药用丁基胶塞---四大药典检测标准异同

Summary

1、Penetrability

[YBB]Take 10 rubber closures, test according to the second method of YBB60072012, the average puncture force does not exceed 10N.

[EP] Fill 10 suitable vials to the nominal volume with water R, fit the closures to be examined and secure with a cap. Using for each closure a new, lubricated long-bevel(1) (bevel angle 12 ± 2°) hypodermic needle with an external diameter of 0.8 mm, pierce the closures with the needle perpendicular to the surface. The force required for piercing, determined with an accuracy of ± 0.25 N (25 gf), is not greater than 10 N (1 kgf) for each closure.

[JP]None

[USP]Fill 10 suitable vials to the nominal volume with water, fit the closures to be examined, and secure with a cap. Using a new hypodermic needle as described above for each closure, pierce the closure with the needle perpendicular to the surface.

Requirement—The force for piercing is no greater than 10 N (1 kgf) for each closure, determined with an accuracy of ± 0.25 N (25 gf).

2、Fragmentation

[YBB]Take 10 rubber closures, test according to the second method of YBB60082012, The total number of fragments does not exceed 5.

[EP] For closures intended to be pierced by a hypodermic needle, carry out the following test. If the closures are to be used for aqueous preparations, place in

12 clean vials a volume of water R corresponding to the nominal volume minus

4 ml, close the vials with the closures to be examined, secure with a cap and

allow to stand for 16 h. If the closures are to be used with dry preparations, close 12 clean vials with the closures to be examined. Using a lubricated long-bevel(1) (bevel angle 12 ±2°) hypodermic needle with an external diameter of 0.8 mm fitted to a clean syringe, inject into the vial 1 ml of water R and remove 1 ml of air ; carry out this operation 4 times for each closure, piercing each time at a different site. Use a new needle for each closure and check that the needle is not blunted during the test. Pass the liquid in the vials through a filter having approxi mately 0.5 μm pores. Count the fragments of rubber visible to the naked eye. The total number of fragments does not exceed

5. This limit is based on the assumption that fragments with a diameter equal to

or greater than 50 μm are visible to the naked eye; in cases of doubt or dispute, the fragments are examined with a microscope to verify their nature and size. [JP] None

[USP] Closures for Liquid Preparations— Fill 12 clean vials with water to 4 mL less than the nominal capacity. Fit the closures to be examined, secure with a

cap, and allow to stand for 16 hours.

Closures for Dry Preparations— Fit closures to be examined into 12 clean

vials, and secure each with a cap.

Procedure— Using a hypodermic needle as described above fitted to a clean

syringe, inject into each vial 1 mL of water while removing 1 mL of air. Repeat this procedure 4 times for each closure, piercing each time at a different site.

Use a new needle for each closure, checking that it is not blunted during the test.

Filter the toatal volume of liquid in all the vials through a single filter with a nominal pore size no greater than 0.5 μm. Count the rubber fragments on the surface of the filter visible to the naked eye.

Requirement— There are no more than 5 fragments visible. This limit is based on the assumption that fragments with a diameter >50 μm are visible to the naked eye. In case of doubt or dispute, the particles are examined microscopically to verify their nature and size.

3、Sealing test of rubber closure and container

[YBB] Take 10 rubber closures into the beaker, boil for 5 min , take out and dry 1h at 70℃ and ready to use. Fill 10 suitable vials to the nominal volume with water, fit the closures to be examined and secure with a cap. Heat in an autoclave so that a temperature of 121 ± 2 °C and maintain at this temperature for 30 min.

Cool to room temperature and then place 24h, Immerse the vials upside down in

a 10% solution of methylene blue R and reduce the external pressure by 25 kPa

for 30 min. Restore atmospheric pressure and leave the vials immersed for 30 min. Rinse the outside of the vials. None of the vials contains any trace of colored solution.

