The effect of ethanol on the formation and physico-chemical properties of particles generated from budesonide solution-based pressurized metered-dose inhalers

Abstract

The aerosol performance of budesonide solution-based pressurized metered-dose inhalers (HFA 134a), with various amounts of ethanol (5-30%, w/w) as co-solvents, was evaluated using impaction and laser diffraction techniques. With the increase of ethanol concentration in a formulation, the mass median aerodynamic diameter was increased and the fine particle fraction showed a significant decline. Although data obtained from laser diffraction oversized that of the impaction measurements, good correlations were established between the two sets of data. Particles emitted from all the five formulations in this study were amorphous, with two different types of morphology - the majority had a smooth surface with a solid core and the others were internally porous with coral-like surface morphology. The addition of ethanol in the formulation decreased the percentage of such irregular-shape particles from 52% to 2.5% approximately, when the ethanol concentration was increased from 5% to 30%, respectively. A hypothesis regarding the possible particle formation mechanisms was also established. Due to the difference of droplet composition from the designed formulation during the atomization process, the two types of particle may have gone through distinct drying processes: both droplets will have a very short period of co-evaporation, droplets with less ethanol may be dried during such period; while the droplets containing more ethanol will undergo an extra condensation stage before the final particle formation.

Novel Simvastatin Inhalation Formulation and Characterisation

“…Aerosols produced from the formulation had identical spherical shape with smooth morphology, suggesting the aerosol particles to be amorphous. The smooth surface morphology probably resulted from the co-evaporation process of ethanol and propellant components, confirming the observations made from the DSC thermogram of SV pMDI particles (37).…”

Water Uptake by Evaporating pMDI Aerosol Prior to Inhalation Affects Both Regional and Total Deposition in the Respiratory System

“…However, these models are based on simple evaporation kinetics as well as the assumption that volatile species are fully evaporated upon entry into an impactor. Such models show reasonable agreement with laser diagnostic measurements for early-phase droplets, but differences in the measured MMAD and distribution are common and are extremely sensitive to formulation and the axial distance of the laser measurement [ 36 , 37 , 38 ].…”

Advances in Device and Formulation Technologies for Pulmonary Drug Delivery

“…The transition from CFC to the hydrofluoroalkane (HFA) propellants occurred more than two decades ago. However, efforts still continue on reformulating pMDI medications to use the new HFA propellants while retaining equivalent efficacy and safety profiles to their original CFC counterparts (157)(158)(159)(160)(161). This is due to physicochemical properties such as the vapor pressure, polarity, and densities of HFA being significantly different from those of CFC, meaning direct formulation transitions are not possible.…”

“…In particular, most surfactants and excipients used in the CFC formulations are virtually insoluble in the new HFA propellants (153). This has led to the development of ethanol as a low-volatility cosolvent in HFA formulations to solubilize approved surfactants, and, more recently, to solubilize some drugs to form solution-based pMDI formulations (159)(160)(161) and eliminate issues associated with suspension stability. However, a reduction of FPF was noted for formulations with higher ethanol concentration partly due to the increased MMAD (159).…”