Laser Diffraction as a PAT Tool for Spray Drying

An investigation into the capabilities of at- and in-line laser diffraction analysis for improved process monitoring and control.

By Paul Wan Sia Heng PhD, BSc (Pharm), Lai Wah Chan, PhD, BSc (Pharm), and Lay Hui Tan, PhD, BSc (Pharm), GEA-NUS Parmaceutical Processing Research Laboratory, Department of Pharmacy, National University of Singapore & Carl Sabin, Process Products Group, Mal

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The FDA’s PAT initiative, in combination with Quality by Design (QbD), encourages the pharmaceutical industry to intensify its focus on efficiency in manufacturing. Conventional production relies heavily on off-line testing of both in-process materials and the end products. The FDA seeks to modernize practice by promoting a shift towards knowledge-based design and development, and the use of analytical tools that can continuously monitor critical processes. For some variables, timely and/or continuous measurements in the operational environment remain a significant technical hurdle, but for others, proven solutions are already commercially available. Particle size is one such variable.

For particulate pharmaceutical systems, particle size is often a critical parameter. It determines drug release characteristics, and can also affect other attributes such as flow, suspension stability and mouth feel. Consequently, particle size is routinely measured in powder-related processes and in many instances laser diffraction is the analytical method of choice. Laser diffraction is a fast, reliable and reproducible technique that is equally suitable for off-, at-, in- or on-line analysis. It can therefore be used from early-stage development, right through into pilot and full-scale production.

The benefits that accrue from using real-time laser diffraction particle size analyzers to monitor milling processes are well-documented and include: increased throughput, better product quality, and reduced wastage. The technology is equally relevant, and beneficial, for other common unit operations such as spray drying. In this study, at- and in-line particle size analyzers were used to monitor and control a pilot-scale spray dryer producing oily microspheres.

Producing Oil-encapsulated Microspheres

Spray drying is widely used throughout the pharmaceutical industry and is a valuable technique for the microencapsulation of a solid or oily liquid. Microencapsulation allows control of the release rate of an active pharmaceutical ingredient and can also prevent degradation and oxidation of the core materials, since the outer coating forms a protective physical barrier. It is an equally useful technique for masking the taste of unpalatable formulations. However, to achieve the required performance characteristics, the particle size of the product microspheres must be tightly controlled.

In this study, the aim was to produce oil-encapsulated microspheres in the size range of 10 to 35 microns. Conventionally, microsphere size is controlled using off-line analytical data produced by periodically sampling from the process. In this case, off-line measurement involved light microscopy interfaced with image analysis. Such a technique is useful for early stage research and development because it provides visual images and valuable information about particle morphology and shape. It is also an effective tool for validating alternative sizing methods.

However, light microscopy and image analysis are not ideal for process monitoring and control. Only a small amount of sample is measured, so data quality is heavily dependent on the extraction and analysis of representative samples. Equally important is that the sampling and measurement process is too slow for real-time monitoring.

Consequently the decision was made to investigate the capabilities of at- and in-line laser diffraction analyzers for improved process monitoring and control.
At- and In-line Particle Sizing Technology for Spray Drying

An Insitec system from Malvern Instruments was selected for this application. The Insitec range of laser diffraction particle size analyzers incorporates at-, in- and on-line options specifically designed for the process arena. These systems are suitable for both wet and dry streams with particles in the size range 0.1 to 2000 microns. For this investigation, the same instrument was used, at different times, for both in- and at-line measurement.


Laser Diffraction as a PAT Tool for Spray Drying
Figure 1: Layout for at- and in-line analysis of the exit stream from
the spray dryer.

When installed in the exit line from the spray dryer (Figure 1), the analyzer measures the entire exiting flow, in its “in-process” state, with no sample preparation. For units with larger throughputs, this may not be an option, in which case on-line analysis, where a portion of the process flow is diverted for measurement, is more appropriate. The in-line system is totally enclosed reducing any risks associated with exposure to the process material. Analysis is fully automated so operator input is minimal, and reproducibility is very high.

For at-line analysis, the instrument is installed close to the product outlet conduit. Samples are extracted manually from the process for measurement, as and when required. In terms of process relevance, this approach shares some of the limitations associated with off-line analysis - although response times are very much faster. Also, it is not possible to recover sample after analysis which could be an issue if the material is extremely valuable or in short supply.

In both configurations, an air purge stops particles adhering to the surface of the optical lenses, so maintaining measurement accuracy. With the at-line system, an additional air supply (introduced via the venturi that is used to draw the sample into the analyzer) provides dispersion before measurement. Careful setting of the flow rate ensures break up of any agglomerates without causing attrition of the primary microspheres.


Monitoring the Process


Laser Diffraction as a PAT Tool for Spray Drying figure 2
Figure 2: Real-time particle size data measured during start-up of the spray dryer.

Real-time data recorded during start-up of the spray dryer are shown in Figure 2. Periods of transient operation, start-up, shut down or a change of product specification, for example, are almost impossible to track effectively with off-line analysis because of the time lags involved. For this process, start-up was estimated to take 10 minutes, so output during this initial period was discarded in order to preserve product quality. The in-line results show that in fact a steady state is reached much more rapidly than this, in just a couple of minutes. Here then the in-line instrument provides the data required to make a precise decision about when to switch over to product collection, thus cutting waste and maximizing plant output.

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