CN116818928A - Separation detection method for impurities in butorphanol tartrate injection - Google Patents
Separation detection method for impurities in butorphanol tartrate injection Download PDFInfo
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- CN116818928A CN116818928A CN202310493418.XA CN202310493418A CN116818928A CN 116818928 A CN116818928 A CN 116818928A CN 202310493418 A CN202310493418 A CN 202310493418A CN 116818928 A CN116818928 A CN 116818928A
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- 239000012535 impurity Substances 0.000 title claims abstract description 99
- GMTYREVWZXJPLF-AFHUBHILSA-N butorphanol D-tartrate Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O.N1([C@@H]2CC3=CC=C(C=C3[C@@]3([C@]2(CCCC3)O)CC1)O)CC1CCC1 GMTYREVWZXJPLF-AFHUBHILSA-N 0.000 title claims abstract description 50
- 229960001590 butorphanol tartrate Drugs 0.000 title claims abstract description 50
- 238000001514 detection method Methods 0.000 title claims abstract description 47
- 238000002347 injection Methods 0.000 title claims abstract description 44
- 239000007924 injection Substances 0.000 title claims abstract description 44
- 238000000926 separation method Methods 0.000 title claims abstract description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 41
- 238000000034 method Methods 0.000 claims abstract description 30
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims abstract description 28
- 235000019796 monopotassium phosphate Nutrition 0.000 claims abstract description 28
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- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 14
- 238000010828 elution Methods 0.000 claims abstract description 8
- 239000008363 phosphate buffer Substances 0.000 claims abstract description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 4
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- 238000003556 assay Methods 0.000 claims 3
- 230000035945 sensitivity Effects 0.000 abstract description 8
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- 229940079593 drug Drugs 0.000 abstract description 3
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- 239000000243 solution Substances 0.000 description 53
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- 239000000047 product Substances 0.000 description 16
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- 238000007865 diluting Methods 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 11
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- 229940095064 tartrate Drugs 0.000 description 11
- 208000002193 Pain Diseases 0.000 description 10
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- 238000005303 weighing Methods 0.000 description 7
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- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
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- IFKLAQQSCNILHL-QHAWAJNXSA-N butorphanol Chemical compound N1([C@@H]2CC3=CC=C(C=C3[C@@]3([C@]2(CCCC3)O)CC1)O)CC1CCC1 IFKLAQQSCNILHL-QHAWAJNXSA-N 0.000 description 3
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- GJOVVPXDEXUSTC-OWCLPIDISA-N Norbutorphanol Chemical group C1CCC[C@@]2(O)[C@H]3CC4=CC=C(O)C=C4[C@]21CCN3 GJOVVPXDEXUSTC-OWCLPIDISA-N 0.000 description 2
- 208000004550 Postoperative Pain Diseases 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
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- Investigating Or Analysing Biological Materials (AREA)
Abstract
The application provides a separation and detection method for impurities in butorphanol tartrate injection, and relates to the technical field of medicine detection. The impurities are IB428 and IB429. The separation detection method comprises the following steps: adopting an HPLC method, taking phenyl bonded silica gel as a filler, adopting a mobile phase A and a mobile phase B to perform gradient elution, and entering a detector to detect, wherein the mobile phase A is potassium dihydrogen phosphate buffer solution-acetonitrile (80-95:5-20); mobile phase B was potassium dihydrogen phosphate buffer-acetonitrile (15-25:75-85). The detection method has the advantages of strong specificity, high sensitivity, good accuracy and convenient operation, and can effectively control the quality of medicines.
Description
Technical Field
The application belongs to the technical field of medicine detection, and particularly relates to a separation detection method for impurities in butorphanol tartrate injection.
Background
Pain is a signal and response of the body to an adverse stimulus or damage, is a symptom possibly accompanied by a plurality of diseases, brings unpleasant subjective feeling and emotional experience, is classified into somatic pain and visceral pain according to action parts, has high somatic pain conduction speed and clear localization, has slow visceral pain transmission speed, has fuzzy pain feeling and is difficult to localize, and visceral pain is more intolerable clinically. Along with the progress of medical technology, patients further require comfort of clinical treatment in pursuing clinical curative effects, analgesic drugs play a great role in clinical use, and opioid analgesics are the principal force army of clinical use, mainly used for relieving acute traumatic sharp pain, postoperative pain and advanced cancer pain.
