Impact of elastomer extractables in pharmaceutical stoppers and seals--material supplier perspectives.
Elastomers have long been adopted for pharmaceutical packaging to preserve drugs and medicines. In the early days, natural rubber was the material of choice and its use was still dominant in developing countries until recently. Due to high impurity levels and permeability, variable quality and latex allergy issues, pharmaceutical stoppers and seals made using natural rubber act as no more than a physical barrier. Today, natural rubber is no longer used for pharmaceutical packaging in most countries and it is being replaced by synthetic rubbers.
Elastomers that meet the requirements of modern day pharmaceutical packaging applications must possess the following characteristics, including: contain low levels of additives and impurities; highly impermeable
to moisture and air, chemically and biologically inert; resistance to aging and heat sterilization; and easy to vulcanize using low levels of 'clean' curatives. Only a few elastomers can fulfill all the above requirements.
Among all commercial elastomers, halobutyl (chlorobutyl and bromobutyl) enjoy a very high degree of success in pharmaceutical packaging applications and are the number one choice worldwide for pharmaceutical stoppers and seals applications today. Halobutyl polymers are highly impermeable to moisture and gases, important for preserving medicines. These polymers are also highly saturated and hence exhibit good oxidation, heat (sterilization) and aging resistance. They are chemically inert and non-polar, and therefore do not lead to absorption of drugs or water. In contrast to regular butyl, halobutyl can be effectively vulcanized by low levels of 'clean' curatives. Stoppers made using halobutyl also exhibit adequate self-sealing, fragmentation, tear strength and other physical property requirements.
Increasing trend for cleanliness
The historical trend of elastomers used for stopper manufacturing is shown schematically in figure 1.
Natural rubber was largely used pre-1940 for pharmaceutical stoppers before regular butyl was invented. Due to its excellent barrier and thermal oxidation resistance, regular butyl was quickly adopted for use in making pharmaceutical stoppers soon after its launch in the early 1940s. Since the 1960s, halobutyl, first chlorobutyl and later bromobutyl, gradually replaced regular butyl as the elastomer for pharmaceutical/ biomedical stopper applications. Today, more than 90% of antibiotic, infusion and biomedical stoppers made in Europe, the U.S. and China are based on halobutyl polymers. The additional advantage of halobutyl over regular butyl is that they can be cured using low levels of clean curatives, including sulfur-free and zinc-free ones. In recent years, the trend of development is towards ever lower leachables and extractables. Polytetrafluoroethene and other coated stoppers were developed by the industry to meet the requirements. These stoppers are expensive and also somewhat defensive in sealing and coring performance. Brominated isobutylene paramethylstyrene terpolymer (BIMSM) is a very clean material that can be vulcanized effectively by low levels of clean curatives and is a good alternative to the expensive coated stopper for sensitive drugs and other demanding applications.
Extractables that affect drug quality/compatibility
The major halobutyl elastomer extractables that can affect drug quality or compatibility are oligomers, halogenated oligomers and other residue additives/by-products present in the polymer. The latter include butylated hydroxytoluene (BHT) and 1,3,5-trimethyl-2,4,6-tris(3,5-di-tert-butyl-4-hydroxybenzyl)benzene (Irganox 1010) antioxidant, calcium stearate slurry aid and epoxidized soy bean oil (ESBO). Oligomers and halogenated oligomers are by-products of the polymerization process. These cyclic molecules, mainly C 13 and C21 species, are created due to a back-biting mechanism involving the isoprene co-monomer, as depicted in figure 2. Some of these oligomers formed can be halogenated during the manufacturing process.
[FIGURE 1 OMITTED]
[FIGURE 2 OMITTED]
The level of residue by-products and additives present in halobutyl and BIMSM elastomers measured via gas chromatography (GC) is shown in table 1. It can be seen that a large proportion of these residue by-products and additives survive the stopper manufacturing process and remain in the stopper. It can also be seen that BIMSM elastomer is of the highest purity and contains no antioxidant, oligomer and ESBO.
The effectiveness of stopper extractables in inducing drug turbidity has been determined and the results are shown in table 2. In these tests, the antibiotics were exposed to a single volatile species (for 18 hours) and its drug turbidity evaluated. This essentially is measuring how effective the individual volatile can form a 'coating' onto the drug powder and prevent them from being dissolved in water. It has been found that the surface area of the drug powder plays an important role (as the high surface area cefodizime is clearly much more sensitive to volatile species in drug turbidity formation). The tests also show that only polar volatiles, including oligomer and BHT, are highly effective in inducing drug turbidity.
