Particle and material characterisation in the pharma industry
In a six part series, Stuart Wakefield, Director MalvernAimil Instruments discusses the particle and material characterisation of pharmaceutical materials. The first in this series discusses ‘the control of particle size in pharma manufacturing’.
Figure 1: Malvern Instruments Mastersizer 2000
Figure 2: Detection of large particles within a pharmaceutical powder
Part 1— Aspects of particle sizing in pharmaceutical manufacturing
Anyone engaged in the development, formulation or manufacture of pharma is likely to have some understanding of the role of particle size in determining the properties and efficacy of a wide range of pharma formulations. Understanding its effects, and being able to measure and control particle size is important at all stages of the drug development and production process, from early stage formulation through to the definition and assessment of parameters critical to quality.
There are many techniques for the determination of particle size and size distribution, each one having advantages and disadvantages which are largely dependent upon the type of material to be measured and the type of information to be obtained from the material in question. The use of sieves for example may be fine for large free flowing material but for sub micron, sticky powders it will be more troublesome and greater care needed. This brief overview will focus mainly on Laser Diffraction, one of the most widely used techniques for particle size analysis in the pharma arena, and will include some specific examples that serve to illustrate why it has been so widely adopted.
So why measure particle size?
A number of highly compelling reasons indicate why particle size measurement is so important, although these may differ slightly according to the drug formulation and type. With novel drug delivery systems, based around nasal, respiratory and transdermal routes, there is increasing need to understand and control particle size. For example, in drug products delivered as sprays, solid dosages or suspensions, particle size can have a significant impact on bioavailability. Here size measurements provide an important in vitro indicator of bioavailability, allowing prediction of the dynamics of drug release. Particle size relates to dissolution rate and therefore time of release into the bloodstream. For sprays, such as those used in asthma treatment, particle size correlates with the site of deposition of the drug in the respiratory tract.
Of equal importance is the part played by particle size in defining stability. Similarly, dose content uniformity can be related back to particle size distribution: large particles are a problem whereas dispersion to a fine particle size can be advantageous. Where this is the case, the FDA recommends that size analysis be carried out (Ref: IGH Topic Q6A: Specifications: Test procedures and acceptance criteria for new drug substances and drug products: chemical substances).
Laser diffraction has become one of the most widely used techniques for particle size analysis throughout the pharmaceutical industry, with applications from product development through to production and quality control. It relies on the fact that particles passing through a laser beam will scatter light at an angle that is directly related to their size. Large particles tend to scatter light at narrow angles with high intensity whereas small particles scatter at wider angles but with low intensity. If the changes in light scattering intensity as a function of angle are measured for a sample, the particle size distribution can be calculated by comparing the measured data with an appropriate scattering model.
A non-destructive and non-intrusive technique, laser diffraction can be used for either dry or wet samples. As it derives particle size data using fundamental scientific principles no external calibration is required; well-designed, modern instruments are easy to set up and run, and require very little maintenance.
Offerings of the technique
A wide dynamic range that typically enables measurement of particles from 0.02 micron to a few millimeters in size without changing the optical configuration. This ensures that both well-dispersed and agglomerated particles are detected.
Flexibility, since its equal applicability to sprays, dry powders, suspensions and emulsions, it allows realistic comparisons of different product formulations
Volume-based particle size distributions that are normally equivalent to weight distributions and are relevant to many processes. These indicate the location of most of the material’s mass in terms of particle size.
Rapid data acquisition with a single measurement across the entire dynamic range complete in one millisecond or less, allowing accurate study of dynamic events and ensuring sampling of the entire size distribution.
Easy verification—As a first principles technique, laser diffraction requires no calibration but can be verified easily using a variety of readily available NIST-traceable standards.
The following are examples of laser diffraction analysis in action, with all work undertaken using the Mastersizer 2000 from Malvern Instruments (Figure 1).
Figure 3: Particle size analysis on indigestion relief liquid
Case study 1—Detecting over-sized material
A key capability of laser diffraction is its ability to detect over-sized particles within a sample. An example is shown in figure 2 for the milling of a pharma material. The user in this case, was interested in determining the ability of laser diffraction to detect large, primary particles within the output of a mill because these contributed to poor content uniformity within a subsequent blending process.
The mill feed had a median particle size of 90 microns, which was reduced to 4 microns through a series of milling processes. To test the sensitivity of the laser diffraction technique in detecting over-sized particles, the final milled material was seeded with small amounts of the mill feed. As can be seen in Figure 2, laser diffraction detected the presence of the coarse particles at 1percent by mass within the sample.
Case study 2—Gauging patient perception
Particle size analysis can help in understanding how a product will be perceived by a patient. Often there is a direct link between particle size and the mouth-feel of suspension-based products, with the size distribution of the active ingredient and the excipients helping to define product attributes such as grittiness and suspension viscosity.
Figure 3 shows the particle size distributions reported for two over-thecounter oral suspension products, one the generic version of the other. The mode of the distribution (the particle size where the largest volume is reported) is similar in each case. However, the generic product contains a significantly higher fine particle fraction.
The presence of the fine particles in the generic product has an impact on the formulation in two ways. First, the product claims to be faster-acting compared to the innovator. This relates to the more rapid solubilisation of the fines than of the coarse particles. Second, the viscosity of the product is much lower (figure 4) as the fines in the suspension effectively lubricate the larger particles as they move within it, making the product easier to swallow.
These findings also help to understand other aspects of the products’ functionality. For instance, the higher viscosity of the innovator product at low shear rates may be advantageous as it will prevent sedimentation during storage. A coarser particle size may also support the claim that the innovator product is long-acting, because the coarse particles will be solubilised more slowly following administration.
There is no doubt that particle size is a significant consideration in the development and production of new pharma products. Particle size relates to many important parameters, which in turn allow prediction of bioavailability. Laser diffraction provides a rapid means of assessing size distributions during product development and quality control. In combination with other types of analysis, such as the determination of rheological parameters, it makes an even greater contribution to improving overall product understanding.
For more details contact:
Stuart Wakefield, Director, MalvernAimil Instruments Pvt Ltd, Mumbai, India Tel:+91 22 391 835 96 firstname.lastname@example.org