[EP]None

[JP]None

[USP] None

4、Self-Sealing Capacity

[YBB]Take the samples from sealing test of rubber closure and container, using for a hypodermic needle (YBB60082012 method 2), pierce each closure 3 times, change the hypodermic needle after it is used 10 times ,piercing each time at a different site.The vials upside down in a 10% solution of methylene blue R and reduce the external pressure by 25 kPa for 30 min. Restore atmospheric pressure and leave the vials immersed for 30 min. Rinse the outside of the vials. None of the vials contains any trace of colored solution.

[EP]For closures intended to be used with multidose containers, carry out the following test. Fill 10 suitable vials to the nominal volume with water R, fit the closures to be examined and secure with a cap. Using for each closure a new hypodermic needle with an external diameter of 0.8 mm, pierce each closure 10 times, piercing each time at a different site. Immerse the vials upright in a 1 g/l solution of methylene blue R and reduce the external pressure by 27 kPa for 10 min. Restore atmospheric pressure and leave the vials immersed for 30 min.

Rinse the outside of the vials. None of the vials contains any trace of coloured solution.

[JP]None

[USP]Procedure—Fill 10 suitable vials with water to the nominal volume. Fit the closures that are to be examined, and cap. Using a new hypodermic needle as described above for each closure, pierce each closure 10 times, piercing each time at a different site. Immerse the 10 vials in a solution of 0.1% (1 g per L) methylene blue, and reduce the external pressure by 27 kPa for 10 minutes.

Restore to atmospheric pressure, and leave the vials immersed for 30 minutes.

Rinse the outside of the vials.

Requirement—None of the vials contain any trace of blue solution.

5、Total Ash

[YBB] Take the rubber closures, test according to YBB600212012, should be comply with the standard.

[EP]The total ash (2.4.16) is within ± 10 per cent of the result obtained with the type sample.

[JP]None

[USP] None

6、Volatile Sulfides

[YBB]Take the rubber closures, according to the YBB60052012, should be comply with the standard.

[EP] Place closures, cut if necessary, with a total surface area of 20 ± 2 cm2 in a 100 ml conical flask and add 50 ml of a 20 g/l solution of citric acid R. Place a piece of lead acetate paper R over the mouth of the flask and maintain the paper in position by placing over it an inverted weighing bottle. Heat in an autoclave at 121 ± 2℃ for 30 min. Any black stain on the paper is not more intense than that of a standard prepared at the same time in the same manner using 0.154 mg of sodium sulphide R and 50 ml of a 20 g/l solution of citric acid R.

[JP]None

[USP] Procedure— Place closures, cut if necessary, with a total surface area of 20 ± 2 cm2 in a 100-mL flask, and add 50 mL of a 20 g per L citric acid solution. In the same manner and at the same time, prepare a control solution in a separate 100-mL flask by dissolving 0.154 mg of sodium sulfide in 50 mL of a 20 g per L citric acid solution. Place a piece of lead acetate paper over the mouth of each flask, and hold the paper in position by placing over it an inverted weighing bottle. Heat the flasks in an autoclave at 121 ± 2℃for 30minutes.

Requirement—Any black stain on the paper produced by Solution S is not more intense than that produced by the control solution.

7、Preparation of Solution S

[YBB] Put a number of uncut closures corresponding to a surface area of about 200 cm2 in a suitable glass container, cover with purified water( sample: water=1:2), boil for 5 min and rinse 5 times with the same volume of purified water. Place the washed closures in a conical flask, add the same volume of water and weigh.

Cover the mouth of the flask with a borosilicate-glass beaker. Heat in an autoclave so that a temperature of 121 ± 2 °C is reached within 20 min to 30 min and maintain at this temperature for 30 min. Cool to room temperature.

Make up to the original mass with purified water. Shake and immediately separate the solution from the rubber by decantation. Shake solution S before each test Blank. Prepare a blank in the same manner using 400 mL of water for purified water.

[EP] Solution S.Introduce a number of uncut closures corresponding to a surface area of about 100 cm2in a suitable glass container, cover with water for injections R, boil for 5 min and rinse 5 times with cold water for injections R.

