Keywords flashing jet - FJ prototype - atomization performance - mass median aerodynamic diameter
Introduction
Inhalation is an administration method in which aerosolized medications are inhaled
into the respiratory tract and further reach the pulmonary system for topical or systemic
applications.[1 ] It is the recommended administration method for asthma and chronic obstructive pulmonary
disease.[2 ] Compared with oral administration, inhalation drug delivery offers several advantages
including lower delivery doses, reduced incidence of systemic side effects, faster
onset of action, and improved bioavailability.[2 ]
[3 ]
[4 ]
An inhalation medication is atomized and delivered through an aerosol device. There
are three main types of aerosol devices: pressurized metered dose inhaler, dry powder
inhaler, and nebulizer, which include jet nebulizer, ultrasonic nebulizer, and vibration
mesh nebulizer. Besides, emerging inhaler and nebulizers have been investigated, such
as vortex nozzle inhaler, plume-control inhaler, air classifier inhaler, turbulent
flow inhaler, flutter inhaler, thermostat jet nebulizer, surface acoustic wave microfluidic
atomizer, condensational growth capillary aerosol generator, and on-chip electrohydrodynamic
atomizer.[5 ]
[6 ]
[7 ]
[8 ]
[9 ]
[10 ]
[11 ]
Critical factors such as dosage level, drug efficacy, drug safety profile, patient
age, disease severity, ease of administration, and cost should be considered when
selecting a suitable inhaler or nebulizer for a patient.[12 ]
[13 ]
[14 ] An ideal inhaler generally provides better usability, lower spray velocity, longer
spray duration, higher fine-particle fraction, and better drug utilization.[15 ] Currently, these attributes are largely showcased by Respimat soft mist inhaler,
but its unique uniblock component restricts the delivery volume to 15 μL, which considerably
diminishes the drug delivery capacity.[16 ]
[17 ]
[18 ]
[19 ] Additionally, drugs with poor solubility are unsuitable for Respimat soft mist inhaler.
Therefore, a novel inhaler that can produce a soft mist with higher atomization volume
and better support for poorly soluble drugs will be a good complement to current inhalers.
Flashing is an instantaneous boiling phenomenon that happens when the external pressure
of a liquid drops below its saturated vapor pressure.[20 ] Under such circumstances, the liquid is “overheated”, and boiling happens. This
process is quicker and more violent than normal ebullition. When flashing liquid flows
through an orifice, a two-phase bubble flow is created. The rapid expansion of the
bubble shatters the liquid flow and aerosol spray is generated.[20 ]
[21 ]
[22 ]
[23 ]
[24 ]
When the flashing happens inside or before the orifice of an atomizer, a flash atomization
happens.[20 ]
[25 ] Spray ejected by the flash atomization has high controllability on droplet size
and distribution pattern. Therefore, flash atomization is widely applied in several
industrial applications such as coating, cooling, dehydration, desalination, aerospace,
and pharmaceutical.[26 ] When the flashing happens after the orifice, a flashing jet is generated.[27 ] Aerosol characteristics of the flashing jet, such as the velocity, spray angle,
and droplet size distribution, can be used to calculate the jetting rate and orifice
diameter of the jet.[28 ]
[29 ] Therefore, this flashing form receives considerable attention in heavy industries
as a measurable feature to estimate the leakage rate of high-pressure vessels or circulation
loops for risk assessment and hazard management.
Liquid pressure, temperature, overheating degree, surface tension, and nozzle geometry
are critical factors that determine the droplet size and distribution of output aerosol
at the flashing jet.[27 ]
[28 ]
[30 ]
[31 ]
[32 ] Currently, multiple theoretical formulas can be used to predict droplet size changes
under different parameter conditions.[20 ]
[33 ]
[34 ] Theoretical droplet size d
d can be calculated through [Equation (1) ]
[21 ]:
Herein, the critical Weber number We
crit was 12.5, which is recommended by a previous study.[27 ] The liquid Reynolds number and the liquid Weber number are defined as [Equation (2) ]:
Where d
f is the initial diameter of the jet, ρ
L is the density of the liquid, u
f is the initial speed of the jet, μ
L is the viscosity coefficient of the liquid, and σL is the surface tension coefficient of the liquid.
