CN113125366A - Method for detecting content of hydrogen sulfide in acetylcysteine solution for inhalation - Google Patents
Method for detecting content of hydrogen sulfide in acetylcysteine solution for inhalation Download PDFInfo
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Abstract
The invention discloses a method for detecting the content of hydrogen sulfide in acetylcysteine solution for inhalation, and belongs to the technical field of drug detection. The method comprises the steps of preparing a 20ppm standard hydrogen sulfide solution from a sodium sulfide solution, and preparing 20ppm H according to a preparation method of a test sample solution2And S, preparing a reference substance solution, namely preparing a test substance solution, a blank solution and a reference substance solution, so as to measure the concentration of the hydrogen sulfide in the test substance solution by using a single-point reference substance method. The invention can accurately measure the hydrogen sulfide content in the acetylcysteine solution for inhalation, further determine the quality of the medicine, and provide an effective and feasible method for strictly controlling the hydrogen sulfide content in the liquid medicine.
Description
Technical Field
The invention belongs to the technical field of medicine detection, and particularly relates to a method for detecting the content of hydrogen sulfide in acetylcysteine solution for inhalation.
Background
Acetylcysteine, chemical name N-acetyl-L cysteine, molecular formula is C5H9NO3S, white or off-white crystalline powder in appearance; has odor similar to Bulbus Allii and hygroscopicity. Is easily soluble in water or ethanol. Acetylcysteine is used as mucolytic agent, and contains sulfydryl in molecular formula, so that disulfide bond in polypeptide can be broken, phlegm viscosity can be reduced, and the polypeptide can be liquefied. At the same time, the fiber in purulent sputum can be broken, so that the sputum can be dissolved not only white sticky sputum but also purulent sputum, the viscosity of the sputum is reduced, the sputum is easy to discharge, and the method is suitable for treating dyspnea caused by a large amount of sticky sputum and expectoration difficulty diseases, and is used for treating respiratory system infection which is characterized by excessive thick mucus secretion, such as acute bronchitis, chronic obstructive pulmonary disease, emphysema, bronchiectasis and thick mucus disease.
The preparation for inhalation is a drug which is administrated through a respiratory tract route, and the administration route has the characteristics of direct target, quick response, convenient use, safety and the like. The acetylcysteine solution for inhalation is an expectorant drug for inhalation developed by Zabon, and the acetylcysteine is taken as a main component and is commonly recommended by organizations such as world health organization, American institute for cardiopulmonary blood and the like as a conventional antioxidant drug for treating Chronic Obstructive Pulmonary Disease (COPD) and pulmonary fibrosis. At present, a plurality of enterprises have marketed products of the type in China, but the quality evaluation report of the acetylcysteine inhalation preparation is less. Cysteine acetate is white or white-like crystalline powder, has odor similar to garlic, and is easy to introduce cystine, cysteine, N' -diacetylcysteine, N, S-acetylcysteine, etc. in the production process. In addition, acetylcysteine is less stable and is oxidized and degraded in solution and when exposed to air, as shown in FIG. 2.
Besides being irritant to mucous membrane, the degradation product of acetylcysteine, hydrogen sulfide, is easily absorbed by skin, lung and inner wall of digestive tract. In blood, hydrogen sulfide gas is converted to alkali sulfide. The sulfhydryl radicals, which may be factors causing systemic pathology, are excreted via the lungs and with the urine. Part of the sulfide is oxidized to form sulfate and thiosulfate, and is discharged with urine. Part of the sulfides may be trapped by natural disulfides (e.g., glutathione) in the blood, and part of the sulfides are excreted as iron sulfide with the feces. For inhalation preparations, the hydrogen sulfide content in the liquid medicine should be strictly controlled.
By searching the prior art at home and abroad, a literature report of a method for detecting the content of hydrogen sulfide in a liquid medicine is not found.
Disclosure of Invention
In view of the shortcomings of the prior art, the present invention aims to provide an effective method for detecting the content of hydrogen sulfide in acetylcysteine solution for inhalation.
In order to achieve the technical purpose, the inventor combines the medicine analysis experience for years, and through a great deal of experimental research and diligent exploration, the following technical scheme is finally obtained: a method for detecting the content of hydrogen sulfide in an acetylcysteine solution for inhalation, which comprises the following steps:
(1) preparing a 20ppm standard hydrogen sulfide solution by using a sodium sulfide solution;
(2) preparing a test solution and a blank solution: transferring the acetylcysteine solution for inhalation to a three-neck flask filled with water to serve as a reaction bottle, wherein a first connector is provided with an air inlet pipe which can be communicated with the bottom of the flask, a second connector is inserted into a dropping funnel filled with hydrochloric acid, and a third connector is provided with an air guide pipe; taking sodium hydroxide solution in a collecting bottle as H2S, a collecting bottle, wherein the reaction bottle and the collecting bottle are connected through the gas guide tube, nitrogen starts to be introduced into the reaction bottle after the system is closed, a hydrochloric acid solution is dropwise added into the reaction bottle by using a dropping funnel when the nitrogen starts to be introduced from a gas inlet, the nitrogen continues to be introduced for 30-40min after the nitrogen introduction is finished, and a gas collecting measuring flask is disconnected; adding an N, N-dimethyl-p-phenylenediamine hydrochloride solution and a ferric trichloride hexahydrate solution into a collection bottle, and reacting to obtain a test solution; substituting water for acetylcysteine solution for inhalation, and preparing blank solution by the same method;
(3) preparation of control solutions: replacing the acetylcysteine solution for inhalation with the standard hydrogen sulfide solution of 20ppm obtained in step (1), and preparing to obtain 20ppm H by the method of step (2)2S, a reference substance solution;
(4) taking the blank solution as a blank contrast, and adopting a spectrophotometerMeasuring the absorbance values of the test solution and the reference solution, and respectively recording as ASample (I)、A20pmmThe hydrogen sulfide content (corresponding to the acetylcysteine content) was calculated as follows:
wherein: cH2S controlAs H in control solution2(ii) the concentration of S;
A20pmmis H2S, comparing the light absorption value of the solution of the reference substance;
Asample (I)The light absorption value of the solution to be detected is obtained;
CacetylcysteineAcetylcysteine concentration in acetylcysteine solution for inhalation;
1000 is expressed as unit conversion factor.
