# Polymers as Stabilizing Excipients for Spray-Dried Protein Formulations

## TL;DR

This study compares different polymers to traditional sugars for stabilizing proteins in spray-dried drug formulations, finding that HPβCD and hydrolyzed gelatin perform better.

## Contribution

The study introduces HPβCD and hydrolyzed gelatin as effective stabilizing excipients for spray-dried protein formulations.

## Key findings

- HPβCD and hydrolyzed gelatin reduced monomer loss in BSA compared to trehalose and mannitol.
- Dextran 20 kDa and NaCMC showed poor stability in spray-dried BSA formulations.
- PXRD and ssFTIR revealed structural and crystallization changes during storage.

## Abstract

Drying is widely used to enhance the storage stability of biologic drug products which are susceptible to degradation in aqueous solutions. Compared to conventional freeze-drying, spray drying offers continuous, high-throughput manufacturing. Stabilizing excipients are critical for protecting proteins from stresses during drying and storage. This study evaluated the potential of polysaccharide- and protein-lysate–based polymeric excipients as alternatives to commonly used stabilizers such as trehalose and mannitol, using bovine serum albumin (BSA) as a model protein.

Spray-dried BSA formulations were prepared with (2-hydroxypropyl)-β-cyclodextrin (HPβCD), hydrolyzed gelatin, dextran 20 kDa, or sodium carboxymethyl cellulose (NaCMC) polymers, either alone or in combination with trehalose or mannitol. Protein stability was assessed by monitoring monomer loss under stressed storage (40°C, 3 months). Crystallinity and changes in the secondary structure were analyzed using powder X-ray diffraction (PXRD) and solid-state Fourier transform infrared spectroscopy (ssFTIR), respectively. Particle size and size distribution, surface morphology and reconstitution time were also evaluated.

Spray-dried BSA formulations containing HPβCD or hydrolyzed gelatin, either alone or with sugars, exhibited lower monomer loss than the trehalose- or mannitol-only formulations. In contrast, formulations with Dextran 20 kDa and NaCMC showed poor stability. PXRD revealed progressive sodium chloride crystallization during storage. ssFTIR detected secondary structure changes in the BSA over 3 months. The spray-dried powders with polysaccharides generally showed longer reconstitution times than those with polymers.

HPβCD and hydrolyzed gelatin improved the physical stability of spray-dried BSA compared to sugar excipients, which highlights their potential use as stabilizing additives.

The online version contains supplementary material available at 10.1007/s11095-025-03996-z.