Liquid resistivity of pharmaceutical propellants using novel resistivity cell – Scientific Reports

The resistivity of pure propellants

The electrical resistivity was determined for three of the most widely used substitutes for CFC and HCFC propellants. After the DC voltage was applied, the recorded current decreased after an initial spike due to polarization effects. Transient charge-carrier drift processes occur due to ions being attracted to or repelled from electrodes based on their polarity. Figure 3A–C show the recorded current plotted as a function of time in the case of each propellant for a set temperature (~ 20 °C). The first peak occurs after a few ms when the charge carriers in the dielectric liquid migrate from one electrode to the other. This duration is known as the time of flight (ToF).

Our tests have shown that stable measurement values could be taken after 10 min and that extended stress does not lead to significant further change. The tests are labelled by the order in which they were performed. It can be seen that the current values measured tend to decrease slightly as the order of the tests increases. This may be because the cell gets flushed with each test with the propellant, and some impurities get removed, leading to measured smaller current values. The measurements were repeated at least five times. Similar diagrams are observed for each of the propellants. The graphs tended to peak with a few hundred nA, with R134a tests peaking at higher currents when the voltage source was switched on at around 2000 nA before stabilising at approximately 50 nA. The 134a tests peaking at higher current values may be because these tests were conducted earlier than the other propellants; therefore, contaminant concentrations may have been slightly higher before being flushed after repeated trials. Initial tests for each propellant tended to peak much higher and settle at slightly higher current values after 10 min. It may be wise to repeat the tests more times until the readings stabilise and discard initial test results due to contaminant fears to attain more reliable results.

The ToF, is determined from the time interval between when the voltage is applied first to the moment of the peak current. The value obtained for all three pure propellants is 1 ms, limited by the time resolution of the current measurement. The charge carrier mobility is then calculated as (mu = frac{{L^{2} }}{ToF cdot V} = frac{{2;{text{mm}}^{2} }}{{1;{text{ms}} cdot 100;{text{V}}}} = 4 cdot 10^{ – 5} frac{{{text{m}}^{{2}} }}{{{text{Vs}}}}). And the drift velocity of the pure propellants is (v = mu cdot E = 2frac{{text{m}}}{{text{s}}}), with a significant uncertainty of at least 50%.

Resistivity for different measuring intervals

Figure 3A–D shows the differences between the resistivity values for different measuring times and various types of propellants. It can be seen that the resistivity for the 10-min values tends to be significantly greater than the one-hour values; this is due to the number of charged particles increasing thereby leading to a downward drift in resistivity. The likeliest mechanism for this is the fate of the charge carriers produced early in the reading is not to disappear once discharged, but to leave some residual fragments that can add to the pool of potential charge carriers, so that the pool of charge carriers keeps increasing with time in the run. This was, however, not the case for the 152a propellant, which demonstrated the opposite relationship, with the 1-h average value for resistivity being slightly larger. Here additional charge carriers are not being created after the original one’s discharge at the electrodes. Instead, the pool of carriers remains roughly constant, with a slight reduction through the run leading to slightly rising resistivity. This could be accounted for by either the carriers surviving discharge to ‘go around and do it again’ as a semi-stable population (i.e. an initial positively charged carrier goes to the cathode, and pick up two electrons thus becoming a negatively charged carrier, goes to the anode, loses two and so on) or being discharged and lost from the carrier population to be replenished by an ionisation process (e.g. the ionisation of water) maintaining a pseudo-constant population.

The 227ea and 134a were found to have a resistivity at least one order of magnitude higher than 152a. This is expected to result from the chemical structure of 152a being C2H4F2 (shown in Fig. 4) where there is a strong attraction between water molecules and the two fluorine atoms due to the high electronegativity of fluorine. When C2H4F2 interacts with water, the highly electronegative fluorine atoms attract the partial positive charges on the hydrogen atoms of water molecules, leading to strong dipole–dipole interactions. This makes the 152a much more susceptible to water contamination.

Figure 4
figure 4

Spatial configuration of R152a, also known as 1,1-Difluoroethane.

The tests were repeated at least three times due to the limited number of samples available. The resulting values of the resistivity for pure R134a, R227ea, and R152a, defined as the mean of the 10-min interval measurements, are (3.02 ± 0.18) ∙ 1010 Ωm, (1.31 ± 0.08) ∙ 1010 Ωm, and (2.37 ± 0.4) ∙ 109 Ωm, respectively. The uncertainties quoted are the standard deviations from the set of measurements taken.

Several small instrumental uncertainties limit the measurement. There is a 0.2% uncertainty in the current measured by the electrometer; the cell constant has an assumed uncertainty of 0.5%; and the applied voltage value has an uncertainty of 1%. Using Gaussian error propagation, the resistivity has a total instrumental uncertainty of about 1.1%. This is smaller than the standard deviations quoted above; the measurement is, therefore not dominated by instrumental uncertainties.

