Willetts, John (2012)
Ph.D. thesis, University of Birmingham.
Dry powder inhaler (DPI) formulations are usually comprised of a mixture of micronised active pharmaceutical ingredient (API) with aerodynamic diameter 1-5 m to allow deposition in the lower airways, and a coarse (~70 micron) excipient, typically \(\alpha\)-lactose monohydrate, used to aid the handling, metering and dosing of the formulation. These components are usually combined in a secondary manufacturing process such as high shear blending (HSB), which is used primarily to distribute the cohesive drug particles throughout the bulk excipient to create a chemically homogeneous formulation.
This thesis explores the use of HSB to produce mimic DPI formulations and assesses the effect of different blending and storage regimes on various physicochemical properties of such powders. A novel fluidised bed elutriation (FBE) technique was developed to test the ability of fine mimic drug particles to separate from coarse particles in such formulations, along with conventional air jet sieve (AJS) and Next Generation Impactor (NGI) studies. Results showed that, generally, blending regimes were seen to have little effect on the in vitro performance of these mimic formulations, with extended storage at high humidity having a more profound effect on the separation of fine particles. Tests on the performance of formulations using the FBE technique showed that fluidisation performance alone is insufficient to identify blending-induced changes; however, analysis of the fine elutriated fraction has shown subtle changes in the populations of particles due to HSB. Notable differences were observed between the mimic cohesive and adhesive drugs, indicating the ability of these tests to identify formulations with different adhesive properties. In addition, a study to determine the specific energy input (SEI) required to achieve chemical homogeneity suggested that extended high shear blending beyond a given energy input may only alter the size distribution of the formulation, and not improve homogeneity, thus having implications for the manufacture of such products.
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