Batch crystallization supersaturation profiles

Although cooling crystallization is the most common method of inducing supersaturation in batch crystallization processes, other methods can be used, as discussed in Chapter 10. For example, evaporation can be used, in which case the profile of the rate of evaporation through the batch can also be optimized7. Indeed, the profiles of both temperature and rate of evaporation can be controlled simultaneously to obtain greater control over the level of supersaturation as the batch proceeds7. However, it should be noted that there is often reluctance to use evaporation in the production of fine, specialty and pharmaceutical products, as evaporation can concentrate any impurities and increase the level of contamination of the final product. 

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. 

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"...

Batch crystallization process control using the first-principles and direct design approaches were discussed. The first-principles approach utilizes crystallization process models, which require the associated determination of crystallization kinetics. The optimal seed characteristics and/or supersaturation profile to obtain the desired product characteristics are then computed. The direct design approach involves feedback control of a state measurement, in this case the solution... 

The quality, productivity, and batch-to-batch consistency of the final crystal product can be affected by the conditions of the batch crystallizer. Several factors considered here include batch cycle time, supersaturation profile, external seeding, fouling control, CSD control, growth rate dispersions, and mixing. 

Figure 10.13 Schematic supersaturation profile in a batch crystallization experiment. (Reproduced with permission from Nyvlt et al. 1985.)...

The supersaturation profile in a batch crystallizer has a profound effect on the nucleation and growth processes and the resulting CSD. It can also affect other factors (e.g., batch cycle time) related to the batch crystallization operation. Figure 10.13 shows schematically a supersaturation profile in a batch crystallization experiment (Nyvlt et al. 1985). At / = 0, the batch crystallizer is filled with a just-saturated solution that contains crystals with a negligible surface area. The solution begins to be supersaturated at a constant rate, and the supersaturation increases until it reaches the limit of the metastable zone (Acmoi)- At this point, nucleation... 

It is important to recognize the similarity of the mathematical form of Eqs. (10.54) and (10.60), and Eqs. (10.55) and (10.61). One may conclude that all batch crystallization processes may be controlled by a properly designed time-profile of the supersaturation-indu-cing quantity (e.g., the cooling or evaporation rate, in the cases discussed in this chapter and the reagent addition rate, in Chapter 6 on precipitation). 

The bulk drug pilot plant must execute unusually varied processing with the requisite degree of control over the process variables, as well as have extraordinary means for data capture on-line (directly from sensors or analyzers in the equipment) and off-line (from samples tested in the laboratoiy and by derivation from raw data e.g., the supersaturation profile of a batch crystallization, the performance of a fermentation cell... 

Figure 9.12. Natural, controlled constant nucleation) and size-optimal cooling modes in a batch crystallizer a) temperature profiles, b) supersaturation profiles...

Cooling crystallization is the preferred option for batch crystallizations as the temperature profile in a reactor can be easily controlled giving perfect control of the supersaturation profile. This curve gives information at which temperature the process has to be started in order to have a reasonable solute/solvent ratio and avoid unnecessary high dilution on the other hand, the solubility at low temperatures fixes the yield that can be achieved with this process. 

The final CSD can be dramatically influenced by the temperature at which a continuous crystallizer is operated or by the temperature profile followed over a batch run, because the crystallizer temperature affects the degree of supersaturation and the growth and nucleation rates. Therefore, the manipulation of variables controlling the cooling rate (e.g., crystallizer jacket temperature, evaporation rate) can be used to influence the CSD. The adjustment of the feed rate to a continuous crystallizer has also been suggested as a means of affecting the CSD (Myerson et al. 1987 Han 1969). 

Furthermore, Jagadesh et al. [18,19] have studied seeded batch-cooling crystallization without temperature control for aqueous potassium alum, and potassium sulfate solutions. In their approach, the solution was cooled according to a natural profile. They succeeded in attaining a monodispersed and relatively narrow CSD by controlling the level of supersaturation in such a way that the existing seed crystals grew and no nucleation occurred. 

The driving force behind crystallization is the supersaturation of the solute in solution. A critical question in the design and operation of batch crystaUization processes is how the supersaturation should vary with time during the batch. This can be achieved by finding optimal temperature profile for cooling crystaUizers or by optimal evaporative rate profile for evaporative crystaUizers. 

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