CN111189935A - High performance liquid chromatography analysis method of dexmedetomidine hydrochloride - Google Patents
High performance liquid chromatography analysis method of dexmedetomidine hydrochloride Download PDFInfo
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Abstract
The invention discloses a high performance liquid chromatography analysis method of dexmedetomidine hydrochloride, which comprises the following steps: preparing a solution; using reverse phase liquid chromatography; and detecting the content of the dexmedetomidine hydrochloride by adopting an external standard method. In the analysis method, octadecylsilane chemically bonded silica is used as a chromatographic column, the specification of the chromatographic column is 250mm x 4.6mm and 5 microns, a mobile phase consists of sodium dihydrogen phosphate solution, acetonitrile and triethylamine, the detection wavelength is 215nm, the flow rate is 1.5ml/min, the column temperature is 30 ℃, the sample injection volume is 20 microns L, and isocratic elution is set according to volume fraction. The high performance liquid phase analysis method of dexmedetomidine hydrochloride provided by the invention has the advantages of practicability, reliability, good stability and strong data reproducibility.
Description
FIELD
The invention relates to the technical field of pharmaceutical analysis, in particular to a high performance liquid chromatography analysis method of dexmedetomidine hydrochloride.
Background
Dexmedetomidine hydrochloride is first marketed in the united states in 3 months in 2000, and is approved to be marketed in japan in 1 month in 2004, and the dexmedetomidine hydrochloride has good clinical application status since the marketing, good curative effect and small side effects, has many unique advantages compared with other sedative drugs, has relatively moderate acting time for postoperative and critical patients, obvious and stable sedative effect, and stable wakefulness, and simultaneously has other effects of reducing the dose of anesthetic, relieving pain, improving the hemodynamic stability during surgery, and the like.
Dexmedetomidine hydrochloride is a new class 3 chemical drug of the national chemical drugs, the quality standard of the product cannot be found in China, and in order to make the product market as soon as possible in China, the quality of the product and the safety of clinical medication are firstly ensured. And the subsequent research and development and production quality of dexmedetomidine hydrochloride are ensured, so the quality of the raw material medicaments and the preparation thereof needs to be controlled. Therefore, research on obtaining a detection method for impurity inspection and content measurement of related substances of dexmedetomidine hydrochloride is very urgent for pharmaceutical manufacturing enterprises.
SUMMARY
The present disclosure relates to a high performance liquid chromatography method for dexmedetomidine hydrochloride, comprising:
measuring by reversed phase liquid chromatography, wherein the chromatographic column is C18 chromatographic column, the mobile phase is composed of sodium dihydrogen phosphate solution, acetonitrile and triethylamine, and isocratic elution is arranged according to volume fraction; and
quantitative analysis is carried out by adopting an external standard method.
Brief description of the drawings
Figure 1 shows a high performance liquid chromatogram of dexmedetomidine hydrochloride blank in example 1.
FIG. 2 shows a high performance liquid chromatogram of dexmedetomidine hydrochloride control in example 2.
FIG. 3 shows a high performance liquid chromatogram of dexmedetomidine hydrochloride test article in example 1.
Detailed description of the invention
In the following description, certain specific details are included to provide a thorough understanding of various disclosed embodiments. One skilled in the relevant art will recognize, however, that the embodiments can be practiced without one or more of the specific details, or with other methods, components, materials, and so forth.
Unless otherwise required by the disclosure, throughout the specification and the appended claims, the words "comprise", "comprising", and "have" are to be construed in an open, inclusive sense, i.e., "including but not limited to".
Reference throughout the specification to "one embodiment," "an embodiment," "in another embodiment," or "in certain embodiments" means that a particular reference element, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment, and furthermore, particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.
Definition of
In the present disclosure, the term "external standard method" refers to a method of quantifying by comparing response signals of a control substance and a component to be measured in a sample using a pure product of the component to be measured as the control substance.
In the present disclosure, the term "isocratic elution" refers to an elution pattern in which the composition and flow rate of a mobile phase are constant over an analysis cycle of a sample component.