Place the washed closures in a wide-necked flask (glass type I, 3.2.1), add 200 ml of water for injections R and weigh. Cover the mouth of the flask with a borosilicate-glass beaker. Heat in an autoclave so that a temperature of 121 ±

2 °C is reached within 20 min to 30 min and maintain at this temperature for 30

min. Cool to room temperature over about 30 min. Make up to the original mass with water for injections R. Shake and immediately separate the solution from the rubber by decantation. Shake solution S before each test

Blank. Prepare a blank in the same manner using 200 ml of water for injections R.

[JP] Wash the rubber closures with water, and dry at room temperature. Place them in a glass container, add water exactly 10 times the mass of the test material, close with a suitable stopper, heat at 121℃ for 1 hour in an autoclave, take out the glass container, allow to cool to room temperature,then take out immediately the rubber closures, and use the remaining solution as the test

solution. Prepare the blank solution with water in the same manner. Perform the following tests with the test solution and the blank solution

[USP] Place whole, uncut closures corresponding to a surface area of 100 ± 10 cm2 into

a suitable glass container. Cover the closures with 200 mL of Purified Water or

Water for Injection. If it is not possible to achieve the prescribed closure surface area (100 ± 10 cm2) using uncut closures, select the number of closures that will most closely approximate 100 cm2, and adjust the volume of water used to the equivalent of 2 mL per each 1 cm2 of actual closure surface area used. Boil for 5 minutes, and rinse five times with cold Purified Water or Water for Injection

Place the washed closures into a Type I glass wide-necked flask (see Containers—Glass 660 ), add the same quantity of Purified Water or Water for Injection initially added to the closures, and weigh. Cover the mouth of the flask with a Type I glass beaker. Heat in an autoclave so that a temperature of 121 ± 2℃ is reached within 20 to 30 minutes, and maintain this temperature for

30 minutes. Cool to room temperature over a period of about 30 minutes. Add

Purified Water or Water for Injection to bring it up to the original mass. Shake, and immediately decant and collect the solution. [NOTE—This solution must be shaken before being used in each of the tests]

Prepare a blank solution similarly, using 200 mL of Purified Water or Water for Injection omitting the closures

8、Appearance of solution

[YBB]According to the part 2 of Chinese pharmacopoeia, 2010 edition of appendixⅨB and appendix IX A, standard solution is not more opalescent than reference suspension II. Standard solution is not more intensely coloured than No.5 reference solution

[EP] Solution S is not more opalescent than reference suspension II for type I closures and is not more opalescent than reference suspension III for type II closures

(2.2.1). Solution S is not more intensely coloured than reference solution GY5

(2.2.2, Method II).

[JP] Place 5 mL of the test solution in a glass-stoppered test tube of about 15 mm in inner diameter and about 200 mm in length, and shake vigorously for 3 minutes.

The foam arisen disappears almost completely within 3 minutes.

[USP] Determination of Turbidity (Opalescence)

Procedure A: Visual Comparison— Use identical test tubes made of colorless, transparent, neutral glass with a flat base and an internal diameter of 15 to 25 mm. Fill one tube to a depth of 40 mm with Solution S, one tube to the same depth with water, and four others to the same depth with Reference Suspensions A, B, C,and D. Compare the solutions in diffuse daylight 5 minutes after preparation of the Reference Suspensions, viewing vertically against a black background. The light conditions shall be such that Reference Suspension A can be readily distinguished from water and that Reference Suspension B can be readily distinguished fromReference Suspension A.

REQUIREMENT—Solution S is not more opalescent than Reference Suspension B for Type I closures, and not more opalescent than Reference Suspension C for Type II closures. Solution S is considered clear if its clarity is the same as that of water when examined as described above, or if its opalescence is not more pronounced than that of Reference Suspension A (refer to Table 3).

Procedure B: Instrumental Comparison—Measure the turbidity of the

Reference Suspensions in a suitable calibrated turbidimeter (see Spectrophotometry and Light Scattering 851 ). The blank should be run and the results corrected for the blank. Reference Suspensions A, B, C, and D represent 3, 6, 18 and 30 Nephelometric Turbidity Units (NTU), respectively. Measure the turbidity of Solution S using the calibrated turbidimeter. REQUIREMENT—The turbidity of Solution S is not greater than that for Reference Suspension B (6 NTU FTU) for Type I closures, and is not greater than that forReference Suspension C (18 NTU FTU) for Type II closures (refer to Table 3).

Determination of Color

Color Standard— Prepare a solution by diluting 3.0 mL of Matching Fluid O (see Color and Achromicity 631 ) with 97.0 mL of diluted hydrochloric acid. Procedure—Use identical tubes made of colorless, transparent, neutral glass with a flat base and an internal diameter of 15 to 25 mm. Fill one tube to a depth of 40 mm with Solution S, and the second with Color Standard. Compare the liquids in diffuse daylight, viewing vertically against a white background. Requirement—Solution S is not more intensely colored than the Color Standard.

9、Acidity or Alkalinity(PH)

[YBB]Take each of 20 ml blank solution and solution S, respectively with KCl solution

1 ml, According to the part

2 of Chinese pharmacopoeia, 2010 edition of

appendixⅥH, the difference between the two may not be over 1.0.

[EP] To 20ml of solution S add 0.1ml of bromothymol blue solution R1. Not more than 0.3ml of 0.01 M sodium hydroxide or 0.8 ml of 0.01 M hydrochloric acid is required to obtain either a blue or a yellow colour, respectively.

[JP] To 20 mL each of the test solution and the blank solution add 1.0 mL each of potassium chloride solution, prepared by dissolving 1.0 g of potassium chloride in water to make 1000 mL. The difference of pH between the two solutions is not more than 1.0

[USP] Bromothymol Blue Solution—Dissolve 50 mg of bromothymol blue in a mixture of 4 mL of 0.02 M sodium hydroxide and 20 mL of alcohol. Dilute with water to 100 mL.

Procedure— To 20 ml of Solution S add 0.1 ml of Bromothymol Blue Solution.

If the solution is yellow, titrate with 0.01 N sodium hydroxide until a blue endpoint is reached. If the solution is blue, titrate with 0.01 N hydrochloric acid until a yellow endpoint is reached. If the solution is green, it is neutral and no titration is required.

Blank Correction—Test 20 mL of Blank similarly. Correct the results obtained for Solution S by subtracting or adding the volume of titrant required for the Blank, as appropriate. (Reference Titrimetry 541 .)

Requirement— Not more than 0.3 ml of 0.01 N sodium hydroxide produces a blue color, or not more than 0.8 ml of 0.01 N hydrochloric acid produces a yellow color, or no titration is required.

10、Absorbance

[YBB] Filter solution S on a membrane filter having approximately 0.45 μm pores.

Measure the absorbance of the filtrate at wavelengths from 220 nm to 360 nm using the blank as compensation liquid. At these wavelengths, the absorbance does not exceed 0.1(according to the part 2 of Chinese pharmacopoeia, 2010 edition of appendixⅣA).

[EP] Carry out the test within 5 h of preparation of solution S. Filter solution S on a membrane filter having approximately 0.45 μm pores rejecting the first few milliliters of filtrate. Measure the absorbance (2.2.25) of the filtrate at wavelengths from 220 nm to 360 nm using the blank (see solution S) as compensation liquid. At these wavelengths, the absorbance does not exceed 0.2 for type I closures or 4.0 for type II closures. If necessary, dilute the filtrate before measurement of the absorbance and correct the result for the dilution. [JP] Read the absorbance of the test solution between 220 nm and 350 nm against the blank solution as directed under Ultraviolet-visible Spectrophotometry <2.54>: it is not more than 0.20.

[USP] Procedure — [NOTE—Perform this test within 5 hours of preparing Solution S.] Filter Solution S through a 0.45-μm pore size filter, discarding the first few mL of filtrate. Measure the absorbance of the filtrate at wavelengths between 220 and 360 nm in a 1-cm cell using the blank in a matched cell in the reference beam. If dilution of the filtrate is required before measurement of the absorbance, correct the test results for the dilution.

Requirement—The absorbances at these wavelengths do not exceed 0.2 for Type I closures or 4.0 for Type II closures.

