Quality Control and Specifications

To date, no monographs have been established for either HFA 227 or HFA 134a in the USA or Europe, so that the specifications are still supplier-related. This is expected to be the status for the next years, although working groups are forming, and a first USP proposal for an HFA 134a monograph has been published [39].

In the case of HFA 134a, two quality standards have already been published: one by the CPMP as mentioned before [1], and one proposed by the FDA in a draft guideline [5]; accordingly, the quality shall comply with these standards.

As seen from the table which lists all impurities mentioned in these standards, sophisticated analytical methods are required to identify and detect all impurities without interference from the others. Solvay has developed a GC-MS method especially for this purpose which allows the control of each of the listed impurities at limits of detection LODs) below 1 ppm (v/ v).

Comparison of the FDA draft proposal for impurity limits in pharmaceutical HFA 134a and CPMP specifications with the Solvay Solkane® 134a pharma quality from three pilot and six production batches (mean values)

The Solvay specifications for Solkane® 227 pharma and Solkane® 134a pharma are listed as follows:

ASHRAE Nomenclature

The American Society of Heating, Refrigerating, and Air Conditioning Engineers (ASHRAE) has created a standard for a Halocarbon Numbering System.

In the Halocarbon Numbering System, the first number gives the number of carbon atoms minus one, followed by (in order) the number of hydrogen atoms plus one and the number of fluorine atoms:

First number:
number of carbon atoms – 1

Second number:
number of hydrogen atoms + 1

Third number:
number of fluorine atoms

All remaining atoms are assumed to be chlorine atoms. An initial zero (indicating a onecarbon compound) is omitted.

For example: 1,1,1,2,3,3,3-heptafluoropropane (INN = apaflurane) has:
three carbon atoms (3–1=2),
one hydrogen atom (1+1=2),
seven fluorine atoms (7=7)
and no chlorine atoms therefore it is named as HFA 227.

When there are two (or more) carbon atoms present, isomers are possible, and these may have identical halocarbon numbers. To distinguish these isomers for ethane derivatives, a lower case letter is added based on the difference in the sum of the atomic masses of the carbon substituents. The designation for the isomer with the smallest difference in the sum of the masses on the two carbon atoms has no letter; the designation corresponding to the next smallest difference has an “a”, the next “b”, etc. Some examples are given below for the isomers of tetrafluoroethane (INN = norflurane).

HFA 134 CHF₂-CHF₂

HFA 134a CH₂ F-CF₃

The Halocarbon Numbering System for linear three-carbon compounds (propane) is similar to that for two-carbon compounds; however, two letters are required to specify the isomer. The first letter refers to the central methylene) carbon atom of the propane. To assign this letter, one calculates the combined atomic mass of the substituents on this carbon atom in the parent compound containing only H, F and/or Cl). The letter “a” represents the largest mass possible, the letter “b” the next largest, etc.

For example:
CF₃ – CHF – CF₃ = HFA 227ea
CF₂H – CF₂ – CF₃ = HFA 227ca

Physical Properties

Nomenclature

Description

Physical Data [SI Units]

Thermal Stability

Refractive Index

Physical Data [US/UK Units]

Thermal Stability

Refractive Index

Vapour Table Wet Vapour Range Solkane® 227 pharma[11] [SI Units]

Density in g/l

Fig. 14: Density of liquid of Solkane® 227 pharma and Solkane® 134a pharma [11] including a 50:50 blend depending on temperature in comparison to CFC blends (CFC 11/12 as 40:60 and CFC 11/12/114 as 18:22:60) [16]

Vapour Table Wet Vapour Range Solkane® 134a pharma[11] [SI Units]

Vapour Pressure in bar

Fig. 15: Vapour pressure of Solkane® 227 pharma and Solkane® 134a pharma [11] including a 50:50 blend depending on temperature in comparison to CFC blends (CFC 11/12 as 40:60 and CFC 11/12/114 as 18:22:60) [16]

Vapour Table Wet Vapour Range Solkane® 227 pharma[11] [US/UK Units]

Density in lb/ft3

Fig. 16: Density of liquid Solkane® 227 pharma and Solkane® 134a pharma [11] including a 50:50 blend depending on temperature in comparison to CFC blends (CFC 11/12 as 40:60 and CFC 11/12/114 as 18:22:60) [16]

Vapour Table Wet Vapour Range Solkane® 134a pharma[11] [US/UK Units]

Vapour Pressure in psia

Fig. 17: Vapour pressure of Solkane® 227 pharma and Solkane® 134a pharma [11] including a 50:50 blend depending on temperature in comparison to CFC blends (CFC 11/12 as 40:60 and CFC11/12/114 as 18:22:60) [16]

Viscosity in mPa·s

Fig. 18: Dynamic viscosity of liquid Solkane® 227 pharma and Solkane® 134a pharma depending on temperature [11]

Surface Tension in mN/m2

Fig. 19: Surface tension of Solkane® 227 pharma and Solkane® 134a pharma depending on temperature [11]

Solubility Parameters/Characteristics

Solubility Values

Solubility Characteristics

Solubility of Water

There is a notable difference in water solubility between HFA 227 and HFA 134a. As shown in Fig. 21, the moisture uptake of HFA 134a is six times higher compared to HFA 227 (measured values) due to its higher polarity. Therefore HFA 227 is preferred for formulations which might change due to water uptake during the MDI shelf life, e.g. for drugs such as sodium cromoglycate, cromoglycic acid, nedocromil sodium, nedocromil, ipratropium bromide, salbutamol sulfate, terbutaline hemisulfate or formoterol. In general, the HFAs are more polar than CFCs and thus more hygroscopic.

