CN113447583A - Method for detecting compatibility of ambroxol hydrochloride sodium chloride injection and packaging material - Google Patents
Method for detecting compatibility of ambroxol hydrochloride sodium chloride injection and packaging material Download PDFInfo
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Abstract
The invention belongs to the technical field of instrument analysis, and discloses a method for detecting compatibility of an ambroxol hydrochloride sodium chloride injection and a packaging material. The detection method comprises a packing material migration experiment and methodology verification, wherein the packing material comprises a medium borosilicate glass ampoule bottle and a brominated butyl rubber plug, and the detection items of the packing material migration experiment comprise 27 elements, an antioxidant, sulfur, 2, 4-di-tert-butylphenol, palmitic acid, stearic acid, p-tert-octylphenol, a plasticizer and bromine. The invention also adopts methodology to verify the determination method and the determination result of the re-detection migration experiment, and through the evaluation of detection limit, quantitative limit, linear range, accuracy, precision and durability, the applicability and the reliability of the determination method of the migration experiment in compatibility research are ensured, the accuracy of the determination result of the migration experiment is also ensured, and a basis is provided for the selection of the packaging material of the ambroxol hydrochloride sodium chloride injection.
Description
Technical Field
The invention relates to the technical field of instrument analysis, in particular to a method for detecting compatibility of an ambroxol hydrochloride sodium chloride injection and a packaging material.
Background
Ambroxol hydrochloride (also called Mushutan) is a new generation respiratory tract mucus regulator, has strong phlegm eliminating effect, can promote the formation of respiratory tract surfactant substances, regulate the secretion of serous and mucous substances, promote metabolism, improve ciliary movement and enhance the eliminating effect of respiratory tract secretions.
The ambroxol hydrochloride injection is widely applied to critically ill patients clinically due to quick response and avoidance of dysphagia, and the dosage of the injection is gradually increased year by year. In recent years, with the deep understanding of the technical guidance principle of the international medicine and domestic medicine industry on the compatibility research of chemical medicines and medicinal glass packaging containers, the influence of the packaging material of injection products on the safety of the medicine quality is more and more discovered and emphasized by people, and with the development of detection technology, a great deal of potential safety hazards of the product quality caused by unreasonable selection of packaging materials due to insufficient research of the packaging materials at the early stage are discovered.
At present, the study on the compatibility of the ambroxol hydrochloride injection and the packing material generally comprises the study on the interaction between the liquid medicine and the packing material, namely the study on the influence of the packing material on the quality of the liquid medicine and the study on the influence of the liquid medicine on the inner surface of the packing material. The research on the influence of the liquid medicine on the inner surface of the packing material is generally observed by adopting a scanning electron microscope, the research on the influence of the packing material on the quality of the liquid medicine relates to a plurality of aspects, such as conventional inspection items of the liquid medicine, migration element experiments, adsorption experiments and the like, instruments such as a liquid chromatograph, a mass spectrometer and the like are required to be used for analyzing elements in the packing material when the detection is carried out, the accuracy of a result can be influenced by the small change of the experimental conditions of the detection instrument, and the repeated experiments for a plurality of times can lead to the increase of workload and the increase of cost. Therefore, it is necessary to provide a stable and accurate detection method for the influence of the packaging material on the quality of the liquid medicine.
Disclosure of Invention
The invention aims to provide a method for detecting the compatibility of an ambroxol hydrochloride sodium chloride injection and a packaging material, so that the applicability and reliability of a migration experiment determination method in compatibility research are ensured, the accuracy of a migration experiment determination result is ensured, and a basis is provided for selecting a packaging material of the ambroxol hydrochloride sodium chloride injection.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a method for detecting compatibility of an ambroxol hydrochloride sodium chloride injection and a packing material, which comprises a packing material migration experiment and methodology verification.
Preferably, in the method for detecting compatibility of the ambroxol hydrochloride sodium chloride injection and the packaging material, the packaging material is a medium borosilicate glass ampoule bottle and a butyl rubber bromide plug.
Preferably, in the method for detecting compatibility of ambroxol hydrochloride sodium chloride injection and the packaging material, the test items of the migration experiment of the packaging material comprise 27 elements, an antioxidant, sulfur, 2, 4-di-tert-butylphenol, palmitic acid, stearic acid, p-tert-octylphenol, a plasticizer and bromine.
