(T1030-04-22) Impact of Solvent Choice in the Spray-Freeze-Drying of Insoluble Excipients

Purpose: The objective of this study was to compare different solvents for spray-freeze-drying (SFD) of inorganic and insoluble substances. Tribasic calcium phosphate (TCP) was selected as a model compound due to its non-reactive and non-soluble nature in two commonly used solvents in the spray-freeze-drying process, namely water and tertiary butanol (TBA). TCP is widely used as a filler/diluent for tablets and capsules, as a glidant to enhance powder flow, next to other applications. It is GRAS listed and accepted in nonparental medicins by the UK and FDA. The substance shows good phyiscal stability in aqueous media and humid conditions. Polyvinylpyrrolidone 25 (PVP) was selected as a binder agent owing to its solubility in both water and TBA. The resulting SFD particles were analyzed for their powder properties, to gain a comprehensive understanding of the impact of solvent choice on SFD particle quality.

Methods: The spray-freeze-drying process was carried out as described by Eggerstedt et al. (Eggerstedt et al., 2012), with slight modifications. Briefly, a TCP suspension containing PVP was sprayed into a cold chamber to produce frozen droplets, which were then freeze-dried to produce a powder. The morphology of the powder was analyzed using a Hitachi SU3500 electron microscope (Tokyo). Samples were prepared by placing a small amount of powder on a carbon-coated aluminium grid and imaging at various magnifications. The angle of repose was determined using the Ph. Eur. method. The powder was poured through a funnel onto a flat surface to form a cone, and the angle of repose was measured. The particle size and sphericity of the powder were analyzed using a Camsizer X-Dry Jet instrument in free fall. Samples were dispersed in air and imaged using a high-speed camera. The particle size distribution of the suspension was measured using a Horiba L960 laser diffraction instrument. The specific surface area of the powder was determined via five point BET analysis. The powder was degassed and analyzed using a Quantachrome NOVA 3200 instrument.

Results: Spray-freeze-drying resulted in an increase in flowability and sphericity, with values of 35.7° and 0.94 for water and 31.7° and 0.93 for TBA, respectively, compared to non-processed TCP powder (38.7° and 0.76, Fig. 2). The samples exhibited narrow monomodal size distributions (Fig. 3). Bulk densities of the SFD particles varied slightly around 0.135 g/ml. Reconstitution of the SFDs resulted in small particles for all formulations (7.88 ± 1.28 µm), which is consistent with the initial particle size used to prepare the TBA samples (8.58 µm), but significantly larger than the particle size used to prepare the water samples (0.11 µm). Furthermore, the choice of solvent had a strong impact on the resulting surface area. When TBA was used as a solvent, the observed surface area was 60.1 m²/g, whereas when water was used, the surface area decreased significantly (21.9 m²/g). SEM images indicate that this effect is due to the different crystallization types of the solvents (Fig. 1).

Conclusion: The increased flowability and sphericity of the particles obtained by SFD can improve the processability of powders, making them easier to handle and more uniform in size, which can be especially relevant for applications where precise dosing is required. As observed in this study, the solvent choice can impact the particle size, flowability, and surface area of the resulting particles, which can be critical parameters in the development of drug delivery systems. By choosing the appropriate solvent, the physical and chemical properties of the particles can be tailored to suit specific drug delivery requirements without changing the composition of the resulting SFD particles

References: Eggerstedt, S. N. et al. (2012) ‘Protein spheres prepared by drop jet freeze drying’, International Journal of Pharmaceutics. Elsevier B.V., 438(1–2), pp. 160–166. doi: 10.1016/j.ijpharm.2012.08.035.

Acknowledgements: The authors thank the German Federal Ministry for Economic Affairs and Energy for financial support (ASG project, grant no. 03ET1643A) as well as Chemische Fabrik Budenheim KG for kindly donating the tribasic calcium phosphate used in this study.

Fig 1: TCP SFDs with water and TBA as solvent in various magnifications. A: photography, B-E: electron microscopy, B: 50x, C: 200x, D: 400x, E: broken particles, 1700x

Fig 2: Flowability of the unprocessed TCP powder and SFD particles

Fig. 3: size distribution of the unprocessed TCP powder and SFD particles