Seeing the Unseen: Why Particle Size Distribution in Ophthalmic Emulsions Matters

Ophthalmic emulsions are advanced drug delivery systems designed to overcome the ocular surface’s physiological barriers while ensuring patient safety and therapeutic efficacy. A key quality attribute (CQA) in such formulations is the particle size distribution (PSD) of the dispersed phase, which has a profound impact on both clinical performance and regulatory compliance.
Particle size directly influences bioavailability, especially for lipophilic drugs encapsulated in the oil phase. Smaller droplets, typically in the submicron range (100–300 nm), provide a higher surface area for drug release, enhancing absorption through the corneal epithelium. (1) (2). Conversely, larger particles (> 10 μm) can cause ocular discomfort, foreign body sensation, or inflammatory responses, thereby reducing patients’ compliance. (3)
Regulatory agencies such as the FDA and EMA impose strict limits on the presence of oversized particles in ophthalmic formulations. The FDA’s guidance for ophthalmic suspensions recommends that the majority of particles be <10 μm, with no more than 0.1% exceeding 25 μm. (4) These criteria are widely referenced for emulsions as well.
From a physical stability perspective, PSD plays a crucial role in preventing phenomena such as coalescence, creaming, or Ostwald ripening, all of which can compromise product uniformity and shelf life. (5) Tight control of PSD ensures consistent drug delivery, minimizes batch-to-batch variability, and meets quality assurance standards during storage and handling.
To characterize PSD, a variety of analytical techniques are routinely employed, including dynamic light scattering (DLS), laser diffraction, optical microscopy, and electron microscopy. (6) (7) (8) These methods are essential in the development and approval of ophthalmic emulsions, where fine droplet sizes (typically ~100–250 nm) contribute to therapeutic efficiency and tolerability. (9) (10)
The zeta potential of cyclosporine A (CsA) plays a critical role in determining colloidal stability, ocular residence time, and biocompatibility. Depending on the pH value, the ionic strength, and the type of emulsifier or stabilizer used for the nanoemulsion, the zeta potential can vary. A sufficiently high magnitude of zeta potential (positive or negative) helps maintain repulsive electrostatic forces between particles or droplets, preventing aggregation and phase separation.
This application report demonstrates the capability of the Litesizer DLS 701 to analyze Restasis®, an ophthalmic emulsion, using dynamic light scattering.

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