CN114674951B - Method for detecting terbutaline sulfate injection and related substances - Google Patents
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Abstract
The invention relates to the technical field of medicine detection methods, in particular to a detection method for measuring terbutaline sulfate injection and related substances, wherein the detection method adopts a high performance liquid chromatography for detection, and the detection conditions comprise that: the mobile phase consists of a mobile phase A and a mobile phase B, wherein the mobile phase A is an ammonium formate-formic acid buffer solution containing 3.75-4.31 g/L of sodium hexanesulfonate and 1.25-1.57 g/L of sodium sulfate, and the pH value is 3.0 +/-0.1; the mobile phase B is methanol; the mixing volume ratio of the mobile phase A to the mobile phase B is 80:20; the detection method can realize simultaneous detection of the degradation impurities of the bulk drugs and the preparations, and has the advantages of high separation degree, good durability and the like.
Description
Technical Field
The invention relates to the technical field of medicine detection methods, in particular to a method for detecting terbutaline sulfate injection and related substances.
Background
Terbutaline Sulfate, known as Terbutaine Sulfate, has the chemical name (+/-) alpha- [ (tert-butylamino) methyl ] -3,5-dihydroxybenzyl alcohol Sulfate (2:1) and the structural formula:
terbutaline sulfate is an adrenergic agonist, can selectively stimulate beta 2 receptors, relax bronchial smooth muscle, inhibit release of endogenous spasmodic substances and edema caused by endogenous media, improve the clearance capability of bronchial mucociliary epithelium, and relax uterine smooth muscle, is mainly used for treating bronchial asthma, chronic bronchitis and other lung diseases accompanied with bronchospasm, can also be used for preventing premature delivery and fetal asphyxia, and has the characteristics of high selectivity, less side effect and the like.
In the production process of the terbutaline sulfate bulk drug, initial material impurities, process impurities, intermediate impurities, degradation impurities and the like are easily introduced, impurity detection methods (shown in table 1) are respectively recorded in Chinese pharmacopoeia (CP 2020), european pharmacopoeia (EP 10.1), united states pharmacopoeia (USP 43) and the like, and limit standards for part or all impurities in the impurity A, B, C, D are formulated for quality control. Furthermore, terbutaline sulfate is prepared into injection. The inventor discovers for the first time in experimental research that in the preparation process and the storage process of the injection, the injection is unstable and is easy to oxidize to generate impurities F, so that the quality of the injection is influenced. The impurity A, B, C, D, F has the following structure:
at present, for the terbutaline sulfate injection formulation, because the impurity A, D is a process impurity in raw material production, only the change of the content of the degradation impurity B, C, F in the preparation and storage processes of the preparation needs to be monitored. Only the United states pharmacopoeia (USP 43) of the pharmacopoeia of various countries describes the quality standards and detection methods thereof. The quality standards include identification, detection of endotoxin in cells, pH and content, and the content detection method is shown in Table 1, but the detection method of related substances and the limit standard thereof are not included.
TABLE 1 terbutaline sulfate content/impurity detection method
As can be seen from table 1, the existing CP, EP, and USP methods do not provide a detection method capable of simultaneously detecting terbutaline sulfate injection and degradation impurities B, C, F, so as to better control the terbutaline sulfate injection, which is a technical problem that those skilled in the art have not yet solved.
Therefore, it is necessary to develop a method for detecting terbutaline sulfate injection and related substances, which can solve the above technical problems.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a method for detecting terbutaline sulfate injection and related substances, which can simultaneously detect degradation impurities B, C, F and establish related substance limit standards, thereby improving the quality control of the terbutaline sulfate injection.
The invention is realized by the following technical scheme:
a method for detecting terbutaline sulfate injection and related substances adopts high performance liquid chromatography for detection, and the detection conditions comprise:
mobile phase: the composition comprises a mobile phase A and a mobile phase B, wherein the mobile phase A is an ammonium formate-formic acid buffer solution containing 3.75-4.31 g/L sodium hexanesulfonate and 1.25-1.57 g/L sodium sulfate, and the pH value is 3.0 +/-0.1; the mobile phase B is methanol; the mixing volume ratio of the mobile phase A to the mobile phase B is 80:20;
the related substances at least comprise impurities C, and the structure of the impurities C is as follows:
the preparation process of the terbutaline sulfate injection comprises the following steps: adding a prescribed amount of terbutaline sulfate (0.05%, w/v) and sodium chloride (0.89%, w/v) into a proper amount of water for injection, adding hydrochloric acid to adjust the pH value to 3.0-4.5, stirring and dissolving completely, then fixing the volume, filtering by a 0.45 mu m filter element, filling, sterilizing at 121 ℃, and preparing the terbutaline sulfate injection with the specification of 0.5mg.
