Design of Median Crystal Diameter Using Gassing Crystallization and

Jan 25, 2016 - Martin Lucke , Iraj Koudous , Maximilian Sixt , Maximilian J. Huter , Jochen Strube. Chemical Engineering Research and Design 2018 133,...
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Design of Median Crystal Diameter Using Gassing Crystallization and Different Process Concepts Tobias Kleetz, Florian Braak, Nils Wehenkel, Gerhard Schembecker, and Kerstin Wohlgemuth* Laboratory of Plant and Process Design, TU Dortmund University, Emil-Figge-Straße 70, 44227 Dortmund, Germany S Supporting Information *

ABSTRACT: The reproducibility of product properties of normal batch cooling crystallizations is often insufficient. For a reliable design of product properties like the median diameter, it is essential to control the nucleation process. An innovative technology to induce nucleation during cooling crystallization is gassing. Therefore, quantification of the influence of gassing and process parameters is important. For this purpose, Design of Experiment approaches were used, investigating a linear cooling profile with constant cooling duration and quadratic cooling profiles with varied cooling duration. Succinic acid/water was used as the model system. The supersaturation where gassing is started was identified as most important design parameter using linear cooling profiles. Using quadratic cooling profiles, the median diameter can be mainly designed by adjusting the cooling duration. By the choice of the cooling profile and gassing supersaturation, it is possible to control the median diameter in a range between 300 and 750 μm. The results show also that independent from the cooling profile, gassing crystallization has an enlarging effect on the median diameter of product crystals. This effect can be used to reduce batch time for crystallization processes. nucleation method.7,14,15 Cavitation bubbles from sonocrystallization were replaced by gas bubbles of synthetic air. Experiments with gassing in combination with a linear cooling profile showed that gassing parameters (like gassing supersaturation, gas volume flow, and gassing duration) have a similar effect on the metastable zone width and the crystal size distribution like parameters from sonocrystallization (ultrasonic frequency, insonation supersaturation, insonation duration, and ultrasonic power).14 In this way, Wohlgemuth et al. concluded that there must be a primary heterogeneous nucleation mechanism where the Gibb’s free energy is reduced by the surface of the gas or cavitation bubble, respectively.15 Therefore, gassing crystallization appears to be a promising alternative to sonocrystallization. The application of gassing during a crystallization process is not completely new. Soare et al., for example, used gassing instead of a stirrer for mixing purposes to reduce secondary nucleation.16 The major difference is that we ensured mixing during the process using a stirrer, and gassing is used within in metastable zone to induce nucleation only. Besides the control of the nucleation step, the control of crystal growth is an important task during batch cooling crystallization, also. At high supersaturation the probability of secondary nucleation during the process is high, whereas at low supersaturation nucleation can be mostly avoided, promoting crystal growth.4,17,18 Common strategies to control super-

1. INTRODUCTION Batch cooling crystallization is often used in chemical, biochemical, and pharmaceutical processes to tailor the properties of the solid product. The product properties determine the efficiency of further process steps; in particular, it is the median diameter which determines the filterability, drying efficiency, or dissolution behavior.1−3 Consequently, it is essential to develop reproducible processes which allow controlling product properties. The median diameter depends on the nucleation event and the following crystal growth.4 Therefore, it is necessary to control nucleation, crystal growth, or both during the process.5 Additionally, agglomeration and breakage processes have to be considered.6 Seeding or the application of ultrasound is widely used to control nucleation.4,7,8 Seeding means the addition of crystals of the same type than the solute into the crystallizer within the metastable zone. In this way, spontaneous primary nucleation at high supersaturation can be avoided.4 Although seeding finds many applications in research and industry, the preparation of seed crystals is still a complex and expensive process, and the addition into the crystallizer always goes along with the risk of contamination.4,7,9 Another way to affect nucleation is the socalled sonocrystallization. Here, ultrasound is used to induce primary nucleation within the metastable zone.8,10−14 Ultrasound creates cavitation bubbles inside a solution which are assumed to affect the nucleation mechanism. Literature14 reports several applications of this technology, but the high energy input into the solution is disadvantageous especially for scale-up purposes.8 Similar to sonocrystallization, Wohlgemuth et al. developed gassing crystallization as an alternative induced © 2016 American Chemical Society

Received: October 6, 2015 Revised: January 14, 2016 Published: January 25, 2016 1320

