Xinafoic acid as a novel excipient to enhance dispersion and stability of spray dried highly hygroscopic inhalable beta-hydroxybutyrate powders

Beta-hydroxybutyrate (BHB) is an endogenous ketone body with promising potentials for treating various respiratory conditions. Direct delivery of BHB as a powder to the lungs provides many therapeutic benefits. However, a major challenge is the high hygroscopicity of BHB powders. While leucine is a widely used excipient to improve powder aerosol performance, this study explores xinafoic acid as a novel dispersion enhancer and powder stabiliser. Inhalable BHB powders with leucine or xinafoic acid were prepared by spray drying BHB with 30% and 50% of the excipient. The spray dried powders were partially crystalline, with < 2% w/w residual solvent by mass. The particles were about 2 μm in size with rough surfaces. Adding 30% and 50% w/w leucine increased the moisture threshold (from 0.1% w/w to about 1% w/w) at 40% relative humidity for recrystallisation, whereas 30% w/w xinafoic acid had a stronger protective effect. Increasing to 50% w/w xinafoic acid further delayed the recrystallisation to 20% w/w at 50% relative humidity. For aerosol performance, spray dried BHB exhibited a fine particle fraction < 5 μm (FPF) of only 2%. The FPF increased to 20% and 40% upon adding 30% w/w and 50% w/w leucine, respectively. The effects of 30% and 50% w/w xinafoic acid were even greater, achieving an FPF of 46% and 50%, respectively. These formulations demonstrate the feasibility of delivering BHB via inhalation as a powder and highlight the potential of xinafoic acid as a novel dispersion enhancer and powder stabiliser.