Expert Insight: What every pharmaceutical scientist should know about particle size analysis

Watch this on demand webinar to find out how particle size analysis can help optimize products and processes throughout pharma development

13 Jan 2021



Dr. Paul Kippax, Pharmaceutical Sector Director at Malvern Panalytical, and Dr. Anne Virden, Product Manager of Micromaterials at Malvern Panalytical

Particle size analysis touches every step of the pharmaceutical development and manufacture workflow, from raw material selection, through to formulation development and quality control. Consequently, it can be tempting to default to one particle sizing method across the entire workflow, rather than adapting to specific requirements.

So, why is optimizing particle size analysis so important? In this on-demand webinar, Dr. Paul Kippax and Dr. Anne Virden take a closer look at the reasons and consider how this information can help with the selection of appropriate methods. The application of technologies including laser diffraction and automated image analysis in materials selection are also considered in this webinar and as well as the impact of formulation processes on product performance.

Read on for more insights from the live Q&A session or register to watch the webinar at any time that suits you.

Q: What is the best technique to identify, detect, quantify, or assess the strength of each agglomerate in bulk product?

PK: In terms of its impact on method development for particle size analysis, if you're interested in agglomerates, then you have to then consider, "Well, if I'm going to mention those agglomerates, how much energy do I put into the sample to disperse it during my particle size analysis? If I put in too much energy, I'll get a primary particle size. But I will then, of course, not see the agglomerates."

This gives us an approach that has been applied by customers using both laser diffraction and image analysis. If you change the dispersion energy used for the material, you can see how the state of agglomeration changes with that energy input. That can be used as not only a measure of the state of agglomeration, but also the energy required in order to disperse those agglomerates.

That is one approach that's being used with our equipment, where customers have obtained, by changing the method parameters, information about the presence of agglomerates, what the strength of those agglomerates are, and whether they can be dispersed. For example, that approach has been used in the development of dry powder inhaler formulations, where dispersion of agglomerates and release of the drug at a primary particle size is important.

Q: What is the effect of temperature on particle size?

AV: In terms of measuring particle size, as long as we keep our temperatures constant, then we can make very effective measurements of particle size. Anything that's based on light sketching, if we've got gradients in temperature, it tends to complicate things. If your temperature is stable, and if the temperature is relevant to how you're using those particles, then we can make effective measurements of particle size.

PK: Another consideration is the material itself. Changes in temperature can change the dissolution properties of materials, so that may be something you're interested in looking at and something that then needs to be considered, in terms of selecting a method.

Temperature can drive some forms of instability as well. This isn't a pharmaceutical example, but in the research that I did, we were looking at protein-stabilized emulsions. If the temperature changed too much, it caused the proteins to become denatured, leading to flocculation within the emulsion.

As long as the temperature's stable, then you can still make a good measurement with either laser diffraction or imaging.

Q: What is the importance of zeta potential in producing stable suspensions for drug products and is there any correlation with proper particle shape and size?

PK: Zeta potential is important when you're working with fine particles. Anne showed the plot of how the force of adhesion between particles changes the function of particle size during her presentation.

As we go below approximately 20 microns in size, the Van der Waals forces, the electrostatic forces between particles become more important, and can drive agglomeration of the particles. One way to then provide a stability for emulsion samples, or even for some suspension products as well, is to increase the zeta potential.

We can add charge stabilization species, or surfactants. If there's a surface charge on the particles, we can change the pH in order to increase that charge, increase the zeta potential, and through doing that, we can create a stable suspension.

Zeta potential tends to become more important as you go down in particle size, into the colloidal range. Then, we start to say, "Well, what can I change in order to impact that zeta potential?" And so, pH, use of stabilizers, the conductivity of the suspension or emulsion will become important parameters.

Q: What are the reasons that particles may have poor flowability?

AV: As they get smaller, the particles are going to get stickier. If they're spherical and small, they're going to clump together. The environmental conditions will have quite an effect on that as well. Charge, static, their likelihood to absorb moisture, those things will also affect flowability.

Q: For Raman spectroscopy in chemical imaging, do you search databases against the analyzed particles to look for its chemical identity followed by quantification? How much of these particles constitute the full sample?

AV: We use reference spectra in order to identify the particles within the formulation. With these reference spectra you can measure yourself from the pure ingredients. If you're blending up this formulation, it's best to measure your own reference spectra, because you know exactly what conditions they have been measured under.

We can also export spectra to a library like Bio-Rad's KnowItAll, which will search through its library to identify the materials. Ultimately, what you can aim to do is measure a certain number of particles. You can then identify them and quantify how much of each material of each chemical identity you have within the blend. 

Learn more about particle size analysis in pharmaceutical processes: Watch this webinar on-demand>>