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2. MATERIALS AND METHODS

saturation use special cooling concepts. Supersaturation control via feedback control is an often reported technology, which requires expensive process analytical technology (PAT), to track solution concentration during the process and control the temperature profile of the crystallizer in dependence of this concentration. Although several applications of PAT at industrial scales were reported in the past years, the application is still a challenging task.2,3,19−21 An easier approach is to control the supersaturation level with parabolic cooling profiles.4,17,22 If the solution of a crystallizer is cooled down with a linear cooling profile, supersaturation increases until spontaneous primary nucleation occurs in form of a nucleation shower and then decreases to a lower level. Applying a parabolic cooling profile, supersaturation can be maintained at a low level during the whole process. Mullin published a concept where the temperature is decreased with a cubic function of time.17 Typical for these kinds of cooling profiles is that cooling starts with a low cooling rate, accelerating at the end of the process, where supersaturation is degraded instantly by the grown crystal mass. These cooling profiles reduce undesired nucleation and promote crystal growth, resulting in larger product median diameters compared to a process with linear cooling profile and the same batch time.18,22 For our purposes, we chose quadratic cooling profiles, where solution temperature is decreased with a quadratic function of time. Supersaturation can still be kept at a low level during the process, but maximum cooling rates are lower compared to those of cubic cooling profiles. Especially for a transfer of crystallizations to bigger scales, where high cooling rates are often challenging to achieve, quadratic cooling profiles constitute a good compromise. As mentioned before, previous work on gassing crystallization focused on the identification of the nucleation mechanism and showed that gassing can be used to affect product properties.7,14,15 Besides gassing parameters, the shape of the cooling profile is known to have an influence on product properties, also. Wohlgemuth et al. used linear cooling profiles for their experiments only. This work considers gassing in combination with linear cooling profiles as well as quadratic cooling profiles. By quadratic cooling profiles, further nucleation during cooling is reduced. The goal of this work is to quantify the impact of gassing on the median diameter of the product crystals and to identify parameters which can be used to design the median diameter. Experiments were carried out in a systematic way using Design of Experiments (DoE). The experiments were evaluated with respect to the median crystal diameter obtainable for the two cooling concepts using linear and quadratic cooling profiles. The paper is organized as follows: The metastable zone width is measured to determine an operating window for gassing crystallization. A first DoE is designed and evaluated for linear cooling profiles. With respect to these results a second DoE is designed and evaluated for quadratic cooling profiles. The impact of gassing and process parameters investigated on the median diameter is given as the effect diagram and discussed. Beneath the median diameter, the width of the crystal size distribution, the agglomeration degree, and the morphology of product crystals are discussed also. Additionally, a comparison to experiments without gassing is made. The results are validated by predicting process parameters and verifying them experimentally.

2.1. Investigated System. Succinic acid was chosen as the solute compound. It was purchased from VWR International GmbH, Germany, with a purity higher than 99.5%. Water (Ultrapure, 0.05 μS/cm, Millipore) was used as solvent. The gassing material was synthetic air (Air Liquide, >99.99%), which was stored in a gas bottle. 2.2. Solubility. Figure 1 shows experimental data of the solubility of succinic acid in water measured in our laboratory together with the

Figure 1. Solubility of succinic acid in water. literature data from Qiu and Rasmuson.23 Solubility was measured gravimetrically in a stirred tank reactor (0.7 L). A solution with an excess of succinic acid was stirred under constant temperature for 16 h until equilibrium was reached. A sample was taken with a tempered syringe and a syringe filter (0.4 μm). The filtrate was dried at 50 °C in an oven until a constant weight was reached. Solubility was then calculated by the mass ratio between solid material and mass fraction of solvent in the filtrate. The temperature dependence of the solubility of succinic acid in water can be described by an exponential function according to eq 1, fitted to the experimental data (see Figure 1),

⎡ g ⎤ c*⎢ SA ⎥ = 29.615 exp(0.0426T[°C]) ⎢⎣ kg water ⎥⎦

(1)

2.3. Experimental Setup. The experimental setup can be seen schematically in Figure 2. Crystallization experiments were carried out in a 1 L LabMax automated laboratory reactor system from Mettler Toledo. The crystallizer was a double jacket with an inner diameter of 100 mm and a spherical bottom. As tempering medium silicone oil was used. A 45° pitched-blade turbine of stainless steel was used as the stirrer. A PT100 temperature probe, placed in the crystallizer, was directly connected to the LabMax system. The crystallizer was additionally equipped with a gassing ring, an ATR-FTIR probe, and a FBRM probe. Software from Mettler Toledo (IControl 5.0, IC IR 4.2, IC FBRM 4.3) was used to control the reactor system and probes. The gassing ring was designed similar to that used by Wohlgemuth et al.15 It was made of stainless steel, had an inner diameter of 50 mm and 24 holes, each with a diameter of 0.5 mm, drilled into the upper side. The gassing ring was placed directly above the stirrer causing an unhindered rise of the gas bubbles. The ring had a distance of 100 mm to the liquid surface, in the unstirred state. For gassing, the volume flow of synthetic air could be adjusted with a needle valve and was measured with a flow meter. Synthetic air was passed through a heated water bath (Twater bath = 45 °C) to saturate synthetic air with water. In this way, evaporation of the solution inside the crystallizer into the gas bubble could be prevented when synthetic air was entering the crystallizer via the gassing ring.15 The ATR-FTIR probe was used to measure solute concentration online. The probe was purged with dry air, whereas the detector was cooled with liquid nitrogen at least 24 h before the experiment started, to ensure robust measurement of IR-spectra. IR-spectra at concentrations between 60 gSA/kgwater and 180 gSA/kgwater were measured over a temperature range of 20 K for calibration, using 1321

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Figure 2. Experimental setup for gassing crystallization experiments.

