Insights into Design Criteria for a Continuous Sonicated Modular

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Insights into Design Criteria for a Continuous Sonicated Modular Tubular Cooling Crystallizer Bing Han, Nnaemeka C. Ezeanowi, Tuomas O. Koiranen, Antti T. Hakkinen, and Marjatta Louhi-Kultanen Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b00700 • Publication Date (Web): 24 Oct 2018 Downloaded from http://pubs.acs.org on October 24, 2018

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Crystal Growth & Design

1

Insights into Design Criteria for a Continuous

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Sonicated Modular Tubular Cooling Crystallizer

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Bing Han1,2, Nnaemeka C. Ezeanowi*,1, Tuomas O. Koiranen*,1, Antti T. Häkkinen1, Marjatta

4

Louhi-Kultanen2

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1School

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of Engineering Science, Lappeenranta University of Technology, P.O. Box 20, FIN53851 Lappeenranta, Finland

2School

of Chemical Engineering, Aalto University, P.O. Box 16100, FI-00076 Aalto (Espoo),

8

Finland

9 10

ABSTRACT: A new designed sonicated continuous modular crystallizer was investigated and

11

developed. The concept and design criteria for the designed crystallizer were examined and studied

12

in cooling crystallization process with three model compounds which were K2SO4, CuSO4 and

13

phthalic acid. Results showed that ultrasound had significant effects, which can enhance the

14

nucleation and avoid clogging in the tubular crystallizer. The present work shows the obtained

15

results when different cooling strategies were studied. Equal supersaturation throughout the

16

crystallization process was the best solution for designing temperature profiles for the modules. In

17

addition to cooling strategy, the residence time is one of the key factors to get feasible operating

18

conditions in the designed crystallizer. Higher yields using ultrasound with phthalic acid

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crystallization as a model compound were obtained compared to classical tubular flow reactor.

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*Tuomas O. Koiranen School of Engineering Science, Lappeenranta University of Technology, P.O. Box 20, FIN-53851, Lappeenranta, Finland. E-mail: [email protected] Phone number: +358 50 4357414

*Nnaemeka C. Ezeanowi School of Engineering Science, Lappeenranta University of Technology, P.O. Box 20, FIN-53851, Lappeenranta, Finland. E-mail: [email protected]

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Crystal Growth & Design 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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Louhi-Kultanen2

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1School

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of Engineering Science, Lappeenranta University of Technology, P.O. Box 20, FIN53851 Lappeenranta, Finland

2School

of Chemical Engineering, Aalto University, P.O. Box 16100, FI-00076 Aalto (Espoo), Finland

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*E-mail: [email protected], [email protected]

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ABSTRACT: A new designed sonicated continuous modular crystallizer was investigated and

37

developed. The concept and design criteria for the designed crystallizer were examined and studied

38

in cooling crystallization process with three model compounds which were K2SO4, CuSO4 and

39

phthalic acid. Results showed that ultrasound had significant effects, which can enhance the

40

nucleation and avoid clogging in the tubular crystallizer. The present work shows the obtained

41

results when different cooling strategies were studied. Equal supersaturation throughout the

42

crystallization process was the best solution for designing temperature profiles for the modules. In

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addition to cooling strategy, the residence time is one of the key factors to get feasible operating

44

conditions in the designed crystallizer. Higher yields using ultrasound with phthalic acid

45

crystallization as a model compound were obtained compared to classical tubular flow reactor. 2 ACS Paragon Plus Environment

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Keywords: Continuous crystallization; Modular crystallizer; Tubular flow; Ultrasound

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1. INTRODUCTION

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When compared with batch or semi-batch crystallization process modes, continuous

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crystallization has many advantages such as smaller volumes required, higher efficiency, higher

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product reproducibility, less cost of labor and operation, and higher flexibility.1,2 All of these are

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considerably important for obtaining reproducible and narrow crystal size distributions, uniform

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particles and specific crystal morphologies. Various designs of continuous pipe crystallizers are

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nowadays getting much more popular than the mixed-suspension mixed-product-removal

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crystallizers because crystal classification effects can be minimized in the tubular reactor.

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Additionally, the scale up is much easier with continuous plug flow crystallizer. However,

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Hohmann et al.3 have pointed out the problematics of clogging and pipe blocking which can be

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minimized using seed generating systems.

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One of the most popular continuous tubular flow crystallizer is the continuous oscillatory baffled

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crystallizer (COBC).2,4 Uniform products can be achieved with plug flow by proper control of

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nucleation and crystal growth rate. With the control of frequency and amplitude of the oscillation,

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particle fluidization and a narrow residence time distribution can be achieved due to intensive

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macro-structure tubular mixing. Meanwhile, the particle size is affected by the set-up and

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operational conditions. NiTech® Solutions Limited5 developed these kinds of crystallizers with

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different size suitable for various application such as chemical synthesis and crystallization.

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Kacker et al.6 investigated residence time distribution of dispersed liquid and solid phase in a

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commercial COBC from NiTech Solutions® and pointed out that operation at relative low

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amplitudes leads to optimal plug flow behavior. 3 ACS Paragon Plus Environment


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To overcome the challenge of curve cooling in plug flow crystallization, Hohmann et al.3 designed

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a continuous cooling crystallization on lab scale by applying the concept of a coiled flow inverter

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(CFI) based on blended helically coiled tubes. Linear cooling or curve cooling employed with

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counter-current air cooling can be operated with this device. Recently, Hohmann et al.7 also

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analyzed the effect of crystal size dispersion in the designed tubular crystallizer by experiments

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and modeling and found that crystal growth and growth rate dispersion were both dominating the

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product size distribution. A narrow product size distribution can be obtained and revealed by

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simulation when using CFI crystallizer in homogeneous suspension flow regime. Small volume

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mean diameters due to decreased tendency of agglomeration and reduced time for crystal growth

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can be obtained at higher flow velocities8. On the other hand, a clear fact is that crystal size

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decreases as sonication time increases.9 In ultrasound assisted continuous tubular reactors

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sonication is manipulated by changing residence time.

