Atomizing into a Chilled Extraction Solvent Eliminates Liquid Gas from a Spray-Freeze Drying Microencapsulation Process

A spray-freeze drying encapsulation process using direct atomization into a chilled extraction solvent (ACES), in the absence of liquefied gas, was developed. Heat transfer models, developed to estimate droplet freezing time (tf), identified ACES conditions where solvent extraction, nonsolvent influx, and droplet deformation were minimized. Calculated tf's for dichloromethane and dichloroethane droplets were 98 and 46 ms, respectively, using atomization into liquid nitrogen (ALN2). For droplets <100 µm, this was shorter than the calculated headspace residence time, indicating freezing precedes cryogen impact. Calculated tf's for ACES ranged from 9 to 36 ms. The longest tf's resulted in collapsed, asymmetric particles with phase-separated cores and high nonsolvent residuals (>10%). Intermediate tf's produced spherical-cap particles with rough exteriors and a mixture of solid and phase-separated structures. The shortest tf's produced smooth, spherical-cap particles with solid cores, resembling particles made by ALN2; residual solvent levels were similar or superior to those with ALN2. Phase separation within droplets, induced upon extraction solvent contact in ACES, was minimized for cases where tf ≤ 12 ms, corresponding to Stefan numbers (Ste) ≥1.3. These results, obtained with cryogen temperatures up to −122°C, demonstrate encapsulation by ACES is possible if freezing is sufficiently rapid, enabling milder operating temperatures. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:4459-4472, 2008