Preferably, in the method for detecting the compatibility of the ambroxol hydrochloride sodium chloride injection and the packaging material, the method for detecting the 27 elements is an ICP-MS method; the detection method of the antioxidant, the sulfur, the 2, 4-di-tert-butylphenol and the p-tert-octylphenol is liquid chromatography; the detection method of the palmitic acid and the stearic acid is gas chromatography; the plasticizer detection method is gas chromatography-mass spectrometry; the bromine detection method is ion chromatography.
Preferably, in the method for detecting compatibility of the ambroxol hydrochloride sodium chloride injection and the packaging material, the methodological verification items comprise detection limit, quantitative limit, linear range, accuracy, precision, specificity and durability.
Preferably, in the method for detecting the compatibility of the ambroxol hydrochloride sodium chloride injection and the packaging material, the detection limit comprises an instrument detection limit and a method detection limit; the quantitative limit comprises an instrument quantitative limit and a method quantitative limit; wherein the instrument detection limit is calculated according to the following formula:
the detection limit of the instrument is 3.3 multiplied by SD/A;
in the formula: SD is standard deviation of CPS obtained by continuous sample introduction for 11 times;
a is the slope of the element standard curve;
the method detection limit is equal to the instrument detection limit;
the instrument quantitative limit is 10 × SD/A;
the method quantitation limit is the instrument quantitation limit.
Through the technical scheme, compared with the prior art, the invention has the following beneficial effects:
the invention establishes a migration element experiment detection method, is assisted by methodology verification, ensures the applicability and reliability of the migration experiment determination method in compatibility research through detection limit, quantitative limit, linear range, accuracy, precision and durability evaluation, also ensures the accuracy of the migration experiment determination result, and provides a basis for selecting the packaging material of the ambroxol hydrochloride sodium chloride injection.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides a method for detecting compatibility of an ambroxol hydrochloride sodium chloride injection and a packing material, which comprises a packing material migration experiment and methodology verification.
Preferably, the packing material comprises a medium borosilicate glass ampoule bottle and a butyl bromide rubber plug.
Preferably, the test items of the package material migration test comprise 27 elements, antioxidant, sulfur, 2, 4-di-tert-butylphenol, palmitic acid, stearic acid, p-tert-octylphenol, plasticizer and bromine.
Preferably, the 27 elements are Li, B, Ti, V, Cr, Mn, Co, Ni, Cu, As, Sr, Y, Zr, Cd, Sb, Ba, Ce, Hg, Pb, Al, K, Mg, Si, Fe, Zn, Pt and Ca; the detection method is an ICP-MS method, and the specific instrument analysis conditions comprise:
adopting an Agilent 7800 inductively coupled plasma mass spectrometer; the power is 1550W; the flow of the auxiliary gas/argon is 0.90L/min; the flow of the atomizing gas (argon) is 1.04L/min; the peristaltic pump was 0.10 rps.
Preferably, the antioxidants are antioxidant BHT, antioxidant 1310, antioxidant 1010, antioxidant 330, antioxidant 1076, and antioxidant 168.
Preferably, the detection method of the antioxidant, the sulfur and the 2, 4-di-tert-butylphenol is liquid chromatography, and the specific instrument analysis conditions comprise:
adopting a Ulimate 3000 liquid chromatograph; the chromatographic column is Aglient5 TC-C18, 4.6 x 250mm, 5 μm; the column temperature was 35 ℃; the leaching procedure is gradient leaching of methanol and 0.1% acetic acid solution, and specifically the leaching procedure is 85% methanol + 15% acetic acid solution in 0-10 min, 100% methanol in 11-24 min and 85% methanol + 15% acetic acid solution in 25-30 min; the flow rate is 1 mL/min; the detection wavelength is 276 nm; the amount of sample was 20. mu.L.
Preferably, palmitic and stearic acids are methyl octadecanoate/stearate, methyl hexadecanoate/palmitate, stearic acid (C18: O) and palmitic acid (palmitic acid) (C16: O); the detection method is gas chromatography, and the specific instrument analysis conditions comprise:
adopting an Shimadzu GC-2010Plus gas chromatograph; the chromatographic column is Agilent DB-35MS 30m 0.25mm 0.25 μm; the temperature raising program is to keep the temperature at 120 ℃ for 1 min; raising the temperature to 200 ℃ at the speed of 20 ℃/min and keeping the temperature for 3 min; heating to 280 deg.C at 10 deg.C/min and maintaining for 3 min; the carrier gas is nitrogen; the flow rate is 1.0 mL/min; the split ratio is 5: 1; the temperature of a sample inlet is 250 ℃; the sample injection amount is 1 mu L, and automatic sample injection is carried out; the FID temperature was 280 ℃.