However, limited experiments are available that establish a direct correlation between
these definitions and practical usage. Therefore, a new correlation derived from experimental
data is being employed. The droplet diameter can be calculated based on the orifice
diameter using the following [Eq. (3) ]
[21 ]
[35 ]:
Where d
O is the orifice diameter, d
str is the droplet diameter at the start point when the flashing transition begins, and
d
end is the droplet diameter at the endpoint when the flashing transition finishes. The
start and end temperatures of this flashing transition process can be calculated based
on the criteria given in [Equation (4) ]:
According to the current flashing theory, obtaining aqueous aerosol particles with
diameters less than 10 μm is achievable for the flashing atomization but difficult
for the flashing jet.[21 ]
[25 ]
[27 ]
[29 ]
[36 ]
[37 ] Although flashing atomization is already used in spray dying applications to generate
super-fine droplets (< 1 μm) for pharmaceutical dry powder production,[34 ] it is rarely used to generate inhalable droplets (2–5 μm) for drug inhalation application.
This may be because the high-pressure differential (> 400 kPa), large expansion chamber
volume, and high energy supply requirements limit the feasibility of miniaturizing
a flashing atomizer into handheld size,[30 ] which is a basic usability requirement for inhalers. On the other hand, current
theoretical and experimental data of the flashing jet focus on large orifice diameter
(> 1 mm), high pressure (> 300 kPa), or high flow rate (> 100 mL/s).[35 ]
[36 ]
[37 ] The possibility and methodology to generate inhalable aerosols remain unknown when
the flashing jet is produced through an inhaler nozzle setting.
In the preliminary work of this study, a flashing jet inhaler prototype (FJ prototype)
was established, which produced small droplets (< 10 μm) with a small orifice (0.4 mm)
and lower liquid pressure (150 kPa) in a single spray (50 μL). The atomization mechanism
of the FJ prototype dose relied on the propellant, and the atomization performance
is not affected by the inhalation flow. Additionally, the spray speed was relatively
slow, and the spray duration could be adjusted in the FJ prototype. The FJ prototype
holds the potential for improving drug delivery efficiency and usability. However,
a significant proportion of large droplets remained in the delivered aerosol, making
it unsuitable for inhalation administration. Therefore, further optimization of atomization
performance is necessary for the FJ prototype.
The study aims to investigate the feasibility of using the current flashing theory
to optimize the atomization performance of the FJ prototype and generate inhalable
aqueous aerosols, and the factors that influence the flashing jet appearance are studied,
including the overheat degree, jetting rate, jetting volume, and liquid type. The
mass median aerodynamic diameter (MMAD) and aerodynamic particle size distribution
(APSD) of output aerosol are used to compare the effects of these factors on atomization
performance. Moreover, drug distribution is measured to evaluate the drug delivery
capacity when active ingredients are included in different liquid types.
Material and Method
Instrument and Materials
The instrument used in the study were: high-performance liquid chromatography (HPLC,
LC-20AT Shimadzu, Japan), aerodynamic particle sizer (APS) model 3321 (TSI Inc., Minnesota,
United States), impactor inlet for pharmaceutical research (IIPR) model 3306 (TSI
Inc., Minnesota, United States), vacuum pump (2XZ(s)-2, SH-Drying Vacuum & Lighting
Equipment Co., Ltd., Shanghai, China), air flow meter LZB-10 (QF-meter, China), glass
microfiber filter (Whatman GF/F, Maidstone, Kent, United Kingdom), analytical balance
XS205DU (Mettler Toledo Ltd., Leicester, United Kingdom), Pari nebulizer, and FJ prototype.
