Cooling Crystallization: Does Gassing Compete with Seeding

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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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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 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)

70 71

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.

4


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Seeding port Gassing ring

87 88

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

145

pump (Mini diaphragm vacuum pump VP 86, VWR). The wet product crystals were dried in a 6


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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.

156 157

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

168

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.

8


cooling crystallization

gassing crystallization

dry seed crystals

800

seed suspension

140 tind

700

d50

600 d50 [µm]

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


120 100

500

80

400 60

300 200

40

100

20

0

tind [min]

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0

197 198

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

211

0.4 K/min.

9



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

212

800 d90-d10 [µm]

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600 400 200 0 0.1 K/min 0.25 K/min 0.4 K/min

213 214

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.

217

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

219

crystals only. The benchmark d50-value for ' = 0.1 K/min was 442±34 µm, shown as black

220

dashed line. Gassing induces nucleation earlier, thus in comparison to normal cooling

221

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

225

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.

227

Comparing the benchmark cooling process with these alternative processes for same d50-values,

228

it is notable that width of CSD (d90-d10) is nearly the same for gassing and normal cooling 10


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229

crystallization process but narrower for the seeding processes (compare Figure 4 bottom).

230

Taking a closer look at the crystal size distributions (Figure 5) it can be seen that for the seeding

231

processes shoulders within the CSDs are visible. These shoulders may be the result of

232

uncontrolled secondary nucleation due to attrition of the seeds or additional primary nucleation.

233

For the latter case supersaturation seems to be generated too fast so that seed crystals cannot

234

degrade it solely and new nuclei are formed out of solution during the cooling process.

235 236 237

238 239

Figure 5 Crystal size distributions of gassing crystallization and seeding with dry seed crystals and seed

240

suspension with a cooling rate of κ = 0.4 K/min together with the benchmark normal cooling crystallization

241

process with a cooling rate of κ = 0.1 K/min.

242

4 Conclusion

243

Gassing crystallization seems to be competitive to the two seeding methods applied in many

244

ways. The reproducibility of gassing crystallization processes is as good as for crystallization

245

with seeding and always better than normal cooling crystallization. Holding times in the

246

metastable zone to produce in-situ seeds are reduced by gassing but are surely not as short as

247

for direct addition of seed crystals. Compared to normal cooling crystallization it is possible to

248

enlarge median crystal product diameters by the application of gassing or seeding. Setting the

249

product of the normal cooling crystallization as benchmark, gassing and seeding allow

250

generating a product with similar d50-values but with a four times faster cooling phase. Of

251

course, the cooling duration is only one part of the process time of a crystallization process.

252

While other parts like preparation and downstream processing maintain equal for all

253

crystallization methods investigated here, it is possible to produce more of a specified product

254

by gassing crystallization or with seeding in the same time resulting in a higher production

255

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

257

was not optimal, since secondary nucleation occurs. The next step to optimize the process

258

further should be to increase seed mass.

259

Both, gassing crystallization and seeding, have in common that additional investment and

260

operating costs are required for the gassing unit or the production of the seed crystals

261

respectively. If a gassing unit is integrated into the process, additional costs are limited to the air

262

(or other gas) used for gassing. The execution of gassing is simple and ensures constant product

263

quality. In general, seeding methods are more complex and prone to error, since there are many

264

more degrees of freedom having an effect on the product properties. Seeding requires more

265

experience of the process designer to ensure constant performance. Once the perfect seeding

266

method and parameters are found, it ensures a slightly better result than gassing crystallization.

267

Anyway, this study showed that gassing crystallization seems to provide a competitive

268

alternative to seeding, which can be applied to many batch crystallization setups with minimal

269

effort. Moreover it could be fully automated which could be advantageous using standard

270

operation procedures.

271 272

Acknowledgement

273

This work was funded by the Ministry of Innovation, Science and Research of the German

274

Federal State of North Rhine-Westphalia (NRW) and by TU Dortmund University through a

275

scholarship from the CLIB-Graduate Cluster Industrial Biotechnology (CLIB2021).

276 277

Supporting Information

278 279

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.

280

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5 References

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(1) Warstat, A. Heuristische Regeln zur Optimierung von Batch-

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Kühlungskristallisationsprozessen, Dissertation: Martin-Luther-Universität Halle-Wittenberg,

284

Halle, 2006.

285

(2) Rohani, S.; Horne, S.; Murthy, K. Control of Product Quality in Batch Crystallization of

286

Pharmaceuticals and Fine Chemicals. Part 1: Design of the Crystallization Process and the Effect

287

of Solvent. Org. Process Res. Dev. 2005, 9, 858–872.

288

(3) Aamir, E.; Nagy, Z.K.; Rielly, C.D. Optimal seed recipe design for crystal size distribution

289

control for batch cooling crystallisation processes. Chem. Eng. Sci. 2010, 65, 3602–3614.

290

(4) Noriaki Kubota; Norihito Doki; Masaaki Yokota; Donepudi Jagadesh. Seeding Effect on

291

Product Crystal Size in Batch Crystallization. J. Chem. Eng. Jpn. 2002, 35, 1063–1071.

292

(5) Loï Mi Lung-Somarriba, B.; Moscosa-Santillan, M.; Porte, C.; Delacroix, A. Effect of seeded

293

surface area on crystal size distribution in glycine batch cooling crystallization: a seeding

294

methodology. J. Cryst. Growth 2004, 270, 624–632.

295

(6) Wohlgemuth, K.; Kordylla, A.; Ruether, F.; Schembecker, G. Experimental study of the effect

296

of bubbles on nucleation during batch cooling crystallization. Chem. Eng. Sci. 2009, 64, 4155–

297

4163.

298

(7) Kleetz, T.; Funke, F.; Sunderhaus, A.; Schembecker, G.; Wohlgemuth, K. Influence of Gassing

299

Crystallization Parameters on Induction Time and Crystal Size Distribution. Cryst. Growth Des.

300

2016, DOI: 10.1021/acs.cgd.6b00895.

301

(8) Kleetz, T.; Braak, F.; Wehenkel, N.; Schembecker, G.; Wohlgemuth, K. Design of Median

302

Crystal Diameter Using Gassing Crystallization and Different Process Concepts. Cryst. Growth

303

Des. 2016, 16, 1320–1328.

304

(9) Warstat, A. Optimierung von Batch Kühlungskristallisationen. Chem Ing. Tech. 2007, 79,

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272–280.

306 307

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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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311 312

Tobias Kleetz, Ricarda Scheel, Gerhard Schembecker, and Kerstin Wohlgemuth*

313

314 315

Gassing crystallization seems to provide a competitive alternative to seeding, which can be

316

applied to many batch crystallization setups with minimal effort. Setting the product of the

317

normal cooling crystallization as benchmark, gassing and seeding allow generating a product

318

with similar d50-values but four times faster. Gassing could be fully automated which could be

319

advantageous using SOPs.

14


Cooling Crystallization: Does Gassing Compete with Seeding

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