Lipophilic Saltsof High Melting Point Drugs ModulateSolid-State Properties and Organic Solubility to Enable Manufacturabilityof Amorphous Solid Dispersions

Abstract Amorphous solid dispersion (ASD) manufacturability is constrained by active pharmaceutical ingredient physicochemical properties; high melting point (Tm) and high glass transition temperature (Tg) limit hot-melt extrusion (HME), and low organic solubility limits spray-drying (SD) throughput. We evaluated lipophilic counterion choice as a solid-state design lever to enable ASD manufacturability by SD or HME. Nine lipophilic salts of atazanavir (ATZ) and mebendazole (MBZ) were prepared with sulfate and sulfonate counterions spanning a range of chain lengths and steric bulk, and characterized by 1H nuclear magnetic resonance spectroscopy, powder X-ray diffraction, differential scanning calorimetry, and polarized light microscopy. Lipophilic salts showed Tm and Tg reductions relative to their free base, with Tg reductions of up to approximately 30 °C. Organic solubility in ethanol, acetone, and tetrahydrofuran improved 2–15× or greater across most salt-solvent combinations. Vacuum compression molding confirmed that a representative lipophilic salt (ATZ-pTSA) enables thermal amorphization at HME-relevant processing temperatures, where the ATZ free base does not fully melt or dissolve into the model polymer. Counterion choice functions as a solid-state design lever for ASD manufacturability through a proposed lattice-packing disruption mechanism that simultaneously reduces Tm and Tg and improves organic solubility.