The sensory neuron can release pain substances to combine with the receptor after receiving the stimulation signal, transmit biological information, and the brain receives the signal, so that the endorphin neuron can release endogenous opioid peptide, the opioid peptide combines with presynaptic and postsynaptic membrane opioid receptors, the pain substances are inhibited from releasing G-coupled protein, the adenylate cyclase function is inhibited, ca 2+ The decrease in influx and the increase in outflow of k+ lead to hyperpolarization of the cell, and the decrease or blockage of the pain signal transmitted upstream. The opioid analgesic can be combined with opioid receptors in different brain regions to simulate the action of endogenous opioid peptide, activate in vivo anti-pain system, raise pain threshold, block the conduction of pain impulse, exert powerful central analgesic effect, and conventional opioid can not completely block the conduction of visceral pain. Visceral pain is an independent risk factor for postoperative chronic pain occurrence, and the incidence rate of visceral pain after abdominal and gynecological operationsUp to 63% and 45%, agonism of kappa opioid receptors is an important way of managing visceral pain.
The butorphanol tartrate injection is used as new opioid receptor agonism-antagonism, and is applied to treat various cancerous pains and postoperative pains, and the main action mechanism is that the agonism kappa receptor plays a spinal cord analgesic role, and when the butorphanol tartrate injection is used together with mu receptor agonism, the mu receptor antagonism can be exerted to alleviate or offset side effects such as respiratory depression of mu receptor.
Considering that adverse reactions in clinic are mostly related to impurity levels, in order to better exert the clinical effects of butorphanol tartrate injection, it is necessary to conduct sufficient impurity researches. The butorphanol tartrate injection is recorded in the Chp2020 edition and USP43, the dextroisomer impurity is listed in the Chinese pharmacopoeia as a specific impurity, the USP43 has no specific impurity, and the butorphanol tartrate nasal spray is 3, 14-dihydroxymorphinan (corresponding to impurity IB 440). The structural formulas of the dextroisomer (corresponding to impurity IB 430) and the 3, 14-dihydroxymorphinan (corresponding to impurity IB 440) of the buprenorphine tartrate listed in the pharmacopoeia are as follows.
The structural formula of the butorphanol tartrate is as follows:
the structural formula of the dexbuprenorphine tartrate is as follows:
IB440 has the formula:
in the research and development process of the butorphanol tartrate injection, the applicant adopts a method in the Chinese pharmacopoeia standard to find that two impurities (IB 428 and IB 429) are obviously increased in the placing process, and IB440 is not detected under the conditions of high temperature for 30 days, long term and acceleration.
The impurity IB428 is a butorphanol dehydration impurity, IB429 is a butorphanol oxidation impurity, and the impurity has a risk of exceeding the limit of identification, so the impurity is controlled according to specific impurity research in the quality standard. Considering that the separation degree of the impurity IB428 and the impurity IB429 is less than 1.5 under the method in the Chinese pharmacopoeia standard and the specificity is poor, the application provides the method for separating and measuring the impurity in the butorphanol tartrate injection by using the HPLC method, the method can effectively separate and measure the IB428 and the IB429 in the butorphanol tartrate injection, and the detection and separation of each impurity in the butorphanol tartrate injection are realized, and the method has high sensitivity, good specificity and accurate and reliable detection result.
Disclosure of Invention
Aiming at the problems existing in the prior art, the application provides a method for separating and detecting impurities in butorphanol tartrate injection, which has strong specificity, high sensitivity and convenient operation. The separated impurities IB428 and IB429 are enriched, and structural identification is carried out, so that the structures of the impurities IB428 and IB429 are clear, and the quality of the medicine can be effectively controlled.
In order to achieve the above purpose, the technical scheme adopted by the application is as follows:
in one aspect, the application provides a method for separating and detecting impurities in butorphanol tartrate injection;
the separation detection method is an HPLC method, and the chromatographic conditions are as follows:
chromatographic column: phenyl bonding silica gel is used as a filler;
mobile phase: mobile phase A and mobile phase B are adopted, wherein mobile phase A is potassium dihydrogen phosphate buffer solution-acetonitrile, and mobile phase B is potassium dihydrogen phosphate buffer solution-acetonitrile;
eluting: gradient elution, elution procedure is as follows:
0-10 minutes, 90% of mobile phase A and 10% of mobile phase B;
10-35 minutes, 90-65% of mobile phase A and 10-35% of mobile phase B;
35-45 minutes, the dosage of the mobile phase A is 65%, and the dosage of the mobile phase B is 35%;
45-45.1 minutes, the dosage of the mobile phase A is 65-90%, and the dosage of the mobile phase B is 35-10%;
45.1-60 minutes, the amount of mobile phase A is 90% and the amount of mobile phase B is 10%.
