Clean elastomers for pharmaceutical device applications

Clean elastomers for pharmaceutical device applications

Introduction

This article provides a synopsis of the paper to be presented on new elastomer

developments for drug delivery devices at the Medical Plastics 2005 European Seminar

and Conference this November. The presentation by Bespak’s Senior Scientist Daljit

Ohbi, will discuss the characteristics and benefits of using elastomers for sealing

applications in drug delivery devices and will showcase the range of proprietary elastomer

compositions developed by Bespak for use in their customer’s pressurised Metered

Dose Inhaler (pMDI) products.

The demand from worldwide regulatory authorities to ensure that drug delivery devices

are safe, reliable and effective in their performance throughout life continues to increase.

Manufacturers must ensure that the materials used in the production of their

pharmaceutical partners’ devices are appropriate for the desired application. The

penalties associated with a reduction in performance, functionality or safety can be

significant, even to the extent of product recall and consequentially substantial financial

penalties.

Various regulatory bodies such as the FDA and ISO 10993-1 – Biological Evaluation of

Medical Devices, provide guidelines on the materials and their assessment for use in

devices such as midi’s. The device is constructed using medical grade plastic materials.

These grades are made from less toxic catalysts and antioxidants and their molecular

constituents controlled in the polymerisation process by the polymer manufacturers.

Typical plastics used in midi’s are PBT (polybutylene- terphthatlate), Nylon and POM

(polyoxymethylene). In the liquid pulmonary devices, HFA propellants such as 134a

(hexa----) and 224 (hexaf--) in mixtures with the drug formulations are used. At ambient

conditions the device pressure is in the region of 5 bars. The device has to deliver

accurate shot weights of medication and must have effective sealing to prevent loss of

propellant and ingress of moisture.

For the sealing application elastomers are used. In medical devices the selected

elastomer composition for sealing is determined both by device performance and the

cleanliness of the elastomer composition.

Elastomers have stable compression recovery characteristics and withstand external

influences such as pressure and temperature, making them ideal for sealing applications.

They are long chain, high molecular weight polymers and are essentially super

condensed gases since their precursor monomers are gaseous. They are amorphous

and have a random coiled long chain molecular configuration. To develop rubbery

engineering properties, various inorganic fillers and organic additives such as crosslinking

agents are mixed with them. The compositions are vulcanised to develop rubbery

properties. Vulcanisation is a thermo chemical reaction during which the long molecular

chains are cross-linked and the elastomeric properties become stable to the effects of

temperature and pressure.

Elastomer Compositions

Elastomers form ideal sealing materials from basic engineering principles. In their

crosslinked state they are elastic and show stress recovery characteristics. They require

smaller deformation forces and in comparison to steel the equivalent strains in rubbers are

10-5 times the value for steel. Elastomers also exhibit very low volume change when

subjected to compressive forces. They have a Poison ratio of 0.499 compared to 0.3 for

steel. The types of base elastomers used in pharmaceutical elastomer sealing

compositions are EPDM (terpolymer: ethylidene norbornene); Butyl, Chlorobutyl and

Bromobutyl; Nitrile and Polychloroprene.

Elastomers are polymers and their constituent monomers such as ethylene, propylene,

isobutylene, butadiene are gaseous and thus in various publications described as super

condensed gases. They are amorphous materials, having low crystallinity and in

comparison to crystalline thermoplastics are more amenable to permeation of gases and

fluids and soften by heat. They have low tensile and compressive strength in comparison

to semi crystalline plastics. In order to convert these elastomers into useful rubbery

materials additives are mixed with them. The additives include inorganic fillers such as clay

and talc and are used to reinforce and stiffen the elastomers. Processing aids are required

for mixing of the fillers; these are low organic molecular weight additives mainly fatty acid

based species and help incorporation of polar inorganic fillers into non-polar elastomers.

Organic additives that function as cross-linking agents are also added to these materials to

enhance their stability at higher temperatures.

