Technology Development for Nasal Delivery Formulation – Spray Particle Size and Morphological Raman Spectroscopy

Using laser diffraction and automated particle imaging technology / Morphologically Directed Raman Spectroscopy (MDRS^®) can support the development of nasal spray products while providing the necessary data for regulatory compliance. We intend to introduce these two techniques.

Overview

Recently, nasal sprays have been attracting attention not only as a localized application but also as a means for systemic therapeutic delivery. In particular, for hormone therapy or migraine medication, the large surface area of the nasal mucosa and abundant blood flow enable rapid absorption of the drug, and proximity to the central nervous system maximizes drug efficacy.

Regulatory Guidelines and the Importance of Analysis for Nasal Sprays

Nasal sprays must be evaluated as a combination of device and formulation, and the particle size of the delivered particles and the active pharmaceutical ingredient (API) within the formulation significantly affect the therapeutic effect. Particles that are too small (below 10μm) may be inhaled into the lungs causing side effects, while particles that are too large may remain in the anterior part of the nose and not reach the target treatment site.

Figure 1 shows particle size data for the API in nasal spray formulations measured before and after spraying.

Therefore, particle size analysis is an essential factor not only in the product design phase but also for quality control and regulatory approval.

Spray Particle Analysis through Laser Diffraction / Spraytec

Laser Diffraction is a technology that allows non-destructive, real-time measurement of particle size in drug spray, optimized for dynamic analysis of spray events. Especially, the Spraytec system collects data at a rapid interval of 0.1ms to finely distinguish between the formation, steady state, and dissipation phases of a spray.

The U.S. FDA recommends focusing on statistically significant particle size information centered around data from the fully stabilized spray phase, which is crucial for ensuring the clinical efficacy and safety of products.

Figure 2 laser diffraction data tracking changes in particle size, Dv10, Dv50, and Dv90, and transmission concentration during nasal spray.

Case Study: Impact of Viscosity Changes on Particle Size

According to experimental results adjusting the concentration of Polyvinylpyrrolidone (PVP) to change viscosity, it was observed that higher viscosity leads to improper spraying and shortens or eliminates the stable spray phase. This is because high-viscosity formulations require more energy to spray.

Figure 3 shows the evolution of droplet size (Dv50) delivery through nasal spray pump for PVP solution in water.

To solve this issue, using the Equadel pump (Aptar Pharma) with an energy storage mechanism made stable spraying possible even for high-viscosity formulations, suggesting that precise control of interactions between device and formulation is achievable.

Utilization of Automated Imaging Technology

Suspension nasal sprays must accurately measure not only spray particles but also particle size of active components within the formulation. The technology used here is Automated Imaging Analysis. This method provides faster and more consistent data than traditional manual microscopy, measuring thousands of particles within minutes for statistically reliable results.

Figure 4 CE (Circle Equivalent) diameter is the diameter of a circle with the same area as the captured 2D image of a particle.

The Morphologi 4 system can distinguish between active ingredients and other particles with similar external shapes based on particle size (CE diameter), shape (circularity, convexity, elongation, etc.), and transparency.

Figure 5 shows that using primary dimensions of particles allows the creation of more size and shape distributions.

Component Analysis Combined with Raman Spectroscopy

To distinguish other particles similar in appearance to the active component, Raman Spectroscopy is combined with image analysis. In particular, Morphologically Directed Raman Spectroscopy uses shape-based filtering to selectively analyze only the particles of interest, significantly reducing measurement time.

Figure 6 shows the measurement sequence of MDRS Morphologically Directed Raman Spectroscopy.

In a practical case, out of approximately 9,000 particles, 450 were classified as API, indicating an API to excipient ratio of about 1:20 in the formulation. Furthermore, particles with elongation greater than 0.4 were automatically classified as non-API, reducing the scope of chemical analysis by up to 66%.

Integrated Analysis Strategy for Drug Delivery Optimization

Successful development and commercialization of nasal sprays require understanding and controlling the precise interaction between device and formulation. Laser Diffraction provides precise real-time analysis of spray dynamics, while Automated Imaging and Raman Spectroscopy contribute to clearly understanding the characteristics and changes of active ingredients.

This integrated analysis strategy is a powerful tool across new drug development, generic comparison, and manufacturing quality control in the pharmaceutical industry and will play a significant role in next-generation technology development, such as dry powder nasal formulations.

• Download original application note: Complementary Technologies for Nasal Spray Development

• Download Food and Drug Safety Guidelines: Equivalence Evaluation of Locally Acting Nasal Formulations