Enhancing Particle-Size Measurement Using Dry Laser-Diffraction Particle-Size Analysis

Across the pharmaceutical industry, laser-diffraction technology is well established for particle-size measurement. Laser diffraction is an efficient method of particle sizing and lends itself to automation as evidenced by the ready availability of highly automated laboratory instruments and real-time sizing technology for pilot and commercial scale applications. Ongoing advancement of the technique offers considerable benefits to the pharmaceutical industry with recent extensions of the application of dry-powder measurement an especially useful innovation.

IMAGE COURTESY OF THE AUTHOR

Although dry particle-size measurement is particularly beneficial for moisture-sensitive materials, it also offers wider efficiency and environmental advantages. Maximizing the use of dry measurement enhances instrument productivity through rapid measurement and cleaning while at the same time minimizing the waste-disposal issues associated with the use of dispersants in wet measurement. Dry measurement, however, relies on being able to efficiently disperse the sample, without causing particle damage, in order to access accurate primary particle-size data. This dry dispersion can be particularly challenging for some of the fine and fragile materials routinely handled by pharmaceutical manufacturers.

In this article, the author contrasts the benefits and limitations of wet- and dry-sample preparation by focusing on the benefits of dry dispersion. The mechanisms that give rise to agglomerate break-up are discussed with reference to different designs of the dispersion unit, and experimental data are presented to show the suitability of different dispersion environments for different types of material.

Preparing samples for particle-size measurement

One of the attractions of laser-diffraction particle-size measurement is that sample-preparation requirements are minimal. That said, it is vital that the particle-size data measured are fully relevant to the application. In some instances, it is the size of particles present in the raw sample that is of interest perhaps because of the need to investigate process performance or to evaluate the agglomeration of a fine material during storage. More usually, however, it is the need for primary particle-size data that drives analysis because particle size defines important attributes such as solubility and bioavailability. This requirement makes it essential to disperse the sample prior to measurement, to break up any agglomerates or aggregates present and ensure that discrete particles are reliably introduced into the measurement zone of the instrument. There are two possible approaches: wet or dry dispersion.

Wet measurement involves the production of a stable suspension using a suitable dispersant. The choice of dispersant will depend upon the solubility of the material to be analyzed; therefore, water-soluble materials often require a suitable organic dispersant. Ultrasound is often applied, in combination with defined levels of agitation, to achieve a homogeneous suspension, and in some instances, additives also will be required for stabilization and wetting. The most advanced laser-diffraction instruments allow wet measurements to be made on very fine powders with particle-size distributions extending down to 0.01 micron in size.

The dispersion mechanisms applied in wet measurement, although effective, are relatively gentle, which means wet measurement can be successfully used for even the finest and most fragile of particles. Wet dispersion is useful for establishing a baseline against which the success of dry dispersion can be judged. The less appealing aspects of wet measurement are that it takes longer than the dry alternative and produces waste in the form of used dispersants and additives. The time required and the production of waste are particular drawbacks for polydispersed samples, where the volume of sample must be large to ensure representative data for every size fraction.

With the latest laser-diffraction instrumentation, dry-powder dispersion can be applied to materials in the particle-size range 0.1 to 3500 microns. The widest possible use of dry dispersion maximizes the productivity of a laser-diffraction analyzer, simultaneously minimizing environmental impact. The challenge, however, is to apply sufficient energy to deagglomerate the sample without causing primary particle damage. Using dry measurement, the sample is dispersed into a compressed air flow. Increasing the pressure of this air makes the dispersion process more energetic, but the design of the disperser is crucial in defining the aggressiveness of the dispersive action. The breadth of samples for which dry measurement is feasible with a given particle-size analyzer, therefore, directly depends on the design of the dry disperser.

Understanding the mechanisms of dry dispersion

The interparticle forces that bind particles together include van der Waals forces, electrostatics, and liquid bonds. As particle size decreases these forces become stronger, thereby making dispersion tougher for finer materials. In dry dispersion, the mechanisms that can be applied are, in order of aggressiveness:

• velocity gradients caused by shear stress

• particle to particle collisions

• particle to wall collisions.

The design of the disperser used dictates which mechanism is applied during measurement. The disperser geometry shown in Figure 1 (a), for example, has no impaction surfaces. As sample drops down from the sample tray into the funnel, it is entrained into the compressed air, which enters at right angles to the powder. Dispersion is achieved by accelerating the particles through the venturi into the measurement zone through the application of shear and as a result of particle–particle collisions. This design is, therefore, suitable for relatively fragile particles.

In the alternative, high-energy venturi shown in Figure 1(b) the inclusion of a 90-degree bend creates an effective impaction zone that brings the third dispersion mechanism into play. For highly cohesive materials, this impaction is a useful strategy, but only if the particles are sufficiently robust to withstand the applied forces.

