The effect of aerodynamic particle size and solid state disorder on salmeterol xinafoate deposition from pressurised metered dose and dry powder inhaler formulations

Abstract

The production of active pharmaceutical ingredients (APIs) generally consists of crystallisation followed by a comminution process which provides limited control over particle size and energises particle surfaces. Both particle size and surface energy may be powder physical attributes that affect the dispersion and deposition of an API. In this study, the Next Generation Impactor (NGI) was used to obtain salmeterol xinafoate (SX) fractions with aerodynamic particle sizes of 6.26 ± 1.80 (stage 2, S2) and 2.24 ± 0.58 μm (stage 4, S4). The fractions and micronised material (M-SX) were assessed for their recrystallization rate constants by differential scanning calorimetry (DSC) as an index of crystalline disorder. Particle sizing demonstrated that the fractions were of similar geometric particle size, indicating that the aerodynamic fractions consisted of particles with different degrees of aggregation. Despite the samples originating from the same bulk material, the following rank order in crystalline disorder was observed: SX-S2 > SX-S4 > M-SX, indicating heterogeneous crystal disorder within the M-SX material. Pressurised metered dose inhaler (pMDI) and dry powder inhaler (DPI) formulations were prepared from the micronized and fractionated SX samples and the aerodynamic deposition showed that for pMDIs the fine particle fraction (FPF) was not affected by the aerodynamic fraction or its crystallinity. For DPIs, formulations prepared from aerodynamically controlled size fractions of SX exhibited higher FPFs compared to M-SX formulations. The crystalline content of the fractions alone could not be related to aerosol performance, indicating heterogeneity and powder structure play a key role in DPI blend performance.