Preferably, the concentration of the potassium dihydrogen phosphate buffer solution in the mobile phase is 20-30mmol/L.
Further preferably, the concentration of the potassium dihydrogen phosphate buffer solution in the mobile phase is 25mmol/L.
Preferably, the pH of the potassium dihydrogen phosphate buffer solution is 2-3.
Further preferably, the pH of the potassium dihydrogen phosphate buffer solution is 2.5.
In the present application, dilute phosphoric acid is used to adjust the pH of the mobile phase potassium dihydrogen phosphate buffer solution.
Preferably, in the mobile phase A, the volume ratio of the potassium dihydrogen phosphate buffer solution to acetonitrile (organic phase) is 80-95:5-20; the volume ratio of the mobile phase may be up to 2% floating.
Further preferably, in the mobile phase A, the volume ratio of the potassium dihydrogen phosphate buffer solution to the acetonitrile is 85-95:5-15.
Still more preferably, in the mobile phase A, the volume ratio of the potassium dihydrogen phosphate buffer solution to the acetonitrile is 90:10, and the volume ratio of the mobile phase can float up to and down to 2%.
Preferably, in the mobile phase B, the volume ratio of the potassium dihydrogen phosphate buffer solution to the acetonitrile is 15-25:75-85; the volume ratio of the mobile phase may be up to 2% floating.
Further preferably, in the mobile phase B, the volume ratio of the potassium dihydrogen phosphate buffer solution to the acetonitrile is 20:80, and the volume ratio of the mobile phase can float up to and down to 2%.
Preferably, the gradient elution is performed as follows:
| time (minutes) | Mobile phase a (%) | Mobile phase B (%) |
| 0 | 90 | 10 |
| 10 | 90 | 10 |
| 35 | 65 | 35 |
| 45 | 65 | 35 |
| 45.1 | 90 | 10 |
| 60 | 90 | 10。 |
Preferably, the HPLC method has chromatographic conditions and a mobile phase flow rate of 0.8-1.2mL/min and a column temperature of 25-35 ℃.
Further preferably, the HPLC method has chromatographic conditions such that the flow rate of the mobile phase is 1.0mL/min, the column temperature is 30 ℃, the sample injection amount is 20. Mu.L, and the detection wavelength is 215nm.
In the application, the detector for detecting by the HPLC method is UV.
In the application, the impurities comprise an impurity IB428 and an impurity IB429; impurity IB428 has the formula C 21 H 27 NO, relative molecular weight (Exact Mass) 309.21, molecular weight 309.45, structural formula:
impurity IB429 has the formula C 21 H 29 NO 3 The relative molecular weight (Exact Mass) was 343.21, the molecular weight was 343.46, and the structural formula was:
on the other hand, the application provides application of the separation detection method in quality detection of butorphanol tartrate injection.
In the method for separating and detecting impurities in butorphanol tartrate injection, the specific sample is prepared as follows:
system applicability solution: about 5mg of each of the impurity IB440, IB429 and IB428 reference substances is weighed, placed in the same 100ml measuring flask, dissolved by adding methanol, diluted to a scale, and shaken uniformly to serve as an impurity stock solution. Weighing about 25mg of buprenorphine tartrate reference substance, placing into a 25ml measuring flask, precisely adding 1ml of impurity stock solution, adding water for dissolving and diluting to scale, and shaking uniformly to obtain the final product.
Sensitivity solution: precisely measuring 1ml of control solution, placing into a 50ml measuring flask, adding water to dilute to scale, and shaking to obtain the final product.
Blank auxiliary material solution: accurately weighing appropriate amount of sodium chloride, citric acid and sodium citrate, dissolving in water, and quantitatively diluting to obtain solution containing 6.4mg of sodium chloride, 6.4mg of sodium citrate and 3.3mg of citric acid in 1 ml.
Blank solution (1 ml:1 mg): taking blank auxiliary material solution to obtain the product.
Blank solution (1 ml:2 mg): taking blank auxiliary material solution, precisely measuring 5ml, placing into a 10ml measuring flask, adding water to dilute to scale, and shaking uniformly to obtain the final product.
Test solution (1 ml:1 mg): and taking the butorphanol tartrate injection (1 ml:1 mg) to obtain the product.
Test solution (1 ml:2 mg): precisely measuring 5ml of the product, placing in a 10ml measuring flask, adding water to dilute to scale, and shaking to obtain the final product.
