Laser diffraction-based particle size analysis is a powerful tool for nasal spray characterisation primarily because it is fast enough to capture droplet size evolution in real time. This article examines its value, and describes studies that explore the effect of formulation viscosity on droplet size, as well as device characteristics, such as orifice diameter of the nasal actuator and spray pump mechanism. Such studies support the faster and more efficient development of nasal spray products.
The regulatory perspectiveRegulatory guidance recommends that nasal sprays are tested as combined products (device and formulation together) to determine reproducible delivery.1–3 Achieving clinical efficacy and good product consistency relies on understanding and controlling the interactions between device and formulation, which together dictate performance. Invitro testing is specified for a range of variables, with droplet size being one of the most important parameters. Droplet size measurements are used to assess:
Quality — the consistency of performance; for example, over the lifetime of the product, from batch-to-batch, or after storage.
Safety — droplets of 10 µm and below may pass through the nasal passages and penetrate into the lungs.3 Consequently, APIs in this fraction will enter the body by pulmonary absorption, rather than by the intended route. Quantifying the extent of this risk and assessing the associated clinical effect is essential.
Efficacy — droplet size influences the site of deposition within the nasal passages, which may affect bioavailability.
The FDA recommends droplet size measurement at several stages of the product life cycle, including: development/optimisation and preclinical/IND trials; stability, robustness and in vitro bioequivalence testing; and batch release.1,2 The European Medicines Evaluation Agency (EMA) sets out similar guidance for droplet sizing as part of product applications,3 although the extension to in vitro bioequivalence testing is not as clearly stated. Such testing allows developers to successfully optimise controllable parameters to meet performance targets and provides quality control for the manufactured product.
The two droplet sizing techniques for nasal spray testing highlighted by the regulators are cascade impaction and laser diffraction. Cascade impaction is a relatively time and labour-intensive technique that allows measurement of the amount of API in the sub -µm aerodynamic fraction, which is important for assessing the potential for pulmonary absorption (as noted above). Laser diffraction, in contrast, is sufficiently rapid to provide real-time size measurement of the whole droplet rather than just the API. Because of this, laser diffraction is an excellent tool to use during the development cycle when the aim is to target a defined droplet size and obtain an early assessment of the percentage of droplets less than 10 µm in size.