CN106680413A - RT-HPLC detecting method of relevant matters of sodium gualenate - Google Patents
RT-HPLC detecting method of relevant matters of sodium gualenate Download PDFInfo
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Abstract
The invention relates to the technical field of drug analysis, and discloses a RT-HPLC detecting method of relevant matters of sodium gualenate. The detecting method includes steps of configuring analysis solution; chromatographic condition; online detection. At present, there is no related complete patent and literature report about the detecting method of the relevant matters of sodium gualenate. The method can effectively detect the existence of various related impurities in relevant matters of sodium gualenate, particularly realize the characteristic peak of sodium gualenate and the characteristic peak of its isomer in a spectrogram, and realize the separation of characteristic peak of sodium gualenate and the characteristic peak of multiple degrading impurities in a spectrogram, thereby guaranteeing controllable quality of the product.
Description
Technical field
The present invention relates to pharmaceutical analysiss technical field, reverse efficient liquid phase of more particularly to a kind of Sodium Azulenesulfonate about material
Chromatographic detection method.
Background technology
Alleged " relevant material (related substances) " is referred in production of raw medicine process in pharmaceutical analysiss
In the material such as initiation material, reagent, intermediate, by-product and the isomer brought into, it is also possible to preparation is in production, storage and transports
The special impurities such as the catabolite, polymer or the crystal conversion that produce during defeated.The synthesis of species and medicine about material
Route is closely related with preparation process, and the change of any one factor of the medicine in synthesis and production process may all cause it
It is different about the species of material, thus detection and control process about material are relative complex.Detection about material is control
The important indicator of drug quality.
Sodium Azulenesulfonate (Sodium Azulene Sulfonate), also known as sodium gualenate, are to spend middle extraction from feverfew
A kind of chemical substance, research in recent years finds that it has following effects：The inflammation for suppressing various inflammation-causing substances to cause, and act on compared with
For lasting；Inflammatory cell is suppressed to discharge histamine by local direct effect；Increase the synthesis of PGE2 in mucosa, promote meat
Bud is formed and epithelial cell is newborn；Reduce pepsic activity.
Sodium Azulenesulfonate, chemical entitled Isosorbide-5-Nitrae-dimethyl -7- isopropyl azulene -3- sodium sulfonates, its structural formula is as follows：
The relevant material of Sodium Azulenesulfonate is as follows：Kessazulen, impurity A, impurity B, impurity C, wherein Kessazulen, are that Sodium Azulenesulfonate is closed
Into the starting material of technique；Impurity A is Sodium Azulenesulfonate isomerss；Impurity B, impurity C are oxidative degradation impurity, above-mentioned impurity
Structure is shown in Table 1.
The each impurity title of the Sodium Azulenesulfonate of table 1 and structure
Both at home and abroad only the total content about material is defined in the published drug standard with regard to Sodium Azulenesulfonate,
And do not limit the content of any single contaminant.Outer pharmaceuticals composition specification (1989) of Pharmacopeia of Japan are recorded to crude drug,
Using adding normal hexane to filter, filtrate is determined relevant material Kessazulen in sample with the method for spectrphotometric method for measuring transmitance, spirit
Sensitivity is low.When Sodium Azulenesulfonate is applied to different preparations as crude drug, the content for detecting its related impurities is needed, judge sodium sulfonate
Whether crude drug is qualified, if need to take correlation means to be controlled.The method of existing document report cannot separate above-mentioned miscellaneous
Matter, cannot more determine its concrete content.
The content of the invention
In order to solve the above problems, the present invention provides a kind of Sodium Azulenesulfonate about the RT-HPLC detection methods of material, passes through
Phenyl silane reversed phase chromatographic column is used, appropriate gradient is adjusted, Sodium Azulenesulfonate characteristic peak is solved miscellaneous with its isomer, oxidation
The detached problem of matter characteristic peak, realizes the control to Sodium Azulenesulfonate crude drug quality, and the method sensitivity is high, specificity
By force, it is simple to operate.
