Real-time particle-size measurement
To improve the efficiency of mill operation, and to deliver more consistent milled particle sizes, an Insitec online particle-size
analyzer (Insitec, Malvern Instruments, Worcestershire, UK) was identified as a possible solution for continuous milling monitoring
and control. This system employs the technique of laser diffraction, a well-established and robust method, and is specifically
designed for easy integration into the manufacturing process. Unlike some PAT instruments that are based on modifications
from a laboratory unit platform, and which tend to be sensitive to the manufacturing environment, the Insitec was designed
to be used on the shop floor. The rugged integrity of the system is well proven across a diverse range of industries. It is
being applied increasingly in the pharmaceutical industry as companies implement PAT.
A pilot-plant trial was performed to demonstrate the feasibility of using the Insitec system on an API milling operation.
A mobile analyzer was installed on-line at the exit of a comminutor mill. With this on-line setup, material is continuously
aspirated from the process stream, through a sample flute, using a venturi eductor, which disperses sample into the measurement
zone and is returned to the process line after analysis. The system has no moving parts and operates 24/7 with very little
manual intervention. The particle-size distribution is measured continuously and reported with a user-defined frequency (once
every 0.25–60 s).
Figure 2 shows particle-size distributions measured during the pilot-plant trial at low, medium, and high mill speeds. The
results of the pilot trial showed the potential of on-line particle-size analysis, demonstrating the ability of the Insitec
to track process variation in real time and produce results that can be used in process and quality control.
Figure 2: Using the Insitec on-line particle size analyzer to detect changes in particle-size distribution resulting from
changes in mill speed, where the blue, red, and black lines show the particle size produced at low, medium, and high mill
Knowledge gained during the pilot-plant trial helped streamline the implementation of on-line particle-size analysis at the
commercial manufacturing site. Here, a spool piece was fabricated to accommodate the probe for the analyzer and to interface
with the standard product containers used to collect powder exiting the mill (see Figures 1 and 3).
Figure 3: Spool piece accommodating the sampling probe for the on-line analyzer and directing sample return toward product
Since sampling bias and incorrect dispersion are the main causes of measurement error, both for laboratory and process analysis,
experimental work was carried out to optimize the process interface. To ensure sampling was representative, particle size
was measured at different points across the diameter of the exit line to detect any segregation and determine a suitable position
for the sampling probe. Measuring particle size as a function of gas flow through the eductor generated a particle-size–flow-rate
plot that was used to determine suitable conditions for dispersion (see Figure 4).
Figure 4: Effect of nitrogen flow through the eductor on measured particle size (flow/size titration) with Dv50 value produced
using established off-line measurement technique superimposed (yellow bar). SCFM is standard ft3/min.
The results of these investigations showed that a single-holed probe extracting sample from the center of the spool piece
produces the most representative sample. The size of the sampling hole was also optimized to ensure an adequate scattering
signal was obtained. A dispersion flow rate of 3 standard ft3/min breaks up any agglomerates without causing primary particle attrition and produces a Dv50 (median particle size by volume)
that is in close agreement with the established off-line method for particle-size measurement.