title: Particle size dependence of polymorphism in spray-dried mannitol.
abstract: The purpose of this project was to investigate the polymorphic variation of spray-dried mannitol model formulations as a function of particle size. Spray-dried powders with varying mannitol polymorphs were produced by adjusting process parameters, using co-solvent and adding a model protein (lysozyme). The obtained dry powders were dispersed into different size fractions using a Next Generation Pharmaceutical Impactor. The mannitol polymorphs in the different size fractions were analyzed using X-ray powder diffraction (XRPD), Fourier transform near infrared (FT-NIR) and Raman spectroscopy. Chemometrics was applied to interpret the FT-NIR and Raman spectra. Different spray-dried mannitol systems were established in this study, which contain mixtures of α- and β-mannitol. The XRPD, FT-NIR and Raman studies showed that the use of ethanol as a co-solvent increased the amount of α-mannitol in the smaller particles. The addition of low levels of lysozyme resulted in more α-mannitol in the smaller particles, while an increased content of lysozyme in spray-dried mannitol system resulted in more β-mannitol in the smaller particle size fraction. In conclusion spray-drying of mannitol based formulations can result in variation in the solid state composition of mannitol as a function of particle size. This finding may be clinically relevant and underlines the need for proper process control of inhalable dry powder produced by spray-drying.
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Yan-Ying
authors.initials: YY
authors.lastname: Lee
authors.forename: Jian X
authors.initials: JX
authors.lastname: Wu
authors.forename: Mingshi
authors.initials: M
authors.lastname: Yang
authors.forename: Paul M
authors.initials: PM
authors.lastname: Young
authors.forename: Frans
authors.initials: F
authors.lastname: van den Berg
authors.forename: Jukka
authors.initials: J
authors.lastname: Rantanen
mesh_terms: D003460:Crystallization; D005079:Excipients / Q000737:chemistry*; D008353:Mannitol / Q000737:chemistry*; D008855:Microscopy, Electron, Scanning; D009113:Muramidase / Q000737:chemistry; D010316:Particle Size; D044367:Phase Transition; D033362:Powder Diffraction; D011208:Powders; D012997:Solvents / Q000737:chemistry; D017550:Spectroscopy, Fourier Transform Infrared; D013059:Spectrum Analysis, Raman; D013499:Surface Properties; D013818:Thermogravimetry; D014961:X-Ray Diffraction
chemical_list: D005079:Excipients; D011208:Powders; D012997:Solvents; D008353:Mannitol; D009113:Muramidase