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Cooling Crystallization: Is Gassing Competetive to Seeding? Tobias Kleetz, Ricarda Scheel, Gerhard Schembecker, and Kerstin Wohlgemuth Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b01781 • Publication Date (Web): 02 Aug 2018 Downloaded from http://pubs.acs.org on August 5, 2018
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Crystal Growth & Design
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Cooling Crystallization:
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Is Gassing Competitive to Seeding?
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Tobias Kleetz, Ricarda Scheel, 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: gassing crystallization, seeding, production capacity, mean crystal size, induction
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time
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Abstract Cooling crystallization processes are most often controlled by adding seed crystals within the
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metastable zone to induce nucleation. Seeding is a challenging task and involves the risk of
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contamination. Its success depends on a lot of aspects, namely seed size and amount, time point
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and place of addition, and experience of the operator. Gassing to induce nucleation is an
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innovative technology which has shown in the past that nucleation control and product design is
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possible. Purpose of this paper is to show that gassing is competitive to seeding during a cooling
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crystallization process. Two different cooling process concepts with and without a holding time
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were considered. As model system succinic acid/water was used.
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Gassing as well as seeding enhances production capacity by shortening the production time by
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a quarter for product crystals with desired mean crystal size in comparison to a normal cooling
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crystallization process. Production capacity is slightly higher for seeding than for gassing, but
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gassing is competitive to seeding in many ways: It is simple and ensures constant product
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quality.
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1 Introduction Cooling crystallization is a frequently used method for separation and purification of
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biochemical and chemical high-priced products. It comes into action especially at the end of the
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process chain when the product should be a highly purified solid. Nucleation and crystal growth
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kinetics of the solute determine the product quality essentially and lay the foundation for further
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downstream processing starting with solid-liquid separation and ending up with drying. Thus,
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control of the kinetics is favorable. The product formed is usually evaluated by the crystal size
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distribution (CSD), mean crystal size, morphology, and purity.
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Nucleation control is mostly realized with the aid of seeding. Therefore seed crystals have to
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be produced in an elaborate process with desired quality, mean size, form and purity. Special
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attention shall be paid to place, time point, and kind of addition (dry crystals or crystals in
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suspension), also. Moreover, a risk of contamination during transfer of these crystals into the
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solution exists. Although this technology often finds its application in industry and research,
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there is no standard procedure for the design of a seeding process for a new product which
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predicts the crystallization behavior properly. Various heuristics exist, which highly depend on
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substance system and set-up. Therefore in pharma industry high effort is made to design a
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reliable seeding process that satisfies the regulatory requirements. In sum, it is a complex task
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and the success depends on the operator also. 1–5
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An innovative method to control nucleation is gassing crystallization. Gas bubbles are
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introduced into the solution within the metastable zone during the cooling crystallization
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process and induce nucleation in a targeted manner. The nucleation mechanism could be
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identified as a heterogeneous one, at which the gas bubble acts as foreign surface and reduces
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Gibb´s free energy to induce nucleation 6. During gassing crystallization different process
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parameters – in addition to the ones of normal cooling crystallization – are available to control
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the nucleation process: Gas volume flow, gassing duration, and gassing supersaturation. The
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latter one corresponds to the temperature within the metastable zone at which gassing is
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started to induce nucleation.
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Previous studies have shown that with gassing crystallization the mean crystal size can be
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controlled and enlarged in comparison to normal batch cooling crystallization independent of
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cooling profile used. The most influential parameter during gassing was identified to be gassing
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supersaturation. Induction time measurements showed that different gassing supersaturations
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applied resulted in different numbers of nuclei induced. In the end, due to the different numbers
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of nuclei product mean crystal size can be tailored. In addition, gassing crystallization
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experiments revealed that reproducibility is enhanced and batch time can be reduced
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remarkably. 7,8
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Aim of this study is to show that gassing crystallization is able to compete with seeding and –
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in addition – makes it possible to increase production capacity. Here, production capacity (PCap)
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is defined as ratio between crystal mass produced with desired product properties and the
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product of total batch volume and total batch time (equation 1). The batch volume is defined as
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the volume of solution at the beginning of the experiment and is therefore constant during the
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whole experiment.
