Materials Identification

Particular Challenges

Reading Scientific Services Ltd (RSSL)

Particle size is a vitally important variable in the ensuring the performance and efficacy of many pharmaceutical products.

For example, it plays a key role in controlling the dissolution and solubility characteristics of solid or suspension delivery systems, thereby impacting on bioavailability of active ingredients. Particle size also plays a role in precipitation from suspension: in general, finer particles make for a more stable suspension. That said, the balance of the repulsive and attractive forces that exist between particles are also a factor. Where the particles have little or no repulsive force then this will lead to aggregation.

Particle Size Analysis

Combining techniques

These are just a couple of examples of how particles affect product performance. There are many others, and understanding the impact of particles is clearly important in the development of drug formulations/specifications, and in any investigation of problems.

To further this understanding, the laboratory can employ several methods and techniques, all of which can give useful information on their own, but which are often more potent when employed in combination.

Laser diffraction

Laser diffraction is a reliable measurement technique for performing particle size analysis and is the sizing technique of choice for quality control (QC) in many sectors. That said, particle size data alone may be insufficient to either fully characterise or define a material. Shape may be just as important, and as imaging technology has become more freely available the influence of shape on performance has become increasingly well-appreciated. Imaging can come into play in detailed development work, more insightful troubleshooting and root cause analysis – helping to explain what really went wrong with a batch. Where two samples behave differently but are classified as identical by size analysis, the shape of the particles may hold the key.

Though a more lengthy procedure than laser diffraction, imaging, in which size data is overlaid with statistically relevant information about shape, is much faster than manual microscopy. Importantly, it is possible to obtain data for tens of thousands of particles in minutes. Parameters such as circularity, convexity and elongation can be defined and used to precisely define the shape distributions of a particle population.

Spectroscopy

The integration of spectroscopy into imaging systems adds a further dimension to automated image analysis. With the addition of Raman spectroscopy, for example, particles may be characterised in terms of size, shape, and chemical composition.

Microscopy

Microscopy and its associated analytical capabilities are very valuable additions to the particle characterisation armoury. Foreign materials, for example, are a specific sub-class of particle that are always unwelcome, but sadly not so uncommon. Microscopy plays a valuable role in foreign material identification, especially when X-ray diffraction (EDX) capabilities are linked to the scanning electron microscope to obtain data on chemical composition. Similarly, this kind of analysis can be useful in assessing the quality of mixing of two ingredients within a tablet.

Whilst SEM with EDX is useful for looking at 'heavy' elements, infrared imaging microscopy can be used to analyse the distribution of organic molecules/particles in complex mixtures such as tablet formulations and sediments.

Rheology

The flow properties of products can be substantially modified through the manipulation of particle size, distribution and shape, and there are sound reasons for pharmaceutical formulators to want to do this. With medicines that are suspensions, for example, viscosity may be controlled to prevent settling during storage. Viscosity is also a key parameter for nasal sprays. Here, the viscosity of the formulation influences the droplet size produced by a specific device.

Dissolution studies

In early phase development it is critical to investigate whether or not particles of the proposed new active will dissolve in the body. Using methods specified in the pharmacopoeia one can mimic the environment of the mouth and gut, and determine where in the GI tract an active is likely to dissolve, and potentially whether it is worth pursuing. One might also investigate if particle size within the finished product has an impact on release rates.

Conclusion

There are many reasons to want to establish, measure and monitor particle characteristics. Many techniques are available that might usefully be applied to obtain the required information. In choosing between these, one must remain aware that answers provided by different techniques to essentially the same question may differ somewhat. However, with care and expertise there is much that can be learned about the particles in pharmaceutical products, and the effect of particle size and morphology on the performance of the end product.

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