From laboratory scale to production

Particles, crystals and droplets are found in many chemical processes in various industries and often pose challenges to scientists and engineers in terms of optimising product quality and process efficiency. Effective characterisation of particle properties, especially particle size and number, enables more effective processing and improved product quality. Offline particle size analysers can be used for particle characterisation, e.g. with laser diffraction technology or sieving. However, technologies are also available that visualise the particle size, number and shape in real time as they naturally occur in the process. These can be used in production and also for laboratory-scale processes such as process development for upscaling.

In-situ measurements of particle systems can be used to minimise or even eliminate disturbances and optimise product quality and yield. When selecting a suitable in-process measurement, not only the complexity of the particle or particle system to be monitored should be taken into account, but also the added value that can be achieved for the overall process. For example, the effect of particle size and shape on the efficiency and duration of filtration steps can be investigated, as can the correlation between particle shape and dissolution rate or efficacy of drugs.

There are many different technologies for the offline and at-line characterisation of suspensions and emulsions, each of which offers the possibility of characterising different physical properties of particles or droplets in suspensions. In the following, real-time monitoring technologies will be presented using application examples in which the tools "ParticleTrack™" with so-called "FBRM^®" (Focused Beam Reflectance Measurement) technology and "EasyViewer™" with a probe microscope with submicron resolution are used. The former tool can be used directly in processes to measure particle count and size in real time. "EasyViewer" is an inline tool with image analysis software for particle size analysis using high-resolution microscopy images.

An immediate measurement of the particles and droplets as they are present in the process can bring benefits for the

• Avoidance of errors in sampling and dilution for offline analysis;
• Avoidance of physical changes to the material due to e.g. filling, transport, storage, sample preparation and offline measurement;
• Continuous real-time monitoring to track process dynamics;
direct monitoring in the event of disturbances or planned process changes.

Drilling, particle tracking and in-process imaging each represent an increasing density of data provided by the measurement. In general, turbidity is a simple but powerful tool for determining the time at which particles change in the process. The turbidity is a mass measurement of the particles that does not provide any information about the size, shape or number of particles. With the "ParticleTrack" tool, it is possible to measure changes in both the number of particles and the particle size. In addition, in-process imaging is well suited for the qualitative understanding of particle and droplet systems. Using the "EasyViewer" with the "iC Vision" software and the "Image2Chords" module, images can be converted into chord length distributions (CLDs) and used to characterise particle mechanisms such as nucleation, growth, dissolution, fracture and morphology change. This can be used to improve yield, purity, filtration and quality. Without sampling or dilution, researchers can visualise crystals, particles and droplets with a high level of detail and track the number, size and shape of particles.

Image 1 is a real in-situ image taken with EasyViewer. The "Image2Chords" module scans the image and when a particle is detected in focus, it measures the distance between the particles. The distance between the particles is called the chord length. The chord length is not the particle size, but is closely related to the particle size. "Image2Chords" scans each image thousands of times across the width of each pixel line and captures thousands of chord lengths that allow the software to create the chord length distribution. A CLD is a dynamic fingerprint of the process that changes as the process changes.

The ability to distinguish between changes in particle number and particle size provides a fundamentally better understanding of the particle system in question. An Image2Chords measurement offers the possibility of creating a fingerprint of the process and monitoring it in real time. This enables a higher level of process understanding and optimisation for good batch-to-batch repeatability or process consistency.

Particle size and number are important parameters as they can have a significant impact on process efficiency and product quality. However, controlling particle morphology is equally important to fulfil product specifications. An example of this is carbamazepine, an anticonvulsant used to prevent and control seizures. Carbamazepine has been problematic in the past in terms of irregular effects. As there are several polymorphic forms with different dissolution rates, control of the desired form is also important for the efficacy of the drug. Figure 2 shows microscopic images and tendon length distributions captured with EasyViewer and Image2Chords analysis to track the morphological changes of carbamazepine. The shift of the chord length distribution to the left and top shows the growth of the needle-shaped crystal due to the transformation.

Evidence-based methods for inline particle characterisation can be used to determine the effects of process parameters in development, scale-ups and production and to identify and initiate improvement measures.

Source: LABO from 23/05/2023