Method for detecting element impurities in polyethylene packaging material

Abstract

The application discloses a method for detecting element impurities in polyethylene packaging materials. The method comprises the following steps: cutting the polyethylene packaging materials, precisely weighing, adding hydrochloric acid solution for reflux extraction, extracting element impurities in the polyethylene packaging materials, and obtaining a test sample solution; and using an inductively coupled plasma mass spectrometer (ICPMS) for detection, controlling the helium flow rate, and determining the test sample solution. According to the requirements of ICH Q3D on element impurities in preparations, the application traces back to the packaging materials in the previous step, studies the element impurities in the packaging materials first, determines the applicability of the packaging materials, and then determines whether the packaging materials can be used for corresponding preparation products, so that the loss of large-scale production of enterprises can be avoided.

Description

Technical Field

[0001] This invention belongs to the field of instrumental analysis technology, and specifically relates to a method for detecting elemental impurities in polyethylene packaging materials. Background Technology

[0002] During the synthesis of low-density polyethylene (LDPE) resin, different catalysts and metallic impurities may be introduced due to variations in suppliers and production methods. These metallic impurities include, but are not limited to, Cd, Pb, As, Hg, Co, V, Ni, Al, Zn, Zr, Ti, Cr, and other extractable metallic elements. Because different manufacturers are involved in confidentiality issues, it is impossible to accurately determine which metallic elements have been added to each type of LDP resin or what metallic elements remain. This poses a certain risk to companies that need to use LDP packaging materials.

[0003] If a method can be established that can simultaneously detect the three types of elements in ICHQ3D as well as some other common metallic elements, an accurate understanding of the elemental impurities that may be contained in each type of low-density polyethylene resin can be obtained. Then, by calculating the specifications of the products (food and pharmaceuticals, etc.) produced by companies using low-density polyethylene packaging materials, it is possible to determine whether there are any risks in using such low-density polyethylene packaging materials before large-scale production, thus avoiding losses for companies.

[0004] CN113447583A discloses a detection method for studying the impact of packaging materials on the quality of pharmaceutical solutions, and uses ICPMS to conduct migration tests on packaging materials, detecting 27 metal elements. However, the packaging material is a glass bottle, not polyethylene, and the migration test only targets the pharmaceutical solution, without extracting the packaging material itself. Therefore, the method is not applicable to the extraction and detection of metal impurities in polyethylene packaging materials. CN114764085A discloses the use of ICPMS technology to detect 15 elements in ultrapure resin materials, but its extraction solution is complex, including nitric acid, hydrochloric acid, and sulfuric acid. Slight misoperation by operators can easily lead to danger, posing a high degree of risk. Furthermore, the extraction process includes steps such as ashing and digestion, making the extraction process complex.

[0005] The Chinese Pharmacopoeia does not contain extraction methods or standard regulations for low-density polyethylene (LDPE). The new edition of the United States Pharmacopeia (USP) does not provide methods for detecting elemental impurities in LDP packaging materials; instead, it stipulates that testing should be performed only when deemed necessary and appropriate by the end user. <1661> The *Evaluation of Plastic Packaging Systems for Pharmaceutical Use and Their Materials of Construction* clearly stipulates that the detection of elemental impurities in packaging materials should include the determination of all relevant elemental impurities, regardless of whether they are included in *<661.1> PLASTIC MATERIALS OF CONSTRUCTION*. However, it does not provide corresponding detection methods. The European Pharmacopoeia's regulations on the content of some elements are not entirely suitable for pharmaceutical companies. For example, elements such as Hg, Pb, Cd, and Sb, which require special attention in finished products, are not explicitly specified in the European Pharmacopoeia. The *ICH Q3D Guideline on Elemental Impurities* does not mention the testing of packaging materials, especially low-density polyethylene. Summary of the Invention

[0006] In order to solve the above-mentioned technical problems, the purpose of this invention is to provide a method for detecting elemental impurities in polyethylene packaging materials.

[0007] To achieve the above-mentioned objectives, the technical solution adopted by this invention is: a method for detecting elemental impurities in polyethylene packaging materials, comprising the following steps: cutting the polyethylene packaging material into small pieces, accurately weighing the pieces, adding hydrochloric acid solution for reflux extraction, extracting elemental impurities from the polyethylene packaging material, and obtaining a test sample solution; using an inductively coupled plasma mass spectrometer (ICPMS) for detection, controlling the helium flow rate, and measuring the test sample solution.

[0008] Furthermore, the above-mentioned method for detecting elemental impurities in polyethylene packaging materials further includes the following steps: preparing a mixed elemental standard storage solution using elemental standard storage solutions; preparing a series of mixed elemental standard working solutions using the mixed elemental standard storage solution; performing detection using an inductively coupled plasma mass spectrometer (ICPMS), controlling the helium flow rate, measuring the series of mixed elemental standard working solutions, and plotting a standard curve.

[0009] Furthermore, in the above-mentioned method for detecting elemental impurities in polyethylene packaging materials, the elements include lithium, beryllium, magnesium, aluminum, arsenic, cobalt, copper, titanium, vanadium, chromium, manganese, nickel, zinc, mercury, gold, thallium, lead, cadmium, antimony, strontium, zirconium, molybdenum, barium, tin, iron, selenium, ruthenium, rhodium, palladium, indium, tungsten, platinum, and iridium.

[0010] Furthermore, in the above-mentioned method for detecting elemental impurities in polyethylene packaging materials, the concentration range of each element except iron in the mixed element standard series working solution is 2-40 ppb, and the concentration range of iron is 4-80 ppb.