Control solution: precisely measuring 1ml of the sample solution, placing in a 100ml measuring flask, adding water to dilute to scale, and shaking to obtain the final product.
Sensitivity solution: 1ml of control solution is precisely measured, placed in a 50ml measuring flask, diluted to a scale with water and shaken well.
Taking blank solution, control solution and sample solution, respectively, performing high performance liquid chromatography analysis, recording chromatogram, and calculating impurity content.
Compared with the prior art, the application has the following beneficial effects:
(1) The HPLC method provided by the application can effectively separate and measure the contents of IB428 and IB429 in the butorphanol tartrate injection, has high sensitivity and strong specificity, and the detection result is reliable and accurate, thereby being beneficial to providing a technical means for detecting impurities in the butorphanol tartrate injection and further controlling the quality of the butorphanol tartrate injection.
(2) The novel impurity discovered by the application can provide a reference standard for quality control of the butorphanol tartrate injection and safety detection of clinical safety medication, thereby ensuring the safety and reliability of clinical medication.
Drawings
FIG. 1 shows butorphanol tartrate 1 H-NMR chart;
FIG. 2 is a diagram of butorphanol tartrate-LC-MS;
FIG. 3 is a diagram showing the impurity IB428- 1 H-NMR chart;
FIG. 4 impurity IB428-LC-MS diagram;
FIG. 5 shows an impurity IB429- 1 H-NMR chart;
FIG. 6 is a diagram of impurity IB 429-LC-MS;
FIG. 7 is a proprietary-blank solution chromatogram;
FIG. 8 is a chromatogram of a specificity-control solution;
FIG. 9 is a chromatogram of a specificity-test solution;
FIG. 10 is a specificity-specificity solution chromatogram;
FIG. 11 is a linear standard graph of butorphanol tartrate;
FIG. 12 is a linear standard graph of IB 440;
FIG. 13 is a linear standard graph of IB 428;
FIG. 14 is a linear standard curve of IB429;
FIG. 15 is a diagram showing the system adaptation of the method for detecting related substances in butorphanol tartrate injection according to the present application.
Detailed Description
The following non-limiting examples will enable those of ordinary skill in the art to more fully understand the application and are not intended to limit the application in any way. The following is merely exemplary of the scope of the application as claimed and many variations and modifications of the application will be apparent to those skilled in the art in light of the disclosure, which are intended to be within the scope of the application as claimed.
The application is further illustrated by means of the following specific examples. The various chemical reagents used in the examples of the present application were obtained by conventional commercial means unless otherwise specified.
In the following examples, the control source information is as follows:
butorphanol tartrate control: chongqing Gift Bunge drug development Co., ltd; lot number: AP041-L01201WS; the content is as follows: 99.7%; IB428 control: chongqing Gift Bunge drug development Co., ltd; lot number: IB428-M00201WS; the content is as follows: 99.7%; IB429 control: chongqing Gift Bunge drug development Co., ltd; lot number: IB429-L00801WS; the content is as follows: 94.5%; IB440 control: chongqing Gift Bunge drug development Co., ltd; lot number: IB440-M00303WS; the content is as follows: 98.8%. In the application, products of different factories have no significant influence on the effect.
The LC-MS detection method for each control is a method conventionally used in the art.
LC-MS diagrams of butorphanol tartrate, impurity IB428 and impurity IB429 are shown in figures 2, 4 and 6, respectively.
Each control 1 The H-NMR detection method is a method conventionally used in the art.
LC-MS diagrams of butorphanol tartrate, impurity IB428 and impurity IB429 are shown in figures 1, 3 and 5, respectively.
Example 1
Chromatographic conditions:
chromatographic column: phenyl-bonded silica gel as filler (medium spectrum red RD-Phenyl,250 mm. Times.4.6 mm,5 μm or chromatographic column with equivalent potency);
mobile phase a:0.025mol/L potassium dihydrogen phosphate solution (pH adjusted to 2.5 with dilute phosphoric acid) -acetonitrile (90:10);
mobile phase B:0.025mol/L potassium dihydrogen phosphate solution (pH adjusted to 2.5 with dilute phosphoric acid) -acetonitrile (20:80).
The linear elution gradient is shown below:
| time (minutes) | Mobile phase a (%) | Mobile phase B (%) |
| 0 | 90 | 10 |
| 10 | 90 | 10 |
| 35 | 65 | 35 |
| 45 | 65 | 35 |
| 45.1 | 90 | 10 |
| 60 | 90 | 10。 |
A detector: UV; detection wavelength: 215nm; flow rate: 1.0mL/min; column temperature: 30 ℃; sample injection volume: 20. Mu.L.
