Enhanced product quality control through separation of crystallization

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Enhanced product quality control through separation of crystallization phenomena in a four-stage MSMPR cascade Marie-Christine Lührmann, Jan Timmermann, Gerhard Schembecker, and Kerstin Wohlgemuth Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b00941 • Publication Date (Web): 18 Oct 2018 Downloaded from http://pubs.acs.org on October 22, 2018

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Crystal Growth & Design

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Enhanced product quality control through separation of

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crystallization phenomena in a four-stage MSMPR cascade

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Marie-Christine Lührmann, Jan Timmermann, Gerhard Schembecker and Kerstin Wohlgemuth*

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TU Dortmund University, Laboratory of Plant and Process Design,

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Emil-Figge-Straße 70, 44227 Dortmund, Germany

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*Corresponding author: E-mail address: [email protected];

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Tel.: +49 (0)231 755 3020; Fax: +49 (0)231 755 2341

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Keywords: continuous crystallization, gassing, MSMPR cascade, primary nucleation threshold,

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product quality control

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ACS Paragon Plus Environment

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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Abstract

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A four-stage cascade of MSMPR crystallizers has been designed and setup for the

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production of L-alanine crystals to achieve an enhanced control of product quality in

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terms of crystal size and size distribution. The cascade is characterized by a local

16

separation of the crystallization phenomena nucleation and crystal growth as well as by

17

the fact that no pumps were used to transfer the suspension from one vessel to the next.

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Instead, a unique vessel design was chosen in which lateral and vertical overflow tubes

19

were installed, which enabled a gentle suspension transfer by gravity. Controlled

20

induction of nucleation was achieved by gassing with synthetic air, leading to crystals

21

with a median diameter of 35 μm. These crystals grew about 85 μm over the entire

22

cascade, whereby agglomeration and breakage were mostly avoided. To reach a steady

23

state operation within the first three stages, a start-up phase of approximately 6.5 hours

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was necessary. The continuous operation of the entire MSMPR cascade could only be

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maintained for over an hour, underlining the complexity and uncertainty involved in the

26

crystallization process.

2


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27

1

Introduction

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In industrial crystallization processes a precisely controlled operation mode is decisive to

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ensure a consistent product quality which is often defined by the crystals’ purity, size

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and size distribution. To meet this challenge, continuously operated crystallizers are

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promising; not only in terms of lower investment and operating costs but also because

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they

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characteristics. Although continuous crystallization is already well established to

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manufacture large volume commodity products like sugar and inorganic salts, batch

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processing remains the method of choice in the pharmaceutical and fine chemical

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sector. In order to satisfy the high demands placed on the products resulting from these

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industry branches, continuous plant and equipment concepts are required that

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guarantee an enhanced control of the product quality attributes mentioned above. 1,2

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1.1

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In the past decades, various types of continuous crystallizers have been described and

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experimentally demonstrated in the literature. One possibility to realize a continuous

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process is the use of a cascade of multistage mixed suspension mixed product removal

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(MSMPR) crystallizers. These stirred vessels currently dominate in industrial

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crystallization processes and are preferably used when high residence times are needed

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which may be the case if the desired crystalline product shows slow nucleation and low

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growth rates. 1 Furthermore, this continuous crystallizer type is characterized by a highly

47

efficient mixing, which has a positive effect on solid-liquid mass transfer preventing

48

fouling and blockage issues.

operate

at

steady

state,

thus

yielding

reproducible

crystalline

product

Continuous crystallization using a cascade of MSMPR vessels

2

A good overview of research works in which MSMPR 3



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cascades have been used for the production of pharmaceutical compounds is given by

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Brown et al. 1. The experimental studies listed by the authors include two to three-stage

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cascades with vessel volumes between 50 mL and 1000 mL and residence times of

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each vessel that range from 15 minutes to 240 minutes.

53

It has already been proven that the local separation of the crucial crystallization

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phenomena – mainly nucleation and crystal growth – in a cascade of crystallizers, can

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contribute to a significant improvement in product quality control. Hence, each stage of a

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process can be controlled independently. The theoretical and experimental results of

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Woo et al.

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controllability of the crystal size distribution (CSD) using a semi-continuous crystallizer

59

setup. Jiang et al.

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by combining continuous seeding from confined impinging jets with a stirred aging

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vessel, the latter one being operated in fed-batch mode at constant supersaturation. The

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dual impinging jets mixed hot and cold saturated solutions to generate uniform

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L-asparagine monohydrate (LAM) crystals with an average size of 20 μm that were

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further grown to a desired size in a stirred tank in which nucleation was suppressed. The

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supersaturation at which growth was controlled varied between ∆c = 3.7 ∙ 10-3 gLAM

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-1 -1 and ∆c = 7.4 ∙ 10-3 gLAM gwater .4 gwater

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In Myerson's research group, MSMPR cascades have already been intensively

68

investigated

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set up a two-stage MSMPR cascade for the polymorphism control of the enantiotropic p-

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aminobenzoic acid at either the α or β polymorph. Thereby, the first stage – the

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nucleation stage – was designed to produce pure crystals of the desired form at steady

3

as well as Jiang et al. 4, for instance, indicate a strong increase in the

5–7.

4

realized a physical separation of the nucleation and the growth step

With regard to a separate control of nucleation and growth, Lai et al. 6

4


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state. These crystals were subsequently fed to the second stage – the growth stage –

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which was designed to achieve an optimum yield. The flow between the two stages was

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realized with a peristaltic pump using an intermittent withdrawal scheme, whereby each

75

withdrawal removed ten percent of the suspension volume every one tenth of a

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residence time. Li et al. 7 investigated the continuous crystallization of cyclosporine from

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acetone solution. The authors conducted a series of comparative studies on one-stage,

78

three-stage and five-stage MSMPR operation with each stage being a 155 mL vessel

79

with overhead mechanical stirring and independent temperature controlling. From one

80

stage to the next, slurry was also removed intermittently as described by Lai et al. 6.

81

Although not explicitly mentioned that a separate control of nucleation and growth was

82

aimed at, within the five-stage setup the residence time was kept comparatively short in

83

the first stage by operating stages two and three as well as four and five at the same

84

temperature respectively. It was found that the CSD was largely decided by the first

85

stage condition.

86

Gao et al.

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production of α-form L-glutamic acid crystals. The first stage was coupled with an

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ultrasonic processor to induce nucleation leading to uniform crystals with an average

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size of 35 μm. The second MSMPR crystallizer was used to grow the crystals to a final

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size of 150 μm. During operation of the second vessel, the authors attached importance

91

to a moderate mechanical stirring at 200 rpm in order to avoid breakage and

92

agglomeration. The solution or suspension was transferred with the help of two

93

peristaltic pumps at a constant volume flow rate of 50 mL min-1 resulting in a total

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residence time in the crystallizer system of 5 to 15 minutes.

8

demonstrated a two-stage continuous MSMPR crystallizer system for the

5



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A disadvantage in the operation of the cascades described above can be seen in the

96

use of peristaltic pumps. Due to the mechanical stress that is caused by the application

97

of pumps within continuous crystallization processes, the crystals tend to attrition and

98

breakage 9. Although this problem is generally known, only a few examples exist in the

99

literature in which the suspension transfer between different vessels is realized without

100

pumps. For example, there are research works in which the transfer is carried out

101

through applying pressure

102

type of suspension transfer can involve considerable construction effort which likely

103

results in high capital costs, especially in the case of larger plant scales. In addition,

104

when applying a vacuum, evaporation of the solvent often leads to undesired nucleation.

105

On the basis of the aforementioned advantages when using continuous cascades of

106

MSMPR crystallizers and the listed disadvantages when applying pumps as well as

107

pressure or vacuum for suspension transfer, the aims of this work are as follows: (i) to

108

design and operate an MSMPR cascade with locally separated zones of nucleation and

109

crystal growth to enhance product quality control and (ii) to realize a simply constructed

110

and gentle suspension transfer between the vessels which enables a fully continuous

111

operation. L-alanine/water, representing a well-known substance system, was chosen as

112

an example system.

