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Insight into mechanisms of de-agglomeration of pharmaceutical powders for inhalation

posted on 09.02.2017, 05:05 by Behara, Srinivas Ravindra Babu
The objective of the research in this thesis was to investigate two aspects of the de-agglomeration of cohesive materials in respiratory delivery, i.e. the influence of cohesive material properties and the influence of the inhaler device characteristics. Firstly, the thesis focussed on the characterisation of cohesive powder behaviour during aerosolisation at a sequence of air flow rates to understanding the micro-structure of the powder bed. This part of the thesis determined the relative de-agglomeration as a function of air flow rate of micronized drugs, in particular salbutamol sulphate (SS) and various lactoses using a simple powder inhaler device. The study was extended to the investigation of the de-agglomeration efficiencies of binary mixtures of SS and lactohale 300 (LH300) in the ratios of SS:LH300 of 1:1, 1:2, 1:4 and 1:8. The data were modelled using non-linear least square regression and sigmoidal equation parameters were used to characterise single components and binary mixtures. Secondly, the thesis determined to correlate kinetics of emptying and kinetics of de-agglomeration for the powders aerosolised from inhaler devices. This second part of the thesis investigated the kinetics of powder emptying and de-agglomeration of single component systems using three model inhaler devices, Rotahaler® (RH), Monodose Inhaler® (MI) and Handihaler® (HH). The study correlated the rate constants for emptying and de-agglomeration for the powders aerosolised from inhaler devices. Due to the differences in inhaler design, the role of pressure drop across the device and sensitivity of the device on powder de-agglomeration was also studied. The primary particle size distribution of the materials was achieved through wet dispersion of powders using laser diffraction. The powders (single components and binary mixtures) were processed with a validated laboratory mixing technique prior to aerosolisation. The content uniformity of binary mixtures was assessed using a validated UV spectrophotometric assay. The real time particle size distributions of the aerosolised plume were obtained using laser diffraction following aerosolisation from inhaler devices at various air flow rates (30-180 l min-1). The in-vitro performance of SS-LH300 mixtures were assessed using custom-made jet diameters of stage 1 of the twin stage liquid impinger with drug assayed by a validated HPLC assay. Images of the powders were captured using scanning electron microscopy. The significance (p<0.05) was obtained from ANOVA and t-test using SPSS software. Relative de-agglomeration vs. air flow rate profiles of SS and LH300 and the estimated parameters obtained from modelling with sigmoid three parameter equation defined comparative powder micro-structures of cohesive powders. The maximum relative de-agglomeration of SS was much higher than LH300 at higher air flow rates. In contrast, the relative de-agglomeration of LH300 was higher than SS at low air flow rates. The de-agglomeration vs. air flow rate profiles of cohesive mixtures of SS and LH300 demonstrated improved powder de-agglomeration with increased content of LH300 in SS-LH300 binary mixtures. The study showed that the cohesive materials did not behave independently and that the particle interactions occurring in the powder bed resulted in SS rich and SS poor regions of the aerosolised plume depending on the air flow rate. The parameters obtained from sigmoid three parameter equation provided an understanding of structural changes of binary mixtures (SS and LH300) and SS with increased proportion of LH300 in the mixture. Prolonged powder emptying was observed with inhaler devices, MI and HH in contrast to RH where powder emptied within a second. The emitted mass vs. time profiles were modelled using a mono-exponential equation to estimate the rate constant of powder emptying (kCCEM). In general, with both materials, the relative kCCEM followed the order: MI


Campus location


Principal supervisor

Peter Stewart

Additional supervisor 1

David A.V. Morton

Additional supervisor 2

Ian Larson

Year of Award


Department, School or Centre

Drug Delivery, Disposition and Dynamics


Doctor of Philosophy

Degree Type



Faculty of Pharmacy and Pharmaceutical Sciences