Further preferably, the method for detecting the content of hydrogen sulfide in the acetylcysteine solution for inhalation as described above, wherein the step (1) of preparing the standard 20ppm hydrogen sulfide solution from the sodium sulfide solution comprises the steps of: precisely measuring 25ml of 0.25% sodium sulfide solution, precisely adding 25ml of 0.05mol/L iodometric titration solution, adding 8ml of 3mol/L hydrochloric acid, titrating with 0.1mol/L sodium thiosulfate titration solution to near-end point, adding starch indicator, titrating to end point, correcting titration result by blank test, and expressing concentration of hydrogen sulfide in ppm as (V isBlank space-VNa2S2O3 eliminating agent)×68.16]And diluted to 20ppm, where VBlank spaceConsumption of the volume of sodium thiosulfate titrant for the blank calibration experiment, VNa2S2O3 eliminating agentThe volume of sodium thiosulfate titration solution consumed in the experiment was calibrated for sodium sulfide solution.
Further preferably, in the method for detecting the content of hydrogen sulfide in the acetylcysteine solution for inhalation, the flow rate of the nitrogen in the step (2) is 1.5 to 2.5L/min.
Further preferably, the method for detecting the content of hydrogen sulfide in the acetylcysteine solution for inhalation as described above, wherein the step (2) of preparing the test sample solution specifically includes the steps of: precision moving suction2ml of acetylcysteine solution is added into a three-neck flask filled with 40ml of water to be used as a reaction bottle, wherein a first connector is provided with an air inlet pipe which can be communicated with the bottom of the flask, a second connector is inserted into a dropping funnel filled with hydrochloric acid, and a third connector is provided with an air guide pipe; taking 50-55ml of 0.1-0.2 mol/L sodium hydroxide solution in a collection bottle as H2S, a collecting bottle, wherein the reaction bottle and the collecting bottle are connected through the gas guide tube, nitrogen starts to be introduced into the reaction bottle after the system is closed, the flow rate of the nitrogen is adjusted to be 2.0L/min, 10ml of 3mol/L hydrochloric acid solution is dropwise added into the reaction bottle through a dropping funnel when the nitrogen starts to be introduced from the gas inlet, after the nitrogen is introduced, the nitrogen continues to be introduced for 30-40min, and the gas collecting measuring bottle is disconnected; and adding 10ml of 0.1% N, N-dimethyl-p-phenylenediamine hydrochloride solution and 5ml of 5% ferric chloride hexahydrate solution into a collection bottle, standing for 20min in a dark place, diluting to 100ml with water, and shaking up to obtain a test solution.
Still further preferably, the method for detecting the content of hydrogen sulfide in the acetylcysteine solution for inhalation as described above, wherein the method for preparing the 0.1% N, N-dimethyl-p-phenylenediamine hydrochloride solution in step (2) comprises: dissolving 0.1g N, N-dimethyl-p-phenylenediamine hydrochloride with 5.4mol/L hydrochloric acid to be diluted to 100 ml; the preparation method of the 5 percent ferric chloride hexahydrate solution comprises the following steps: 5g of ferric chloride hexahydrate is dissolved and diluted to 100ml by 1mol/L hydrochloric acid.
Further preferably, in the method for detecting the content of hydrogen sulfide in the acetylcysteine solution for inhalation, in the step (4), a detection wavelength for testing the sample solution and the reference solution by using a spectrophotometer is 665-667 nm.
Compared with the prior art, the method for detecting the content of the hydrogen sulfide in the acetylcysteine solution for inhalation has the following advantages and remarkable progress:
(1) the invention is proved by a plurality of laboratories to have good reproducibility.
(2) The method is simple to operate, easy to control and good in indexes such as linearity and recovery rate.
(3) The invention can accurately measure the hydrogen sulfide content in the acetylcysteine solution for inhalation, further determine the quality of the medicine, and provide an effective and feasible method for strictly controlling the hydrogen sulfide content in the liquid medicine.
Drawings
FIG. 1: hydrogen sulfide (H)2S) collecting device diagrams;
FIG. 2: acetylcysteine degradation pathway map;
FIG. 3: scanning the result of the blank solution at full wavelength;
FIG. 4: full-wavelength scanning results of the reference solution;
FIG. 5: scanning the result of the full wavelength of the test solution;
FIG. 6: h2A linear relation graph of S in the range of 5ppm to 50 ppm.