The method is subjected to methodological verification, and verification items comprise specificity, quantitative limit, detection limit, linearity and durability, and specifically comprise the following steps:
(1) Specialization of
Preparation of blank solution (1 mL:1 mg): taking blank auxiliary material solution to obtain the product.
Preparation of blank solution (lmL:2 mg): taking a blank auxiliary material solution, precisely measuring 5mL, placing in a 10mL measuring flask, adding water to dilute to a scale, and shaking uniformly to obtain the product. The chromatogram of the specific blank solution is shown in FIG. 7.
Preparation of test solutions (1 mL:1 mg): and taking the butorphanol tartrate injection (lmL:lmg) to obtain the medicine.
Preparation of test solution (1 mL:2 mg): precisely measuring 5mL of buprenorphine tartrate injection (lmL:2 mg), placing into a 10mL measuring flask, diluting with water to scale, and shaking.
Preparation of control solution: precisely measuring 1mL of buprenorphine tartrate injection (lmL:1 mg), placing in a 100mL measuring flask, diluting with water to scale, and shaking. The chromatogram of the specific control solution is shown in FIG. 8.
Preparing positioning solutions of various impurities: taking about 2mg of each of the impurity IB428 reference substance, the impurity IB429 reference substance and the impurity IB440 reference substance, respectively placing into 100mL measuring flasks, adding methanol for dissolution and dilution to scale, shaking uniformly, taking the mixture as each impurity stock solution, precisely taking 1mL, respectively placing into 10mL measuring flasks, diluting to scale with water, and shaking uniformly to obtain the product.
Preparation of a mixed solution (specific solution): taking a butorphanol tartrate injection (lmL:2 mg), precisely measuring 5mL, placing in a 10mL measuring flask, precisely measuring 1mL of each impurity stock solution, placing in the measuring flask, diluting to a scale with water, and shaking uniformly to obtain the product.
Preparing tartaric acid positioning solution: about 3mg of tartaric acid is taken and placed in a 10mL measuring flask, water is added for dissolution, dilution is carried out to the scale, and shaking is carried out uniformly, thus obtaining the product.
And precisely measuring 20 mu L of each of the blank solution, the sample solution, the impurity positioning solution and the mixed solution, performing sample injection detection, and recording a chromatogram. The specific detection results are shown in Table 1, and the chromatogram of the specific sample solution (with the concentration of 1 mg/mL) is shown in FIG. 9; the specific solution chromatograms are shown in fig. 10.
TABLE 1
The results show that: the blank solution does not interfere with sample detection, the separation degree of each impurity in the specific solution and the front and rear impurities is more than 1.5, the separation degree is good, and the separation detection method provided by the application has good specificity.
(2) Quantitative limit
Impurity concentrated solution: taking about 0.0125g of each of the buprenorphine tartrate reference substance, the impurity IB428, the impurity IB429 and the impurity IB440 reference substance, precisely weighing, placing into a 25mL measuring flask, adding methanol for dissolving and diluting to a scale, and shaking uniformly.
Impurity stock solution: taking an impurity concentrated solution, precisely weighing 2ml, placing in a 50ml measuring flask, and adding water to dilute to a scale. Shaking up.
Quantitative limiting solution: precisely measuring 1ml of impurity stock solution, placing in a 100ml measuring flask, diluting with water to scale, and shaking to obtain (6 parts prepared in parallel).
According to the chromatographic conditions, 20 mu L of the solution is precisely measured, injected into a liquid chromatograph, a chromatogram is recorded, and the RSD% of the peak areas of 6 parts of buprenorphine tartrate and impurities is calculated. The quantitative limit results are shown in tables 2 to 5. Wherein, table 2 shows the quantitative limit test results of impurity IB440, table 3 shows the quantitative limit test results of butorphanol tartrate, table 4 shows the quantitative limit test results of impurity IB429, and table 5 shows the quantitative limit test results of impurity IB 428.
TABLE 2
TABLE 3 Table 3
TABLE 4 Table 4
TABLE 5
The results show that: the signal-to-noise ratio of each peak of the 6 quantitative limiting solution is more than 10, and the Relative Standard Deviation (RSD) of the peak area of each impurity peak is less than 10%. When the concentration of the sample is 1mg/mL, the impurity A (IB 428), the impurity B (IB 429), the impurity C (IB 440) and other single impurities (calculated by butorphanol tartrate) can be accurately quantified when the concentration of the sample exceeds 0.02% of the concentration of the sample.