113

To achieve the first aim, nucleation and crystal growth were locally separated in different

114

vessels. The design and the choice of operating conditions of the nucleation vessel have

115

already been explained in detail in a previous paper

116

placed on the design and the choice of suitable operating conditions for the growth

10

or vacuum

11

or a combination of both

14.

12,13.

However, this

Hence, the focus of this article is

6


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117

vessels as well as for the entire cascade consisting of a nucleation vessel and three

118

growth vessels.

119

In the context of the second objective, a gravimetric transfer by means of a lateral – as

120

described in

121

conventional peristaltic pumps. Therefore, such a suspension transfer concept is

122

investigated in this study. Referring to this, the selection of a suitable growth vessel

123

design is also of decisive importance, which is described in more detail in the following

124

section.

125

1.2

126

Mixing in a continuously stirred vessel has an essential influence on the conditions

127

under which crystals nucleate and grow and therefore plays a key role in the

128

crystallization process. Since a growing crystal removes the solute from the

129

supersaturated solution surrounding it, the solute concentration at the crystal surface

130

and in the bulk can be considerably different. Mixing links this local microenvironment of

131

a crystal with its macroenvironment and a high degree of homogeneity implies a

132

significant reduction of the concentration difference between these two environments.

133

In batchwise operated solid-liquid agitated systems, only complete suspension of the

134

crystals is required. This means that all particles are lifted off the vessel bottom and

135

should meet Zwietering‘s 1-2 seconds criteria

136

towards obtaining a homogeneous suspension which implies that the suspension

137

conditions should be completely homogeneous even at the liquid surface – known as

138

100 % cloud height criterion.

14

– or vertical overflow tube appears to be an appropriate alternative to

Solid-liquid suspension

17

16.

15

With continuous flow, the aim shifts

Consequently, rapid and effective mixing and thus a 7



Page 8 of 46

139

homogeneous suspension in an MSMPR vessel lead to a more uniform crystalline

140

product in terms of its size and size distribution.

141

In addition, the attainment of a homogeneous suspension is indispensable when

142

transferring the suspension via a lateral or vertical overflow tube, as used in this work. In

143

the past decades much work has been invested in improving the crystallizer design to

144

increase the degree of suspension homogeneity. In the field of continuous

145

crystallization, only Aeschbach and Bourne

146

discharge the crystal suspension. Thereby, their objective was to find a suitable vessel

147

design that would allow a homogeneous steady state suspension in a continuous stirred

148

tank crystallizer. Their continuous stirred tank which at the end showed the best mixing

149

conditions consisted of a 1 L beaker of 104 mm width in which four baffles of 10 mm

150

width were positioned at a distance of 5 mm from the wall. Additional positive effects on

151

the hydrodynamics in the vessel were achieved by the use of a concentrically mounted

152

draft tube, in which an upward conveying propeller stirrer of 50 mm width and a profiled

153

tank bottom caused a strong vertical circulation in the vessel. The stirring speed was

154

selected to 1250 rpm which represented a compromise to ensure adequate mass

155

discharge of the solids and to avoid the introduction of gas bubbles as well as particle

156

breakage. The product removal took place in the area of high velocities directly above

157

the draft tube through a lateral overflow tube of 8 mm width. Although Aeschbach and

158

Bourne carried out intensive research and achieved promising results, their work does

159

not seem to have been well accepted neither in industry nor in university research. In

160

this work, a unique continuous MSMPR vessel – based on the one presented by

161

Aeschbach and Bourne

18

18

have used a lateral overflow tube to

but with significant changes as described in detail in Section 8


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162

2.2.2 – has been designed, set up and evaluated with regard to the homogeneity of the

163

suspension. The suspension homogeneity was evaluated by so-called washout

164

experiments.

165

2.2.3. Subsequently, the corresponding vessel was integrated as a growth vessel in the

166

MSMPR cascade.

167

1.3

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The goal of this work was to enhance the control of product quality with regard to crystal

169

size and its distribution. For this purpose, a cooling crystallization for the production of L-

170

alanine using a four-stage cascade of MSMPR crystallizers was realized. Thereby, the

171

temperature should be cooled from 50 °C to 30 °C. The upper temperature was chosen

172

so that the aqueous amino acid solution is easy to handle, in the sense that the solute

173

does not crystallize on the vessels’ inner walls at higher temperatures due to

174

evaporation effects. The lower temperature was selected to ensure cooling of the

175

vessels by means of cooling water even at higher ambient temperatures in the summer

176

months. In this way, the use of thermostats with an internal cooling function could be

177

avoided.

178

For the best possible control of the crystallization process, the temperature levels of the

179

individual vessels must be selected in such a way that spontaneous nucleation does not

180

occur. For material systems that tend to show a narrow metastable zone width (MZW) in

181

batch cooling crystallizations, this may mean that also the temperature steps in the

182

cascade have to be selected being very small. In order to decide on a maximum

183

possible temperature step between two vessels in a cascade, the temperature at which

19–21

The experimental procedure for these tests is explained in Section

Selecting operating conditions

9



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spontaneous nucleation happens must be determined experimentally. Since the

185

molecules of a solution are permanently replaced in continuous mode, the measurement

186

of the MZW or the induction time, as known from batchwise operated vessels, is not

187

possible. In a previous paper, we introduced the procedure of measuring the primary

188

nucleation threshold (PNT) in continuous operation to identify the maximum possible

189

temperature step between the feed tank and the nucleation vessel

190

determination of the maximum possible temperature step between two vessels within

191

the growth zone of the cascade, there is the characteristic feature that prior crystals are

192

already present in the supersaturated solution. This circumstance further reduces the

193

metastable limit for the birth of new crystals compared to the PNT. The value at which

194

birth of new crystals occurs in the presence of prior crystals is called secondary

195

nucleation threshold (SNT). Accordingly, it is more likely that secondary nucleation will

196

be the dominant phenomenon in the growth vessels. It should be noted that the PNT as

197

well as the SNT value do not only depend on the temperature but also on the residence

198

time and its distribution. For this reason, it was found that the PNT can be measured

199

experimentally by a stepwise reduction of the temperature with holding times between

200

the individual temperature steps, so that the value is determined successively. During

201

the holding time the system gets a chance to overcome kinetic limitations meaning that

202

solute molecules in the solution are given sufficient time to form clusters that exceed the

203

critical radius to form stable nuclei. Thus, the holding time is selected in such a way that

204

all molecules which entered the vessel at the beginning of the holding time have left it

205

again at the end of the holding time. Therefore, residence time measurements are

206

required, which is described in more detail in Section 2.2.4. The measurement of the

14.

Regarding the

10


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207

SNT appears to be very complex. On the one hand, specific solid contents, crystal sizes

208

and size distributions should be known for each cascade stage and vessel respectively

209

in order to take into account their potential influences on the SNT value. On the other

210

hand, the analytical evaluation is challenging. By making use of the naked eye method it

211

is nearly impossible to distinguish between breakage and secondary nucleation in the

212

case of very small seed crystals. When using conductivity probes a difficulty is seen in

213

distinguishing between crystal growth and secondary nucleation. Based on the

214

challenges mentioned above, the PNT value is determined for a first approximation of

215

the SNT value. Thereby, a safety margin is applied to the value determined, assuming

216

that, under the selected operating conditions, neither the PNT nor the SNT are

217

exceeded during operation of the cascade.

218

A self-constructed conductivity probe representing a cheap and easy-to-build process

219

analytical tool was used to monitor the nucleation process. For details regarding this

220

conductivity probe and the experimental procedure for the measurement of PNTs, the

221

reader is referred to our previous paper 14.

222 223

2

Materials and Methods

224

2.1

225

L-alanine (Evonik Industries AG, 99.6 % purity) was used as solute and ultrapure water

226

(0.05 µS cm-1), obtained through a deionizing system (Milli-Q® Integral System), was

227

chosen as solvent. The solubility curve of L-alanine is described by the following

228

equation 22.