Materials and chemical reagents used in the study were: methanol (16891140) and acetonitrile
(Z2611440), obtained from CNW Technologies GmbH, Germany; phosphoric acid (20120920),
sodium dihydrogen phosphate dehydrate (20170209), sodium dihydrogen phosphate (20170417),
and sodium chloride (20161207), obtained from Sinopharm Chemical Reagent Co., Ltd.,
Shanghai, China. Salbutamol sulfate (cpc-007–1712005, SPH Sine Pharmaceutical Laboratories
Co., Ltd., Shanghai, China), salbutamol sulfate solution (SAL) for inhalation (ventolin
[VEN], 5 mL/mL, C713079, GlaxoSmithKline, United Kingdom), budesonide (BD131102, Hubei
Gedian Humanwell Pharmaceutical Co., Ltd., Hebei, China), and budesonide suspension
(BUD) for inhalation (pulmicort respules [PUL]; 2 mL:1 mg, 318703, Astra-zeneca, United
States). Methanol and acetonitrile were of chromatographic grade, and all other reagents
were of analytical grade. Purified water was used throughout the study.
FJ Prototype
The FJ prototype consists of an atomization block, temperature control module, pressure–volume
control module, and liquid pool ([Fig. 1A ]). The temperature control module contains a thermistor temperature sensor, a 25 W
ceramic heater, and a temperature controller. The pressure–volume control module contains
a metering pump, a pressure sensor, an actuation pusher, and a pressure chamber. Moreover,
this module connects the liquid pool and the atomization block. The whole prototype
is powered by a 50 W DC power.
Fig. 1 Diagrammatic view of the FJ prototype. (A ) Prototype composition; (B ) actuation process; (C ) partial photo of atomization block; (D ) top view of the atomization block under different conditions. FJ, flashing jet inhaler.
The atomization process of the FJ prototype includes two steps: preparation and actuation.
In the preparation stage, a certain amount of liquid is extracted from the liquid
pool and pumped into the pressure chamber. Next, the chamber pressure is raised above
the saturation pressure of the target overheating temperature. Additionally, the pressure
chamber is heated to the overheating temperature. The chamber pressure is adjusted
by the position of the actuation pusher and maintained by a check valve outside the
chamber. The heating and stabilization process is controlled by the temperature control
loop between the ceramic heater and the temperature sensor.
During the actuation, the pusher is inserted into the chamber to further increase
the liquid pressure. When the liquid pressure is higher than the orifice sealing threshold,
the orifice opens releasing overheated liquids as a flashing jet ([Fig. 1B ]). The jetting rate and duration are controlled by the insertion rate of the pusher.
The orifice sealing threshold is controlled by the locking strength of the atomization
block and the orifice diameter.
APSD and MMAD Measurement
The APSD of the delivered aerosol was measured by the APS based on the time of flight
(TOF) analysis. The IIPR, which has a United States Pharmacopeia/European Pharmacopeia
(USP/Ph Euro) inlet and an APS sampling probe, was integrated with the APS.
The background flow rate of the APS/IIPR system was set as 28.3 L/min, while the sampling
flow rate of the APS probe was set as 0.062 L/min with a sampling pressure of 1.2 cm
in the water manometer (approximately 117.68 Pa). As a result, 0.2% of the delivered
aerosol that penetrated through the USP/Ph-Euro inlet was extracted as the initial
sample. Filter makeup air was mixed with the initial sample twice before it enters
the TOF spectrometer in APS, which leads to the total dilution rate of the delivered
aerosol being 1:400.
Aerosol Instrument Manager (version 7.3.0.0, TSI Inc., Minnesota, United States) was
used for data calculation and display. The sampling mode of aerosol was settled as
summing and the measured results of APSD were displayed as channel date. Stokes correction
scatter mode was not applied. Dilution/efficiency file <00400to1.e21> was used as
the data compensation algorithm. The measuring range of MMAD was 0.523 to 20 μm.
Dosage Measurement
The USP throat, 4.7 μm single-stage impactor, and outlet filter in the APS/IIPR system
were used to measure the drug dosage of the delivered aerosol. After atomization,
the atomization block of the FJ prototype, connecter, USP throat, and impact plates
were washed by the mobile phase. Thereinto, the lotion of the atomization block was
considered as the device residual dosage sample, the lotions of connecter and USP
throat were merged as throat residual dosage sample, and the lotions of impact plates
were merged as the large particle dosage (LPD) sample. The glass microfiber filter,
which was loaded on the outlet holder in IIPR, was soaked and ultrasonicated for 30 minutes
in the mobile phase. Subsequent filtration after 0.22 μm filtration was used as fine
particle dosage (FPD) samples. All samples were measured by the HPLC.