Detailed Description
The technical solution of the present invention is further described in detail by the following specific examples. However, it will be understood by those skilled in the art that the following examples are illustrative of the present invention only and should not be construed as limiting the scope of the present invention. In addition, the specific technical operation steps or conditions not indicated in the examples are performed according to the technical or conditions described in the literature in the field or according to the product specification. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available. In addition, the preparation method of the 0.1% N, N-dimethyl-p-phenylenediamine hydrochloride solution in the example is as follows: dissolving 0.1g of N, N-dimethyl-p-phenylenediamine hydrochloride by using 5.4mol/L hydrochloric acid to be diluted to 100 ml; the preparation method of the 5 percent ferric chloride hexahydrate solution in the embodiment comprises the following steps: 5g of ferric chloride hexahydrate is dissolved and diluted to 100ml by 1mol/L hydrochloric acid.
Example 1: detection of hydrogen sulfide content in acetylcysteine solution for inhalation
(1) Preparing a test solution and a blank solution: precisely transferring 2ml (about 0.2g corresponding to acetylcysteine) of the product into a round-bottom three-neck flask containing 40ml of water to serve as a reaction bottle, and putting 1ml of 5mol/L sodium hydroxide solution and 50ml of water into a collection bottle to serve as H2And S, collecting the bottles. As shown in the figure (or the like), the nitrogen flow rate was adjusted to 2.0L/min, the reaction flask and the collection flask were connected and after the system was closed, the introduction of nitrogen was started, and dropwise addition was made using a dropping funnel10ml of 3mol/L hydrochloric acid solution, after which nitrogen was passed on for 30 minutes and the collection bottle was disconnected. To a collection bottle were added 10ml of 0.1% N, N-dimethyl-p-phenylenediamine hydrochloride solution (prepared with 5.4mol/LHCl solution) and 5ml of 5% ferric chloride hexahydrate solution (prepared with 1M HCl), and the mixture was left to stand in the dark for 20 minutes. Diluting with water to 100ml, shaking to obtain sample solution, and preparing blank solution without inhalation medicinal liquid by the same method. The absorbance values of the test solution and the blank solution were recorded at a wavelength of 667 nm.
(2) Preparation of control solutions: precisely measuring 25ml of 0.25% (w/v) sodium sulfide solution, adding the sodium sulfide solution into a conical flask containing 25ml of iodometric titration solution (0.05mol/L) and 8ml of 3mol/L hydrochloric acid, titrating the sodium thiosulfate titration solution (0.1mol/L) to the near end point, adding starch indicator solution, titrating to the end point, and correcting the titration result by using a blank test. Each 1ml of the iodometric titration solution (0.05mol/L) corresponded to 68.16 of a 0.25% (w/v) sodium sulfide solution in ppm as the concentration of hydrogen sulfide. At this concentration, the solution was diluted with water to a concentration corresponding to 20ppm of hydrogen sulfide. 2ml of a 20ppm hydrogen sulfide solution was precisely transferred and prepared in accordance with the test solution preparation method, and this solution was used as a control solution.
(3) And (3) measuring the content of hydrogen sulfide in the test solution: measuring absorbance values of the sample solution and the reference solution at 667nm wavelength by spectrophotometry (Chinese pharmacopoeia 2015 general rules 0401), respectively recorded as ASample (I)、A20pmmThe content of hydrogen sulfide relative to acetylcysteine is calculated according to the following formula:
wherein: cH2S controlAs H in control solution2(ii) the concentration of S;
A20pmmis H2S, comparing the light absorption value of the solution of the reference substance;
Asample (I)The light absorption value of the solution to be detected is obtained;
CacetylcysteineAcetylcysteine solution for inhalationThe concentration of acylcysteine;
1000 is expressed as unit conversion factor.
Example 2: h2Analysis of the S content determination method
Analysis of influence on Hydrogen sulfide (H) in the product2S) the following three factors exist for determining the accuracy of the limit: 1)20ppm (H)2S) preparing a reference substance solution; 2) collecting hydrogen sulfide; 3) and (4) measuring hydrogen sulfide. From these three points, we can control hydrogen sulfide (H) in the product2S) limit determination was developed as follows:
1)20ppm(H2s) preparation of control solutions
Sodium sulfide (Na)2S) the principle and formula of calibration are as follows:
the reaction process of the sodium sulfide calibration solution comprises the following steps: na (Na)2S+I2＝2NaI+S↓；I2+2Na2S2O3＝Na2S4O6+2 NaI; the iodine reacts with sodium sulfide firstly, and then the excessive iodine reacts with sodium thiosulfate;
blank correction: i is2+2Na2S2O3＝Na2S4O6+2NaI, blank correction for Na consumption2S2O3That is, the actual amount of iodine added.
If the sample loading sequence is not correct, the following may occur: na (Na)2S+2HCl＝2NaCl+H2S↑；I2+H2And (2) reacting sodium sulfide with hydrochloric acid to generate hydrogen sulfide, and volatilizing the hydrogen sulfide to cause inaccurate calibration. Therefore, the sample loading sequence should strictly follow the following criteria: adding iodometric titration solution, adding hydrochloric acid solution, adding sodium sulfide solution, and titrating with sodium thiosulfate.
② the calculation formula of the concentration of the sodium sulfide solution expressed by ppm of hydrogen sulfide is as follows:
ppm(H2S)＝(Vblank space-VNa2S2O3 eliminating agent)×68.16
Wherein, VBlank space: blank calibration experiment volume (ml) of sodium thiosulfate titrant consumed
V: sodium sulfide solution calibration volume (ml) of sodium thiosulfate titration solution consumed in experiment
As can be seen from the calculation formula, the consumption volume of the sodium thiosulfate titration solution directly influences the calculation accuracy of the ppm number of the hydrogen sulfide, so the concentration of the sodium sulfide solution influences the consumption volume of the sodium thiosulfate titration solution.
