Antisolvent batch crystallization

In the proposed continuous evaporative crystallization approach, a fixed amount of sohd compound obtained from a batch crystallization was slurried in a crystallizer in a solvent mixture of ethanol and n-butyl acetate. (n-Butyl acetate replaced acetone as the antisolvent.) n-Butyl acetate has a higher boiling point than ethanol. Therefore, as described below, ethanol can be readily removed by evaporation. 

Classification of batch crystallizers and batch crystallization operations according to the means by which supersaturation is created is still a widely accepted method. Therefore, the discussion of such operations may include cooling crystallization, evaporative crystallization, vacuum crystallization, antisolvent crystallization, reaction (reactive) crystallization, etc. The vacuum crystallization operation can be considered as a combination of the evaporative and cooling crystallization and thus will not be discussed separately. Reaction crystallization (precipitation) is discussed in detail in Chapter 6. 

In this type of batch crystallization, a solute is crystallized from a primary solvent by the addition of a second solvent (antisolvent) in which the solute is relatively insoluble. The antisolvent is miscible with the primary solvent and brings about a solubility decrease of the solute in the resulting binary solvent mixture. 

In the direct design approach, a desired supersaturation profile that falls between the solubility curve and the metastable limit of the system is followed based on feedback control of the concentration measurement. This is in contrast to the traditional first-principles approach, where a desired temperature profile or antisolvent addition rate profile is followed over time such as shown in Fig. 14. For a cooling crystallization, the direct design approach follows a setpoint profile that is solution concentration vs. temperature (or solvent-antisolvent ratio) as opposed to temperature (or addition rate) vs. time. Because the desired crystallizer temperature is determined from an in-situ solution concentration measurement, the batch time is not fixed. 

Rather, the batch time varies from batch to batch depending on the kinetics of the crystallization. As shown below, the direct design approach for antisolvent crystallization is implemented in a very similar manner. 

Fig. 15 shows an example of the direct design approach implemented for the isothermal antisolvent crystallization of acetaminophen (paracetamol) from acetone-water mixture. A constant relative supersaturation (Ac/c ) setpoint profile was followed. The flow rate setpoint of the antisolvent was calculated every minute based on the solution concentration measured using the IR spectra so that a setpoint supersaturation profile was followed. The change in solution concentration and antisolvent flow rate during the batch is shown in Fig. 16. After an initial start-up...

Fig. 15 Direct design approach using concentration measurement for seeded antisolvent crystallization of paracetamol (acetaminophen) from acetone-water mixture. The concentration-% solvent profile of the batch, the setpoint profile, and the solubility curve are shown. The setpoint followed is that of a constant relative supersaturation Ac/c = 0.04 g/mLsolvent+antisolvent"...

Fig. 17 FBRM counts during seeded batch antisolvent crystallizations of paracetamol from water/acetone with secondary nucleation and with minimum secondary nucleation.

For solvent systems with a window of operating temperature, proper selection of the method of supersaturation generation (e.g., cooling and antisolvent addition) and mode of crystallization (e.g., batch vs. semicontinuous) can also affect the overall crystal growth rate. In many instances in which solvent or impurity rejection becomes critical, adequate mixing to avoid local high supersaturation can be critical. Examples 9-2 and 10-4 illustrate two cases of rejection of impurities and residual solvent. These examples show how various means are applied to overcome these complications. 

Figure 8-3 Concentration profiles for crystallization by evaporation when the batch volume is held constant while an antisolvent is being added.

In the batch-mode operation, the conversion of free acid to the sodium salt was carried out in an etha-nol/acetone mixture. The sodium salt solution was prepared in the ethanol solution. The antisolvent acetone was added to the batch at 45 C to 50°C, with a trace amount of seed added to promote crystallization. The initial solids crystallized in the solution were a mixture of crystalline and amorphous materials. After extended aging, the amorphous material converted to needle-shaped crystalline material. The slurry was cooled, filtered, and washed with acetone. The wet cake was vacuum dried at 50°C. 

Typical arrangements for the antisolvent, salt formation, and pH shift crystallizations are the batch and semibatch arrangements. All crystallizations involve the mixing of two reactants this can occur, as shown in Figure 9.4, either via the mixing of two streams or by the addition of one component to the second residing in the vessel. 

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