Improved Inhalation Behavior of Steroid KSR-592 in Vitro with Jethaler® by Polymorphic Transformation to Needle-Like Crystals (β-Form)

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Abstract
Purpose. The aim of the present study was to improve the dry powder inhalation behavior of steroid KSR-592 with lactose by altering the crystal shape and the particle size of the drug for use in a newly designed inhalation device, Jethaler®. Method. The shape of the crystals was changed by polymorphic transformation of original crystal (α-form) to β-form by agitating α-form crystals in hexane containing 5% ethanol. The inhalation properties of the resultant crystals in vitro were evaluated with a twin impinger and cascade impactor. Results. Needle-like crystals (β-form) with dimensions of 1.8 μm in width × 41μm in length were obtained by the polymorphic transformation, the kinetics of which was described by the Avrami equation. The β-form crystals loaded on lactose particles were easily separated and crushed into fine particles in the airstream produced in the Jethaler®, which increased dramatically the respirable fraction (RF) deposited in the twin impinger (43.8%) and the fine particle fraction (FPF) of the cascade impactor (FPF = 39.3%) compared with their values for the original crystals (RF = 5.8%, FPF = 4.7%). Conclusion. The dry powder inhalation properties of steroid KSR-592 (platelike crystal, α-form) were improved dramatically by changing the crystal shape to a needle-like shape by the polymorphic transformation to the β-form.