Design of Experiments, Hirshfeld Surface Analysis, and Pharmacokinetics Predictions of Carbachol‐Loaded Solid Lipid Nanoparticles for Ocular Delivery

Carbachol (CCH) is a potent acetylcholine receptor agonist of hydrophilic and charged nature, which poses challenges in solid lipid nanoparticles (SLN) formulation development. In silico ADME predictions revealed extremely low lipophilicity (Log P o/w = −3.53) and poor membrane permeation (Log K p = −10.30 cm/s), while 2D fingerprint analysis showed that 35.1% of intermolecular contacts are H∙∙∙Cl/Cl∙∙∙H interactions, which indicates a highly hydrophobic environment that may compromise CCH encapsulation into SLN. Design of experiments (DoE) was employed to optimize the production process by evaluating the impact of homogenization speed and time on the particle size and zeta potential of CCH‐loaded SLN. The CCH‐loaded SLN were further characterized using rheology, thermal analysis, and Fourier‐transform infrared (FT‐IR) spectroscopy to assess their physical and chemical properties. The integration of computational tools with experimental characterization provided molecular‐level insights into drug‐lipid incompatibility, establishing a rational framework for formulation optimization. This study represents a novel approach, as to our knowledge CCH has not been previously encapsulated in SLN, offering a potential breakthrough in ophthalmic drug delivery.