The Sodium Azulenesulfonate of the present invention is comprised the following steps about the detection method of material RT-HPLC：
A) Allocation Analysis solution
B) chromatographic condition
Chromatographic column is reversed phase chromatographic column, and the mixed liquor with acid or phosphate aqueous phase solution and organic faciess is described as mobile phase
Aqueous phase solution is faintly acid, and described organic faciess are selected from methanol；Using gradient elution method, the gradient elution method mobile phase
Middle water phase volume ratio is by 0,8~12,39~44,48~53,55~58min time points, water phase volume ratio is 95-98%, 85-
90%th, 85-90%, 30-40%, 25-30% carry out gradient elution；
C) machine is determined on
Analytical solution 5-30 μ l injections high performance liquid chromatograph made by step a) is taken, chromatography is carried out, and records color
Spectrogram.
Preferred version, step a) the sample analysis solution is prepared and follows claimed below：It is molten with methanol-aqueous phosphatic
Solution sample, makes analytical solution, and organic faciess percent by volume is more than 50% in described methanol-aqueous phosphatic.The step
In rapid b) chromatographic condition, efficient liquid phase flow velocity is set as 0.8-1.2ml/min；Column temperature be 25-50 DEG C, adopt Detection wavelength for
220-300nm UV-detector；
In certain embodiments, the filler of the reversed phase chromatographic column is phenyl silane bonded silica gel chromatographic column or octadecane
Base silane bonded silica gel chromatographic column or eight alkyl silane bonded silica gel chromatographic columns, preferably phenyl silane bonded silica gel chromatographic column.
In certain embodiments, the specification of the reversed phase chromatographic column is：Column length is between 100mm to 300mm, chromatograph column internal diameter
Between 1mm to 10mm, particle diameter between 1 μm to 10 μm, preferably specification be 4.6mm × 250mm, 5 μm of phenyl silane bonded silica
Glue chromatographic column.
In certain embodiments, the concentration of the phosphate solution is 0.001-0.05mol/L, pH 2.0-4.0, preferably
The concentration of phosphate solution is 0.02mol/L, pH 2.7-3.5.
In certain embodiments, the phosphate is sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, di(2-ethylhexyl)phosphate
One of hydrogen potassium, dipotassium hydrogen phosphate, preferably phosphoric acid potassium dihydrogen.
In certain embodiments, the A phases are phosphate solution-methanol, and the volume ratio of the phosphate solution-methanol is
10:90-80:20, preferred volume ratio is 80:20.
Preferred version is：Step a) methanol-aqueous phosphatic sample dissolution, makes analytical solution, and described methanol-
Organic faciess percent by volume is more than 50% in aqueous phosphatic；Step b) is for reversed phase chromatographic column for the condition of gradient elution
Column length 250mm, diameter 4.6mm, the phenyl silane bonded silica gel chromatographic column of 5 μm of packing material size, mobile phase be with 0.02mol/L,
3.0 potassium dihydrogen phosphates of pH-methanol is A phases, in mobile phase A phases-methanol ratio by 0,10,40,50,58min time points, A
Phase volume ratio carries out gradient elution, flow velocity 1.0ml/min for 97%, 88%, 85%, 35%, 30%；30 DEG C of column temperature, detects ripple
Long 245nm；Step c) takes analytical solution injection high performance liquid chromatograph made by step a), carries out chromatography, and records color
Spectrum.
In certain embodiments, the sample is Sodium Azulenesulfonate or its related preparations.The Sodium Azulenesulfonate related preparations are
Tablet, granule.
Said method analysis can be used to separate impurity A, impurity B, impurity C, Kessazulen, Sodium Azulenesulfonate in sample.
The present invention can effectively determine the presence of various related impuritieses in Sodium Azulenesulfonate solution, especially realize in spectrogram
Sodium Azulenesulfonate characteristic peak and Sodium Azulenesulfonate isomerss characteristic peak and its related starting material, oxidation impurities characteristic peak point
From.The separating degree of each impurity is all higher than 1.5, and wherein Sodium Azulenesulfonate reaches 3.5 with its isomerss separating degree, tailing factor
Less than 2.5, theoretical cam curve is more than 8000.A kind of relevant substance method of detection Sodium Azulenesulfonate of this technology invention, the detection
Method is simple, quick, sensitivity is high, accuracy is high.
The detection of said method may insure the quality controllable of product.
Description of the drawings
The chromatogram of Fig. 1, the mobile phase condition of embodiment 1；
The chromatogram of Fig. 2, the mobile phase condition of embodiment 2；
The chromatogram of Fig. 3, the gradient wash of embodiment 3.