Chromatographic Conditions
For salbutamol sulfate, a Kromasil C18 (4.6 mm × 250 mm, 5 μm) column was used with
the mobile phase comprising phosphate buffer solution–methanol (85:15, v/v), detection
wavelength of 276 nm, flow rate of 1.0 mL/min, injection volume of 20 μL, and column
temperature of 35°C.
For budesonide assessment, an Inertsil ODS-SP C18 (4.6 mm × 250 mm, 5 μm) column was
used with the mobile phase consisting of phosphate buffer solution–acetonitrile (58:42,
v/v), detection wavelength of 246 nm, flow rate of 1.0 mL/min, injection volume of
20 μL, and column temperature of 35°C.
Statistical Analysis
Data were managed and analyzed with the SPSSAU data analytics platform. Data were
expressed in the form: mean ± standard deviation. One-way ANOVA (analysis of variance)
was employed to evaluate data dependency. A statistically significant difference was
set as the p -value is less than 0.05.
Results
Reference Output
The APS/IIPR system was used to measure the APSD and MMAD of output aerosol. However,
the potential shrinking caused by the sampling flow results in deviations from the
original droplet diameter.[38 ]
[39 ] Droplet sizes determined by the APS/IIPR system alone are not suitable to evaluate
the atomization performance. Among the numerous jet nebulizers, the Pari nebulizer
is widely recognized for its atomization performance. The Pari nebulizer was used
as a reference device because it produces aqueous aerosol, similar to the output of
the FJ prototype. The MMAD and APSD of aerosol output at 60 seconds of the Pari nebulizer
were used to assess the atomization performance of the FJ prototype.
Normal saline (NS) was nebulized by the Pari nebulizer with a 2 mL initial filling
volume. The MMAD of its aerosol output in 60 seconds was 2.50 ± 0.81 μm (n = 6). The APSD is shown in [Fig. 2 ].
Fig. 2 APSD of NS at the Pari nebulizer. APSD, aerodynamic particle size distribution; NS,
normal saline.
Overheat Degree
The overheat degree △T is the difference between the liquid temperature (T
L ) and the liquid boiling point (T
boiling ) corresponding to the current ambient temperature, according to [Equation (5) ]:
A higher overheat degree leads to a more drastic flashing process, whereas it also
leads to lower liquid surface tension and viscosity. With increasing overheat degrees,
three stages may exist: (1) jetting stage, where no flashing happens or the flashing
is not strong enough to break the jet; (2) rupturing stage, where flashing is strong
enough to break the jet into aerosol; (3) full flashing stage, where flashing disintegrates
the jet violently near the nozzle. Multiples overheat degrees of 10, 20, 30, and 50°C
were used as flashing conditions to evaluate the output changes of the FJ prototype.
NS was jetted by the FJ prototype in a jetting volume of 40 μL, a jetting rate of
20 μL/s, a jetting pressure of 150 kPa, and a jetting duration of 2 seconds. Atomization
output at different temperatures is shown in [Fig. 3A ].
Fig. 3 (A ) FJ prototype output at different temperatures. (B ) Atomization performance at different overheat degrees (n = 6). *p < 0.05. (C ) APSD of NS at different overheat degrees. APSD, aerodynamic particle size distribution;
FJ, flashing jet inhaler; NS, normal saline.
No data were obtained at the 10°C overheat degree because the flashing was not strong
enough to break the jet into an aerosol. Moreover, two FJ prototype devices were used
in the test, while the second one was repeatedly tested three times on other days
to validate the repeatability and reproducibility.
Measured MMAD decreased with increased overheat degree. Significant differences were
found between the 40 and 50°C overheat degrees in all test groups ([Fig. 3B ]). APSDs at different overheat degrees are shown in [Fig. 3C ].