[0011] Furthermore, in the above-mentioned method for detecting elemental impurities in polyethylene packaging materials, the concentration of the hydrochloric acid solution is 0.05M-0.2M, preferably 0.1M.

[0012] Furthermore, in the above-mentioned method for detecting elemental impurities in polyethylene packaging material, the solid-liquid ratio of the polyethylene packaging material to the 0.1M hydrochloric acid solution is 20g:40-50mL, preferably 20g:40mL.

[0013] Furthermore, in the above-mentioned method for detecting elemental impurities in polyethylene packaging materials, reflux extraction is performed for 0.5-3 hours, preferably 1 hour.

[0014] Furthermore, in the above-mentioned method for detecting elemental impurities in polyethylene packaging materials, the reflux temperature is 100-150℃, preferably 120℃.

[0015] Furthermore, the above-mentioned method for detecting elemental impurities in polyethylene packaging materials uses ICPMS for detection, with the helium flow rate controlled at 3.3-4.1 mL / min.

[0016] Furthermore, in the above-mentioned method for detecting elemental impurities in polyethylene packaging materials, when the elements to be determined are lithium, beryllium, magnesium, aluminum, arsenic, cobalt, copper, titanium, vanadium, chromium, manganese, nickel, zinc, mercury, gold, thallium, lead, cadmium, antimony, strontium, zirconium, molybdenum, barium, and tin, the helium flow rate is controlled at 3.8 mL / min; when the elements to be determined are iron, selenium, ruthenium, rhodium, palladium, indium, tungsten, platinum, and iridium, the helium flow rate is controlled at 3.3 mL / min.

[0017] Furthermore, in the above-mentioned method for detecting elemental impurities in polyethylene packaging materials, the polyethylene includes low-density polyethylene.

[0018] The beneficial effects of this invention are:

[0019] 1. This invention, based on the ICH Q3D requirements for elemental impurities in formulations, traces back to the packaging material, first studies the elemental impurities in the packaging material to determine its applicability, and then determines whether it can be used in the corresponding formulation product, thus avoiding losses to the company's large-scale production.

[0020] 2. Generally, the detection of elemental impurities depends on the intended use of the product. For injectable formulations, only the 10 elements required for injectable formulations are tested, while for inhaled formulations, only the 14 elements required for inhaled formulations are tested. However, the detection method in this application not only covers Class 1A, 2A, 2B, and 3 elemental impurities specified in the ICH Q3D Elemental Impurity Guidelines, as well as other elemental impurities such as Al, Fe, Mg, Mn, Zn, and W, but also includes Be, Zr, Ti, Sr, and In. This method provides more comprehensive and time-saving detection, allowing for the identification of specific elemental impurities in the low-density polyethylene packaging material under study using a single method. This enables the determination of which products (oral, inhalation, or injection) the material can be used in, ensuring product safety.

[0021] 3. In this application, 0.1M hydrochloric acid solution is preferably used for reflux extraction of elemental impurities in low-density polyethylene. Compared with ultrasonic and microwave extraction, the hydrochloric acid reflux extraction method of this application will not cause chemical changes in the packaging material, and can fully extract the elemental impurities contained in the low-density polyethylene packaging material. In addition, the elemental impurities have good solubility and stability in 0.1M hydrochloric acid solution.

[0022] 4. Compared to the use of nitric acid and sulfuric acid, the hydrochloric acid extract of this application has a simpler composition, and hydrochloric acid does not have the strong oxidizing properties of nitric acid and sulfuric acid, resulting in a higher safety factor, moderate concentration, and a simpler extraction process. The hydrochloric acid reflux extraction used in this application not only has higher extraction efficiency but also facilitates subsequent ICPMS detection operations.

[0023] 5. The ICPMS detection method used in this application is not the conventional standard mode; this invention employs the helium collision mode (KED). Many types of elemental impurities, during their passage through the nebulizer and sampling cone into the quadrupole mass deflector, can combine with other impurities or elements, leading to false results by inflating or deflating the measured element content. Generally, the more elements present, the more difficult they are to detect. This invention explored different KED helium flow rates for different elements, and determined the mass number and Rpq value for element detection, enabling accurate determination of each element. All methodological validation items met the requirements. Using Ge, Y, Tb, and Bi as internal standards (40 ppb), the correlation coefficients (r) for all 33 elements were greater than 0.995, the detection limits were all within the range of 0.000918 ppb to 0.361770 ppb, the recoveries were all within the range of 93.5% to 125.0%, and the RSD was ≤10.0%. Detailed Implementation

[0024] Instrument: NexION 1000G Inductively Coupled Plasma Mass Spectrometer

[0025] Ultrapure water: conductivity 18.2 MΩ . cm

[0026] Elemental standard storage solutions:

[0027] All elemental standard stock solutions were 1000 μg / mL and purchased from the National Center for Analysis and Testing of Nonferrous Metals and Electronic Materials. The elemental reference standards were: lithium (Li), beryllium (Be), magnesium (Mg), aluminum (Al), arsenic (As), cobalt (Co), copper (Cu), titanium (Ti), vanadium (V), chromium (Cr), manganese (Mn), nickel (Ni), zinc (Zn), mercury (Hg), gold (Au), thallium (Tl), lead (Pb), cadmium (Cd), antimony (Sb), strontium (Sr), zirconium (Zr), molybdenum (Mo), barium (Ba), tin (Sn), iron (Fe), selenium (Se), ruthenium (Ru), rhodium (Rh), palladium (Pd), indium (In), tungsten (W), platinum (Pt), and iridium (Ir).