The chromatogram of Fig. 4, the gradient wash of embodiment 4.
The chromatogram of Fig. 5, the gradient wash of embodiment 5.
Specific embodiment
With reference to Figure of description and specific embodiment, the present invention is described in detail.These embodiments are only used for
Illustrate the present invention rather than limit the scope of the present invention.The test method of unreceipted actual conditions in the following example, generally
According to normal condition or according to the condition proposed by manufacturer.Additionally, any similar to described content or impartial method
And material all can be used in the inventive method.Preferable implementation described in text only presents a demonstration with material and is used.
Embodiment one
(1) instrument and chromatographic condition
High performance liquid chromatograph：U3000 highly effective liquid phase chromatographic systems and work station；
Chromatographic column：The phenyl silane bonded silica gel chromatographic column of SUPELCOSILLC-DP (4.6mm × 250mm, 5 μm)
Configuration 0.02mol/L potassium dihydrogen phosphates (with phosphorus acid for adjusting pH to 3.0) are A phases, A phases-methanol in mobile phase
Ratio by 0,5,15,40,45,46,52min time points, A phase volume ratios are 88%, 88%, 60%, 25%, 25%, 88%,
88% carries out gradient elution, flow velocity 1.0ml/min；30 DEG C of column temperature, Detection wavelength 245nm；
(2) experimental procedure
Sodium Azulenesulfonate reference substance, impurity A, impurity B, impurity C and Kessazulen reference substance are taken respectively each appropriate, use solvent
[0.02mol/L potassium dihydrogen phosphates (with phosphorus acid for adjusting pH to 3.0)-methanol (30:70) every ml] is made containing Sodium Azulenesulfonate
0.5mg, other each impurity respectively contain the system suitability solution of 5 μ g, used as analytical solution；
The μ l of above-mentioned analytical solution 10 are taken, chromatograph of liquid is injected, chromatogram is recorded.As a result accompanying drawing 1 is seen, it can be seen that this
Sodium Azulenesulfonate main peak and its isomerss impurity A peak fail complete baseline separation under part.
Embodiment two
(1) instrument and chromatographic condition
High performance liquid chromatograph：U3000 highly effective liquid phase chromatographic systems and work station；
Chromatographic column：The phenyl silane bonded silica gel chromatographic column of SUPELCOSILLC-DP (4.6mm × 250mm, 5 μm)
Configuration 0.02mol/L potassium dihydrogen phosphates (with phosphorus acid for adjusting pH to 3.0) are A phases, A phases-methanol in mobile phase
Ratio by 0,5,15,45,50,51,55min time points, A phase volume ratios are 88%, 88%, 70%, 40%, 25%, 88%,
88% carries out gradient elution, flow velocity 1.0ml/min；30 DEG C of column temperature, Detection wavelength 245nm；
(2) experimental procedure
Sodium Azulenesulfonate reference substance, impurity A, impurity B, impurity C and Kessazulen reference substance are taken respectively each appropriate, use solvent
[0.02mol/L potassium dihydrogen phosphates (with phosphorus acid for adjusting pH to 3.0)-methanol (30:70) every ml] is made containing Sodium Azulenesulfonate
0.5mg, other each impurity respectively contain the system suitability solution of 5 μ g, used as analytical solution；
The μ l of above-mentioned analytical solution 10 are taken, chromatograph of liquid is injected, chromatogram is recorded.As a result accompanying drawing 2 is seen, it can be seen that this
Sodium Azulenesulfonate main peak and its isomerss impurity A peak still fail complete baseline separation under part.