In the present disclosure, in liquid chromatography, the term "primary filtrate" refers to the liquid that has just flowed out, i.e., functions to rinse the filter membrane; the term "secondary filtrate" refers to a liquid obtained by discarding the primary filtrate and then discharging the primary filtrate.
Detailed Description
The present disclosure relates to a high performance liquid chromatography method for dexmedetomidine hydrochloride, comprising:
measuring by reversed phase liquid chromatography, wherein the chromatographic column is C18 chromatographic column, the mobile phase is composed of sodium dihydrogen phosphate solution, acetonitrile and triethylamine, and isocratic elution is arranged according to volume fraction; and
quantitative analysis is carried out by adopting an external standard method.
In certain embodiments, the chromatography column is sized (250mm x 4.6mm, 5 μm).
In certain embodiments, the volume ratio of the sodium dihydrogen phosphate solution, acetonitrile and triethylamine in the mobile phase is 65:35: 0.3.
In certain embodiments, the concentration of the sodium dihydrogen phosphate solution is from 0.005 to 0.01 mol/L.
In certain embodiments, the concentration of the sodium dihydrogen phosphate solution is 0.008 mol/L.
In certain embodiments, the mobile phase further comprises an acid-base agent.
In certain embodiments, the acid-base agent is selected from phosphoric acid, hydrochloric acid, sodium hydroxide, aqueous ammonia, or mixtures thereof.
In certain embodiments, the acid-base agent is selected from phosphoric acid.
In certain embodiments, the pH of the mobile phase is from 4.0 to 8.0.
In certain embodiments, the mobile phase has a pH of 6.5.
In certain embodiments, the pH of the mobile phase is adjusted by an acidifying or alkalizing agent.
In certain embodiments, the detection wavelength of the chromatography column is from 205nm to 220 nm.
In certain embodiments, the detection wavelength of the chromatography column is 215 nm.
In certain embodiments, the flow rate of the chromatography column is from 1.0ml/min to 2.0 ml/min.
In certain embodiments, the flow rate of the chromatography column is 1.5 ml/min.
In certain embodiments, the column temperature of the chromatography column is from 25 ℃ to 35 ℃.
In certain embodiments, the column temperature of the chromatography column is 30 ℃.
In certain embodiments, the sample size of the chromatography column is from 10. mu.L to 30. mu.L.
In certain embodiments, the sample size of the chromatography column is 20 μ L.
In certain embodiments, a solution, comprises: a test sample solution, an impurity reference solution, a content reference solution and a blank auxiliary material solution.
In certain embodiments, the test solution consists of dexmedetomidine hydrochloride formulation and a diluent;
in certain embodiments, the contaminant control solution is prepared by diluting a test sample solution;
in certain embodiments, the content control solution is composed of dexmedetomidine hydrochloride control and a diluent.
In certain embodiments, the dexmedetomidine hydrochloride control solution is dexmedetomidine hydrochloride neat.
In certain embodiments, the placebo solution consists of the formulation's corresponding placebo and diluent.
In certain embodiments, the dexmedetomidine hydrochloride formulation is selected from the group consisting of dexmedetomidine hydrochloride raw material, dexmedetomidine hydrochloride tablet, dexmedetomidine hydrochloride injection, or dexmedetomidine hydrochloride oral suspension.
In certain embodiments, the diluent is a mobile phase.
In certain embodiments, a method of preparing a test solution comprises:
mixing dexmedetomidine hydrochloride with a diluent to obtain a first mixture; and
and filtering the supernatant of the first mixture to obtain a secondary filtrate, wherein the secondary filtrate is the test solution.
In certain embodiments, the first mixture is further subjected to sonication, centrifugation, or the like.
In certain embodiments, the sonication temperature is from 40 ℃ to 50 ℃.
In certain embodiments, the sonication temperature is 45 ℃.
In certain embodiments, the sonication time is from 20min to 40 min.
In certain embodiments, the sonication time is 30 min.
In certain embodiments, the centrifugation speed is 2000rpm/min to 4000 rpm/min.
In certain embodiments, the centrifugation speed is 3000 rpm/min.