Preferably, the related substances further comprise at least one of impurities B and F, and the impurities B, F have the structure:
preferably, the chromatographic column uses an octadecylsilane bonded silica column.
Preferably, the concentration of ammonium formate in the mobile phase A is 0.049-0.051 mol/L.
Preferably, the column temperature is 30 to 40 ℃.
Preferably, the flow rate of the mobile phase is 0.8 to 1.2mL/min.
Preferably, the injection volume is 50 μ L.
Preferably, the detection wavelength is 276nm.
The detection method of the invention also comprises other conventional steps: preparing a test solution, a control solution and a reference solution, and detecting the test sample.
In addition, the detection method of the present invention may further comprise preparation of a system-compatible solution, and the like.
The invention also relates to a method for simultaneously detecting three compounds, which have the following structures:
detecting by adopting high performance liquid chromatography, wherein the detection conditions comprise:
mobile phase: the composition comprises a mobile phase A and a mobile phase B, wherein the mobile phase A is an ammonium formate-formic acid buffer solution containing 3.75-4.31 g/L sodium hexanesulfonate and 1.25-1.57 g/L sodium sulfate, and the pH value is 3.0 +/-0.1; the mobile phase B is methanol; the mixing volume ratio of the mobile phase A to the mobile phase B is 80:20.
preferably, the chromatographic column uses an octadecylsilane bonded silica column.
Preferably, the concentration of ammonium formate in the mobile phase A is 0.049-0.051 mol/L.
Preferably, the column temperature is 30 to 40 ℃.
Preferably, the flow rate of the mobile phase is 0.8 to 1.2mL/min.
Preferably, the injection volume is 50 μ L.
Preferably, the detection wavelength is 276nm.
More preferably, in the method, an octadecylsilane chemically bonded silica gel column is adopted as a chromatographic column, the ammonium formate concentration in the mobile phase A is 0.049-0.051 mol/L, the column temperature is 30-40 ℃, the flow rate of the mobile phase is 0.8-1.2 mL/min, the sample injection volume is 50 mu L, and the detection wavelength is 276nm.
Compared with the prior art, the method for detecting the terbutaline sulfate injection and the related substances has the advantages that:
(1) the invention relates to a method for detecting terbutaline sulfate injection and related substances, which adopts ammonium formate-formic acid buffer solution of sodium hexanesulfonate and sodium sulfate as a mobile phase A and methanol as a mobile phase B, and mixes the mobile phase A and the mobile phase B according to a volume ratio of 80 to 20 to form the mobile phase, so that preparation degradation impurities B, C, F can be detected simultaneously, the separation degree of each impurity is high, and the detection method has good durability.
(2) The invention realizes the simultaneous detection of the degradation impurities of the bulk drugs and the preparations by optimizing the mobile phase in the prior art, and establishes the limit standard of the related substances of the injection: the separation degree between related substances and main peaks is more than 2, the impurity B, C, F is less than or equal to 0.5 percent, other single impurities are less than or equal to 0.5 percent, and the total impurity is less than or equal to 2.0 percent, so that the control on the quality of the terbutaline sulfate injection is improved.
Drawings
FIG. 1 is a liquid chromatogram of a solution suitable for use in the system of example 1.
FIG. 2-1 shows the results of the detection of the substances related to the self-prepared terbutaline sulfate injection in example 2.
Fig. 2-2 is a partial enlarged view of fig. 2-1.
FIG. 3-1 is a liquid chromatogram of a solution suitable for use in the system of comparative example 1.
Fig. 3-2 is a partial enlarged view of fig. 3-1.
FIG. 4 is a liquid chromatogram of a solution suitable for use in the system of comparative example 2.
FIG. 5 is a liquid chromatogram of a solution suitable for use in the system of comparative example 3.
Detailed Description
The invention is further described below in conjunction with specific embodiments, and the advantages and features of the invention will become more apparent as the description proceeds. These examples are illustrative only and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
The types and manufacturer information of instruments, reagents and reference substances used in the examples and comparative examples of the invention are as follows:
1. the instrument comprises the following steps:
agilent 1260 high performance liquid chromatograph
2. Reagent:
hexane sulfonic acid sodium salt (ion pair reagent, chromatogram pure, chinese medicine group)
Sodium sulfate (analytically pure, group of national medicine)
Ammonium formate (analytically pure, shanghai Ling Fenghua Chemicals reagent, inc.)