=
∙
(1)
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2 Materials and Methods
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2.1 Investigated System
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Succinic acid (purchased from Wittich Umweltchemie GmbH) was used as solute with purity
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higher than 99.5 %. Ultrapure water (0.05 µS/cm, Millipore) was used as solvent. Equation (2)
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shows a correlation for the solubility of succinic acid in water 8. Synthetic air (Air Liquide,
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> 99.99%) stored in a gas bottle was used for gassing.
g csat SA =29.615 ×exp(0.0426 ×T °C) kgwater
(2)
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2.2 Experimental Setup
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Crystallization experiments were carried out in a 1 L LabMax® automated laboratory reactor
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system (Mettler ToledoTM). The experimental setup can be seen schematically in Figure 1. A
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detailed description of the setup is published elsewhere 8. The crystallizer was double jacketed
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with an inner diameter of 100 mm and a spherical bottom. The crystallizer was equipped with a
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stirrer, a gassing ring, an ATR-FTIR probe, and a FBRM probe, which were introduced into the
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crystallizer through the lid. The gassing ring was made of stainless steel, had an inner diameter
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of di = 50 mm and 24 holes, each with a diameter of di = 0.5 mm, drilled into the upper side. The
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FBRM probe was installed acting as baffle but was not used for particle measurement in this
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study. At the top of the crystallizer a seeding port is available.
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Crystal Growth & Design
Seeding port Gassing ring
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Figure 1 Schematic drawing of experimental setup
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2.3 Operating Procedures of Crystallization Experiments
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Figure 2 shows the temperature profiles as function of time for the experiments. The saturation
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temperature of Tsat = 39.6 °C (csat = 160 gSA/kgwater) and the final temperature of Tfinal = 20 °C
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were fixed for all experiments. Every experiment started with a preparation phase (t < 0 min), in
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which succinic acid crystals were dissolved in 1 L of water by increasing temperature from room
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temperature to starting temperature as soon as possible. Here, it was kept constant 10 K above
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Tsat for one hour, assuring same thermal history. Two different process alternatives were than
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performed in the execution phase. In both cases, cooling with a rate of κ = 0.25 K/min was
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started until the initial temperature Tinitial was reached at which gassing (Tgassing) or seeding
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(Tseeding) was applied, respectively. This was done because of two reasons: First, because we
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want to give the system the same thermal history, as mentioned before. Second, we want to save
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time but want to limit the undershoot during the holding time experiments and also when
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cooling rate is reduced. The stirrer speed was set to 300 rpm.
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For the first process alternative (linear cooling with holding time, dashed black line)
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temperature was held constant to give the nuclei induced time to grow until supersaturation
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was consumed and concentration reached a constant value (gray line), which was tracked with
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the aid of the ATR-FTIR probe. This means that the holding time is not a fixed time but rather is
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finished when solution concentration reached a constant value for about 5 minutes. When
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concentration is constant it is assumed that nuclei induced has consumed supersaturation
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during their growth fully. In fact if only a few nuclei are formed holding time is longer since they
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need more time to grow and consume supersaturation and vice versa. The resulting holding time
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at constant temperature is called induction time tind. Afterwards the suspension was cooled
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down with a cooling rate of κ = 0.25 K/min to Tfinal. The concentration follows more or less the
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solubility curve since supersaturation is consumed directly by the crystals available.
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For the second process alternative (linear cooling only, solid black lines) the holding time was
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omitted and suspension was cooled down with different cooling rates (κ = 0.1, 0.25, or 5
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0.4 K/min). This was done to show the opportunity of saving time (tBatch) for enhanced
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production capacity. The batch time is the only variable here, since crystals mass produced
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mProduct is constant due to equal saturation and end temperatures of all experiments and batch
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volume is also constant for all processes, since experiments are carried out in the same
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equipment (compare equation 1).
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To determine the initial temperatures for the gassing and seeding experiments the metastable
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zone width of the normal cooling crystallization in dependence of cooling rate was measured
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first.
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For gassing experiments the gassing temperature was chosen to Tgassing = 39 °C which was equal
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to a supersaturation of ∆cgassing = 4 gSA/kgwater, the gas volume flow to V gassing = 200 L/h, and
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gassing duration to tgassing = 55 s.