Figure 3. Experimental procedure for crystallization experiments using linear or quadratic cooling profiles. Mettler Toledo software ICQuant. Partial least-squares regression was used to develop a prediction model for the concentration of succinic acid in water. Concentration could be measured with a total accuracy of 1 gSA/kgwater. The FBRM probe was used to track crystal counts per second which could be used as a measure for crystal density of the solution. The probe was placed with a 45° angle in the solution and was equipped with an additional baffle to enhance detection performance. 2.4. Experimental Procedure. The experimental procedure for all crystallization experiments was the same, unless otherwise mentioned. Figure 3 summarizes the experimental procedure for crystallization experiments including linear and quadratic cooling profiles. Solution was prepared with 1 kg of water and 0.16 kg of succinic acid. For the duration of 60 min, solution was held with 10 K above saturation temperature (Tsat = 39.6 °C). Stirring speed was 300 rpm, satisfying the 1 s-criterion. In the case of linear cooling, the solution was cooled into the metastable zone with a cooling rate of κ = 0.25 K/min, until gassing supersaturation Δcgassing was reached. Gassing was then executed with a predefined volume flow V̇ gassing. For the gassing duration tgassing, the stirrer was turned off resulting in less turbulence and consequently less deformation of the gas bubbles, which enhanced reproducibility. For time saving aspects, in the case of a quadratic cooling profile, the solution was first cooled with a cooling rate of κ = 0.5 K/min until Tsat was reached. Our experience showed that the cooling rate above Tsat has no influence on the product properties. For cooling to Δcgassing, the cooling rate was reduced to κ = 0.25 K/min to have the same cooling rate within the metastable zone like for the

linear cooling profile. Afterward, the stirrer was turned on again, and the final cooling profile was started until the final temperature of Tfinal = 20 °C was reached. In the case of a linear cooling profile, a constant cooling rate of κ = 0.25 K/min was applied further, resulting in an overall batch time of τbatch, LC = 120 min. As batch time we counted the time after the 1 h holding step. In the case of quadratic cooling, after gassing at Δcgassing the solution was heated up immediately to a lower supersaturation Δcstart with a heating rate of κ = 1 K/min. This step was necessary to prevent further nucleation at high supersaturation. When a supersaturation of Δcstart = 10.53 gSA/kgwater was achieved, the quadratic cooling profile was started, where the temperature decreases with a quadratic function of time. The shape of the quadratic cooling profile was determined by the cooling duration τcooling, QC, which affects the maximum cooling rates during the process. Figure 3 shows quadratic cooling profiles for the shortest (τcooling, QC, min = 72 min) and longest (τcooling, QC, max = 240 min) cooling duration. The overall batch time for the quadratic cooling profiles varied accordingly between τbatch, QC = 110−280 min. In all cases the suspension was harvested from the crystallizer at Tfinal = 20 °C. Mother liquor was filtered from the crystals with a vacuum pump (Mini diaphragm vacuum pump VP 86, VWR, Germany), using a funnel filter and filter paper with a pore size of 2 μm. Afterward, crystals were dried for 1 min in a fluidized bed dryer (TG 200, Retsch, Germany) with a volume flow of 45 l/h and a drying temperature of 60 °C. Product crystals were weighed, and the drying process was repeated until the weight was constant. A preliminary 1322