Formic acid (analytically pure, national medicine group)
Methanol (chromatographically pure, TEDIA)
3. Comparison products:
and (3) standard substance: terbutaline sulfate (purity 99.8%, china institute for testing food and drug)
Impurity B (purity 98.1%, TRC)
Impurity C (purity 100.0%, EP)
Impurity F (purity 98.7%, TLC)
Example 1
The system applicability test for detecting the terbutaline sulfate injection and related substances by the high performance liquid chromatography comprises the following test conditions:
a chromatographic column: agilent ZORBAX Eclipse Pl-C18 (250X 4.6mm,5 μm);
mobile phase: putting 4.08g of sodium hexanesulfonate, 1.41g of sodium sulfate and 3.15g of ammonium formate into a 1000mL measuring flask, adding about 960mL of water, adding formic acid (about 8 mL) to adjust the pH value to 3.0, diluting with water to a scale, and shaking to completely dissolve to obtain the mobile phase A. Mixing 800mL of mobile phase A and 200mL of methanol (mobile phase B) uniformly;
detection wavelength: 276nm;
column temperature: 30 ℃;
flow rate: 1.0mL/min;
sample introduction volume: 50 mu L of the solution;
system applicability solution: taking appropriate amount of terbutaline sulfate standard substance and B, C, F reference substance, adding mobile phase for dissolving, and quantitatively diluting to obtain solution containing terbutaline sulfate 0.5mg and B, C, F each 2.5 μ g per 1 mL.
The detection result is shown in figure 1 and table 2, the separation degree of the impurity C and the main peak is 2.38, the requirement that the separation degree is more than 2 is met, the impurities B, C, F are effectively separated within 20min, the impurity B, C, F is less than or equal to 0.5%, the other single impurities are less than or equal to 0.5%, the total impurities are less than or equal to 2.0%, and the method can be used for quality control of terbutaline sulfate injection.
Table 2 example 1 test method system applicability results
| Attribution | RT(min) | Degree of separation |
| Impurity F | 6.07 | / |
| Impurity B | 10.76 | 12.76 |
| Impurity C | 13.50 | 5.69 |
| Terbutaline | 15.19 | 2.38 |
Determining the concentration of sodium hexanesulfonate in the mobile phase A to be 3.75-4.31 g/L and the concentration of sodium sulfate to be 1.25-1.57 g/L according to a durability test; the concentration of ammonium formate in the mobile phase A can be 0.049-0.051 mol/L; the pH of the buffer in mobile phase a may be 3.0 ± 0.1; the column temperature is 30-40 ℃; the flow rate is 0.8-1.2 mL/min.
Example 2
Detecting terbutaline sulfate injection and related substances, wherein the detection conditions are as follows:
a chromatographic column: agilent ZORBAX Eclipse Pl-C18 (250X 4.6mm,5 μm);
mobile phase: putting 4.08g of sodium hexanesulfonate, 1.41g of sodium sulfate and 3.15g of ammonium formate into a 1000mL measuring flask, adding about 960mL of water, adding formic acid (about 8 mL) to adjust the pH value to 3.0, diluting with water to a scale, and shaking to completely dissolve to obtain a mobile phase A. Mixing 800mL of mobile phase A and 200mL of methanol (mobile phase B) uniformly;
detection wavelength: 276nm;
column temperature: 30 ℃;
flow rate: 1.0mL/min;
sample introduction volume: 50 mu L of the solution;
test solution: taking 5 terbutaline sulfate injection, mixing well, taking appropriate amount as sample solution (0.5 mg/mL);
the preparation method of the self-made terbutaline sulfate injection comprises the following steps: adding a prescribed amount of terbutaline sulfate (0.05%, w/v) and sodium chloride (0.89%, w/v) into a proper amount of water for injection, adding hydrochloric acid to adjust the pH value to 3.0-4.5, stirring and dissolving completely, then fixing the volume to 400L, filtering by a 0.45 mu m filter element, filling, sterilizing at 121 ℃, and preparing the terbutaline sulfate injection with the specification of 0.5mg.
Control solution: precisely measuring a proper amount of standard substance, and quantitatively diluting with a mobile phase to prepare a solution containing about 0.5 mu g of terbutaline sulfate in each 1 mL;
precisely measuring the test solution and the reference solution, respectively injecting into a liquid chromatograph, and recording the chromatogram until the retention time of the main component peak is 3 times.