A super-clean elastomer for pharmaceutical packaging
BIMSM, also known as Exxpro specialty elastomer, is the fourth generation of polyisobutylene based polymer launched by ExxonMobil in the early 1990s. It is the cleanest elastomer available today that is suitable for pharmaceutical packaging applications. This polymer has a fully saturated backbone and therefore provides excellent heat and oxidative aging resistance. It also contains no oligomer, antioxidant and epoxidized soy bean oil. BIMSM can be cured efficiently via the benzylic bromine sites and requires only low levels of curatives for effective vulcanization. The structure of BIMSM elastomer is shown in figure 3.
Drug turbidity: Formation mechanism and measurement
Figure 4 shows schematically the drug turbidity formation mechanism. During the storage period, volatile species will migrate from the stopper to the stored drug powder. Some of the volatile species will eventually be adsorbed onto the surface of the drug powder and render them insoluble in water. Higher amounts of volatile species will lead to a more non-soluble drug powder and higher drug turbidity. Through trans mission electron microscopy (TEM), we can identify the non-soluble drug powder in reconstituted solution. The particle size ranges from tens to hundreds of nanometers in diameter.
[FIGURE 3 OMITTED]
[FIGURE 4 OMITTED]
Drug turbidity can be quantitatively measured via light scattering technique. The amount of non-dissolved drug powder in the reconstituted drug solution quantitatively correlates to the intensity of scattered light and can be expressed in nephelometric turbidity units (NTU). A modern day turbidimeter can detect turbidity to an accuracy of 0.01 NTU.
Drug turbidity studies have been carried out on various commercial stoppers made via the same process and cured by similar curatives. In these studies, 100 mg of antibiotic drug powder, sourced directly from a drug manufacturer, was stored in thoroughly cleaned glass vials fitted with 20 mm diameter stoppers. The vials were then put up-side-down (to allow the drug powder to contact the stopper) and allowed to be conditioned in an oven set at 40[degrees]C. After different periods of storage (up to 12 months), the drug powders in different vials were reconstituted with 3 ml of millipore water and the turbidity of the solution determined using a turbidimeter.
[FIGURE 5 OMITTED]
[FIGURE 6 OMITTED]
Figure 5 shows that stoppers made using BIMSM have extraordinary low drag turbidity. This is due to the fact that BIMSM contains the least amount of residue additives and by-products. The stopper made using bromobutyl with a low BHT level also fares better in comparison to the one made using bromobutyl with a higher level of BHT antioxidant.
In a second study, the effect of elastomer type used for making the stopper on drug turbidity is investigated. The drag powder used for this study is cephazolin, also sourced directly from a drug manufacturer. It can be seen from figure 6 that commercial regular butyl stoppers exhibit the highest drag turbidity, followed by natural rubber stoppers. The high drug turbidity of regular butyl stoppers could result from the type and level of curatives used. Bromobutyl stoppers have much lower drug turbidity. Coated bromobutyl stoppers have very low drug turbidity as expected, since the coating acts as a barrier and minimizes chemical species migrating out. The BIMSM stopper is comparable to a coated bromobutyl stopper in terms of drug turbidity for this particular antibiotic.
Stopper extractable evaluation
To reveal the effectiveness of BIMSM and coated BIMSM stoppers in reducing the amount of extractables, a study has been conducted to evaluate and compare solvent extractables present in different commercial stoppers. Both high performance gas chromatography (HPLC) and gas chromatography--mass spectrometry (GC-MS) techniques were employed for the study. To perform the tests, thoroughly cleaned glass vials fitted with different 2 mm stoppers were filled with 10 ml of high purity ethanol. The samples were then turned up-side-down to allow the solvent to be in contact with the stopper and stored for a period of three months at room temperature. Any non-volatile extractables in the ethanol were then analyzed using HPLC; while the volatile extractables were determined via GC-MS. Tests were also conducted via isopropyl alcohol extraction and yield similar results. In this case, 20 g of stopper or 10 g of polymer were refluxed for one hour at the boiling temperature of isopropyl alcohol (100 ml).
[FIGURE 7 OMITTED]
Figure 7 shows the HPLC chromatograms of extractables resulting from isopropyl alcohol (IPA) extraction of three different elastomers used for stopper manufacturing. It is clearly shown that B1MSM exhibits the least amount of extractable.
Figure 8 compares the level of ethanol extractables of various commercial BIMSM stoppers from different manufacturers. The extractable HPLC peak areas at the same retention time are shown in table 3 and figure 8.