In certain embodiments, the centrifugation time is from 2min to 8 min.
In certain embodiments, the centrifugation time is 5 min.
In certain embodiments, the first mixture supernatant is filtered using a filter membrane.
In certain embodiments, the filter pore size is 0.45 μm.
Example 1
High performance liquid chromatography conditions:
a chromatographic column: octadecylsilane chemically bonded silica is used as a filling material, and the specification is 4.6 multiplied by 250mm and 5 mu m; the mobile phase is 0.008mol/L sodium dihydrogen phosphate solution, acetonitrile, triethylamine 65:35:0.3, the pH value is adjusted to 6.5 by phosphoric acid, and isocratic elution is carried out;
the detection wavelength is 215 nm; the flow rate is 1.5 ml/min; the column temperature is 30 ℃; the injection volume is 20 mu L; diluent agent: a mobile phase.
The experimental steps are as follows:
solution preparation:
taking about 25mg of dexmedetomidine hydrochloride as a raw material, precisely weighing, placing in a 100ml volumetric flask, adding a proper amount of diluent for dissolving and diluting to a scale, and shaking uniformly to serve as a test solution; precisely measuring 1ml of the test solution, placing the test solution in a 100ml measuring flask, adding a diluent to dilute the test solution to a scale, and shaking up to obtain a reference solution. The mobile phase was taken as a blank solution. Precisely measuring 20 μ l each of the blank solution, the reference solution and the sample solution, injecting into a liquid chromatograph, and recording a liquid chromatogram as shown in FIG. 1.
Dexmedetomidine hydrochloride content is the reference concentration x dexmedetomidine hydrochloride peak area// V
(peak area of control X peak concentration of dexmedetomidine hydrochloride) X100%
Theoretical plate number 16 × (retention time/peak width)2Or theoretical plate number 5.54 × (retention time/half peak width)2
Wherein:
concentration of the reference substance: peak area of 0.0025mg/ml dexmedetomidine hydrochloride: 10368366
Peak area of control: 104961 Demedetomidine hydrochloride peak concentration: 0.25mg/ml
Retention time: 12.498min Peak Width: 0.9
The impurities are calculated according to a self-contrast method without adding a correction factor, and the content is 99 percent according to an external standard method.
The result shows that the blank solvent does not interfere the content detection of the dexmedetomidine hydrochloride raw material. In the dexmedetomidine hydrochloride control solution, the separation degree meets the requirement, the peak shape is good, the peak purity is good, the theoretical plate number is 3085 (more than 2000), the tailing factor is less than 1.5, and the standard is met.
The analysis method provided by the invention completes methodology verification according to the Chinese pharmacopoeia 2015 edition, and comprises a systematic adaptability test, a destructive test, an influence factor test, a recovery rate test and a durability test. Through the verification, the analysis method provided by the invention is practical and reliable and has better stability.
Example 2
High performance liquid chromatography conditions:
a chromatographic column: octadecylsilane chemically bonded silica is used as a filling material, and the specification is 4.6 multiplied by 250mm and 5 mu m; the mobile phase is 0.008mol/L sodium dihydrogen phosphate solution, acetonitrile, triethylamine 65:35:0.3, the pH value is adjusted to 6.5 by phosphoric acid, and isocratic elution is carried out;
the detection wavelength is 215 nm; the flow rate is 1.5 ml/min; the column temperature is 30 ℃; the injection volume is 20 mul; diluent agent: a mobile phase.
The experimental steps are as follows:
solution preparation:
taking a proper amount of dexmedetomidine hydrochloride tablets, grinding, precisely weighing (equivalent to 50mg of dexmedetomidine hydrochloride), placing in a 100ml volumetric flask, adding a proper amount of diluent, carrying out ultrasonic treatment at 45 ℃ for 30min, fixing the volume of the diluent to a scale, shaking up, centrifuging at 3000RPM for 5min, taking supernatant, filtering with a 0.45 mu m filter membrane, and taking the subsequent filtrate as a test solution; precisely measuring 1ml of a test solution, placing the test solution into a 100ml measuring flask, adding a diluent to dilute the test solution to a scale, and shaking up the test solution to be used as a reference solution; taking a proper amount of tablet blank auxiliary materials, placing in a 1000ml volumetric flask, adding a proper amount of diluent, performing ultrasonic treatment at 45 ℃ for 30min, fixing the volume of the diluent to a scale, shaking up, centrifuging at 3000RPM for 5min, taking supernatant, filtering with a 0.45 mu m filter membrane, and taking the filtrate as blank auxiliary material solution.