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experiment showed that a washing step had no influence on product properties and thus was omitted for this work. 2.5. Measurement of Metastable Zone Width. Gassing should be started in a crystal clear solution inside the metastable zone. Consequently, it was necessary to measure the metastable zone width (MZW) first to determine an operating window for gassing crystallization. The metastable zone width was determined 3-fold, using cooling crystallization without gassing. Experiments were started with a concentration of 160 gSA/kgwater, which meant a saturation temperature of Tsat = 39.6 °C. After 1 h holding at 10 K above saturation temperature, solution was cooled with a constant cooling rate of κ = 0.25 K/min. The nucleation temperature Tnuc was determined with the aid of FBRM probe, in accordance to Mitchell et. al.24 When the total number of chord counts exceeded a value of 5 #/s in the range less than 1000 μm, the corresponding temperature was interpreted as Tnuc. 2.6. Analysis of Product Crystals. The impact of the different gassing and process parameters was evaluated regarding the volumetric crystal size distribution (CSD) and its characteristic values, the morphology of the product crystals, and their agglomeration degree. Characteristic values of the CSD are the median crystal diameter d50 and the width of the CSD, described by the difference between d90 and d10. The CSD and the characteristic values were determined with laser diffraction (LS 13 320 laser diffraction particle size analyzer, Beckmann Coulter, Germany), using a Tornado Dry Powder System. Therefore, the dried product crystals were divided into eight samples of equal mass using an automated sample divider (Rotary sample divider laborette 27, Fritsch). In each case, two facing samples were combined to one sample. Two of these samples were then analyzed. Morphology of the crystals was investigated with an optical microscope (Motic SMZ-168) with a cold light source (Schott KL 1500 LCD). The Software Motic Images Plus 2.0 was used to take pictures with a 3.0 MP camera (Moticam 2300). Agglomeration degree (Ag) is described by the amount of agglomerates in relation to all crystals analyzed. Crystals were categorized manually using scanner images (Scanner Epson Perfection V750 Pro) and an image analysis tool.6 2.7. Design of Experiments. DoE was used to identify gassing and process parameters with impact on d50. A central composite design was chosen, considering the effect of single input factors and interactions as well as nonlinear relations.25,26 The DoE consisted of a 2k full factorial design with a cube, representing factor levels −1 and +1, center points, representing factor level 0, and a star with 2 k points. Here, k equals the number of input factors. For this work, a separate DoE was investigated for the linear and the quadratic cooling profile. Using a linear cooling profile, gas volume flow V̇ gassing, gassing duration tgassing, and gassing supersaturation Δcgassing were selected as input factors (k = 3). They were assumed to have an effect on the amount of nuclei induced (see section 1) and thus on the properties of the product crystals. The standard deviation was calculated by the execution of four center point experiments, resulting in a total of 18 experiments. For this design, the star value α was calculated to ±1.41.25,26 The response of the DoE was the median diameter d50. The second process concept considered in this work used quadratic cooling profiles. On the basis of the results of the DoE with linear cooling profiles, only Δcgassing was further considered. Additionally, the cooling duration τcooling, QC of the quadratic profile was assumed to have an effect on nucleation and growth because it strongly affects the resulting cooling rates. Therefore, two factors (k = 2) were investigated only. Again, standard deviation was calculated by a 4fold execution of the center point experiment, resulting in a total of 12 experiments. The star value α was calculated to ±1.21 for this case.25,26 The DoE was evaluated with respect to the response d50 also. A factor or a factor interaction was interpreted to have a significant effect on the response if exceeding a confidence interval of 95%. The confidence intervals were calculated using the standard deviation of the center point experiments and the Student’s distribution.25,26 The results of the DoE’s are quadratic regression models which describe the relationship between significant gassing and process parameters and the response.25,26

3. RESULTS AND DISCUSSION 3.1. Metastable Zone Width. The nucleation temperature Tnuc where the number of chord counts exceeded 5 #/s and the corresponding supersaturation Δcnuc are summarized in Table 1. Since broad deviations in MZW measured using normal cooling crystallization is common, we consider all results for the mean value. Table 1. Metastable Zone Width Using Cooling Crystallization without Gassing and a Linear Cooling Profilea Tnuc [°C]

a

Δcnuc [gSA/kgwater]

31.17 33.48 31.38

48.27 36.71 47.26

32.01 ± 1.04

44.08 ± 5.25

Cooling rate κ = 0.25 K/min, stirring speed R = 300 rpm.

3.2. Gassing and Linear Cooling Profile. Results of the DoE. The DoE for gassing in combination with a linear cooling profile was carried out with the factor levels presented in Table 2. The gas volume flow was varied in a range between 200 l/h and 500 l/h. Higher V̇ gassing resulted in gas jets, with an undefined surface. With respect to a good reproducibility of gassing crystallization processes, defined gas bubbles were favored. Lower V̇ gassing led to an uneven flow through the holes of the gassing unit, resulting in a bad distribution of gas bubbles in the solution and thus a worse reproducibility. Gassing duration was varied between 20 and 90 s. Longer tgassing might result in crystallization at the openings of the gassing ring, leading to a blockage. We assume that the gas bubble in combination with the uneven surface of the openings of the gassing ring promoted crystallization in those cases. The maximum value for Δcgassing was calculated from the average value of Δcnuc (section 3.1). Wohlgemuth et al. concluded that a crystal clear solution is guaranteed if the MZW, measured in this way, is multiplied with the factor 0.7.7 With the aid of Tsat = 39.6 °C the minimum solution temperature, where gassing should be executed was calculated to Tgassing,min = 34.29 °C and the corresponding maximum supersaturation to Δcgassing,max = 32.38 gSA/kwater. The minimum value was selected to Δcgassing = 5.22 gSA/kgwater, to provide a minimum amount of supersaturation. Figure 4 shows the result as effect diagram. The effect Δcgassing (C), on d50 is the only one exceeding the 95% confidence interval and thus the only significant parameter within the parameter ranges investigated. It has a negative effect of −57.98 μm, meaning that increasing Δcgassing from factor level −1 to 1 decreases the value of d50 by about 58 μm. Gas volume flow and gassing duration have no significant effects on d50. Even no quadratic or factor interaction is significant. This result can be explained with a look at the nucleation mechanism. A high supersaturation goes along with a high driving force for nucleation. If gassing is applied at high Δcgassing, a larger amount of nuclei is induced, compared to an experiment with low Δcgassing. After gassing, cooling of the solution continues. Nuclei grow to crystals, competing on succinic acid molecules in solution for growth. Consequently, if many nuclei have been induced, the succinic acid molecules distribute on more crystals, resulting in smaller d50 of the final 1323

