By Chris Aiken, RSSL Physical Sciences Laboratory Manager
Sometimes it's the smallest details that have the biggest impact on pharmaceutical performance. That's certainly true when it comes down to the properties of particles and their impact on pharmaceutical performance. Subtle changes in particle size, shape and distribution can have a major impact on pharmaceutical solubility, stability and efficacy.
It's no surprise therefore that particle analysis often forms part of the basic characterisation of the physical, structural and behavioural attributes of Active Pharmaceutical Ingredients (APIs), excipients, and final drug products. Such analysis is often performed for QC release, pharmacopoeial testing, process development and troubleshooting. However, it is often worthwhile to further interrogate the physico-chemical properties of materials even if they are not reported as part of a manufacturer’s Certificate of Analysis (CoA). This is because this type of extended characterisation can help to identify the (potential) cause of variations in the behaviour of particles and finished product attributes during drug development and formulation. It's also useful in spotting potential problems when evaluating new suppliers, changing or adding manufacturing sites, or scaling up production.
Of course, the value and utility of data gleaned from such analyses will depend on the specific tests that are carried out. However, the bottom line is that spending some time on properly characterising materials before making potentially critical R&D, formulation or manufacturing decisions will more often than not save more time and money further down the line. For example, thorough particle characterisation can help to prevent API and final product wastage. It can even potentially prevent failure during clinical trials, preempt processing or manufacturing issues, and avoid repeated batch failure (OOS results) during production.
Impact of physical characteristics on dissolution
The dissolution rate of APIs is a good example of a property that is impacted by a number of different physical characteristics such as morphology (shape), particle size, pore size/specific surface area. Dissolution testing provides an indication of bioavailability in the patient, and conducting these tests throughout the product life cycle, from R&D to stability testing, will highlight changes in bioavailability during formulation, or during manufacturing scale up, and so indicate whether extended or rapid-release claims for the final product can be supported. Particle size and dissolution are also critical in the generics sector, to demonstrate equivalence.
A thorough characterization of particle attributes and behaviour also provides valuable insights into processability, ease of tableting, and consistency or uniformity of solid dosage forms. Even minor inconsistencies in particle size, shape or size distribution can affect processing efficiency and batch equivalence so it's worth paying extra attention to these parameters when scaling up manufacture. Thorough characterization of the APIs, excipients and final products under real-world conditions can help to identify these issues, so that processes and formulations can be adjusted.
It is critical that the methods used to characterise materials and products are accurate and precise, since characterisation data collected during stability testing of batches for clinical trials will generally have to be included in a regulatory submission dossier. Despite this, it is not uncommon for validated methods to exhibit unidentified deficiencies (e.g. reliability issues in their robustness, repeatability and intermediate precision) until such a time as they are transferred out to other laboratories. This underlines how thorough method development and validation studies can help to reduce the risk of method failure.
The problem of using different/inappropriate methods becomes apparent when comparing a material of interest (perhaps an excipient or API) from different suppliers. In this situation, the basic chemical and physical information in CoAs may well indicate that materials from different suppliers are equivalent. However, if the analytical methods used by one supplier are not reliable, or if the two suppliers differ significantly in the methodologies they use for characterisation, then subtle differences between the materials or products might not be identified. Yet, these differences may have a significant impact from a functional or behavioural perspective. In effect, the application of unsuitable or inaccurate analytical techniques could mask key differences between materials that, in extreme cases, might affect drug efficacy, and even lead to the failure of clinical trials or drug recalls.
Physico-chemical analytical techniques
A wide range of particle characterisation techniques are available to investigate the attributes of APIs, excipients and bulking agents, both in a solid form and when in suspension. Laser diffraction or static light scattering is a commonly used technique for obtaining the particle size distribution of materials via wet or dry dispersion over the 0.01 µm to 3500 µm size range (airjet and mechanical sieving are also still commonly applied for this purpose). Dynamic light scattering is a technique used to measure zeta potential, and enables nanoparticle size analysis up to 10 µm. Zeta potential is a measure of the repulsive forces between particles and can help to indicate the likelihood of agglomeration, which is useful as a stability predictor.
Microscopy techniques are applied to characterise the morphology (shape) of particles, which in turn impacts on flow properties and friability of the material. Powder flow measurements (e.g. via shear cell, or tapped/bulk density) provide insight into how powders behave under compressive and shear forces. This understanding facilitates comparisons between materials and the selection of the most appropriate flow properties for the desired functionality. Specific surface area (Brunauer, Emmett and Teller; BET) analysis also provides information on pore sizes, to support understanding of the dissolution properties of APIs and other materials.
When the same product is made at two different sites using exactly the same starting materials, the end product may be affected significantly by environmental conditions, such as temperature or humidity. These can impact on processing or handling factors, such as material storage, transit or the tableting process. Dynamic vapour sorption (DVS/GVS) analysis delivers valuable information about humidity-sensitive materials and their appropriate storage conditions and, for example, how certain humidity levels can detrimentally impact the physical state of amorphous materials.
Rheological characterisation can provide in-depth understanding of the flow behaviour of liquid and semi-solid formulations. This information helps formulators to select appropriate excipients that will achieve the desired flow behaviour and ultimately achieve/quantify long-term drug product stability.
Understanding the physico-chemical properties of materials can be key to understanding the performance of pharmaceutical products, and to resolving any problems. By combining appropriate techniques into an analytical characterisation suite it is possible to gain a greater understanding of these properties and potentially expose critical differences between materials. The additional information can, in turn, inform decision making, formulation and process optimisation, as well as help to scale up manufacturing and more seamlessly transfer processes to additional manufacturing sites or contract research organisations (CROs).
While some of the larger pharmaceutical companies may have a range of these testing modalities available in house, for the smaller pharma organisations, virtual companies and CROs, this testing may well have to be outsourced.
An ideal partner for this analytical work will offer multidisciplinary services and state-of-the-art, validated instrumentation and methods, which will enable them to carry out analyses that are tailored to the client’s exact requirements, whether for individual APIs, excipients or bulking agents, or for the drug product. For more information on RSSL’s physical characterisation services, please visit www.rssl.com