Preferably, the method for detecting the tert-octylphenol is liquid chromatography, and the specific instrument analysis conditions refer to the detection method of the antioxidant, the sulfur and the 2, 4-di-tert-butylphenol.
Preferably, the plasticizers are DIBP, DBP and DEHP; the detection method is a gas chromatography-mass spectrometry method, and the specific instrument analysis conditions comprise:
adopting an Agilent 8860-5977B gas chromatography mass spectrometer; the chromatographic column was HP-5MS, 30m 0.25mm 0.25 μm; heating at 60 deg.C for 1 min; raising the temperature to 220 ℃ at the speed of 20 ℃/min and keeping the temperature for 1 min; raising the temperature to 280 ℃ at the speed of 5 ℃/min and keeping the temperature for 5 min; the carrier gas is helium; the sample injection mode is non-shunting; the flow rate is 1.0 mL/min; the temperature of a sample inlet is 250 ℃; the sample injection amount is 1 mu L, and automatic sample injection is carried out; the temperature of the transmission line is 280 ℃; the solvent delay was 6 min.
Preferably, the bromine detection method is ion chromatography, and the specific instrumental analysis conditions comprise:
ICS-1000 ion chromatography is adopted; the chromatographic column is Analytical, 4mm × 250 m; the column temperature is 30 ℃; the sample injection amount is 200 mu L; the mobile phase is 5mmoL/L potassium hydroxide solution; the flow rate is 1.0 mL/min; isocratic elution.
Preferably, the methodological validation items include detection limits, quantitation limits, linear range, accuracy, precision, specificity, and durability.
Preferably, the detection limit comprises an instrument detection limit and a method detection limit; the quantitation limit includes an instrument quantitation limit and a method quantitation limit.
Further preferably, the instrument detection limit for detecting 27 elements of an item is calculated as follows:
the detection limit of the instrument is 3.3 multiplied by SD/A;
in the formula: SD is standard deviation of CPS obtained by continuous sample introduction for 11 times;
a is the slope of the element standard curve;
the method detection limit is equal to the instrument detection limit;
the instrument quantitative limit is 10 × SD/A;
the method quantitation limit is the instrument quantitation limit.
Preferably, the linear range measuring method for the detection items is:
preparing a series of working curve solutions of each detection item by adopting a standard substance, carrying out sample injection detection according to a specified detection method, drawing by taking the concentration (x) of a target substance in the standard solution as a horizontal coordinate and the response value (y) of the target substance as a vertical coordinate, carrying out linear regression or quadratic equation regression by adopting a least square method, and inspecting a linear range through a correlation coefficient (r).
Preferably, the method for measuring the accuracy of the detection item includes:
adding standard substances with low, medium and high concentration levels in a linear range into samples of each detection item, preparing 3 samples in parallel at each concentration level, detecting according to instrument conditions, and calculating the recovery rate, wherein the recovery rate (w%) is calculated by the following formula:
w％＝(m-m0)÷M×100％
in the formula:
m-found, in units of μ g/L;
m 0-matrix content, unit μ g/L;
m-addition level, in units of μ g/L;
measured value is the actual value-substrate content.
Preferably, the precision of the test items includes instrument precision, method precision and intermediate precision.
Example 1
The invention provides a method for detecting the compatibility of an ambroxol hydrochloride sodium chloride injection and a packing material, which comprises a packing material migration experiment and methodology verification;
wherein, the basic information of the ambroxol hydrochloride and sodium chloride injection is as follows:
the manufacturer: harbin Tri pharmaceuticals GmbH;
the prescription composition is as follows: 0.03g of ambroxol hydrochloride and 0.9g of sodium chloride;
specification: 100mL of: 30mg of ambroxol hydrochloride and 0.9g of sodium chloride;
storage conditions were as follows: sealing and shading for preservation;
maximum daily dose: 200 mL;
the basic information of medium borosilicate glass ampoules is:
the manufacturer: shandong province pharmaceutical glass products, Inc.;
specification: 100 mL;
the components: SiO 22、Al2O3、B2O4、K2O、Na2O、Fe2O3、CeO2、ZnO、BaO；
The basic information on brominated butyl rubber stoppers is:
the manufacturer: pharmaceutical materials of Hualan, Jiangsu Co Ltd;
specification: phi 26;
the components: brominated butyl rubber, calcined kaolin, sulfur, p-tert-octyl phenolic vulcanized resin, zinc oxide, magnesium oxide, carbon black, titanium dioxide, PET, FEP, ETFE and PTFE.