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Table 2. Factors (A−C) and Levels Investigated Using the Linear Cooling Profilea level A B C a

factor

−α = −1.41

−1

0

1

+α = 1.41

volume flow [l/h] gassing duration [s] gassing supersaturation [gSA/kgwater]

200 (201.5) 20 5.22

250 (245) 30 9.20

350 55 18.80

450 (455) 80 28.40

500 (498.5) 90 32.38

Calculated factor values in brackets were slightly changed for the experiments for technical reasons.

and the center point experiments of the DoE for a linear cooling profile. Also shown are the corresponding results for d90-d10 and the Ag. Gas volume flow was 350 l/h and gassing duration was 55 s for all experiments. The standard deviations, resulting from the center point experiments, indicate a good reproducibility. Decreasing Δcgassing from the highest value (32.38 gSA/kgwater) to the lowest value (5.22 gSA/kgwater) d50 increases by roughly 90 μm. An increase of d50 goes along with an increase of d90-d10 but also with a reduction of Ag. The nucleation mechanism model we use to explain our results for the effect of Δcgassing on d50 also holds true to explain these findings. As mentioned before, gassing at higher Δcgassing leads to a larger amount of nuclei induced with a bigger total crystal surface. Consequently, supersaturation generated by cooling is degraded faster by growth, reducing further nucleation during cooling to Tfinal. As a result, d90-d10 is narrower for higher Δcgassing. According to the conclusions above, larger amounts of nuclei induced lead to smaller crystals which are prone to agglomerate, leading to higher values of Ag for higher Δcgassing.4 The general effect of gassing on d50 can be seen best if comparing results of this DoE to results of experiments without gassing. Gassing results in an enlargement of the d50 from 292.17 μm (no gassing) to over 400 μm, depending on the choice of Δcgassing (Table 3). Figure 5 shows the temperature

Figure 4. Effect diagram for the response d50 using linear cooling profiles. Hatched columns show significant effects, black columns insignificant effects. A: gas volume flow [l/h], B: gassing duration [s], C: gassing supersaturation [gSA/kgwater]. Constant process parameter: R = 300 rpm. Experimental data are available online as Supporting Information (see Table S1).

product. Since tgassing has no significant effect, it can be concluded that it is necessary to execute gassing for a short duration only. Nuclei seem to be induced at the beginning of gassing, and the amount does not increase for longer gassing durations. Gas volume flow has no significant influence also. Either this could mean that the amount of nuclei induced does not depend on the size of the gas bubble surface area, or the difference of the gas bubble surface created by the different V̇ gassing used was not high enough in the range investigated. As a result of the DoE, a regression model (eq 2) is developed which is valid for the parameter ranges investigated only (Table 2). In eq 2, the factor level of Δcgassing is represented by xC. Using gassing in combination with a linear cooling profile, it is possible to design d50 by the choice of Δcgassing and the corresponding regression model (eq 2). d50[μm] = 459.21 − 28.98xC

(2)

Comparison of Product Properties of Gassing and Normal Cooling Crystallization. Table 3 shows the results for d50 from experiments with the lowest (−α) and the highest (+α) Δcgassing

Figure 5. Temperature and supersaturation profile of two experiments with and without gassing and a linear cooling profile with constant cooling rate of 0.25 K/min. Gassing parameters were V̇ gassing = 350 l/h, tgassing = 55 s, Δcgassing = 5.22 gSA/kgwater.