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The seeding process was designed as recommended by Warstat 9. The temperature of seed
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addition was chosen to Tseeding = 37.7 °C (∆cseeding = 12.43 gSA/kgwater) which equals 30 % of the
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smallest MZW measured for crystallization process with cooling rate of 0.25 K/min. This cooling
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rate was chosen since this is the smallest cooling rate for seeding process (as well as for gassing
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crystallization). Processes with the addition of dry seeds as well as a seed suspension were
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performed. The dry seed crystals were produced by sieving product crystals of former
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experiments. They were sieved to a product fraction with crystal sizes between 150 µm and
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350 µm with a d50 = 241.8 µm (See supporting information for CSD and microscopic pictures,
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Figure S1). The seed crystals mass mseed was calculated with equation 3 to 9.5 g. As characteristic
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length LSeed the d50 was chosen. The desired product crystal length LProduct was 539 µm, which
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resulted from the gassing crystallization experiments, which were executed before.
mseed = 137
mProduct LS3eed
(3)
L3Product -L3Seed
In order to prepare the seed suspension, a suspension of water with an excess of succinic acid
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was stirred at Tseeding=37.7 °C in a double jacket vessel for at least 48 h. Right before the
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experiment, a defined mass of the suspension was filtered to get a saturated solution
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(msaturated solution = 22.95 g, csat=147.6 gSA/kgwater) and then mixed with a desired mass of the dry
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seed crystals (mseed = 9.5 g). The mass of the saturated solution added was 2 % of the total mass
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of the starting solution of the crystallization experiment.
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When Tfinal was reached, the crystals were first harvested from the crystallizer and then
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separated from the mother liquor with a funnel filter, filter paper (pore size 2 µm) and a vacuum
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pump (Mini diaphragm vacuum pump VP 86, VWR). The wet product crystals were dried in a 6
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Crystal Growth & Design
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fluidized bed dryer (TG200, Retsch) with a volume flow of 45 L/h at 60 °C for 1 min. Drying
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procedure was repeated at least five times until constant weight of the sample was reached.
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The dry product crystals were divided into eight samples of equal mass using an automated
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sample divider (Rotary sample divider laborette 27, Fritsch). This procedure was repeated until
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a sample of approximately 5 g was left. Then, the sample was analyzed with the aid of a laser
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diffraction analyzer (LS 13 320, Beckman Coulter) with a Tornado Dry Powder System with
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respect to the volumetric crystal size distribution (CSD) and its characteristic values. The
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median crystal diameter is represented by d50 and the width of the crystal size distribution by
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the difference between d90 and d10. In order to evaluate measuring errors, all experiments have
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been performed twice unless otherwise mentioned.
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Figure 2 Experimental procedures for crystallization experiments applied for gassing crystallization,
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crystallization with seeding and normal cooling crystallization. Displayed are the preparation phase
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(t0 min) for linear cooling only (solid lines) and an exemplary profile
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for linear cooling with holding time (dashed line); The gray line shows schematically the concentration
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profile measured with ATR-FTIR probe during the process with holding time.
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3 Results and Discussion
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3.1.1 Linear Cooling Crystallization With Holding Time
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Many crystallization processes utilize an isothermal holding time in the metastable zone to
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produce in situ seed crystals, which can then be processed further, or to give seed crystals the
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time to grow at constant supersaturation. In both cases the resulting MZW is reduced. A measure 7
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for the duration of this holding time is the induction time tind, which gives also information about
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nucleation kinetics. In this section tind is evaluated for all crystallization methods considered in
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this paper. Usually, short induction times are favorable, but product crystal properties,
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especially the d50-value, should not be neglected.
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Figure 3 shows the induction times at T = 39 °C and the median diameters after subsequent
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cooling with ' = 0.25 K/min to Tfinal = 20 °C for the four methods investigated. The induction
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time is the longest for normal cooling crystallization and reduced by gassing. The addition of dry
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seed crystals as well as seed suspension reduces tind further to below 15 min. The d50-values of
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the normal cooling crystallization and gassing crystallization experiments are larger than those
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of the seeding methods. For induction time and median diameter the application of gassing and
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the addition of seeds enhance reproducibility (compare error bars given).
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Gassing induces nucleation and thus supersaturation present at Tgassing can be degraded faster
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compared to normal cooling crystallization, at which nuclei have to be created out of the
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solution. After the addition of seeds a large crystal surface is instantaneously present which can
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be used directly for crystal growth. Thus, supersaturation is degraded very fast, leading to a
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short tind.
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The amount of nuclei induced after normal cooling crystallization and gassing crystallization
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seem to be similar, because median diameters are in the same range7. The d50-values of the
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seeding experiments are smaller compared to normal cooling crystallization and gassing
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crystallization, which indicates that the surface present for crystal growth of seed crystals
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added, is higher than the surface of nuclei induced and grown to crystals after induction time by
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gassing or normal cooling crystallization. In other words: the chosen mass of seed crystals was
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too high. Shoulders within the CSDs of the seeding experiment indicate that secondary
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nucleation seems to play an important role during the holding time.
