Preparation of theophylline inhalable particles by wet milling and spray drying; the influence of mannitol as a co-milling agent

M. Malamatari, S. Somavarapu, M. Bloxham, G. Buckton

This study aims to prepare inhalable theophylline particles by formulating the drug with mannitol. The effect of mannitol as a co-milling agent on the micromeritic, solid state properties and aerosolisation performance of the engineered particles was investigated. Theophylline suspensions were produced by wet bead milling in isopropanol alone and in the presence of mannitol and were further solidified by spray drying. The spray dried suspension of theophylline consisted of elongated particles of a mean particle size of 4.64 ± 0.87 μm. The spray dried suspension of theophylline and mannitol consisted of submicron theophylline particles embedded in a porous mannitol framework, with a mean particle size of 2.18 ± 0.30 μm. In both formulations, the drug retained the crystalline state of the raw drug (theophylline anhydrous form I). Inclusion of mannitol during the wet bead milling step of theophylline resulted in formulations which after spray drying exhibited a two-fold increase in the fine particle fraction compared to the spray dried theophylline suspensions without mannitol. The enhanced aerosolisation performance of the spray dried suspensions of theophylline containing mannitol can be attributed to their smaller size, spherical morphology and increased specific surface area that can be used as an indicator of their porosity. Overall, simultaneous wet milling of a drug in the presence of mannitol in an organic solvent followed by spray drying may be an applicable formulation approach for enhancing the aerosolisation performance of (moderately) water-soluble drugs

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