Quality by design optimisation of isothermal dry particle coating for enhanced buccal permeation of vancomycin

The formulation and manufacture of macromolecules for oral delivery present persistent challenges owing to high molecular weight, pH sensitivity and manufacturing complexity. Consequently, over 90% of FDA-approved biologics are administered by invasive methods. Buccal delivery offers a promising non-invasive alternative, as it bypasses first-pass metabolism, avoids gastrointestinal degradation, and can improve patient compliance. Here we evaluate isothermal dry particle coating (iDPC) as a scalable, solvent-free approach to enhance buccal permeation by forming ion-pair coatings on drug particles. In iDPC, centrifugal and gas-drag forces promote systematic collisions between host and guest particles, here vancomycin and L-glutamic acid, yielding uniform surface coverage that facilitates buccal permeation. This study utilised a Design of Experiments (DoE) methodology within a Quality by Design (QbD) framework to optimise iDPC processing for vancomycin, a Biopharmaceutics Classification System (BCS) Class III glycopeptide with poor oral bioavailability. A Central Composite Face (CCF) design was utilised to investigate the interactive effects of five critical process parameters (CPPs): pre-processing time, processing time, nitrogen flow rate, drum speed and amino acid concentration, on two critical quality attributes (CQAs): content uniformity and 60-minute permeation across TR146 buccal epithelium. Regression modelling identified that increases in L-glutamic acid concentration and drum speed were the key factors enhancing permeation, while processing time and drum speed were the key variables improving content uniformity. A predictive 4D design space identified operating regions with a high probability of simultaneously meeting prespecified targets (permeation ≥ 40% and RSD ≤ 5%). The models demonstrated strong fit (R 2 = 0.767 for permeation; 0.774 for content uniformity), with non-significant lack-of-fit, and performance improved markedly, with content uniformity ranging from 0.93 to 6.29% RSD and permeation increasing from 36% to 60% under optimised conditions. Mechanistic analysis indicated that drag from the nitrogen curtain impacted the fluidisation of cohesive L-glutamic acid fine particles, while total energy input promoted deagglomeration and dispersion, thereby improving uniformity. These findings demonstrate that iDPC is a robust manufacturing approach for buccal delivery of biologics, providing controlled particle level modification without the use of solvents. The QbD-driven DoE establishes clear links between CPPs and CQAs, supports the development of control strategies, and provides a basis for regulatory flexibility in the non-invasive delivery of large molecule therapeutics.