Particle size dependence of polymorphism in spray-dried mannitol

Yan-Ying Lee, Jian X. Wu, Mingshi Yang, Paul M. Young, Frans van den Berg, Jukka Rantanen

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    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.
    Original languageEnglish
    Pages (from-to)41-48
    Number of pages8
    JournalEuropean Journal of Pharmaceutical Sciences
    Issue number1-2
    Publication statusPublished - 2011


    • Spray-drying
    • Polymorphic form
    • Mannitol
    • X-ray powder diffraction
    • Fourier transform near infrared spectroscopy
    • Raman microscopy


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