(3) Detection limit
Detection limit solution: and precisely transferring 3mL of quantitative limiting solution, placing into a 10mL measuring flask, diluting to a scale with methanol, and shaking uniformly to obtain the final product. Taking the solution, precisely measuring 20 mu L according to the chromatographic conditions, injecting the solution into a liquid chromatograph, continuously injecting the sample for 3 times, recording the chromatogram, and obtaining the detection limit result shown in Table 6.
TABLE 6
The results show that: the detection limit concentration of the impurity IB440 is 0.0620 mug/mL, which is equivalent to 0.006% of the concentration of the sample, the continuous sample injection 3-needle peak area RSD is 1.5%, which is smaller than 15%, and the signal to noise ratio is larger than 3; the detection limit concentration of the AP041 is 0.061l mug/mL, which is equivalent to 0.006% of the concentration of the sample, the continuous sample injection 3-needle peak area RSD is 14.7%, which is smaller than 15%, and the signal to noise ratio is larger than 3; the detection limit concentration of the impurity IB429 is 0.0587 mug/mL, which is equivalent to 0.006% of the concentration of the sample, the continuous sample injection 3-needle peak area RSD is 1.9 and less than 15%, and the signal to noise ratio is more than 3; the detection limit concentration of the impurity IB428 is 0.0597 mug/mL, which is equivalent to 0.006% of the concentration of the sample, the continuous sample injection 3-needle peak area RSD is 2.9 and less than 15%, and the signal to noise ratio is greater than 3. The impurity can be detected, and the detection sensitivity of the method is high.
(4) Linearity and range
Linear stock solution 1: taking about 25mg of butorphanol tartrate as a reference, precisely weighing, placing into a 50mL measuring flask, adding methanol for dissolution, diluting to a scale, and shaking uniformly to obtain the product (0.5 mg/mL).
Linear stock solution 2: taking a butorphanol tartrate reference substance, an impurity IB428 reference substance, an impurity IB429 reference substance and an impurity IB440 reference substance which are respectively about 25mg, precisely weighing, putting into a 50mL measuring flask, adding methanol to dissolve and dilute to a scale, shaking uniformly, taking the solution as a linear concentrated solution, precisely weighing 2mL, putting into a 50mL measuring flask, adding water to dilute to the scale, and shaking uniformly to obtain the product (20 mug/mL). Linear solution l: taking linear liquid storage 2, precisely measuring 1mL, placing in a 100mL measuring flask, adding water for dilution to a scale, and shaking uniformly to obtain the product (0.2 mug/mL).
Linear solution 2: taking linear liquid storage 2, precisely measuring 5mL, placing in a 100mL measuring flask, adding water for dilution to a scale, and shaking uniformly to obtain (l mug/mL).
Linear solution 3: taking linear liquid storage 2, precisely measuring 5mL, placing in a 50mL measuring flask, adding water to dilute to a scale, and shaking uniformly to obtain the product (2 mug/mL).
Linear solution 4: taking linear liquid storage 2, precisely taking 3mL, placing in a 20mL measuring flask, adding water to dilute to scale, and shaking uniformly to obtain (3 mug/mL).
Linear solution 5: taking linear liquid storage 2, precisely measuring 5mL, placing in a 25mL measuring flask, adding water for dilution to a scale, and shaking uniformly to obtain the product (4 mug/mL).
Linear solution 6: taking linear liquid storage 1, precisely taking 1mL, placing in a 100mL measuring flask, adding water for dilution to scale, and shaking uniformly to obtain (5 mug/mL).
Linear solution 7: taking linear liquid storage 1, precisely measuring 1mL, placing in a 50mL measuring flask, adding water for dilution to a scale, and shaking uniformly to obtain (l 0 mug/mL).
Linear solution 8: taking linear liquid storage l, precisely measuring 1mL, placing in a 25mL measuring flask, adding water for dilution to a scale, and shaking uniformly to obtain the product (20 mug/mL).
And precisely measuring each concentration of linear solution by 20 mu 1 sample injection detection, and recording a chromatogram. The correction factor was calculated by linear regression using the peak area (a) as the ordinate and the concentration (C) as the abscissa. The results are shown in tables 7-11, FIGS. 11-14. Wherein, table 7 is the linear results of butorphanol tartrate; table 8 shows the linear results of impurity IB 440; table 9 shows the linear results for impurity IB429; table 10 shows the linear results for impurity IB 428; table 11 shows the correction factor results.