System investigated

11



-1 ] = 0.11238 exp(9.0849 10 -3 ϑ * (°C)) c [galaninegsolution

Page 12 of 46

(1)

229

For the residence time measurements sodium chloride (VWR Chemicals, GPR

230

RECTAPUR®, ≥ 99 % purity) was used as tracer substance.

231

2.2

232

2.2.1 Setup of the cascade

233

The entire MSMPR cascade consisted of a small volume 34 mL (suspension volume)

234

nucleation vessel

235

Therefore, the cascade had a total suspension volume of Vsusp ≈ 1150 mL including the

236

peripheral tubes. A schematic drawing of the complete setup is given in Figure 1. A

237

photograph of the cascade is attached in the Supplemental Material.

Experimental setup and procedure

14

and three growth vessels with approximately 370 mL each.

238 12


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239 240 241 242

Figure 1: Schematic drawing of the four-stage cascade of continuous MSMPR crystallizers with separated zones of the crystallization phenomena nucleation and crystal growth as well as feed tank zone

243

All vessels within the cascade were made of borosilicate glass and equipped with a

244

double jacket for heating or cooling, respectively. A total of five thermostats (C25P,

245

Haake; CC-202C and CC-K6, Huber) were installed so that each vessel could be

246

individually temperature-controlled. The feed solution was prepared in a 10 L feed tank

247

and then fed into the nucleation vessel with the help of a peristaltic pump (PD 5201,

248

Heidolph). Nucleation was induced through gassing with synthetic air at 48 °C to carry

249

out the nucleation process in a controlled manner

250

of the growth vessel is described in the following section.

251

2.2.2 Design and setup of growth vessel

252

A schematic drawing and a photograph of the growth vessel built is shown in Figure 2.

253 254

Figure 2: Schematic drawing and photograph of the growth vessel

14,23–26.

The detailed design and setup

13



Page 14 of 46

255

The growth vessel had a total capacity of V ≈ 600 mL with an inner diameter of

256

d = 90 mm. It was completely made of borosilicate glass and equipped with a double

257

jacket for cooling or heating, respectively, as described in the previous section. In order

258

to avoid crystalline incrustations on the vessel’s inner wall, the filling level of the

259

thermostating fluid in the jacket was kept at the filling level of the suspension inside the

260

growth vessel. A draft tube with an inner diameter of d = 48 mm was positioned

261

concentrically in the middle of the vessel to direct the flow along the desired path. In

262

addition, four vertical baffles arranged at 90° angles with a width of approximately one

263

eleventh of the vessel diameter were attached to the vessel’s wall which favored the

264

turbulence intensity between the solid surface and the liquid film inside the vessel. For a

265

certain flexibility in the height of the filling level and accordingly in the residence time, a

266

vertical overflow tube was used instead of a permanently installed lateral overflow tube

267

as used by Aeschbach and Bourne

268

of d = 3 mm and was fixed to the bottom of the vessel in a height-adjustable manner. It

269

was also assumed that a vertical installation instead of a lateral installation would avoid

270

sedimentation problems. Furthermore, it was found that a slight angulation of the

271

overflow tube in the direction of the draft tube leads to an enhanced discharge of the

272

crystals. To further improve the flow pattern, a profiled bottom in the form of a cone was

273

used. A four-bladed 45° pitched blade turbine with a diameter of d = 45 mm was

274

positioned concentrically in the center of the draft tube. The stirrer, which conveyed

275

axially upwards, was also made of borosilicate glass and was driven by an overhead

276

stirrer of type HT-50DX (witeg Labortechnik GmbH). During the continuous experiments

277

the vessel was not completely filled which resulted in a suspension volume of

18.

This vertical overflow tube had an inner diameter

14


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278

Vsusp = 370 ± 5 mL, depending upon the vessel geometry and the position of the

279

vertical overflow tube. Since all three growth vessels were handmade by TU Dortmund

280

University’s glassblowing workshop, there were small differences in the geometries of

281

the vessels, especially in the curvature of the cone’s surface. The lid of the growth

282

vessel contained four inlets: One inlet in the middle for concentric arrangement of the

283

stirrer and three others for placing the feeding tube, a Pt100 for temperature monitoring

284

and the conductivity probe for monitoring the steady state.

285

2.2.3 Measurement of the solid phase’s residence time distribution

286

Washout experiments were used to measure the residence time distribution (RTD) of the

287

solid phase and simultaneously evaluate the homogeneity of the suspension in the

288

growth vessel whose design and setup was described in the previous section. In

289

general, the experimental procedure of a washout experiment is as follows. A known

290

mass of solids m0 is fed into a stirred tank and suspended in a liquid assuring that

291

neither dissolution nor growth occurs. The mass of solids remaining in the vessel m (θ),

292

while particles are being washed out with the liquid stream, is then measured as a

293

function of time. Thereby, no additional solid material is added to the feed stream so that

294

a solid-free feed stream is fed to the vessel during the entire washout experiment. With

295

an ideal homogeneous operation of the vessel, it is expected that the function of the

296

solid mass remaining in the tank follows the known exponential decay. 21 W(θ) =

m(θ) m0

(2)

297

In the resulting diagram W is plotted against the dimensionless residence time θ which is

298

formed as a quotient of the time t and the space time τ. Due to the suspension’s volume 15



Page 16 of 46

299

of Vsusp ≈ 370 mL and a volume flow rate of V ≈ 10 mL min-1 the space time was

300

calculated to τ ≈ 37 min.

301

A characteristic value which is determined from the W function is the mean residence

302

time t . t =

∫

∞

t W(θ) dt

(3)

0

303

For a reliable evaluation, the operating conditions of the washout experiments, e.g.

304

stirrer speed, feed volume flow rate, filling height of the crystallizer and discharge

305

properties, must be the same as in the continuous crystallization experiments. It should

306

be noted that a washout experiment cannot be carried out in a crystallizing system due

307

to crystal growth and attrition. For this reason, model systems are often used which have

308

the same properties such as crystal shape, crystal density, liquid density and viscosity.

309

Alternatively, washout experiments can also be conducted using seed crystals in a

310

saturated solution.

311

reflects the real process conditions.

312

In a first step an aqueous solution of L-alanine saturated at room temperature was

313

prepared, which was equilibrated for 48 hours. For this purpose, a thermostated feed

314

tank with a filling volume of 3 L was used. Sufficient mixing in the feed tank was ensured

315

by a magnetic stirrer. The growth vessel was set up as shown in Figure 2. At the

316

beginning of a washout experiment, the growth vessel was filled with the saturated

317

solution up to 90 % of the later filling height using a peristaltic pump (PD 5201,

318

Heidolph). To ensure that no undissolved substances or foreign particles enter the

319

vessel, the solution was sucked in through a glass frit of porosity 4. The solid-free,

19,20

The latter variant was chosen in this work because it best

16


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320

saturated L-alanine solution was fed into the vessel at a constant volume flow rate of V

321

≈ 10 mL min-1. During the filling process, the stirrer speed was gradually increased so

322

that when the 90 % filling level was reached, a stirrer speed of n = 450 rpm was

323

attained, which was kept constant during the entire washout experiment. This value

324

represented a trade-off between a sufficiently high mixing rate and an acceptable vortex,

325

so that no bubbles tore off on the stirrer blades. Subsequently, a known mass of L-

326

alanine seed crystals, in this case 13.314 g (3.45 % w/w) of the size fraction 560 to 710

327

μm, was suspended in the vessel. This mass corresponds to the mass of L-alanine,

328

which would theoretically crystallize during a cooling crystallization from 50 °C to 30 °C.

329

The selected seed crystal size fraction represented a worst case estimation in the form

330

of the largest possible grown crystals, adopted from batch cooling crystallization of

331

L-alanine

332

in a previous paper

333

Since the mass of crystals remaining in the vessel ideally follows the function of an

334

exponential decay, the overflowing suspension was initially collected in beakers every

335

two minutes, after approximately a half of the residence time every five minutes and

336

after approximately three residence times every ten minutes. In total, the overflow was

337

collected for at least five residence times. The mass of seed crystals remaining in the

338

vessel after five residence times was also collected and filtered via a vacuum suction

339

filter system. Crystals adhering to the vessel’s wall were rinsed out of the vessel with

340

saturated solution. The evaluation of the washout experiment was carried out

341

gravimetrically. For the drying step, all washout samples were first transferred to a

342

drying oven operated at 70 °C (FED 53, Binder) for 24 hours. After most of the water

27.

