Powder analysis: The next level

Powder characterisation has long been recognised as a fundamental pillar of the optimisation of oral therapeutics, as the vast majority of APIs are in powder form. Yet that understanding of its importance does not make the process any less complex. There are many characteristics to consider and the sheer number of variables that have a bearing on power behaviour make the ultimate performance of an API hard to predict.

Finding the right balance of flowability, solubility, consistency, purity and stability is essential, which means techniques used to measure these characteristics come under the spotlight. Powders contain particles, liquid and air, all of which influence properties such as flow, along with a host of other variables in the system – for example, the degree of aeration – so the range of techniques required extends from bulk powder measurement down to the examination of internal particle structure. In such a complex model, and with so many powder and particle characterisation available, there is great potential to consume valuable time and resources, so research is increasingly focused on making this stage of oral drug formulation as efficient as possible.

The tools of the trade

The sheer number of powder testing methods used in the pharmaceutical industry is an unmistakable indicator that powder characterisation is not only important to the quality of the final product, but also fraught with difficulty.

Rheology – the study of flow behaviour – uses many different techniques to assess consolidation, aeration, powder flow, compressibility, permeability, stability, variable flow rate and more. Some techniques are simple in nature, while others are technically more complex.

At the simple end of the spectrum there are techniques such as the angle of repose – a measurement of the angle produced by the powder on a surface when poured through a funnel – which affects the ability of a powder to flow. Flow rate through an orifice, which depends largely on the type of container used, the size and shape of the orifice, and the measurement method, is a good indicator of overall flowability.

Then there is the Carr index – also known as Carr’s compressibility index – which gives an indication of the compressibility of a powder by using measures of its true density (ρT) and bulk density (ρB). It can, in fact, be used as an indirect measure of the bulk density, size and shape, surface area, moisture content and cohesiveness of materials because all of these factors can influence the observed compressibility index.

Many of these simpler techniques are intuitively useful because they seem logical and yield useful data, but they can be prone to their own problems. Reproducibility and process relevance are, for example, common stumbling blocks, and in some cases a difference in testing parameters – as with the measurement of flow through an orifice – can result in differences in outcome.

Need for more complex analysis arises from the many shortcomings of any individual test. For instance, the angle of repose test may be attractive because of its simplicity, but provides only a single number description of a powder, when many other factors must be brought into the equation. Hence the need for powder characterisation techniques such as moisture content analysis, surface area analysis – often using the Brunauer, Emmett and Teller (BET) technique, which is the most common method used with powders and porous materials – and the measurement of particle size, shape and morphology.

As certain factors, including compressibility percentage (CPS), and flow function coefficient (FFC), can be significantly affected by the size of particle in powdered material, particle characterisation using a host of different methodologies may also be required.

Among these techniques are solid state characterisation using X-ray diffraction analysis (XRD) to investigate crystalline material structures to assess factors such as atomic arrangement and crystallite size, and measurement of the size distribution of particles in suspensions using dynamic laser light scattering.

Additionally, particle morphology, size, size distribution and shape analysis using the laser light scattering techniques can provide invaluable data on size and shape for an API within a multicomponent blend or suspension. Light microscopy and light obscuration testing image analysis can determine colour, shape parameters and size, electron microscopy and spectroscopy can determine the elemental make-up of particles in a powder, and measures of zeta potential (can be used to optimise the formulations of suspensions, emulsions and protein solutions) of particles in suspension can improve formulation stability.

Detailed testing is essential because of the number of variables that can influence powder behaviour. It is important to know whether differences in behaviour are due to particle size, shape, roughness, the degree of aeration, the level of moisture or any other factor. It may be tempting to stop at measuring particle size, shape and composition, but in preparation of oral dosage for the pharmaceutical industry, this will not suffice.

Efficient and reproducible measurement and testing techniques are the key to producing clean data that enables the optimal characterisation of powders for use in pharmaceuticals, where there must be a clear distinction between what is an anomaly in the substance and what is an analytical artefact. While there are several ways to improve reproducibility in the testing and characterisation phase for pharmaceutical powders, including simple agitation to dissipate the particles and allow excess air to escape from the sample, more sophisticated approaches may be required to not only improve the quality of the data, but also make the testing phase more efficient. Automation is increasingly the cornerstone of efficient analytical procedures, as it vastly reduces the potential for human error.

Focus on efficiency

The need for greater efficiency in the characterisation of powders for pharmaceutical use has led to a growing body of research into how key parameters can be assessed faster and with greater accuracy. The paper ‘Comprehensive powder flow characterization with reduced testing’ by Chendo et al, published last year, is a prime example.

The paper notes that powder flow is a critical attribute of pharmaceutical blends to ensure tablet weight uniformity and production of tablets with consistent and reproducible properties. The study then proceeds to characterise different powder blends with a number of different rheological techniques so as to understand how particles’ attributes and interaction between components within the formulation generate different responses when analysed by different rheological tests.

The goal of the research was to find ways in which the number of tests in early development phases could be kept to a minimum by performing only those characterisation processes that yield the best data on the flowability attributes. Looking at two cohesive powders – spray-dried hydroxypropyl cellulose (SD HPMC) and micronised indomethacin (IND) – formulated with other four commonly used excipients, the team’s results showed that powder flowability is affected by particle size, bulk density, morphology, and interactions with lubricating agents.

The results of the experiments confirmed that simple tests such as angle of repose, compressibility percentage, and FFC are greatly influenced by particle size. Conversely, the specific energy (SE) and the effective angle of internal friction (φe) were shown to be more closely related to particle morphology and materials interaction lubricants.

The paper concluded that “since both FFC and φe parameters are generated from the yield locus test, data suggest that a number of different powder flow features may be understood only by applying this test, avoiding redundant powder flow characterisation, as well as extensive time and material spent in early development formulation stages”.

Other research, including ‘Mechanical characterization of pharmaceutical powders by nanoindentation and correlation with their behavior during grinding’, by Baraldi et al, also seeks to add the body of knowledge around controlling the size of powder particles in the design of pharmaceutical products in processes such as powder milling, the efficiency of which has a direct impact on the mechanical properties of powder particles.

What emerges from this growing body of research is that the most common characterisation methods used to evaluate pharmaceutical powder properties may well have been standardised with the aim of providing common and simple procedures, but the existing standards for powder property analysis are still prone to error and their reproducibility may be limited. As a result, the data they yield may not be suitable for today’s high-end product development processes.

Powder characterisation is a highly complex process that, as of now, suffers from a lack of theoretical knowledge. While its importance is understood, there is an urgent need to refine and improve characterisation processes for today’s pharmaceutical products.