Jetting Rate
The jetting rate influences the initial velocity of the flashing jet. The interaction
of air and jet directly causes the disturbance in the air–liquid interface, which
weakens the constraint effect of surface tension. Therefore, a higher jetting rate
may improve the atomization performance in the same flashing strength.
NS was used as the atomization liquid, the jetting volume was 40 μL, and jetting rates
of 15, 20, and 25 μL/s were evaluated. Besides, the effect of jetting rate in different
overheat degrees was assessed by determining MMAD and APSD of the FJ prototype at
20, 30, 40, and 50°C.
Our data showed that at low overheat degrees (20 and 30°C), the aerosol MMAD tends
to decrease with the increase of jetting rate, but the difference is not significant.
At high overheat degrees (40 and 50°C), the aerosol MMAD decreased significantly between
the injection rate of 15 and 20 μL/s, but did not decrease further when the jetting
rate increased to 25 μL/s ([Fig. 4A ]). APSDs for different jetting rates at 20 and 50°C overheat degrees are shown in
[Fig. 5A ].
Fig. 4 (A ) Atomization performance at different jetting rates (n = 6). *p < 0.05. (B ) MMAD of delivered aerosol at different jetting volumes. (C ) MMAD of different atomization liquids at FJ prototype and Pari nebulizer. *p < 0.05. FJ, flashing jet inhaler; MMAD, mass median aerodynamic diameter.
Fig. 5 (A ) APSD of normal saline at different jetting rates; (B ) APSD of normal saline at different jetting volumes; (C ) APSD of different atomization liquids at FJ prototype and Pari nebulizer. APSD,
aerodynamic particle size distribution; FJ, flashing jet inhaler.
Jetting Volume
The jetting volume and jetting rate determine the spray duration of one actuation.
Moreover, larger volumes may lead to different pressure distributions in the pressure
chamber, which may further influence the atomization performance of the FJ prototype.
For NS as the atomization liquid, an overheat degree of 40°C, a jetting rate of 20
μL/s, and jetting volumes of 40, 50, 60, 80, 90, and 100 μL were used as test conditions.
The MMAD and APSD of the FJ prototype were measured to evaluate the effect of jetting
volume.
The MMAD slightly decreased with increased jetting volume at the test condition, but
no significant difference was found ([Fig. 4B ]). APSDs for different jetting volumes at 40°C overheat degree and 20 μL/s jetting
rate are shown in [Fig. 5B ].
Atomization Liquid
The flashing behavior could be determined by the overheat degree, specific heat capacity,
and vaporization latent heat of the liquid during jetting. Thereinto, the specific
heat capacity and vaporization latent heat are influenced by the active ingredient
and excipients in prescription.
NS, SAL, VEN, BUD, and PUL were used as the atomization liquid. Test conditions were
set as follows: overheat degree, 40°C; jetting rate, 25 μL/s, and jetting volume:
50 μL. The atomization liquid was evaluated by determining the drug distribution and
MMAD of the FJ prototype. Furthermore, VEN and PUL, atomized with a Part nebulizer,
were used as reference groups. As shown in [Fig. 4C ], the MMAD of VEN and PUL at the FJ prototype was lower than those of SAL and BUD.
The MMAD of VEN at the FJ prototype was significantly higher than that of the Pari
nebulizer, while the MAMD of PUL at the FJ prototype was significantly lower than
that of the Pari nebulizer. When the atomization liquid was NS, there is no significant
difference between the FJ prototype and Pari nebulizer. Dosage measurement results
of drug distribution are listed in [Table 1 ], while the APSD of different liquids is shown in [Fig. 5C ] below.