Therefore, we examined the concentration of the sodium sulfide solution, and prepared 0.4% (w/v) sodium sulfide solution, 0.25% (w/v) sodium sulfide solution, the volume of sodium thiosulfate titration solution consumed by 0.15% (w/v) sodium sulfide solution, and the dilution process of 20ppm, and the results are shown in Table 1.
Table 1: investigation of configuration method
| Name (R) | Consumption of sodium thiosulfate volume (ml) | Preparation of 20ppm Hydrogen sulfide solution |
| Blank solution | 24.50 | —— |
| 0.4％(w/v)Na2S solution | 1.20 | 0.63ml → 50ml measuring flask for mother liquor |
| 0.25％(w/v)Na2S solution | 9.85 | Transfer mother liquor 1.0ml → 50ml measuring flask |
| 0.15％(w/v)Na2S solution | 15.80 | Transfer mother liquor 1.7ml → 50ml measuring flask |
In summary, the following steps: the sodium thiosulfate solution consumed by 0.4% (w/v) sodium sulfide solution is 1.20ml, the consumption is too low, errors are easy to generate, but the sampling amount is too small when preparing 20ppm hydrogen sulfide solution, and the operation and the control are not easy; the sodium thiosulfate solution consumed by the 0.15% (w/v) sodium sulfide solution is 15.80ml, more, and more solution needs to be removed when 20ppm hydrogen sulfide solution is prepared; the consumption of the sodium thiosulfate solution consumed by 0.25 percent (w/v) of the sodium sulfide solution and the preparation sampling amount of the 20ppm hydrogen sulfide solution are moderate, the operation is convenient, and the error is relatively small. Therefore, the method selects 0.25% (w/v) sodium sulfide solution as a calibration object.
2) Collection of hydrogen sulfide
Collecting hydrogen sulfide in a reference solution: firstly, sodium sulfide is converted into hydrogen sulfide in a reaction bottle, and simultaneously nitrogen is blown to a collecting bottle, and the hydrogen sulfide reacts with sodium hydroxide in the collecting bottle to be converted into sodium sulfide.
Reaction bottle: na (Na)2S+2HCl＝2NaCl+H2S ↓ (nitrogen charging)
Collecting a bottle: h2S+2NaOH＝Na2S+2H2O
Collecting hydrogen sulfide in the sample solution: the sample is added into the reaction bottle, the hydrogen sulfide in the sample is blown to the collection bottle by nitrogen, and the hydrogen sulfide reacts with the sodium hydroxide in the collection bottle to be converted into sodium sulfide.
Collecting a bottle: h2S+2NaOH＝Na2S+2H2O
Thus, it can be seen that: when the reference solution hydrogen sulfide is collected, the stability of the sodium sulfide solution in the reaction bottle after calibration, the concentration of hydrochloric acid, the nitrogen flow time and the amount of the sodium hydroxide solution as a collecting solution all influence the result of hydrogen sulfide collection. When the sample solution hydrogen sulfide is collected, the nitrogen flow rate and the nitrogen introducing time in the reaction bottle and the using amount of the sodium hydroxide solution as a collecting liquid influence the result of hydrogen sulfide collection.
We therefore used the same apparatus and collection conditions, considering from the several factors mentioned above:
[ Collection ] 2ml of 20ppm hydrogen sulfide solution was removed precisely and placed in a round bottom three-necked flask containing 40ml water as a reaction flask, one of which was equipped with an inlet tube that could lead to the bottom of the flask, one of which was inserted into a dropping funnel containing hydrochloric acid, the other of which was equipped with an air duct that led to a collection device containing 1ml of 5mol/L sodium hydroxide solution and 50ml water. Connecting the reaction bottle and the collection bottle, introducing nitrogen from the gas inlet after the system is closed, dropwise adding 10ml of 3mol/L hydrochloric acid by using a dropping funnel, continuously introducing nitrogen for 30 minutes after the system is closed, and disconnecting the gas collection bottle. To a collection bottle were added 10ml of 0.1% N, N-dimethyl-p-phenylenediamine hydrochloride solution (5.4mol/LHCl solution) and 5ml of 5% (w/v) ferric chloride hexahydrate solution (formulated with 1M HCl), and the mixture was left to stand in the dark for 20 minutes. Diluting with water to scale, shaking, and making into test solution. The absorbance values of the test solution and the blank solution were recorded at 665nm wavelength.
Stability investigation after calibration of A sodium sulfide solution
Taking calibrated sodium sulfide solution (i.e. 20ppm (H)2S) solution) are respectively placed for 0 hour, 4 hours and 6 hours, 20ppmH placed for different time is precisely transferred22ml of S solution, hydrogen sulfide was collected under the same conditions in the same manner, and absorbance was measured at 665 nm. The results are shown in Table 2.
Table 2: sodium sulfide solution stability survey after calibration
| Standing time (h) | Absorbance value (λ 665nm) | Corresponding to 0h |
| 0 | 0.382 | ---- |
| 4 | 0.364 | 95.3％ |
| 6 | 0.354 | 92.7％ |
And (4) conclusion: the sodium sulfide solution is easy to degrade, so that the sodium sulfide solution needs to be prepared for use at present, namely, not more than 4 hours.
