Impact of solid content on the bulk properties of lyophilized powders

Abstract

Interest in oral delivery of biological drug products, commonly prepared through lyophilization, is surging. Typically, low solid content solutions are employed for lyophilization to enhance mass transfer and minimize drying time. Yet, this approach often results in lyophilized powders with low bulk density and poor flowability, challenging downstream processing steps that are required for oral product development. Increasing solid content in a starting solution can, in theory, increase the density of lyophilized cakes and powders with higher bulk density post-milling. However, the effectiveness of improving powder density and flowability using a higher solid content has not been experimentally verified. In addition, the impact of using a higher solid content on other physicochemical properties of lyophilized materials remains uncertain. To address the knowledge gaps, we lyophilized three common bulk cryoprotectants at two different solid contents (5% and 10%) and systematically evaluated their solid-state properties, bulk density, flowability, compaction characteristics, and physical stability. We found that powders prepared at a higher solid content (10%) exhibited higher bulk density, but they still failed to meet the requirements for easy oral product development. A change in solid content also leads to different solid-state properties, compaction behaviors, and stability, highlighting the importance of thorough characterization of lyophilized materials when solid content is changed in the course of oral solid dosage formulation development.

Keywords: Compaction properties; Density; Flowability; Lyophilization; Mannitol; Physical stability; Solid content; Sucrose; Trehalose.