CS230859B1 - Method of defect indicating for medicinal rubber stoppers - Google Patents

Abstract

The invention solves a method of determining safety of rubber coves in health care solution sodium chloride at a concentration of 0.9% and 10.0% w / v. The essence of the invention is characterized in that in the sodium chloride solution 0.9% and 10.0% w / v). after putting plugs in contact with this solution for a period of time 30 minutes, at 120 ° C, under pressure 0.101 325 MPa and at least 24 hours after cooling Determines the appearance of the solution view of plug, current acidity, conductivity, foreign organic matter spectrophotometric in the wavelength range of 220 to 360 nm, proof for arsenic, barium, borates, aluminum, magnesium, heavy metals in two ways, titanium, calcium, strontium, iron, zinc, ammonium salts, amines, phosphates, sulphates, sulphides, acid sulphides, thiosulphates and quantitative determination sodium chloride.

Description

The present invention provides a method of determining the safety of medical rubber stoppers in a saline solution of a concentration O, ^{9, 0} / o and 10.0 '% w.

The principle of the invention is characterized in that it is present in 0.9% and 10.0% w / v sodium chloride solution. after contacting the stopper with this solution for 30 minutes, at 120 ° C, at a pressure of 100 psig and at least 24 hours after cooling, it determines the appearance of the solution, the appearance of the stopper, actual acidity, conductivity, foreign wavelength spectrophotometric range 220 to 360 nm, evidence of arsenic, barium, borates, aluminum, magnesium, heavy metals in two ways, titanium, calcium, strontium, iron, zinc, ammonium salts, amines, phosphates, sulfates, sulfides, acid sulfides, thiosulfates and quantitative determination of sodium chloride.

The present invention provides a method for the determination of the safety of rubber plugs in healthcare in 0.9% and 10.0% w / v sodium chloride solution.

The method of determining the safety of rubber plugs in health care on model solutions according to CSN 62 1156 - Testing of rubber for health purposes - has proved to be unsatisfactory and far from practical. It is necessary to approach testing for model solutions which characterize part of a wide variety of infusion solutions and are basically basic solutions, simple to be able to judge the high quality of the solution itself as well as the packaging material including the rubber stopper. In the monograph for isotonic sodium chloride solution, CsL3 requires monitoring of the appearance of the solution, the sodium and chloride identity test, the purity test for the measurement of actual acidity by electrometric measurement, and the determination of the sodium chloride content by argentometric titration with potentiometric indication. ON 86 4421 with effect from 1.1.1966 for isotonic sodium chloride solution also does not require purity tests.

Based on experimental results, it has been shown that it is possible to carry out tests on possible migrating components and are listed in the description of the design.

Summary of the invention consists in removing under-test plugs for medical use of the method for setting the safety of medical rubber stoppers, characterized in that the sodium chloride concentration of 0.9% and 10.0 ^a / o hmot./obj . after contacting the stopper with this solution for 30 minutes at 120 ° C and at a pressure of 100 psig and at least 24 hours after cooling, the CsL3 test shall be supplemented by determining the appearance of the stopper, conductivity measurement, extraneous organic matter spectrophotometrically in the 220 to 360 nm, test for purity on arsenic, barium, borate, aluminum, magnesium, heavy metals in two ways, titanium, calcium, zinc, iron, ammonium and amine salts, phosphates, sulphates, sulphides, acid sulphides and thiosulphates.

Extending the method of determining the safety of rubber plugs in health care with a model solution of sodium chloride at a concentration of 0.9% and 10.0% w / v, after contacting the plug with this solution for 30 minutes, at a temperature of 120 ° C and pressure The approximation in practice for direct use in the manufacture of infusion solutions containing sodium chloride shall be approximated by monitoring the appearance of the stopper, the measurement of the conductivity, the extraneous organic matter spectrophotometrically in the wavelength range 220 to 360 nm, and proof of ion purity arsenic, barium, borates, aluminum, magnesium, heavy metals in two ways, titanium, calcium, iron, zinc, ammonium and amine salts, phosphates, sulphates, sulphides, acid sulphides, thiosulphates confirms the possibility of using rubber plugs for the sodium chloride solution circuit, or monitoring the possible interaction of the stopper with the manufactured infusion solution of this type, the possibility of monitoring migrating substances to the ro and confirming the quality of the infusion solution towards the quality of the rubber stopper.

Execution example

The sodium chloride solution is prepared from a substance meeting the requirements for the preparation of infusion solutions. Dissolve in pyrogen-free water for injection meeting the requirements of the current Pharmacopoeia t. no. ČsL3 technology used for the preparation of infusion solutions.

The 500 ml infusion bottles are washed well, bottle washing technology adapts to the washing machine program.

The bottles are soaked for 24 hours in a sodium phosphate degreasing solution of Na 3 PO 4 (30 g / L) and chloramine BS (5 g / L) for degreasing and disinfection. After this time, the bottles are rinsed well in running water for about 1.5 minutes and rinsed for another 1.5 minutes in hot water at 80 ° C, the bottles are rinsed with neutralizing citric acid solution (20g / L), rinsed with warm water 1.5 minutes with cold drinking water for 1.5 minutes and pyrogen-free water so that 100 ml of water is consumed per bottle. After thoroughly washing the bottles sterilized for 120 minutes at 180 C with hot air ^L0, the end of sterilization, the bottles filled with the prepared solution of 400 ml of sodium chloride solution and stopper was well washed with plugs. Does the washing technology of the plugs be modified by washing the rubber plugs under running water to remove surface particles? and coarse debris. They are soaked in a detergent degreaser Dubaryl (or other suitable for this purpose) (5g / L), then rinsed well with potable water, pouring on 4X stoppers, distilled water 2X, then distilled water is poured on the stoppers and the stoppers are boiled 10. minutes, the water is decanted and rinsed 3X in pyrogen-free water. The stoppers are poured with pyrogen-free water and the plugs are sterilized for 30 minutes at 120 ° C. After cooling, the pyrogen-free water from the corks is poured off and the corks are ready to stop the bottles.

The bottles after filling and stoppering are sterilized at 120 ° C for 30 minutes down the throat. At the same time, under the same conditions, prepare a blank sample as the reference sample in the glass.

After sterilization, the solutions are allowed to cool and tests are carried out after 24 hours.

Under the same technological conditions, a concentrated solution may also be prepared by sterilizing 3 stoppers immersed in the sodium chloride solution to be examined.

a weight ratio of 8 g of stopper per 100 ml of sodium chloride solution. At the same time, prepare a reference solution without stopper, under the same conditions as with the stopper. The sodium chloride solution is tested as follows:

1. Appearance of solution - change in clarity, color, odor and mechanical impurities against the reference solution is monitored.

2. The appearance of the stopper - the change of the stopper after sterilization is monitored, the puncture capability, fragmentation, tackiness, tightness after injection and the like are tested.

3. Acute acidity - the pH of the solution is measured electrometrically at a suitable pH meter. Examine the difference between the measured values in the test solution and the reference solution.

4. Conductivity - measured on a suitable conductometer. The measured value must not be higher in the test solution than in the reference solution.

5. Foreign organic contaminants - Measure the spectral absorption curve over the wavelength range 220 to 360 nm, in 10 nm increments.

The absorbance of the sample and of the reference solution are monitored.

Identity tests

6. Sodium - To 5,0 ml of the test solution add 2,0 ml of 100 g / L potassium carbonate solution, the solution remaining clear. If 4.0 ml of potassium hexahydroxoantimonate solution are added and reheated, a white crystalline precipitate precipitates after a while. The precipitation of the precipitate is promoted by rubbing with a glass rod (Na ⁺ ).

Preparation of potassium hexahydroxoantimonate solution g Dissolve potassium hexahydroxoantimonate potassium in 95 ml of boiling water. The solution is cooled rapidly, 50 ml of 50 g / L potassium hydroxide solution, 5.0 ml of 0.1 mol / L hydroxide solution c (NaOH) are added and the solution left to stand for 24 hours. The liquid is then filtered and the filtrate is made up to 150 ml with water.

Sensitivity test: To 10 ml of the tube add 7 ml of sodium chloride solution c (NaCl) = 0,1 mol / L, mix, within 15 minutes a white, slightly crystalline precipitate must be formed. Prepared when needed.

7. Chlorides - To 5,0 ml of the test solution add 5,0 ml of water, 1,0 ml of dilute sulfuric acid solution and 3 drops of silver nitrate solution c (AgNO3) = 0,1 mol / L. A white crystalline precipitate precipitates, readily soluble in dilute α8 ammonia, insoluble in concentrated nitric acid (Cl ^- j).

