Scale-Up of Air-Assisted Solvent Extraction for Reproducible Poly(L-lactide) Microspheres: Batch Variability, Residual Dichloromethane, Injectability, and Hydroxyapatite Composite Characterization

This original research article evaluates the scale-up of an air-assisted emulsion–solvent extraction process for injectable poly(L-lactide) (PLLA) microspheres. Six manufacturing batches were compared at two nominal scales. A tenfold increase in PLLA loading reduced batch-mean d50 from 21.56 ± 0.74 to 7.56 ± 0.42 µm while recovery remained 84–87%. Residual dichloromethane was 6–7 ppm in linked batches and below 20 ppm in an independent HS-GC–MS assessment. A reconstitution screen identified 0.4% sodium carboxymethylcellulose, 2.55% mannitol, and 0.1% polysorbate 20 as the only tested vehicle that reconstituted and passed freely through a 26 G needle. Bright-field micrographs showed predominantly circular profiles consistent with spherical PLLA microspheres. The study identifies scale-dependent hydrodynamics, solvent clearance, morphology, and injectability as critical development attributes.