Appendix XX E. Poly(Ethylene - Vinyl Acetate) for Containers and Tubing for Total Parenteral Nutrition Preparations

(Ph. Eur. method 3.1.7)

DEFINITION

Poly(ethylene - vinyl acetate), complying with the following requirements, is suitable for the manufacture of containers and tubing for total parenteral nutrition preparations. It is obtained by copolymerisation of mixtures of ethylene and vinyl acetate.

Content of vinyl acetate:

— material used for containers: a defined quantity of not more than 25 per cent;

— material used for tubing: a defined quantity of not more than 30 per cent.

PRODUCTION

Depending on the intended use of the polymers, they may contain additives to optimise their processing or their chemical, physical and mechanical properties. Unless otherwise justified and authorised, these additives are chosen from the following list, which specifies for each substance the maximum permitted content.

Poly(ethylene - vinyl acetate) may contain not more than 3 of the following antioxidants:

— butylhydroxytoluene (plastic additive 07): maximum 0.125 per cent;

— pentaerythrityl tetrakis[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate] (plastic additive 09): maximum 0.2 per cent;

— octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate (plastic additive 11): maximum 0.2 per cent;

— tris(2,4-di-tert-butylphenyl) phosphite (plastic additive 12): maximum 0.2 per cent;

— 2,2′,2″,6,6′,6″-hexa-tert-butyl-4,4′,4″-[(2,4,6-trimethyl-1,3,5-benzenetriyl)trismethylene]triphenol (plastic additive 10): maximum 0.2 per cent.

It may also contain:

— oleamide (plastic additive 20): maximum 0.5 per cent;

— erucamide (plastic additive 21): maximum 0.5 per cent;

— calcium stearate or zinc stearate or a mixture of both: maximum 0.5 per cent;

— calcium carbonate or potassium hydroxide: maximum 0.5 per cent;

— colloidal silica: maximum 0.2 per cent.

The supplier of the material must be able to demonstrate that the qualitative and quantitative composition of the type sample (see chapter 3.2.2. Plastic containers and closures for pharmaceutical use for the definition of ‘type sample′) is satisfactory for each production batch.

CHARACTERS

Appearance

Beads, granules or, after transformation, translucent sheets or tubing of varying thickness or samples of finished objects.

Solubility

Practically insoluble in water, soluble in hot aromatic hydrocarbons, practically insoluble in anhydrous ethanol, in methanol and in hexane, which dissolves, however, low molecular mass polymers.

It burns with a blue flame.

The temperature at which the substance softens changes with the vinyl acetate content: from about 100 °C for contents of a few per cent to about 70 °C for contents of 30 per cent.

IDENTIFICATION

If necessary, cut the samples of the material to be examined into pieces of maximum dimension on a side of not greater than 1 cm.

Infrared absorption spectrophotometry (2.2.24).

Preparation To 0.25 g add 10 mL of toluene R and boil under a reflux condenser for about 15 min. Place a few drops of the solution on a sodium chloride slide or on a disc of potassium bromide R and evaporate the solvent in an oven at 80 °C.

Alternatively, the spectrum may be recorded directly on a cut piece of suitable size (sheets), granules or hot pressed films by attenuated total reflection (ATR).

Absorption maxima (tolerance: ± 5 cm^-¹) At 2920 - 2850 cm^-¹, 1740 cm^-¹, 1240 cm^-¹, 1020 cm^-¹, 720 cm^-¹ and 610 cm^-¹.

The spectrum obtained is identical to that obtained with the material selected for the type sample.

TESTS

If necessary, cut the samples of the material to be examined into pieces of maximum dimension on a side of not greater than 1 cm.

Solution S1

Place 2.0 g in a conical borosilicate-glass flask with a ground-glass neck. Add 80 mL of toluene R and boil under a reflux condenser for 90 min, with constant stirring. Allow to cool to 60 °C and add, with constant stirring, 120 mL of methanol R. Filter the solution through a sintered-glass filter (16) (2.1.2). Rinse the flask and the filter with 25 mL of a mixture of 40 mL of toluene R and 60 mL of methanol R, add the rinsings to the filtrate and dilute to 250 mL with the same mixture of solvents.

Solution S2

Place 25 g in a borosilicate-glass flask with a ground-glass neck. Add 500 mL of water R and boil under a reflux condenser for 5 h. Allow to cool and decant. Reserve a portion of the solution for the test for appearance of solution and filter the rest through a sintered-glass filter (16) (2.1.2). Use within 4 h of preparation.

Appearance of solution

Solution S2 is clear (2.2.1) and colourless (2.2.2, Method II).

Acidity or alkalinity

To 100 mL of solution S2 add 0.15 mL of BRP indicator solution R. Not more than 1.0 mL of 0.01 M sodium hydroxide is required to change the colour of the indicator to blue. To 100 mL of solution S2 add 0.2 mL of methyl orange solution R. Not more than 1.5 mL of 0.01 M hydrochloric acid is required to reach the beginning of the colour change of the indicator from yellow to orange.

Absorbance (2.2.25)

Maximum 0.2, determined between wavelengths of 220 nm and 340 nm on solution S2.

Reducing substances

To 20 mL of solution S2 add 1 mL of dilute sulfuric acid R and 20 mL of 0.002 M potassium permanganate. Boil under a reflux condenser for 3 min and cool immediately. Add 1 g of potassium iodide R and titrate immediately with 0.01 M sodium thiosulfate, using 0.25 mL of starch solution R as indicator. Carry out a blank titration. The difference between the titration volumes is not more than 0.5 mL.

Amides and stearates

Thin-layer chromatography (2.2.27).

Test solution Evaporate 100 mL of solution S1 to dryness in vacuo at 45 °C. Dissolve the residue in 2 mL of acidified methylene chloride R.