There are a number of combination factors for elastomer and their additive selection for

sealing materials for medical devices:

¬ Service temperature and length of service requirements

¬ Environmental and chemical resistance

¬ Engineering/design requirements

¬ Permeability to gases and fluids

¬ Processability

¬ Toxicity

¬ Low leachable species.

The elastomer must be compatible with the environment it is exposed to. It must not be

swollen or degraded by the chemicals it is exposed to. It must not swell, degrade and

leach out chemical species so as to contaminate the medicament. In midi’s the elastomer

is exposed to HFA and ethanol and must have low permeability to ingress of moisture and

maintain uniform elastic properties throughout the life of the device.

Filler dispersion

For the elastomer to have consistent mechanical and sealing properties, a uniform

additive and filler dispersion and distribution within the elastomer matrix is necessary. The

uniform filler dispersion also enhances filler- elastomer interactions especially in

compositions where the filler is coated with a coupling agent. Good dispersion of

accelerators promotes uniform cross-linking in the elastomer composition. Filler and

additive dispersion is facilitated by the incorporation of processing or dispersion aids.

These are low molecular weight organic compounds based on fatty acids and low

molecular weight olefin polymers such as polyethylene. These additives do not form part

of the crosslinked network and may diffuse out to the surface and therefore are potential

leachables and contaminants for medicaments. In medical devices the leachable content

has to be kept very low, consequently the use of these materials must be avoided. This

poses challenges in the mixing process, since without the processing aids lengthy mixing

time and heat generation by shearing is detrimental to the elastomer composition. The

accelerators are heat sensitive and premature cross-linking also known as scorching can

occur. This will lead to poor flow of the material during the moulding of components.

Dispersion of additives and fillers can be obtained by designing and control of the mixing

parameters. The mixing cycle has to be long enough to distribute and disperse the

additives in the formulation, otherwise agglomerates of filler are formed and these can

dislodge in the medical container or form potential weak sites for rupture and premature

failing of the seal.

Bespak, a leading designer, developer and manufacturer of specialty medical devices has

developed a range of proprietary elastomer compositions for dispensing asthmatic

medications. In 2005 Bespak commissioned a state-of-the-art elastomer mixing and

moulding plant to produce clean elastomer compositions. The Bespak elastomer

compositions are based on EPDM, Butyl, polychloroprene, and nitrile polymers. The

compositions have been designed for uniformity of filler and additive dispersion, long

ageing resistance to maintain stable properties through the life of the drug delivery

device. The satisfactory device performance in terms of low leakage and drug delivery

shot weight has been determined at ambient and elevated temperatures. The potential

leachable species from the compositions have been characterised qualitatively and

quantitatively by analysing acetone extracts by gas chromatography and mass

spectroscopy. A toxicity assessment on the identified species has been carried out. The

elastomer compositions have also been tested and meet the USP requirements for

Pressurised Metered Dose Inhalers (pMDI’s).

Conclusion

Elastomers form ideal sealing materials, however not all are suitable for medical devices.

Their elastomer compositions contain base elastomer and a variety of organic additives

and fillers that are necessary either for cross-linking, stabilisation or as processing aids.

During their mixing cross-contamination from other materials can also occur. There are

thus many potential chemical species that can migrate out and be a source of

contaminants for medicaments.

For medical device applications elastomers that contain low level residues of polymerising

catalyst are selected. The level of elastomer additives is minimised and dedicated mixing

equipment used for their production. This helps in avoiding cross-contamination form

other materials.

Elastomer mix cycles should be carefully designed to be long enough to disperse fillers

and additives but also that they do not cause premature cross-linking of the elastomers.

Bespak is commissioning an Elastomer Plant for the mixing and moulding of medical

elastomers. It has developed proprietary elastomers formulations based on EPDM, Butyl,

Nitrile and polychloroprene. The formulations have low leachables and have been

assessed for safe use in pulmonary medical devices.

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