[0028] Preparation of mixed element standard stock solutions:

[0029] Take the standard stock solutions of each element with a concentration of 1000 μg / mL, dilute them stepwise with 0.1 M hydrochloric acid and make up to volume, then mix them to prepare a mixed element standard stock solution.

[0030] The mixed element standard stock solution contains: lithium (Li) 1.0 μg / mL, beryllium (Be) 1.0 μg / mL, magnesium (Mg) 1.0 μg / mL, aluminum (Al) 1.0 μg / mL, arsenic (As) 1.0 μg / mL, cobalt (Co) 1.0 μg / mL, copper (Cu) 1.0 μg / mL, titanium (Ti) 1.0 μg / mL, vanadium (V) 1.0 μg / mL, chromium (Cr) 1.0 μg / mL, manganese (Mn) 1.0 μg / mL, nickel (Ni) 1.0 μg / mL, zinc (Zn) 1.0 μg / mL, mercury (Hg) 1.0 μg / mL, gold (Au) 1.0 μg / mL, thallium (Tl) 1.0 μg / mL, and lead. Pb 1.0 μg / mL, Cadmium (Cd) 1.0 μg / mL, Antimony (Sb) 1.0 μg / mL, Strontium (Sr) 1.0 μg / mL, Zirconium (Zr) 1.0 μg / mL, Molybdenum (Mo) 1.0 μg / mL, Barium (Ba) 1.0 μg / mL, Tin (Sn) 1.0 μg / mL, Iron (Fe) 2.0 μg / mL, Selenium (Se) 1.0 μg / mL, Ruthenium (Ru) 1.0 μg / mL, Rhodium (Rh) 1.0 μg / mL, Palladium (Pd) 1.0 μg / mL, Indium (In) 1.0 μg / mL, Tungsten (W) 1.0 μg / mL, Platinum (Pt) 1.0 μg / mL, Iridium (Ir) 1.0 μg / mL.

[0031] The mixed element standard stock solution was used in Examples 1 and 2 below.

[0032] Example 1

[0033] A method for detecting elemental impurities in polyethylene packaging materials, comprising the following steps:

[0034] Step 1: Prepare a mixed elemental standard storage solution using elemental standard storage solutions.

[0035] Furthermore, the elements include 33 elements such as lithium, beryllium, magnesium, aluminum, arsenic, cobalt, copper, titanium, vanadium, chromium, manganese, nickel, zinc, mercury, gold, thallium, lead, cadmium, antimony, strontium, zirconium, molybdenum, barium, tin, iron, selenium, ruthenium, rhodium, palladium, indium, tungsten, platinum, and iridium.

[0036] Step 2: Prepare a series of working solutions for mixed element standards using mixed element standard storage solutions.

[0037] In the mixed element standard series working solutions, the concentration range of each element except Fe is 2-40 ppb, and the concentration range of Fe is 4-80 ppb.

[0038] Step 3: Preparation of test sample solution: Cut the polyethylene packaging material into small pieces, weigh them accurately, add hydrochloric acid solution and reflux to extract the elemental impurities in the polyethylene packaging material, and make up the volume of the extract to obtain the test sample solution.

[0039] Furthermore, the concentration of the hydrochloric acid solution is 0.05M-0.2M.

[0040] Furthermore, the concentration of the hydrochloric acid solution is 0.1M.

[0041] Furthermore, the solid-liquid ratio of the polyethylene packaging material to the 0.1M hydrochloric acid solution is 20g:40-50mL.

[0042] Furthermore, the solid-liquid ratio of the polyethylene packaging material to the 0.1M hydrochloric acid solution is 20g:40mL.

[0043] Further, reflux extraction for 0.5-3 hours.

[0044] Furthermore, reflux extraction was performed for 1 hour.

[0045] Furthermore, the reflux temperature is 100-150℃.

[0046] Furthermore, the reflux temperature is 120°C.

[0047] Step 4: Use ICPMS for detection, control the helium flow rate, and measure the mixed element standard series working solutions and the test sample solutions.

[0048] Furthermore, ICPMS was used for detection, with the helium flow rate controlled at 3.3-4.1 mL / min.

[0049] Furthermore, when determining the elements lithium, beryllium, magnesium, aluminum, arsenic, cobalt, copper, titanium, vanadium, chromium, manganese, nickel, zinc, mercury, gold, thallium, lead, cadmium, antimony, strontium, zirconium, molybdenum, barium, and tin, the helium flow rate is controlled at 3.8 mL / min; when determining the elements iron, selenium, ruthenium, rhodium, palladium, indium, tungsten, platinum, and iridium, the helium flow rate is controlled at 3.3 mL / min.

[0050] (I) Exploring the Helium Flow Rate

[0051] The mass number condition was optimized for the isotopic abundance ratios of each element. The isotopic abundance ratios of elements Be, Al, As, Co, Mn, Au, and Rh were 100.0%, so no optimization of the mass number condition was performed.

[0052] Methods: Twenty-six elements (excluding Be, Al, As, Co, Mn, Au, and Rh, with relatively high abundance) were selected for exploration. Working standard solutions with concentrations ranging from 2 to 40 ppb (4 to 80 ppb for Fe) were prepared using elemental standard storage solutions. A NexION 1000G inductively coupled plasma mass spectrometer was used for detection at a helium flow rate of 3.8 mL / min. Standard curves were plotted with concentration on the x-axis and elemental signal on the y-axis, and the linear equations were derived. The results are shown in Table 1. Simultaneously, standard solutions sd3 with a theoretical concentration of 10 ppb for each element and a Fe concentration of 20 ppb were measured, and the relative standard deviations between the measured and theoretical concentrations were calculated. The results are also shown in Table 1.

