Influence of Humidity on the Electrostatic Charge and Aerosol Performance of Dry Powder Inhaler Carrier based Systems

Abstract

To investigate the influence of storage relative humidity (RH) on the aerosolisation efficiency and tribo-electrification of carrier based dry powder inhaler (DPI) formulations using the next generation impactor (NGI) in vitro methodology and the electrostatic low pressure impactor (ELPI). Micronised salbutamol (d (0.5) 1.48 +/- 0.03 microm) was blended with 63-90 microm sieve fractioned alpha-lactose monohydrate carrier and stored at a range of humidities (0-84% RH). The aerosolisation efficiency after storage for 24 h periods was investigated using the NGI. The same experiment was conducted using the ELPI, with corona charger switched off, to measure the net charge vs. mass deposition profile. Significant variations in the aerosolisation efficiency of the formulation were observed with respect to storage RH. In general, the fine particle fraction aerosol performance measured by NGI and ELPI (fraction with mass median aerodynamic diameter <4.46 and 4.04 microm, respectively) followed a positive parabola with aerosol performance increasing over the range 0-60% RH before decreasing >60% RH. Analysis of the ELPI charge data suggested that the micronised salbutamol sulphate had an electronegative charge when aerosolised from lactose based carriers, which was most electronegative at low RH. Increased storage RH resulted in a reduction in net charge to mass ratio with the greatest reduction at RH >60%. The aerosol performance of this binary system is dependent on both electrostatic and capillary forces. The use of the ELPI allows a degree of insight into how these forces affect formulation performances after storage at different RH.

The Role of Carrier in Dry Powder Inhaler

“…Many different non-lactose carriers have been investigated, such as cyclodextrins, dextrose, glucose monohydrate, maltitol, maltose, raffinosepentahydrate and xylitol.Anhydrous glucose is already used in the marketed product Bronchodual ® (Boehringer) (Pilcer et al, 2010).Sucrose, trehalose and raffinose are non-reducing sugars and as such have the advantage that they will not undergo the Maillard browning reaction with proteins (Ógáin et al, 2011). But in contrast to lactose monohydrate which was found to only take up moisture on its surface, and showing only a small reduction in its FPF after storage at 75% RH (Young et al, 2007;Zeng etal., 2007), a main difficulty with these sugars, especially with the more hygroscopic substances -sorbitol, maltitol and xylitol -has attributed to their sensitivity to humidity. In fact, the capillary forces, arisen from the dynamic condensation of water molecules onto particle surfaces, seem to be less prominent with mannitol and lactose as carriers, probably because of their less hygroscopic characteristics than the other carbohydrates (Zeng et al, 2007;Young et al, 2007).…”

“…But in contrast to lactose monohydrate which was found to only take up moisture on its surface, and showing only a small reduction in its FPF after storage at 75% RH (Young et al, 2007;Zeng etal., 2007), a main difficulty with these sugars, especially with the more hygroscopic substances -sorbitol, maltitol and xylitol -has attributed to their sensitivity to humidity. In fact, the capillary forces, arisen from the dynamic condensation of water molecules onto particle surfaces, seem to be less prominent with mannitol and lactose as carriers, probably because of their less hygroscopic characteristics than the other carbohydrates (Zeng et al, 2007;Young et al, 2007). However, it was proposed that the difficulties arising from their hygroscopicity can be overcome by adding an ultrafine hydrophobic excipient to the powder blend .Comparing the different forms of mannitol, lactose and maltitol mixed with terbutaline sulfate resulted in higher FPF with crystallized mannitol for terbutaline sulfate (Saint-Lorant et al, 2007).Hooton et al, used beta cyclodextrin, lactose, raffinose, trehalose and xylitol for the formulation of salbutamol sulfate DPI and applied the cohesive-adhesive balance technique for analyzing quantitative AFM measurements to interpret inhalation behavior of drug.…”

Devices for Dry Powder Drug Delivery to the Lung

“…Due to interparticulate forces, i.e., mechanical interlocking, capillary, electrostatic, and van der Waals forces (26), micronized powders are very adhesive/cohesive, spontaneously forming agglomerates. The extent of the partial and consequently of the combined forces is dependent on powder properties such as particle size, morphology, shape, and material (27), as well as on environmental factors, e.g., relative humidity (28). Since the extent of agglomeration negatively affects the fraction of the inhaled powder, which is within the respirable range (29), these agglomerates must be effectively deagglomerated prior to or during the processes of aerosolization and inhalation (30).…”

Electrostatics of pharmaceutical inhalation aerosols

“…As expected, the fine particle dose charge-to-mass ratio decreased with increasing storage RH for a salbutamol sulfate/lactose binary dry powder blend. [21] On the other hand, the effect of RH of the dispersion air on DPI particle charging is more complex and drug-dependent. Aerosols from Pulmicort and Bricanyl Turbohalers showed distinctly different charging behaviour when the dispersion air RH varied from 15 to 90% RH.…”

“…[18,19] The extent and trends of charging were affected by storage and dispersion relative humidities. [21,22] Metered dose inhalers (MDIs)…”