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Compared to normal cooling crystallization, gassing crystallization as well as seeding can
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improve reproducibility and reduce induction times, the latter enhancing production capacity
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especially for crystallization processes with a holding time. Even though seeding is highly
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reproducible and results in the highest production capacity, the benchmark median diameter is
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not reached, which shows that resulting product properties depend on quality of seed crystals
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and experience of the operator.
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cooling crystallization
gassing crystallization
dry seed crystals
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seed suspension
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d50
600 d50 [µm]
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500
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300 200
40
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20
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tind [min]
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Figure 3 Induction times (diamonds) and median diameters (bars) for normal cooling crystallization (green)
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gassing crystallization (gray), and seeding (blue) with dry seed crystals or seed suspension
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3.1.2 Linear Cooling Crystallization Without Holding Time
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In industrial processes the aim is often to produce product crystals with a median diameter as
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large as possible while minimizing fines as well as processing time. But with a faster cooling
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process the controllability of product properties is reduced considerably. Therefore, normally
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slow cooling rates are applied. For this reason, the possibility to reduce batch times while
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maintaining the median diameter with the help of gassing crystallization and seeding is
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investigated, since controllability and reproducibility are enhanced as shown before. The
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benchmark for the d50-value obtained is set to the value for normal cooling crystallization with a
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cooling rate of ' = 0.1 K/min. Figure 4 shows the median diameters d50 and width of CSD (d90-
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d10) for normal cooling crystallization, gassing crystallization, and seeding with dry seeds and
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seed suspension in dependence of the cooling rate, which is varied between ' = 0.1, 0.25, and
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0.4 K/min.
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Crystal Growth & Design
d50 [µm]
cooling crystallization gassing crystallization dry seed crystals seed suspension 600 500 400 300 200 100 0 0.1 K/min 0.25 K/min 0.4 K/min
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800 d90-d10 [µm]
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600 400 200 0 0.1 K/min 0.25 K/min 0.4 K/min
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Figure 4 Median diameter (top) and width of CSD (bottom) for cooling crystallization (green), gassing
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crystallization (gray), and seeding with dry seed crystals or seed suspension for varying cooling rates
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Regarding normal cooling crystallization, the higher the cooling rates the smaller the d50-values.
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This results from the fact that the faster supersaturation is generated the later kinetically
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inhibited nucleation processes occur leading to more nuclei, which then can grow to smaller
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crystals only. The benchmark d50-value for ' = 0.1 K/min was 442±34 µm, shown as black
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dashed line. Gassing induces nucleation earlier, thus in comparison to normal cooling
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crystallization fewer nuclei are produced, which then can grow to crystals with larger median
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diameter. This works for higher cooling rates as well. Similarly, this happens for the seeding
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methods. Seed crystals added at a low supersaturation can grow to larger crystals. The
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benchmark is reached by gassing crystallization as well as crystallization with seeding with a
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cooling rate of ' = 0.4 K/min. Therewith, it is possible to obtain a similar d50-value using gassing
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or seeding with a cooling process four times faster than for normal cooling crystallization.
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Comparing the benchmark cooling process with these alternative processes for same d50-values,
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it is notable that width of CSD (d90-d10) is nearly the same for gassing and normal cooling 10
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crystallization process but narrower for the seeding processes (compare Figure 4 bottom).
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Taking a closer look at the crystal size distributions (Figure 5) it can be seen that for the seeding
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processes shoulders within the CSDs are visible. These shoulders may be the result of
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uncontrolled secondary nucleation due to attrition of the seeds or additional primary nucleation.
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For the latter case supersaturation seems to be generated too fast so that seed crystals cannot
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degrade it solely and new nuclei are formed out of solution during the cooling process.
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Figure 5 Crystal size distributions of gassing crystallization and seeding with dry seed crystals and seed
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suspension with a cooling rate of κ = 0.4 K/min together with the benchmark normal cooling crystallization
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process with a cooling rate of κ = 0.1 K/min.
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4 Conclusion
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Gassing crystallization seems to be competitive to the two seeding methods applied in many
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ways. The reproducibility of gassing crystallization processes is as good as for crystallization
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with seeding and always better than normal cooling crystallization. Holding times in the
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metastable zone to produce in-situ seeds are reduced by gassing but are surely not as short as
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for direct addition of seed crystals. Compared to normal cooling crystallization it is possible to
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enlarge median crystal product diameters by the application of gassing or seeding. Setting the
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product of the normal cooling crystallization as benchmark, gassing and seeding allow
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generating a product with similar d50-values but with a four times faster cooling phase. Of
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course, the cooling duration is only one part of the process time of a crystallization process.