The calibration factor of the impurity B, C, F is obtained through the methodology verification as follows: impurity B correction factor of 0.79, impurity C correction factor of 0.23, and impurity D correction factor of 0.15.
The detection results are shown in fig. 2-1, fig. 2-2 and table 3, the chromatogram of the test solution contains impurity peaks, the peak area of the impurity C multiplied by the correction factor 0.23 is not more than 5 times (0.5) of the main peak area of the control solution, the peak area of the impurity B multiplied by the correction factor 0.79 is not more than 5 times (0.5) of the main peak area of the control solution, the peak area of the impurity F multiplied by the correction factor 0.15 is not more than 5 times (0.5) of the main peak area of the control solution, other single impurities are not more than 5 times (0.5) of the main peak area of the control solution, and the sum of the peak areas of all the impurities is not more than 20 times (2.0) of the main peak area of the main component of the control solution, so that the test solution meets the impurity limit standard and is a qualified terbutaline sulfate injection product.
Table 3 example 2 test method system applicability results
| Attribution | RT(min) | Degree of separation | Peak area (%) |
| Impurity F | 6.13 | / | 0.57 |
| 7.84 | 6.51 | 0.01 | |
| Impurity B | 10.74 | 8.79 | 0.19 |
| Impurity C | 13.46 | 6.24 | 0.01 |
| Terbutaline | 15.09 | 2.42 | 99.20 |
| 27.03 | 12.92 | 0.02 |
Comparative example 1
The method for detecting the content of terbutaline sulfate injection in United states Pharmacopeia (USP 43) is used for a systematic applicability test for detecting related substances, and the test conditions are as follows:
a chromatographic column: agilent ZORBAX Eclipse Pl-C18 (250X 4.6mm,5 μm);
mobile phase: 5.49g of sodium hexanesulfonate and 3.15g of ammonium formate are taken and placed in a 1000mL measuring flask, about 960mL of water is added, formic acid (about 8 mL) is added to adjust the pH value to 3.0, the mixture is diluted to the scale with water and shaken to be completely dissolved, and the mobile phase is obtained. Mixing 770mL of mobile phase A and 230mL of methanol (mobile phase B);
detection wavelength: 276nm;
column temperature: 30 ℃;
flow rate: 1.0mL/min;
sample injection volume: 50 mu L of the solution;
system applicability solution: taking appropriate amount of terbutaline sulfate standard substance and B, C, F reference substance, adding mobile phase for dissolving, and quantitatively diluting to obtain solution containing terbutaline sulfate 0.5mg and B, C, F each 2.5 μ g per 1 mL.
The detection results are shown in fig. 3-1, fig. 3-2 and table 4, and the degree of separation of the impurity C from the main peak is 1.33, which does not meet the requirement of the degree of separation > 2. Therefore, the experimental conditions of the high performance chromatography need to be optimized to solve the problem of the separation degree of the impurity C and the main peak, so as to achieve the purpose of simultaneously detecting the impurity B, C, F in the injection.
Table 4 comparative example 1 test method system applicability results
| Attribution | RT(min) | Degree of separation |
| Impurity F | 5.01 | / |
| Impurity B | 7.34 | 7.19 |
| Impurity C | 8.88 | 4.00 |
| Terbutaline | 9.51 | 1.33 |
Comparative example 2
The system applicability test for detecting the terbutaline sulfate injection and related substances by the high performance liquid chromatography comprises the following test conditions:
a chromatographic column: agilent ZORBAX Eclipse Pl-C18 (250X 4.6mm,5 μm);
mobile phase: 5.49g of sodium hexanesulfonate and 3.15g of ammonium formate are taken, placed in a 1000mL measuring flask, added with about 960mL of water, added with formic acid (about 8 mL) to adjust the pH value to 3.0, diluted to the scale with water and shaken to be completely dissolved to obtain the mobile phase. Mixing 800mL of mobile phase A and 200mL of methanol (mobile phase B) uniformly;
detection wavelength: 276nm;
column temperature: 30 ℃;
flow rate: 1.0mL/min;
sample introduction volume: 50 mu L of the solution;
system applicability solution: taking appropriate amount of terbutaline sulfate standard substance and B, C, F reference substance, adding mobile phase for dissolving, and quantitatively diluting to obtain solution containing terbutaline sulfate 0.5mg and B, C, F each 2.5 μ g per 1 mL.