A detailed description of the preparation of the seed crystals used is given 28.

The measurement started with the beginning of the first overflow.

17



Page 18 of 46

343

had evaporated, the samples were dried for another week at 50 °C in a vacuum drying

344

oven (Heraeus VT 6130, Thermo Scientific). In order to subtract the solute in the

345

saturated solution from the mass of the L-alanine seed crystals, four concentration

346

samples each of approximately 5 mL were taken before and after the experiment.

347

It should be emphasized that the seed crystals could not be collected without the mother

348

liquor. A continuous filtration and washing process during the washout experiment could

349

not be implemented in such a way that the solute did not crystallize out of the solution,

350

which would have falsified the results.

351

2.2.4 Measurement of the liquid phase’s residence time distribution

352

As explained in Section 1.3, for the selection of suitable operating conditions which allow

353

a precisely controlled crystallization process, it becomes necessary to determine the

354

PNT. For this purpose, residence time measurements of the liquid phase are required

355

since all volume elements of the solution that are introduced at the beginning of the

356

holding time should have flowed through the growth vessel until the end of the holding

357

time.

358

For the residence time measurements, an aqueous sodium chloride solution was chosen

359

as tracer substance. Thereby, a concentration of 0.63 % w/w was used in order to

360

ensure a linear correlation between the change in current signal and the change in

361

tracer concentration. The sodium chloride solution was prepared in the same 3 L feed

362

tank as applied in the solid phase RTD experiments. The measurement was carried out

363

at ambient temperature of about 22 °C and the growth vessel was operated at 450 rpm.

364

Using a peristaltic pump (PD 5201, Heidolph), the sodium chloride solution was 18


Page 19 of 46 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


365

transferred to the growth vessel with a constant volume flow rate of V ≈ 10 mL min-1.

366

While the washout function W represents the response to a negative step change as

367

tracer input signal, the cumulative distribution function F represents the response to a

368

positive step change. Therefore, the F curve directly represents the proportion of the

369

volume elements that have left the vessel at a time θ after addition at a time θ = 0.

370

Since the current I measured is proportional to the solution’s conductivity and thus its

371

concentration, the cumulative distribution function F was calculated based on the current

372

signal. F(θ) =

I(θ) I0

21,29

(4)

373

The RTD is graphically illustrated by the RTD function E. The area below the E curve

374

between two time points θ and θ + ∆ θ indicates the probability with which a volume

375

element that has entered the vessel at a time θ has left it again in the time interval

376

between θ and θ + ∆ θ. The RTD function E results from the differential of the

377

cumulative distribution function F. 29 dF(θ) = E(θ) dt

(5)

378

As a characteristic value, analogous to the washout function W, the mean residence

379

time t is also calculated for the liquid phase. ∞

t =

∫ t E(θ) dt

(6)

0

19



Page 20 of 46

380

2.2.5 Determination of the primary nucleation threshold

381

In the following, the PNT measurement is explained using the example of the first growth

382

vessel being operated at the highest temperature within the growth zone. First, an

383

aqueous L-alanine solution was prepared in the thermostated 3 L feed tank. The

384

operating temperature of the preceding vessel in the cascade was selected as the

385

saturation temperature of the solution – in the case of the first growth vessel, the

386

solution’s saturation temperature was the operating temperature of the nucleation vessel

387

of 48 °C

388

superheated by ∆T = 5 K for at least one hour. During the entire PNT experiment, the

389

temperature in the feed tank was kept constant at ϑ = 53 °C to guarantee the transfer of

390

a crystal-free solution to the nucleation vessel. In these experiments, too, the solution

391

was sucked in through a glass frit of porosity 4 so that any undissolved substances or

392

foreign particles retained in the feed tank. The growth vessel was filled at ϑ = 51 °C

393

before being cooled down to ϑ * = 48 °C after approximately one to two residence times.

394

A beaker was positioned below the growth vessel to collect the solution discharged.

395

After the growth vessel had reached a constant temperature of ϑ * = 48 °C, the

396

temperature was reduced in steps of ∆T = 2 K with holding times of θ = 5 (this value

397

derived from the results of the liquid phase RTD experiments as explained in Section

398

3.2) in between. At the start of the PNT experiment, it was taken care that no crystal

399

deposits or incrustations, which could later lead to undesired nucleation, were present in

400

the growth vessel. The time of setting the first temperature step was selected as θ = 0.

401

In all experiments, the time at which crystals were first detected with the naked eye was

402

also noted in order to evaluate the sensitivity of the conductivity probe. The PNTs of the

14.

To ensure a complete dissolution of all solids, the suspension was

20


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403

second and third growth vessel were measured in the same way as described for the

404

first growth vessel.

405

2.2.6 Start-up and operation of the four-stage MSMPR cascade

406

The continuous crystallization experiments were carried out in the entire cascade setup

407

as depicted in Figure 1. Initially, an aqueous L-alanine solution with a concentration of

408

-1 c = 0.177 galanine gsolution , corresponding to a saturation temperature of ϑ * = 50 °C, was

409

prepared in the feed tank which had a total capacity of 10 L. Again, a transfer of solid-

410

free solution had to be guaranteed, so that the solution was superheated by ∆T = 5 K for

411

at least one hour at a stirrer speed of n = 950 rpm and a glass frit of porosity 4 was

412

installed. Throughout the continuous crystallization, the temperature in the feed tank was

413

kept constant at ϑ = 55 °C. The same thermostat also heated the feed tube and the tube

414

in which the synthetic air flowed to the nucleation vessel, so that the temperature was

415

kept constant in these tubes at ϑ = 55 °C as well. Preheating of the synthetic air had the

416

advantage that a temperature drop due to cold air flowing into the supersaturated

417

solution in the nucleation vessel could be avoided. Additionally, before entering the

418

nucleation vessel, the gas was passed through a washing bottle in which the synthetic

419

air was saturated with water (not depicted in Figure 1). In this way, evaporation of the

420

solvent into the gas bubbles was prevented 26.

421

After preparation of the L-alanine solution in the feed tank, the nucleation vessel was

422

completely filled at ϑ = 53 °C before being cooled down to ϑ = 48 °C, thus achieving a

423

supersaturated state of the solution. A gassing temperature close to the saturation curve

424

was selected in order to be able to control the nucleation step at a low supersaturation of 21



Page 22 of 46

425

-1 . Furthermore, this temperature was higher than the PNT ∆c = 3.0 ∙ 10-3 galanine gsolution

426

which was in the temperature range of 40.5 °C to 42.5 °C (see Section 3.3), so that

427

spontaneous nucleation was avoided

428

n = 500 rpm. After a holding time of two residence times at ϑ = 48 °C, gassing was

429

started. A flow meter combined with a needle valve (also not shown in Figure 1) was

430

installed in the gas line for controlling and adjusting the gas flow rate at V = 20 L h-1. In

431

order not to exceed the PNT of the first growth vessel, it was waited until a steady state

432

– monitored and detected by making use of the conductivity probe – had been reached

433

in the nucleation vessel. Therefore, before a connection to the growth zone was

434

established, the solution or suspension flowing out of the nucleation vessel was

435

collected in a beaker. During the setting of the steady state in the nucleation vessel, the

436

first growth vessel was filled with an externally prepared L-alanine solution saturated at

437

46 °C (this value derived from the results of the PNT measurements as described in

438

Section 3.3). As explained for the nucleation vessel, the filling process was carried out at

439

a temperature increased by ∆T = 3 K, in this case ϑ = 49 °C, to dissolve any solid

440

particles and to avoid undesired nucleation in the growth zone. Also for the second and

441

third growth vessel, a solution saturated at 44 °C or 42 °C respectively was prepared

442

externally and filled into the growth vessel at a temperature increased by ∆T = 3 K in

443

each case. Here, too, the first and second growth vessel as well as the second and third

444

growth vessel were not connected until the preceding vessel had reached the steady

445

state. Analogous to the nucleation vessel, the growth vessels were therefore equipped

446

with a conductivity probe for detecting the steady state.

