Effects of in situ ionization on ibuprofen-loaded solid lipid nanoparticles: physicochemical properties and interactions with Carbopol and xanthan gum hydrogels

Abstract

The poor aqueous solubility of ibuprofen remains a major challenge in drug development. Conventional formulation strategies primarily employ co-solvents or strong alkaline agents such as sodium hydroxide. Therefore, ibuprofen-loaded solid lipid nanoparticles (SLNs) were developed using an inorganic salt-mediated in situ ionization approach to improve drug incorporation and topical application. SLNs were prepared using the hot-melt homogenization method with beeswax as the lipid matrix. Different inorganic salts (K₂CO₃, Na₂CO₃, and Na₃PO₄) were employed to induce in situ ionization during nanoparticle formation. The obtained SLNs were incorporated into hydrogel systems containing Carbopol or xanthan gum. The interactions between SLNs and hydrogels were evaluated with respect to physicochemical characteristics, rheological properties, and ex vivo skin permeation. Formulations prepared without alkaline agents or at drug-to-alkaline molar ratios exhibited phase separation and poor stability. In contrast, in situ ionization at a 1:1 molar ratio produced homogeneous SLNs with uniform nanoparticles (200 nm), zeta potential values around − 20 mV, and encapsulation efficiency of up to 70.25%. FTIR and DSC analyses confirmed the conversion of crystalline ibuprofen into a less crystalline or amorphous salt form within the lipid matrix. Na₃PO₄ produced SLNs with higher surface charge and improved physical stability, whereas K₂CO₃ and Na₂CO₃ generated smaller and more homogeneous nanoparticles. Interestingly, potassium salts demonstrated superior permeation compared to sodium salts. The obtained results demonstrate that in situ ionization is an effective strategy for developing SLN-based topical delivery systems for poorly water-soluble drugs.