Investigation of hydrochloric acid concentration
Precision pipetting of 2ml of 20ppmH2And S, according to a collecting mode, except that 5mol/L hydrochloric acid solution, 3mol/L hydrochloric acid solution and 1mol/L hydrochloric acid solution are respectively added into a separating funnel, the other conditions are the same, hydrogen sulfide is collected, and the light absorption value is measured at 665 nm. The results are shown in Table 3.
Table 3: investigation of hydrochloric acid solution concentration
| Hydrochloric acid concentration (mol/L) | Absorbance value (λ 665nm) |
| 5 | 0.321 |
| 3 | 0.351 |
| 1 | 0.328 |
And (4) conclusion: the use of 5mol/L hydrochloric acid solution and 1mol/L hydrochloric acid solution has lower absorbance, which indicates that the concentration of the hydrochloric acid solution is too high or too low, for H2Since S production is affected, a hydrochloric acid solution of 3mol/L is selected.
Investigation of the amount of sodium hydroxide solution C
Precision pipetting of 2ml of 20ppmH2And S, according to the collecting mode, collecting hydrogen sulfide under the same conditions except that 3ml, 2ml, 1ml and 0.5ml of 5mol/L sodium hydroxide solution are respectively added into a collecting bottle, and measuring the light absorption value at 665 nm. The results are shown in Table 4.
Table 4: sodium hydroxide solution concentration investigation
| The amount of sodium hydroxide solution (5mol/L) is used | Absorbance value (λ 665nm) |
| 3 | 0.327 |
| 2 | 0.352 |
| 1 | 0.345 |
| 0.5 | 0.247 |
And (4) conclusion: when the amount of the 5mol/L sodium hydroxide solution is 0.5ml and 3ml, incomplete collection or other reactions occur, resulting in a low absorbance value, and therefore the amount of the 5mol/L sodium hydroxide solution should be not less than 1ml and not more than 2 ml.
D flow of nitrogen
Under the above conditions, nitrogen gas is introduced at flow rates of 2.0L/min, 4.0L/min and 6.0L/min for 30min, hydrogen sulfide is collected, and light absorption value is determined at 665 nm. The results are shown in Table 5.
Table 5: nitrogen flux investigation
| Nitrogen flow (L/min) | Absorbance value (λ 665nm) |
| 2 | 0.340 |
| 4 | 0.327 |
| 6 | 0.317 |
And (4) conclusion: the nitrogen flow is too high, which easily causes the absorbance value to be lower, so the nitrogen flow is controlled at 2.0L/min.
E nitrogen introduction time
Under the above conditions, nitrogen gas was introduced for 20min, 30min and 40min, and after collecting hydrogen sulfide, the absorbance was measured at 665 nm. The results are shown in Table 6.
Table 6: investigation of Nitrogen supply time
| Nitrogen time (min) | Absorbance value (λ 665nm) |
| 20 | 0.282 |
| 30 | 0.345 |
| 40 | 0.347 |
And (4) conclusion: when the nitrogen is introduced for 20min, the absorbance value is low, and the absorbance is basically consistent when the nitrogen is introduced for 30min and 40min, so that the nitrogen introduction time is not less than 30 min.
3) Determination of hydrogen sulfide
Collecting and post-treating hydrogen sulfide:
after collection, the sample was completely reacted (i.e., reaction time) and the absorbance value that the solution was stable and might affect, so we examined the reaction time and measured the absorbance values at 0h, 26h, 72h and 96h of reaction, respectively. The results are shown in Table 7.
Table 7: reaction time and stability investigation
| Reaction time and stability | Absorbance value (λ 665nm) |
| 0h | 0.382 |
| 26h | 0.382 |
| 72h | 0.380 |
| 96h | 0.380 |
And (4) conclusion: the solution after reaction is stable, and the absorbance value is unchanged after 96 h.
Example 3: research on specialization
[ blank solution ] to a three-necked round-bottomed flask was added 40ml of water as a reaction flask, and 1ml of 5mol/L sodium hydroxide solution and 50ml of water were taken in a collection flask as H2And S, collecting the bottles. Connecting the reaction bottle and the collection bottle, regulating the flow of nitrogen to be 2.0L/min after the system is closed, dropwise adding 10ml of 3mol/L hydrochloric acid solution by using a dropping funnel when the nitrogen is introduced from the air inlet, continuously introducing the nitrogen for 30 minutes after the nitrogen is introduced, and disconnecting the gas collection measuring bottle. To a collection flask were added 10ml of a 0.1% N, N-dimethyl-p-phenylenediamine hydrochloride solution and 5ml of a 5% ferric chloride hexahydrate solution, and the mixture was left to stand for 20 minutes in the dark. Diluted to 100ml with water and shaken up as a blank solution.
[ control solution ] precisely transferring 2ml of 20ppm hydrogen sulfide solution into a round-bottom three-necked flask containing 40ml of water to serve as a reaction bottle, and placing 1ml of 5mol/L sodium hydroxide solution and 50ml of water in a collection bottle to serve as H2And S, collecting the bottles. Connecting the reaction bottle and the collection bottle, regulating the flow of nitrogen to be 2.0L/min after the system is closed, dropwise adding 10ml of 3mol/L hydrochloric acid solution by using a dropping funnel when the nitrogen is introduced from the air inlet, continuously introducing the nitrogen for 30 minutes after the nitrogen is introduced, and disconnecting the gas collection measuring bottle. Adding 0.1% N, N-dimethyl pair to the collection flask10ml of phenylenediamine hydrochloride solution and 5ml of 5% ferric chloride hexahydrate solution were left to stand for 20 minutes in the dark. Diluted to 100ml with water and shaken up to give a control solution.
