By Chris Aiken, RSSL Physical Sciences Laboratory Manager
Particle analysis and material characterisation are important processes for understanding drug performance, assessing product quality and informing decisions about the manufacture, processing, storage and transport of pharmaceutical products. Even small variations in particle shape, size and distribution can significantly influence the behaviour of pharmaceutical products including their stability, solubility and efficacy. This article explores the impact of particle characteristics on pharmaceutical products and highlights the value of particle analysis in understanding (and optimising) the structural, physical and behavioural properties of drugs, APIs (Active Pharmaceutical Ingredients) and excipients.
Particle Analysis and Characterisation
Particle analysis and characterisation are frequently carried out during pharmacopeial testing, troubleshooting, process development and quality control (QC release), but it is often beneficial to examine the physio-chemical properties of materials further, even if this information is not presented on the manufacturer's Certificate of Analysis. The additional information can help pharmaceutical companies understand the possible reasons behind any variance in the function of products throughout the development and formulation process. It is also valuable in identifying potential issues involved in buying from new suppliers, moving or adding manufacturing facilities and upscaling manufacturing.
The potential benefits and applications of data from particle analysis vary according to the specific tests performed, but in general, time spent on particle characterisation of initial materials will pay dividends informing critical decisions in research and design, manufacturing and formulation to save both money and effort at a later stage. For instance, rigorous particle characterisation assists manufacturers in reducing wastage of active pharmaceutical ingredients and finished products. Testing and optimisation can reduce the chance of failure in clinical trials, avoid problems in processing and production, and prevent recurring batch failures (out of specification results) in pharmaceutical manufacturing.
Physical Characteristics and Dissolution
The rate of dissolution in active pharmaceutical ingredients is affected by many physical properties including particle size, shape (morphology), specific surface area and pore size. The dissolution rate has a large influence on the bioavailability of the drug i.e. its ability to have an active effect on the patient. Monitoring the changing characteristics of a drug from the research and development stage through to stability testing allows researchers to build a clear picture of how bioavailability varies during preparation or following a move to expanded manufacturing facilities. This in turn indicates whether claims for rapid release drug products are borne out by the commercialised products. Dissolution rate and particle size are also important in demonstrating the equivalence of generic drugs.
Detailed studies of particle properties and behaviour can help specialists understand factors such as the consistency, processability, uniformity and ease of tabletting in solid dosage forms. Even small variations in the size, shape and size distribution of particles can influence batch equivalence and processing efficiency. Therefore, it is important to monitor these qualities closely when upscaling manufacturing processes. Formulations and manufacturing processes can be optimised and adjusted in light of lessons learned while monitoring the performance of excipients, active pharmaceutical ingredients and drug products in real-world situations.
The results obtained from particle characterisation and testing will generally need to be listed in a regulatory submission dossier, so it is important to apply precise and accurate methods for material and product characterisation. However, validated methods are frequently found to display unidentified flaws and shortcomings (such as inconsistency in their repeatability, robustness and in-lab precision) up to the point where they are exported to other laboratories. This highlights the importance of rigorous method development and validation to mitigate the risk of test methods proving inadequate.
The drawbacks in applying inconsistent or inappropriate research methods become clear when comparing APIs, excipients and other substances derived from different suppliers. The fundamental physical and chemical parameters reported on a Certificate of Analysis will often suggest that materials from different sources are equivalent, but if the suppliers use differing, or unreliable methods for characterisation then subtle variations in products and APIs may go unnoticed.
Whilst these differences maybe small in themselves, they can have serious consequences for the behaviour and function of the end products. Sometimes, the use of inaccurate or inappropriate testing methodologies may obscure significant variations in pharmaceutical goods and materials, potentially leading drugs to fail in clinical trials, or necessitating drug recalls.
Physio-Chemical Analysis Methods
A broad range of methods are available to study particle parameters in excipients, bulking agents and API’s either in suspension or in solid form. Static light scattering (laser diffraction) is typically employed to measure particle size in wet or dry dispersions of particles between 0.01 micrometers and 3500 micrometers across. Zeta potential measurement can be obtained by dynamic light scattering (DLS) techniques, which indicates the amount of repulsive force acting between particles, and is an important indicator of material stability.
DLS also allows for the determination of particle size in nanoparticles up to 10 micrometers in diameter.
Particle shape (morphology) affects the friability (susceptibility to crumbling) and can be measured via microscopy imaging techniques. Powder flow properties such as tapped and bulk density and data from shear cell measurements enable manufacturers to anticipate how products will behave under the influence of compressive and shear forces. This knowledge can be used to decide between different excipients (and suppliers thereof) dependent on the desired function and behaviour. Pore sizes and specific surface area of API’s may be measured using BET (Brunauer, Emmet and Teller), which informs product developers on the potential dissolution attributes.
Even when two manufacturing sites employ precisely the same materials from the same suppliers, the properties of the end products may vary significantly due to processing differences such as in environmental factors including humidity and temperature. These factors can affect the behaviour of the raw materials and finished product during storage, transport and tabletting. Further information on humidity-sensitivity can be obtained through dynamic or gravimetric vapour sorption (DVS/GVS), which helps understand how specific levels of humidity may have an undesirable affect on the physical properties of excipients and API’s. For instance, information on the likelihood for caking to occur, or transitions from amorphous to crystalline structure in materials can be obtained, thus influencing decisions about suitable storage and processing conditions.
Viscosity measurement and rheological characterisation offer detailed insights into the flow properties of drug products, to guide the selection of excipients and improve stability and delivery.
Outsourcing Material Characterisation and Testing
Studying physio-chemical characteristics can be hugely important in understanding the effectiveness of pharmaceuticals and overcoming issues with pharmaceutical products. These properties are most easily comprehended by combining a suite of tests for analytical characterisation to reveal important variations in starting materials and drug products, and understand the underlying factors that influence their behaviour. This knowledge can be used to inform decisions relating to manufacturing (e.g. during scale-up) and stability problems.
Often, larger pharmaceutical companies will have a broad set of testing methods at their disposal internally, but smaller organisations including virtual companies and other contract research organisations, may need to outsource their material characterisation and testing responsibilities. RSSL are an experienced partner for carrying out such analytical research. They use cutting-edge, validated methods and instrumentation to perform analysis work adjusted to meet each client's specific requirements for testing active pharmaceutical ingredients, bulking agents, excipients and drug products.
Visit https://www.rssl.com/ for further information on our pharmaceutical characterisation services.