Comparison of measured resistivity to other published results

Table 2 compares the results to data from other published literature. Feja9 analysed liquid R134a at varying temperatures. His results indicate that the resistivity of R134a is temperature-independent and in the order of 108 Ωm. However, our measured values are on the order of 1010 Ωm for ambient temperatures and saturation pressures for liquid phase measurements. A similar trend is observed when comparing the results to those obtained by Fellows et al.8. The measurements for R152a, which were performed to serve as a reference, correspond well to existing data. However, the measured value of the DC resistivity for R134a is about a factor of 45 higher.

Table 2 The measured resistivity values [Ohm m] obtained from the 10-min intervals, compared to values quoted in other literature.

As the resistivity is highly dependent on the water content and other impurities of the tested substance and the value of the applied field strength, such deviations are not unusual. The maximum water content present in our propellants, according to the manufacturer’s specifications, is about 10 ppm. As described above, the measurement’s uncertainties are assumed to contribute further to the detected deviations.

Maintaining the quality of the test fluid sample is very important because its electrical properties are susceptible to contamination and impurities. This is one of the reasons why it is very hard to compare measurements from various researchers because of differences in the purity level of the test fluid sample. Also, comparing properties between researchers can be difficult because the temperature and pressure are not always given.

There are several reasons for these significant discrepancies; one is possible impurities. Water content, for example, strongly influences the resistivity; the resistivity decreases when water is added. This study prepared the samples very carefully to minimise moisture contamination. Also, before the propellants were inserted into the cell, the transfer was handled with additional precautions: a heat gun was used on the transfer cylinder, and its nuts were loosened to evaporate and flush out any residual moisture. Moreover, no plastic pipes were used as all these HFAs are considered highly hygroscopic and can even make plastic parts more likely to introduce water via diffusion phenomena. The maximum water content present in our propellants, according to the manufacturer’s specifications, is at most 10 ppm.

The resistivity also tends to be a strong function of the electric field. Lower test voltages can be another reason for higher resistivity measurements compared to previous researchers. But in this measurement, applying voltages above 100 V was impossible due to spacing between anode and cathode (2-mm) to avoid dielectric breakdown.

Additionally, there are differences in the experimental setup. Feja9 used a modified cell arrangement according to IEC 60247 without guard ring. The absence of a guard ring forced him to calibrate the test cell with a well-known liquid in advance.

To summarise, several factors make comparisons to other experiments difficult: the purity level of the test fluid sample directly influences electrical properties, but temperature, pressure, and applied voltage values also have an impact. The improved and custom-designed cell used for this measurement is also likely to contribute to a more accurate result than the literature.

The resistivity of mixtures of propellants with water or ethanol

Fellows et al.8 and Feja9 studied the DC resistivity of pure R134a and R152a. However, this study presents further information regarding the resistivity of mixtures of propellants with moisture and ethanol.

Figure 5 shows the resistivity values for the 152a and 134a propellants with different water concentrations (134a: 46, 174, 250, 500 ppm; 152a: 50, 277, 448, 896 ppm). Moisture content will ionise in the electrical field, meaning the water molecules undergo electrolysis and split into hydrogen ions H+ and hydroxide OH. The hydrogen ions react with the water molecules at a low rate, forming hydronium ions, H3O+. These charge carriers reduce the resistivity and will then respond with the electrons from the cathode and anode, forming dihydrogen H2 and water H2O and oxygen O2.

Figure 5
figure 5

Graphs showing the resistivity values of 134a and 152a propellant mixtures with different concentrations of water: (A) 134a + water, (B) line graph of 134a + water, (C) 152a + water, and (D) line graph of 152a + water. The average room temperature for the set of measurements with R134a was 23.6 °C, and the average room humidity was 39.7%. For the measurements taken with 152a, the average room temperature was 27.6 °C, and the average room humidity was 42%.

The values for 134a water concentrations can be seen to decrease exponentially in resistivity with increasing water concentrations before levelling off at 500 ppm of moisture. There is an initial significant decline in resistivity between the pure propellant and the addition of 46 ppm of moisture, resulting in order of magnitude decrease in resistivity. The graph for 152a and moisture shows a similar pattern with similar resistivity values for the different moisture concentrations, where the concentration of 900 ppm of moisture showed a resistivity value that had plateaued relative to the 500 ppm value. This plateau shows that added water concentrations may no longer significantly affect the resistivity of the mixture. This may be due to added water concentrations that cause the resistivity to approach the value for water.

As has already been observed in Fig. 5, 134a has about an order of magnitude higher resistivity than 152a, even at similar water concentration levels. This is understood to be related to the different ionic mobility. The dipole moments of the propellants are 2.06 Cm for 134a and 2.26 Cm for 152a, which means that 152a is a more powerful dipole.