[0053] Table 1. Determination results of 26 elements (those with higher abundance) at a helium flow rate of 3.8 mL / min.

[0054]

[0055]

[0056]

[0057]

[0058] As shown in Table 1, the linearity and relative standard deviation of Fe, Se, Ru, Pd, In, W, Pt, and Ir under a helium flow rate of 3.8 mL / min still need further optimization, while the validation results for other elements are generally better at mass numbers with higher abundance. Therefore, the helium flow rate was adjusted for elements Fe, Se, Ru, Pd, In, W, Pt, and Ir, and the detection was performed again. The results are shown in Table 2.

[0059] Table 2. Determination results of 8 elements at different helium flow rates.

[0060]

[0061]

[0062] As shown in Table 2, the validation results for elements Fe, Se, Ru, Pd, In, W, Pt, and Ir were all good at a flow rate of 3.3 mL / min. For elements Fe, Ru, In, Pd, W, Pt, and Ir, the element mass number with the larger abundance ratio was selected. For element Se, the validation results were better at a mass number of 77.9173.

[0063] Based on Tables 1 and 2, it was finally determined that in the method of the present invention, ICPMS was used for detection, and the helium flow rate for measuring 33 elements in the mixed element standard series working solution and the test sample solution is shown in Table 3.

[0064] Table 3. Mass numbers of 33 elements and helium flow rates (helium flow rate unit: mL / min)

[0065] element Li Be Mg Al As Co Cu Ti V mass number 7.016 9.0122 23.9850 26.9815 74.9216 58.9332 62.9298 47.948 50.944 Helium flow rate 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 element Cr Mn Ni Zn Hg Au Tl Pb Cd mass number 51.9405 54.9381 59.9332 63.9291 201.9710 196.967 204.975 207.977 111.903 Helium flow rate 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 element Sb Sr Zr Mo Ba Sn Fe Se Ru mass number 120.904 87.9056 89.9043 97.9055 137.905 119.902 56.9354 77.9173 101.904 Helium flow rate 3.8 3.8 3.8 3.8 3.8 3.8 3.3 3.3 3.3 element Rh Pd In W Pt Ir mass number 102.905 105.903 114.904 183.951 194.965 192.963 Helium flow rate 3.3 3.3 3.3 3.3 3.3 3.3

[0066] (II) Exploration of Extraction Conditions for Low-Density Polyethylene Packaging Materials

[0067] Considering that both nitric acid and sulfuric acid have strong oxidizing properties, accidents can easily occur if operators are not careful; and sulfuric acid is not suitable for use in ICPMS analysis instruments, nor is it suitable as an extraction solvent. Therefore, this application explores the extraction of low-density polyethylene packaging material using hydrochloric acid of different concentrations.

[0068] The content of various elemental impurities in low-density polyethylene packaging materials is calculated using the following formula:

[0069]

[0070] In the formula, Wx represents the content of each element impurity to be measured in the sample, in μg / g.

[0071] C1 represents the concentration of the element to be tested in the blank solution, in ng / mL.

[0072] C2 represents the concentration of the element to be measured in the sample solution, in ng / mL.

[0073] V is the volume of the sample solution, in mL.

[0074] M0 is the mass of the sample, in grams.

[0075] Recovery rate: The recovery rate is the ratio of the difference between the result obtained with spiked substance and the result obtained without spiked substance, to the theoretical value of the added standard substance.

[0076] Relative standard deviation: RSD% of 6 results.

[0077] 1. Impact of extraction method

[0078] 1) Prepare a series of working solutions for mixed element standards using mixed element standard stock solutions.

[0079] In six clean 50 mL volumetric flasks, precisely add 2 mL, 1 mL, 0.5 mL, 0.2 mL, 0.1 mL, and 0 mL of the above mixed element standard stock solution, respectively, and dilute to the mark with 0.1 M hydrochloric acid to prepare a series of working solutions for the mixed element standard.

[0080] 2) Preparation of test sample solution

[0081] 2.1) Preparation of test sample solution by 0.1M hydrochloric acid reflux extraction:

[0082] Cut low-density polyethylene bottles into 1cm × 2cm samples, with a total mass of 20g. Accurately weigh 12 20g samples and place them in round-bottom flasks, dividing them into 4 groups. One group contains only the sample, while the other three groups are accurately filled with 0.25mL, 0.50mL, and 0.75mL of mixed element standard stock solution, respectively. Then, add 40mL of 0.1M hydrochloric acid solution to each group and reflux at 120℃ for 1h. Transfer the extract to a 50mL volumetric flask and dilute to volume with 0.1M hydrochloric acid solution.

[0083] 2.2) Preparation of test sample solution by microwave extraction with 0.1M hydrochloric acid:

[0084] Cut the low-density polyethylene bottle into 4g samples. Accurately weigh 12 4g samples and place them in microwave digestion vessels, dividing them into 4 groups. One group contains only the sample, while the other three groups are accurately added with 0.05mL, 0.10mL, and 0.15mL of mixed element standard stock solution, respectively. Then, add 8mL of 0.1M hydrochloric acid solution to each group and microwave extract at 100℃ for 1h. Transfer the extract to a 10mL volumetric flask and dilute to volume with 0.1M hydrochloric acid solution.