Table 3. Median Diameter d50, width of CSD d90-d10 and Agglomeration Degree Ag for the DoE Experiments with the Lowest and Highest Supersaturation and the Center Point Experimentsa xC −α = −1.41 0 +α = 1.41

Δcgassing [gSA/kgwater]

d50 [μm]

d90-d10 [μm]

Ag [%]

5.22 18.80 32.38 no gassing

494.98 459.2 ± 7.4 404.63 292.17 ± 25.1

716.94 653.1 ± 11.7 630.03 544.6 ± 98.16

58.58 80.36 86.87 76.05

and supersaturation profiles of one experiment with and without gassing, each. Gassing reduces the maximum supersaturation from 48 gSA/kgwater to less than 20 gSA/kgwater. This shows again that the application of gassing leads to a defined the amount of nuclei induced during this linear cooling profile. As a result, a spontaneous nucleation shower can be avoided and bigger d50 be achieved. Concluding, gassing in combination with a linear cooling profile can be used to produce crystals with remarkable larger

V̇ gassing = 350 l/h, tgassing = 55 s, κ = 0.25 K/min. Results of experiments without gassing for comparison. a

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Table 4. Factors (A and B) and Levels Investigated Using Quadratic Cooling Profiles level A B

factor

−α = −1.21

−1

0

1

+α = 1.21

cooling duration [min] gassing supersaturation [gSA/kgwater]

72 10.53

86.58 12.18

156 19.78

225.42 27.00

240 28.47

d50 than produced with normal cooling crystallization with a better reproducibility. 3.3. Gassing and Quadratic Cooling Profile. Results of the DoE. As a result of the first DoE (section 3.2), here, the gassing supersaturation is investigated further with a quadratic cooling profile only. Gas volume flow and gassing duration were shown to have no significant effects on d50 (section 3.2). Consequently, these parameters were fixed to 350 l/h and 55 s and were not considered any further. In addition to Δcgassing, the duration of the quadratic cooling profile τcooling, QC was used as input parameter of the DoE. The cooling duration determined the maximum cooling rate of the profile. It was assumed that it has a great influence on secondary nucleation and growth effects and thus on d50. The factor levels are presented in Table 4. Cooling duration was varied between 72 and 240 min. The minimum value was limited by the maximum cooling rate possible for the experimental setup, which was κ = 0.5 K/min. The maximum value was chosen to realize the execution of the complete experiment (preparation, execution, downstream) during 1 day in the laboratory. Gassing supersaturation was varied between 10.53−28.47 gSA/kgwater. The minimum value was limited by the starting supersaturation Δcstart = 10.53 gSA/ kgwater of the quadratic cooling profile. Gassing supersaturations lower than Δcstart would mean a cooling step from Δcgassing to Δcstart. To provide identical experimental conditions for every experiment of the DoE, gassing supersaturations bigger than Δcstart were considered only, resulting in a short heating step after gassing. Maximum Δcgassing was reduced further from 32.38 gSA/kgwater (compare DoE section 3.2) to 28.47 gSA/ kgwater to avoid primary nucleation. Small temperature undershoots between cooling to Δcgassing and heating to Δcstart could result in primary nucleation. Figure 6 shows the results of the DoE using quadratic cooling profiles. The cooling duration (A) has a linear significant effect on d50. The positive effect of 158.99 μm means that an enhancement of τcooling, QC from factor level −1 to 1 results in an enlargement of d50 of around 159 μm. The gassing supersaturation (B) has a nonlinear significant effect on d50, whereas the factor interaction between A and B has a significant effect also. An explanation for the significant effect of τcooling, QC can be given by regarding further nucleation and growth during cooling from Δcstart to Tfinal. If applying a quadratic cooling profile with τcooling, QC = 72 min the cooling rates are higher, compared to a cooling profile with τcooling, QC = 240 min. Higher cooling rates result in higher temperature gradients between cooling jacket and bulk solution, causing higher local supersaturation, which cannot be degraded by growth solely in the present case. The consequence is a promotion of further nucleation. A higher amount of nuclei grow to comparatively more smaller crystals competing for growth on the one hand and with a higher tendency for agglomeration on the other hand.4 The interaction (AB) of Δcgassing and τcooling, QC can be explanined with the aid of a contour plot which is shown in

Figure 6. Effect diagram for the response d50 using quadratic cooling profiles. Hatched columns show significant effects, black columns insignificant effects. A: cooling duration [min], B: gassing supersaturation [gSA/kgwater]. Constant gassing parameters: V̇ gassing = 350 l/ h, tgassing = 55 s, constant process parameter: Δcstart = 10.53 gSA/kgwater, R = 300 rpm. Experimental data are available online as Supporting Information (see Table S2).

Figure 7. Displayed is the dependency of d50 from Δcgassing and τcooling, QC. For short τcooling, QC the d50 is at around 600 μm,

Figure 7. Contour plot of the response d50 [μm] for the interaction between τcooling, QC (A) and Δcgassing (B).

independent of Δcgassing chosen. Only for long τcooling, QC,, d50 can be controlled in a range between 718 and 756 μm. Here we can see again the trend that higher Δcgassing result in smaller d50 because more nuclei are created and compete for growth during cooling. For lower τcooling QC, we assume that the amount of nuclei induced by gassing is compensated by further nucleation during cooling, since cooling rates are higher. Concluding, the linear effect of τcooling, QC dominates this interaction. This can also be seen in the effect diagram (see Figure 6). Here, the effect of τcooling, QC (A) is 5.7 fold higher than the nonlinear effect of Δcgassing (B). For this reason, τcooling, QC can be considered as main design parameter. 1325

