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

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.