Particle Characterization is Critical for Drug Performance

The characteristics of particles–whether formulated into a suspension, capsule, or tablet–can have a tremendous impact on the performance of a drug product. Particle analysis is, therefore, a critical tool for drug manufacturers throughout the drug development and commercialization process. Ian Treviranus, product line manager for particle characterizationwith HORIBA Scientific, spoke with Cynthia Challener, editor of the Pharmaceutical Sciences, Manufacturing & Marketplace Report, about different particle-characterization techniques and recent developments in the field.

Importance of particle characteristicsPharmaceutical Sciences, Manufacturing and Marketplace Report: Why is particle-size analysis important in the pharmaceutical industry?

Treviranus (HORIBA): Particle characteristics can have a tremendous impact on the behavior of an API and/or a formulated drug product. Smaller particles tend to dissolve more rapidly and thus have higher bioavailability. A uniform particle size (narrow particle-size distribution) will similarly improve performance compared to drugs with a random distribution of particle sizes. The appropriate surface charge is important for preventing aggregation and agglomeration of particles in suspensions and emulsions, and therefore impacts stability. The surface area of a solid dosage drug plays a role in its dissolution profile. The properties of coatings applied to particles (i.e., thickness, uniformity) also affect drug performance. Finally, processability can be impacted, such as in tableting systems, where particles with certain shapes exhibit much better flow behavior than others.

Learning with lightPharmaceutical Sciences, Manufacturing and Marketplace Report: For what applications in the pharmaceutical industry is particle-size analysis useful/valuable and what technologies are typically used?

Treviranus (HORIBA): Particle characterization is critical throughout the entire drug development and commercialization process. Because particle properties play such a major role in the performance of both APIs and formulated products, these characteristics must be determined in the earliest stages of drug development. Once particle properties are defined in an FDA submission, the manufacturer must ensure that those specifications are met as the drug progresses through clinical trials and on to commercial production. Often, not only the specified methods, but the same instruments (makes and models) are used at each stage to ensure consistent analysis results.

The two most common technologies used in the pharmaceutical industry for particle characterization are laser diffraction (LD) and dynamic light scattering (DLS). LD is useful for particles ranging from tens of nanometers to a few millimeters while DLS is appropriate for particles that are a few nanometers to about one micrometer in diameter. Other techniques include optical image analysis, surface area analysis, and sedimentation analysis.

LD and DLS are used to determine particle size, particle-size distribution, and particle dispersion in a formulated tablet or capsule as well as to measure the properties of tablet and particle coatings. More recently, laser diffraction has proven to also be applicable to the evaluation of protein agglomeration. DLS, meanwhile, can be used to determine the zeta potential of particles in suspensions or emulsions. The zeta potential is a measurement of the difference in the charge on the surface of a particle and the background; a higher number indicates greater stability and reduced likelihood of agglomeration. Optical imaging techniques are used for particle-shape analysis while surface-area analysis provides information on the porosity of a tablet, which affects its dissolution rate.

Incremental improvements add upPharmaceutical Sciences, Manufacturing and Marketplace Report: What recent developments in particle analysis technology are being applied in the pharmaceutical industry, and what advantages/benefits do they provide?

Treviranus (HORIBA): Much of the advances in particle-analysis technology occur on an incremental basis through cooperation between instrument manufacturers and their pharmaceutical industry customers. With laser diffraction, iterative small improvements in polishes, light sources, detectors, computer algorithms, and noise subtraction add up over time to new capabilities for new applications. For example, laser diffraction previously was discounted as a technique for the determination of protein agglomeration. Today, however, LD performance has been shown to indeed be suitable for the reliable quantification of protein aggregation, even at very low concentrations.

For dynamic light scattering, there have been significant improvements with respect to its use for the determination of zeta potentials. The interest in zeta potential measurements has grown rapidly in recent years, and instrument manufacturers have responded by making incremental improvements in DLS to improve performance.

The need to properly characterize nanoparticles is also driving interest in newer technologies, especially in Europe. Since 2011 when the European Commission Joint Research Center (JRC) published its definition of nanoparticles and recommended the use of number-based analyses, which involve looking at individual nanoparticles, something that LD and DLS cannot do, there has been growing interest in methods such as nano tracking analysis (or nanoparticle tracking analysis, NTA) and nanocoulter counters. There is an expectation that the JRC definition will eventually become regulation in Europe, and the US will ultimately adopt something similar. Nanoparticle characterization is an issue for any product that contains nanoparticles that will be used by consumers, including medicines that are ingested or applied to the skin in some way.

Proteins remain a challengePharmaceutical Sciences, Manufacturing and Marketplace Report: What issues/limitations remain with particle size analysis in the pharmaceutical industry today, and what efforts are being made to address them?

Treviranus (HORIBA): The holy grail of particle analysis is to develop instruments that can cover a wider range of particle sizes or types, provide as much new information as possible, and do so in one instrument that is easy to use. For example, HORIBA is working to combine its experience in spectroscopic chemical identification with its particle-characterization systems. Marrying particle-size analysis with optical analysis and/or surface area analysis is another opportunity that the industry is exploring.

With respect to limitations, protein-aggregation analysis remains a real challenge. There is no one instrument at this time that can provide quantitative results over the entire size range from the smallest protein to the larger aggregate. Many biopharmaceutical customers are also looking for improvements in zeta potential analysis systems. One major flaw of this analytical method is the fact that, when the electric fields are applied to the samples, currents are generated. Pharmaceutical customers were reporting both variability in results for repeated tests and a trending of results in one direction, indicating that samples were being destroyed or degraded. Damage to sample cells is also a problem. Both can be extremely costly, particularly if it means larger sample sizes are required and the material is not recoverable for further analysis.

This issue is one that HORIBA has chosen to tackle. By replacing the precious metal electrodes typically used for zeta potential measurements with specially designed pressed graphite electrodes, it is possible to conduct the analysis with a much lower electric field. As a result, only a weak current is generated that does not damage the sample cell or the sample, which provides consistent results that our customers can have confidence in. Furthermore, the graphite electrodes are extremely durable and don’t need to be replaced for the lifetime of the instrument.