Mannitol, leucine and trehalose have been widely used in spray-dried formulations, especially for inhalation formulations. The effects of these excipients on protein physical stability in spray-dried solids were studied here using bovine serum albumin (BSA) as a model protein. The spray-dried solids were characterized with scanning electron microscopy (SEM), powder X-ray diffraction (PXRD) and solid-state Fourier-transform infrared spectroscopy (ssFTIR) to analyze particle morphology, crystallinity and secondary structure change, respectively. Advanced solid-state characterizations were conducted with solid-state hydrogen-deuterium exchange (ssHDX) and solid-state nuclear magnetic resonance (ssNMR) to explore protein conformation and molecular interactions in the context of the system physical stability. Trehalose remained amorphous after spray drying, and was miscible with BSA, forming hydrogen bonds to maintain protein conformation whereby this system showed the least monomer loss in the stability study. Both crystalline and amorphous forms of mannitol were detected in the spray-dried BSA-mannitol solids by ssNMR, which led to partial loss of stability to BSA. Leucine showed the strongest crystallization tendency after spray drying and did not provide a stabilizing effect due to substantial immiscibility and phase separation with BSA as a result of crystal formation. This study demonstrates the pivotal role of advanced solid-state characterization techniques in understanding the physical stability of spray-dried protein solids.

Advanced solid-state characterization to understand the impact of protein-excipient interactions on aggregation of spray dried protein solids

ACS Fall 2021

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