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Ultrasound has been used in many areas including medical diagnostics, thermoplastic welding,

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cleaning of surfaces, wastewater treatment and food industry.10 It has also been employed in new

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fields such as preparation of amorphous and nanostructured materials.11,12 Recently, the use of

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sonocrystallization, that is crystallization assisted by ultrasound, in pharmaceutical and fine

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chemical industry has attracted more interest of researchers because of the viability of this

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technology. In addition, Zhang et al.13 had earlier reviewed the progress of continuous

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crystallization in pharmaceuticals. Sonocrystallization is considered as an easy to use and easy to

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control technique, and the end product with target crystal size, shape and polymorphs can be

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obtained.14 That is because the metastable zone width (MZW) can be narrowed by introducing

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ultrasound, and ultrasound can disrupt the formed crystal aggregates.1 Furthermore, the effects of

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ultrasound on crystal growth was theoretically studied in literature15 and was pointed out that the 4 ACS Paragon Plus Environment

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growth rate depends on the magnitude of the supersaturation driving force. Arakelyan15 also

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highlighted that the crystal growth rate can be doubled at low supersaturation by ultrasound,

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whereas there is no remarkable effect at high supersaturation. Induction time can also be affected

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by ultrasound, as induction time decreases with increase in ultrasound power.16 Besides these, the

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use of ultrasound can not only reduce the crystallization time but can also offer a clean and efficient

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tool to improve the existing process.

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Some studies have demonstrated that the use of ultrasound can drastically reduce fouling in

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microchannel heat exchangers because of flow changes of the particle suspensions.17-20 As

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proposed by Rossi et al.,19 transient cavitation of bubbles induced by sonication played a

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significant role for promoting nucleation with observations from the experiments and numerical

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simulations. Recently, a sonicated tubular crystallization system, to control particle size without

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clogging, was successfully designed and specified for an active pharmaceutical ingredient (API)

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compound.21 In addition, a crystallizer cascade can offer economic advantages over a single-body

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crystallizer of the same volume.22 Several continuous MSMPR multistage cooling crystallizers

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have been reported in literature.23-25 Furthermore, Siddique et al.26 successfully applied sonication

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to initialize crystallization in COBC without fouling or agglomeration issues for lactose. However,

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the yield was relatively low compared to when operated with a sonicated batch crystallizer due to

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insufficient seeds produced by limited ultrasound power. Continuous sonocrystallization of

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acetylsalicylic acid in a tubular crystallizer with multiple cooling sections has been investigated in

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literatures.27,28 Ultrasound was used at the initial period to generate seed crystals before multiple

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cooling stages in their system.

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Lawton et al.2 have demonstrated continuous plug flow crystallizer operation with oscillatory

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baffled reactor (OBR), and Ruecroft & Burns29 have made patent application combining 5 ACS Paragon Plus Environment


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ultrasound and pipe modules for antisolvent crystallization. This is different from the current

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research work where ultrasound is applied continuously to each cooling stage. To our best

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knowledge, the cooling strategies of continuous tubular flow crystallization integrated with

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ultrasound have not been studied widely. Therefore, in the present work the ultrasound technology

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and continuous modular crystallization are combined to investigate operational availability of the

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whole process and crystal properties with different selected model compounds in order to design

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a tubular crystallizer for a specific application. It is expected to overcome the challenges of channel

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clogging and suspension pumping with ultrasound in the designed continuous tubular flow

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crystallizer. Three model compounds comprising of inorganic and organic substances were

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selected to investigate the design criteria for the ultrasonically assisted crystallizer concerning

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cooling crystallization.

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2. EXPERIMENTAL SECTION

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2.1 Materials

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Three model compounds, K2SO4 (≥ 99 % purity), CuSO4 (100 % purity) and phthalic acid (99

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% purity) with analytical grade, were used in the crystallization experiments of the present work.

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Deionized water was used as the solvent for all the compounds.

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2.2 Experimental set-up and method

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The experimental set-up shown in Figure 1 consisted of a stirred feed tank, a peristaltic pump

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(Masterflex Pump Easy Load II 77201-62), three modular crystallizers separately immersed into

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three ultrasound baths (Bandelin sonorex digitec DT102H, 35 kHz) equipped with thermostats

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(Lauda), and a collection unit. The feed tank was a jacketed glass reactor with a capacity of 4.5 L 6 ACS Paragon Plus Environment

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equipped with a pitched blade turbine impeller and a thermostat (Lauda). A modular crystallizer

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was made from a spiraled EN 1.4307 / AISI 304 L stainless steel pipe, which was 12 m or 18 m in

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length (depending on the experiment), had an inner diameter of 4 mm and 1 mm wall thickness.

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No polishing was done to the inner walls of the pipe. Each 12 m stainless steel pipe was wound in

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an oval shape of 14 cm in length and 9.5 cm in width, whereas the 18m stainless steel pipes were

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wound in an oval shape of 17.5 cm in length and 10.5 cm in width. The wound pipes were placed

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into a 3L ultrasound bath for each module. Three modules with same configuration were installed

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in series.

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A certain amount of saturated solution was firstly prepared in the feed tank at temperature which

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was 5.0 °C higher than the equilibrium temperature of the saturated solution in order to dissolve

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all the solids at the beginning. The temperature of the feed solution was controlled by a thermostat.

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Different temperatures were set at each modular tubular crystallizer according to the designed

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cooling strategy. The final outlet temperature of the crystallized solution was fixed at 20.0 °C.

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Before the experiment, thermostats and ultrasound baths were started to keep the temperature and

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ultrasound power steady in the modular crystallizers. The feed solution was pumped by a peristaltic

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pump to the first, second and third modular tubular crystallizers serially. If the process can be

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operated without clogging for three or more times of residence time, then it was defined as a

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feasible operating condition.

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Finally, the suspensions were filtered with a vacuum filter and the crystals were dried in an oven.

