(M1330-02-12) Annealing as a Tool to Tailor Powder Morphology in Spray Freeze Drying

Purpose: Annealing is a well-established process step in conventional freeze-drying to promote ice crystal growth and optimize the drying behaviour. However, its suitability in spray freeze drying (SFD), which involves the atomization of a solution followed by rapid freezing, remains largely unexplored. The objective of this study was to investigate the effect of different annealing conditions on the powder morphology, flowability, and physical characteristics of spray freeze-dried trehalose formulations.

Methods: Aqueous trehalose solutions (5% w/w) were atomized and frozen under two different spray-freezing temperatures (-120°C and -160°C). Frozen particles were either dried directly or subjected to annealing under defined conditions: 3 hours at –40 °C, one week below the glass transition temperature of the maximally freeze-concentrated fraction (Tg’), or one week slightly above Tg′. Drying was performed at two freeze-drying temperatures (20°C and -25°C) for 44 hours under 0.05 mbar pressure. The dried powders were characterized by thermogravimetric analysis (TGA2, Star System, Mettler Toledo) for residual moisture, scanning electron microscopy (SEM, SU3500 Hitachi) for morphology, dynamic image analysis (DIA, Camsizer X2, Retsch) under free-fall and dispersion pressure for particle size and shape, X-ray powder diffraction (XRPD, X’Pert MRD Pro, PANalytical) and specific surface area was measured using BET (Belsorp Mini, Retsch) with nitrogen adsorption.

Results: All samples remained amorphous as confirmed by XRPD (fig. 1). Non-annealed samples showed the typical open-pore structure formed via ice templating (fig. 2, A). Short-term annealing at –40 °C for 3 hours led to morphological changes, with the development of more compact, honeycomb-like structures. These powders exhibited only slightly reduced flowability and slightly increased fragility, reflected in an elevated proportion of non-spherical particles under free-fall DIA and a shift towards smaller particles under dispersion pressure (fig 2, B). Prolonged annealing below Tg′ intensified sintering effects and caused partial fusion of adjacent particles (fig. 3, A), further compromising handling properties. Annealing slightly above Tg′ markedly accelerated these changes and resulted in severe structural collapse under dispersion pressure. Specific surface area consistently decreased with the extent of annealing with values around 14.3±2.9, 3.8± 0.5, and 3.1±0.2 m²/g for the non, 3 hours and one week annealed samples, respectively. Median particle size measured under dispersion pressure remained unchanged for all non-friable samples, as did bulk density with values between 363 and 405 µm and 0.03 and 0.04 g/cm³ for median particle size and bulk densities respectively. This indicates that the reorganization of water molecules did not affect the overall particle volume, for instance by outward water migration during annealing. Cross sections of the particles (fig. 3, B and C) show the disruption of the fine, lamellar ice-templated framework in the short-term annealed sample to the formation of thicker, but less organized and less interconnected trehalose sheets in the annealed sample.

Conclusion: This study demonstrates that annealing can be used to modulate morphology and physical properties of SFD powders. Short-term storage promotes morphological changes of the dry powder particles and a slight increase in cohesiveness. Long term (168h) storage below Tg’ results in sintering of adjacent particles, while annealing above Tg′ results in structural collapse. While the singular particles volume remained largely unaffected, the progressive decrease in flowability was accompanied by a loss in specific surface area. This shows, that adding a short annealing step after spray-freezing can be utilized if recrystallization of the solvent is wished, without compromising the powders flowability.

Acknowledgements: The authors thank the German Federal Ministry for Economic Affairs and Energy for financial support (ASG project, grant no. 03EN4086A)


XRPD of the unprocessed excipient (bottom) and non-annealed as well as annealed SFDs at different freezing and drying temperatures.


SEM morphology of particle collectives and respective size distribution for each row in free fall and with dispersion pressure.


Sintering during storage of frozen particles (A) and comparison of solid framework in cross sections of SFD particles, either after storage at -40°C for 3h (B) or one week at -25°C (C).