Table 1
Results of dosage measurements
FJ prototype
Pari nebulizer
SAL
VEN
BUD
PUL
VEN
PUL
Device (%ND)
19.9 ± 4.5
22.0 ± 4.3
20.5 ± 8.2
25.1 ± 7.9
11.6 ± 7.7
9.2 ± 2.1
Throat (%ND)
34.3 ± 3.6
20.6 ± 3.3[a ]
37.2 ± 11.5
36.4 ± 2.2
28.5 ± 5.6
27.2 ± 5.1
LPD (%ND)
26.0 ± 1.6
7.1 ± 2.9[a ]
19.2 ± 9.6
8.4 ± 2.1
6.9 ± 1.2
25.0 ± 6.4
FPD (%ND)
19.7 ± 1.9
50.4 ± 3.7[a ]
23.1 ± 6.6
30.1 ± 5.6
53.1 ± 7.2
38.6 ± 5.1
DD (%ND)
107.8 ± 8.0
97.7 ± 8.8
117.9 ± 10.1
89.9 ± 7.9
110.7 ± 6.0
99.5 ± 9.4
MMAD (μm)
4.9 ± 1.8
2.1 ± 0.2
6.6 ± 2.9
2.5 ± 0.5
1.7 ± 0.2
4.6 ± 0.2
Abbreviations: %ND, percent of the nominal dose; BUD, budesonide suspension; FJ, flashing
jet inhaler; MMAD, mass median aerodynamic diameter; NS, normal saline; PUL, pulmicort
respules; SAL, salbutamol sulfate solution; VEN, ventolin.
Note: Data were expressed as mean ± standard deviation of three parallels.
a Significant difference compared with SAL solution at FJ prototype.
The normal dosage (ND) was calculated using the jetting volume and liquid concentration
according to [Equation (6) ]:
The ND at the FJ prototype was 250 μg for the SAL and VEN and 25 μg for the BUD and
PUL, while at the Pari nebulizer was 800 and 80 μg for the VEN and PUL, respectively.
Device (%ND) is the residual dosage proportion of the atomization block at the FJ
prototype and the upper part of the nebulizer cup at the Pari nebulizer respectively.
Throat (%ND) is the residual dosage proportion of connector and USP throat. LPD (%ND)
and FPD (%ND) are the LPD proportion and FPD proportion, respectively. Delivered dosage
(DD) is the sum of measured dosage, while DD (%ND) is the recovery rate of atomized
dosage.
Discussion
Effect of Overheat Degree
The degree of overheat determines the boiling strength of the flashing jet, and a
higher overheat degree leads to better atomization performance.[27 ] This factor has been extensively studied by various researchers, leading to the
development of several empirical formulas that describe the relationship between the
overheat degree and the mean droplet diameter of the output aerosol.[27 ]
[29 ]
[37 ]
Although the prediction results of particle size distribution are different in these
formulas, it is recognized that there are three stages of size change trends as the
overheat degree increases: mechanical breakup, transition, and fully flashing ([Fig. 6 ]).[25 ]
[35 ]
[36 ] In the fully flashing stage, a fully flashed point is reached, beyond which there
exists a cut-off value for the overheat degree. At this point, the reduction rate
of particle size decelerates, and eventually, a constant value is achieved.
Fig. 6 Three changing stages of MMAD with increasing overheat degree. MMAD, mass median
aerodynamic diameter.
In this study, output aerosols of the FJ prototype at 20 to 40°C overheat degree belong
to the transition stage, while the 50°C output belongs to the fully flashing stage
([Fig. 3A ]). As the overheat degree increased, the proportion of large droplets in the APSD
rapidly decreased and almost disappeared at the fully flashing stage ([Fig. 3C ]). The disappearance of large droplets is the main cause of the MMAD reduction in
the transition stage.
At low overheat degrees, a normal distribution of fine droplet sizes is observed.
Following the increment of overheat degree, the proportion of the fine droplets is
increased because large droplets are further broken into small droplets. The median
of the fine droplet size is also decreased in this process. When the large droplets
are gone, this shift becomes the dominant factor in MMAD change, which corresponds
to the slow decline stage between the fully flashed and cut-off points (interval between
point B and C). Droplet shrinkage caused by evaporation is the main cause of the change.[30 ] Due to the liquid's latent heat of vaporization approximately three orders of magnitude
higher than the specific heat capacity, the residual heat after flashing breakup causes
a minor change in droplet diameter.
The limitation of the evaporation rate is a possible cause of the cut-off value of
MMAD (interval after point C). The humidity of the surrounding air of the aerosol
in this stage is probably saturated due to the evaporation that happens in the flashing
and large droplet breakup process. Hence, the evaporation rate is constrained to a
minimum value. No evaporation would happen until additional saturated moisture content
provided by the air convection is larger than the evaporation rate of the flashing
process.
