“An in-depth understanding of the effect of drug distribution within and between particles as a function of formulation processes by applying O-PTIR may allow pharmaceutical scientists and regulatory agencies to evaluate the quality of newer generic DPIs, hence aid in the approval of abbreviated new drug applications.”
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Reporting in International Journal of Pharmaceutics, researchers at The University of Sydney, Monash University, National Taiwan University, and the University of Alabama at Birmingham have demonstrated a proof-of-concept application of optical photothermal infrared spectroscopy (O-PTIR) for nanochemical analysis of pharmaceutical dry powder inhaler (DPI) formulations. Current pharmacopoeial methods for evaluating particle size and chemical analysis does not provide the chemical map of drug distribution across the particles. The research team addressed this limitation by using O-PTIR to characterize the distribution of drugs and excipients across spray-dried DPI particle fractions collected at stages 1-7 of a Next Generation Impactor (NGI).
The study examined two formulations prepared by spray drying: one from solution and one from suspension, both containing fluticasone propionate (FP), salmeterol xinafoate (SX), and lactose. O-PTIR analysis successfully identified characteristic peaks for FP (1746, 1702, 1661, and 1612 cm⁻¹), SX (1582 cm⁻¹), and lactose (1080 cm⁻¹) across all particle size fractions. For solution-spray dried formulations, spectral profiles showed homogeneous distribution with consistent lactose-to-FP peak intensity ratios across stages 1-7, reflecting the uniform composition expected from dissolved components in the feed solution. The lactose-FP IR peak ratio remained relatively constant with values ranging from 5.9 to 13.6 across all stages.
In contrast, suspension-spray dried formulations exhibited marked heterogeneity in drug-excipient distribution across all the particle size fractions. Chemical mapping at 1080 cm⁻¹ (lactose) and 1662 cm⁻¹ (FP) revealed that lactose content decreased significantly from larger to smaller particle fractions, with the lactose-FP peak ratio decreasing tenfold from 3.2 at stage 1 to 0.3 at stage 7. Principal component analysis further confirmed these findings, with the first principal component (accounting for 82% of variance) showing sharp peaks at lactose-specific wavenumbers (1166, 1140, 1116, 1094 cm⁻¹), while the second component (9% of variance) highlighted FP-specific peaks. The eigenspectrum also revealed differences in lactose crystallinity between formulations, with sharper peaks at 1260, 900, and 875 cm⁻¹ characteristic of crystalline lactose in the suspension formulation but not in the solution formulation, indicating predominantly amorphous lactose in the latter.
O-PTIR spectroscopy proved to be a powerful analytical platform for solid-state evaluation of pharmaceutical DPI formulations. The technique enables spatially resolved chemical composition analysis at the submicron scale, providing particle-to-particle variation data. The qualitative chemical compositions from O-PTIR correlated well with conventional wet chemical assays while offering additional insights into drug-excipient distribution, molecular form and crystallinity that directly affect aerosol performance and therapeutic efficacy. This capability makes O-PTIR particularly valuable for screening physicochemical properties of complex multi-drug DPI formulations and potentially supporting regulatory evaluation of generic DPI products.
Authors:
Dipesh Khanal, Jinhee Kim, Jing Zhang, Wei-Ren Ke, Mark M. Banaszak Holl, Hak Kim Chan
Advanced Drug Delivery Group, Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney
