Analysis of the differences and similarities of the test methods of non-volatile matter between the medical plastic bottle and related parts

Medical plastic bottle is an excellent packaging container for medicine

It has the advantages of high strength, strong internal pressure resistance, light weight, easy to carry and convenient filling

It is widely used in the packaging of oral solid drugs and oral liquid drugs

With the plastic packaging gradually becoming an important branch of pharmaceutical packaging, the global demand for pharmaceutical plastic bottles is increasing at a rate of 4.3% per year, and it is developing rapidly in the direction of multi varieties and specialization

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Technical requirements for pharmaceutical plastic bottles and components - the drug package system composed of non-volatile pharmaceutical plastic bottles and related components, whose quality, safety and use performance have an important impact on the quality of drugs

The results show that the air permeability and moisture permeability of polymer containers, the leaching of additives and the adsorption of drugs will threaten the stability of drugs

Therefore, in 1981, the State Administration of medicine formulated and issued the (separator) code of the A pharmaceutical packaging regulation, measures for the administration of pharmaceutical packaging (for Trial Implementation), was implemented nationwide

By 2015, the food and Drug Administration had issued 130 national standards for packaging materials and containers that directly contact with pharmaceuticals

These regulations and standards provided the legal basis for the quality and performance management of pharmaceutical packaging materials and required that they must meet the pharmaceutical requirements and meet the standards for the protection of human health and safety

According to the national standard for drug packaging materials implemented on December 1, 2015, the medical plastic bottles mainly refer to polyester bottles, polypropylene bottles and high-density polyethylene bottles

The relevant components include the oral solid medical low-density polyethylene moisture-proof combination bottle cap and medical aluminum plastic sealing gasket

In the standard, inspection items include appearance, identification, tightness, water vapor transmission, burning residue, non-volatile matter, etc

In terms of non-volatile matter, it refers to a kind of substance that migrates into the drug on the contact material of the drug

These substances come from packaging materials, containers and sealed components

Taking plastics as an example, it is a kind of polymer material which is formed under special conditions by addition polymerization or polycondensation in different monomer forms and by adding certain additives

When the plastic packaging materials contact with the drugs, the monomers, oligomers, additives, cross-linking agents, curing agents, plasticizers, etc

diffuse to the drug surface, and then are solvated or dissolved, so as to migrate to the drugs

When patients take these drugs, the above substances accumulate in the human body for a long time, causing irreversible damage to organs, immune system and reproductive system

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The similarities and differences of non-volatile test methods for pharmaceutical plastic bottles and components are based on the national standards for drug packaging materials implemented on December 1, 2015

Next, the author compares the similarities and differences of non-volatile test methods for pharmaceutical plastic bottles and related components

2.1 according to the material classification of oral liquid medicine bottle and external liquid medicine bottle, the oral liquid medicine bottle includes polypropylene bottle, high-density polyethylene bottle and polyester bottle

The external liquid medicine bottle mainly refers to high-density polyethylene bottle

The nonvolatile test method of this kind of medical plastic bottle is as follows: 2.1.1 prepare the test solution, take 3 parts of the inner surface area of the flat part of the product (divided into small pieces with a length of 5cm and a width of 0.3cm), place them in the conical bottle with a plug, add some water, shake and wash the small pieces, discard the water, and repeat the operation once

After drying at 30-40 ℃, soak 200ml of water (70 ℃ ± 2 ℃), 65% ethanol (70 ℃ ± 2 ℃), n-hexane (58 ℃ ± 2 ℃) for 24 hours, take it out and cool it to room temperature, use the same batch of test solvent to supplement the original volume as the test solution, and use the same batch of water, 65% ethanol, n-hexane as the blank solution

2.1.2 nonvolatile test Accurately measure 50ml of water, 65% ethanol, n-hexane test solution and blank solution respectively, and put them into a constant weight evaporating dish, evaporate them in water bath, dry them at 105 ℃ for 2 hours

After cooling, accurately weigh them

The difference between the water nonvolatile residue and blank solution residue shall not exceed 12.0mg; the difference between the 65% ethanol nonvolatile residue and blank solution residue shall not exceed 50.0mg; the difference between the n-hexane nonvolatile residue and blank solution residue shall not exceed 50.0mg The difference between the residue and the blank liquid color shall not exceed 75.0mg

2.2 oral solid medicine bottles are mainly polypropylene bottles, high-density polyethylene bottles and polyester bottles

The test method of nonvolatile substance is the same as that of oral liquid medicine bottle

The only difference (separator) is that the washing process needs to be repeated twice in the preparation of test solution

2.3 the sealing gasket of oral solid medicine bottle is mainly made of composite film and cardboard through adhesive

For different materials of oral solid medicine bottles, the structure of composite membrane is also different

According to the national standard of packaging materials and containers for drugs in direct contact, the mouth of oral solid medical polypropylene bottle should be sealed with sealing gasket made of PET / Al / PP composite film, The sealing gasket made of PET / Al / PET composite film shall be used for sealing the mouth of oral solid medical polyester bottle, and the sealing gasket made of PET / Al / PE composite film shall be used for sealing the mouth of oral solid medical high density polyethylene bottle

Compared with the test method of non-volatile substances in medicinal bottles, the sample size, washing and soaking, and the sampling amount and test result requirements of the test solution preparation link of sealing gasket are different

(1) The inner surface area of sealing gasket is 600cm2, and small pieces of samples with a length of 3cm and a width of 0.3cm are divided

Compared with the test sample size of the medicinal bottle, the length is reduced by 2cm and the width remains unchanged

(2) Wash and soak to prepare sealing gasket in three parts of conical flask with stopper, without washing and drying procedures, add water (70 ℃± 2 ℃), 65% ethanol (70 ℃± 2 ℃), n-hexane (58 ℃± 2 ℃) 200ml to soak for 2 hours, cool to room temperature, supplement to the original volume with the same batch of test solvent as the test solution, and use the same batch of water, 65% ethanol, n-hexane as the blank solution

It should be noted that the soaking time is shortened to 2 hours compared with that in the non-volatile substance test of medicinal bottles

(3) The test method of nonvolatile substance of the sealing gasket is the same as that of the medicine bottle

The difference is that the sampling quantity of the test solution and the blank solution increases to 100ml

The standard stipulates that the difference between water nonvolatile residue, 65% ethanol nonvolatile residue, n-hexane nonvolatile residue and blank residue of sealing gasket shall not exceed 30.0mg

2.4 oral solid medicine low density polyethylene moisture-proof combination bottle cap oral solid medicine low density polyethylene is an oral solid medicine plastic bottle cap with low density polyethylene (LDPE) as the main raw material, silica gel desiccant (silica gel: macromolecule sieve 4:6) and cardboard as the barrier material

The test method of non-volatile matter of this kind of material is quite different from that of medicine bottle, which is shown in the increase of sample preparation specification, the proportion of test solution to be prepared, and the limit requirements of test results, etc

2.4.1 for the preparation of the test solution, take 3 parts of the cap body (small pieces with a length of 1cm and a width of 1cm) respectively, put them into conical bottles with plugs, add some water, shake and wash the small pieces, discard the water, and repeat the operation twice

Water (70 ℃± 2 ℃), 65% ethanol (70 ℃± 2 ℃), n-hexane (58 ℃± 2 ℃) are respectively soaked for 24 hours according to the proportion of weight and volume of extraction solution (0.2g / ml), then they are taken out and cooled to room temperature, supplemented to the original volume with the same batch of test solvent as the test solution, with the same batch of water, 65% ethanol, n-hexane as the blank solution, and the following tests are carried out

2.4.2 nonvolatile test Accurately measure 50ml of water, 65% ethanol, n-hexane test solution and blank solution respectively, and put them into a constant weight evaporating dish, evaporate them in water bath, dry them at 105 ℃ for 2 hours

After cooling, accurately weigh them

The difference between the water nonvolatile residue and blank solution residue shall not exceed 12.0mg; the difference between the 65% ethanol nonvolatile residue and blank solution residue shall not exceed 50.0mg; the difference between the n-hexane nonvolatile residue and blank solution residue shall not exceed 50.0mg The difference between residue and blank residue shall not exceed 200.0mg

With the implementation of the new national standard for pharmaceutical packaging, the test of non-volatile substances in pharmaceutical plastic bottles and components will become a necessary project for pharmaceutical enterprises and pharmaceutical packaging enterprises

However, the efficiency, accuracy and security of testing has become a new problem to be solved

In the process of nonvolatile test, evaporation, drying and weighing are indispensable steps, which are also time-consuming steps

It usually takes at least 4 hours to test the nonvolatile substance manually

In the process, it is necessary to manually move the container with test solution and blank solution between evaporation, drying and weighing equipment

The test process is tedious and monotonous, and the manual operation has a great impact on the test results

In addition, some test reagents are toxic, such as n-hexane

This is a kind of low toxic liquid, which enters the human body through respiratory tract, skin and other ways

Long term contact can cause chronic poisoning symptoms such as headache and numbness, threatening human health

In recent years, the automatic development of non-volatile matter test of medicine bottle and its components is more and more intense

The use of automatic equipment can automatically complete the evaporation, drying and weighing process, avoid the repetitive test operation of the test personnel, and improve the test efficiency

In this paper, the nonvolatile items of the oral solid medical polypropylene bottle and the medical polyester / aluminum / polypropylene sealing gasket were tested manually and automatically

The instrument used in the automatic test was Labthink C830 transfer and nonvolatile substance tester

From the test results, the deviation of the two test methods is small, the relative deviation is 0.7% and 1.2%

From the point of view of test time, the time of automatic test method is only 70% ~ 80% of that of manual test

This is because C830 instrument integrates the functions of evaporation, drying and weighing, which saves the moving time of reagents and the start-up preparation time of test device in manual test

At the same time, the application of the International (separator) advanced rapid evaporation technology will keep the reagent in the state of the least rapid evaporation before boiling, further reducing the evaporation time

In terms of safety, the automation equipment has designed a special gas tight recovery system for reagent vapor, which not only enhances the safety of testers, but also realizes the efficient recovery of reagents and reduces the test cost

Conclusion pharmaceutical plastic bottle is an important pharmaceutical packaging system at present and in the future

According to the national standard for drug packaging materials implemented on December 1, 2015, "non-volatile substances" are necessary items for the inspection of pharmaceutical plastic bottles and related components, such as sealing gasket and combination bottle cap, which are related to drug safety and personal health of patients

Through the comparison, it is found that there are great differences between the test process and the limit requirements of the non-volatile substances of the pharmaceutical plastic bottle and its related components, and the relevant testing workers should pay more attention to them.