Purity tests

8. Arsenic - the stage of the draft general article to ČsL4 is tested as follows:

Pipette 20.0 ml of test solution into the flask of the arsenic instrument, add 5.0 ml of fuming hydrochloric acid], arsenic-free, 2.0 ml of potassium iodide solution (150 g / L) and 0,5 ml of tin (II) chloride solution. (400 g / L), concentrated arsenic-free concentrated hydrochloric acid. The mixture is mixed thoroughly and allowed to stand for 15 minutes to reduce arsenic compounds, if present, to arsenites. Meanwhile, cotton impregnated with lead acetate solution (100 g / L) is placed in a glass tube connecting the two parts of the apparatus, 3.0 ml of pyridine silver diethylamidodithium carbonate solution is measured to kill the retina and to the absorption tube. Carefully introduce 3.0 g of arsenic-free granulated zinc into the instrument and immediately close the flask by attaching it to the instrument, leaving the escaping hydrogen through the absorption tube for 60 minutes. If the evolution of hydrogen is weakened, an additional portion of fuming hydrochloric acid, arsenic-free, or a small amount of stannous chloride is added to the label to activate the zinc.

The test is also performed with the reference solution. The pyridine solution of silver diethylamidodithium carbonate must not be more intensely colored in the test solution than in the reference solution.

Preparation of a pyridine solution of silver diethylamidodithium carbonate

Dissolve 0.5 g of silver diethylamidodithium carbonate (CsH5) 2NCS, SAg in freshly distilled pyridine per 100 ml of solution and filter into a dry, dark ground glass bottle with the solution standing for about 2 weeks.

9. Barium and strontium - test taken from CSN 62 1156 - Chemical testing of rubber in water leach as follows:

To 5.0 ml of the test solution add 0.20 ml of 500 g / L dilute sulfuric acid solution. Within 2 hours, the test solution must not change more than the reference solution under the same conditions.

10. Borates - Tested according to a method adapted to the method of testing rubber bays in health care as follows:

To 5.0 ml of the test solution add 1.0 ml of dilute hydrochloric acid (10 g / L) drop by drop of turmeric paper. Prepare a standard solution.

The turmeric paper must not stain more intensely with the sample than the paper dropped with the reference solution.

11. Aluminum - shall be tested according to a method adapted for the method of testing rubber plugs in health care as follows:

To 5.0 ml of the test solution add 0.20 ml of ammonium acetate solution (10 g / L) and 0.20 ml of aurintricarbonate ammonium ammonium salt solution or tetraoxyflavinol (1.0 g / L) and add 0.5 ml of saturated ammonium carbonate solution (1 g / ml). The test solution should not be more intensely colored than the reference solution prepared under the same conditions.

12. Magnesium, calcium - the stage is generally tested for Cs4 as follows:

To 10.0 ml of the test solution add dilute ammonia solution to the basic reaction, 2.0 ml of ammonium chloride solution (100 g / L), 5.0 ml of sodium hydrogen phosphate solution (50 g / L) and mix thoroughly.

Within 15 minutes after the addition of the sodium hydrogen phosphate solution, the solution must not become more cloudy than the reference solution under the same conditions as the test solution.

13. Heavy metals - is tested according to the draft general article for ČsL4 in the manner of I. and II. as follow:

Method I. To 10.0 ml of the test solution add 0.50 g of ammonium chloride and, after dissolution, 1 drop of dilute ammonia solution (100 g / l, 3 drops of sodium sulphide and mix).

Within 2 minutes of the addition of sodium sulphide, the test solution shall not be more intensely colored than the reference solution under the same conditions.

Method II. - To a further 10,0 ml of the test solution, add 1,0 ml of dilute acetic acid solution (60 ml / LJ, 2,0 ml of hydrogen sulphide water) and mix.

Within 5 minutes of the addition of hydrogen sulphide, the test solution must not be more intensely colored than the reference solution under the same conditions.

14. Titanium - shall be tested according to a method adapted for the method of testing rubber stoppers used in health care as follows:

Acidify 5.0 ml of the test solution with 2.0 ml of dilute sulfuric acid solution (100 g / LJ) and add 5.0 ml of hydrogen peroxide solution (30 ml / L). equal conditions.