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Morphology and crystal size of the solids obtained from cooling crystallization were analyzed by

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an automatic image analyzer (Malvern Morphologi G3). About 75000 product crystals were

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analyzed for each experiment. The crystal yield was calculated from the total mass of the crystals

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obtained at the end of the experiments. 7 ACS Paragon Plus Environment


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Figure 1. Flow diagram of the modular continuous crystallization system

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2.3 Effect of Residence time

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The residence time of the solution in the crystallizer is an important factor in continuous

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crystallization and it is determined by the set flow rate. Furthermore, the flow velocity should be

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high enough to avoid settling of crystals in the tube and still suitable to experience enough

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residence time for crystallization in the system. The Reynolds number (Re) for the flow in the

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crystallizer were in the range of 260 – 1300. Hence, all the flow rates used in the experiment

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provided laminar flow in the tube. In order to get test runs of feasible operating conditions, various

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flow rates were firstly investigated with model compounds K2SO4 and CuSO4. These preliminary

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experiments were carried out with pipes that were 12 m in length and had 4 mm inner diameter

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and 1 mm wall thickness. Table 1 shows the flow rates, their corresponding residence times and

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flow velocities in the pipe used in the current study.

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Table 1. Flow rates, residence times and flow velocities in the modular crystallizer.

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Flow rate Q, ml/min 49 60 75 100 120

Residence time τ, min 9.23 7.54 6.03 4.52 3.77

Flow velocity in the pipe vf, cm/s 6.50 7.96 9.95 13.26 15.92

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2.4 Effect of cooling strategy

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The present study used modular tubular crystallizers in continuous cooling crystallization that

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enabled the supersaturation to be easily and accurately controlled. Control strategy plays a critical

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role to achieve feasible operating conditions,30 as employed in the current system. Three cooling

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strategies which were equal concentration difference (equal supersaturation), equal temperature

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difference and equal supersaturation ratio were used. The cooling temperature profile for each

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experiment was calculated on the basis of the selected cooling strategy, and calculated

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temperatures are maintained for each module

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Due to the results from the initial experiments regarding the influence of residence time, the

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flow rate of 75 ml/min as an optimal condition was used to study the cooling strategy. In addition,

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the length of the steel pipe in each module was increased to 18 m to accommodate longer residence

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times. Other dimensions such as pipe diameter and thickness were kept the same. Thus, in order

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to keep a constant production rate because the residence times changes with the longer pipes, the

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initial concentration of model compounds used in the 18 m pipe was calculated in relation to the

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conditions used in 12 m pipe.

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2.4.1 Supersaturation (ΔC)

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The equal concentration difference in the three modules was initially considered. It ensures each

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module or crystallization stage to reach the same supersaturation as shown in Figure 2a, Figure 3a, 9 ACS Paragon Plus Environment


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and Figure 4a for the different model compounds. Since there were three modules in these set of

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experiments, the supersaturation (ΔC) was shared equally to each module by calculation from the

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initial and final concentrations based on the solubility curve. The corresponding temperatures of

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the resulting concentrations were then used to set the cooling temperature profile.

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Figure 2. Solubility curve of K2SO4 showing equal supersaturation (a), equal temperature

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difference (b), and equal supersaturation ratio (c) in each module in a temperature range from 63.0

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°C  20.0 °C (adapted from docbrown.info31).

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2.4.2 Temperature difference (ΔT)

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Mersmann and Rennie22 introduced a continuous multistage cooling crystallization process

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involving eight countercurrent crystallizers in series. This concept can help to avoid excess local 10 ACS Paragon Plus Environment

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supersaturation in each stage. It means that the temperature drop should be equal in each module

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as shown in Figure 2b, Figure 3b, and Figure 4b for the different model compounds. In this case,

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the concentration difference in each module varies and it depends on the solubility of the model

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compound.

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Figure 3. Solubility curve of CuSO4 showing equal supersaturation (a), equal temperature

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difference (b), and equal supersaturation ratio (c) in each module in a temperature range from 53.2

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°C  20.0 °C (adapted from docbrown.info31).

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2.4.3 Supersaturation ratio (S)

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Supersaturation ratio (S=C/C*) is another way to express supersaturation level in the system.

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The supersaturation ratio is calculated as the ratio of the initial concentration and expected final 11 ACS Paragon Plus Environment


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concentration at the exit of the module based on the solubility curve of the model compound. Thus,

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equal supersaturation ratio in each module was taken into account as a design method. In this case,

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the concentration difference decreases gradually with the modules, which can be clearly seen in

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Figure 2c, Figure 3c, Figure 4b and Table 2 for the different model compounds.

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Figure 4. Solubility curve of phthalic acid having equal supersaturation (a), equal temperature

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difference and equal supersaturation ratio (b), in each module in a temperature range from 60.0 °C

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 20.0 °C (adapted from Stephen and Stephen32).

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2.5 Effect of supersaturation ratio

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To understand the influence of supersaturation ratio on crystallization more deeply, various

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experiments with phthalic acid with different supersaturation ratios in the range from 1.20 to 1.90,

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as shown in Table 3, were performed with 3-stage modular crystallizer. Same experimental

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procedure as shown in section 2.2 was used with the same residence time of 9.05 min in every

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experiment. Crystal size distributions were examined with Morphologi G3.

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2.6 Effect of ultrasound 12 ACS Paragon Plus Environment

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Effect of ultrasound was investigated with phthalic acid for the studied continuous crystallizer.

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Two steel pipes having lengths of 12 m and 18 m were used. Same configuration but only one

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module which had spiraled pipes was considered here for cooling crystallization of phthalic acid

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in the temperature range from 35.0 °C to 20.0 °C. 3 liters of feed solution saturated at 35.0 °C was

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first prepared. The temperature of the thermostat used for the tubular crystallizer was set to 20.0

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°C. Seeding was done in coherence with Linga’s33 recommendation for seeding in industrial

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crystallizers. Hence, 0.2 g (about 0.3 % of final crystals) seeds with average size of 11 µm was

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added to the saturated solution to initiate crystallization. Five flow rates were used for the cooling

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crystallization processes of phthalic acid with ultrasound while three flow rates were used for the

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experiments without ultrasound. In this case, the product crystals were analyzed with Malvern Size

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Analyzer (Mastersizer 3000) to determine the particle size distributions. Clear filtrates were

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weighed and dried in the oven to determine the concentration of the soluble materials in the mother

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liquor. This method was used for crystal yield determination.

