Vol. 2, Issue 2, Part A (2025)

Poor adherence to daily oral antipsychotics and exposure variability motivate long-acting injectables (LAIs), yet hydrophobic active pharmaceutical ingredients challenge release predictability, manufacturability, and injectability. This study applied a Quality by Design (QbD) framework to develop two LAI platforms for a poorly water-soluble antipsychotic: a nanomilled nanosuspension and a PLGA in-situ forming depot (ISFD). A priori definition of the Quality Target Product Profile and critical quality attributes (CQAs) guided risk assessment and a two-stage Design of Experiments (DoE). Screening and response-surface designs mapped material attributes and critical process parameters—stabilizer identity/level, milling time/energy, polymer ratio/molecular weight, and solvent fraction—to particle-size distribution, PDI, zeta potential, viscosity, syringeability, and in-vitro release. Analytical methods included laser diffraction/DLS for PSD, XRPD/DSC for solid state, rheology for viscosity, texture analysis for syringeability (21-25 G), and a small-volume, sink-maintaining release method. The optimized nanosuspension achieved D50 ≈ 1. 02 μm, PDI 0. 18, zeta −24 mV, viscosity 48 mPa·s, syringeability 28 N (23 G), 24-h burst 9. 8%, and 90-day release 96%. The PLGA ISFD (50: 50, 30% w/w) showed 24-h burst 8. 1% and 90-day release 93% with syringeability 33 N. An intentionally off-target nanosuspension (broader PSD, weaker stabilization) exceeded burst and force limits and under-released long-term, validating design-space boundaries. ANOVA and lack-of-fit testing supported model adequacy; edge-of-space batches confirmed proven acceptable ranges. Results demonstrate that disciplined control of PSD and rheology minimizes burst, maintains ≤35 N injection forces across common gauges, and enables monthly-quarterly coverage. A lifecycle control strategy consistent with ICH Q8/Q9/Q12 operationalizes scale-up, tech transfer, and change management. Collectively, these findings provide a regulator-aligned, patient-centered pathway to robust LAIs for poorly soluble antipsychotics.