Effect of Jetting Rate and Volume
When the jetting rate increases, the influence on the flashing jet embodies in the
increased jet speed and changes in pressure gradient within the orifice. A higher
jet speed strengthens the air disturbance on the liquid jet, which produces smaller
droplets after jet rupture.[40 ] This explains the shift of APSD at 50°C ([Fig. 5A ]). However, the turbulence rupture of liquid jet requires an extra jetting distance
for distribution development.[41 ] In the flashing jet atomization process, flashing happens before the air disturbance
is strong enough to influence the droplet production. In a low overheat degree, the
shift of APSD is also observed, but large droplets caused by low flashing strength
raised the MMAD ([Fig. 5A ]). Hence the effect of jetting rate on MMAD is weaker than the overheat degree.
The jetting rate is controlled by the advance rate of the pusher in the FJ prototype.
Therefore, the change in jetting volume has limited impact on the jetting rate and
atomization performance ([Fig. 5B ]). When the jetting rate is fixed, the jetting volume determines the spray duration
of the FJ prototype.
A longer spray duration can lower the requirement on patient cooperation skill and
improve the drug utilization for inhalers.[1 ] However, the prolonged duration can also reduce the inhalation administration effect
because the aerosol delivered before or after the inspiration will be wasted. The
duration of deep inspiration for healthy population is approximately 5 to 15 seconds,
while a normal inspiration is approximately 1 to 2 seconds. However, the actual inspiration
duration of a user is highly uncertain in clinical environments.[42 ]
[43 ]
[44 ]
An ideal spray duration should be able to complete the drug delivery within one inspiration.
In consideration of the deviation caused by user skills, the spray duration of 1.5
to 2.5 seconds may be suitable for one deep inspiration to balance the benefit between
the patient cooperation difficulty and delivery dosage loss.
When a high atomization volume is required, the spray duration can be controlled within
the 1.5 to 2.5 seconds and limited the impact on atomization performance by adjusting
the jetting rate at the FJ prototype. Consequently, there is a potential advantage
at the FJ prototype on poorly soluble drug atomization, in which a high solvent volume
is required to deliver adequate drug dosage.
Effect of Liquid Type
The MMAD of SAL is larger than that of NS at the FJ prototype. This change is directly
related to the increment in large droplet (> 5 μm) proportion in SAL ([Figs. 2 ] and [5C ]). The APSD change is probably caused by the rise of boiling point, which correspondingly
decreased the overheat degree while the overheat temperature was not changed. The
solution boiling point is related to its molality, and therefore, different overheat
temperatures are required to obtain the same overheat degree in different liquid prescriptions.
A lower proportion of large droplets in the APSD of VEN is observed in the FJ prototype
([Fig. 5C ]) compared with SAL. This observation is attributed to the decrease in surface tension
in VEN, which is caused by the presence of benzalkonium chloride in VEN prescription.
In the same overheat degree, a lower surface tension leads to lower MMAD, consistent
with other atomization mechanisms associated with liquid jets.[45 ]
[46 ]
[47 ]
Due to the presence of suspension, it is difficult to tell whether the fine particles
of APSD was measured from aerosol droplets or powder particles when the BUD and PUL
were used. At the current stage, it is certain that the absence of large particles
in [Fig. 5C ] is also a result of a lower surface tension, which can be attributed to the inclusion
of polysorbate 80 in the prescription of the PUL. Additionally, the significant difference
in MMAD between BUD and PUL at the FJ prototype can likely be attributed to the use
of micronized budesonide as the active ingredient in the PUL.
As a reference group, the APSD of VEN at the Pari nebulizer showed a normal distribution.
Measured MMAD is approximately 1 μm lower than reported results in other studies.[48 ]
[49 ]
[50 ] This bias is consistent with existing studies comparing the measured results between
APS, next-generation impactor (NGI), and Andersen cascade impactor (ACI).[39 ]
It is worth noting that the MMAD at the FJ prototype is smaller than the Pari nebulizer
when PUL is used. A possible explanation of this difference is the potential promoting
effect of suspended particles on flashing and droplet size reduction caused by evaporation.
