As a model capsule-based DPIs, Spiriva® Handihaler® was purchased from Boehringer Ingelheim Japan Ltd. Spiriva® Handihaler® is a typical capsule-based DPIs, used for the treatment of COPD and for reducing COPD exacerbations. A dry powder in Spiriva® inhalation capsules containing tiotropium bromide (TIO) as the main component was used as a model drug. The capsule contained 5.5 mg of a powder formulation consisting of 18 µg micronized tiotropium (as bromide hydrate, 22.5 µg) with coarse lactose monohydrate (24 (link)). The Handihaler® (Boehringer Ingelheim Japan Ltd.) was used as a model high resistance device for capsule-based DPIs (device specific resistance 3.03 Pa* min2/l2) (25 (link)). Size 3 capsules with different compositions were supplied by Qualicaps, Co., Ltd. (G-Cap, gelatin capsule; PEG/G-Cap, gelatin capsule containing 5% PEG4000 as plasticizer; and HPMC-Cap, HPMC capsule). PEG/G-Cap is a gelatin capsule that is resistant to cracking due to the presence of PEG. HPMC-Cap is resistant to cracking under dry conditions and may be filled with highly hygroscopic drugs. Each capsule was stored at 15-25˚C and under 40-50% relative humidity (RH) in a glass desiccator. The characteristics of each capsule are presented in Table I. All other reagents and solvents were of analytical or HPLC grade.