Microstructural Characterization of Dry Powder Inhaler Formulations Using Orthogonal Analytical Techniques

Abstract

Purpose: For locally-acting dry powder inhalers (DPIs), developing novel analytical tools that are able to evaluate the state of aggregation may provide a better understanding of the impact of material properties and processing parameters on the in vivo performance. This study explored the utility of the Morphologically-Directed Raman Spectroscopy (MDRS) and dissolution as orthogonal techniques to assess microstructural equivalence of the aerosolized dose of DPIs collected with an aerosol collection device.

Methods: Commercial DPIs containing different strengths of Fluticasone Propionate (FP) and Salmeterol Xinafoate (SX) as monotherapy and combination products were sourced from different regions. These inhalers were compared with aerodynamic particle size distribution (APSD), dissolution, and MDRS studies.

Results: APSD testing alone might not be able to explain differences reported elsewhere in in vivo studies of commercial FP/SX drug products with different Advair® strengths and/or batches. Dissolution studies demonstrated different dissolution rates between Seretide™ 100/50 and Advair® 100/50, whereas Flixotide™ 100 and Flovent® 100 had similar dissolution rates between each other. These differences in dissolution profiles were supported by MDRS results: the dissolution rate is increased if the fraction of FP associated with high soluble components is increased. Principle component analysis was used to identify the agglomerate classes that better discriminate different products.

Conclusions: MDRS and dissolution studies of the aerosolized dose of DPIs were successfully used as orthogonal techniques. This study highlights the importance of further assessing in vitro tools that are able to provide a bridge between material attributes or process parameters and in vivo performance.

Keywords: bioequivalence; dissolution; dry powder inhaler; orthogonal analytical techniques; raman spectroscopy.

Fig. 1

Confidence intervals of the sampling distribution for FP/Lac.

Fig. 2

Normalized mean APSD profiles of FP against delivered dose label claim at 60 L/min for Seretide™ Accuhaler™100/50, Advair® Diskus® 100/50, Advair® Diskus® 250/50, Advair® Diskus® 500/50, Flixotide™ Accuhaler™ 100 and Flovent® Diskus.® 100.

Fig. 3

Mean cumulative mass (%) dissolution profiles of the FP ISM dose of Seretide™ Accuhaler™ 100/50, 250/50 and 500/50, DPIs collected at 60L/min with a USP inlet and pre-separator connected to the ADC apparatus. Error bars show standard deviations of 3 repeated measurements. Data previously published [23].

Fig. 4

Mean cumulative mass (%) dissolution profiles up to 30 min (zoomed in from 120 min) of the FP ISM dose of Seretide™ Accuhaler™ 100/50, Advair® Diskus® 100/50, Flixotide™ Accuhaler™ 100 and Flovent® Diskus® 100, DPIs collected at 60L/min with a USP inlet and pre-separator connected to the ADC apparatus. Error bars show standard deviations of 3 repeated measurements.

Fig. 5

Mean cumulative mass (%) dissolution profiles up to 30 min (zoomed in from 120 min) of the FP ISM dose of Seretide™ Accuhaler™100/50, Advair® Diskus®100/50, Flixotide™ Accuhaler™100 and Flovent® Diskus® 100, DPIs collected at 60 L min⁻¹ with a medium-sized OPC throat and pre-separator connected to the ADC apparatus. Error bars show standard deviations of 3 repeated measurements.

Fig. 6

Mean cumulative mass (%) dissolution profiles up to 30 min (zoomed in from 120 min) of the FP formulated powder of Seretide™ Accuhaler™ 100/50, Advair® Diskus® 100/50, Flixotide™ Accuhaler™ 100 and Flovent® Diskus® 100, DPIs. Error bars show standard deviations of 3 repeated measurements.

Fig. 7

Chemical classification of FP agglomerates of the ISM dose of Advair® Diskus® 100/50, Advair® Diskus® 250/50 and Advair® Diskus® 500/50 DPIs collected at 60 L min⁻¹ with a USP inlet and pre-separator connected to the ADC apparatus. Quantities are a percentage by number and an average of 6 independent measurements of at least 3000 particles.

Fig. 8

Chemical classification of FP agglomerates of the ISM dose of Advair® Diskus® 100/50 and Seretide™ Accuhaler™100/50 DPIs collected at 60 L min⁻¹ with a USP inlet and pre-separator connected to the ADC apparatus. Quantities are a percentage by number and an average of 6 independent measurements of at least 3000 particles.

Fig. 9

Chemical classification of FP agglomerates of the ISM dose of Flovent® Diskus® 100 and Flixotide™ Accuhaler™ 100 DPIs collected at 60 L min⁻¹ with a USP inlet and pre-separator connected to the ADC apparatus. Quantities are a percentage by number and an average of 6 separate measurements of at least 3000 particles.

Fig. 10

Principal component analysis of MDRS data for Seretide™ Accuhaler™ 100/50, Advair® Diskus® 100/50, Flixotide™ Accuhaler™ 100 and Flovent® Diskus® 100 DPIs. Points show principal component scores for repeat measurements of each formulation and vectors represent the contribution of each chemical class to the principal components.