The analytical interest threshold (AET) is calculated from the daily maximum usage of the human injected allowable daily exposure (PDE) in combination with the drug.
The allowable daily exposure (PDE) For injection is obtained from ICH Q3D, guidance documents (guiding On The Specification Limits For residual amounts Of Metal Catalysts Or Metal Reagents) issued by EMEA/CHMP at 21 st.22008, 2.21 th, guide documents (guiding On The Specification Limits For residual amounts Of Metal Catalysts Or Metal Reagents) issued by national food and drug administration centers For drug review, documents issued by The national food and drug administration centers For drug review, and The allowable maximum intake calculated by related toxicology, PDE For extract is not available from literature, toxicity databases, and when related toxicity tests are not performed, Safety thresholds (SCT) are used For evaluation.
The specification of the ambroxol hydrochloride and sodium chloride injection indicates that the specification of the injection is 100mL, the ambroxol hydrochloride is 30mg and the sodium chloride is 0.9g, the maximum dose per day does not exceed 60mg, namely the AET is calculated by 200 mL:
in the formula: AET — analysis attention threshold;
PDE-the maximum amount of each element allowed to be ingested per day,. mu.g/day;
m-maximum daily dose, mL/day.
The test items of the packing material migration experiment comprise 27 elements, antioxidant, sulfur, 2, 4-di-tert-butylphenol, palmitic acid, stearic acid, p-tert-octylphenol, plasticizer and bromine, and the calculated PDE and AET values are shown in Table 1.
TABLE 1 migration test PDE and AET values for test items
The ambroxol hydrochloride sodium chloride injection is contacted with the packing material for 0 month and 6 months and is accelerated for 6 months, the components migrated out of the packing material are detected, the specific detection items comprise 27 elements, antioxidant, sulfur, 2, 4-di-tert-butylphenol, palmitic acid, stearic acid, p-tert-octylphenol, plasticizer and bromine, and the results are shown in table 2.
TABLE 2 migration test item 0 month and 6 month test results
From the results in the above table, it can be seen that the quantitative detection of the detection items was performed on the samples of 0 month and 6 months, and the results showed that none of the substances exceeded the AET value, indicating that the detection items in the packaging material did not have significant migration phenomenon to the drug under the conditions.
The invention also carries out methodology verification on the detection method in the migration experiment, and the methodology verification items comprise detection limit, quantitative limit, linear range, accuracy, precision and durability, so as to carry out 'recheck' on the detection method and the result of the migration experiment, ensure the applicability and reliability of the measurement method of the migration experiment and also ensure the accuracy of the measurement result of the migration experiment.
1. Verification of 27 element methodologies:
the detection limit and the quantification limit were determined by the above analysis conditions of the ICP-MS apparatus and the calculation formula, and the results are shown in Table 3.
Table 327 detection limits and quantitation limits for elements
As can be seen from Table 3, the detection limit and the quantification limit of the 27 elements are lower than the AET value thereof, and the requirement of the compatibility test on the detection sensitivity can be satisfied.
The linear range test results are shown in table 4.
Linear Range test results for the 427 elements of Table
As can be seen from Table 4, the linear range of the 27 elements is wide, the correlation coefficient r is between 0.9995 and 1.0000, and the requirement of compatibility research and determination can be met.
The accuracy was measured according to the above calculation formula, and the results are shown in Table 5.
TABLE 5 accuracy test results
According to the requirement of an analysis method verification guiding principle 9101 in the fourth part of pharmacopoeia of the people's republic of China (2020 edition), the average recovery rate of 27 elements is between 80.3 and 114.6 percent, and the RSD values are all less than 10 percent, thereby meeting the requirement of the pharmacopoeia, and showing that the established method has better accuracy and can meet the requirement of compatibility determination.
The results of the instrument precision measurements are shown in Table 6.
