Control of Supersaturation

The first to avoid in all these crystallizers is the primary (spontaneous) nucleation as only the secondary nucleation can be used to steer the nucleation rate via the energy input and thereby the particle sizes that shall be produced (see equation for 

In this example, it is assumed that desupersaturation is complete when point 0 is again reached. For this case, it is dear that the level of the supersaturation produced at the level of the solution depends on the redrculation flow rate. High recirculation flow rates reduce the supersaturation produced there (dilution), while low redrculation flow rates increase it. The redrculation flow rate, adjusted to the production output, is therefore the most important design parameter in industrial crystallizers. Where the production outputs are the same, this parameter is equal for all crystallizer designs. The required recirculation flow rate depends on the metastable zone width. If this is not known, it has to be determined beforehand by means of measurements. In practice, half of the metastable zone width is used for determining the required redrculation flow rate. Therefore, 

This is mainly of importance where the mass balance resulting from the crystallization process would produce values that were too low for the suspension density. In this case, special measures have to be taken, as explained below. In general, suspension densities of between 15 and 25% by mass are sufficient in order to achieve an adequate desupersaturation rate. 

With these measures and specifications relating to the level of supersaturation and suspended crystallized mass, it is generally possible to obtain sufficiently granular (coarse enough) crystallized masses, so that separation with centrifuges can be performed. 

Mean Crystal Size and Crystal Size Distribution 

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Control of supersaturation is an important factor in obtaining crystal size distributions of desired characteristics, and it would be useful to have a model relating rate of cooling or evaporation or addition of diluent required to maintain a specified supersaturation in the crystallizer. Contrast this to the uncontrolled situation of natural cooling in which the heat transfer rate is given by... 

V. Liotta and V. Sabesan, Monitoring and feedback control of supersaturation using ATR-ETIR to produce an active pharmaceutical ingredient of a desired crystal size, Org. Process Res. Dev., 8, 488-494 (2004). 

The demand for increasing control of physical attributes for final bulk pharmaceuticals has necessitated a shift in emphasis from control of nucleation to control of growth. This trend is also finding application for control of purity and improved downstream handling for both intermediates and final bulk products. The obvious critical factors then become seeding and control of supersaturation. Quantification of these factors for each growth process is essential for development of a scalable process. Much of the discussion to follow focuses on the growth process and methods to minimize nucleation. 

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. 

As in polymoiphism, the presence of solvate can present a challenge for drug development beyond crystallization (Variankaval et al. 2007). It is crucial to have a good description of equilibrium solubility behaviors under different operating conditions. Seeding and control of supersaturation are also required to control the crystallization process. Example 7-5 shows the development of the crystallization process in producing the correct polymorph. 

Nucleation must also be minimized by tight control of supersaturation in processes involving resolution of optical isomers. In some cases, nucleation must be avoided to prevent the formation of undesired polymorphs. 

Control of supersaturation Achievable Excellent at low S Excellent at high S... 

Control of supersaturation is difficult in cooling operations when the solubihty slope is high and small temperature changes result in creation of supersaturation ratios outside the metastable region either globally or locally (i.e., at the cooling surfaces). 

The above equations show that of the remaining parameters, seeding temperature and length of the initial cool-down period were most significant. This reemphasizes the importance of control of supersaturation in this process. 

The method presented here is a semibatch process from the point of view of the slurry concentration, but it is semicontinuous by virtue of constant supersaturation and temperature driving force. Initially, S-ibu-S-lys seed is charged to the crystaUizer and R/S-ibu-S-lys slurry is fed to the dissolver. During the course of resolution, S-ihu-S-lys is grown selectively in the crystallizer and R-ibu-S-lys is left in the dissolver. The resolution is achieved by the proper use of seed and control of supersaturation to grow the correct diastereomer. 

Variables. Polymorph solubilities, control of supersaturation, ciystal growth rate... 

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. 

However, the authors have participated in development and scale-up of some successfiil reactive crystallization processes, and the examples to follow (Examples 10-1 and 10-2) are included to illustrate the concepts and application of the principles discussed above in these processes. These developments were based on the three essential concepts of seeding, control of supersaturation and promotion of growth, as described above. The key variables are, therefore,... 

Issues Minimize nucleation of the undesired isomer—strict control of supersaturation... 

Control of supersaturation via pressure, temperature and antisolvent concentration... 

After the control of supersaturation, control of nuclei formation is the most important consideration in the design of crystallization equipment. If a constant number of crystals are maintained in the crystallizer, then a constant surface area for crystal growth will be available. This will result in good control of product size. 

There are several common problems encountered in the use of crystallization in the pharmaceutical industry (1) the control of supersaturation (and PSD) in a batch crystallizer (2) the effective use of seed (3) efficient measurement of solubilities in multiple solvent systems to maximize purification and yield and (4) identification and retention of the most stable polymorphic form. 

To prevent plugging, avoid having natural sumps for suspension type crystallizers. Control the degree of supersaturation. For crystallizers operated with cooling or evaporative crystallization, the supersaturation occurs near the heat exchange surface. For antisolvent or reaction crystallizers, the key control of supersaturation is often local mixing. Differentiate among the different types of impurity to solve... 

As a rule of thumb, pigments whose intermolecular interactions are mainly defined by Ji-jr-interactions within stacks tend to form needles or rods parallel to the stacking direction. Typical examples are the phthalocyartines (Figure 8-12a). Only P.B.15 3 may be obtained in the form of platelets by defined control of supersaturation during the pigment synthesis. ... 

Only P.B.15 3 may be obtained in the form of platelets by defined control of supersaturation during the pigment synthesis [59]. 

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