Continuous supersaturation, control

Crystallization batches range from 30,000 to 60,000 Hters for each pan. Continuous centrifugals are typically used for second, third, and affination steps continuous vacuum pans are less common but are used in the U.S. for intermediate strikes. Most horizontal batch crystallizers have been replaced by continuous units, and all are designed for controlled cooling of the massecuite to maintain supersaturation. 

Surface Spiral Step Control. Many crystals grow faster at small supersaturation than allowed by Equation 7. This lead Frank (17) to suggest that steps may also originate from the presence of a screw dislocation, and that this kind of steps is not destroyed by spreading to the crystal edge, but continues infinitely. The rate law according to this theory is parabolic (7). We shall use the following version of the kinetic equation (10)... 

Preferential crystallisation is one option for optical resolution on a manufacmr-ing scale. Online polarimetry and refractometry have been used to d3mamically optimise the process for resolution of DL-threonine in aqueous solution by variation of process parameters such as degree of supersaturation, seed quantity, initial enantiomeric excess and scale [148]. The method is claimed to be suitable for control of quasi-continuous processes. 

As described in previous chapters in Part II, liquid-continuous impinging streams (LIS) has the feature of very efficient micromixing and can provide a uniform and controllable supersaturation environment for the crystallization process, favoring the production of uniformly large-sized crystalline also, it has been proved experimentally that, to an extent, LIS can enhance crystal-growth rate. For industrial application, Wu [237] designed and patented the impinging stream crystallizer, the structure of which is shown in Fig. 17.3. 

These problems are avoided if a continuous process is employed for the precipitation however, this makes higher demands on the process control. In a continuous process all parameters as temperature, concentrations, pH, and residence times of the precipitate can be kept constant or altered at will. Continuous operation is, for instance, used for the precipitation of aluminum hydroxide in the Bayer process. Bayer aluminum hydroxide is the main source for the production of cata-lytically active aluminas. The precipitation step of the Bayer process is carried out continuously. An aluminum solution supersaturated with respect to Al(OH)3, but not supersaturated enough for homogeneous nu-cleation, enters the precipitation vessel which already contains precipitate so that heterogeneous precipitation is possible. The nucleation rate has to be controlled very carefully to maintain constant conditions. This is usually done by controlling the temperature of the system to within 2-3 degrees [7]. 

Two notable methods to produce microcellular foams include gas supersaturation in combination with an extrusion process developed by MIT/Trexel [84-86] and the continuous extrusion process by Dow [87,88]. Super-insulating materials are made by the encapsulation of a filler material inside a barrier film, aluminum foil, or metallized film. These materials exhibit 5-7 times the R-value of typical nonvacuum insulating materials depending on vacuum level and barrier and filler type. Uses for these VIPs (vacuum insulation panels) include refrigeration and controlled-temperature shipping containers. 

A primary example is the resolution of optical isomers by continuous crystallization in fluid beds. Control of low supersaturation by control of the temperature difference between the continuous feed and the seed bed is critical to maintaining an essentially all-growth regime in which the individual isomers grow on their respective seeds in separate crystalfi-zers. The seed beds in both crystallizers are massive in relation to the amount of racemic solution passing through in order to present sufficient seed area to maintain low supersaturation. Uncrystallized isomers in the overhead streams are recycled to dissolve additional racemic feed. Crystal size is maintained by sonication. See Examples 7-6 and L1-6 for a discussion of resolution of optical isomers by continuous crystallization. 

Although widely practiced for production of industrial chemicals, continuous evaporation for crystallization is rarely if ever used in pharmaceutical operations. Although continuous operation has the advantages of using massive seeding and increased control of supersaturation and the crystal surface area, the throughput necessary for its application is rarely, if ever, achieved for final bulk drug substances. In addition, continuous operation to achieve the conditions for crystallization (as discussed above for resolution of optical isomers) is often not... 

It should be noted that development of the crystallization processes in most of the examples presented in later chapters occurred before the availability of many of the online measurement and control methods that are now available. Utilization of these methods would have aided both the process development and the manufacturing operations. The literature that describes these methods—for example, feedback control of supersaturation for crystallization (Nonoyama et al. 2006 Zhou et al. 2006)—is now extensive, and the instrumentation to carry out the measurements and control continues to be improved. 

The process illustrated here is a simple modification of a previous example. Shown in Fig. 7-25, this modified process prepares the crude ding as a slurry in a feed vessel. The slurry feed was continuously charged to a dissolver that was maintained at a temperature of about 50 C. The feed rate was controlled such that the slurry was put into solution in the dissolver, and the dissolved solution charged continuously to the crystallizer through an in-line filter to remove extraneous insoluble particles and traces of the undissolved product. The crystallizer contained the seed slurry with the correct form at a lower temperature, about 25 C. The crystallizer slurry was continuously filtered through a ceramic cross-flow Alter system with a pore size of 0.2 p-m, and the clear permeate was sent back to the dissolver for further solubilization of product. This was inn until the feed tank was empty and all supersaturation was relieved. The critical parameters for successful development of this process were solubilities of the polymorphs, seeding, and control of supersaturation. 

Continuous (steady-state) process for tight control of supersaturation, unchanging with time. 

When close control of an operating parameter (e.g., supersaturation) is required for a process, a continuous operation should be considered. The success of sonication in this case proves, once again, that the manufacture of high-value products (such as phanuaceuticals) can often tolerate technologies which are unusual in the production of less expensive materials. 

When designing a continuous crystallizer, the designer wishes to control the degree of supersaturation in the lower limits of the intermediate region. In continuous crystallization, it is necessary to replace each crystal removed from the process with a new nuclei. It is also necessary to provide some degree of crystal size classification if a uniform crystal size is to be obtained. 

If the supersaturation generated during the cycle is not completely removed, the level of supersaturation attained during the following cycle is increased. This increase from cycle to cycle will continue until the supersaturation level of the solution exceeds the metastable region and enters the labile region, where spontaneous nucleation occurs. The occurrence of spontaneous nucleation means loss of control of crystal size. 

Usually the crystallization equipment is charged with a clear feed solution. As this solution is saturated, it is important to control the increase in supersaturation as the labile region is approached. This is important since the formation of an excessive number of nuclei will cause a continuous crystallizer system to have an extremely long period before desired crystal... 

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