Precisely measuring blank adjuvant solution, sample solution and reference solution 20 μ l each, injecting into liquid chromatograph, and recording liquid chromatogram, as shown in FIGS. 2 and 3.
Dexmedetomidine hydrochloride content is the reference concentration x dexmedetomidine hydrochloride peak area// V
(peak area of control X peak concentration of dexmedetomidine hydrochloride) X100%
Theoretical plate number 16 × (retention time/peak width)2Or theoretical plate number 5.54 × (retention time/half peak width)2
Wherein: concentration of the reference substance: 0.005mg/ml dexmedetomidine hydrochloride peak area: 2087581
Peak area of control: 21806 peak concentration of dexmedetomidine hydrochloride: 0.5mg/ml
Retention time: 12.498min Peak Width: 0.9
The impurities were calculated according to the self-control method without correction factors, and the content was 95.7% according to the external standard method.
The result shows that the blank auxiliary materials do not interfere the content detection of the dexmedetomidine hydrochloride sustained release tablets and the impurity detection thereof. The dexmedetomidine hydrochloride sustained release tablets can effectively separate impurities, the separation degree is more than 1.5, the peak shape is good, the peak purity is good, the theoretical plate number is 3085 (more than 2000), the tailing factor is less than 1.5, and the dexmedetomidine hydrochloride sustained release tablets meet the standard.
The content result of the dexmedetomidine hydrochloride sustained release tablet is equivalent to 99.7 percent of the marked amount, and key impurities in the dexmedetomidine hydrochloride sustained release tablet can be accurately measured. Meanwhile, the dexmedetomidine hydrochloride sustained release tablet is subjected to a destructive test, degraded impurities are effectively separated, the separation degree is greater than 1.5, and the purity of a main peak is good.
The analysis method provided by the invention completes methodology verification according to the Chinese pharmacopoeia 2015 edition, and comprises a systematic adaptability test, a destructive test, an influence factor test, a recovery rate test and a durability test. Through the verification, the analysis method provided by the invention is practical and reliable and has better stability.
Example 3
High performance liquid chromatography conditions:
a chromatographic column: octadecylsilane chemically bonded silica is used as a filling material, and the specification is 4.6 multiplied by 250mm and 5 mu m; the mobile phase is 0.008mol/L sodium dihydrogen phosphate solution, acetonitrile, triethylamine 65:35:0.3, the pH value is adjusted to 6.5 by phosphoric acid, and isocratic elution is carried out; the detection wavelength is 215 nm; the flow rate is 1.5 ml/min; the column temperature is 30 ℃; the injection volume is 20 mul; diluent agent: a mobile phase.
The experimental steps are as follows:
solution preparation:
taking a proper amount of dexmedetomidine hydrochloride injection (equivalent to 50mg of dexmedetomidine hydrochloride), precisely measuring, placing in a 100ml volumetric flask, adding a proper amount of diluent, carrying out ultrasonic treatment at 45 ℃ for 5min, fixing the volume of the diluent to a scale, shaking uniformly, centrifuging at 3000RPM for 5min, taking supernatant, filtering with a 0.45 mu m filter membrane, and taking the subsequent filtrate as a test solution; precisely measuring 1ml of a test solution, placing the test solution into a 100ml measuring flask, adding a diluent to dilute the test solution to a scale, and shaking up the test solution to be used as a reference solution; taking a proper amount of blank auxiliary materials of the injection, placing the blank auxiliary materials in a volumetric flask of 100ml, adding a proper amount of diluent, carrying out ultrasonic treatment at 45 ℃ for 5min, fixing the volume of the diluent to a scale, shaking up, centrifuging at 3000RPM for 5min, filtering by using a filter membrane of 0.45 mu m, and taking the subsequent filtrate as a blank auxiliary material solution;
precisely measuring blank adjuvant solution, sample solution and reference solution, respectively 20 μ l, injecting into liquid chromatograph, and recording liquid chromatogram.
Wherein: concentration of the reference substance: 0.005mg/ml dexmedetomidine hydrochloride peak area: 2087581
Peak area of control: 21806 peak concentration of dexmedetomidine hydrochloride: 0.5mg/ml
Retention time: 12.498min Peak Width: 0.9
The impurities were calculated according to the self-control method without correction factors, and the content was 95.7% according to the external standard method.
The result shows that the blank auxiliary materials do not interfere the content detection of the dexmedetomidine hydrochloride injection and the impurity detection thereof. In the reference solution, the separation degree of dexmedetomidine hydrochloride meets the requirement (both are more than 1.5), the peak shape is good, the peak purity is good, the theoretical plate number is 3085 (more than 2000), the tailing factor is less than 1.5, and the standard is met.
Example 4
High performance liquid chromatography conditions:
a chromatographic column: octadecylsilane chemically bonded silica is used as a filling material, and the specification is 4.6 multiplied by 250mm and 5 mu m; the mobile phase is 0.008mol/L sodium dihydrogen phosphate solution, acetonitrile, triethylamine 60:40:0.5, and isocratic elution is carried out; the detection wavelength is 215 nm; the flow rate is 1.5 ml/min; the column temperature is 30 ℃; the injection volume is 20 mu L; diluent agent: a mobile phase.
The experimental steps are as follows:
solution preparation:
taking a proper amount of dexmedetomidine hydrochloride oral suspension (equivalent to 50mg of dexmedetomidine hydrochloride), precisely measuring, placing in a 100ml volumetric flask, adding a proper amount of diluent, carrying out ultrasonic treatment at 45 ℃ for 5min, fixing the volume of the diluent to a scale, and shaking uniformly. Centrifuging at 3000RPM for 5min, collecting supernatant, filtering with 0.45 μm filter membrane, and collecting filtrate as sample solution; precisely measuring 1ml of a test solution, placing the test solution into a 100ml measuring flask, adding a diluent to dilute the test solution to a scale, and shaking up the test solution to be used as a reference solution; taking a proper amount of tablet blank auxiliary materials, placing in a 100ml volumetric flask, adding a proper amount of diluent, performing ultrasonic treatment at 45 ℃ for 5min, fixing the volume of the diluent to a scale, shaking up, centrifuging at 3000RPM for 5min, filtering with a 0.45 mu m filter membrane, and taking the subsequent filtrate as a blank auxiliary material solution.
Precisely measuring 20 μ l of each of blank adjuvant solution, reference solution and sample solution, injecting into liquid chromatograph, and recording liquid chromatogram.
Wherein: concentration of the reference substance: 0.005mg/ml dexmedetomidine hydrochloride peak area: 2087581
Peak area of control: 21806 peak concentration of dexmedetomidine hydrochloride: 0.5mg/ml
Retention time: 12.498min Peak Width: 0.9
The impurities were calculated according to the self-control method without correction factors, and the content was 95.7% according to the external standard method.
The result shows that the blank auxiliary materials do not interfere the content detection of the dexmedetomidine hydrochloride oral suspension and the impurity detection thereof. In the reference solution, the separation degree of dexmedetomidine hydrochloride meets the requirement (both are more than 1.5), the peak shape is good, the peak purity is good, the theoretical plate number is 3085 (more than 2000), the tailing factor is less than 1.5, and the standard is met.
From the foregoing it will be appreciated that, although specific embodiments of the disclosure have been described herein for purposes of illustration, various modifications or improvements may be made by those skilled in the art without departing from the spirit and scope of the disclosure, and that such modifications or improvements are intended to be within the scope of the appended claims.
