(T1130-06-35) Freeze-Dried-Microspheres: Low Density, Flowability and Processibility

Purpose: Spray-freeze-drying (SFD) can manufacture a product with the combined advantages of freeze-drying and spray-drying: a gentle process, resulting in a low density, flowable powder with a high solubility. Those lyospheres® exhibit excellent processing-properties for the pharmaceutical industry. Remarkably, processability has never been systematically tested for SFD-products. Here, we explore the design of a mechanically stable free-flowing low-density freeze-dried sphere. Physicochemical properties of excipients and their solid content in solution can lead to a wide range of viscosities, a property that is expected to influence spraying speed and particle size. Also, bulk density and mechanical stability of the dry lyosphere® originates in the choice of excipient but can be manipulated by adjusting the solid content of the solution and therefore of the dry sphere. A mechanically stable powder exhibits a higher sphericity, which should lead to an increase in flowability. We explore the whole SFD-process in respect to increasing solid content: starting with viscosity of the spraying solution, spraying speed, sphericity and size of the produced particles, their mechanical stability, resulting bulk density and flowability. The presented findings support a deeper understanding of significant processing factors in the emerging field of SFD.

Methods: Five solutions of 1:1 Mannitol and Kollidon® 25 were prepared in solid contents of 2.5, 5, 10, 15 and 20 %. The pycnometric densities and viscosities of the solutions were measured and subsequently spray-freeze-dried, as described by Eggersted [1]. In short, the spraying-solution is fed into a droplet generator (FMP, Erlangen) and atomised with a 100 µm nozzle. The generated droplets freeze during free-fall in a chamber, which is cooled to – 130 °C with liquid nitrogen and collected in a glass vessel at the bottom. During spraying, the spraying-speed was determined by weight loss of sample solution. The frozen spheres were then transferred to a freeze-dryer (Alpha 1-4 LSC Plus, Martin Christ, Erlangen) and dried at 20 °C and 0.02 mbar for 48 hours. The dry particles were analysed regarding particle size distribution and sphericity using a Camsizer X2 module (Haan, Germany), flowability via Hausner Index (HI, as described in the Ph. Eur. 2.9.15) and scanning electron microscopy (SEM, Hitachi SU3500, Tokyo). Mechanical stability was analysed by the comparison of median particle size before and after swinging-mill experiments as describes in Ph. Eur 2.9.41.

Results: Measured viscosities range between 1.00 ± 0.05 mPa∙s for 2.5 % and 3.07 ± 0.04 mPa∙s for 20 % solid content. Spraying-speed only differed slightly between solutions with an average of 672.45 ± 9.00 g/h. SEM analysis showed an increase in particle size and sphericity with increasing solid content. Particles with 2.5 % solid content were visibly broken, and the surface of the structures were highly porous and lamellar. Particle size analysis confirm those results regarding both properties with average sphericities of > 0.91 for the 10, 15 and 20 % formulation. After swinging-mill-experiments, the median particle size of the 2.5 % solid content formulation decreased further (225 ± 48 µm to 136 ± 3 µm, p = 0.01), while median particle size of the 5, 10, 15 and 20 % formulations did not change significantly (p-Values p = 0.05, 0.12, 0.08 and 0.27 respectively), indicating a mechanically stable product for all formulations with solid content ≥ 5 %. All formulations ≥ 10 % exhibit good or excellent flowing-characteristics (HI = 1.04 ± 0.02, 1.10 ± 0.01 and 1.13 ± 0.01), even though their bulk densities were measured < 0.15 g/ml. For solid contents ≥ 10 % bulk-densities p<sub>bulk are equal to c_sol[g/ml] = p<sub>bulk[g/ml] ∙ 0.74, whereas c_sol is the concentration of the spraying solution, indicating that the particles fill a container comparable to the “close-packing of equal spheres” arrangement.

Conclusion: SFD is a viable technique to produce a highly spherical and mechanically stable powder in a variety of densities and particle sizes made from solutions with various viscosities, while exhibiting only one tenth of the bulk-density of a spray-dried product. Further research is needed to explore different excipients and changes in nozzle size to establish formulation strategies for a wide range of substances, so each excipient can be designed as a high-quality product, while keeping excellent flowability with all the advantages of freeze-drying.

References: [1] S. N. Eggerstedt, M. Dietzel, M. Sommerfeld, R. Süverkrüp, and A. Lamprecht, “Protein spheres prepared by drop jet freeze drying,” Int. J. Pharm., vol. 438, no. 1–2, pp. 160–166, 2012.

Acknowledgements: The authors thank the German Federal Ministry for Economic Affairs and Energy for financial support (ASG project, grant no. 03ET1643A).


Fig 1: SEM-imaging overview lyospheres® 15 % solid content


Fig. 2: SEM-Imaging of lyospheres® with increasing solid content A to E: 2.5, 5, 10, 15, 20 %


Fig. 3 Density, Median Particle Size, Hausner-Index and Mechanical Stability of lyospheres® with increasing solid content