[ test solution ] precisely transferring 2ml (about 0.2g corresponding to acetylcysteine) of the product into a round-bottom three-neck flask containing 40ml of water to serve as a reaction bottle, and putting 1ml of 5mol/L sodium hydroxide solution and 50ml of water into a collection bottle to serve as H2And S, collecting the bottles. Connecting the reaction bottle and the collection bottle, regulating the flow of nitrogen to be 2.0L/min after the system is closed, dropwise adding 10ml of 3mol/L hydrochloric acid solution by using a dropping funnel when the nitrogen is introduced from the air inlet, continuously introducing the nitrogen for 30 minutes after the nitrogen is introduced, and disconnecting the gas collection measuring bottle. To a collection flask were added 10ml of a 0.1% N, N-dimethyl-p-phenylenediamine hydrochloride solution and 5ml of a 5% ferric chloride hexahydrate solution, and the mixture was left to stand for 20 minutes in the dark. Diluting with water to 100ml, and shaking to obtain test solution.
Scanning the blank solution, the reference solution and the sample at 380-800 nm wavelength as shown in FIG. 3, FIG. 4 and FIG. 5. According to the full-wavelength scanning result, the reference solution and the test solution have maximum absorption at 667nm, the blank solution has no absorption, and the 667nm wavelength is selected for point selection and absorption value detection. The results are shown in Table 8.
Table 8: point selection detection result
| Name of solution | λ667nmAbsorption number |
| Blank solution | 0.000 |
| Control solution | 0.344 |
| Test solution | 0.254 |
And (3) knotting: the absorption value of the blank solution at 667nm is less than 0.01, and the absorption values of the reference solution and the test solution at 667nm are both greater than 0.1. Therefore, 667nm is selected as the detection wavelength, and the specificity meets the requirement.
Example 4: linear and Range study
【H2S standard solution ] is ready for use. Precisely measuring 25ml of 0.25% (w/v) sodium sulfide solution, precisely adding 25ml of iodometric titration solution (0.05mol/L) and 8ml of 3mol/L hydrochloric acid, titrating to the near-end point by using sodium thiosulfate titration solution (0.1mol/L), adding starch indicator solution, titrating to the end point, and correcting the titration result by using a blank test. Each 1ml of iodometric solution (0.05mol/L) corresponded to 68.16 of a 0.25% (w/v) sodium sulfide solution, and the concentration of hydrogen sulfide [ ppm (H/H) ] was expressed in ppm2S)＝(VBlank space-VNa2S2O3 eliminating agent)×68.16]。
With H2The concentration of the S standard solution was diluted with water to a solution containing hydrogen sulfide at 5ppm, 10ppm, 20ppm, 30ppm, 40ppm, and 50ppm (25% to 250% of the level of the control, and 20ppm at 100%). 2ml of the hydrogen sulfide solution of each concentration was precisely transferred, and a linear solution was prepared according to the test solution preparation method. The linear solutions were each measured at 667nm wavelength according to the method and absorbance values were recorded. The results are shown in Table 9, FIG. 6.
Table 9: linear result
And (3) knotting: as can be seen from FIG. 6, H2S is in the range of 5ppm to 50ppm, the linear equation is that y is 0.0161x +0.0071, and the linear correlation coefficient R is2R is greater than 0.995, 0.9984. The linear range meets the requirement and the linear relation is good.
Example 5: study of accuracy
[ acetylcysteine solution for inhalation ] 10g of acetylcysteine raw material is weighed in a 100ml beaker, 20ml of purified water is added, 23ml of 10% NaOH is added, the pH value is adjusted to 6.7-6.9, the solution is transferred to a 100ml measuring flask, and water is added to fix the volume and shake the solution uniformly for later use.
【H2S standard solution ] is ready for use. Precisely measuring 25ml of 0.25% (w/v) sodium sulfide solution, precisely adding 25ml of iodometric titration solution (0.05mol/L) and 8ml of 3mol/L hydrochloric acid, titrating to the near-end point by using sodium thiosulfate titration solution (0.1mol/L), adding starch indicator solution, titrating to the end point, and correcting the titration result by using a blank test. The concentration of hydrogen sulfide [ ppm (H) (0.05mol/L) in ppm per 1ml of iodine titration solution (0.05mol/L) corresponds to 68.16 in 0.25% (w/v) sodium sulfide solution2S)＝(VBlank space-VNa2S2O3 eliminating agent)×68.16]。
【20ppmH2S control solution ] with H2The concentration of the S standard solution was diluted with water to a solution containing hydrogen sulfide equivalent to 20 ppm. 2ml of the hydrogen sulfide solution of each concentration was precisely transferred, and a 20ppm control solution was prepared in accordance with the test solution preparation method.
[ acetylcysteine blank solution for inhalation ] 2ml of acetylcysteine solution for inhalation was precisely pipetted and prepared according to the test sample solution method as acetylcysteine blank solution for inhalation.
【10ppmH2S test solution with H2The concentration of the S standard solution was diluted with water to a solution containing hydrogen sulfide equivalent to 10 ppm. Precisely transferring 10ppm hydrogen sulfide solution and 2ml acetylcysteine solution for inhalation into a three-neck round-bottom flask, and preparing 10ppm H according to the preparation method of test solution2S test solution. Three portions were prepared in parallel.