Another possible reason is that the atomization performance of the FJ prototype is
less sensitive to the change of liquid viscosity. When stabilizing excipients in the
PUL significantly affect the aerosol output at the Pari nebulizer, minimal changes
are observed in the FJ prototype.
Device residual levels at the FJ prototype were higher than the Pari nebulizer. Adherence
droplets around the orifice were observed in the beginning and ending stage of jetting
at the FJ prototype. In the flashing process, these adherence droplets rapidly evaporated,
leading to residual drug accumulation around the orifice. However, no significant
difference of device residual level was found among the four atomization liquids at
the FJ prototype ([Table 1 ]), which indicates that liquid characteristics may have minimal impact on the device
residual level.
The orifice structure is considered as a potential critical feature that may affect
the device residual. On the one hand, the diameter, depth, and shape of the orifice
determine the jet characteristic,[51 ] which further affect the adherence activity around the orifice. On the other hand,
the outer surface shape around the orifice influences the evaporation and accumulation
activity around the orifice. An improved orifice design may further decrease the device
residual level of the FJ prototype. It is necessary to study the effects of orifice
structures on atomization performance in future studies.
Research Limitations
The NGI or ACI was not used in this study for measuring the MMAD and FPD, because
the NS was used throughout the study, which is not suitable for the impactor-based
measurement of MMAD. The APS/IIPR system was used because it can measure droplet size
without relying on HPLC, thus allowing for the measurement of NS aerosol.
It is important to note that the APS/IIPR is not widely accepted as a device for measuring
MMAD, and the measured MMAD serves as a reference value. Considering the Pari nebulizer
was used as the reference device, it is reasonable to conclude that the atomization
performance of the FJ prototype is comparable to the Pari nebulizer, when the design
of FJ prototype and the liquid prescription are further refined, the NGI or ACI would
be better options for the MMAD measurement.
The Pari nebulizer was used as a reference device due to several factors. First, the
Pari nebulizer produces an output of aqueous aerosol, which is similar to the output
of the FJ prototype. Additionally, the Pari nebulizer allows for easy interchangeability
of atomization liquids, making it a convenient choice for comparison. However, it
is worth noting that the nebulizer operates as a continuous atomization device, which
is different from the FJ prototype. In future studies, a more suitable option for
comparison would be the soft mist inhaler Respimat. This is because it also delivers
fine aqueous aerosol, and it shares similarities with the FJ prototype. Furthermore,
the low delivery dosage limitation of Respimat aligns with one of its main drawbacks,
whereas the FJ prototype potentially offers an advantage in high delivery doses.
The images of output aerosol at different temperatures ([Fig. 3A ]) were taken under normal laboratory conditions, the photographic environment was
not fully controlled. When capturing images of aqueous aerosol, slight changes in
camera settings and lightning conditions may significantly influence the image quality.
Ideally the high-speed cameras in a controlled darkroom environment with a controlled
near-end artificial light source should be used for image capture. The images presented
in [Fig. 3A ] can only be used for observing the phenomena rather than precise quantitative analysis.
Conclusion
In summary, the atomization performance of the FJ prototype is influenced by the overheat
degree, jetting rate, and jetting liquid type, while the changes of jetting volume
have a limited impact on aerosol output. The increase in overheat degree led to a
decrease in MMAD, attributed to the enhanced flashing strength. Similarly, an increase
in jetting rate resulted in a decrease in MMAD due to the increased air disturbance.
The variation in atomization performance with different liquid types may be attributed
to changes in boiling behavior.
For atomization liquids such as NS, VEN, and BUD, the FJ prototype can provide comparable
output aerosol with the Pari nebulizer. This suggests the feasibility of generating
aqueous aerosol for inhalation administration using the flashing jet method. Furthermore,
the FJ prototype shows potential for delivering high solvent volumes or high-concentration
suspensions in a single spray. Additionally, the flashing jet technique holds promise
for atomizing suspensions or poor soluble drugs.