14.

The stirrer speed in the nucleation vessel was

22


Page 23 of 46 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


447

3

Results and Discussion

448

3.1

449

The results of the solid phase’s RTD measurements are presented as the mass of

450

L-alanine crystals of the size fraction 560 to 710 μm remaining in the vessel as a

451

function of the dimensionless residence time, measured from the first overflow as

452

starting point (θ = 0). The washout experiment was performed twice and the mean value

453

is plotted in Figure 3.

454 455 456 457

Figure 3: RTD measurements of the solid phase showing the washout function W against the residence time θ (V = 10.3 mL min-1, n = 450 rpm, m0,alanine = 13.314 g)

458

Corresponding to the expectations, the W function follows the course of an exponential

459

decay. However, the overall W curve lies significantly above the curve of the ideal

460

continuous stirred tank reactor (CSTR) (dashed line in Figure 3), suggesting that the

461

crystals are discharged much slower than in the ideal case. An ideal CSTR is based on

Measurement of the solid phase’s residence time distribution

23



Page 24 of 46

462

the assumption that the flow at the inlet is completely and instantly mixed into the bulk of

463

the reactor. The reactor and the outlet stream have identical, homogeneous

464

compositions at all times. It follows that an ideal CSTR has an exponential distribution.

465

In the case of a real CSTR, it is impossible to obtain such fast mixing. Based on the

466

exponential fit of the W curve and corresponding to Equation 3, the mean residence time

467

of the crystals is calculated to t = 60 min. Hence, the residence time of the solid particles

468

is much higher than the space time of τ = 35.9 min. At the end of the washout

469

experiment, after five residence times, a mass of approximately m = 0.6 g remained in

470

the vessel, which corresponds to 4.5 % w/w of the original mass m0 = 13.314 g. It is not

471

surprising that the crystals are not completely washed out after five residence times.

472

With decreasing crystal mass in the course of the experiment, the probability that a

473

crystal will find its way through the overflow tube decreases as well. In addition, the

474

probability of crystal-crystal collisions, which might promote the discharge of the solid

475

particles, is also reduced. It should be emphasized again that the washout experiment

476

was a worst-case scenario in the form of the maximum crystallizing mass and the

477

maximum crystal size expected. It is assumed that the W curve of smaller particles will

478

be closer to the ideal curve. In summary, a sufficient washout of the L-alanine crystals

479

from the saturated solution within five residence times was demonstrated.

480

For a qualitative evaluation of the degree of suspension homogeneity, Figure 4 presents

481

a series of photographs showing the growth vessel over the time course of the washout

482

experiment.

24


Page 25 of 46 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


483 484 485 486 487 488

Figure 4: Series of images of the growth vessel showing the time course of the washout of L-alanine of the size fraction 560 to 710 μm from saturated solution (V = 10.3 mL min-1, n = 450 rpm, m0,alanine = 13.314 g)

489

The decreasing turbidity in the growth vessel clearly shows that the mass of L-alanine is

490

greatly reduced over time. In the last picture, which was taken after five residence times,

491

only a few crystals are visible. Furthermore, the images prove the successful and

492

efficient transfer concept by means of a vertical overflow tube as well as the

493

achievement of a homogeneous suspension through installation of a concentrically

494

mounted draft tube, the four vertical baffles and the profiled bottom. A 100 % cloud

495

height was reached and no crystal deposits were observed at the bottom of the vessel at

496

any time. 25



Page 26 of 46

497

It was also aimed to demonstrate whether the vessel design chosen has led to

498

mechanical stress on the crystals, which causes breakage and attrition. For this reason,

499

light microscopic images (Bresser TRM301 equipped with MikroCam SP 5.1) of the

500

initial (Figure 5a) and final crystals (Figure 5b) were taken for a qualitative comparison.

501 502 503 504 505 506

Figure 5: Dry L-alanine seed crystals of the fraction 560 to 710 μm before the washout experiment (a, left) and remaining L-alanine seed crystals at the end of the washout experiment after filtration and drying (b, right)

507

the crystals during the washout experiment over five residence times. Although rounded

508

edges at the crystals’ corners as well as small defects on the crystals’ surfaces are

509

visible in Figure 5b, no major breakage was observed. Thus, the microscopic images

510

also underpin the successful proof-of-concept.

511

3.2

512

In the following, the results of the residence time measurements of the liquid phase in

513

the form of the cumulative distribution function F (left) and the RTD function E (right) are

The two microscopic images reveal that there was no excessive mechanical stress on

Measurement of the liquid phase’s residence time distribution

26


Page 27 of 46 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


514

presented. For a direct comparison of the RTDs of the liquid (primary axis, blue) and the

515

solid phase (secondary axis, red), the respective results are juxtaposed in Figure 6.

516 517 518 519 520

Figure 6: Cumulative distribution function F (left) and RTD function E (right, primary axis, blue) as well as washout function W (right, secondary axis, red) for the growth vessel (V ≈ 10 mL min-1, n = 450 rpm)

521

crystallizer. The experimental data of the F curve shows small fluctuations, especially in

522

its rear, stationary range. Consequently, the cumulative distribution function was fitted

523

using a logistic regression. This fitted curve represents the basis for calculating the E

524

curve. Looking at the E curve, it is noticeable that, analogous to the W curve, there exist

525

deviations from the RTD behavior of an ideal CSTR (dashed line in Figure 6). For

526

instance, there is a finite delay before E reaches its maximum value and the length of

527

the delay reflects the rate of mixing inside the vessel. Corresponding to Equation 7, the

528

mean residence time is calculated to t = 29.5 min. Therefore, in contrast to the crystals’

529

mean residence time, the liquid’s mean residence time is noticeably lower than the

530

space time of τ ≈ 37 min, which is also illustrated by the RTD function in Figure 6. A

531

similar RTD of the liquid phase was also found for the nucleation vessel

Both the F curve and the E curve follow the expected course of a single-stage MSMPR

14.

The 27



Page 28 of 46

532

observation that solids spend a longer time in a continuous crystallizer than the liquid

533

was also made by Ejim et al.

534

continuous oscillatory flow baffled crystallizer (COBC). In addition, the results obtained

535

indicate that all volume elements have left the growth vessel after approximately five

536

residence times which is in good accordance with the ideal CSTR curve.

537

After the nucleation vessel and the growth vessels were connected for the entire setup,

538

residence time distribution measurements of the liquid phase were also carried out in the

539

four-stage MSMPR cascade. Thereby, the liquid phase’s mean residence time was

540

calculated to t = 94.9 min, whereas the space time of the whole cascade setup was τ ≈

541

115 min. Accordingly, the ratio of t to τ determined in the cascade is almost identical to

542

that measured in the growth vessel. The corresponding diagrams are given in the

543

Supplemental Material.

544

3.3

545

Based on the results of the RTD experiments, the holding time between the individual

546

temperature steps during the PNT measurements was selected to five residence times.

547

In order to compensate for variations in the measurement signals of the individual

548

conductivity probes in the growth vessel, the values of the current were normalized

549

between 0 and 1. The diagram in Figure 7 shows the result of the PNT measurement for

550

the first growth vessel (GV1) of the MSMPR cascade.

30

as well as Kacker et al.