Claims (10)
1. A high performance liquid chromatography method for dexmedetomidine hydrochloride, comprising:
measuring by reversed phase liquid chromatography, wherein the chromatographic column is C18 chromatographic column, the mobile phase is composed of sodium dihydrogen phosphate solution, acetonitrile and triethylamine, and isocratic elution is arranged according to volume fraction; and
quantitative analysis is carried out by adopting an external standard method.
2. The analytical method according to claim 1, wherein the chromatographic column has a size of (250mm x 4.6mm, 5 μm), the volume ratio of the sodium dihydrogen phosphate solution, acetonitrile and triethylamine in the mobile phase is 65:35:0.3, and the concentration of the sodium dihydrogen phosphate solution is 0.005 to 0.01mol/L, preferably 0.008 mol/L.
3. An assay method according to claim 1 or 2, wherein the mobile phase further comprises an acid-base agent selected from phosphoric acid, hydrochloric acid, sodium hydroxide, aqueous ammonia or mixtures thereof, preferably the acid-base agent is selected from phosphoric acid.
4. The assay of any one of claims 1 to 3, wherein the pH of the mobile phase is from 4.0 to 8.0, preferably 6.5, wherein the pH of the mobile phase is adjusted by the acidifying agent.
5. The assay of claim 4, wherein: the detection wavelength of the chromatographic column is 205nm to 220nm, and preferably the detection wavelength of the chromatographic column is 215 nm; the flow rate of the chromatographic column is 1.0ml/min to 2.0ml/min, preferably the flow rate of the chromatographic column is 1.5 ml/min; the column temperature of the chromatographic column is 25 ℃ to 35 ℃, and preferably the column temperature of the chromatographic column is 30 ℃; the sample amount of the chromatographic column is 10 to 30 mu L, and preferably the sample amount of the chromatographic column is 20 mu L.
6. The assay of claim 4 or 5, further comprising the preparation of a pre-liquid chromatography detection solution comprising:
a test solution, wherein the test solution consists of the dexmedetomidine hydrochloride preparation and a diluent;
an impurity control solution prepared by diluting the test sample solution;
a content control solution, wherein the content control solution consists of a dexmedetomidine hydrochloride control and a diluent; and
the blank auxiliary material solution consists of blank auxiliary materials corresponding to the preparation and a diluent.
7. The assay of any one of claims 4 to 6, wherein: the dexmedetomidine hydrochloride preparation is selected from dexmedetomidine hydrochloride raw material, dexmedetomidine hydrochloride tablet, dexmedetomidine hydrochloride injection or dexmedetomidine hydrochloride oral suspension; preferably the diluent is a mobile phase.
8. The assay of claim 7, wherein the test solution is prepared by a method comprising:
mixing dexmedetomidine hydrochloride with a diluent to obtain a first mixture; and
and filtering the supernatant of the first mixture to obtain a secondary filtrate, wherein the secondary filtrate is the test solution.
9. The assay of claim 7 or 8, wherein the first mixture is further subjected to sonication, centrifugation, preferably at a temperature of from 40 ℃ to 50 ℃, more preferably at a temperature of 45 ℃, preferably for a time of from 20min to 40min, more preferably for a time of 30 min; preferably, the centrifugation rotation speed is 2000rpm/min to 4000rpm/min, more preferably, the centrifugation rotation speed is 3000rpm/min, preferably, the centrifugation time is 2min to 8min, and more preferably, the centrifugation time is 5 min.
10. An assay method as claimed in any one of claims 7 to 9 wherein the first mixture supernatant is filtered using a filter membrane, preferably the filter membrane has a pore size of 0.45 μm.
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Address after: 219 Furong Zhongsi Road, Xishan Economic and Technological Development Zone, Wuxi City, Jiangsu Province, 214000 Applicant after: Zhuohe Pharmaceutical Group Co.,Ltd. Address before: 219 Furong Zhongsi Road, Xishan Economic and Technological Development Zone, Wuxi City, Jiangsu Province, 214000 Applicant before: Zhuohe Pharmaceutical Group Co.,Ltd. |
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Application publication date: 20200522 |