It can be observed that except for the stearate (retention time 1.84 mins.) that is present in the BIMSM, the other non-volatile extractables are likely curatives and additives used for stopper manufacturing. The result also indicates that coating of the BIMSM stopper reduces, but does not eliminate, non-volatile extractables.
Figure 9 and table 4 compare the level of ethanol extractables of various commercial bromobutyl stoppers from different manufacturers. The scanning electron micrographs of tetrafluoroethene-coated bromobutyl stopper and polyvinylidene fluoride-coated BIMSM stopper are shown in figure 10. The nature of the coating and elastomer has been confirmed through Fourier transform infrared spectroscopy (FTIR) analysis. It can be observed from table 4 that, apart from BHT (retention time 2.12 mins.) and stearate (retention time 1.83 rains.), all other non-volatile extractables are likely derived from curatives or other additives used for stopper manufacturing. It is also shown that bromobutyl stoppers exhibit higher levels of non-volatile extractable in comparison to that of BIMSM stoppers (note the difference in relative concentration scale of figures 8 and 9). Furthermore, coated bromobutyl stoppers, despite having lower levels of extractable, exhibit new extractables (A, B, C) not present in the non-coated stoppers.
[FIGURE 8 OMITTED]
[FIGURE 9 OMITTED]
In order to identify and quantify the volatile extractables of the stoppers, GC-MS technique was adopted. This technique can identify and detect volatile extractables at low ppm levels. The volatile extractables of BIMSM stoppers and coated B1MSM stoppers are shown in table 5. An example of the GC-MS spectrum is shown in figure 11.
It is observed that for stoppers C and F, all the volatile extractables, except the paraffin wax, are originated from the polymer. For stopper A, additional species as well as a low level of BHT that is not present in BIMSM elastomer are also detected. Furthermore, coating of BIMSM stopper A only reduces, but does not eliminate, volatile extractables.
Table 6 shows the level of volatile ethanol extractables of various bromobutyl and coated bromobutyl stoppers as determined via GC-MS. Extractables such as C16 and C18 acid/ester and derivatives, BHT and oligomers are originated from the bromobutyl polymer. Other extractables detected are unknown curative or additive, wax and sulfur. It should be noted that coating reduces the level of volatile extractable, but can also introduce new types of extractables.
Management of change--material supplier perspective
As an elastomer supplier to the healthcare industry, we understand and are committed to product quality and consistency. The following changes to our halobutyl products took place in the last few years: (1) vegetable-base calcium stearate, (2) cocatalyst and (3) bale wrap. In each case, trial product was subjected to internal evaluation to ensure that there were no changes in molecular characteristics and product parameters. Tests conducted include nuclear magnetic resonance (NMR) for molecular structure; gas chromatography (GC) for oligomer and residue monomer/solvent; gel permeation chromatography (GPC) for molecular weight distribution; and inductively coupled plasma--atomic emission spectroscopy (ICP-AES) for residue metal contents.
[FIGURE 10 OMITTED]
Application tests are also carried out to confirm that compound performances are equivalent. Communication to customers then follows and trial product is made available for evaluation. Implementation of any change will only take place after approvals from customers are obtained.
The increasing demand by end users for pharmaceutical stoppers and seals with a low level of extractables and leachables has put pressure on both stopper manufacturers and raw material suppliers in the healthcare industry. Elastomer constitutes 50% of a typical pharmaceutical stopper, and its cleanliness is of vital importance to ensure low levels of extractables and leachables.
Due to its relative high cleanliness and barrier performance, halobutyl remains the number one choice worldwide for pharmaceutical stoppers and seals that can satisfy a wide range of applications. However, certain drugs are highly sensitive to residue impurities, and coated stoppers are more and more being used for their packaging. In this article, we have shown that stoppers made with BIMSM elastomer that contains zero antioxidant, oligomer and ESBO exhibit similar drug turbidity performance as coated stoppers. An isopropyl alcohol extraction study also shows that BIMSM elastomer contains a lesser amount of non-volatile extractable in comparison to halobutyl. Furthermore, BIMSM stoppers contain less volatile and nonvolatile extractables in comparison to stoppers made using halobutyl.
