Safety of Pharmaceutical Nanosuspensions in Drug Delivery: Evidence, Knowledge Gaps, and Safety-By-Design Strategies

Poor aqueous solubility remains a major barrier to small-molecule drug development. Pharmaceutical nanosuspensions, composed mainly of drug nanocrystals stabilized by small amounts of excipients, can improve dissolution and have been translated into several oral products and long-acting injectables. However, their simple compositions do not make them biologically inert. Nanosizing changes the surface area, dissolution, interfacial properties, aggregation, and interactions with biological fluids, thereby affecting local and systemic safety. This review examines nanosuspension safety from a product-level perspective. It focuses on formulation states generated during storage, handling, administration, and biological exposure, with attention to particle-size distribution, large-particle tails, stabilizer coverage and free excipient, crystal form, dissolution behavior, redispersibility, and in-use stability. These attributes are linked to blood compatibility, complement activation, immune responses, route-specific toxicity, biodistribution, macrophage-associated retention, depot persistence, clinical experience, and regulatory translation. Current evidence supports nanosuspensions under well-controlled conditions, especially for oral nanocrystal products and selected long-acting injectables. Key uncertainties remain for repeated intravenous use, chronic pulmonary exposure, particle-specific biodistribution, depot reversibility, long-term tissue exposure, and vulnerable populations. Safety assessment should, therefore, connect critical quality attributes with route-relevant exposure and biological responses, providing a basis for safety by design.