Strategies to Enhance Nanocrystal Formulations for Overcoming Physiological Barriers Across Diverse Routes of Administration.

Poor aqueous solubility and bioavailability limit the translation of new drug candidates into clinical applications. Nanocrystal formulations offer a promising approach for improving the dissolution rate and saturation solubility. These formulations are applicable for various routes of administration, with each presenting unique opportunities and challenges posed by the physiological barriers. The development of nanocrystal formulation requires comprehensive understanding of these barriers and the biological environment, along with strategic modulation of particle size, surface properties, and charge to facilitate improved bioavailability to the target site. This review focuses on applications of nanocrystals for diverse administration routes and strategies in overcoming anatomical and physiological delivery barriers. The orally administered nanocrystals benefit from increased solubility, prolonged gastrointestinal retention, and enhanced permeation. However, the nanocrystals, due to their small size and high surface area, are susceptible to aggregation in the presence of gastric fluids and are more prone to enzymatic degradation compared to the macrocrystalline form. Although nanocrystal formulations are composed of pure API, the application of excipients like stabilizers reduces the aggregation and improves formulation stability, solubility, and bioavailability. Some excipients can facilitate sustained drug release. Emerging research in nanocrystals include their application in blood-brain barrier transport, intranasal delivery, stimuli responsiveness, multifunctionality, and diagnostic purposes. However, the challenges related to toxicity, scale-up, and clinical translation still need further attention. Overall, nanocrystal engineering serves as a versatile platform for expanding the therapeutic potential of insoluble drugs and enabling dose reduction for existing drugs, which can minimize toxicity and improve bioavailability at lower dosages.