Evaluation of granulated lactose as a carrier for DPI formulations 1: effect of granule size

Abstract

The objective of this study was to investigate the effect of large granulated lactose carrier particle systems on aerosol performance of dry powder inhaler formulations. Granulated lactose carriers with average sizes ranging from 200 to 1,000 μm were prepared and subsequently fractionated into separate narrow size powders. The fractionated granulated lactose (GL) samples were characterized in terms of size, specific surface area, surface roughness, morphology, density, flowability, and solid-state. The in vitro aerosolization performance was performed on the different size fractions of GL samples from a commercial inhaler device (Aerolizer®) with a model formulation (2% w/w salbutamol sulfate). The cascade impaction parameters employed were 60 or 90 L/min with standard (aperture size, 0.6 mm) or modified piercing holes (aperture size, 1.2 mm) of the inhaler loaded capsules. It was shown that the largest size fraction formulation (850-1000 μm) had a slight improvement in the fine particle fraction (FPF) compared to immediately preceding size fractions, explained by a smaller adhesive force between drug and carrier. Compared to commercial piercing holes, enlarged piercing holes generated a slight decreasing trend of FPF as the lactose powder sizes increased from 200-250 μm to 600-850 μm, perhaps due to the reduced detachment force by flow forces. The size, surface roughness, density, and flowability of lactose carrier as well as device design all contributed to the aerosol dispersion performance of granulated lactose-based adhesive mixtures. It was concluded that poorer or enhanced redispersion performance is not an inherent property to the significantly large size of granulated lactose carriers as previously contended.

Fig. 1

Particle size distribution (PSD) of salbutamol sulfate

Fig. 2

Blending uniformity of lactose granules-based DPI formulations as function of the mean carrier diameter. (n = 5 × 3)

Fig. 3

SEM micrographs of a Pharmatose 100 M, b GL 212–250 μm granulated lactose, c GL 425–600 μm granulated lactose, d GL 850–1,000 μm granulated lactose sieve fractions. Scale bars denote 200 μm

Fig. 4

Particle size obtained by a laser diffraction (d10, d50, and d90%) and b by image analysis SEM pictures

Fig. 5

The DSC thermographs of all granulated lactose

Fig. 6

a BET surface area and roughness for granulated lactose carriers with different size fractions: GL 212–250 μm, GL 250–300 μm, GL 300–425 μm and GL 425–600 μm, GL 600–850 μm and GL 850–1000 μm; b and roughness of GL particles. All GL particles have similar specific surface area and larger GL particles have rougher surfaces

Fig. 7

SEM pictures of granulated lactose GL 212–250 μm blended with 2% SBS. Scale bar denotes 20 μm