The Influence of Lactose Pseudopolymorphic Form on Salbutamol Sulfate–Lactose Interactions in DPI Formulations

Abstract

A series of 63- to 90-μm sieve-fractioned lactose pseudopolymorphs were investigated in terms of carrier functionality for dry powder inhaler (DPI) formulations. Stable α-anhydrous, α-monohydrate, and β-anhydrous were chosen as model pseudopolymorphs. In addition, the β-anhydrous was further purified to remove residual α-monohydrate content (β-treated). The carriers were investigated in terms of morphology, particle size, crystallinity, and surface energy using inverse gas chromatography. Furthermore, the lactose samples carrier performance was evaluated by studying the aerosolization efficiency of the model drug, micronized salbutamol sulfate, from drug–carrier blends using a next generation impactor (NGI). In general, the aerosol performance of drug from carrier followed the rank order α-monohydrate > β-anhydrous > β-treated > α-anhydrous. Significant difference in carrier size was observed, specifically with relation to the amount of fines (where a rank order of β-treated > β-anhydrous > α-monohydrate > α-anhydrous. No direct relationship between fine content and particle morphology was observed. In comparison, an inverse relationship between surface energy and aerosolization efficiency was found, where a plot of fine particle fraction (aerodynamic diameter < 4.46 μm) against total surface energy resulted in R² = .977. Such observations are most likely due to increased particle carrier adhesion and reduced drug liberation during the aerosolization process, indicating surface chemistry (in this case due to the existence of different pseudopolymorphs) to play a dominating role in DPI systems.

Keywords:

• lactose
• polymorph
• IGC
• in vitro
• DPI
• dry powder inhaler

ACKNOWLEDGMENTS

The authors would like to thank Kjell Jarring (Astra Zeneca R&D, Lund, Sweden) for his assistance in XRPD measurement and analysis; and extensive input and discussion.