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3. RESULTS AND DISCUSSION

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3.1 Effect of residence time

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Potassium sulphate. Various residence times shown in Table 1 were checked for K2SO4 with

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equal concentration difference (1.63 g/100g water) in the range of 46.8 °C to 20.0 °C. The

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corresponding supersaturation ratios in modules 1, 2 and 3 were 1.11, 1.13 and 1.15, respectively.

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The experimental results show that the system was blocked when operated with a residence time

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of 9.23 mins. All the other flow rates could offer feasible operations with the continuous modular

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crystallizer, their yield and average particle sizes are presented in Figure 5. The reason for the

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blockage might be the existence of excessive supersaturation in the module and low flow velocity, 13 ACS Paragon Plus Environment


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which is also pointed out by Furuta et al.21 Crystal yield relates to the supersaturation level of the

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whole cooling process. It means that the yield could be increased by increasing the initial

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concentration. Thus, two other experiments were carried out with higher initial concentration

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corresponding to a temperature of 60.0 °C, at residence times of 9.23 and 3.77 mins, to verify if a

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feasible operating condition could be achieved. Hence, a feasible operating condition was observed

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with the residence time of 3.77 mins. Whereas, a blockage occurred with the residence time of

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9.23 mins due to the presence of excessive supersaturation in the module and low flow velocity.

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Furuta et al. 21 also reported same reason for blockages in their tubular crystallizer.

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Copper sulphate. Due to the blockage which occurred in the continuous crystallization of K2SO4

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with the residence time of 9.23 mins, this residence time was not considered for CuSO4

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crystallization. Same cooling profile with equal concentration difference was firstly employed with

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cooling crystallization of CuSO4 since feasible operating conditions were achieved while using the

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cooling strategy in K2SO4 crystallization. However, the blockage occurred for trial runs carried

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out with residence times of 7.54, 6.03 and 3.77 mins with equal concentration difference of 4.10,

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4.77 and 6.43 g/100g water corresponding to the initial temperatures 49.2, 53.0 and 60.0 °C,

280

respectively. Because of this, equal supersaturation ratio was considered with the same initial

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temperatures and flow rates, but there was not any operation that led to a feasible operating

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condition. As Figure 2 and Figure 3 show, the solubility of CuSO4 in water is much higher than

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the solubility of K2SO4, and the solubility curve of CuSO4 is more non-linear. Hence, sudden

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temperature decrease in the module leads to high supersaturation and thus results in clogging of

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the crystallizer. Due to the aforementioned reasons, the initial temperature should be decreased to

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achieve lower supersaturation level. Finally, three feasible operating conditions were observed


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from experiments carried out with residence times of 6.03, 4.52 and 3.77 mins in the temperature

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range from 43.0 to 20.0 °C by applying the cooling strategy of equal supersaturation ratio (1.13).

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Figure 5 shows the average crystal sizes (D[4,3]) based on volume distribution of different

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samples obtained from feasible operating conditions of various residence times and yields for both

291

compounds, K2SO4 and CuSO4. The crystal size of K2SO4 was always bigger than the size of

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CuSO4 - crystals. This may be due to the differences in crystal properties that drive the nucleation

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and growth. For both compounds, the crystal size increased with the decrease of residence time

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and then reduced at shortest residence time. Raphael et al.34 observed that average crystal sizes

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decreases with shorter residence times and was in line with results from Lawton et al.2, whereas

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Ruecroft et al.10 reported that with continuous sonication smaller crystals are formed with longer

297

residence times. Hence, the reason for the variation in average crystal sizes might be the combined

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effect of ultrasound and residence time.

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Furthermore, higher yield was obtained with the residence time of 6.03 mins, equivalent to a

300

flow rate of 75 ml/min, for both compounds as shown in Figure 5. It indicates that the flow rate of

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75 ml/min for the 3 stage reactor gave better results for the both model compounds. Therefore, this

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flow rate was used to investigate cooling strategy of the modular crystallizer shown in section 3.2.

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Figure 5. Crystal sizes of different samples obtained from feasible operating conditions of various

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residence times and yields for both compounds K2SO4 and CuSO4.

307 308

3.2 Effect of cooling strategy

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Due to the increase of pipe length, the residence time was 9.05 mins when flow rate 75 ml/min

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was used. In order to keep constant production rate after increasing the pipe length, the initial

311

temperatures used in the new configuration which was scaled up based on the observed feasible

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conditions obtained from section 3.1 for K2SO4 and CuSO4 were 63.0 °C and 53.2°C, respectively.

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Based on these parameters, supersaturation, supersaturation ratio and temperature in each module

314

were calculated as shown in Table 2 and used for comparison of investigated cooling strategies.

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Potassium sulphate. Feasible operating conditions were obtained with the design method of

316

equal concentration difference and equal temperature difference from continuous cooling

317

crystallization of K2SO4, but the experiments designed by equal supersaturation ratio (S) failed.

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As shown in Table 2, the first module had much higher supersaturation (∆C) than module 2 and 3

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when equal supersaturation ratio (S) was used. It also indicates that equal supersaturation ratio

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provided faster cooling rates in the first module compared with the other two methods which led

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to crash nucleation. Hartel35 reported that rapid cooling can cause the formation of higher amount 16 ACS Paragon Plus Environment

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of nuclei and high supersaturation can lead to encrustation. Those may be the main reasons for

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clogging with the equal supersaturation ratio cooling strategy. Crystal size distribution of K2SO4

324

with different cooling conditions are presented in Figure 6a. It can be seen that larger crystals were

325

obtained from the conditions with equal supersaturation (∆C) compared to equal temperature

326

difference.

327

Copper sulphate. Continuous cooling crystallization of CuSO4 in the continuous pipe were

328

carried out with the three designed cooling strategies in the temperature range from 53.2 °C to 20.0

329

°C. Figure 6b shows the crystal size distribution of CuSO4 obtained from continuous sonicated

330

crystallization with different cooling strategies. It shows that crystals were largest with equal

331

temperature difference. Then, slightly bigger particles were crystallized from equal supersaturation

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ratio (S) than with equal supersaturation (∆C).