[0085] 2.3) Preparation of sample solution for ultrasonic extraction with 0.1M hydrochloric acid:

[0086] Cut the low-density polyethylene bottle into 20g samples. Accurately weigh 12 20g samples and place them in beakers, dividing them into 4 groups. One group contains only the sample, while the other three groups are accurately filled with 0.25mL, 0.50mL, and 0.75mL of mixed element standard stock solution, respectively. Then, add 40mL of 0.1M hydrochloric acid solution to each group and extract by sonication for 1 hour. Transfer the extract to a 50mL volumetric flask and dilute to volume with 0.1M hydrochloric acid solution.

[0087] 3) ICPMS was used for detection, and the helium flow rate was controlled to determine the mixed element standard series working solutions and the test sample solutions.

[0088] The mixed element standard series working solutions were detected on an ICPMS (helium flow rate as shown in Table 3). A calibration curve was plotted with the signal of each element in the mixed element standard series working solutions as the ordinate and the concentration of each element in the mixed element standard series working solutions as the abscissa. The blank solution, the sample solution extracted by 0.1M hydrochloric acid reflux extraction (sample and 3 spiked samples), the sample solution extracted by 0.1M hydrochloric acid microwave extraction (sample and 3 spiked samples), and the sample solution extracted by 0.1M hydrochloric acid ultrasonic extraction (sample and 3 spiked samples) were then measured. The instrument automatically provided the concentration values ​​of each analyte in the blank solution, sample solution, and spiked sample solution. The recovery rate of each of the 33 elements was calculated under each extraction condition. The results of the recovery rate and relative standard deviation of the elements under different extraction conditions are shown in Table 4.

[0089] Table 4: Exploration of Experimental Conditions for Sample Pretreatment

[0090] Reflux extraction with 0.1M hydrochloric acid 0.1M hydrochloric acid ultrasonic extraction Microwave extraction with 0.1M hydrochloric acid Recovery rate 93.5％-125.0％ 65％-120％ 75.3％-143.2％ Relative standard deviation 3.28％ 7.15％ 12.5％

[0091] As shown in Table 4, different extraction methods using 0.1M hydrochloric acid yielded the following results: ultrasonic extraction showed the lowest elemental content and recovery rate, likely due to the lack of temperature control during ultrasonic extraction, leading to incomplete extraction at lower temperatures; while microwave extraction showed a higher recovery rate but also a larger relative standard deviation, likely due to the more severe extraction conditions resulting in significant differences in the extraction degree between parallel samples. Therefore, this invention preferably employs reflux extraction to extract elemental impurities from polyethylene packaging materials.

[0092] 2. Effect of hydrochloric acid concentration on extraction

[0093] 1) Prepare a series of working solutions for mixed element standards using mixed element standard stock solutions.

[0094] In six clean 50 mL volumetric flasks, precisely add 2 mL, 1 mL, 0.5 mL, 0.2 mL, 0.1 mL, and 0 mL of the above mixed element standard stock solution, respectively, and dilute to the mark with 0.1 M hydrochloric acid to prepare a series of working solutions for the mixed element standard.

[0095] 2) Preparation of test sample solution

[0096] 2.1) Preparation of test sample solution by 0.1M hydrochloric acid reflux extraction:

[0097] Cut low-density polyethylene bottles into 1cm × 2cm samples, with a total mass of 20g. Accurately weigh 12 20g samples and place them in round-bottom flasks, dividing them into 4 groups. One group contains only the sample, while the other three groups are accurately filled with 0.25mL, 0.50mL, and 0.75mL of mixed element standard stock solution, respectively. Then, add 50mL of 0.1M hydrochloric acid solution to each group and reflux at 120℃ for 1h. Transfer the extract to a 50mL volumetric flask and dilute to volume with 0.1M hydrochloric acid solution.

[0098] 2.2) Preparation of test sample solution by 0.05M hydrochloric acid reflux extraction:

[0099] Cut low-density polyethylene bottles into 1cm × 2cm samples, with a total mass of 20g. Accurately weigh 12 20g samples and place them in round-bottom flasks, dividing them into 4 groups. One group contains only the sample, while the other three groups are accurately filled with 0.25mL, 0.50mL, and 0.75mL of mixed element standard stock solution, respectively. Then, add 50mL of 0.05M hydrochloric acid solution to each group and reflux at 120℃ for 1h. Transfer the extract to a 50mL volumetric flask and dilute to volume with 0.05M hydrochloric acid solution.

[0100] 2.3) Preparation of test sample solution by 0.2M hydrochloric acid reflux extraction:

[0101] Cut low-density polyethylene bottles into 1cm × 2cm samples, with a total mass of 20g. Accurately weigh 12 20g samples and place them in round-bottom flasks, dividing them into 4 groups. One group contains only the sample, while the other three groups are accurately filled with 0.25mL, 0.50mL, and 0.75mL of mixed element standard stock solution, respectively. Then, add 50mL of 0.2M hydrochloric acid solution to each group and reflux at 120℃ for 1h. Transfer the extract to a 50mL volumetric flask and dilute to volume with 0.2M hydrochloric acid solution.

[0102] 3) ICPMS was used for detection, and the helium flow rate was controlled to determine the mixed element standard series working solutions and the test sample solutions.