TABLE 7
TABLE 8
| Linearity of | Concentration (μg/ml) | Peak area | Corresponds to the concentration of the test sample (%) | Linear regression equation |
| 1 | 0.2023 | 4.656 | 0.02 | y＝23.227x+0.1052 |
| 2 | 1.0117 | 23.794 | 0.10 | r |
| 3 | 2.0234 | 47.193 | 0.20 | 1.0000 |
| 4 | 3.0351 | 70.417 | 0.30 | Y-axis intercept percentage (%) |
| 5 | 4.0468 | 94.156 | 0.40 | 0.22 |
TABLE 9
Table 10
TABLE 11
The results show that: the impurity IB440 has good linear relation in the concentration range of 0.2023-4.0468 mug/mL, the linear equation is Y=23.227 X+0.1052, the correlation coefficient is 1.0000, the Y-axis intercept is 0.1052, and the concentration peak area is 0.22% of 100%, which is less than 10%;
the impurity IB429 has good linear relation in the concentration range of 0.1899-3.7981 mug/mL, the linear equation is Y=22.2870X+0.0169, the correlation coefficient is 1.0000, the correlation coefficient is greater than 0.995, the Y-axis intercept is 0.0169, and the concentration peak area is 0.04% of 100%, which is less than 10%;
impurity IB428 has good linear relation in the concentration range of 0.2049-4.0981 mug/mL, the linear equation is Y=26.001X+0.5801, the correlation coefficient is 1.0000, the Y-axis intercept is 0.5801, and the concentration peak area is 1.07% of 100%, and is less than 10%;
the buprenorphine tartrate has good linear relation in the concentration range of 0.2007 mu g/mL-20.5940 mu g/mL, the linear equation is Y=16.618 X+0.2994, the correlation coefficient is 1.0000 and is more than 0.995, the Y-axis intercept is 0.2994, and the Y-axis intercept is 0.89% of the peak area of 100% concentration and is less than 10%.
(5) Durability of
Preparation of test solution (lmL: lmg): and (5) taking the butorphanol tartrate injection, and pouring the butorphanol tartrate injection into a sample injection bottle.
Preparation of control solution: precisely measuring 1mL of the sample solution (lmL:lmg) in a 100mL measuring flask, diluting with water to a scale, and shaking uniformly to obtain the final product.
Preparation of test solution (lmL:2 mg): precisely measuring 5mL of butorphanol tartrate injection, placing the injection in a 10mL measuring flask, diluting with water to the scale, and shaking uniformly to obtain the product.
Preparation of control solution: precisely measuring the sample solution (lmL:2 mg) in a 100mL measuring flask, diluting with water to scale, and shaking.
The sample injection detection is performed by precisely measuring 20 mu L of each of the sample solution and the control solution which are respectively placed for 0, 4, 8, 12 and 24 hours at room temperature, and the chromatograms are recorded. The durability test results are shown in table 12.
Table 12
The results show that: the single impurity and the total impurity are not obviously changed within 24 hours, the solution stability is good, and the method has good durability.
Wherein, the impurity identification limit is not exceeded and the change is not obvious.
Fig. 15 is a system adaptation map of the separation detection method for detecting related substances in butorphanol tartrate injection.
Example 2
Based on the chromatographic conditions described in example 1, the detection conditions were replaced according to table 13, and the other HPLC chromatographic conditions and parameters were the same, and separation detection of butorphanol tartrate and impurities was performed.
The specific results are shown in Table 13.
TABLE 13
The results show that: the different chromatographic conditions under the conditions of the examples 1-2 are changed, the separation degree of the impurities IB440, IB429 and IB428 in the butorphanol tartrate is more than 1.5, and when the impurity is more than 0.02%, the method can be accurately and quantitatively detected, and has good specificity and higher sensitivity for detecting the impurities IB440, IB429 and IB428 in the butorphanol tartrate.
Comparative example 1
The HPLC method in the standard of the Chinese pharmacopoeia of 2020 edition is used for separating and detecting the impurities.
The preparation method of the solution was the same as in example 1.
The results of the specificity test are shown in Table 14.
TABLE 14
The results show that: under the condition of comparative example 1, the butorphanol tartrate peak, the IB428 peak and the adjacent peaks are not completely separated, and the separation degree is poor.
Comparative example 2
Unlike example 1, the ratio of mobile phase was different: the volume ratio of the mobile phase A potassium dihydrogen phosphate buffer solution to the acetonitrile is 75:25, and the volume ratio of the mobile phase B potassium dihydrogen phosphate buffer solution to the acetonitrile is 25:75.
