The Steps from Batchwise to Continuous Crystallization for a Fine Chemical: A Case Study

Abstract

Many processes to produce fine chemicals and precursors of pharmaceuticals are still operated in batchwise mode. However, recently, more producers have taken a change to continuous operation mode into consideration, performing studies and trials on such a change, while some have even already exchanged their production mode from batchwise to continuous operation. In this paper, the stepwise development from an initial idea to industrial implementation via laboratory testing and confirmation is revealed through the example of an organic fine chemical from the perspective of a crystallization plant manufacturer. We begin with the definition of the objectives of the project and a brief explanation of the advantages of continuous operation and the associated product properties. The results of the laboratory tests, confirming the assumptions made upfront, are reported and discussed. Finally, the implementation of an industrial plant using a draft tube baffled (DTB) crystallizer and the final product properties are shown. Product properties such as crystal size distribution, crystal shape, related storage stability and flowability have successfully been improved.

Nucleation in continuous flow cooling sonocrystallization for coiled capillary crystallizers

“…The continuous operation of small-scale equipment is of utmost importance for accelerated process development [1][2][3][4]. It is not necessary to switch the operation mode from small scale batch to the continuous production of bigger quantities, smallest quantities can already be continuously produced, and similar equipment concepts can be transferred more easily to larger scales [5].…”

Continuous Miniaturized Draft Tube Baffle Crystallizer with Particle Screw for Supportive Suspension Discharge

“…There are different discharging methods besides using a conventional (peristaltic) pump, such as gravimetric transfer with an overflow tube, combined pressure/vacuum, only vacuum, or, as presented here, a newly developed particle screw supporting the solid discharge.…”

“…For avoiding confining settled crystals, often, the outlet of a crystallizer tank is at the bottom. Therefore, the suspension can be removed discontinuously by inducing a proper vacuum . Vacuum can also be combined with pressure .…”

Advances in Industrial Crystallization

“…Continuous crystallization as a common operation mode for most bulk chemical manufacturing processes has recently gained much interest from the pharmaceutical industry, and is thus, again focus of academic research [4,18,[21][22][23][24]. Even though the basics were developed until the 80s, there is still a great need for upscaling procedures [22], general process development [23], and new ideas for the efficient upstream and downstream combination [24].…”

“…Continuous crystallization as a common operation mode for most bulk chemical manufacturing processes has recently gained much interest from the pharmaceutical industry, and is thus, again focus of academic research [4,18,[21][22][23][24]. Even though the basics were developed until the 80s, there is still a great need for upscaling procedures [22], general process development [23], and new ideas for the efficient upstream and downstream combination [24]. The examples studied cover a broad range of applications as an industrially relevant fine chemical produced in a Draft Tube Baffled (DTB) crystallizer, at targeted particle-related properties [22], a continuous fine chemical enantiomer separation in coupled fluidized bed crystallizers [23], and the continuous synthesis of a chiral drug intermediate via an integrated biocatalysis-crystallization concept [24].…”