Felipe Guizze, Sophia Sueyoshi, Helena Castilho, Mônica F Z J Toledo, Jeanine Giarolla
The aqueous solubility and membrane permeability of Biopharmaceutics Classification System (BCS) class II and IV drugs, such as furosemide (FUR), sulfadiazine (SDZ), verapamil (VEP), mefloquine (MEF), and the bioactive compound quercetin (QUE), are low. Thus, affecting the oral bioavailability of these drugs. In our study, we aimed to design drug-modified low-generation poly(amidoamine) (PAMAM) dendrimer complexes to improve solubility and permeability. The PAMAM dendrimers (G0 and G1) were synthesized via a divergent approach that combined Michael addition and amidation reactions, using 1,4-diaminobutane as the core. Drug-dendrimer complexes were prepared at molar ratios of 1:1, 3:1, and 5:1 by co-dissolution in methanol, followed by solvent removal and aqueous extraction. The reduction in crystallinity was classified using a polarized light microscopy-based scoring system ranging from CCCC (fully crystalline) to AAAA (fully amorphous), enabling qualitative assessment of amorphization following dendrimer incorporation. Polarized light microscopy revealed complete amorphization (AAAA) in specific systems at a 1:1 molar ratio. Solubility studies at pH 1.2, 6.8, and 7.4 showed significant increases, with quercetin reaching nearly 5-fold higher concentrations for the PAMAM-G1 1:1. Parallel Artificial Membrane Permeability Assay (PAMPA) experiments showed variable permeability responses across drug: dendrimer ratios and pH conditions. PAMAM dendrimer complexes were able to considerably enhance the solubility of BCS class II and IV drugs through amorphization and non-covalent interactions. We expect that these systems will further improve key biopharmaceutical properties directly associated with the bioavailability of other poorly water-soluble drug candidates.