And (3) carrying out separation detection on butorphanol tartrate and impurities under the same chromatographic conditions and parameters of other HPLC.
The results of the specificity test are shown in Table 15.
TABLE 15
The results show that: under the condition of comparative example 2, the separation degree of the buprenorphine tartrate peak, the IB428 peak and the IB429 peak from the adjacent peaks is less than 1.5, the buprenorphine tartrate peak, the IB428 peak and the IB429 peak are not completely separated, and the specificity is poor.
Comparative example 3
Unlike example 1, the concentration of the potassium dihydrogen phosphate buffer solution in the mobile phase was 50mmol/L.
And (3) carrying out separation detection on butorphanol tartrate and impurities under the same chromatographic conditions and parameters of other HPLC.
The results of the specificity test are shown in Table 16.
Table 16
The results show that: under the conditions of comparative example 3, the separation of the IB428 peak and the IB429 peak was poor.
Comparative example 4
Unlike example 1, the procedure for gradient elution was different, specifically:
| time (minutes) | Mobile phase a (%) | Mobile phase B (%) |
| 0 | 90 | 10 |
| 10 | 90 | 10 |
| 35 | 50 | 50 |
| 45 | 50 | 50 |
| 45.1 | 90 | 10 |
| 60 | 80 | 20。 |
And (3) carrying out separation detection on butorphanol tartrate and impurities under the same chromatographic conditions and parameters of other HPLC.
The specific detection results are shown in Table 17.
TABLE 17
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The results show that: under the conditions of comparative example 4, the IB429 peak was poorly separated from butorphanol tartrate.
The results show that: under the conditions of comparative examples 1 to 4, the separation between part of impurities was poor, and the separation requirement was not satisfied. The specificity of the impurities IB440, IB429 and IB428 in the buprenorphine tartrate detected by the method is low.
Finally, it should be noted that the above description is only for illustrating the technical solution of the present application, and not for limiting the scope of the present application, and that the simple modification and equivalent substitution of the technical solution of the present application can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present application.
Claims (10)
1. The separation and detection method for the impurities in the butorphanol tartrate injection is characterized by comprising the following steps of:
chromatographic column: phenyl bonding silica gel is used as a filler;
mobile phase: mobile phase A and mobile phase B are adopted, wherein mobile phase A is potassium dihydrogen phosphate buffer solution-acetonitrile, and mobile phase B is potassium dihydrogen phosphate buffer solution-acetonitrile;
eluting: gradient elution, elution procedure is as follows:
0-10 minutes, 90% of mobile phase A and 10% of mobile phase B;
10-35 minutes, 90-65% of mobile phase A and 10-35% of mobile phase B;
35-45 minutes, the dosage of the mobile phase A is 65%, and the dosage of the mobile phase B is 35%;
45-45.1 minutes, the dosage of the mobile phase A is 65-90%, and the dosage of the mobile phase B is 35-10%;
45.1-60 minutes, the amount of mobile phase A is 90% and the amount of mobile phase B is 10%.
2. The separation detection method according to claim 1, wherein the concentration of the potassium dihydrogen phosphate buffer solution in the mobile phase is 20 to 30mmol/L.
3. The separation detection method according to claim 2, wherein the concentration of the potassium dihydrogen phosphate buffer solution in the mobile phase is 25mmol/L.
4. The separation detection method according to claim 1, wherein the pH of the potassium dihydrogen phosphate buffer solution is 2 to 3.
5. The separation detection method according to claim 1, wherein the volume ratio of potassium dihydrogen phosphate buffer solution to acetonitrile in the mobile phase a is 80-95:5-20.
6. The separation assay of claim 5, wherein the mobile phase a has a volume ratio of potassium dihydrogen phosphate buffer solution to acetonitrile of 85-95:5-15.
7. The separation assay of claim 1, wherein the volume ratio of potassium dihydrogen phosphate buffer solution to acetonitrile in mobile phase B is 15-25:75-85.
8. The separation assay of claim 7, wherein the mobile phase B has a volume ratio of potassium dihydrogen phosphate buffer solution to acetonitrile of 20:80.
9. The method according to claim 1, wherein the HPLC chromatographic conditions have a mobile phase flow rate of 0.8-1.2mL/min, a column temperature of 25-35 ℃, a sample injection amount of 20. Mu.L, and a detection wavelength of 215nm.
10. Use of the separation detection method according to any one of claims 1-9 for quality detection of butorphanol tartrate injections.
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