Instrument precision test result of 627 elements in table
According to the general rule 9101 of analytical method verification guidelines in the fourth part of the pharmacopoeia of the people's republic of China (2020 edition), as can be seen from table 6, the RSD of 27 elements is 0.8% -5.5%, and the RSD values in the test all meet the requirements of the pharmacopoeia, which shows that the established method has better precision.
The method for measuring the precision comprises the following steps: 6 equal samples were taken, 10 times the quantitative limit of the target substance was added, the samples were treated and measured according to the established method, the content of each element in each sample was calculated, and the RSD of the results of 6 times each element was calculated, and the results are shown in Table 7.
Method precision results for 727 elements in Table
According to the general rule 9101 of analytical method verification guidelines in the fourth part of the pharmacopoeia of the people's republic of China (2020 edition), as can be seen from table 7, the RSD of 27 elements of the invention is 0.2% -8%, and the test results meet the requirements, indicating that the method has better repeatability.
The method for measuring the intermediate precision comprises the following steps: according to a repeatability method, 6 parts of solutions to be detected are prepared again, different analysts measure intermediate precision samples at different times, analyst A and analyst B perform comparison analysis on the data of method precision, and 12 detection results RSD are calculated at the same time, and the results are shown in Table 8.
TABLE 827 intermediate precision results for elements
According to the general rule 9101 of analytical method verification guidelines in the fourth part of the pharmacopoeia of the people's republic of China (2020 edition), as shown in Table 8, the RSD of 27 elements is 0.3% -7.8%, and the test results meet the requirements, which indicates that the method has better intermediate precision.
The durability test method comprises the following steps: the ICP-MS acquisition time and the number of acquisition repetitions were varied and the results are shown in table 9.
Table 927 durability test results of elements
According to the analysis method verification guideline 9101 in the fourth part of the pharmacopoeia of the people's republic of China (2020 edition), as shown in table 9, the recovery rates of all elements can meet the requirements of the pharmacopoeia by changing the instrument conditions within a small range, which indicates that the established method has better durability and can meet the requirements of compatibility determination.
2. Antioxidant, sulfur, 2, 4-di-tert-butylphenol methodology verification
Detection limit and quantitation limit: taking a stock solution (1mg/mL) of the detection item, diluting the stock solution by using a conventional solution step by step, injecting a sample according to the analysis condition of the instrument, and determining the detection limit (S/N ≈ 3) and the quantification limit (S/N ≈ 10) of the map area of each component, wherein the result is as follows: the limit of sulfur detection is 0.005 mu g/mL, and the limit of quantification is 0.01 mu g/mL; the detection limit of 2, 4-di-tert-butylphenol and antioxidant BHT is 0.015 mu g/mL, and the quantification limit is 0.03 mu g/mL; the detection limit of the antioxidant 1310, the antioxidant 1010 and the antioxidant 330 is 0.025 mu g/mL, and the quantification limit is 0.05 mu g/mL; the detection limit of the antioxidant 1076 and the antioxidant 168 was 0.05. mu.g/mL, and the quantification limit was 0.1. mu.g/mL. The detection limit and the quantification limit are both lower than the AET value, and the requirement of a compatibility test on the detection sensitivity can be met.
Linear range: the linear relationship among antioxidant, sulfur and 2, 4-di-tert-butylphenol is shown in Table 10. As can be seen from the table, the linear relation of the standard curve is good, the correlation coefficient r is 0.9999-1.0000, and the requirement of compatibility research and determination can be met.
TABLE 10 antioxidant, Sulfur, 2, 4-di-tert-butylphenol Linear relationship
Accuracy: by adding standard substances with low, medium and high concentration level quantitative limits into the samples, 3 samples are prepared in parallel at each concentration level, the recovery rate is calculated according to the recovery rate formula, and the result is as follows:
the recovery rates of the antioxidant, the sulfur and the 2, 4-di-tert-butylphenol are all between 105.0% and 115.8%, the RSD values are all less than 10%, the pharmacopoeia requirements are met, and the established method has better accuracy.
Precision of the instrument: RSD of the antioxidant, the sulfur and the 2, 4-di-tert-butylphenol is between 0.25 percent and 1.49 percent, and all meet the requirements of pharmacopoeia, which shows that the established method has better precision.
The method has the following precision: respectively taking 6 parts of samples, adding the quantitative limit concentration of 1ug/mL, detecting, calculating the RSD of 6 times of results, and obtaining the result that the RSD of the antioxidant, the sulfur and the 2, 4-di-tert-butylphenol are all between 0.28 and 2.33 percent and meet the requirements of pharmacopoeia.