31

who measured the RTDs in a

Determination of the primary nucleation threshold

28


Page 29 of 46 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


551 552 553 554 555

Figure 7: PNT measurement for the first growth vessel (GV1) of the MSMPR cascade showing the normalized current I (primary axis, blue) and the temperature ϑ (secondary axis, red) against the residence time θ (V = 10.1 mL min-1, n = 450 rpm)

556

As expected, the conductivity strongly depends on the temperature, which is indicated

557

by the fact that the signal of the current follows the temperature curve for more than

558

eight residence times. A drop in the current at a constant temperature is only observed

559

once the nucleation shower has occurred. The drop in the current signal is detected at

560

the second ∆T = 2 K temperature step when cooling down to 44 °C after a holding time

561

of about three residence times. However, few first crystals were detected with the naked

562

eye much earlier, shortly after the temperature of 44 °C was reached (see dotted line in

563

Figure 7). Before the current signal finally dropped, an increased nucleation was already

564

observed during the holding time, carefully it could also be described as a nucleation

565

shower. Based on this observation, it was very surprising that the conductivity

566

measurement did not react more sensitively, as it was found in the experiments for the

567

PNT measurement in the nucleation vessel

14.

A possible explanation for the delayed 29



Page 30 of 46

568

detection of the nucleation shower compared to the measurement in the nucleation

569

vessel could lie in the different vessel volumes. Since the growth vessel has about ten

570

times the suspension volume of the nucleation vessel – 370 mL compared to 34 mL – it

571

exhibits a certain degree of sluggishness. Obviously, in the case of the growth vessel,

572

comparatively more solutes have to change from the liquid to the solid state before the

573

conductivity probe can detect a difference in the concentration of the solution. It was

574

further found that the PNT value for the growth vessel is much lower than for the

575

nucleation vessel, where a temperature step from 50 °C to 40.5 °C was possible before

576

the onset of nucleation. Based on the results in Figure 7, the PNT value of the first

577

growth vessel was set at 44 °C, which meant that a temperature step of just 4 K in total

578

could be achieved. It is most likely that the larger surface-to-volume ratio in the growth

579

vessel due to the additional installations, e.g. the draft tube and the four vertical baffles,

580

and the resulting increased turbulence intensity will contribute to a reduction in the PNT.

581

Since crystals were detected neither with the naked eye nor with the conductivity probe

582

at 46 °C, this temperature was selected as the operating temperature for the first growth

583

vessel in the cascade. In this respect, it was further assumed that also the SNT would

584

not be exceeded at this temperature, as explained in Section 1.3. Consequently, for the

585

PNT measurement of the second growth vessel (GV2) an L-alanine solution saturated at

586

46 °C was utilized. The following Figure 8 illustrates the results of the PNT

587

measurements for the second and third growth vessel (GV3).

30


Page 31 of 46 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


588 589 590 591 592

Figure 8: PNT measurement for the second (GV2, left) and third growth vessel (GV3, right) of the MSMPR cascade showing the normalized current I (primary axis, blue) and the temperature ϑ (secondary axis, red) against the residence time θ (V = 10 mL min-1, n = 450 rpm)

593

Interestingly, the current signal in both diagrams shows a very similar course to the

594

current signal in the PNT measurement for the first growth vessel (Figure 7). In both

595

cases, a drop in current after a certain holding time at a constant temperature is

596

observed, again with a total temperature step of ∆T = 4 K. In the second growth vessel

597

the holding time is slightly more than three residence times, in the third growth vessel it

598

is only about two residence times. In the latter case, though, first few crystals were

599

already visible to the naked eye during the cooling process from 42 °C to 40 °C. It is

600

already known from batch cooling crystallization that there exists a dispersion between

601

repeated experiments for measuring MZWs which is generally traced back to the

602

statistical nature of the nucleation process. This statistical nature of nucleation could

603

also be a potential explanation for the slightly different times of the onset of nucleation or

604

the current drop, respectively. The operating temperatures of the second and third

605

growth vessel were selected according to the procedure for the first growth vessel to

606

44 °C and 42 °C. 31



Page 32 of 46

607

In conclusion, the PNT measurements yielded similar results for the same vessel

608

volume and design. Furthermore, it is already evident at this point that the desired

609

cooling crystallization from 50 °C to 30 °C cannot be realized with the selected number

610

of three vessels without avoiding spontaneous nucleation.

611

3.4

612

Figure 9 shows the results of the conductivity measurements in the four different

613

MSMPR vessels during the continuous crystallization experiment. It should be noted that

614

the respective current signals were measured one after the other and not in parallel,

615

since only one function generator was available as voltage source. For this reason, the

616

residence time displayed refers only to the respective vessel in which the measurement

617

was taken and thus is always starting at θ = 0.

Start-up and operation of the four-stage MSMPR cascade

32


Page 33 of 46 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


618 619 620 621 622 623 624

Figure 9: Conductivity measurements during the continuous crystallization of L-alanine in the four-stage MSMPR cascade showing the normalized current I (primary axis, blue) and the temperature ϑ (secondary axis, red) against the residence time θ (V = 10 mL min-1, nNV = 500 rpm, nGV = 450 rpm); a: nucleation vessel (NV), b: first growth vessel (GV1), c: second growth vessel (GV2), d: third growth vessel (GV3)

625

It is apparent that the induction of nucleation by the introduction of synthetic air after

626

approximately two residence times in the nucleation vessel causes a steep drop in the

627

current signal at almost constant temperature (Figure 9a). Although a slight decrease in

628

temperature occurs immediately after opening the gas supply, the thermostat quickly

629

adjusts the temperature. Accordingly, the decrease in the solution’s conductivity is

630

clearly due to primary heterogeneous nucleation

631

fluctuation in the current signal because of the presence of gas bubbles, it is assumed

14.

Even if there is a noticeable

33



Page 34 of 46

632

that the nucleation vessel has reached a steady state after about 8-12 residence times.

633

A similar result was also found in a previous study

634

the nucleation vessel was connected to the first growth vessel. The latter contained an

635

externally prepared saturated L-alanine solution at 46 °C. As seen in Figure 9b, a small

636

increase in the current signal is evident after the two vessels have been connected. This

637

was expected, since the solution saturated at 46 °C was initially mixed with the solution

638

saturated at 48 °C from the preceding nucleation vessel. However, the further course of

639

the current signal is surprising, since it was supposed that the value of the current signal

640

would fall back to the originally measured value of the solution saturated at 46 °C when

641

the resulting supersaturation is reduced by growth of the crystals. It is interesting to note

642

that a similar course of the current signal was also measured in the second (Figure 9c)

643

and third growth vessel (Figure 9d). Since all three L-alanine solutions were prepared

644

externally in the same preparation tank, it is assumed that the solutions provided in the

645

growth vessels were slightly supersaturated rather than saturated. This might explain the

646

current curves shown in Figure 9b-d. The noises in the measurement signals of GV2

647

and GV3 are traced back to the fact that the multimeter switched to a more accurate

648

measurement range (increased number of decimal digits) after the solution had reached

649

a certain concentration. The first and the second growth vessel, GV1 and GV2, reached

650

a steady state after about four residence times. This might also be true for GV3, but

651

there were further fluctuations in the current signal which might indicate another change

652

in the solution’s concentration. Thus, before all four vessels of the cascade were finally

653

connected, a start-up phase of approximately 6.5 hours was needed. Figure 10 depicts

14.

After reaching the steady state,

34


Page 35 of 46 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


654

light microscopic images of the L-alanine crystals taken from the four different vessels

655

when these were in steady state except for the third growth vessel.

656 657 658 659 660 661 662 663

Figure 10: Series of light microscopic images showing the L-alanine suspension discharged from the four different MSMPR vessels of the cascade; the bar corresponds to a size of 100 μm; a: nucleation vessel (NV), b: first growth vessel (GV1), c: second growth vessel (GV2), d: third growth vessel (GV3)

664

nucleation vessel to the third growth vessel. An evaluation of the microscopic images

665

with ImageJ resulted in an increase in the median diameter of ∆d50 = 85 μm from NV to

666

GV3 based on crystals leaving the nucleation vessel with a size of d50 = 35 μm.

667

However, no reliable quantitative evaluation of the CSD was possible, as too few

668

microscopic images with too few crystals on them were taken overall. The result would

The four pictures show a considerable growth of the L-alanine crystals from the

35



Page 36 of 46

669

therefore not be representative. Accordingly, the specified values should also be treated

670

with caution. The microscopic images showing the crystals discharged from the growth

671

vessels (Figure 10b-d) demonstrate that neither primary nor secondary nucleation

672

occurred in these vessels. Only a few small crystal fragments and agglomerates,

673

especially in the case of the second growth vessel (Figure 10c) are recognizable. At this

674

point, it may be stated that with the help of the vessel design chosen and the carefully

675

selected operating conditions, the aim of an enhanced control of product quality through

676

the local separation of the crystallization phenomena of nucleation and crystal growth

677

has been achieved to some extent.

