Optimized Milling Approaches for Scalable Production of Ritonavir Nanocrystals: from Process Design to Bioperformance Evaluation.

The development of nanoformulations aims to overcome the biopharmaceutical limitations associated with conventional drug delivery. Reducing the particle size to the nanometric scale enhances drug solubility, dissolution rate, and bioavailability. In this study, the development and quality control of ritonavir nanocrystals are described by using applied experimental milling approaches. Ritonavir nanosuspensions were initially prepared at a small scale using an Ultra-Turrax Tube Drive, in which 200 and 500 μm beads were identified as the most efficient for particle size reduction. The process was then successfully scaled up by using a bead mill, achieving particle sizes of approximately 300 nm within 30 min, followed by spray-drying. Solid-state characterization by XRD, TGA, DSC, and hot-stage microscopy confirmed that the nanocrystals retained Form II ritonavir throughout processing. The resulting nanocrystals were physically stable and exhibited a marked improvement in dissolution, particularly in a discriminative dissolution medium (0.04 M POE10LE). Process optimization was achieved by balancing bead sizes and steric stabilizers, such as PVP K30 and HPMC. Biodistribution studies using [