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While other parts like preparation and downstream processing maintain equal for all
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crystallization methods investigated here, it is possible to produce more of a specified product
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by gassing crystallization or with seeding in the same time resulting in a higher production
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capacity. The CSDs of the product obtained from seeding show a shoulder, which may be 11
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disadvantageous and shows that even the use of design strategies proposed in literature process
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was not optimal, since secondary nucleation occurs. The next step to optimize the process
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further should be to increase seed mass.
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Both, gassing crystallization and seeding, have in common that additional investment and
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operating costs are required for the gassing unit or the production of the seed crystals
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respectively. If a gassing unit is integrated into the process, additional costs are limited to the air
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(or other gas) used for gassing. The execution of gassing is simple and ensures constant product
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quality. In general, seeding methods are more complex and prone to error, since there are many
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more degrees of freedom having an effect on the product properties. Seeding requires more
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experience of the process designer to ensure constant performance. Once the perfect seeding
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method and parameters are found, it ensures a slightly better result than gassing crystallization.
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Anyway, this study showed that gassing crystallization seems to provide a competitive
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alternative to seeding, which can be applied to many batch crystallization setups with minimal
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effort. Moreover it could be fully automated which could be advantageous using standard
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operation procedures.
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Acknowledgement
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This work was funded by the Ministry of Innovation, Science and Research of the German
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Federal State of North Rhine-Westphalia (NRW) and by TU Dortmund University through a
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scholarship from the CLIB-Graduate Cluster Industrial Biotechnology (CLIB2021).
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Supporting Information
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In the supporting information file Figure S1 is provided showing the crystal size distribution and microscopic pictures of seed crystals used and notations for abbreviations and symbols.
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(1) Warstat, A. Heuristische Regeln zur Optimierung von Batch-
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Kühlungskristallisationsprozessen, Dissertation: Martin-Luther-Universität Halle-Wittenberg,
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Halle, 2006.
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(2) Rohani, S.; Horne, S.; Murthy, K. Control of Product Quality in Batch Crystallization of
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Pharmaceuticals and Fine Chemicals. Part 1: Design of the Crystallization Process and the Effect
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of Solvent. Org. Process Res. Dev. 2005, 9, 858–872.
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(3) Aamir, E.; Nagy, Z.K.; Rielly, C.D. Optimal seed recipe design for crystal size distribution
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control for batch cooling crystallisation processes. Chem. Eng. Sci. 2010, 65, 3602–3614.
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(4) Noriaki Kubota; Norihito Doki; Masaaki Yokota; Donepudi Jagadesh. Seeding Effect on
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Product Crystal Size in Batch Crystallization. J. Chem. Eng. Jpn. 2002, 35, 1063–1071.
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(5) Loï Mi Lung-Somarriba, B.; Moscosa-Santillan, M.; Porte, C.; Delacroix, A. Effect of seeded
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surface area on crystal size distribution in glycine batch cooling crystallization: a seeding
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methodology. J. Cryst. Growth 2004, 270, 624–632.
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(6) Wohlgemuth, K.; Kordylla, A.; Ruether, F.; Schembecker, G. Experimental study of the effect
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of bubbles on nucleation during batch cooling crystallization. Chem. Eng. Sci. 2009, 64, 4155–
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(7) Kleetz, T.; Funke, F.; Sunderhaus, A.; Schembecker, G.; Wohlgemuth, K. Influence of Gassing
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Crystallization Parameters on Induction Time and Crystal Size Distribution. Cryst. Growth Des.
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2016, DOI: 10.1021/acs.cgd.6b00895.
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(8) Kleetz, T.; Braak, F.; Wehenkel, N.; Schembecker, G.; Wohlgemuth, K. Design of Median
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Crystal Diameter Using Gassing Crystallization and Different Process Concepts. Cryst. Growth
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(9) Warstat, A. Optimierung von Batch Kühlungskristallisationen. Chem Ing. Tech. 2007, 79,
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Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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For Table of Contents Used Only
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Cooling Crystallization:
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Is Gassing Competitive to Seeding?
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Tobias Kleetz, Ricarda Scheel, Gerhard Schembecker, and Kerstin Wohlgemuth*
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Gassing crystallization seems to provide a competitive alternative to seeding, which can be
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applied to many batch crystallization setups with minimal effort. Setting the product of the
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normal cooling crystallization as benchmark, gassing and seeding allow generating a product
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with similar d50-values but four times faster. Gassing could be fully automated which could be
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advantageous using SOPs.
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ACS Paragon Plus Environment