333

Phthalic acid. An organic compound, phthalic acid, was selected to be used in the modular

334

reactor. In temperature range from 60.0 °C to 20.0 °C, continuous cooling crystallization

335

experiments of phthalic acid in the tubular crystallizer offered feasible operating conditions with

336

three different cooling strategies. As shown in Table 2, equal supersaturation ratio provides the

337

same cooling profile with equal temperature difference due to its solubility curve (adapted from

338

Stephen & Stephen32) shown in Figure 4. The crystal size distributions of phthalic acid obtained

339

by various cooling conditions are shown in Figure 6c. As can be seen, there are no significant

340

differences in crystal sizes between equal supersaturation and equal temperature difference (or

341

equal supersaturation ratio). However, agglomerates are observed in Figure 6c since the CSDs

342

were analyzed using the Morphologi G3 which measures crystal sizes by surface imaging. The

343

potential reason for the agglomeration, hence the uneven CSDs, is that the supersaturation step in

344

the last module is larger with equal temperature difference compared to equal supersaturation. 17 ACS Paragon Plus Environment


Page 18 of 34

345 346

Table 2. Investigated cooling strategies for modular cooling crystallization with the residence time

347

of 9.05 mins and the obtained product yields of the model compounds. Conc., ΔC, g/100g g/100g S H2O H2O

Equal Compound Unit Condition

ΔC

K2SO4

ΔT

S

ΔC CuSO4

ΔT

ΔT, oC

Equivalent Yielda, % temp, oC

Feed

18.73

63.0

Module 1

16.20

2.54

1.16 15.05

48.0

Module 2

13.66

2.54

1.19 14.21

33.7

Module 3

11.12

2.54

1.23 13.75

20.0

Feed

18.73

Module 1

16.32

2.41

1.15 14.34

48.7

Module 2

13.77

2.55

1.19 14.34

34.3

Module 3

11.12

2.65

1.24 14.34

20.0

Feed

18.73

Module 1

15.74

2.99

1.19 17.63

45.4

Module 2

13.23

2.51

1.19 13.96

31.4

Module 3

11.12

2.11

1.19 11.42

20.0

Feed

35.13

Module 1

30.32

4.81

1.16 9.52

43.7

Module 2

25.51

4.81

1.19 10.99

32.7

Module 3

20.70

4.81

1.23 12.65

20.0

Feed

35.13

Module 1

29.60

5.52

1.19 11.05

42.2

Module 2

24.86

4.74

1.19 11.05

31.1

24

63.0 11

63.0 Not a feasible operating condition

53.2 74

53.2 49x


Page 19 of 34 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


S

ΔC

Phthalic acid

S / ΔT

348

Module 3

20.70

4.16

1.20 11.05

20.0

Feed

35.13

Module 1

29.45

5.68

1.19 11.39

41.8

Module 2

24.69

4.76

1.19 11.15

30.7

Module 3

20.70

3.99

1.19 10.62

20.0

Feed

2.74

Module 1

1.99

0.75

1.38 7.47

52.5

Module 2

1.24

0.75

1.60 11.03

41.5

Module 3

0.50

0.75

2.51 21.55

20.0

Feed

2.74

Module 1

1.55

1.19

1.77 13.35

46.7

Module 2

0.88

0.67

1.77 13.35

33.3

Module 3

0.50

0.38

1.77 13.35

20.0

53.2 79

60.0 63

60.0 39

a = yield calculated from recovered dry product crystals, x = filter cloth torn during recovery

349



Page 20 of 34

350 351

Figure 6. Crystal size distribution of K2SO4 (a), CuSO4 (b) and phthalic acid (c) crystallized by

352

applying different cooling operating conditions at constant residence time of 9.05 mins in the

353

continuous sonicated reactor.

354 355

As a summary, almost all the model compounds crystallized from different cooling profiles in

356

the continuous sonicated cooling crystallization process with a constant residence time achieved

357

the highest yield when equal supersaturation was chosen as is shown in Table 2. Although, equal

358

supersaturation ratio gave the highest actual yield for CuSO4 but the actual yield was in the same

359

range with that was obtained with equal supersaturation. It indicates that the supersaturation in

360

each module is equally constant and this implies that the supersaturation in each crystallizer can

361

be controlled accurately. This is consistent with the recommendation that was pointed out by 20 ACS Paragon Plus Environment

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362

Mersmann and Rennie.22 They suggested that cooling rates could be fixed by constant

363

supersaturation in the cooling period. Therefore, equal supersaturation between modules is the

364

optimal cooling strategy in the modular crystallizer. However, there are no clear trends

365

corresponding to crystal size distributions probably because the kinetics and crystal properties of

366

different compounds are different. An additional reason may also be the impact of ultrasound as

367

there are possibilities of the crystals to observe a growth – attrition – growth sequence. It means

368

that crystal size can increase or decrease due to ultrasound because the induction of ultrasound at

369

different stages have different effects on crystals.14,36 Further studies of induction times are needed.

370 371

3.3 Effect of supersaturation ratio

372

Different initial temperatures were used to achieve different supersaturation ratios for phthalic

373

acid cooling crystallization at equal ΔS in each module as shown in Table 3. Continuous cooling

374

crystallization experiment of phthalic acid with equal supersaturation ratio of 1.20 did not result

375

in crystal production. This may be due to the extremely low supersaturation of the whole process.

376

The experiment with supersaturation ratio of 1.90 failed due to blockage problems, which were

377

most probably caused by too high supersaturation and faster cooling rate in the first module which

378

led to encrustation and high nucleation rate.35,37 Finally, there was blockage in the crystallizer.

379

However, the continuous experiments with other supersaturation ratios could be carried out

380

without blockage.