The HFC molecules cluster around the charged ions, but for 152a the ionic solvated cluster is smaller than that for 134a. This means that drag against the rest of the liquid medium as the ion moves in the cell field will be less, and the ionic velocity will be higher, leading to a higher cell current and lower resistivity for 152a.

Figure 6 shows the resistivity values for the 152a and 134a propellants with different ethanol concentrations. Trace moisture can influence these studies, but due to the precautions taken, the moisture concentration is less than 10 ppm and, therefore, will have a negligible impact compared to the dominant effect of ethanol. It is expected that ethanol will be ionised in the electrical field via the reaction24:

$${text{CH}}_{{3}} {text{CH}}_{{2}} {text{OH}} to {text{CH}}_{{3}} {text{CH}}_{{2}} {text{O}}^{ – } + {text{ H}}^{ + }$$

and the hydrogen ion then instantly associates with non-ionised ethanol via:

$${text{H}}^{ + } + {text{ CH}}_{{3}} {text{CH}}_{{2}} {text{OH}} to {text{CH}}_{{3}} {text{CH}}_{{2}} {text{OH}}_{{2}}^{ + }$$

Figure 6
figure 6

Graphs showing the resistivity values of 134a and 152a propellant mixtures with different concentrations of ethanol: (A) 134a + ethanol, (B) line graph of 134a + ethanol, (C) 152a + ethanol, and (D) line graph of 152a + ethanol. The average room temperature for the set of measurements with R134a was 24.5 °C, and the average room humidity was 40.3%. For the measurements taken with 152a, the average room temperature was 25.4 °C and the average room humidity was 47%.

The two ions CH3CH2OH2+ and CH3CH2O will lower the energy of the carried charge by virtue of the larger molecule, providing a considerable redistribution of the charge by polarising the bonds within the molecule. Ethanol charge dissipation is more potent than HFC solvation, meaning at low ethanol concentrations (less than 1%), the ions are surrounded by a much smaller HFC solvent cage, which is also more tenuously attached. But when ethanol concentration rises, a ‘hybrid’ solvation is formed, where both HFC and neutral ethanol molecules make up the solvation cage.

As displayed in Fig. 6, the resistivity drops with an increasingly large ethanol concentration. However, the resistivity plateaus at a concentration of approximately 4% and then slowly rises again. At ethanol levels below 4%, there is an increase in charge carriers, a slight decrease in cage sizes, and less drag on the HFA carrier medium, leading to an increase in current and a reduction in resistivity.

An explanation for the plateau and subsequent rise of resistivity for larger ethanol concentrations can be found by assuming that the rate at which negative ethanol ions are created slows down and is no longer proportional to the ethanol concentration.

Instead, hydrogen bonding will occur with an increased presence of ethanol molecules, both for neutral ethanol molecules and for ethanol ions. Hydrogen bonding25 is a weak form of coupling between polar molecules; in this case, the partially negatively charged oxygen ion will bond with the partially positively charged hydrogen ion of another ethanol molecule. Hydrogen bonding is enhanced for the negatively charged ethanol ion CH3CH2O because the oxygen carries an even larger partial negative charge.

Consequently, larger clusters of charge carriers and a larger solvent cage are formed, and their ionic mobility and drift velocity drop; hence, this new dynamic state increases the resistivity of the propellant mixture. Further studies with varying temperatures and larger sample sizes should be conducted to more precisely estimate the concentration at which the plateau and turn-around effects occur.

The ToF for the mixtures was estimated as previously for the pure propellants by determining the time interval between when the voltage was switched on and when the peak current occurred. The current as a function of time was measured at least three times for each concentration value. However, the result is again limited by the time resolution of the measurement and was therefore again determined as 1 ms, leading to the same drift velocities of (v = 2frac{{text{m}}}{{text{s}}}) with a considerable uncertainty of at least 50%.

In Fig. 7, the measured resistivity graphs as a function of either the water or the ethanol concentration are superimposed for propellants 134a and 152a, indicating a similar behaviour for both materials.

Figure 7
figure 7

Graphs showing the change in resistivity for two different propellant mixtures with (A) different concentrations of water and (B) ethanol.

Knowing precisely how moisture and ethanol content influence resistivity can help improve medical inhaler formulations and increase their effectiveness. The resistivity of the propellant used in MDIs must be controlled and maintained at a fixed value; otherwise, an electrical charge will accumulate, which will prevent the uniform dissipation of the drug aerosol and limit the deposition of the pharmaceutical in the human lungs. More studies are needed to quantify the dependence of the electrical properties of propellants on a variety of conditions, for example, different temperatures and air humidity levels.

Furthermore, the studies performed with 152a are crucial to assessing its potential to be used as a propellant in MDIs, replacing 134a and 227ea in the future. The risk of being ignited during charge accumulation must be minimised, and therefore the resistivity properties of the pure substance and in mixture with water and ethanol have been extensively investigated. The sample provided by the sponsoring pharmaceutical company and we have no control over the range for extension. That is the reason the values for the range are different.