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

Abstract

As pulmonary drug deposition is a function of aerosol particle size distribution, it is critical that the dynamics of particle formation and maturation in pMDI sprays in the interim between generation and inhalation are fully understood. This paper presents an approach to measure the evaporative and condensational fluxes of volatile components and water from and to solution pMDI droplets following generation using a novel technique referred to as the Single Particle Electrodynamic Lung (SPEL). In doing so, evaporating aerosol droplets are shown capable of acting as condensation nuclei for water. Indeed, we show that the rapid vaporisation of volatile components from a volatile droplet is directly correlated to the volume of water taken up by condensation. Furthermore, a significant volume of water is shown to condense on droplets of a model pMDI formulation (hydrofluoroalkane (HFA), ethanol and glycerol) during evaporative droplet ageing, displaying a dramatic shift from a core composition of a volatile species to that of predominantly water (non-volatile glycerol remained in this case). This yields a droplet with a water activity of 0.98 at the instance of inhalation. The implications of these results on regional and total pulmonary drug deposition are explored using the International Commission of Radiological Protection (ICRP) deposition model, with an integrated semi-analytical treatment of hygroscopic growth. Through this, droplets with water activity of 0.98 upon inhalation are shown to produce markedly different dose deposition profiles to those with lower water activities at the point of inspiration.

Keywords: aerosol hygroscopic growth; deposition modelling; metered dose inhaler; spray plume aging; water condensation.

Figure 1

Schematic representation of the evolution of the size distribution for an idealised pMDI spray. (A) The change in droplet size distribution at different phases of aerosol ageing following initial generation. (B) Attaching a spacer to the pMDI provides sufficient time for droplet ageing to occur, such that the large droplets of pMDI sprays evaporate to form an aerosol with a smaller, narrower size distribution.

Figure 2

Experimental setup used to measure the rapid evaporation of droplets originally consisting of volatile solvents. (A) Schematic of the electrode orientation and air flow directions used to levitate and condition an individual droplet. The inset photo shows an individual droplet (radius < 10 µm) trapped by the electrodynamic field and illuminated by the laser. (B) Top-down view of the levitation region of the SPEL, indicating the orientation of the droplet dispenser, laser, and cameras used to position and collect the phase function of the levitated droplet. The concentric circles indicate the relative position of the high voltage and ground electrodes. (C) Photograph of the syringe pump used to cool the syringe and droplet dispenser used to produce individual HFA droplets that can be injected into the SPEL. The inset photo shows the cool vapour encompassing the region holding the HFA loaded syringe, which maintains the temperature between −50 and −55 °C.

Figure 3

The equilibration of a single 10.5 µm diameter glycerol–water solution droplet (initial water activity of the droplets, derived from the starting solution concentration of 10% w/v, is set at 0.98), through the evaporation of water, into three RH environments (20, 70 or 98%) before subsequent growth in 99.5% RH. The 3.0 s holding time in the model was used to ensure that the water activity of the aerosol at the point of inhalation (t = 0 s) was stable at the desired value.

Figure 4

Evaporation of pure ethanol (experimental) droplets in an airflow of various RH. In each case, the evaporation rate of a pure water probe droplet was used to estimate the RH following the method of Davies [62].

Figure 5

Exploring the underlying processes that govern the transition of a rapidly evaporating (volatile) droplet at elevated RH into a water droplet. (A) Evaporation measurements of individual droplets of various initial compositions in an air flow with an RH ~85 %. (B) Equivalence of the mass of water accumulated by a droplet if the vaporization enthalpy of 1-propanol from a droplet of initial radius of 21.3 µm was entirely balanced by the condensation energy of water. Ultimately, this would be equivalent to a pure water droplet with a radius of 14 µm and a mass of 11.4 ng. (C) The phenomenological relationship between the enthalpy required for evaporation of a volatile droplet and the enthalpy liberated on condensation of water. Both are normalised by the time during which the early dynamics change the droplet from a pure volatile to pure water droplet. When the time taken for the transformation is not considered (inset), the relationship between the enthalpies is not as clearly defined.

Figure 6

(A) Dynamic behaviour of a pharmaceutical aerosol for inhalation following aerosolization into 89% RH. The size and proportions of the inset pie charts are drawn to scale. (B) The change in water activity of the glycerol phase in an HFA/ethanol/glycerol droplet increases from 0 to 0.98 during the 0.3 s following droplet generation while the volatile HFA and ethanol evaporate. The final water activity is calculated from the change in size in the droplet in (A) using the hygroscopic growth curve of glycerol as shown. Note that the presence of the ethanol and HFA in the droplet will ensure that the droplet does not track the exact relationship observed in (B), but only arrives at the point indicated at 0.3 s following volatile loss and water condensation.

Figure 7

The condensational growth of a pre-equilibrated log normal droplet distribution (initial droplet diameter MMAD 10.5 µm, GSD 1.8 µm) upon inhalation. The three graphs illustrate the condensational growth during inhalation into the respiratory system (99.5 % RH). At t = 0 s, the aerosol droplet distribution has been pre-equilibrated (not shown) at 20% RH (A), 70% RH (B), or 98% RH (C). Each shade of grey (240 in total) follows the growth of an individual droplet within the model with a specific pre-equilibrated size.

Figure 8

(A) The structure of the ICRP model with integrated semi-analytical hygroscopic growth model. Values inside the circles represent the residence time for the region. The cumulative time is presented above each at the exit point of a region. (B) The change in the log-normal distribution of glycerol–water solution droplet diameters at time corresponding to the ICRP model for three simulations in which the RH for equilibrium prior to inhalation is either 20, 70 or 98%. Fraction/Δ ln(d) is the fraction of the particle population lying between the interval between ln(d) and ln(dp) + d ln(dp) [56].

Figure 9

The regional and total deposition profiles of a log-normal distribution of droplets (emitted droplet size MMAD: 10.5 µm, GSD: 1.8), equilibrated in a spacer chamber at either 20, 70 or 98% RH prior to inhalation. (A) Deposition fraction in the ET region for different droplet diameters. (B) Deposition fraction in the BR region for different droplet diameters. (C) Deposition fraction in the AI region for different droplet diameters. (D) Total deposition fractions for different droplet diameters. N.B. The abscissa corresponds to the droplet diameters prior to inhalation and subsequent hygroscopic growth.

Figure 10

The regional and total dosage depositions in the respiratory system of two glycerol droplet distributions (MMAD: 7.5, 10.5, GSD: 1.8, 1.8) initially equilibrated in either 20, 70 or 98% RH.