381

The crystal size distributions and average crystal sizes of phthalic acid obtained from the feasible

382

operating conditions are presented in Figure 7. It shows that the crystal size distribution is getting

383

narrower with the increase of supersaturation ratio as presented in Figure 7a and the average

384

crystal size (D[4,3]) decreases with increase in equal supersaturation ratio as shown in Figure 7b. 21 ACS Paragon Plus Environment


Page 22 of 34

385

It can be attributed to the effect of ultrasound and the supersaturation level in the first module

386

which increased with the increase of supersaturation ratio and thus lead to generation of small

387

nuclei which provided much more interface for crystal growth. Although Ni & Liao38 and Kaneko

388

et al.39 reported that bigger crystals are produced with higher supersaturation, however, the inverse

389

relationship of the average crystal size and supersaturation ratio is coherent with production of

390

smaller crystals at high supersaturation as reported by Sarig et al.40 The yield as shown in Table 3

391

indicates that the highest yield was obtained with the supersaturation ratio of 1.54 with the

392

residence time of 9.05 mins which might be the optimal condition for this specific residence time.

393 394

Table 3. The saturation concentrations of phthalic acid at equilibrium for each module and

395

equivalent temperatures showing equal module supersaturation ratios.

Unit

C*, g/l00 g H2O

Feed

0.86

Module 1

0.72

1.20

0.14

28.5

Module 2

0.60

1.20

0.11

24.2

Module 3

0.50

1.20

0.10

20.0

Feed

1.24

Module 1

0.91

1.36

0.33

34.3

Module 2

0.67

1.36

0.24

27.1

Module 3

0.50

1.36

0.17

20.0

Feed

1.80

Module 1

1.17

1.54

0.63

40.1

Module 2

0.76

1.54

0.41

30.0

S

∆C, g/l00 g H2O

Saturation temp., oC

Yielda,%

32.8 no crystals

41.4 24

50.2 59


Page 23 of 34 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

396


Module 3

0.50

1.54

0.26

20.0

Feed

2.50

Module 1

1.46

1.71

1.04

45.2

Module 2

0.85

1.71

0.61

32.6

Module 3

0.50

1.71

0.35

20.0

Feed

2.74

Module 1

1.55

1.77

1.19

46.7

Module 2

0.88

1.77

0.67

33.3

Module 3

0.50

1.77

0.38

20.0

Feed

3.39

Module 1

1.79

1.90

1.60

50.0

Module 2

0.94

1.90

0.85

35.0

Module 3

0.50

1.90

0.44

20.0

57.8 39

60.0 39

65.0 Not a feasible operating condition

a = yield calculated from recovered dry product crystals

397

398 399

Figure 7. Crystal size distributions (a) and average crystal size D[4,3] (b) of phthalic acid obtained

400

from continuous sonicated cooling crystallizer with equal supersaturation ratio in each module

401

with different supersaturation ratios (different initial temperature) at a residence time of 9.05 mins.



Page 24 of 34

402 403

3.4 Effect of ultrasound

404

For all of the studied experimental conditions without ultrasound, small amount of crystals were

405

obtained from the crystallization process, which were not enough for analysis. This was because

406

the residence times were short as shown in Table 4 and there was no ultrasound to induce

407

nucleation in the system.1 With ultrasound, only one experiment had similar problem, of no

408

produced crystal, when a flow rate of 150 ml/min and 12 m pipe were used because of the short

409

residence time which was probably lower than the induction time, hence there was a reduced effect

410

of ultrasound with this operating condition. From Table 4, it is observed that the actual yield was

411

always higher for sonicated experiments compared to non-sonicated experiments at a specific

412

residence time. Thus, it indicates that the crystallization process was enhanced significantly by

413

ultrasound. Moreover, encrustation can be avoided by using ultrasound assisted crystallization.37

414

Figure 8 shows the crystal size distributions and average crystal sizes of phthalic acid obtained

415

from cooling sonocrystallization process. The CSDs show wider distributions for lower flow rates

416

(higher residence time) for the 12 m and 18 m pipes, represented in Figure 8a and Figure 8b

417

respectively, compared to the higher flow rates in the experiment. However, the CSDs were not

418

consistent probably due to the effect of ultrasound and the possible relationship between available

419

residence times and induction times of phthalic acid.

420

More so, a sequence of decrease in average crystal size and yield was observed with increase in

421

flow rate as presented in Table 4 and Figure 8c respectively. This was due to the short residence

422

time crystals spent in the crystallizer, not giving enough time for crystals to grow immediately

423

after nucleation induced by ultrasound. Another reason for this is the possibility of the residence

424

time being very close to the induction time which was not studied. Using the 18 m pipe and the 24 ACS Paragon Plus Environment

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425

flow rate of 150 ml/min without using ultrasound, the yield was unreliable due to temperature

426

variation during the filtration of the product suspension. When the flow rate of 50 ml/min and 18

427

m pipe were used, the particle size was very similar with the crystals obtained with flow rate of

428

100 ml/min. This might be due to the classification of crystals in the pipe with such low flow

429

velocity.

430

Interestingly, the yields obtained from ultrasound experiments were higher compared to those

431

without ultrasound, at the same condition as seen in Table 4. Since ultrasound can reduce the

432

induction time,1,10 hence, nucleation begins earlier for such experiments carried out with

433

ultrasound thereby offering more yield.

434 435

Table 4. Results of phthalic acid samples obtained from cooling crystallization with and without

436

ultrasound in the one module crystallizer having inner diameter of 4 mm. Pipe length, m

Ultrasound

ON 12

OFF

18

ON

Flow rate, Residence ml/min time, mins

Conc. of mother liquor, Yieldb, % g/100g water

50

3.02

0.69

59

75

2.01

0.81

31

100

1.51

0.78

37

120

1.26

0.79

34

150

1.01

0.81

31

50

3.02

0.74

47

100

1.51

0.83

27

150

1.01

0.83

27

50

4.52

0.71

54



OFF

437

Page 26 of 34

75

3.02

0.75

45

100

2.26

0.77

39

120

1.88

0.81

31

150

1.51

0.81

31

50

4.52

0.79

36

100

2.26

0.78

37

150

1.51

0.76

42*

b = yield calculated from mother liquor concentration, * = unreliable.

438

439 440

Figure 8. Crystal size distributions of phthalic acid from 12 m pipe (a) and 18 m pipe (b) and their

441

average crystal sizes (c), obtained from cooling sonocrystallization process with one module.

