The aerosol challenge

Patient safety remains the number one priority when it comes to drug delivery and that includes the production of a non-CFC aerosol. DuPont has produced a number of CFC alternatives in the search for the perfect pharmaceutical propellant.

	Dymel 134a has similar properties to CFC-12, which comprised 65% of the total CFC market.

The road to producing a safe and acceptable pharmaceutical aerosol has been long and challenging. In 1989, the Montreal Protocol, an international treaty designed to protect the ozone layer, called for the phase-out of chlorofluorocarbons (CFCs). Among CFC applications were pharmaceutical aerosols using CFC propellants to deliver drugs via the lungs with metered dose inhalers (MDIs).

Replacing old propellants
Alternatives to CFCpropellants must satisfy many criteria in addition to environmental acceptability. The primary issue is patient safety. Changing propellants impacts the complete aerosol package and painstaking effort is required to assure that performance will be as good as or better than the proven products currently in use. Most importantly, physical properties of the propellants must allow workable formulations within the available technology.

The primary alternative propellants to replace CFCs in pharmaceutical aerosols are hydrofluoroalkane HFA-134a (1,1,1,2- tetrafluoroethane) and HFA-227ea (1,1,1,2,3,3,3- heptafluoropropane). DuPont™ Dymel® 134a/P (HFA-134a) resembles CFC- 12, the most widely used pharmaceutical aerosol propellant, which comprised about 65% of the total CFC market for the MDI application. Dymel 134a/P is thermally and hydrolytically stable, and inert towards conventional solvents and active ingredients. DuPont™ Dymel 227ea/P (HFA-227ea) has a lower vapour pressure than Dymel 134a/P, and so can be used in MDIs to lower the pressure of Dymel 134a/P formulations, much the way CFCs 11 and 114 were used to lower the pressure of CFC-12 formulations. Dymel 227ea/P has similar properties to Dymel 134a/P, but tends to be more expensive because it is more fluorinated.

Pharmaceutical manufacturers have been working diligently to develop products using these alternatives and have, so far, spent over $1 billion in reformulating MDIs to HFA propellants. The first HFAbased MDI was introduced in 1995, and progress with investment since then has been significant and steady toward phase-out of all CFCcontaining products.

In reformulating to HFA propellants, one of the opportunities is blending propellants, similar to what was done with CFCs. This technique provides more options in customising propellant properties to better match the formulation. Dymel 134a/P and Dymel 227ea/P are completely compatible and miscible with each other, and thus allow optimising desired properties by blending the two.

Blending for suspensions
In a suspension MDI, the drug is relatively insoluble in the propellant and so drug particles are maintained as a slurry inside the can. While the drug substance is usually more chemically stable in the solid state than when dissolved, there are still complex dispersion- and device-related challenges in formulating a stable microcrystalline suspension MDI. In many cases, the surfactants that are permissible for inhalation drug formulation are better suited to the interfacial chemistry of CFC products and there is a lengthy road to approval of new surfactants. The formulator’s task can be constrained to the standard MDI surfactants.

In these cases, the propellant can play a beneficial role via a technique called density balancing. Since the propellant in most cases is the liquid medium in which the drug is dispersed, adjusting the density of the propellant to better match the bulk density of the drug can help maintain a stable dispersion. Density balancing is accomplished by blending propellants, and blending Dymel 134a/P and Dymel 227ea/P provides a range of density options that can assist suspension formulations.