Dipole Moments^[16]

Water Solubility in HFA 134a

Fig. 20: Illustration of the experimental results for water solubility in HFA 134a in liquid phase ^{[20, 21]}

Moisture Uptake

Sources of Moisture Uptake in MDIs:

Due to partial pressure differences inside and outside of the MDI, moisture uptake takes place by diffusion.

Possible Effects of Moisture Uptake:

• Improves solubility of polar substances in the propellants
• Reduces the solubility of lipophile, hydrophobic substances
• Increases probability that sensitive substances become oxidised during shelf live
• Increases the corrosion risk of aluminium cans over the shelf life
• Agglomeration of suspended drug substances
• Influences the discharge behaviour of the active substances

Solubility of Oxygen and Nitrogen

Solubility of Nitrogen in HFA 134a

Solubility of Oxygen

During the manufacture of MDIs (metered dose inhalers), organic molecules (for example active substances e.g. sodium cromoglycate), tensides (e.g. oleic acid) and solubilisers e.g. ethanol) are suspended or solubilised in HFA 227 and/or HFA 134a. Because organic molecules can be oxidised by oxygen, it is important for the manufacture of MDIs to know the solubility of oxygen in the propellant being used (such as Solkane® 227 pharma and Solkane® 134a pharma).		Gases like oxygen and nitrogen always form equilibria with pressurised liquefied gases in the gas phase and the liquid phase. These equilibria depend on temperature, filling factor and total pressure. Therefore, the figures show precisely determined values but only for one temperature, one filling factor and a specific amount of gas. The most important result is that there is a big difference between the oxygen and nitrogen content in the gas phase compared to the liquid phase.

Fig. 23/24: Typical content of oxygen and nitrogen in Solkane® 227 pharma and Solkane® 134a pharma

Influence of Ethanol on HFA227 and HFA 134a

Ethanol is widely used as an exipient in pharmaceutical formulations for MDIs because of its miscibility with the HFA propellant and the positive influence on the solubility of organic molecules due to the higher polarity. The addition of ethanol increases the polar/hydrophobic characteristics of a formulation.

The addition of ethanol also increases the moisture uptake capacity of the MDI formulation. Furthermore, in the case of HFA 134a the addition of ethanol slightly reduces the pressure of the propellant. Adding ethanol to a formulation also reduces the density of the mixture.

The pressure versus mixture curves (Fig. 25) were derived from measured data (Hoechst 90/91).

Chemical Behaviour

Material Compatibility

The material compatibility is tested to determine the specifications for materials suitable for the manufacture of pharmaceutical aerosols (e.g. composition of seals, metering chambers, gaskets, seats or stems).

Aspects analysed include changes in weight, volume, length, width, shore hardness, appearance (e.g. bubble formation), permeability of water and amount of extractables.

Classification of Materials for Use in MDIs

(1) Strong swelling behaviour and presence of bubbles
(2) Permeability of water
(3) Bubble formation on material surface
(4) Strong swelling
(5) Recommended in the absence of mineral oil or alkyl benzene
(6) If technical specification designs allow, e.g. PTFE used in connection with metal joints

	Fig. 27: Extractables from plastics: 1.) Polyethylene (PE), 2.) Polyamide 6.6 (PA), 3.) Polyacetal (POM), 4.) Poly(butylene terephthalate) (PBT), and 5.) Polypropylene (PP) after immersion in HFA 227/5 wt % EtOH and HFA 134a/5 wt % EtOH for 500 h at 80°C; Polytetrafluoroethylene (PTFE) produced zero extractables
	Fig. 28: Extractables from elastomers 7.) Acrylonitrile-butadiene rubber (NBR), 8.) Ethylene-propylene-diene rubber (EPDM) and 9.) Chloroprene rubber (CR) after immersion in HFA 227/5 wt% EtOH and HFA 134a/5 wt % EtOH for 500 h at 80°C

Evaluation Criteria for Material Compatibility

There is a large range of elastomers and plastics on the market with different trade names which are made of similar raw materials and which are only distinguished by certain additives. These additives may affect the thermal and mechanical stability, the swelling properties, as well as the resistance to aging of elastomers and plastics.

When assessing complete systems, it is necessary to include the compability characteristics of the drug formulation.