Intermediate precision: according to the intermediate precision detection method of 27 elements, the result is 2.00-4.75%, and the requirements of pharmacopoeia are met.
Durability: the original instrumental analysis conditions were: column temperature: 35 ℃; flow rate: 1.0 mL/min; initial ratio: 85: 15; the method adjusts 1 to the flow rate of 0.9 mL/min; the method is adjusted to the column temperature of 30 ℃; method adjustment 3 is flow phase ratio column 83: 17; the result shows that the recovery rate is 108.20-116.70%, the requirements of pharmacopeia are met, and the durability is good.
3. Palmitic acid and stearic acid methodological validation
Detection limit and quantitation limit: taking a stock solution (1mg/mL) of the methyl palmitate and the methyl stearate, diluting the stock solution with an N-hexane solution step by step, injecting samples according to the analysis conditions of the instrument, and determining the detection limit (S/N is approximately equal to 3) and the quantification limit (S/N is approximately equal to 10) of the map region of each component, wherein the result is as follows: the detection limit of palmitic acid is 0.474mg/L, and the quantification limit is 1.896 mg/L; the detection limit of stearic acid is 0.476mg/L, the quantification limit is 1.906mg/L, and the detection limit and the quantification limit are lower than the AET value thereof, so that the requirement of a compatibility test on the detection sensitivity is met.
Linear range: methyl palmitate: y 3679.39 x-948.663, r is 0.9999;
methyl stearate: y 3822.02 x 894.265, r is 0.9999.
The results show that: the linear relation between the palmitic acid and the stearic acid is good at the concentration of 0.5-100 mg/L.
Accuracy: by adding standard substances with low, medium and high concentration level quantitative limits into the samples, 3 samples are prepared in parallel at each concentration level, the recovery rate is calculated according to the recovery rate formula, and the result is as follows: the recovery rate of palmitic acid is 97.21%, the recovery rate of stearic acid is 94.57%, the RSD value is less than 10%, the requirements of pharmacopoeia are met, and the established method has better accuracy.
Precision of the instrument: the RSD of palmitic acid is 1.41%, and the RSD value of stearic acid is 2.22%, which both meet the pharmacopoeia requirements, indicating that the established method has better precision.
The method has the following precision: the RSD of palmitic acid is 5.68%, and the RSD of stearic acid is 5.64%, which meets the test requirements.
Intermediate precision: according to the intermediate precision detection method of 27 elements, the results show that the RSD of palmitic acid is 5.27 percent and the RSD of stearic acid is 6.34 percent, and the requirements of pharmacopoeia are met.
Durability: the original instrumental analysis conditions were: the temperature of a sample inlet is 250 ℃, and the flow rate is 1.0 mL/min; the method is adjusted to 1, wherein the temperature of a sample inlet is 260 ℃, and the flow rate is 1.0 mL/min; the method 2 is adjusted to be that the temperature of a sample inlet is 260 ℃ and the flow rate is 1.2 mL/min; the method is adjusted to 3, wherein the temperature of a sample inlet is 250 ℃, and the flow rate is 1.2 mL/min. The result shows that the recovery rate is 90.78-105.77%, the requirements of pharmacopeia are met, and the durability is good.
4. Verification of p-tert-octylphenol methodology
Detection limit and quantitation limit: taking a standard solution with the concentration of about 1.0mg/mL to gradually dilute the solution by methanol, injecting the sample according to the analysis condition of the instrument, and measuring the detection limit (S/N ≈ 3) and the quantification limit (S/N ≈ 10) of the instrument of the components, wherein the result is as follows: the detection limit is 0.05 mug/mL, the quantification limit is 0.1 mug/mL, and the detection limit and the quantification limit are lower than the AET value thereof, so that the requirement of a compatibility test on the detection sensitivity can be met.
