Downstream processing crystallization

Tailoring of the particle size of the crystals from industrial crystallizers is of significant importance for both product quality and downstream processing performance. The scientific design and operation of industrial crystallizers depends on a combination of thermodynamics - which determines whether crystals will form, particle formation kinetics - which determines how fast particle size distributions develop, and residence time distribution, which determines the capacity of the equipment used. Each of these aspects has been presented in Chapters 2, 3, 5 and 6. This chapter will show how they can be combined for application to the design and performance prediction of both batch and continuous crystallization. 

Thus, methods are now becoming available such that process systems can be designed to manufacture crystal products of desired chemical and physical properties and characteristics under optimal conditions. In this chapter, the essential features of methods for the analysis of particulate crystal formation and subsequent solid-liquid separation operations discussed in Chapters 3 and 4 will be recapitulated. The interaction between crystallization and downstream processing will be illustrated by practical examples and problems highlighted. Procedures for industrial crystallization process analysis, synthesis and optimization will then be considered and aspects of process simulation, control and sustainable manufacture reviewed. 

Crystallization process control is desirable from a number of standpoints. The primary objective is often to meet customer requirements by achieving consistent product quality to a desired specification of crystal size, size distribution and purity. Secondly, process requirements often dictate maintenance of stable crystallizer operation, the avoidance of fines and encrustation, and the minimization of subsequent downstream processing. 

Jones, A.G., 1985b. Crystallization and downstream processing interactions. In POW-TECH 85, Institution of Chemical Engineers. Sympos. Ser. No. 91. Rugby Institution of Chemical Engineers, pp. 1-11. 

Figure 4.16 Pressurized fixed-bed reactor synthesis of L-aspartic acid from fumarate applying a plug flow reactor followed by a crystallization step for downstream processing...

An alternative approach is taken in the production of monosodium glutamate (MSG) which, unlike interferon, is secreted into the fermentation broth. The stages of downstream processing for MSG are shown in Figure 14.3. Again, a variety of unit operations, including centrifugation, crystallization, vaporization, and fixed-bed adsorption, are used in this process. 

Downstream processing may consist of several operations such as liming to precipitate the metabolite as the calcium salt, washing of the precipitate with water to remove soluble impurities, acidification using strong acids to convert the salt in its free acid form. The acidic liquor may be demineralized using IER, decolorized using active carbons, concentrated under vacuum, and finally crystallized. 

Because of the high potential of alkaloid-based alkylations for synthesis of amino acids, several groups focused on the further enantiomeric enrichment of the products [20]. In addition to product isolation issues, a specific goal of those contributions was improvement of enantioselectivity to ee values of at least 99% ee during downstream-processing (e.g. by crystallization). For pharmaceutical applications high enantioselectivity of >99% ee is required for optically active a-amino acid products. 

Adding up the times of all steps, an industrial scale production takes roughly 3 weeks, of which 2 weeks are devoted to the fermentation and about 1 week is required for the downstream processing. Derivatization at positions 3 and 7 to yield an API is not included. Starting from 7-ACA, these processes may take 1 day each for the derivatization plus the time for purification, crystallization, and drying. The resulting bulk active cephalosporin can then be sterilized and formulated for marketing. 

The purity of a crystalline product depends on the nature of the other species in the mother liquor from which the crystals are produced, the physical properties of the mother liquor, and the processing that occurs between crystallization and the final product (downstream processing). Impurities can find their way into the final product through a number of mechanisms the formation of occlusions, trapping of mother liquor in physical imperfections of the crystals or agglomerates, adsorption of species onto crystal surfaces, as part of chemical complexes (hydrates or solvates), or through lattice substitution. 

The basis utilized by Petrides et al.15 is 1500 kg of purified BHI per year. They indicate that this represents 10-15% of the world demand.17 In essence, the following downstream steps are involved in sequence during synthetic BHI production. The fermentation step (not a downstream step) is also included to provide some continuity. The steps are fermentation, cell harvesting, cell disruption, inclusion body recovery, inclusion body solubilization, enzymatic conversion, refolding, sulfitolysis, CNBr cleavage, final purification steps, and crystallization. In the flow chart provided by Petrides et al.15, a surge tank separates the upstream from the downstream processes. This tank is in between the fermentor and the downstream processing steps. 

Downstream processing of riboflavin from fermentation is straightforward, as the product precipitates from the fermentation broth. The crystals are collected by differential centrifuging and a pure product is obtained after repeated crystallization [143]. Roche has replaced its chemical production of riboflavin by the biotechnological process in 2000, with a 50% savings in production costs [54] as well as a 75% reduction in the use of non-renewable materials and very significantly reduced emissions into the environment [144]. 

In some cases, the fine crystals or precipitates resulting from high supersaturation (often in the range from 0.1 to 10 ini) aie desired in order to meet specific needs for downstream processing or formulation. In most cases, however, these fine particles are not desired since they can be very difficult to handle in downstream processing—notably filtration, washing, and drying. 

Issues Crystals formed by reaction are thin needles with an aspect ratio of >10.1 and a diameter of 2 p,m—unsuitable for downstream processing or formulation... 

A number of drivers force the downstream technology development towards innovative high-end applications on the one hand, but also towards revisiting robust technology of the low-end type that works well with small molecules and commodity proteins on the other hand. Examples are precipitation, crystallization, and filtration to name but a few. A robust downstream process must be simple, with quality, yield, productivity, and overall economics as the primary goals and an integrated design with compatible unit operations. 

Downstream processing of APIs using filtration and drying is often underestimated and can frequently be a bottleneck in API manufacturing processes. It is therefore vital to keep these downstream unit operations in mind when a salt form or API candidate is selected or when the crystallization process is designed. 

Downstream processing Simple - crystallization, ultrafiltration, recrystallization no organic solvent extraction Complex, stepwise... 

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