[0103] The mixed element standard series working solutions were detected on an ICPMS (helium flow rate as shown in Table 3). A calibration curve was plotted with the signal of each element in the mixed element standard series working solutions as the ordinate and the concentration of each element in the mixed element standard series working solutions as the abscissa. The blank solution, the 0.1M hydrochloric acid reflux extraction method test sample solution (sample and 3 spiked samples), the 0.2M hydrochloric acid reflux extraction method test sample solution (sample and 3 spiked samples), and the 0.05M hydrochloric acid reflux extraction method test sample solution (sample and 3 spiked samples) were then measured. The instrument automatically provided the concentration values ​​of each analyte in the blank solution, sample solution, and spiked sample solution. The recovery rate of each of the 33 elements under each extraction condition was calculated. The results of the recovery rate and relative standard deviation of the elements under different extraction conditions are shown in Table 5.

[0104] Table 5: Exploration of the optimal concentration range of hydrochloric acid extract

[0105] Reflux extraction with 0.1M hydrochloric acid Reflux extraction with 0.2M hydrochloric acid Reflux extraction with 0.05M hydrochloric acid Recovery rate 93.5％-125.0％ 95.0％-132.2％ 70.7％-95.2％ Relative standard deviation 3.28％ 6.25％ 2.52％

[0106] As can be seen from Table 5, when the extraction solvent concentration is 0.05M hydrochloric acid, the extraction is incomplete and the element content is low. When 0.2M hydrochloric acid is used as the extraction solvent, the extraction results are not much different from those of 0.1M hydrochloric acid. From the perspective of saving costs, the preferred concentration of hydrochloric acid in this invention is 0.1M.

[0107] 3. Effect of hydrochloric acid extraction time on extraction

[0108] 1) Prepare a series of working solutions for mixed element standards using mixed element standard stock solutions.

[0109] In six clean 50 mL volumetric flasks, precisely add 2 mL, 1 mL, 0.5 mL, 0.2 mL, 0.1 mL, and 0 mL of the above mixed element standard stock solution, respectively, and dilute to the mark with 0.1 M hydrochloric acid to prepare a series of working solutions for the mixed element standard.

[0110] 2) Preparation of test sample solution

[0111] 2.1) Preparation of test sample solution for 0.5h extraction method:

[0112] Cut low-density polyethylene bottles into 1cm × 2cm samples, with a total mass of 20g. Accurately weigh 12 20g samples and place them in round-bottom flasks, dividing them into 4 groups. One group contains only the sample, while the other three groups are accurately filled with 0.25mL, 0.50mL, and 0.75mL of mixed element standard stock solution, respectively. Then, add 50mL of 0.1M hydrochloric acid solution to each group and reflux at 120℃ for 0.5h. Transfer the extract to a 50mL volumetric flask and dilute to volume with 0.1M hydrochloric acid solution.

[0113] 2.2) Preparation of sample solution for 1h extraction method:

[0114] Cut low-density polyethylene bottles into 1cm × 2cm samples, with a total mass of 20g. Accurately weigh 12 20g samples and place them in round-bottom flasks, dividing them into 4 groups. One group contains only the sample, while the other three groups are accurately filled with 0.25mL, 0.50mL, and 0.75mL of mixed element standard stock solution, respectively. Then, add 50mL of 0.1M hydrochloric acid solution to each group and reflux at 120℃ for 1h. Transfer the extract to a 50mL volumetric flask and dilute to volume with 0.1M hydrochloric acid solution.

[0115] 2.3) Preparation of test sample solution for 2h extraction method:

[0116] Cut low-density polyethylene bottles into 1cm × 2cm samples, with a total mass of 20g. Accurately weigh 12 20g samples and place them in round-bottom flasks, dividing them into 4 groups. One group contains only the sample, while the other three groups are accurately filled with 0.25mL, 0.50mL, and 0.75mL of mixed element standard stock solution, respectively. Then, add 50mL of 0.1M hydrochloric acid solution to each group and reflux at 120℃ for 2 hours. Transfer the extract to a 50mL volumetric flask and dilute to volume with 0.1M hydrochloric acid solution.

[0117] 2.4) Preparation of test sample solution for 3h extraction method:

[0118] Cut low-density polyethylene bottles into 1cm × 2cm samples, with a total mass of 20g. Accurately weigh 12 20g samples and place them in round-bottom flasks, dividing them into 4 groups. One group contains only the sample, while the other three groups are accurately filled with 0.25mL, 0.50mL, and 0.75mL of mixed element standard stock solution, respectively. Then, add 50mL of 0.1M hydrochloric acid solution to each group and reflux at 120℃ for 3h. Transfer the extract to a 50mL volumetric flask and dilute to volume with 0.1M hydrochloric acid solution.

[0119] 3) ICPMS was used for detection, and the helium flow rate was controlled to determine the mixed element standard series working solutions and the test sample solutions.

[0120] The mixed element standard series working solutions were detected on an ICPMS (helium flow rate as shown in Table 3). A calibration curve was plotted with the signal of each element in the mixed element standard series working solutions as the ordinate and the concentration of each element in the mixed element standard series working solutions as the abscissa. The blank solution, the 0.5h extraction method test sample solution (sample and 3 spiked samples), the 1h extraction method test sample solution (sample and 3 spiked samples), the 2h extraction method test sample solution (sample and 3 spiked samples), and the 3h extraction method test sample solution (sample and 3 spiked samples) were then measured. The instrument automatically provided the concentration values ​​of each analyte in the blank solution, the sample solution, and the spiked sample solution. The recovery rate of each of the 33 elements under each extraction condition was calculated. The results of the recovery rate and relative standard deviation of the elements under different extraction conditions are shown in Table 6.