【20ppmH2S test solution with H2The concentration of the S standard solution was diluted with water to a solution containing hydrogen sulfide equivalent to 20 ppm. Precisely transferring 20ppm hydrogen sulfide solution and 2ml acetylcysteine solution for inhalation into a three-neck round-bottom flask, and preparing 20ppm H according to the preparation method of test solution2S test solution. Three portions were prepared in parallel.
【30ppmH2S test articleSolutions with H2The concentration of the S standard solution was diluted with water to a solution containing hydrogen sulfide equivalent to 30 ppm. Precisely transferring 30ppm hydrogen sulfide solution and 2ml acetylcysteine solution for inhalation into a three-neck round-bottom flask, and preparing 30ppm H according to the preparation method of test solution2S test solution. Three portions were prepared in parallel.
Respectively taking the above 20ppmH2S, measuring the reference substance solution, the acetylcysteine blank solution for inhalation and the sample solution according to a method under the wavelength of 667nm (the general rule 0401 in the Chinese pharmacopoeia of the current edition), and recording the absorbance value. The results are shown in Table 10.
Table 10: recovery results
Calculating the formula: recovery rate was 20 ═ a (a)i-A0)/ATo pair
AiAdding standard sample solution absorbance value;
A0blank absorbance values for acetylcysteine solution for inhalation;
Ato pairAbsorbance values for control solutions.
And (3) knotting: as can be seen from Table 10, H2The recovery rate of S concentration in the concentration range of 50-150% is 86.0-98.8%, and RSD (n is 9) is less than 10%, indicating that the method has good accuracy.
Example 6: study of precision
(1) Precision of measurement
20ppm of H was taken2S control solution, 6 repeated measurements were made at a wavelength of 667nm, and the average value and RSD of the 6 measurements were calculated, and the results are shown in Table 11.
Table 11: measurement precision
| Serial number | 1 | 2 | 3 | 4 | 5 | 6 | Mean value of | RSD |
| Absorbance value | 0.348 | 0.348 | 0.348 | 0.348 | 0.348 | 0.348 | 0.348 | 0.00 |
And (3) knotting: the reference solution is tested for 6 times repeatedly, and the RSD of the light absorption value is 0.00 percent, which meets the requirement.
(2) Repeatability of
【20ppm H2S control solution ] with H2The concentration of the S standard solution was diluted with water to a solution containing hydrogen sulfide equivalent to 20 ppm. 2ml of a 20ppm hydrogen sulfide solution was precisely transferred, and a 20ppm reference solution was prepared according to the test solution preparation method.
[ test solution ] 2ml of this product (about 0.2g of acetylcysteine) was precisely pipetted and prepared according to the test solution preparation method. 6 parts are prepared in parallel.
The above solutions were measured at a wavelength of 667nm, and the average value and RSD of the measurement results were calculated, and the results are shown in Table 12.
Table 12: repeatability of
And (3) knotting: the self-product is repeatedly measured for 6 times, and the RSD of the hydrogen sulfide content of the self-product is 1.60 percent, thereby meeting the requirement.
(3) Intermediate precision
6 parts of the test article were prepared on different days by different persons in accordance with the reproducibility, the absorbance was measured at a wavelength of 667nm, and the average value and RSD of 12 parts of the results were calculated, and the results are shown in Table 13.
Table 13: intermediate precision
And (3) knotting: on different days, the content of the self-prepared product is repeatedly measured by different analysts 6 times, 12 times, the RSD of the content of the self-prepared product is 4.33 percent, and the requirement is met.
Example 7: study of solution stability
Take 20ppmH2S the reference substance solution and the sample solution are placed at room temperature for 0h, 24h, 48h, 72h, 96h and 120h in a dark place, the light absorption value is measured at the position of 667nm wavelength, the average value and RSD are calculated, and the result is shown in a table 14.
Table 14: stability of solution
And (3) knotting: the reference solution is placed at room temperature for 120 hours in a dark place, and the RSD of the absorbance is 0.52 percent; the test solution is placed at room temperature for 96 hours in a dark place, the RSD of the absorbance is 0.32 percent, and the experimental requirements are met.
Example 8: study of durability
According to generation and collection of H2The process and principle of S, for factors affecting generation and collection: the hydrochloric acid concentration, nitrogen flow rate, nitrogen charging time, and the amount of 5mol/L sodium hydroxide solution were finely adjusted and the wavelength was measured, and the results are shown in Table 15.
Table 15: durability
*: 1 is a normal condition
And (3) knotting: the durability of the method is examined by properly adjusting the concentration of acid salt, sodium hydroxide, the flow and time of nitrogen gas and the detection wavelength, and the result shows that the RSD of the hydrogen sulfide measurement result in the test article is 2.01% under each test condition, and the durability is good.
And (4) conclusion: the methodological researches such as specificity, linearity and range, accuracy, precision, solution stability, durability and the like prove that the method is feasible and is suitable for detecting the hydrogen sulfide in the acetylcysteine solution for inhalation.
