“Optical photothermal infrared spectroscopy (O-PTIR) was employed to investigate the BHB–excipient interactions and particle surface coverage of excipients… Chemical maps of BHB and excipient (leucine or xinafoic acid) were overlaid to qualitatively assess particle surface coverage.”
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Reporting in the Journal of Drug Delivery Science and Technology, researchers at the University of Sydney investigated the development of inhalable dry powder formulations of beta-hydroxybutyrate (BHB), an endogenous ketone body with potential for treating pulmonary conditions including asthma, lung injury, and respiratory viral infections. The central challenge was BHB’s extreme hygroscopicity — it deliquesces within minutes of ambient exposure — which severely impairs aerosol performance. The study evaluated xinafoic acid as a novel excipient, comparing it against the widely used dispersibility enhancer leucine, at 30% and 50% w/w loadings.
Aerosol performance testing showed that spray-dried BHB alone produced a fine particle fraction below 5 µm (FPF) of only 1.8%. Adding leucine at 30% and 50% w/w increased the FPF to 20.2% and 39.5%, respectively. Xinafoic acid showed greater effect, achieving FPFs of 46.2% and 52.1% at the same loadings. Moisture stability testing further confirmed xinafoic acid’s protective advantage: at 50% w/w, the powder absorbed 20.1% w/w moisture before recrystallizing at 50% relative humidity, compared with 0.93% w/w for the equivalent leucine formulation.
To understand the mechanisms behind these performance differences, O-PTIR was employed to investigate drug–excipient molecular interactions and excipient distribution across particle surfaces. Spectral analysis of BHB–leucine formulations revealed peak shifts and new absorption bands consistent with hydrogen-bonding and ionic interactions between the carboxylate group of BHB and the ammonium group of leucine. In the BHB–xinafoic acid formulations, disappearance of specific BHB C-O stretching bands and emergence of aromatic ring bands confirmed xinafoic acid incorporation and molecular interaction with BHB. Chemical imaging maps, acquired at wavenumbers specific to each component, showed that leucine was surface-enriched — consistent with its known shell-forming behaviour — while xinafoic acid was distributed homogeneously across particle surfaces alongside BHB. This co-distribution was attributed to the conversion of xinafoic acid to sodium xinafoate during preparation, increasing its aqueous solubility and enabling co-precipitation with BHB during spray drying.
O-PTIR provided spatially resolved, single-particle chemical information that directly linked surface chemistry to aerosol performance and moisture stabilization outcomes. The ability to simultaneously map multiple components at their characteristic infrared wavenumbers — and to overlay those maps for direct visual comparison of surface coverage — enabled the researchers to distinguish the fundamentally different surface distribution behaviours of leucine and xinafoic acid. These insights informed the mechanistic interpretation of why corrugated xinafoic acid particles outperformed hollow leucine particles in dispersion efficiency, and why the stabilisation mechanisms of the two excipients differ.
Authors:
Waiting Tai, Dipesh Khanal, Pancy Tsz Hei Kwong, Grace Tsz Yan Yau, Patricia Tang, Chih-Chin Shih, Hak-Kim Chan
Advanced Drug Delivery Group, Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
