Lactose based crystalline solid dispersions to enhance ibuprofen solubility via hot-melt extrusion: A design of experiments approach

Poor aqueous solubility limits the oral bioavailability of many drugs. This study developed polymer-free, carbohydrate-based crystalline solid dispersions (CSDs) of ibuprofen (IBU) using hot-melt extrusion (HME) as a solvent-free and scalable manufacturing approach. Crystalline carbohydrate carriers, mannitol, sorbitol, xylitol, maltitol, lactose monohydrate, pregelatinized starch, and microcrystalline cellulose were screened to enhance solubility and dissolution. Lactose monohydrate showed superior performance and was selected for further optimization. Drug-carrier interactions were confirmed by FTIR and ¹H NMR. A Box–Behnken design evaluated the effects of drug loading (20–50% w/w), extrusion temperature (85-115°C), and feed rate (0.5-1.3 g/min). Drug loading and temperature significantly influenced solubility, while dissolution was primarily governed by drug loading. The optimized formulation (20% w/w IBU, 115°C, 0.9 g/min) achieved an ∼8-fold solubility increase (∼348 µg/mL) and ∼33% drug release within 60 minutes in water. DSC and PXRD confirmed retained crystallinity, while reduced particle size and a six-fold increase in specific surface area contributed to enhanced performance. Three-month stability studies showed no significant changes in solid-state properties or dissolution. Lactose-based CSDs prepared via HME provide a stable and effective platform for improving poorly soluble drugs.