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The purpose of this study was to characterise the role of agglomeration on salmeterol xinafoate (SX) dispersion from mixtures for inhalation by varying the SX concentration and the proportion of fine lactose (FL). SX concentrations and SX:FL ratios ranged from 1.0% to 5.0% (w/w) and from 1:0 to 1:8, respectively. The in vitro deposition of SX was measured using a twin stage impinger (TSI). The aerosol was characterized by particulate capture in the TSI stages and subsequent imaging by scanning electron microscopy and by real-time particle sizing. The presence of coarse lactose reduced SX dispersion compared with SX alone, and the dispersion was independent of SX concentration. SX dispersion in binary mixtures of SX and FL was independent of SX:FL ratio and was similar to that of carrier-based mixtures with high particulate loads. Increased concentrations of SX and proportions of FL in carrier-based mixtures resulted in increased SX dispersion. Agglomerate formation coincided with increased dispersion. The study demonstrated that agglomeration is one of the important factors in SX dispersion from carrier-based mixtures at high particulate loads.

Reactive high gravity controlled precipitation (HGCP) was carried out to produce salbutamol sulphate (SS) particles suitable for inhalation. Aqueous solutions of free salbutamol base and sulphuric acid were mixed intensely inside a HGCP reactor to form the particles. Spray drying was employed to obtain dry powders. Physical properties of the powders were characterised by scanning electron microscopy, X-ray powder diffraction, thermal gravimetric analysis and dynamic water vapour sorption. Aerosol performance of the powders was measured using an Aeroliser connected to a multiple stage liquid impinger operating at 60 L/min. The results showed that the reactive HGCP powder, comprising primary SS sub-micron particles (approximately 100 nm in width and approximately 500 nm in length) packed into loose spherical agglomerates of about 2 microm in diameter, is of the same polymorphic form as the raw crystalline material, has a high specific surface area (24.7 +/- 0.1 m(2)/g), but a low moisture content (0.2%) and low moisture uptake (1.4% at RH 90%). The aerosol performance of the reactive HGCP powder is excellent, showing FPF(loaded) and FPF(emitted) of 76 +/- 5% and 83 +/- 7%, respectively, with low capsule and device retention. In conclusion, reactive HGCP followed by spray drying is suitable to produce stable crystalline powders of salbutamol with enhanced inhalation properties.

The influence of processing on the performance of carrier material used in dry powder inhalers was investigated. alpha-Lactose monohydrate crystals were processed by ball milling for cumulative time durations and their properties evaluated. As expected, milling reduced the median particle diameter while increasing fine particulate (<10 microm) and amorphous levels. Recrystallization of these partially amorphous samples resulted in a reduction in fines, elimination of amorphous material with little change in median diameter. To study the effects of processing on aerosolization performance, blends of lactose monohydrate with a model drug (nedocromil sodium trihydrate), were evaluated using an in vitro multistage liquid impinger (MSLI) model. In general, milling and storage of the carriers at high humidity (prior to blending) had a significant (ANOVA, p < 0.05) effect on the fine particle fractions (FPF; <6.8 microm). These effects were attributed predominantly to the fines content, showing a strong correlation between increased fines and FPF (R(2) = 0.974 and 0.982 for milled and recrystallized samples, respectively). However, this relationship only existed up to 15% fines concentration, after which agglomerate-carrier segregation was observed and FPF decreased significantly. These results suggest that, after processing, high-dose drug formulation performance is dominated by the presence of fines., ((c) 2007 Wiley-Liss, Inc. and the American Pharmacists Association.)