The effect of co-spray drying with polyethylene glycol on the polymorphic state of mannitol carrier particles for dry powder inhalation

Atsutoshi Ito, Mitsuhide Tanimoto, Hideki Yano, Michiko Kumon, Kazuhiro Inoue, Shuichi Yada, Naoki Wakiyama

The design of a carrier particle is important for the development of dry powder inhalation (DPI)
formulations. Most DPI formulations rely on lactose as a carrier particle; however, lactose has several disadvantages with DPI formulations. In this study we focused on mannitol as an alternative carrier to lactose. Spray drying was reported as challenging to produce α-mannitol, as β-mannitol is obtained in almost all cases. The polymorphic state of a carrier particle is reported as one of the properties which affect the aerosolization performance of DPI formulations. To control the polymorphic state and to evaluate its effect for the aerosolization performance was considered to be important for the development of DPI formulations. The purpose of this study is to control the polymorphic state and to selectively produce α-mannitol by spray drying, instead of β-mannitol. The effect of polyethylene glycol (PEG) 4000 on a polymorphic state of mannitol was investigated. Powder X-ray diffraction studies showed that spray drying mannitol without PEG 4000 completely produced β-mannitol. In contrast, mannitol/PEG 4000 (PEG 4000 concentration was above 1%) co-spray dried products were found to be completely α-mannitol. It can be estimated that the molecular mobility of mannitol in the presence of PEG 4000 must have been slower than that of mannitol alone and reduced molecular mobility inhibited the transformation from α-mannitol nuclei into β-mannitol nuclei during the spray drying process. Consequently, controlling the polymorphic state and selectively producing α-mannitol by spray drying was successful by adding above 1% of PEG 4000

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