Controlled Extraction on Rubber Elastomer (RE) - PQRI

1 IntroductionA bromobutyl Rubber formulation was moulded into 11cm x 11cm x test plates. The plates were sandwiched between two sheets of coated paper. The plates were stacked and placed in a plastic bag and submitted to the Product Quality Research Institute (PQRI) to perform Controlled Extraction studies. The test plates were characterized by Extraction using multiple solvents and included silylation of the aqueous extracts. The extracts were analyzed for volatiles, semivolatiles, nonvolatiles and inorganic constituents.

2 In addition, the headspace volatiles were evaluated. The extractables were identified as confirmed, confident or tentative. Amounts of extractables were estimated in g/g relative to an internal standard. BackgroundPharmaceutical elastomers are compounded to impart certain physical properties such as resilience, resistance to abrasion, compression set, and low permeability to vapor and gases. This formulation was made on a pilot scale for PQRI with the following ingredients added to a brominated isobutylene isoprene copolymer, cured with 4,4 -dithiodi-morpholine/polyisobutylene: aluminum oxide, titanium dioxide zinc oxide, magnesium oxide paraffinic oil and carbon black.

3 Elastomer Material Pharmaceutical ApplicationsBrominated isobutylene isoprene copolymerExperimental ConditionsExtractionSoxhletRefluxSonicat ionSealed VesselIPA5g/125mL 16 hrsHPLC/UV/ hrsHPLC/UV/MSGC/MSN/AN/AHexane5g/125mL 16 hrsHPLC/UV/ hrsHPLC/UV/MSGC/MSN/AN/A 1:1 IPA:H20N/A5g/200mL55C/3daysHPLC/UV/MSGC/ FID N/A5g/200ml55C/3daysHPLC/UV/MSGC/FID 2hrsICP/MS5g/200ml 121C/1hrHPLD/UV/MSGC/FID Sample Solvent = 15cm2/125mL; 5g = 20 cm2/125mL; and/200mL Analytical TechniquesGC/FID/MS; LC/UV/MS.

4 ICP/MSSystem SuitabilityInternal Standards: Irganox 415 and Bisphenol M and 2-Fluorobiphenyl, 1,4 DioxaneLCStandard: Caprolactam, Butylated Hydroxy Toluene (BHT), Diphenylamine, Monoethylhexylphthalate (MEHP), Stearic Acid, Dethylhex-ylphthalate (DEHP), Bisphenol A, Irganox 1010, Irganox 168 Headspace Standard: Methanol, Acetic Acid, Cyclohexanone, Toluene, Trimethylsilianol, 2-ethylhexanolGC Standard: Grob MixtureTMS Derivitized Underivitized N/A= Not analyzedHeadspace 1g/20mL @ 80-120C GC/FID/MSHeadspace AnalysisA System Suitability mixture was prepared in PEG 200.

5 A standard mixture of methanol, acetic acid, cyclohexanone, toluene, trimethylsilanol and 2-ethylhexanol was prepared at a concentration 10-20 g/mL; the sensitivity concentration was g/vial. 1,4 Dioxane was used as an internal standard. Trace amounts of C6H12 (1 g/g) was the main constituent found in the headspace; this would be typical of a solvent used in the polymerization process. Other minor peaks <1 g/g were seen mostly related to butyl oligomers. The results are tabulated in Table 1 Headspace First Pass Results; the chromatograms are shown in Figure 1 Early Eluting Compounds and Figure 2 Late Eluting 1 Headspace Early Eluting Compounds Table 1 Headspace First Pass ResultsRT, minConc, g/g IDFormulaStructure/ Fragmentation CAS# Unknown - no ms signalNANANAU nknown , methyl-C6H12 96-37-7 Confident C6H12 39, 43, 45, 58 NAUnknown ,4-Dioxane C4H8O2123-91-1 Internal Unknown Butyl Oligomer relatedNAm/z 29, 41, 57, 68, 82, 97, 109, 124, 137, 165.

6 180 NAUnknown Butyl Oligomer relatedNAm/z 29, 43, 57, 69, 81, 97, 109, 123, 137, 151, 165, 180 NAUnknown UnknownNAm/z 29, 41, 57, 67, 79, 97, 109, 123, 133, 145, 160, 179, 191 NAUnknownGas Chromatography (GC) AnalysisRelatively volatile and semi-volatile compounds were analyzed by GC using a non-polar capillary column with a temperature range of 40-300 C. Detection strategies employed Flame Ionization (FID) and Mass Spectrometry (MS). Extracts were analyzed directly and derivatized using BSTFA with 1% TMCS. System Suitability requirements are listed in Table 2.

7 The System Suitability chromatographic peaks are identified in Table 3. Standard chromatograms of Derivatized and Undervatized Grob Mixture (initial and final runs) in sealed vessels are shown in Figures 3 and 4, respectively. Table 2 GC System Suitability RequirementsCriterionAcceptance CriterionEarly Runs, Un-Derivatized(DB-5HT column with m film)Final Runs, Derivatized(DB-5MS column with m film)Signal to Noise (S/N)All peaks, S/N GT 102-Ethyl-hexanoic acid has lowest S/N, observed over a range from 13 - 212-Ethyl-hexanoic acid has lowest S/N, observed over a range from 13 - 21 ResolutionProtocol: GT for critical pair Amended by study coordinator: or betterTwo critical pairs.

8 Be-tween undecane and 1-non-anal between 1-nonanal and 2,6-dimethyl phenolUndecane and 1-non-anal is critical pair: to ShapeTailing factor LT peaks, tailing LT is worst case: to ConsistencyNo significant differences between chromatograms at beginning and end of runDegradation of critical pair resolution over course of runConsistent resolution throughout runTable 3 System Suitability Chromatographic PeaksCompounds Observed in Grob Mix Peak ID (1)Derivitized Compound Figure 3 Underivitized Compound Figure 412,3-Butanediol [2 TMS]Decane 2 Undecane1-Octanol32-Ethyl hexanoic acid [TMS]Undecane42,6-Dimethyl aniline 1- Nonanal51-Octanol [TMS]2,6-Dimethyl phenol62,6-Dimethylphenol [TMS]2-Ethylhexanoic acid7 Methyl Decanoate2,6-Dimethyl aniline8 Nonanoic acid [TMS]

9 Methyl decanoate9 Methyl UndecanoateMethyl undecanoate10 Methyl DodecanoateDicyclohexylamine11--------Me thyl dodecanoateFigure 3 Dervatized Grob Mixture Initial and Final Runs GC/FID ObservationsTentatively identified compounds from the sealed vessel extractions are listed in Table 4, concentrations estimated relative to of the Rubber extracts ( , and IPA/H2O) from the sealed vessels extractions are shown in Figure 5 (underivatized) and Figure 6 (derivatized). Internal standard peaks are (1 = Irganox 415, 25mg/L and 2 = Bisphenol M, 1 mg/L).

10 Table 4 GC Peaks Associated with Organic Extractables from RE Material; Sealed Vessel ExtractionInformation Related to the GC Peaks Associated with Organic Extractables from RE Material; Sealed Vessel Extraction (See Figure 2)Peak #RT (min) Tentative IdentificationCAS RNMaximum Conc, 2,6-di-tert-butyl-4-methyl phenol128-37-0 Methyl dodecanoate111-82-0 acid143-07-7 [TMS] Compound ,2-Benzenecarboxylic acid, monoethylester2306-33-4 Methyl Tetradecanoate124-10-7 acid [TMS]544-63-8 Tri-tert.