Harnessing the Potential of Phospholipids as Pharmaceutical Excipients: A Versatile Platform for Customized Drug...

This review critically examines phospholipids as pharmaceutical excipients, focusing on physicochemical properties, self-assembly behavior, drug delivery applications, translational limitations, and future opportunities in customised therapeutics.

Phospholipids have evolved from inert excipients into multifunctional materials that modulate drug stability, bioavailability, release kinetics, and targeted delivery. Their amphiphilic architecture enables diverse supramolecular systems-liposomes, lipid nanoparticles (LNPs), liquid crystalline depots, and hybrid polymer-lipid carriers-central to drug delivery. A narrative review evaluated preclinical, clinical, and industrial data on phospholipid chemistry, phase behaviour, nanocarrier architectures, oral bioavailability enhancement, biologics and nucleic acid delivery, oxidative stability, manufacturing scalability, and regulatory compliance, emphasising links between composition, structure, and in-vivo performance.

Packing geometry influences self-assembly into lamellar, cubic, and hexagonal phases, shaping release behaviour across small molecules, biologics, and nucleic acids. PEGylated liposomes can substantially prolong systemic circulation relative to conventional formulations. Doxil and AmBisome demonstrate reductions in cardiotoxicity and nephrotoxicity, respectively. Ionizable lipid nanoparticles containing DSPC enable siRNA delivery in Patisiran and mRNA-vaccine delivery in Comirnaty, although their lipid compositions differ. Phospholipid-containing oral formulations may improve bioavailability of selected BCS Class II compounds through mixed-micelle solubilisation and lymphatic transport. Oxidative instability, anti-PEG immunogenicity, IVIVC limitations, and batch variability remain challenges, mitigated by antioxidants, saturated lipid substitution, and Raman monitoring.

Phospholipids represent a programmable excipient platform used in numerous approved lipid-based drug products. Advances in synthetic lipid engineering, AI-guided design, and personalised medicine are expected to expand their impact across gene therapy, biologics, and long-acting therapeutics.