Figure 1: The design of a disperser in a laser-diffraction system defines its flexibility for dry-powder measurement. Figure 1 (a) shows the design suitable for more fragile samples. Figure 1 (b) shows the impaction dispersion mechanism required to handle robust, cohesive powders. (ALL FIGURES ARE COURTESY OF THE AUTHOR.)

The latest laser-diffraction systems (e.g., Mastersizer 3000, Malvern Instruments) offer multiple dispersion-configuration options that streamline the use of different geometries to allow users to apply alternative set-ups for different materials. By simultaneously enabling precise control of the powder-feed rate and the pressure of the compressed air, such systems enable the manipulation of dispersion to achieve robust dry measurement for a wide range of sample types as illustrated in the following case study.

Case study: Identifying an optimal dry dispersion method for a lactose-based formulation

In an experiment to identify the optimal method for the dry measurement of a lactose-based formulation, various tests were carried out using a dry-dispersion engine (Aero S, Malvern Instruments) of a laser-diffraction system (Mastersizer 3000, Malvern Instruments), which can be configured with either a standard (see Figure 1[a]) or a high-energy (see Figure 1[b]) venturi geometry. With both dispersers, a standard pressure titration was carried out; that is particle size was measured as a function of the pressure of the compressed air used for dispersion. In addition, a wet dispersion of the formulation was measured to set a baseline for the evaluation of dry methods.

Figure 2 shows the pressure-titration results for both venturis with data sets overlaid for dry and wet measurement. These results indicate that with the standard design, agglomerates are still present at air pressures in the region of 0.5 to 1 bar. A pressure of 3 bar is required for complete dispersion and to achieve close agreement between the wet and dry data.

Figure 2: Pressure-titration data for a lactose formulation shows close agreement between the wet (blue) and dry measurement obtained with a compressed air pressure of 3 bar with (a) the standard venturi (upper plot) and at 1 bar with (b) the more aggressive venturi (lower plot). US refers to after ultrasound; HE refers to high energy.

Analogous data for the high-energy venturi reflect the more aggressive nature of the dispersion mechanisms applied and show close agreement between the wet and dry results at an air pressure of approximately 1 bar. At higher pressures, there is evidence of primary particle breakdown with the reported particle size becoming smaller than that measured using the wet method.

These data suggest that either disperser could be chosen for analysis of the formulation provided that an appropriate air pressure was selected, but this conclusion raises a question: Are both dispersers equally suitable for this application or is one more appropriate than the other?

By examining how Dv50 (i.e., the median particle size based on a volumetric particle-size distribution) changes as a function of applied air pressure (see Figure 3), it is possible to identify the standard, less energetic venturi as the better choice. With the high-energy venturi, although the results match with wet measurement at 1 bar, any variation in pressure, to either side of that figure, produces a mismatch between dry and wet data. This mismatch suggests that the measurement result will be sensitive to slight variations in air pressure and that the method is not inherently robust.

In contrast, with the standard venturi, particle size is stable across a 1-bar pressure window, from 3 to 4 bar. This greater stability indicates that measurement with the standard venturi will be inherently more robust and that less aggressive dispersion is preferable for this relatively fragile powder.

Figure 3: Comparing pressure-titration data for the two venturis shows that the standard, less energetic design offers more robust measurement and a working pressure envelope that extends from 3 to 4 bar. DV50 is the median particle size based on a volumetric particle-size distribution.

Conclusion

Recent advances in laser-diffraction particle-sizing instrumentation have extended the measurement range of the technique, extending up to 3500 microns, and significantly improved the ease of use of these systems, a key determinant of general laboratory productivity. Equally importantly, however, recent instruments have brought enhanced dry- powder dispersion capability. Relative to wet measurement, dry-laser diffraction particle-size analysis is faster and has a lower environmental footprint because no dispersants are required. Developments in this area, therefore, offer significant practical benefit.

The latest laser-diffraction systems have dry-dispersion engines with a choice of disperser geometries, backed up with precise control, both of sample feed rate and the pressure of the compressed air used for dispersion. Such systems allow the user to control the mechanisms applied to disperse the sample, and most crucially, to efficiently disperse samples without impaction, where impaction must be avoided. As a result, modern laser-diffraction systems extend robust dry measurement to a wide range of sample types, including to materials that are both cohesive and relatively fragile. Such advances mark an important step forward that further enhances the suitability of laser diffraction for efficient particle-size measurement.

Carl Levoguer is a product marketing manager, laser particle-sizing and imaging, Malvern Instruments, Enigma Business Park, Grovewood Road, Malvern, Worcestershire, WR14 1XZ UK, tel. +44 (0) 1684 892456; fax +44 (0) 1684 892789, carl.levoguer@malvern.com

Submitted Nov. 29. 2012; Accepted Jan. 30, 2013.