Co-milled API-lactose systems for inhalation therapy: impact of magnesium stearate on physico-chemical stability and aerosolization performance

Context: Particle micronization for inhalation can impart surface disorder (amorphism) of crystalline structures. This can lead to stability issues upon storage at elevated humidity from recrystallization of the amorphous state, which can subsequently affect the aerosol performance of the dry powder formulation. Objective: The aim of this study was to investigate the impact of an additive, magnesium stearate (MGST), on the stability and aerosol performance of co-milled active pharmaceutical ingredient (API) with lactose. Methods: Blends of API-lactose with/without MGST were prepared and co-milled by the jet-mill apparatus. Samples were stored at 50% relative humidity (RH) and 75% RH for 1, 5, and 15 d. Analysis of changes in particle size, agglomerate structure/strength, moisture sorption, and aerosol performance were analyzed by laser diffraction, scanning electron microscopy (SEM), dynamic vapor sorption (DVS), and in-vitro aerodynamic size assessment by impaction. Results: Co-milled formulation with MGST (5% w/w) led to a reduction in agglomerate size and strength after storage at elevated humidity compared with co-milled formulation without MGST, as observed from SEM and laser diffraction. Hysteresis in the sorption/desorption isotherm was observed in the co-milled sample without MGST, which was likely due to the recrystallization of the amorphous regions of micronized lactose. Deterioration in aerosol performance after storage at elevated humidity was greater for the co-milled samples without MGST, compared with co-milled with MGST. Conclusion: MGST has been shown to have a significant impact on co-milled dry powder stability after storage at elevated humidity in terms of physico-chemical properties and aerosol performance.