As shown in fig. 4 and table 5, the degree of separation of impurity C from the main peak was 1.77, and the degree of separation was not satisfied with the requirement of > 2. Therefore, the condition of the HPLC test needs to be further optimized to solve the problem of the separation degree of the impurity C and the main peak, so as to achieve the simultaneous detection of the impurity B, C, F in the injection.
TABLE 5 comparative example 2 test method System suitability results
| Attribution | RT(min) | Degree of separation |
| Impurity F | 5.02 | / |
| Impurity B | 7.37 | 7.71 |
| Impurity C | 8.93 | 4.21 |
| Terbutaline | 9.68 | 1.77 |
Comparative example 3
The system applicability test for detecting the terbutaline sulfate injection and related substances by the high performance liquid chromatography comprises the following test conditions:
a chromatographic column: agilent ZORBAX Eclipse Pl-C18 (250X 4.6mm,5 μm);
mobile phase: taking 4.08g of sodium hexanesulfonate, 1.41g of sodium sulfate and 3.15g of ammonium formate, placing the materials into a 1000mL measuring flask, adding about 960mL of water, adding formic acid (about 8 mL) to adjust the pH value to 3.0, diluting the materials to a scale with water, and shaking the materials until the materials are completely dissolved to obtain a mobile phase. Mixing 770mL of mobile phase A and 230mL of methanol (mobile phase B);
detection wavelength: 276nm;
column temperature: 30 ℃;
flow rate: 1.0mL/min;
sample introduction volume: 50 mu L of the solution;
system applicability solution: taking appropriate amount of terbutaline sulfate standard substance and B, C, F reference substance, adding mobile phase for dissolving, and quantitatively diluting to obtain solution containing terbutaline sulfate 0.5mg and B, C, F each 2.5 μ g per 1 mL.
As shown in fig. 5 and table 6, the detection results only detected impurities B, F and terbutaline, and not detected impurity C, which is not suitable for the purpose of simultaneously detecting impurity B, C, F in the injection.
TABLE 6 comparative example 2 test method System suitability results
| Attribution | RT(min) | Degree of separation |
| Impurity F | 6.06 | / |
| Impurity B | 11.07 | 13.48 |
| Impurity C | Not detected out | / |
| Terbutaline | 15.61 | 6.51 |
The above detailed description is specific to one possible embodiment of the present invention, and the embodiment is not intended to limit the scope of the present invention, and all equivalent implementations or modifications without departing from the scope of the present invention should be included in the technical scope of the present invention.
Claims (7)
1. A method for detecting terbutaline sulfate injection and related substances is characterized in that high performance liquid chromatography is adopted for detection, and the detection conditions comprise:
mobile phase: the composite material consists of a mobile phase A and a mobile phase B, wherein the mobile phase A is an ammonium formate-formic acid buffer solution containing 3.75 to 4.31g/L sodium hexane sulfonate and 1.25 to 1.57g/L sodium sulfate, and the pH value is 3.0 +/-0.1; the mobile phase B is methanol; the mixing volume ratio of the mobile phase A to the mobile phase B is 80:20;
the chromatographic column adopts an octadecylsilane chemically bonded silica gel column, and the detection wavelength is 276nm;
the related substances at least comprise an impurity C and at least one of an impurity B and an impurity F, and the impurity B, C, F has the structure that:
2. the detection method according to claim 1, wherein the concentration of ammonium formate in the mobile phase A is 0.049 to 0.051mol/L.
3. The detection method according to claim 1, wherein the column temperature is 30 to 40 ℃.
4. The detection method according to claim 1, wherein the flow rate of the mobile phase is 0.8 to 1.2mL/min.
5. The detection method according to claim 1, wherein the injection volume is 50 μ L.
6. A method for simultaneously detecting three compounds, wherein the three compounds have the following structures:
detecting by adopting high performance liquid chromatography, wherein the detection conditions comprise:
mobile phase: the composite material consists of a mobile phase A and a mobile phase B, wherein the mobile phase A is an ammonium formate-formic acid buffer solution containing 3.75 to 4.31g/L sodium hexane sulfonate and 1.25 to 1.57g/L sodium sulfate, and the pH value is 3.0 +/-0.1; the mobile phase B is methanol; the mixing volume ratio of the mobile phase A to the mobile phase B is 80:20; the chromatographic column adopts an octadecylsilane chemically bonded silica gel column, and the detection wavelength is 276nm.
7. The method according to claim 6, wherein the concentration of ammonium formate in the mobile phase A is 0.049-0.051mol/L, the column temperature is 30-40 ℃, the flow rate of the mobile phase is 0.8-1.2mL/min, and the sample injection volume is 50 μ L.
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