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Table 5. Median Diameter d50, Width of CSD d90-d10 and Agglomeration Degree Ag for the DoE Experiments with the Shortest and Longest Cooling Duration and the Center Point Experimentsa

a

βA

τcooling [min]

Δcgassing [gSA/kgwater]

d50 [μm]

d90-d10 [μm]

Ag [%]

−α = −1.21 0 α = 1.21

72 156 240 72 240

19.78 19.78 19.78 no gassing no gassing

551.81 663.70 ± 3.97 756.84 484.97 ± 17.92 656.98 ± 0.27

866.33 1016.78 ± 24.87 1084.09 685.86 ± 17.28 899.13 ± 13.41

53.24 n.d. 17.89 50.67 17.86

V̇ gassing = 350 l/h, tgassing = 55 s. Results for experiments without gassing for comparison.

Figure 8. Microscopic pictures of crystals of a sieved fraction between 500 and 800 μm from experiments of the DoE with quadratic cooling profiles. On the left τcooling, QC, min = 72 min, on the right τcooling, QC, max = 240 min.

Figure 9. Temperature and supersaturation profiles for experiments with and without gassing and quadratic cooling profile. Left: τcooling, QC, min = 72 min, right: τcooling, QC, max = 240 min. Constant parameters: Δcgassing = 19.78 gSA/kgwater, Δcstart = 10.53 gSA/kgwater, V̇ gassing = 350 l/h, tgassing = 55 s, R = 300 rpm.

The positive nonlinear effect of Δcgassing cannot be explained solely with the nucleation mechanism model we used before. We expected a negative linear effect of Δcgassing because higher amounts of nuclei induced should result in smaller d50 for the quadratic cooling profile also. Further nucleation can be the reason why a conclusion from Δcgassing to the amount of nuclei induced is not possible in this case. This assumption is supported by the interpretations of the contour plot (Figure 7). Gassing supersaturation has an influence for long τcooling, QC only where further nucleation is reduced. Equation 3 gives the regression model for the median diameter and is valid for the parameter ranges investigated only (Table 4).

Comparison of Product Properties of Gassing and Normal Cooling Crystallization. The cooling duration can be used to design d50. By enhancing τcooling, QC from the shortest duration (72 min) to the longest (240 min) considered in this work, d50 is enlarged by roughly 200 μm (see Table 5). This counts for experiments with gassing as well as for experiments without gassing. With increasing d50, the value for d90-d10 is increasing and Ag is reduced remarkably. Microscopic pictures of crystals of a sieved fraction between 500 and 800 μm show the difference between crystals from the experiment with τcooling, QC, min = 72 min and τcooling, QC, max = 240 min (Figure 8). On the left side picture (72 min), we observe a mixture of single crystals and agglomerates, whereas on the right side picture (240 min) we see mostly single crystals. Single crystals of succinic acid crystallized out of water look like plates. The crystals of the experiments from the right

d50[μm] = 663.70 + 79.5xA − 14.01x B − 9.36xAB + 8.46x Bx B

(3) 1326

DOI: 10.1021/acs.cgd.5b01428 Cryst. Growth Des. 2016, 16, 1320−1328

Crystal Growth & Design

Article

4. CONCLUSIONS The purpose of this paper is to show that gassing crystallization in combination with different cooling profiles applied can be used to design median crystal diameter d50. Independent of the cooling profile, gassing affects an enlargement of the d50 of about 70 to 200 μm compared to the same cooling profile without gassing. By selecting different gassing parameters and cooling concepts the median diameter of our succinic acid crystals can be designed in a range between 300 and 750 μm. At the same time, agglomeration processes are reduced and the width of the CSD (d90-d10) increases for product crystals with increasing d50. Comparing processes with and without gassing, it can be concluded that identical crystal properties can be received, but with gassing the batch time of a cooling crystallization process can be reduced remarkably. Next step for the investigation of gassing crystallization processes is the transferability of the findings of this paper to bigger scales and other substance systems.