678

Unfortunately, a successful continuous operation of the entire cascade – once the

679

second and third growth vessels were connected after a start-up phase of 6.5 hours –

680

could only be maintained for just over an hour, corresponding to a residence time in the

681

cascade of θcascade ≈ 0.6. After this time, despite all the precautions taken, an undesired

682

spontaneous nucleation seems to have occurred in the first growth vessel, as indicated

683

by Figure 11.

684 36


Page 37 of 46 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


685 686 687 688 689 690

The image shows large, highly agglomerated crystals as well as small needle-shaped

691

crystals, which appear to have newly formed

692

afterwards also for the subsequent growth vessels. Due to the now uncontrolled

693

processes, the connecting tube between the first and second growth vessel became

694

blocked after another half hour. This clogging is also noticeable in the conductivity signal

695

at θGV3 ≈ 3.3 measured in the third growth vessel (see Figure 9d). Although the

696

blocking could be released manually, controlled operation of the MSMPR cascade was

697

no longer possible at this point.

698

It can only be speculated about possible reasons for the sudden occurrence of

699

nucleation in the growth vessels. Since at some point, fluctuations occurred in the

700

volume flow rate of the gas stream, it might have been the case that not enough nuclei

701

were formed in the nucleation vessel. This in turn would have meant that the

702

supersaturation would no longer be decreased but increased instead so that a higher

703

supersaturated solution would then have entered the growth zone and the PNT or more

704

likely the SNT value would have been exceeded. It is also conceivable that evaporation

705

effects on the vessel’s inner wall at the gas/liquid phase interface could have led to

706

crystal incrustations. If such incrustations had formed which could then have entered the

707

slightly supersaturated solution in the growth vessel, this could also cause an

708

uncontrolled nucleation process. Possibly, it was also an interaction of these

709

phenomena.

Figure 11: Light microscopic image showing the L-alanine suspension discharged from the first growth vessel of the continuous cascade after 12 residence times; the bar corresponds to a size of 100 μm

32.

Similar images were taken shortly

37



Page 38 of 46

710

4

Conclusions and Outlook

711

The aim of this contribution was to demonstrate that the local separation of the

712

crystallization phenomena nucleation and crystal growth in a cascade of MSMPR

713

crystallizers would lead to an enhanced product quality control. The four-stage cascade

714

built was composed of a small 34 mL nucleation vessel and three 370 mL growth

715

vessels. Induced nucleation by gassing was successfully implemented in the nucleation

716

vessel, which yielded L-alanine crystals with a median diameter of 35 µm. Thereby, the

717

continuous induction of nucleation was maintained for more than 9 hours. Within the

718

growth zone, a specific vessel design consisting of a stirred vessel with a profiled

719

bottom, a concentrically arranged draft tube and a vertical overflow tube was utilized.

720

This design enabled a homogeneous suspension of the crystals grown, which was

721

characterized by a 100 % cloud height in each of the growth vessels. From the

722

nucleation vessel to the second growth vessel the individual vessels were operated until

723

a steady state was reached, corresponding to a start-up phase of about 6.5 hours. The

724

continuous operation of the entire MSMPR cascade was maintained for over one hour,

725

which led to an increase in the crystals’ median diameter of 85 µm. As a result, L-

726

alanine crystals with a median diameter of 120 µm were obtained at the end of the

727

cascade. Approximately one hour after the last growth vessel had been connected, an

728

undesired nucleation occurred in the growth zone, so that in future work there remains

729

further optimization potential with regard to the realization of the local separation of

730

nucleation and growth. In order to gain a better insight into the ongoing processes,

731

parallel measurement of the conductivity probes in all four vessels should be

732

implemented. It is also essential to guarantee a stable operation of the gassing process 38


Page 39 of 46 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


733

by realization of a constant gas volume flow rate. In summary, the results of this work

734

prove that the locally decoupled control of the crystallization phenomena nucleation and

735

crystal growth in different vessels of an MSMPR cascade is difficult and challenging.

736

This holds particularly true if the substance system to be crystallized shows low PNT or

737

low SNT values, respectively. In this case, the use of a cascade which allows the

738

separate control of nucleation and crystal growth seems to be inadequate, since it

739

implies a large number of vessels in order to achieve high yields. The resulting

740

investment costs may not be profitable.

741

Nevertheless, the design of the cascade chosen seems to be promising in many aspects

742

and a first step towards gaining a deeper understanding of the complex processes that

743

happen during the continuous crystallization of pharmaceutical and fine chemical

744

products has been taken.

39



Page 40 of 46

745

5 Acknowledgements

746

The authors would like to express their special thanks to Mr. Klaus Hirschfeld and his

747

team from the glassblowing workshop of TU Dortmund University. Without their

748

inventiveness and creativity in the implementation of vessel construction, this work

749

would not have been possible.

750 751

Supporting Information

752

Supporting Information Available: Photograph of the four-stage cascade of MSMPR

753

crystallizers (Figure S1) and results of residence time measurements including the

754

cumulative distribution function F and the RTD function E for the four-stage MSMPR

755

cascade (Figure S2). This material is available free of charge via the Internet at

756

http://pubs.acs.org.

757

40


Page 41 of 46 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


758

Notation

759

Abbreviations

760

CSD

crystal size distribution

761

CSTR

continuous stirred tank reactor

762

GV

growth vessel

763

LAM

L-asparagine monohydrate

764

MSMPR

mixed suspension mixed product removal

765

MZW

metastable zone width

766

NV

nucleation vessel

767

PNT

primary nucleation threshold

768

rpm

rounds per minute

769

RTD

residence time distribution

770

SNT

secondary nucleation threshold

771 772

Symbols

773

c

concentration

[g g-1]

774

∆c

supersaturation

[g g-1]

775

d50

median volume crystal diameter

[µm]

776

E

RTD function

[s-1]

777

F

cumulative distribution function

[-]

778

I

current

[A]

779

m

mass

[g]

780

n

stirrer speed

[rpm] 41



Page 42 of 46

781

t

time

[min]

782

t

mean residence time

[min]

783

∆T

temperature difference

[K]

784

V

volume

[mL]

785

V

volume flow rate

[mL min-1]

786

W

washout function

[-]

787 788

Greek letters

789

θ

residence time

[-]

790

ϑ

temperature

[°C]

791

ϑ∗

saturation temperature

[°C]

792

𝜏

space time

[s]