442 26 ACS Paragon Plus Environment

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443

4. CONCLUSION

444

Continuous cooling crystallization of three model compounds (K2SO4, CuSO4 and phthalic acid)

445

were carried out in a new modular sonicated tubular crystallizer. Feasible conditions were obtained

446

from successful operating processes running without pipe blockage for three or four times of the

447

residence time. The residence time is a critical factor for yield and crystal size according to results.

448

The yield is affected by nucleation and crystallization time which can relate to supersaturation left

449

in the reactor outlet with short residence times.

450

The cooling strategy did not have a clear relation to the crystal size distributions. This might be

451

due to the difference of solubilities, crystal growth, nucleation kinetics, and crystal properties for

452

each compound. Equal supersaturation could be used as the best option to design temperature

453

profiles for cooling crystallization. This is because each module would ideally have equal

454

concentration difference and thus leads to moderate local supersaturation which could reduce the

455

opportunity of crystals to block the pipes. More so, equal supersaturation produces higher yields

456

in cases where short residence times are used. This is favoured especially in targeting production

457

increase with continuous systems.

458

Furthermore, the design criteria were evaluated with the studied three model compounds.

459

Ultrasound plays a critical role, which can enhance the crystallization process significantly and

460

avoid clogging. From results, the use of ultrasound offered higher yields compared to experiments

461

without ultrasound. Boundary conditions such as residence time and cooling strategy as the key

462

issues have to be taken into account when designing a continuous tubular sonocrystallizer. As

463

further studies optimization between the process residence time and the supplied ultrasound

464

intensity is needed.

465 27 ACS Paragon Plus Environment


466

AUTHOR INFORMATION

467

Corresponding Author

468

*E-mail: [email protected]

469

Phone number: +358 50 4357414

470

*E-mail: [email protected]

471

Notes

472

The authors declare no competing financial interest

Page 28 of 34

473 474

ACKNOWLEDGEMENT

475

The authors thank the Finnish Funding Agency for Technology and Innovation, Tekes, for their

476

financial support. The authors also thank M.Sc. Juhani Pouta for his contribution to the

477

experimental work.

478 479

REFERENCES

480

1. Tung, H.; Paul, E.; Midler, M.; McCauley, J. In Crystallization of Organic Compounds:

481

An Industrial perspective. Hoboken, NJ: John Wiley & Sons, Inc., 2009; Chapter 7, pp.

482

143-144.

483

2. Lawton, S.; Steele, G.; Shering, P.; Zhao, L.; Laird, I.; Ni, X-W. Continuous

484

crystallization of pharmaceuticals using a continuous oscillatory baffled crystallizer.

485

Org. Process Res. & Dev. 2009, 13, 1357-1363. 28 ACS Paragon Plus Environment

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486

3. Hohmann, L.; Gorny, R.; Klaas, O.; Ahlert, J.; Wohlgemuth, K.; Kockmann, N. Design

487

of Continuous tubular cooling crystallizer for process development on lab-scale. Chem.

488

Eng. Technol. 2016, 39, 1268-1280.

489

4. Zhao, L; Raval, V.; Briggs, N. E. B.; Bhardwaj, R. M.; McGlone, T.; Oswald, I. D. H.;

490

Florence, A. J. From discovery to scale-up: α-lipoic acid: nicotinamide co-crystals in a

491

continuous oscillatory baffled crystalliser. Cryst. Eng. Comm. 2014, 16 (26), 5769-5780.

492 493

5. NiTech®

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http://www.nitechsolutions.co.uk/products. [Accessed September 25, 2018].

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6. Kacker, R.; Regensburg, S. I.; Kramer, H. J. M. Residence time distribution of dispersed

495

liquid and solid phase in a continuous oscillatory flow baffled crystallizer. Chem. Eng.

496

J. 2017, 317, 413-423.

497

7. Hohmann, L.; Greinert, T.; Mierka, O.; Turek, S.; Schembecker, G.; Bayraktar, E.;

498

Wohlgemuth, K.; Kockmann, N. Analysis of crystal size dispersion effects in a

499

continuous coiled tubular crystallizer: experiments and modeling. Cryst. Growth Des.

500

2018, 18, 1459-1473.

501

8. Eder, R. J. P.; Radl, S.; Schmitt, E.; Innerhofer, S.; Maier, M.; Gruber-Woelfler, H.;

502

Khinast, J. G. Continuously seeded, continuously operated tubular crystallizer for the

503

production of active pharmaceutical ingredients. Cryst. Growth Des. 2010, 10, 2247-

504

2257.

505 506

9. Kim, H. N.; Suslick, K. S. The effects of ultrasound on crystals: Sonocrystallization and sonofragmentation. Crystals 2018, 8, 280. 29 ACS Paragon Plus Environment


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10. Ruecroft, G.; Hipkiss, D.; Ly, T.; Maxted, N.; Cains, P. W. Sonocrystallization: the use

508

of ultrasound for improved industrial crystallization. Org. Process Res. & Dev. 2005, 9,

509

923-932.

510 511

11. Bang, J. H.; Suslick, K. S. Application of ultrasound to the synthesis of nanostructured materials. Adv. Mater. 2010, 22, 1039-1059.

512

12. Li, H. X; Li, H.; Zhang, J.; Dai, W. L.; Qiao, M. H. Ultrasound-assisted preparation of a

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highly active and selective Co-B amorphous alloy catalyst in uniform spherical

514

nanoparticles. J. Catal. 2007, 246, 301-307.

515 516 517 518 519 520

13. Zhang, D.; Xu, S.; Du, S.; Wang, J.; Gong, J. Progress of pharmaceutical continuous crystallization. Engineering, 2017, 3, 354-364. 14. Dhumal, R. S.; Biradar, S. V.; Paradkar, A. R.; York, P. Ultrasound assisted engineering of lactose crystals. Pharm. Res. 2008, 25, 2835-2844. 15. Arakelyan, V. S. Effect of ultrasound on crystal growth from melt and solution. Acta Phys. Hung. 1987, 61, 185-187.

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16. Vancleef, A.; Seurs, S.; Jordens, J.; Van Gerven, T.; Thomassen, L.C.J.; Braeken, L.