[0121] Table 6: Exploration of sample extraction time using hydrochloric acid

[0122] Extraction for 1 hour Extraction time 0.5 hours Extraction time 2 hours Extraction time 3 hours Recovery rate 93.5％-125.0％ 86.8％-122.6％ 106.6％-138.9％ 97.5％-133.6％ Relative standard deviation 3.28％ 5.03％ 8.25％ 7.29％

[0123] As can be seen from Table 6, extending the extraction time does not significantly improve the results of element extraction. Therefore, the present invention preferably uses 0.1M hydrochloric acid for reflux extraction for 1 hour.

[0124] In summary, the method and application for trace element impurity analysis of low-density polyethylene packaging materials provided by this invention have good detection effect on elemental impurities in low-density polyethylene packaging materials, with excellent detection accuracy and precision. It is suitable for promotion in the field of analytical testing and has broad development prospects.

[0125] Example 2

[0126] A method for detecting elemental impurities in polyethylene packaging materials, comprising the following steps:

[0127] Step 1: Prepare a mixed elemental standard storage solution using elemental standard storage solutions.

[0128] All elemental standard storage solutions had a concentration of 1000 μg / mL and were purchased from the National Nonferrous Metals and Electronic Materials Analysis and Testing Center.

[0129] The mixed element standard stock solution contains: lithium (Li) 1.0 μg / mL, beryllium (Be) 1.0 μg / mL, magnesium (Mg) 1.0 μg / mL, aluminum (Al) 1.0 μg / mL, arsenic (As) 1.0 μg / mL, cobalt (Co) 1.0 μg / mL, copper (Cu) 1.0 μg / mL, titanium (Ti) 1.0 μg / mL, vanadium (V) 1.0 μg / mL, chromium (Cr) 1.0 μg / mL, manganese (Mn) 1.0 μg / mL, nickel (Ni) 1.0 μg / mL, zinc (Zn) 1.0 μg / mL, mercury (Hg) 1.0 μg / mL, gold (Au) 1.0 μg / mL, thallium (Tl) 1.0 μg / mL, and lead. Pb 1.0 μg / mL, Cadmium (Cd) 1.0 μg / mL, Antimony (Sb) 1.0 μg / mL, Strontium (Sr) 1.0 μg / mL, Zirconium (Zr) 1.0 μg / mL, Molybdenum (Mo) 1.0 μg / mL, Barium (Ba) 1.0 μg / mL, Tin (Sn) 1.0 μg / mL, Iron (Fe) 2.0 μg / mL, Selenium (Se) 1.0 μg / mL, Ruthenium (Ru) 1.0 μg / mL, Rhodium (Rh) 1.0 μg / mL, Palladium (Pd) 1.0 μg / mL, Indium (In) 1.0 μg / mL, Tungsten (W) 1.0 μg / mL, Platinum (Pt) 1.0 μg / mL, Iridium (Ir) 1.0 μg / mL.

[0130] Step 2: Prepare a series of working solutions for mixed element standards using mixed element standard storage solutions.

[0131] In the mixed element standard series working solutions, the concentration range of Fe is 4-80 ppb, and the concentration range of the other elements is 2-40 ppb.

[0132] Step 3: Preparation of the test sample solution: Take low-density polyethylene packaging material, cut it into small pieces, and take a total sample weight of 20g. After accurate weighing, place it in a round-bottom flask, add 40mL of 0.1M hydrochloric acid solution, and reflux at 120℃ for 1h to extract elemental impurities from the polyethylene packaging material. Transfer the extract to a 50mL volumetric flask and dilute to volume with 0.1M hydrochloric acid solution. Prepare a blank solution at the same time.

[0133] Step 4: Use ICPMS for detection. As shown in Table 3, control the helium flow rate and measure the mixed element standard series working solutions, test sample solutions and blank solutions.

[0134] Table 7 Operating parameters of the NexION 1000G inductively coupled plasma mass spectrometer

[0135] Instrument parameters Parameter value Instrument parameters Parameter value carrier gas Argon RF power 1600W Atomizing airflow rate 1.02L / min Auxiliary airflow velocity 1.2L / min plasma flow rate 15L / min Rated voltage 220-240VAC Argon partial pressure gauge pressure 0.6~0.8Mpa peristaltic pump speed -42rpm Acquisition mode KED Collision Mode KED gas helium pressure 172±34Kpa Helium flow rate 3.8 and 3.3 Points Time 1000ms Number of repetitions 3 Rpq 0.25 Dwell Time 50ms

[0136] Table 8. Linear relationships of elements in the working solutions of the mixed element standard series.

[0137]

[0138]

[0139] (a) Precision test

[0140] Take 0.5 mL of the mixed elemental standard stock solution and dilute to 50 mL with 0.1 M hydrochloric acid. Inject the sample 6 times consecutively and record the absorption intensity. The results are shown in Table 9.

[0141] Table 9

[0142]

[0143]

[0144] As shown in Table 9, the RSD% of each element in 6 consecutive measurements was less than 20.0%, indicating that the instrument has good precision.

[0145] (II) Limit of Detection and Limit of Quantification

[0146] The blank solution was injected 11 times repeatedly. The detection limit for each element was three times the standard deviation of the multiple blanks, and the quantitation limit for each element was ten times the standard deviation of the multiple blanks. The results are shown in Table 10.

[0147] Table 10

[0148]

[0149] The limits of detection and limits of quantitation are shown in Table 10.

