Next-Generation Propellants for pMDIs: Seal Material Challenges and Sustainable Alternatives to P-134a

Pressurized metered dose inhalers (pMDI’s) have long been a safe and effective means of delivering inhaled pharmaceuticals for the treatment of asthma and other respiratory ailments.  MDI’s were originally developed to use the propellant P-12, dichlorodifluoromethane.  However, with the recognition that CFC propellants were a significant contributor to the depletion of ozone in the upper atmosphere, the use of P-12 was phased out, being replaced with 1,1,1,2-tetrafluoroethane, also known as P-134a.

The industry is now looking to make another wholesale change to the propellants used in metered dose inhalers for a number of reasons.  First and foremost, P-134a has a relatively high Global Warming Potential (GWP) of 1,300.   While the amount of propellant released over the life of a metered dose inhaler is quite small compared to that present in a refrigeration system or a non-medicinal aerosol, the number of inhalers used globally over the course of year result in a meaningful amount of propellant entering the atmosphere.  In addition, P-134a meets the technical definition of perfluorinated alkyl substance (PFAS) due to the presence of carbon atom bonded to three fluorine atoms.  With the regulatory attention being given to all such substances, it may be time for the industry to move away from P-134a.

Leading candidates for next-generation propellants

The two leading candidates for a next-generation propellant appear to be difluoroethane (P-152a) and trans-1,3,3,3-tetrafluoropropene (P-1234ze.)  Both propellants have pros and cons to consider when replacing P-134a, and these impact seal material selection when sealing the different propellants.

P-1234e

P-1234ze has many things going for it, but it’s certainly not perfect.  In terms of seal material compatibility, extensive testing has already been done with its nearly identical twin, R-1234yf.  The automotive industry has already made the switch in mobile air conditioning from R-134a to R-1234yf.  The ethylene-propylene (EPDM) and acrylonitrile-butadiene (NBR and HNBR) seal materials that have been used for years in R-134a applications function just as well in R-1234yf.  It is not a leap to expect the same similarity of performance with the EPDM and NBR seal materials that have long been used in pMDI’s.  Because it is a larger molecule than P-134a, P-1234ze also exhibits less permeation through seal materials over time.  P-1234 also has zero ozone depletion potential and a GWP of less than 1 (less than carbon dioxide.)  However, it is designed to decompose in the environment, and one of the potential decomposition products has a GWP of almost 15,000.  Another decomposition product is trifluoroacetate, which can contaminate ground water and is very difficult to remove once dissolved.  Even though P-1234ze is technically an olefin, meaning it has at least one carbon-carbon double bond, and not an alkane, it is still classified as a perfluorinated alkyl substance (PFAS) under some regulations.

P-152a faces other challenges

In addition to being extremely flammable, it is also an intoxicant.  While the exposure from proper use of a pMDI is well below the published toxicity levels, there have been documented fatalities related to intentional abuse.  The GWP of P-152a is reasonably low 124, and it is not classified as a PFAS, so it is unlikely to be impacted by PFAS legislation.  From a seal compatibility standpoint, P-152a is noticeably more able to permeate through most seal materials than P-134a.  With EPDM, permeation loss over long periods of time could impact the shelf life of an assembled pMDI.  Parker’s existing pMDI EPDM and NBR materials may still be acceptable in a P-152 pMDI application, but this gradual loss of propellant should be evaluated for a particular application. 

Parker is developing materials for P152a

Parker is also developing a next-generation low permeation material specifically for P-152a pMDI’s based on butyl rubber technology.  Butyl rubber is well-known for having extremely low permeation with small gaseous molecules, and compatibility with other substances is very similar to that of EPDM.  Mechanically, butyl rubber behaves much differently than EPDM and NBR.  In addition to low permeation, Parker’s development work focuses on minimizing the extractible content from the finished rubber material, and specifically the elimination of potentially toxic byproducts of the cure reaction, as well as the elimination of pigments.

For more information on Parker’s drug delivery devices visit us online or contact us directly at oesmailbox@parker.com (859-335-5101).