Embodiment three
(1) instrument and chromatographic condition
High performance liquid chromatograph：U3000 highly effective liquid phase chromatographic systems and work station；
Chromatographic column：The phenyl silane bonded silica gel chromatographic column of SUPELCOSILLC-DP (4.6mm × 250mm, 5 μm)
Configuration 0.02mol/L potassium dihydrogen phosphates (with phosphorus acid for adjusting pH to 3.0)-methanol is A phases, wherein water phase and first
Alcohol phase volume ratio is 80:20, in mobile phase the ratio of A phases-methanol by 0,10,40,50,58,58.1,63min time points, A phases
Volume ratio carries out gradient elution, flow velocity 1.0ml/min for 97%, 88%, 85%, 35%, 30%, 97%, 97%；Column temperature 30
DEG C, Detection wavelength 245nm；
(2) experimental procedure
Sodium Azulenesulfonate reference substance, impurity A, impurity B, impurity C and Kessazulen reference substance are taken respectively each appropriate, use solvent
[0.02mol/L potassium dihydrogen phosphates (with phosphorus acid for adjusting pH to 3.0)-methanol (30:70) every ml] is made containing Sodium Azulenesulfonate
0.5mg, other each impurity respectively contain the system suitability solution of 5 μ g, used as analytical solution；
The μ l of above-mentioned analytical solution 10 are taken, chromatograph of liquid is injected, chromatogram is recorded.As a result as shown in accompanying drawing 3 and table 1, can
Each peak separating degree can be reached and efficiently separated under the conditions of to find out this, wherein Sodium Azulenesulfonate main peak and its isomerss impurity A
Peak is kept completely separate, and separating degree is 3.05, and each peak theoretical cam curve is all higher than 8000.
The chromatographic results table of 1 embodiment of table 3
Example IV
(1) instrument and chromatographic condition
High performance liquid chromatograph：U3000 highly effective liquid phase chromatographic systems and work station；
Chromatographic column：The phenyl silane bonded silica gel chromatographic column of SUPELCOSILLC-DP (4.6mm × 250mm, 5 μm)
Configuration 0.02mol/L potassium dihydrogen phosphates (with phosphorus acid for adjusting pH to 2.8)-methanol is A phases, wherein water phase and first
Alcohol phase volume ratio is 80:20, in mobile phase the ratio of A phases-methanol by 0,10,40,50,58,58.1,63min time points, A phases
Volume ratio carries out gradient elution, flow velocity 0.8ml/min for 97%, 88%, 85%, 35%, 30%, 97%, 97%；Column temperature 30
DEG C, Detection wavelength 245nm；
(2) experimental procedure
Sodium Azulenesulfonate reference substance, impurity A, impurity B, impurity C and Kessazulen reference substance are taken respectively each appropriate, use solvent
[0.02mol/L potassium dihydrogen phosphates (with phosphorus acid for adjusting pH to 3.0)-methanol (30:70) every ml] is made containing Sodium Azulenesulfonate
0.5mg, other each impurity respectively contain the system suitability solution of 5 μ g, used as analytical solution；
The μ l of above-mentioned analytical solution 10 are taken, chromatograph of liquid is injected, chromatogram is recorded.As a result accompanying drawing 4 is seen.
Embodiment five
(1) instrument and chromatographic condition
High performance liquid chromatograph：U3000 highly effective liquid phase chromatographic systems and work station；
Chromatographic column：The phenyl silane bonded silica gel chromatographic column of SUPELCOSILLC-DP (4.6mm × 250mm, 5 μm)
Configuration 0.02mol/L potassium dihydrogen phosphates (with phosphorus acid for adjusting pH to 3.2)-methanol is A phases, wherein water phase and first
Alcohol phase volume ratio is 80:20, in mobile phase the ratio of A phases-methanol by 0,10,40,50,58,58.1,63min time points, A phases
Volume ratio carries out gradient elution, flow velocity 1.2ml/min for 97%, 88%, 85%, 35%, 30%, 97%, 97%；Column temperature 30
DEG C, Detection wavelength 245nm；
(2) experimental procedure
Sodium Azulenesulfonate reference substance, impurity A, impurity B, impurity C and Kessazulen reference substance are taken respectively each appropriate, use solvent
[0.02mol/L potassium dihydrogen phosphates (with phosphorus acid for adjusting pH to 3.0)-methanol (30:70) every ml] is made containing Sodium Azulenesulfonate
0.5mg, other each impurity respectively contain the system suitability solution of 5 μ g, used as analytical solution；
The μ l of above-mentioned analytical solution 10 are taken, chromatograph of liquid is injected, chromatogram is recorded.As a result accompanying drawing 5 is seen.
