Spray drying of particles intended for inhalation - Investigation of significant process variables and product characteristics, with focus on degradation and solid state properties

University dissertation from Dept. of Pharmaceutics, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-21 00 Copenhagen, Denmark

Abstract: The interest in spray drying for production of inhalable particles has grown considerably since the late 1980s. However, which process variables that control degradation and the solid state properties have not been subject to extensive research. This thesis deals with how important characteristics of inhalation particles can be controlled, i.e. particle size, morphology, degradation and crystallinity. The spray drying was performed in laboratory scale and pilot plant scale. Insulin, lactose, mannitol, melezitose, myo-inositol, raffinose and trehalose were used. In addition, in one study, the effect of an additive, polyethylene glycol (PEG), on the crystallinity of a material with a high glass transition temperature (Tg °C) (lactose) was studied. Particles within the inhalable size range, < 5 micrometers, were produced of insulin and the carbohydrates. The particle size was shown to be decreased by decreased feed concentration, increased nozzle gas/feed flow mass ratio and decreased inlet gas temperature (insulin). The particle morphology depends on the starting material. Degradation of insulin could be avoided at mild drying conditions (outlet gas temperature below 120 °C). The degradation increased at increased inlet gas temperature and outlet gas temperature. Mannitol and myo-inositol were crystalline after spray drying while the other carbohydrates were amorphous. A comparison of the obtained crystallinities and the conditions in the spray dryer during processing (gas- and product temperatures, gas relative humidities etc.) showed that substances with a Tg below room temperature will become crystalline and those with a Tg above 100 °C amorphous. The crystallization temperature (Tc °C) must not exceed the outlet gas temperature (Tout °C) and the Tg must be about 50 °C below the Tout to obtain a crystalline product. The addition of PEG to lactose increased the crystallinity of lactose at increased PEG concentration and at decreased PEG molecular weight. PEG 200 resulted in the most crystalline samples (50-60% crystallinity of the lactose/PEG samples at a plateau level) and the mechanism for the effect of PEG is discussed in the thesis.

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