11、Reducing Substances

[YBB] To 20.0 mL of solution S add 1 mL of dilute sulfuric acid R and 20.0 mL of

0.002 M potassium permanganate. Boil for 3 min. Cool. Add 0.1 g of potassium

iodide R and titrate immediately with 0.01 M sodium thiosulfate until the color

turned light brown , using 5 drops of starch solution R as indicator. Carry out a

titration using 20.0 mL of the blank. The difference between the titration

volumes is not greater than7.0mL.

[EP] Carry out the test within 4 h of preparation of solution S. To 20.0 ml of solution S add 1 ml of dilute sulphuric acid R and 20.0 ml of 0.002 M potassium permanganate. Boil for 3min. Cool. Add 1 g of potassium iodide R and titrate immediately with 0.01 M sodium thiosulphate, using 0.25 ml of starch solution R as indicator. Carry out a titration using 20.0 ml of the blank. The difference between the titration volumes is not greater than 3.0 ml for type I closures and

7.0 ml for type II closures.

[JP] Measure 100 mL of the test solution in a glass-stoppered,Erlenmyer flask, add

10.0 mL of 0.002 mol/L potassium permanganate VS and 5 mL of dilute

sulfuric acid, and boil for 3 minutes. After cooling, add 0.10 g of potassium iodide,stopper, mix by shaking, then allow to stand for 10 minutes,and titrate

<2.50> with 0.01 mol/L sodium thiosulfate VS(indicator: 5 drops of starch TS).

Perform the blank test in the same manner, using 100 mL of the blank solution.

The difference in mL of 0.002 mol/L potassium permanganate VS required between the tests is not more than 2.0 mL.

[USP] Procedure— [NOTE—Perform this test within 4 hours of preparing Solution S.] To 20.0 mL of Solution S add 1 mL of diluted sulfuric acid and 20.0 mL of

0.002 M potassium permanganate. Boil for 3 minutes. Cool, add 1 g of

potassium iodide, and titrate immediately with 0.01 M sodium thiosulfate, using

0.25 mL of starch solution TS as the indicator. Perform a titration using 20.0

mL of blank and note the difference in volume of 0.01 M sodium thiosulfate

required.

Requirement—The difference between the titration volumes is not greater than 3.0 mL for Type I closures and not greater than 7.0 mL for Type II closures.

12、Residue on evaporation

[YBB]Evaporate 100 mL of solution S and blank solution to dryness on a water-bath and dry at 100 °C to 105 °C. The residue weighs not more than 4.0 mg. [EP]Evaporate 50.0 ml of solution S to dryness on a water-bath and dry at 100 °C to 105 °C. The residue weighs not more than 2.0 mg for type I rubber and not

more than 4.0 mg for type II rubber.

[JP]Measure 100 mL of the test solution, evaporate on a water bath to dryness, and dry the residue at 1059 C for 1 hour.The mass of the residue is not more

than 2.0 mg.

[USP]None

13、Ammonium

[YBB] Precision measuring 10 ml of solution S, adding alkaline potassium iodide solution 2 ml, place 15 minutes, should not be color; if it colored , compare with reference solution (with 2.0 ml ammonium chloride solution (take ammonium

chloride 31.5 mg, add right amount chlorine free water and dissolve diluted to

1000 ml), 8 ml blank reference solution, 2ml alkaline potassium mercuric iodide solution for mixing), should not be more intensely colored (0.0002%)

[EP] maximum 2 ppm.

Dilute 5 ml of solution S to 14 ml with water R. The solution complies with limit test A.

[JP]None

[USP] Alkaline Potassium Tetraiodomercurate Solution— Prepare a 100 mL solution containing 11 g of potassium iodide and 15 g of mercuric iodide in water.

Immediately before use, mix 1 volume of this solution with an equal volume of

a 250 g per L solution of sodium hydroxide.

Test Solution— Dilute 5 mL of Solution S to 14 mL with water. Make alkaline if necessary by adding 1 N sodium hydroxide, and dilute with water to 15 mL.

Add 0.3 mL of Alkaline Potassium Tetraiodomercurate Solution, and close the container.