Claims (10)
1. RT-HPLC detection method of a kind of Sodium Azulenesulfonate about material, it is characterised in that comprise the following steps：
A) testing sample analytical solution is configured
B) chromatographic condition
Chromatographic column is reversed phase chromatographic column, the A phases with the mixed liquor of acid or phosphate aqueous phase solution and methanol as mobile phase, the water
Phase solution is faintly acid, and B phases are methanol, and A, B mix into mobile phase；Using gradient elution method, the gradient elution method
In mobile phase water phase volume ratio by 0,8~12,39~44,48~53,55~58min time points, A phases account for the volume of mobile phase
Than carrying out gradient elution for 95-98%, 85-90%, 85-90%, 30-40%, 25-30%；
C) machine is determined on
Analytical solution injection high performance liquid chromatograph made by step a) is taken, chromatography is carried out, and records chromatograph.
2. RT-HPLC detection methods as claimed in claim 1, it is characterised in that
Step a) configures testing sample analytical solution concrete grammar：With methanol-aqueous phosphatic sample dissolution, analysis is made molten
Liquid, organic faciess percent by volume is more than 50% in described methanol-aqueous phosphatic；
In step b) chromatographic conditions, efficient liquid phase flow velocity is set as 0.8-1.2ml/min；Column temperature is 25-50 DEG C, using detection ripple
A length of 220-300nm UV-detector.
3. RT-HPLC detection methods as claimed in claim 1, it is characterised in that the reversed phase chromatographic column is selected from phenyl silane
Bonded silica gel chromatographic column, octadecylsilane chemically bonded silica chromatographic column or eight alkyl silane bonded silica gel chromatographic columns.
4. RT-HPLC detection methods as claimed in claim 3, it is characterised in that the specification of the reversed phase chromatographic column is：Column length
Between 100mm to 300mm, between 1mm to 10mm, particle diameter is between 1 μm to 10 μm for chromatograph column internal diameter.
5. RT-HPLC detection methods as claimed in claim 1, it is characterised in that the concentration of the phosphate solution is
0.001-0.05mol/L, pH 2.0-4.0, the phosphate selected from sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate,
Potassium dihydrogen phosphate, dipotassium hydrogen phosphate；The acid is selected from phosphoric acid.
6. RT-HPLC detection methods as claimed in claim 5, it is characterised in that the phosphate solution is 0.02mol/L phosphorus
Acid dihydride potassium solution, adjusts pH to 2.7-3.5.
7. RT-HPLC detection methods as claimed in claim 1, it is characterised in that the A phases are phosphate solution-methanol, institute
The volume ratio for stating phosphate solution-methanol is 90:10~80:20.
8. RT-HPLC detection methods as claimed in claim 1, it is characterised in that the step b) is the gradient elution bar
It is column length 250mm, diameter 4.6mm, the phenyl silane bonded silica gel chromatographic column of 5 μm of packing material size that part is reversed phase chromatographic column, is flowed
Be mutually with 3.0 potassium dihydrogen phosphates of 0.02mol/L, pH-methanol as A phases, in mobile phase A phases-B Phase Proportions by 0,10,40,
50th, 58min time points, A phase volume ratios carry out gradient elution, flow velocity 1.0ml/min for 97%, 88%, 85%, 35%, 30%；
30 DEG C of column temperature, Detection wavelength 245nm.
9. RT-HPLC detection methods as claimed in claim 1, it is characterised in that the sample is Sodium Azulenesulfonate or it is related
Preparation.
10. the purposes of any one of claim 1-9 method, it is characterised in that methods described is used to separating impurity A in sample, miscellaneous
Matter B, impurity C, Kessazulen, Sodium Azulenesulfonate.
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| CN103385863A (en) * | 2013-08-05 | 2013-11-13 | 四川国康药业有限公司 | Sodium azulene sulfonate sustained-release preparation |
| CN103393592A (en) * | 2013-08-05 | 2013-11-20 | 四川国康药业有限公司 | Sodium azulene sulfonate gel and its preparation method and use |
| CN103512976A (en) * | 2013-09-18 | 2014-01-15 | 河北凯盛医药科技有限公司 | Analysis and detection method of azulene sulfonate isomer and salt thereof |
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2016
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| CN1903185A (en) * | 2006-08-04 | 2007-01-31 | 徐文凯 | Dispersion tablets and its prepn. method |
| CN103385863A (en) * | 2013-08-05 | 2013-11-13 | 四川国康药业有限公司 | Sodium azulene sulfonate sustained-release preparation |
| CN103393592A (en) * | 2013-08-05 | 2013-11-20 | 四川国康药业有限公司 | Sodium azulene sulfonate gel and its preparation method and use |
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