Linear range: precisely weighing about 10mg of p-tert-octylphenol reference substance, placing the reference substance in a 10mL volumetric flask, dissolving the reference substance with methanol, quantitatively diluting the reference substance to scale, and gradually diluting the reference substance with methanol to obtain standard solutions with the concentrations of about 0.01 mu g/mL, 0.05 mu g/mL, 0.1 mu g/mL, 0.5 mu g/mL, 1.0 mu g/mL, 5.0 mu g/mL, 10.0 mu g/mL and 20.0 mu g/mL; and respectively injecting samples according to the chromatographic conditions, and recording chromatograms. And (3) performing linear regression calculation on the concentration (x) by using the peak area (y) to obtain a linear regression equation and a correlation coefficient, wherein the result is as follows:
y is 0.1068x +0.0068 and r is 0.9999. The results show that: the linear relation is good, the correlation coefficient r is 0.9999, and the requirement of compatibility research and determination can be met.
Accuracy: by adding standard substances with low, medium and high concentration level quantitative limits into the samples, 3 samples are prepared in parallel at each concentration level, the recovery rate is calculated according to the recovery rate formula, and the result is as follows:
when the addition content of the p-tert-octylphenol is respectively 0.5 mu g/mL, 0.8 mu g/mL and 1.0 mu g/mL, the average recovery rates are respectively 99.8%, 97.9% and 100.0%, the RSD values are all less than 10%, the pharmacopoeia requirements are met, and the established method has better accuracy.
Precision of the instrument: adding a p-tert-octylphenol standard substance with the concentration of 5 times of the limit of quantitation into a sample, then testing for 6 times, calculating the Relative Standard Deviation (RSD) according to the measurement result, wherein the result is 0.83%, and the method meets the pharmacopoeia requirements, and shows that the established method has better precision.
The method has the following precision: respectively taking 6 parts of samples, adding a certain level of quantitative limit concentration, detecting, calculating the content of each part of sample, and calculating the RSD of 6 results, wherein the result is 3.83%, and the requirements of pharmacopoeia are met.
Intermediate precision: according to the intermediate precision detection method of 27 elements, the result is 0.44%, and the requirements of pharmacopoeia are met.
Durability: the original instrumental analysis conditions were: column temperature: 35 ℃; flow rate: 1.0 mL/min; initial ratio: 15: 85; method adjustment 1 is flow phase ratio column 17: 83; the method is adjusted to the column temperature of 30 ℃; the method is adjusted to 3, the flow rate is 0.9 mL/min; the result shows that the recovery rate is between 106.02% and 118.7%, the requirements of pharmacopoeia are met, and the durability is good.
5. Plasticizer methodology verification
Detection limit and quantitation limit: diluting DBP, DIBP and DEHP reference substances with N-hexane solution step by step to prepare a detection limit determination solution, injecting sample according to the analysis conditions of the instrument, and determining to obtain the detection limit (S/N is approximately equal to 3) and the quantification limit (S/N is approximately equal to 10) of each component, wherein the result is as follows: the detection limit of DBP, DIBP and DEHP for three plasticizers is 0.005mg/L, the quantification limit is 0.01mg/L, the detection limit and the quantification limit are lower than the AET value, and the requirement of a compatibility test on the detection sensitivity can be met.
Linear range: DBP: y is 165.036322X-326.303933, r is 0.9987;
DIBP: y is 175.721315X-945.510787, r is 0.9992;
DEHP: Y42.390692X +94.001354, r is 0.9999; indicating a good linear relationship.
Accuracy: taking 10.0mL ambroxol hydrochloride sodium chloride injection, adding a proper volume of n-hexane for extraction, ensuring that the volume of the n-hexane is 10mL, collecting an n-hexane layer, preparing 3 samples in parallel at each concentration level, and measuring, wherein the result shows that: the recovery rate is 79.32-113.40%, the RSD values are less than 10%, the requirements of pharmacopoeia are met, and the established method has better accuracy.
Precision of the instrument: taking 10.0mL ambroxol hydrochloride sodium chloride injection, adding 0.025mL10 mu g/mL plasticizer stock solution, adding a proper amount of n-hexane for extraction, ensuring that the volume of the added standard solution and the volume of the n-hexane are 10mL, collecting the n-hexane layer, injecting samples according to the analysis conditions of the instrument, and respectively repeating the determination for 6 times, wherein the result shows that: RSD of DBP, DIBP and DEHP are respectively 2.71%, 2.86% and 1.26%, and the RSD meets the requirements of pharmacopeia, and the established method has good precision.
The method has the following precision: the RSD of DBP, DIBP and DEHP is respectively 3.09%, 3.23% and 2.47%, and the RSD meets the test requirements.
Intermediate precision: according to the intermediate precision detection method of 27 elements, the RSD of DBP, DIBP and DEHP are respectively 4.59%, 5.26% and 2.20%, and all the RSD meets the test requirements.