[FIGURE 11 OMITTED]
Tetrafluoroethene and polyvinylidene coating can reduce the amount of extractables from stoppers, but it is not a total barrier to extractables and leachables. In some cases, new volatile extractables are identified in coated stoppers not present in non-coated ones. For BIMSM stoppers, most extractables originated from curatives or additives adopted for stopper manufacturing. BIMSM stoppers with very low extractables can be achieved by the proper choice of curatives and minimizing the use of additives in stopper manufacturing.
by Wai Keung Wong, ExxonMobil Chemical Europe
Table 1--additive and residual by-product present in halobutyl/BIMSM elastomer and bromobutyl stopper Halogenated monomer BIMSM Chlorobutyl (ppm) elastomer elastomer Halogenated C4 -- ~1-2 Halogenated C5 0 ND Oligomer (ppm) C8 0 <5 X C8 0 <5 C 13 0 500 X C13 0 250 C21 0 1,500 X C21 0 150 Additive (wt. %) BHT/(Irganox 1010) 0 0.05 Calcium stearate 1.3 1.2 Stearic acid <0.2 -- ESBO -- -- Azonitrile <0.1 -- Halogenated Typical monomer Bromobutyl bromobutyl (ppm) elastomer stopper Halogenated C4 ~1-2 ND Halogenated C5 ND ND Oligomer (ppm) C8 <5 ND X C8 <5 ND C 13 50 20 X C13 1,000 100 C21 1,000 400 X C21 250 400 Additive (wt. %) BHT/(Irganox 1010) <0.1/(<0.05) 0.03/(<0.01) Calcium stearate 2.0-2.5 NM Stearic acid -0.25 NM ESBO 1.30 NM Azonitrile -- -- ND--not detected; NM--not measured Table 2--provoked turbidity after 18h exposure of antibiotics to single evaporated test volatile Apalcillin Test volatile (non-polar) (0.16 [m.sup.2]/g) n-hexane <5 Cyclohexane 5 Hexane isomers <5 Test volatile (polar) Octamethyltrisiloxane (silicon oil) <5 Dexamethyltetrasiloxane (silicon oil) <5 Oligomer <5 Antioxidant (BHT) 21 Cefodizime Test volatile (non-polar) (>100 [m.sup.2]/g) n-hexane 5 Cyclohexane <5 Hexane isomers <5 Test volatile (polar) Octamethyltrisiloxane (silicon oil) 42 Dexamethyltetrasiloxane (silicon oil) 74 Oligomer 176 Antioxidant (BHT) 172 Table 3--level of extractables of BIMSM and coated BIMSM stoppers as indicated by HPLC peak area Retention time BIMSM Coated BIMSM BIMSM (minutes) A BIMSM A C F 1.49 1,919 1.84 66,244 65,742 2,601 5.86 37,261 9,099 1,832 17,986 6.93 7,134 12.39 31,377 2,124 13.20 12,803 14.86 8,369 Table 4--level of extractables of bromobutyl and coated bromobutyl stoppers indicated by HPLC peak area Retention time Coated Coated (minutes) BB I BB J BB M H L 1.66 35,130 1.83 75,920 86,170 37,730 2.12 20,000 30,000 19,722 8,961 4,530 2.94 212,822 162,878 4,202 12,511 15,631 3.47 4,314 3.97 2,595 4,748 5.85 64,748 109,248 12.41 46,146 Table 5--volatile extractables (in ppm) of BIMSM and coated BIMSM stoppers as determined by GC-MS BIMSM BIMSM BIMSM BIMSM A A coated C F 2-chloro-4-tert. pent 2.6 2.6 Vazo 27 13 18 2.3 1,9-cyclohexadecadien 7.1 2.6 C16 acid/ester and de 1.9 0.4 76 2.6 C18 acid/ester and de 1.3 0.5 65 3.9 Unknown A (curative) 9.8 1.1 Paraffin wax (nC23-nC29) 74 BHT 0.3 0.05 Table 6--volatile ethanol extractibles determined by GC-MS BB D BB K BB I BB J C16 acid/ester and derivatives 5.9 13 11 12 C18 acid/ester and derivatives 6 6 4.4 3.4 Unknown B (curative) Unknown C (curative) S6 + S8 (curative) 5.9 12 Paraffin wax (nC23-nC29) ~70 ~40 ~35 BHT 44 32 31 C13 oligomer 5.9 3.6 3.2 C21 oligomer 1.4 49 44 38 BB H BB L BB M coated coated C16 acid/ester and derivatives 141 0.4 1 C18 acid/ester and derivatives 116 0.5 1 Unknown B (curative) 2.8 Unknown C (curative) 45 S6 + S8 (curative) Paraffin wax (nC23-nC29) ~12 ~7 BHT 0.8 2.7 C13 oligomer 2.7 0.7 2 C21 oligomer 58 8 12
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|Author:||Wong, Wai Keung|
|Date:||Jun 1, 2009|
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