title: L-Leucine as an excipient against moisture on in vitro aerosolization performances of highly hygroscopic spray-dried powders.
abstract: L-Leucine (LL) has been widely used to enhance the dispersion performance of powders for inhalation. LL can also protect powders against moisture, but this effect is much less studied. The aim of this study was to investigate whether LL could prevent moisture-induced deterioration in in vitro aerosolization performances of highly hygroscopic spray-dried powders. Disodium cromoglycate (DSCG) was chosen as a model drug and different amounts of LL (2-40% w/w) were added to the formulation, with the aim to explore the relationship between powder dispersion, moisture protection and physicochemical properties of the powders. The powder formulations were prepared by spray drying of aqueous solutions containing known concentrations of DSCG and LL. The particle sizes were measured by laser diffraction. The physicochemical properties of fine particles were characterized by X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and dynamic vapor sorption (DVS). The surface morphology and chemistry of fine particles were analyzed by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and time-of-flight secondary ion mass spectrometry (ToF-SIMS). In vitro aerosolization performances were evaluated by a next generation impactor (NGI) after the powders were stored at 60% or 75% relative humidity (RH), and 25°C for 24h. Spray-dried (SD) DSCG powders were amorphous and absorbed 30-45% (w/w) water at 70-80% RH, resulting in deterioration in the aerosolization performance of the powders. LL did not decrease the water uptake of DSCG powders, but it could significantly reduce the effect of moisture on aerosolization performances. This is due to enrichment of crystalline LL on the surface of the composite particles. The effect was directly related to the percentage of LL coverage on the surface of particles. Formulations having 61-73% (molar percent) of LL on the particle surface (which correspond to 10-20% (w/w) of LL in the bulk powders) could minimize moisture-induced deterioration in the aerosol performance. In conclusion, particle surface coverage of LL can offer short-term protection against moisture on dispersion of hygroscopic powders.
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales 2006, Australia; School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Siping
authors.initials: S
authors.lastname: Sun
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Thaigarajan
authors.initials: T
authors.lastname: Parumasivam
authors.affiliation: Future Industries Institute, University of South Australia, Mawson Lakes, South Australia 5095, Australia.
authors.forename: John A
authors.initials: JA
authors.lastname: Denman
authors.affiliation: CSIRO Manufacturing, Bayview Avenue, Clayton, Victoria 3168, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gengenbach
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Patricia
authors.initials: P
authors.lastname: Tang
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China. Electronic address: maoshirui@syphu.edu.cn.
authors.forename: Shirui
authors.initials: S
authors.lastname: Mao
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales 2006, Australia. Electronic address: kim.chan@sydney.edu.au.
authors.forename: Hak-Kim
authors.initials: HK
authors.lastname: Chan
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning / Q000379:methods; D002626:Chemistry, Pharmaceutical / Q000379:methods; D058995:Dry Powder Inhalers / Q000379:methods; D005079:Excipients / Q000737:chemistry*; D006813:Humidity; D007930:Leucine / Q000737:chemistry*; D008855:Microscopy, Electron, Scanning / Q000379:methods; D010316:Particle Size; D056951:Photoelectron Spectroscopy / Q000379:methods; D011208:Powders / Q000737:chemistry; D013499:Surface Properties; D017155:Wettability; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D000336:Aerosols; D005079:Excipients; D011208:Powders; D007930:Leucine
keywords: Disodium cromoglycate; Dry powder inhalers; Fine particle fraction; Moisture protection; Spray drying; l-Leucine