocity

in

axial

direction Density [kg/m3]


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78x63mm (300 x 300 DPI)


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Langmuir

76x63mm (300 x 300 DPI)


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

79x64mm (300 x 300 DPI)


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Langmuir

338x190mm (300 x 300 DPI)


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

168x94mm (300 x 300 DPI)


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Langmuir

155x93mm (300 x 300 DPI)


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

114x70mm (300 x 300 DPI)


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Langmuir

121x72mm (300 x 300 DPI)


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

149x159mm (300 x 300 DPI)


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Langmuir

140x80mm (300 x 300 DPI)


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

137x65mm (300 x 300 DPI)


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Langmuir

139x64mm (300 x 300 DPI)


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

132x81mm (300 x 300 DPI)


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Langmuir

184x75mm (300 x 300 DPI)


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