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Online real-time measurements of multidimensional particle size distributions (nD-PSD)

Examples

Time-resolved 1D PSD of the seeded growth of paracetamol crystals during cooling crystallization
Time-resolved 1D PSD of the seeded growth of paracetamol crystals during cooling crystallization.
Time-resolved 1D PSD of the seeded growth of paracetamol crystals and nucleation during cooling crystallization
Time-resolved 1D PSD of the seeded growth of paracetamol crystals and nucleation during cooling crystallization.

Collaborations

Prof. Colin Jones at LA/EPFL


Crystallization processes, especially for pharmaceutical and food substances, need to be monitored and observed carefully in order to guarantee constant high product quality. The most important product property of a crystallization batch, besides high purity, is the particle size distribution (PSD) of the resulting crystals. The PSD determines important product properties such as tabletability, flowability, solubility, stability, bioavailability, and in the case of pharmaceuticals even bio-functionality. Such properties are critically influenced by the distribution of sizes and shapes of crystals, which must be characterized through the so called multi-dimensional particle size distribution (nD-PSD), i.e. the distribution of probabilities of the occurrence of certain combinations of two, three or more characteristic dimensions in the particle population.

Hence, there is a need for monitoring tools to follow the change in particle size and shape on-line, without affecting the process, that are usable in a wide range of process parameters, and that deliver consistent and trust-able results. Well controlled and monitored processes may lead to significant better products. In addition, these tools, may also be used to improve the understanding of crystallization processes when modeling dynamic systems.

For the observation of a crystallization process, a manifold of measurement techniques exists. Commonly used off-line techniques enable the assurance of a certain product quality, especially in terms of chemical composition, after the product has been obtained from the process. However, crystal shape, size and polymorph are determined during the crystallization process itself, and therefore continuous measurements of these characteristics is required.

This project aims at developing an image analysis based measurement tool which uses a flow through cell to generate pictures of crystals in solution from perpendicular directions (see figure 1). The flow through cell is attached to a sampling loop (figure 2) which features a controllable dilution stream to regulate the suspension density inside the channel, hence providing usability for a wide range of possible process conditions.

A fast parallelized image processing algorithm allows to read the actual size of the particles in real-time. Figure 3 shows a time resolved example in which the equivalent sphere diameter was analyzed and its development was monitored continuously during a batch cooling crystallization process.

Figure 3: Animated time-resolved 1D PSD of the seeded growth of paracetamol crystals during cooling crystallization
Figure 3: Animated time-resolved 1D PSD of the seeded growth of paracetamol crystals during cooling crystallization.

Publications

[1] Kempkes, M., Vetter, T., Mazzotti, M.: Monitoring the particle size and shape in the crystallization of paracetamol from water, Chem Eng Res Des (2009)
[2] Kempkes, M., Vetter, T., Mazzotti, M.: Measurement of 3D particle size distributions by stereoscopic imaging, Chem Eng Sci (2010), 65 (4), 1362-1373.

 

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