Pharmaceutical Technology
The Influence of Mechanical Processing of Dry Powder Inhaler Carriers on Drug Aerosolization Performance

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ABSTRACT

The influence of processing on the performance of carrier material used in dry powder inhalers was investigated. α-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 µm) 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 µm). These effects were attributed predominantly to the fines content, showing a strong correlation between increased fines and FPF (R2 = 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.

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INTRODUCTION

Dry powder inhalers (DPI) are a novel route for drug delivery, with the capability of targeting disease states both locally (in the case of lung diseases such as asthma), and systemically (e.g. in the delivery of proteins and peptides). For effective deposition in the lower airways and deep lung, drug particles with aerodynamic particle sizes of <5 µm are required. However, such systems are highly cohesive due to the high surface area to mass ratio of the particulates. Cohesive systems pose a

Materials

Micronized nedocromil sodium trihydrate (NST) was obtained from Sonafi-Aventis (Cheshire, England). Crystalline α-lactose monohydrate (Lactochem® crystals) was obtained from Borculo Domo (Zwolle, The Netherlands). Water was purified by reverse osmosis (MilliQ, Millipore, Molsheim, France). Analytical grade chloroform and n-octane were obtained from Biolab (Victoria, Australia) and Fluka (Germany), respectively.

Preparation of Lactose Monohydrate Samples

Mechanical treatment of lactose monohydrate samples was achieved by comminution in a

Particle Sizing of Processed Lactose Monohydrate Samples and NST

Particle size analysis of NST gave median diameter of 1.10 µm with 90% particles less than 5.40 µm, suggesting the model drug was suitable for inhalation and DPI studies.

The influence of milling time on the particle size distributions of both freshly milled and recrystallized lactose monohydrate samples was investigated. As expected, the milling process resulted in a significant reduction (ANOVA, p &lt; 0.05) in the median particle diameter with respect to time (Fig. 1). Such observations are

CONCLUSION

Industrial processing of carrier materials used in DPI systems induces changes in the physical properties of the particles. Here, a simple ball milling process was used to produce particles which exhibited a reduced particle size, increased levels of fines and amorphous material. In addition, variation in storage conditions of the processed excipient was also shown to induce changes in fines and amorphous content. When used in a high dose DPI system, significant changes in the FPF were observed

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Published online in Wiley InterScience (www.interscience.wiley.com).

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