(Positive reaction can prove 0.01 mg Ti, the reaction is canceled by Cr and Fe

15. Calcium and strontium - is tested according to the draft general article for CsL4 as follows:

To 10.0 ml of the test solution add dilute sodium hydroxide solution to the basic reaction, 2.0 ml of ammonium oxalate solution and mix thoroughly.

Within 15 minutes of the addition of ammonium oxalate, the test solution must not become more cloudy than the reference solution under the same conditions.

16. Iron - Tested according to a method adapted for the method of testing rubber plugs in health as follows:

To 10.0 ml of the test solution, add a few K2S2O3 potassium persulfate crystals, a few drops of dilute hydrochloric acid solution and heat. After addition of sodium rhodanide solution NaCNS, the solution shall not be more intensely colored red than the reference solution under the same conditions.

18. Zinc - tested according to the Compendium medicamentorum for water leach as follows:

After addition of 10 drops of 50 g / l potassium ferrocyanide solution, 10.0 ml of the test solution must not become more cloudy than the reference solution under the same conditions.

19. Ammonium salts and amines - according to the proposal of the general article ČsL4 is tested as follows:

To 10.0 ml of the test solution add 0.50 ml of Nessler-Winkler reagent, shake vigorously.

After 5 minutes, the test solution must not be more intensely rye-colored than the reference solution under the same conditions.

Preparation of Nessler-Winkler reagent

Dissolve 1.0 g of mercuric iodide and 5,0 g of potassium bromide in 10 ml of water, add 20 ml of sodium hydroxide solution (120 g / L) and make up to 100 ml with water. After 24 hours, filter, using a clear colorless solution. It is protected from light.

20. Phosphates - Tested according to a method adapted for the method of testing rubber stoppers as follows:

Pipette 10.0 ml of the test solution into a 25 ml metal tin Erlenmeyer flask, add a few sodium chloride crystals and 5 drops of ammonium molybdate solution in sulfuric acid. The test sample must not be more intensely blue than the reference solution under the same conditions.

Preparation of ammonium molybdate in sulfuric acid

Dissolve 2.0 g of ammonium molybdate in 20 ml of water and pour into 60 ml of dilute sulfuric acid solution (500 g / L).

21. Sulphates - according to the proposal of the General Purpose, it is tested as follows:

To 10.0 ml of the test solution add 0.5 ml of dilute hydrochloric acid solution, add 1.0 ml of barium chloride solution (100 g / L) and shake vigorously for one minute.

Within 15 minutes after shaking, the test solution must not become turbid more than the reference solution under the same conditions.

22. Sulphides, acid sulphides - tested according to ČSN 62 1156 - Chemical testing of rubber for health - for water leachate - as follows:

After addition of sodium acetate (10 g / L) solution, 5.0 ml of the test solution must not be more intensely colored than the reference solution under the same conditions.

23. Thiosulphates - tested according to ČSN 62 1156 - Chemical testing of rubber for health purposes as follows:

To 5.0 ml of the test solution add a few drops of silver nitrate solution c (AgNO3) = 0.1 mol / L. The test solution must not be more intensely colored than the reference solution under the same conditions.

Claims (5)

SUBJECT Method of determining the safety of rubber stoppers in health care characterized in that in a sodium chloride solution at a concentration of 0.9% and 10.0% w / v, after contacting the stopper with this solution for 30 minutes, at a temperature of 120 ° C , at a pressure of 0.101 325 MPa and at least 24 hours after cooling, the appearance of the solution, the appearance of the stopper, the acute acidity, the conductivity, the foreign or quantitative determination are determined. 24. Sodium chloride - To 5.0 ml of the test solution add 25 ml of dilute sulfuric acid, titrate from the microburette with silver nitrate solution c (AgNOs) = 0.1 mol / L, stirring potentiometrically to silver and saturated calomel. electrode. 1.0 ml of silver nitrate solution c (AgNCD) = 0.1 mol / L corresponds to 0.005844 grams of NaCl. When monitoring new rubber compounds or changing auxiliaries in the manufacture of medical plugs, it is necessary to monitor whether auxiliary components are used that have not been tested in the above-mentioned proposal and need to be supplemented by monitoring the leachability of these substances. To accelerate the aging information of the rubber stoppers, the method of Compendium medicamentorum leaching in a weight ratio of 8 g of rubber stopper and 100 ml of sodium chloride solution may also be carried out. Possibility of testing sodium chloride infusion solution to confirm the quality and to avoid undesirable effects of the rubber stopper on the finished product.