Ammonium Standard Solution— Prepare a solution of ammonium chloride in water (1 ppm NH4). Mix 10 mL of the 1 ppm ammonium chloride solution with

5 mL water and 0.3 mL of Alkaline Potassium Tetraiodomercurate Solution.

Close the container.

Requirement—After 5 minutes, any yellow color in the Test Solution is no darker than the Ammonium Standard Solution (no more than 2 ppm of NH4 in Solution S).

14、Extractable Zinc

[YBB] Filter solution S on a membrane filter having approximately 0.45μm pores, Precision measuring filtrate 10 ml, add 1 ml 2 mol/L of hydrochloric acid and 3 drops of potassium ferrocyanide test solution(weight 4.2 g potassium ferrocyanide trihydrate, dissolve and diluted with water to 100 ml, shake evenly, this product should be new prepared) for mixing, should not be color; if it colored, compare with reference solution( with 3 ml standard zinc solution (weight 44.0g Zinc sulfate seven hydrated compounds, with new boiled and cooled purified water dissolved and diluted to 1000 ml, this product should be new prepared), shall not be deeper(0.0002%)，7ml blank reference solution, 1ml 2mol/L hydrochloric acid and 3 drops of potassium ferrocyanide solution for mixing), should not be more intensely colored.(0.0003%)

[EP] maximumof 5 μg of extractable Zn per millilitre of solution S.

Atomic absorption spectrophotometry (2.2.23, Method I). Test solution. Dilute

10.0 ml of solution S to 100 ml with 0.1 M hydrochloric acid.

Reference solutions. Prepare the reference solutions using zinc standard solution

(10 ppm Zn) R diluted with 0.1 M hydrochloric acid.

Source: zinc hollow-cathode lamp.

Wavelength: 213.9 nm.

Flame: air-acetylene.

[JP]To 10.0 mL of the test solution add diluted dilute nitric acid (1 in 3) to make 20 mL, and use this solution as the sample solution. Further, to 1.0 mL of Standard Zinc Solutionfor atomic absorption spectrophotometry add diluted nitricacid (1 in 3) to make exactly 20 mL, and use this solution asthe standard solution. Perform the tests according to the Atomic Absorption Spectrophotometry <2.23>,using these solutions, under the following conditions.

The absorbanceof the sample solution is not more than that of the standardsolution.

Gas: Combustible gasóAcetylene.

Supporting gasóAir.

Lamp: Zinc hollow-cathode lamp.

Wavelength: 213.9 nm.

Standard Zinc Solution for atomic absorption spectrophotometry: Measure exactly 10 mL of the Standard Zinc Stock Solution, and add water to make exactly 1000 mL. Prepare before use. One mL of this solution contains 0.01 mg of zinc(Zn).

[USP] Test Solution—Prepare a Test Solution by diluting 10.0 mL of Solution S to 100 mL with 0.1N hydrochloric acid. Prepare a test blank similarly, using the Blank forSolution S.

Zinc Standard Solution— Prepare a solution (10 ppm Zn) by dissolving zinc sulfate in 0.1 N hydrochloric acid.

Reference Solutions—Prepare not fewer than 3 Reference Solutions by diluting the Zinc Standard Solution with 0.1 N hydrochloric acid. The concentrations of zinc in these Reference Solutions are to span the expected limit of the Test Solution.

Procedure—Use a suitable atomic absorption spectrophotometer (see Spectrophotometry and Light Scattering 851 ) equipped with a zinc hollow-cathode lamp and an air–acetylene flame. An alternative procedure such as an appropriately validated inductively coupled plasma analysis (ICP) may be used.

Test each of the Reference Solutions at the zinc emission line of 213.9 nm at least 3 times. Record the steady readings. Rinse the apparatus with the test blank solution each time, to ensure that the reading returns to initial blank value.

Prepare a calibration curve from the mean of the readings obtained for each Reference Solution. Record the absorbance of the Test Solution. Determine the ppm zinc concentration of the Test Solution using the calibration curve.

Requirement— Solution S contains not more than 5 ppm of extractable zinc.