FWF - conti-crystallisation - Development of a versatile continuous-flow crystallizer

Project: Research project

Description

Developement of a novel tubular crystallizer which employs seeding and fluid plugs to allow control of crystal growth and fluid mechanics while precisely controlling the temperature and supersaturation.


The aim is to develop and test a versatile continuously operated crystallizer system, which is based on the growth
of seeds to product particles in a tube. Due to the tubular appearance and the small inner dimensions of the
crystallizer in the few millimeter range, it is possible to adjust the temperatures along the tubing according to the
needs of the crystallization. Thus, the product can be manipulated under controlled conditions. Furthermore narrow
residence time distributions of the crystals in the tube result in narrow crystal size distributions (CSDs) of the
product particles. The process should be applicable for fine chemicals, food supplements and especially for
manufacturing active pharmaceutical ingredients (APIs).
Both, particle shape and size have an influence on the solubility of an API-particle and hence on the bioavailability
of the substance. Thus, bulk properties such as the crystal size and shape distribution (CSSD) are important quality
attributes of powders. Furthermore, downstream processes (e.g., filtering, washing, drying etc.) and the handling
abilities (e.g., flowability, tabletability) of the particles are positively affected by narrow CSDs and favorable
crystal shapes. Furthermore the polymorph modification of the crystalline product needs to be controlled tightly
since different crystal structures result in different physical properties of the particles and often in different crystal
shapes. Again bioavailability and product handling may be compromised. Size, shape as well as the corresponding
distributions, and polymorphic modification are important product quality attributes. In order to obtain product
crystals with desired features it is important to control numerous critical process parameters (CPP) during a
crystallization unit operation.
CPP that can be controlled tightly and adjusted individually in order to affect the outcome of the crystallization
process in the tube include (i) seed loadings, (ii) temperatures, (iii) cooling gradients, (iv) solution concentrations
and the (v) residence time of the crystals in the tubing (i.e.; altering flow rates of the suspension in the tubing or
lengths of the tubing respectively). Additionally solvent mixtures or additives to affect solvate formation or shapes
of product crystals can be employed.
The simple tubular geometry with the small diameter allows for online control of the entire feed- and product
stream in respect to the CPP and the quality attributes of the final crystals. Thus, many ideas of the process
analytical technology (PAT) and quality by design (QbD) initiatives can be realized in this novel continuous
crystallization concept.
Moreover this crystallizer system can be, if combined with additional reactor segments, used to develop multi-layer
or coated crystals with highly defined properties.
The continuous tubular crystallizer will be tested for several substances and the influence of the CPP on the quality
attributes of the product particles. Despite the small geometry the system should be able to handle considerable
amounts of product in a g/min. scale.
Simulations concerning the liquid- (differential mass and heat transfer) and solid phase (population balance
equation) will be performed. This will help to design the experiments and to develop and understand a robust
continuous crystallization process in the flow through device.
StatusFinished
Effective start/end date1/05/1330/06/17