522

Reducing the induction time using ultrasound and high-shear mixing in a continuous

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crystallization process. Crystals 2018, 8, 326.

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17. Flowers, B. S.; Hartman, R. L. Particle handling techniques in microchemical processes. Challenges 2012, 3, 194-211.


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18. Hartman, R. L. Managing solids in microreactors for the upstream continuous processing of fine chemicals. Org. Process Res. Dev., 2012, 16, 870−887.

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19. Rossi, D.; Jamshidi, R.; Saffari, N.; Kuhn, S.; Gavriilidis, A.; Mazzei, L. Continous-flow

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sonocrystallization in droplet-based microfluidics. Cryst. Growth Des. 2015, 15, 5519-

530

5529.

531 532

20. Wu, K.; Kuhn, S. Strategies for solids handling in microreactors. Chim. Oggi 2014, 32, 62-66.

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21. Furuta, M.; Mukai, K.; Cork, D.; Mae, K. Continuous crystallization using a sonicated

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tubular system for controlling particle size in an API manufacturing process. Chem. Eng.

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Process. 2016, 102, 210-218.

536 537 538 539

22. Mersmann, A.; Rennie, F. W. In Crystallization Technology Handbook; Mersmann, A., Ed.; Second Edition, Marcel Dekker: New York, 2001; Chapter 9, pp. 393-444. 23. Alvarez, A. J.; Singh, A.; Myerson, A. S. Crystallization of cyclosporine in a multistage continuous MSMPR crystallizer. Cryst. Growth Des. 2011, 11, 4392-4400.

540

24. Li, J.; Trout, B. L.; Myerson, A. S. Multistage continuous mixed-suspension, mixed-

541

product removal (MSMPR) crystallization with solids recycle. Org. Process Res. Dev.

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2016, 20, 510-516.

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25. Power, G.; Hou, G.; Kamaraju, V. K.; Morris, G.; Zhao, Y.; Glennon, B. Design and

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optimization of a multistage continuous cooling mixed suspension, mixed product

545

removal crystallizer. Chem. Eng. Sci. 2015, 133, 125-139. 31 ACS Paragon Plus Environment


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26. Siddique, H.; Brown, C. J.; Houson, I.; Florence, A. J. Establishment of a continuous

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Res. Dev. 2015, 19, 1871-1881.

549

27. Eder, R. J. P.; Schrank, S.; Besenhard, M. O.; Roblegg, E.; Gruber-Woelfler, H.; Khinast,

550

J. G. Continuous sonocrystallization of acetylsalicylic acid (ASA): control of crystal size.

551

Cryst. Growth Des. 2012, 12, 4733-4738.

552 553 554 555

28. Besenhard, M. O.; Neugebauer, P.; Ho, C. D.; Khinast, J. G. Crystal size control in a continuous tubular crystallizer. Cryst. Growth Des. 2015, 15, 1683-1691. 29. Ruecroft, G.; Burns, J. An apparatus and process for producing crystals. Patent application: WO 2010/079350 A2, 2010.

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30. Su, Q.; Nagy, Z. K.; Rielly, C. D. Pharmaceutical crystallization processes from batch to

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continuous operation using MSMPR stages: Modelling, design, and control. Chem. Eng.

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559

31. Docbrown.info. Gas and Salt Solubility in Water and Solubility Curves. Online, 2000;

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[Accessed 6 Jul. 2015].

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32. Stephen, H.; Stephen, T., Eds. In Solubilities of Inorganic and Organic Compounds; Pergamon Press, 1963; 2nd ed., Vol. 1, Part 1, pp. 438-439. 33. Linga, Å. In Effects of Seeding on the Crystallization Behaviour and Filtration Abilities of an Aromatic Amine. Master's thesis: NTNU, 2017; pp 3-90. 32 ACS Paragon Plus Environment

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34. Raphael, M.; Rohani, S.; Sosulski, F. Isoelectric precipitation of sunflower protein in a tubular precipitator. Can. J. Chem. Eng. 1995, 73, 470–483. 35. Hartel, R. W. In Handbook of Industrial Crystallization; Myerson, A. S., Ed.; Butterworth-Heinemann: Boston, 2002; Second Edition, Chapter 13, pp. 287-303. 36. Louhi-Kultanen, M.; Karjalainen, M.; Rantanen, J.; Huhtanen, M.; Kallas, J. Crystallization of glycine with ultrasound. Int. J. Pharm. 2006, 320, 23-29.

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37. Myerson, A. S.; Ginde, R. In Handbook of Industrial Crystallization; Myerson, A. S.,

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Ed.; Butterworth-Heinemann: Boston, 2002; Second Edition, Chapter 2, pp. 33-62.

574

38. Ni, X.; Liao, A. Effects of Cooling Rate and Solution Concentration on Solution

575

Crystallization of L-Glutamic Acid in an Oscillatory Baffled Crystallizer. Cryst. Growth

576

Des. 2008, 8(8), 2875-2881.

577

39. Kaneko, S.; Yamagami, Y.; Tochihara, H.; Hirasawa, I. Effect of Supersaturation on

578

Crystal Size and Number of Crystals Produced in Antisolvent Crystallization. J. Chem.

579

Eng. Japan 2002, 35(11), 1219-1223.

580

40. Sarig, S.; Eidelman, N.; Glasner, A.; Epstein, J. A. The effect of supersaturation on the

581

crystal characteristics of potassium chloride. J. appl. Chem. Biotechnol. 1978, 28, 663 -

582

667.

583



584

Page 34 of 34

“For Table of Contents Use Only”

585


586


587


588

Louhi-Kultanen2

589 590

TABLE OF CONTENTS GRAPHIC

591 592 593

SYNOPSIS

594

Process parameters were studied in a continuous sonicated modular cooling crystallizer with

595

inorganic and organic model compounds. Equal supersaturation as a crystallization design strategy

596

allows high yields especially with short processing times. Smaller crystals and higher yields can

597

be obtained using ultrasound in continuous crystallization systems. Residence time is an important

598

design variable of such systems.


Insights into Design Criteria for a Continuous Sonicated Modular

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