Insight into de-agglomeration of mechanofused salbutamol sulphate powders for inhalation
Creators: name: Shi, Jiani
Publisher: name: Monash University
Year: 2017
Subjects: Uncategorized

description: The objective of the research in this thesis was to investigate three aspects of the de-agglomeration of micronized salbutamol sulphate mechanofused with magnesium stearate for respiratory delivery: 1) The influence of the magnesium stearate coating (1 % (w/w) , 2% (w/w) and 5% (w/w) in the powder mixture) used in mechanofusion on the extent of deagglomeration of the salbutamol sulphate. 2) The effect of magnesium stearate coating on the rate of de-agglomeration. 3) To explain the de-agglomeration behaviours of the cohesive powders using calculated tensile strengths of uncoated and mechanically dry coated salbutamol sulphate powders. Firstly, the thesis focussed on the characterisation of cohesive powder behaviour during aerosolization at a sequence of air flow rates to understand the de-agglomeration behaviour. The raw materials were processed with a well characterised laboratory mechanofusion technique prior to aerosolization. The realtime particle size distributions of the aerosolized plume were obtained using Spraytec® laser diffraction from a Rotahaler® device at various air flow rates (45-120 L/min). The significance (p&lt;0.05) was obtained from ANOVA and t-test using SPSS software. The relative de-agglomeration of the magnesium stearate coated salbutamol sulphate was much higher than the uncoated salbutamol sulphate at all air flow rates. Among the three magnesium stearate coated salbutamol sulphate powders, the salbutamol sulphate coated with 2% (w/w; (2% powder)) magnesium stearate showed the best de-agglomeration properties, followed by the salbutamol sulphate coated with 5%(w/w; (5% powder)) magnesium stearate. The salbutamol sulphate coated with 1 % (w/w; (1 % powder)) magnesium stearate was not de-agglomerated as well as the 2% (w/w) and 5% (w/w) powders, but still was significantly improved compared to the uncoated salbutamol sulphate. The relative de-agglomeration versus air flow rate profiles were then subsequently modelled applying a three parameters sigmoidal equation. The estimated parameters provided an approach to represent and characterise the relative de-agglomeration behaviour of each cohesive powder and defined powder micro-structures of cohesive powders. Secondly, the study was extended to investigate the difference in the de-agglomeration rate between the uncoated and coated salbutamol sulphate powders. The rate constants of de-agglomeration were calculated from the data collected from the Spraytec® laser diffraction particle sizing of the aerosol plume. The emitted fine particle mass vs. time profiles were modelled using a mono-exponential equation to estimate the rate constant of powder de-agglomeration (kd). At high air flow rates, the coated salbutamol sulphate powders generally presented with higher kd values; flow rate did not affect the rate of de-agglomeration of the uncoated salbutamol sulphate. There was no obvious evidence indicating that mechanofusion increased rates of de-agglomeration and there was no relationship between the amount of coating used in the mechanofusion process and kd value. Mechanofusion therefore appeared only to increase the extent of de-agglomeration. Large variability associated with Rotahaler® was expected due to variable capsule orientation and chaotic motion of the capsule in the unrestricting volume of the capsule chamber. Thirdly, the thesis correlated the de-agglomeration behaviour to tensile strengths of the cohesive salbutamol sulphate powders. According to the tensile strength equation (Kendall and Stainton, 2001a) [equation not displayed] where ø is the packing fraction, W is the work of adhesion and dp is the diameter of the particle. The de-agglomeration of the salbutamol sulphate powders was related to the determining parameters of the tensile strength (particle size, packing fraction and work of cohesion). When using the individual distributions of these parameters, only the work of cohesion was consistent with increased de-agglomeration. The work of cohesion profiles indicated that the coated salbutamol sulphate powders had lower energy distributions hence lower tensile strength than the uncoated powders. The packing fraction of the coated salbutamol sulphates were larger than the uncoated salbutamol sulphate, the low packing fraction of the uncoated powder led to a paradoxical low tensile strength. The packing sizes were slightly reduced by mechanofusion process which was consistent with an increased tensile strength and reduced de-agglomeration. This complex interplay meant that the overall increased de-agglomeration observed in the relative de-agglomeration profile could not be fully explained by the Kendall and Stainton Equation. The tensile strength can not be estimated due to the uncertainty in extrapolation of the work of cohesion. Monte Carlo simulation, necessary to determine the tensile strength, required the work of cohesion data to be extrapolated to 100% surface coverage; however the results generated from IGC only covered less than 7% of the surface for these salbutamol sulphate powders. The remaining 93% surface coverage data were extrapolated using equations of best fit line, but it was recognised that this approximation caused large uncertainties and errors. Therefore the tensile strength distributions would contain these major uncertainties and were not determined. The outcomes of this thesis provided an approach to characterise the cohesive powders, enabling a better understanding of micro-structures of the cohesive powders for inhalation and possibly provide a new methodology to screen drug powders in the future developing process. The work also provided a unique mechanistic insight into the contrasting aerosolization behaviours of the micronized drug, before and after surface modification.