side picture have a rounded shape resulting from attrition during the long cooling duration. These observations are supported by the determination of agglomeration degrees and characteristic values of the CSD of these experiments (see Table 5). The Ag of the experiment with τcooling, QC, min = 72 min is about 3-fold higher than for the experiment with τcooling, QC, max = 240 min. Further nucleation during cooling is also the reason why d90-d10 is narrower for shorter τcooling, QC. Although Δcgassing is not a strong design parameter for this process concept, gassing has still an enlarging effect on d50. In comparison to identical experiments without gassing, we observe a remarkable enlargement of d50 by 70−100 μm (see Table 5). Figure 9 displays the temperature and supersaturation profiles for the shortest (left) and longest (right) τcooling, QC for experiments with and without gassing. By gassing at Δcgassing = 19.78 gSA/kgwater, a controlled amount of nuclei is induced, which begins to grow to crystals at Δcstart. Supersaturation at Δcstart is degraded immediately by the nuclei induced. This process is observed for short as well as for long τcooling, QC. Without gassing, the induction process takes longer, resulting in a nucleation shower with a high and uncontrollable amount of nuclei. For a short τcooling, QC the nucleation shower occurs at Δc = 26.48 gSA/kgwater and for a long τcooling, QC at Δc = 13.94 gSA/kgwater. As a result, the d50 of the product crystals is smaller for a process without gassing, because the amount of nuclei from the spontaneous nucleation shower is remarkably higher. For this process concept, gassing has a lower effect using shorter τcooling, QC, because of secondary nucleation, created by higher cooling rates. The nuclei created by secondary nucleation affect, that d50 is additionally reduced, because they compete with others for growth. Concluding, for the process concept using a quadratic cooling profile, d50 can be controlled primarily by the choice of the τcooling QC. Gassing supersaturation has a significant effect on d50 also. 3.4. Design of Median Crystal Diameter Using Regression Models. In order to demonstrate that the regression models allow predicting d50 correctly (see section 3.2 and 3.3) we wanted to design product crystals of succinic acid with a d50 of 625 μm exemplarily. Therefore, we applied a quadratic cooling profile in combination with gassing. Gassing and process parameters could be chosen in the ranges investigated for the DoE (Table 4). Since we think that Δcgassing has not to be considered as design parameter, we chose it to Δcgassing = 15 gSA/kgwater randomly. Solving eq 3, the necessary cooling duration resulted in a value of τcooling, QC = 124.62 min. These two parameters and the fixed gassing and process parameters from section 3.3 were used for the experiment, which was repeated once to show reproducibility. Results are given in Table 6. The median diameter of the resulting product crystals differs approximately 5 μm from the desired 625 μm only.

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.5b01428. Experimental data of Design of Experiments for linear and quadratic cooling profiles (PDF)

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τcooling [min]

d50 [μm]

d90-d10 [μm]

15

124.62

629.83 ± 4.38

949.7 ± 72.7

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel.: +49 (0)231 755 3020. Fax: +49 (0)231 755 2341. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work is funded by the Ministry of Innovation, Science and Research of the German Federal State of North RhineWestphalia (NRW) and by TU Dortmund University through a scholarship from the CLIB-Graduate Cluster Industrial Biotechnology (CLIB2021).

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ABBREVIATIONS ATR-FTIR attenuated total reflectance Fourier transform infrared spectroscopy CSD crystal size distribution DoE design of experiments FBRM focused beam reflectance measurement IR infrared LC linear cooling MZW metastable zone width PAT process analytical technology QC quadratic cooling SA succinic acid Symbols

A, B, C Ag Δcgassing

Table 6. Result of Median Diameter d50 and Width of CSD d90-d10 for Experiments of a Design Examplea Δcgassing [gSA/kgwater]

ASSOCIATED CONTENT

Δcgassing, max Δcnuc

Δcstart = 10.53 gSA/kgwater, V̇ gassing = 350 l/h, tgassing = 55 s, R = 300 rpm. a

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input factors of the DoE agglomeration degree [%] supersaturation, where gassing is started [gSA/ kgwater] maximum supersaturation, where gassing is started [gSA/kgwater] supersaturation when nucleation occurs [gSA/ kgwater] DOI: 10.1021/acs.cgd.5b01428 Cryst. Growth Des. 2016, 16, 1320−1328

Crystal Growth & Design Δcstart d50 d90-d10 R Tfinal Tgassing, min Tnuc Tsat tgassing V̇ gassing xi

Article

(25) Kleppmann, W. In Taschenbuch Versuchsplanung; Hanser: München, Wien, 2008; Vol. 5. (26) Montgomery, D. C. In Design and Analysis of Experiments; John Wiley & Sons, Inc.: Hoboken, NJ, 2013; Vol. 8.

supersaturation where a quadratic cooling profile is started [gSA/kgwater] median crystal size [μm] width of the crystal size distribution [μm] stirrer speed [rpm] final temperature of the cooling profile [°C] minimum temperature, where gassing can be started [°C] temperature, where nucleation occurs [°C] saturation temperature [°C] duration of the gassing process [s] gas volume flow [l/h] factor level of input factors of the DoE

Greek letters

α κ τbatch, LC τbatch, QC τcooling, QC

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star value for the central composite design in DoE cooling rate [K/min] batch time of an experiment with linear cooling profile [min] batch time of an experiment with quadratic cooling profile [min] cooling duration of a quadratic cooling profile [min]

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DOI: 10.1021/acs.cgd.5b01428 Cryst. Growth Des. 2016, 16, 1320−1328