Example 9: comparative study
The method is adopted to detect the content of hydrogen sulfide in the acetylcysteine solution for inhalation in the same batch; meanwhile, the content of hydrogen sulfide in the acetylcysteine solution for inhalation in the same batch is detected by a method of not controlling factors (hydrochloric acid concentration, nitrogen flow, nitrogen charging time, sodium hydroxide solution dosage and detection wavelength) influencing generation and collection, and the results are compared as follows:
table 16: comparison results
Claims (7)
1. A method for detecting the content of hydrogen sulfide in an acetylcysteine solution for inhalation, which is characterized by comprising the following steps:
(1) preparing a 20ppm standard hydrogen sulfide solution by using a sodium sulfide solution;
(2) preparing a test solution and a blank solution: transferring the acetylcysteine solution for inhalation to a three-neck flask filled with water to serve as a reaction bottle, wherein a first connector is provided with an air inlet pipe which can be communicated with the bottom of the flask, a second connector is inserted into a dropping funnel filled with hydrochloric acid, and a third connector is provided with an air guide pipe; taking sodium hydroxide solution in a collecting bottle as H2S, a collecting bottle, wherein the reaction bottle and the collecting bottle are connected through the gas guide tube, nitrogen starts to be introduced into the reaction bottle after the system is closed, a hydrochloric acid solution is dropwise added into the reaction bottle by using a dropping funnel when the nitrogen starts to be introduced from a gas inlet, the nitrogen continues to be introduced for 30-40min after the nitrogen introduction is finished, and a gas collecting measuring flask is disconnected; adding an N, N-dimethyl-p-phenylenediamine hydrochloride solution and a ferric trichloride hexahydrate solution into a collection bottle, and reacting to obtain a test solution; substituting water for acetylcysteine solution for inhalation, and preparing blank solution by the same method;
(3) preparation of control solutions: replacing the acetylcysteine solution for inhalation with the standard hydrogen sulfide solution of 20ppm obtained in step (1), and preparing to obtain 20ppm H by the method of step (2)2S, a reference substance solution;
(4) taking the blank solution as a blank control, measuring the absorbance values of the test solution and the reference solution by a spectrophotometer, and respectively recording as ASample (I)、A20pmmThe content of hydrogen sulfide relative to acetylcysteine is calculated according to the following formula:
wherein: cH2S controlAs H in control solution2(ii) the concentration of S;
A20pmmis H2S, comparing the light absorption value of the solution of the reference substance;
Asample (I)The light absorption value of the solution to be detected is obtained;
CacetylcysteineAcetylcysteine concentration in acetylcysteine solution for inhalation;
1000 is expressed as unit conversion factor.
2. The method for detecting the content of hydrogen sulfide in acetylcysteine solution for inhalation according to claim 1, wherein the step (1) of preparing a standard 20ppm hydrogen sulfide solution with sodium sulfide solution comprises: precisely measuring 25ml of 0.25% sodium sulfide solution, precisely adding 25ml of 0.05mol/L iodometric titration solution, adding 8ml of 3mol/L hydrochloric acid, titrating with 0.1mol/L sodium thiosulfate titration solution to near-end point, adding starch indicator, titrating to end point, correcting titration result by blank test, and expressing concentration of hydrogen sulfide in ppm as (V isBlank space-VNa2S2O3 eliminating agent)×68.16]And diluted to 20ppm, where VBlank spaceConsumption of the volume of sodium thiosulfate titrant for the blank calibration experiment, VNa2S2O3 eliminating agentThe volume of sodium thiosulfate titration solution consumed in the experiment was calibrated for sodium sulfide solution.
3. The method for detecting the content of hydrogen sulfide in an acetylcysteine solution for inhalation according to claim 1, wherein the flow rate of the nitrogen gas in the step (2) is 1.5 to 2.5L/min.
4. The method for detecting the content of hydrogen sulfide in acetylcysteine solution for inhalation according to claim 1, wherein the step (2) of preparing the sample solution comprises the following steps: precisely transferring 2ml of acetylcysteine solution for inhalation to a three-neck flask filled with 40ml of water to be used as a reaction bottle, wherein a first connector is provided with an air inlet pipe which can be communicated to the bottom of the flask, a second connector is inserted into a dropping funnel filled with hydrochloric acid, and a third connector is provided with an air guide pipe; taking 50-55ml of 0.1-0.2 mol/L sodium hydroxide solution in a collection bottle as H2S collecting bottle, connecting the reaction bottle and the collecting bottle through the gas guide tube, and introducing nitrogen into the reaction bottle after the system is closed to regulate the nitrogenThe gas flow is 2.0L/min, when nitrogen is introduced from the gas inlet, 10ml of 3mol/L hydrochloric acid solution is dripped by using a dropping funnel, after the nitrogen is introduced for 30-40min, the gas collection measuring flask is disconnected; and adding 10ml of 0.1% N, N-dimethyl-p-phenylenediamine hydrochloride solution and 5ml of 5% ferric chloride hexahydrate solution into a collection bottle, standing for 20min in a dark place, diluting to 100ml with water, and shaking up to obtain a test solution.
5. The method for detecting the content of hydrogen sulfide in acetylcysteine solution for inhalation according to claim 4, wherein the 0.1% solution of N, N-dimethyl-p-phenylenediamine hydrochloride is prepared by the following steps: 0.1g N, N-dimethyl-p-phenylenediamine hydrochloride was dissolved in 5.4mol/L hydrochloric acid and diluted to 100 ml.
6. The method for detecting the content of hydrogen sulfide in acetylcysteine solution for inhalation according to claim 4, wherein the 5% ferric chloride hexahydrate solution is prepared by the following steps: 5g of ferric chloride hexahydrate is dissolved and diluted to 100ml by 1mol/L hydrochloric acid.
7. The method for detecting the content of hydrogen sulfide in acetylcysteine solution for inhalation according to claim 1, wherein the detection wavelength of the spectrophotometric instrument used in step (4) for testing the sample solution and the control solution is 665-667 nm.
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