Scale-up of crystallization process

As mentioned previously, scale-up of crystallization processes from the laboratory is far from straightforward. Various parameters need to be maintained to be as close to those used in the laboratory as possible in order to reproduce the results from the laboratory. For scale-up, supersolubility, agitation (and its effect on secondary nucleation throughout the vessel), fraction of solids in the slurry, seed number and sizes, contact time between growing crystals and liquid all need to be maintained. 

The use of variable-speed drives in pilot plant and manufacturing plant vessels is recommended for development and scale-up of crystallization processes. This capability provides the opportunity for critical experimentation at the pilot plant scale to determine the effect of impeller speed on PSD and other variables. On the manufacturing scale, the ability to change impeller speed is the most readily adjustable parameter for manipulation on scale-up. Modem variable-frequency drives provide an excellent means to vary speed over a wide range. The added cost of variable-speed capability is minimal compared to all other methods of changing mixing... 

Literally speaking, the scale-up of crystallization processes may frequently appear to be a mission impossible, or at least a demanding endeavor, as changing the size of a crystallizer drastically affects numerous important parameters governing the crystallization process. ... 

Zlota, A.A., Tools for Rapid Scale-up of Crystallization Processes, presented at the AIChE National Meeting, San Francisco, 2003. 

Stirring is typically the most critical parameter in scale-up of crystallization processes, namely, for batch crystallizations. Two aspects have to be considered ... 

From the applications point of view, mutual diffusion is far more important than self-diffusion, because the transport of matter plays a major role in many physical and chemical processes, such as crystallization, distillation or extraction. Knowledge of mutual diffusion coefficients is hence valuable for modeling and scaling-up of these processes. 

Clearly, the key to a successful scale-up of this process is to maintain the mixing time at the pilot plant and factory scale below the threshold which would cause the process to move down the curve of Fig. 6-2. This can be best accomplished by using a special mixing device, such as an impinging jet, to approach the same mixing time at all scales. The reader can find more information on impinging jets and crystallization in Section 6.6.3 and Examples 9-5 and 9-6. 

Gahn, C. and Mersman, A., 1999b. Brittle fracture in crystallization processes Part B. Growth of fragments and scale-up of suspension crystallizers. Ibid. pp. 1283-1292. 

Crystallization Process Systems brings together essential aspects of the concepts, information and techniques for the design, operation and scale up of particulate crystallization processes as integrated crystal formation and solid-liquid separation systems. The focus of the book, however, is on crystallization only dealing with related unit operations as far as is necessary. It is therefore... 

AM Collins, C Maslin, RJ Davies. Scale-up of a chiral resolution using cross-linked enzyme crystals. Org Process Res Dev 2 400-406, 1998. 

Genck, W. J. (2000). The effects of mixing on scale-up—how crystallization and precipitation react. Chem. Process., 63,47. [256]... 

The first method of enantiomeric separation by direct crystallization is the mechanical technique use by Pasteur, where he separated the enan-tiomorphic crystals that were simultaneously formed while the residual mother liquor remained racemic. Enantiomer separation by this particular method can be extremely time consuming, and not possible to perform unless the crystals form with recognizable chiral features (such as well-defined hemihedral faces). Nevertheless, this procedure can be a useful means to obtain the first seed crystals required for a scale-up of a direct crystallization resolution process. When a particular system has been shown to be a conglomerate, and the crystals are not sufficiently distinct so as to be separated, polarimetry or circular dichroism spectroscopy can often be used to establish the chirality of the enantiomeric solids. 

Collins, A. M. Maslin, C. Davies, R. J., Scale-Up of a Chiral Resolution Using Cross-Linked Enzyme Crystals Org. Process Res. Dev 1998, 2, 400. 

This book also includes chapters on the properties of organic compounds (Chapter 2), polymorphism (Chapter 3) and the kinetics of crystallization (Chapter 4), critical issues (Chapter 5), and mixing effects in crystallization (Chapter 6). Chapter 11 includes areas of current crystallization research and development we thought worth mentioning and also some unique crystallization processes that have special features to be considered in process development. To assist in the thought process for organization of a new crystallization process, Chapter 11 also contains a suggested protocol for development and scale-up of a crystallization operation. 

In addition, scale-up of a nucleation-dominated process is difficult to predict, unless the generation of supersaturation is well controlled. The difficulties associated with stirred-batch crystallization scale-up relying on nucleation were highlighted by Nyvlt (1971, p. Ill) ... 

Several investigators have developed models for the effectiveness of collisions that lead to agglomeration including Nyvlt et al. (1985) and Sohnel and Garside (1992). This complex interaction of hydrodynamics and crystallization physical chemistry is difficult to predict or describe but can be critical to the successful operation and scale-up of a crystallization process. In particular, for reactive crystallization in which high supersaturation levels are inherently present, agglomeration is very likely to occur as the precipitate forms. Careful control may be necessary to avoid extensive agglomeration, as outlined in Section 5.4.3. below and in Examples 10-1 and 10-2 for reactive crystallization. 

The critical nature of these interactions is the key factor in causing difficulty in scale-up of nucleation-based crystallization processes—even with small quantities of seed. 

The above discussion of the potential negative effects from reverse addition (oiling out, poor crystal form, agglomeration) is necessarily qualitative, since this procedure, more so than many others, is strongly system dependent. The results could be satisfactory or unacceptable, depending on process requirements. Scale-up of reverse addition is particularly difficult because of the large deviations from equilibrium that are implicit in its implementation. 

Development and scale-up of reactive crystallization/precipitation processes can present some of the most difficult challenges in the field. The reader is referred to the quotation in Section 10.1.2 above as a reminder of this difficulty. 

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