Reference solution (a) Dissolve 20 mg of stearic acid CRS (plastic additive 19) in 10 mL of methylene chloride R.

Reference solution (b) Dissolve 40 mg of plastic additive 20 CRS in 20 mL of methylene chloride R.

Reference solution (c) Dissolve 40 mg of plastic additive 21 CRS in 20 mL of methylene chloride R.

PlatesTLC silica gel F₂₅₄ plate R (2 plates).

A. Mobile phase: anhydrous ethanol R,trimethylpentane R (25:75 V/V).

Application 10 µL.

Development Over a path of 10 cm.

Drying In air.

Detection Spray with a 2 g/L solution of dichlorophenolindophenol, sodium salt R in anhydrous ethanol R and heat in an oven at 120 °C for a few minutes to intensify the spots.

Limit Any spot corresponding to plastic additive 19 in the chromatogram obtained with the test solution is not more intense than the spot in the chromatogram obtained with reference solution (a).

B. Mobile phase A: hexane R.

Mobile phase Bmethanol R,methylene chloride R (5:95 V/V).

Application 10 µL.

Development A Over a path of 13 cm with mobile phase A.

Drying A In air.

Development B Over a path of 10 cm with mobile phase B.

Drying B In air.

Detection Spray with a 40 g/L solution of phosphomolybdic acid R in anhydrous ethanol R and heat at 120 °C until spots appear.

Limit Any spots corresponding to plastic additive 21 or plastic additive 20 in the chromatogram obtained with the test solution are not more intense than the spots in the chromatograms obtained with reference solutions (b) and (c) respectively.

Phenolic antioxidants

Liquid chromatography (2.2.29).

Solvent mixtureacetonitrile R,tetrahydrofuran R (50:50 V/V).

Test solution (a) Evaporate 50 mL of solution S1 to dryness in vacuo at 45 °C. Dissolve the residue in 5.0 mL of the solvent mixture.

Test solution (b) Evaporate 50 mL of solution S1 to dryness in vacuo at 45 °C. Dissolve the residue in 5.0 mL of methylene chloride R.

Reference solution (a) Dissolve 25.0 mg of butylhydroxytoluene CRS (plastic additive 07), 40.0 mg of plastic additive 10 CRS, 40.0 mg of plastic additive 09 CRS and 40.0 mg of plastic additive 11 CRS in 10 mL of the solvent mixture. Dilute 2 mL of the solution to 50.0 mL with the solvent mixture.

Reference solution (b) Dissolve 40.0 mg of plastic additive 11 CRS and 40.0 mg of plastic additive 12 CRS in 10 mL of methylene chloride R. Dilute 2 mL of the solution to 50.0 mL with methylene chloride R.

Column:

— size: l = 0.25 m; Ø = 4.6 mm;

— stationary phase: octadecylsilyl silica gel for chromatography R (5 µm).

Mobile phasewater R,tetrahydrofuran R,acetonitrile R (10:30:60 V/V/V).

Flow rate 1.5 mL/min.

Detection Spectrophotometer at 280 nm.

Injection 20 µL of test solution (a) and reference solution (a).

System suitability: reference solution (a):

— resolution: minimum 2.0 between the peaks due to plastic additive 09 and plastic additive 10;

— number of theoretical plates: minimum 2500, calculated for the peak due to plastic additive 07.

Limits:

— the chromatogram obtained with test solution (a) shows only principal peaks corresponding to the peaks in the chromatogram obtained with reference solution (a) with a retention time greater than 2 min;

— the areas of the peaks in the chromatogram obtained with test solution (a) are not greater than those of the corresponding peaks in the chromatogram obtained with reference solution (a), except for the last peak eluted in the chromatogram obtained with reference solution (a).

If the chromatogram obtained with test solution (a) shows a peak with the same retention time as the last antioxidant eluted from reference solution (a), carry out the test as described with the following modifications.

Mobile phasewater R,2-propanol R,methanol R (5:45:50 V/V/V).

Injection 20 µL of test solution (b) and reference solution (b).

System suitability: reference solution (b):

— resolution: minimum 2.0 between the peaks due to plastic additive 11 and plastic additive 12.

Limits:

— the chromatogram obtained with test solution (b) shows only principal peaks corresponding to the peaks in the chromatogram obtained with reference solution (b) with a retention time greater than 3 min;

— the areas of the peaks in the chromatogram obtained with test solution (b) are not greater than those of the corresponding peaks in the chromatogram obtained with reference solution (b).

Sulfated ash (2.4.14)

Maximum 1.2 per cent, determined on 5.0 g.

ASSAY

Introduce 0.250 g to 1.000 g of the substance to be examined, according to the vinyl acetate content of the copolymer to be examined, into a 300 mL conical flask with a ground-glass neck containing a magnetic stirrer. Add 40 mL of xylene R. Boil under a reflux condenser with stirring for 4 h. Stirring continuously, allow to cool until precipitation begins before slowly adding 25.0 mL of alcoholic potassium hydroxide solution R1. Boil again under a reflux condenser with stirring for 3 h. Allow to cool with continued stirring, rinse the condenser with 50 mL of water R and add 30.0 mL of 0.05 M sulfuric acid to the flask. Transfer the contents of the flask into a 400 mL beaker; rinse the flask with 2 quantities, each of 50 mL, of a 200 g/L solution of anhydrous sodium sulfate R and 3 quantities, each of 20 mL, of water R and add all the rinsings to the beaker containing the initial solution. Titrate the excess sulfuric acid with 0.1 M sodium hydroxide, determining the end-point potentiometrically (2.2.20). Carry out a blank titration.

1 mL of 0.05 M sulfuric acid is equivalent to 8.609 mg of vinyl acetate.