[0150] (III) Repeatability Test

[0151] Accurately weigh approximately 20g of shredded low-density polyethylene pharmaceutical eye drop bottle and place it in a round-bottom flask. Accurately add 0.5mL of mixed element standard stock solution and 40mL of 0.1M hydrochloric acid solution, and reflux for 1h. Transfer the extract to a 50mL volumetric flask and dilute to volume with 0.1M hydrochloric acid. The results are shown in Table 11.

[0152] Table 11

[0153]

[0154]

[0155] As shown in Table 11, the detection amounts of each element were basically consistent, and the RSD% were all less than 20%, indicating good method repeatability.

[0156] (iv) Recovery test

[0157] Accurately weigh approximately 20g of shredded low-density polyethylene pharmaceutical eye drop bottle and place it in a round-bottom flask. Prepare nine parallel aliquots, and accurately add 0.25mL, 0.50mL, and 0.75mL of mixed elemental standard stock solution to each. Then, add 40mL of 0.1M hydrochloric acid solution to each and reflux for 1 hour. Transfer the extract to a 50mL volumetric flask and dilute to volume with 0.1M hydrochloric acid solution. The recovery rate experimental data are shown in Table 12.

[0158] Table 12 Results of Recovery Rate Experiment

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170] As shown in Table 12, the recoveries of each element were between 70% and 150%, and the RSD% were all less than 20%, indicating good method accuracy.

[0171] (V) Examples of practical applications:

[0172] Testing revealed that the total content of all elemental impurities in this batch of low-density polyethylene (LDPE) packaging material was 0.17306 μg / g. Taking Ni as an example, the Ni content was 0.00244 μg / g. Assuming this batch of packaging material is used to produce single-dose LDPE eye drop vials, each vial weighs approximately 1.4263g, and the Ni content in one vial is 0.0035 μg. The eye drops produced from these vials have a volume of 0.4 mL. Assuming all Ni migrates into the eye drops, the Ni concentration from the LDPE packaging material in the eye drops would be 0.009 μg / mL. Then, by comparing the specific usage and dosage of the eye drops with the PDE value of Ni, it can be determined whether this batch of packaging material can be used to produce single-dose LDPE eye drop vials. Other elements can be determined using the same method.

Claims

1. A method for detecting an element impurity in a polyethylene packaging material, characterized by, The detection method comprises the following steps: The polyethylene packaging material is cut into pieces, weighed accurately, and then extracted by refluxing in a hydrochloric acid solution with a concentration of 0.05M-0.2M to extract the element impurities in the polyethylene packaging material and obtain a sample solution; the sample solution is detected by an inductively coupled plasma mass spectrometer (ICPMS) with a controlled helium flow rate.

2. The method for detecting the element impurities in the polyethylene packaging material according to claim 1, characterized in that, The detection method further comprises the following steps: preparing a mixed element standard stock solution by using element standard stock solutions; preparing a mixed element standard series working solution by using the mixed element standard stock solution; detecting the mixed element standard series working solution by the ICPMS with a controlled helium flow rate, and drawing a standard curve.

3. The method for detecting element impurities in polyethylene packaging material according to claim 1 or 2, characterized in that, The elements include lithium, beryllium, magnesium, aluminum, arsenic, cobalt, copper, titanium, vanadium, chromium, manganese, nickel, zinc, mercury, gold, thallium, lead, cadmium, antimony, strontium, zirconium, molybdenum, barium, tin, iron, selenium, ruthenium, rhodium, palladium, indium, tungsten, platinum and iridium.

4. The method for detecting the element impurities in the polyethylene packaging material according to claim 3, characterized in that, In the mixed element standard series working solution, the concentration of each element except iron ranges from 2ppb to 40ppb, and the concentration of iron ranges from 4ppb to 80ppb.

5. The method for detecting the element impurities in polyethylene packaging material according to claim 1 or 2, characterized in that, The concentration of the hydrochloric acid solution is 0.1M.

6. The method for detecting the element impurities in the polyethylene packaging material according to claim 5, characterized in that, The solid-liquid ratio of the polyethylene packaging material to the 0.1M hydrochloric acid solution is 20g:40-50mL.

7. The method for detecting the element impurities in the polyethylene packaging material according to claim 6, characterized in that, The solid-liquid ratio of the polyethylene packaging material to the 0.1M hydrochloric acid solution is 20g:40mL.

8. The method for detecting element impurities in polyethylene packaging material according to claim 1 or 2, characterized in that, The reflux extraction is performed for 0.5-3h, and the reflux temperature is 100-150℃.

9. The method for detecting the element impurities in the polyethylene packaging material according to claim 8, characterized in that, The reflux extraction is performed for 1h.

10. The method for detecting the element impurities in the polyethylene packaging material according to claim 8, characterized in that, The reflux temperature is 120℃.

11. The method for detecting the element impurities in polyethylene packaging material according to claim 1 or 2, characterized in that, The detection is performed by the ICPMS with a controlled helium flow rate of 3.3-4.1mL / min.

12. The method for detecting the element impurities in the polyethylene packaging material according to claim 11, characterized in that, When the elements to be detected are lithium, beryllium, magnesium, aluminum, arsenic, cobalt, copper, titanium, vanadium, chromium, manganese, nickel, zinc, mercury, gold, thallium, lead, cadmium, antimony, strontium, zirconium, molybdenum, barium and tin, the helium flow rate is controlled to be 3.8mL / min; when the elements to be detected are iron, selenium, ruthenium, rhodium, palladium, indium, tungsten, platinum and iridium, the helium flow rate is controlled to be 3.3mL / min.

13. The method for detecting element impurities in polyethylene packaging material according to claim 1 or 2, characterized in that, The polyethylene includes low-density polyethylene.

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