Durability: the original instrumental analysis conditions were: the temperature of a sample inlet is 250 ℃, and the flow rate is 1.0 mL/min; the method is adjusted to 1, wherein the temperature of a sample inlet is 250 ℃, and the flow rate is 1.2 mL/min; the method 2 is adjusted to be that the temperature of a sample inlet is 260 ℃ and the flow rate is 1.2 mL/min; the method is adjusted to 3, wherein the injection port temperature is 260 ℃ and the flow rate is 1.0 mL/min. The result shows that the recovery rate is 82.22-109.69%, the requirements of pharmacopeia are met, and the durability is good.
6. Bromine methodology validation
Detection limit and quantitation limit: diluting the standard solution with concentration of about 1.0mg/mL with water step by step, injecting sample according to the analysis condition of the instrument, and determining the detection limit (S/N > 3) and the quantification limit (S/N > 10) of the instrument of the component, wherein the result is as follows: the detection limit is 50ng/mL, the quantification limit is 100ng/mL, and the detection limit and the quantification limit are lower than the AET value thereof, so that the requirement of a compatibility test on the detection sensitivity can be met.
Linear range: 1.0357x-26.135, r is 0.9981; indicating a good linear relationship.
Accuracy: the recovery rate is 98.58%, the RSD value is less than 10%, and the requirements of pharmacopoeia are met, which shows that the established method has better accuracy and can meet the requirements of compatibility determination.
Precision of the instrument: the RSD of bromine is measured to be 2.77 percent, thereby meeting the requirements of pharmacopoeia and showing that the established method has better precision.
The method has the following precision: the RSD of bromine was found to be 2.63%, meeting the test requirements.
Intermediate precision: according to the intermediate precision detection method of 27 elements, the result is that the RSD of bromine is 6.58 percent, and the test requirement is met.
Durability: the flow rate of the original instrument under the analysis condition is 1.0mL/min, the flow rate is 0.9mL/min through the method adjustment 1, and the flow rate is 1.1mL/min through the method adjustment 2, and the result shows that the recovery rate is 100.29-102.75%, the pharmacopoeia requirements are met, and the durability is good.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (6)
1. A method for detecting the compatibility of an ambroxol hydrochloride sodium chloride injection and a packing material is characterized by comprising a packing material migration experiment and methodology verification.
2. The method for detecting the compatibility of the ambroxol hydrochloride and sodium chloride injection with the packaging material as claimed in claim 1, wherein the packaging material comprises a medium borosilicate glass ampoule bottle and a butyl rubber bromide stopper.
3. The method for detecting the compatibility of the ambroxol hydrochloride and sodium chloride injection with the packaging material as claimed in claim 2, wherein the test items of the packaging material migration experiment include 27 elements, antioxidant, sulfur, 2, 4-di-tert-butylphenol, palmitic acid, stearic acid, p-tert-octylphenol, plasticizer and bromine.
4. The method for detecting the compatibility of the ambroxol hydrochloride sodium chloride injection and the packaging material as claimed in claim 3, wherein the 27 element detection method is an ICP-MS method; the detection method of the antioxidant, the sulfur, the 2, 4-di-tert-butylphenol and the p-tert-octylphenol is liquid chromatography; the detection method of the palmitic acid and the stearic acid is gas chromatography; the plasticizer detection method is gas chromatography-mass spectrometry; the bromine detection method is ion chromatography.
5. The method for detecting the compatibility of the ambroxol hydrochloride and sodium chloride injection with the packaging material as claimed in claim 1, wherein the methodological validation items comprise detection limit, quantitative limit, linear range, accuracy, precision and durability.
6. The method for detecting the compatibility of the ambroxol hydrochloride sodium chloride injection and the packaging material according to claim 5, wherein the detection limit comprises an instrument detection limit and a method detection limit; the quantitative limit comprises an instrument quantitative limit and a method quantitative limit;
wherein the instrument detection limit is calculated according to the following formula:
the detection limit of the instrument is 3.3 multiplied by SD/A;
in the formula: SD is standard deviation of CPS obtained by continuous sample introduction for 11 times;
a is the slope of the element standard curve;
the method detection limit is equal to the instrument detection limit;
the instrument quantitative limit is 10 × SD/A;
the method quantitation limit is the instrument quantitation limit.
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