793 794

Indices

795

susp

suspension

42


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796

6 References

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(1) Brown, C. J.; McGlone, T.; Florence, A. J. Continuous Crystallization. In Continuous Manufacturing of Pharmaceuticals; Kleinebudde, P., Khinast, J., Rantanen, J., Eds.; John Wiley & Sons, Ltd.: Chichester, UK, 2017; pp 169–226. (2) Brown, C. J.; McGlone, T.; Yerdelen, S.; Srirambhatla, V.; Mabbott, F.; Gurung, R.; L. Briuglia, M.; Ahmed, B.; Polyzois, H.; McGinty, J. et al. Enabling precision manufacturing of active pharmaceutical ingredients: Workflow for seeded cooling continuous crystallisations. Mol. Syst. Des. Eng. 2018, 3, 518–549. (3) Woo, X. Y.; Tan, R. B. H.; Braatz, R. D. Precise tailoring of the crystal size distribution by controlled growth and continuous seeding from impinging jet crystallizers. CrystEngComm 2011, 13, 2006. (4) Jiang, M.; Wong, M. H.; Zhu, Z.; Zhang, J.; Zhou, L.; Wang, K.; Ford Versypt, A. N.; Si, T.; Hasenberg, L. M.; Li, Y.-E. et al. Towards achieving a flattop crystal size distribution by continuous seeding and controlled growth. Chem. Eng. Sci. 2012, 77, 2–9. (5) Alvarez, A. J.; Singh, A.; Myerson, A. S. Crystallization of Cyclosporine in a Multistage Continuous MSMPR Crystallizer. Cryst. Growth Des. 2011, 11, 4392–4400. (6) Lai, T.-t. C.; Cornevin, J.; Ferguson, S.; Li, N.; Trout, B. L.; Myerson, A. S. Control of Polymorphism in Continuous Crystallization via Mixed Suspension Mixed Product Removal Systems Cascade Design. Cryst. Growth Des. 2015, 15, 3374–3382. (7) Li, J.; Lai, T.-t. C.; Trout, B. L.; Myerson, A. S. Continuous Crystallization of Cyclosporine: Effect of Operating Conditions on Yield and Purity. Cryst. Growth Des. 2017, 17, 1000–1007. (8) Gao, Z.; Zhu, D.; Wu, Y.; Rohani, S.; Gong, J.; Wang, J. Ultrasound-assisted crystallization in a twostage continuous MSMPR crystallizer system. In 17 AIChE Annual Meeting - Conference Proceedings, 2017; 214e. (9) Cui, Y.; O’Mahony, M.; Jaramillo, J. J.; Stelzer, T.; Myerson, A. S. Custom-Built Miniature Continuous Crystallization System with Pressure-Driven Suspension Transfer. Org. Process Res. Dev. 2016, 20, 1276–1282. (10) Power, G.; Hou, G.; Kamaraju, V. K.; Morris, G.; Zhao, Y.; Glennon, B. Design and optimization of a multistage continuous cooling mixed suspension, mixed product removal crystallizer. Chem. Eng. Sci. 2015, 133, 125–139. (11) Wittering, K. E. Multi-component Crystallisation in the Continuous Flow Environment. Ph.D. Thesis, University of Bath, 2015. (12) Peña, R.; Nagy, Z. K. Process Intensification through Continuous Spherical Crystallization Using a Two-Stage Mixed Suspension Mixed Product Removal (MSMPR) System. Cryst. Growth Des. 2015, 15, 4225–4236. (13) Yang, Y.; Song, L.; Nagy, Z. K. Automated Direct Nucleation Control in Continuous Mixed Suspension Mixed Product Removal Cooling Crystallization. Cryst. Growth Des. 2015, 15, 5839– 5848. (14) Lührmann, M.-C.; Termühlen, M.; Timmermann, J.; Schembecker, G.; Wohlgemuth, K. Induced nucleation by gassing and its monitoring for the design and operation of an MSMPR cascade. Chem. Eng. Sci. 2018, 31, 840-849. 43



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(15) Green, D. Crystallizer Mixing: Understanding and Modeling Crystallizer Mixing and Suspension Flow. In Handbook of Industrial Crystallization, 2nd ed.; Myerson, A. S., Ed.; Butterworth-Heinemann: Woburn, 2002; pp 181–199. (16) Zwietering, T. N. Suspending of solid particles in liquid by agitators. Chem. Eng. Sci. 1958, 8, 244–253. (17) Atiemo-Obeng, V. A.; Penney, W. R.; Armenante, P. Solid-Liquid Mixing. In Handbook of industrial mixing: Science and practice; Paul, E. L., Atiemo-Obeng, V. A., Kresta, S. M., Eds.; WileyInterscience: Hoboken N.J., 2004; pp 543–582. (18) Aeschbach, S.; Bourne, J. R. The Attainment of Homogeneous Suspension in a Continuous Stirred Tank. Chem. Eng. J. 1972, 4, 234–242. (19) Mersmann, A. Quality of Crystalline Products. In Crystallization Technology Handbook, 2nd ed., rev. and expanded.; Mersmann, A., Ed.; Marcel Dekker: New York, 2001; pp 285–322. (20) Garside, J.; Mersmann, A.; Nývlt, J. Measurement of crystal growth and nucleation rates, 2nd ed.; Institution of Chemical Engineers: UK, 2002. (21) Nauman, E. B. Residence Time Distributions. In Handbook of industrial mixing: Science and practice; Paul, E. L., Atiemo-Obeng, V. A., Kresta, S. M., Eds.; Wiley-Interscience: Hoboken N.J., 2004; pp 1–16. (22) Wohlgemuth, K.; Schembecker, G. Modeling induced nucleation processes during batch cooling crystallization: A sequential parameter determination procedure. Comput. Chem. Eng. 2013, 52, 216–229. (23) Wohlgemuth, K.; Ruether, F.; Schembecker, G. Sonocrystallization and crystallization with gassing of adipic acid. Chem. Eng. Sci. 2010, 65, 1016–1027. (24) Kleetz, T.; Funke, F.; Sunderhaus, A.; Schembecker, G.; Wohlgemuth, K. Influence of Gassing Crystallization Parameters on Induction Time and Crystal Size Distribution. Cryst. Growth Des. 2016, 16, 6797–6803. (25) Kleetz, T.; Pätzold, G.; Schembecker, G.; Wohlgemuth, K. Gassing Crystallization at Different Scales: Potential to Control Nucleation and Product Properties. Cryst. Growth Des. 2017, 17, 1028– 1035. (26) Kleetz, T.; Braak, F.; Wehenkel, N.; Schembecker, G.; Wohlgemuth, K. Design of Median Crystal Diameter Using Gassing Crystallization and Different Process Concepts. Cryst. Growth Des. 2016, 16, 1320–1328. (27) Terdenge, L.-M.; Heisel, S.; Schembecker, G.; Wohlgemuth, K. Agglomeration degree distribution as quality criterion to evaluate crystalline products. Chem. Eng. Sci. 2015, 133, 157–169. (28) Ostermann, M.-C.; Termühlen, M.; Schembecker, G.; Wohlgemuth, K. Growth Rate Measurements of Organic Crystals in a Cone-Shaped Fluidized-Bed Cell. Chem. Eng. Technol. 2018, 41, 1165–1172. (29) Fogler, H. S. Elements Of Chemical Reaction Engineering, 4th ed.; Pearson Education, Inc.: London, UK, 2006. (30) Ejim, L. N.; Yerdelen, S.; McGlone, T.; Onyemelukwe, I.; Johnston, B.; Florence, A. J.; Reis, N. M. A factorial approach to understanding the effect of inner geometry of baffled meso-scale tubes on solids suspension and axial dispersion in continuous, oscillatory liquid–solid plug flows. Chem. Eng. J. 2017, 308, 669–682. 44


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(31) Kacker, R.; Regensburg, S. I.; Kramer, H. J. Residence time distribution of dispersed liquid and solid phase in a continuous oscillatory flow baffled crystallizer. Chem. Eng. J. 2017, 317, 413–423. (32) Tan, W.; Yang, X.; Duan, X.; Zhang, X.; Qian, G.; Zhou, X. Understanding supersaturationdependent crystal growth of L-alanine in aqueous solution. Cryst. Res. Technol. 2016, 51, 23–29.

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Page 46 of 46

883

For Table of Contents Use Only

884

Enhanced product quality control through separation of

885

crystallization phenomena in a four-stage MSMPR cascade

886

Marie-Christine Lührmann, Jan Timmermann, Gerhard Schembecker and Kerstin Wohlgemuth*

887

TU Dortmund University, Laboratory of Plant and Process Design,

888 889 890

Emil-Figge-Straße 70, 44227 Dortmund, Germany *Corresponding author: E-mail address: [email protected];

891

Tel.: +49 (0)231 755 3020; Fax: +49 (0)231 755 2341

892

893 894 895 896 897 898 899 900

The continuous operation of an MSMPR cascade, in which the crystallization phenomena of nucleation and growth are locally separated, is challenging but provides promising results with regard to enhanced product quality control. It turns out that the design of the vessels plays a crucial role. As a result, nucleation is induced by gassing in a small-volume vessel, so that the residence time of the crystals in the first stage is minimized. Crystal growth takes place in three subsequent vessels specifically designed to gently convey the suspension by gravity. 46


Enhanced product quality control through separation of crystallization

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