CN106706789A - Method for detecting related substances in drotaverine hydrochloride injection by high performance liquid chromatography - Google Patents
Method for detecting related substances in drotaverine hydrochloride injection by high performance liquid chromatography Download PDFInfo
- Publication number
- CN106706789A CN106706789A CN201611221591.0A CN201611221591A CN106706789A CN 106706789 A CN106706789 A CN 106706789A CN 201611221591 A CN201611221591 A CN 201611221591A CN 106706789 A CN106706789 A CN 106706789A
- Authority
- CN
- China
- Prior art keywords
- drotaverine
- solution
- mobile phase
- ketone
- drotaverine hydrochloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 CCOc1ccc(Cc2c(cc(*)c(OCC)c3)c3ccn2)cc1OCC Chemical compound CCOc1ccc(Cc2c(cc(*)c(OCC)c3)c3ccn2)cc1OCC 0.000 description 2
- XNAVJZOYAFVQEX-UHFFFAOYSA-N CCOc1ccc(C(c2c3)NCCc2cc(OCC)c3OCC)cc1C Chemical compound CCOc1ccc(C(c2c3)NCCc2cc(OCC)c3OCC)cc1C XNAVJZOYAFVQEX-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
Landscapes
- Physics & Mathematics (AREA)
- Biochemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
The invention discloses a method for detecting related substances in drotaverine hydrochloride injection by high performance liquid chromatography. The method comprises the following steps: (a) preparing a test sample liquid: preparing a test sample liquid from a to-be-measured sample by using a solvent; and (b) detecting: with octadecylsilane bonded silica gel as chromatographic column packing, a phosphate buffer as a mobile phase A, acetonitrile as a mobile phase B and methanol as a mobile phase C, detecting the test sample liquid by a gradient elution method, wherein the detection wavelength is 244nm. By adopting the method for detecting active pharmaceutical ingredients of drotaverine hydrochloride by high performance liquid chromatography, the related substances in the active pharmaceutical ingredients of drotaverine hydrochloride can be separated and detected quickly, effectively and accurately, the product quality of the drotaverine hydrochloride injection is improved, and the medication safety of patients is enhanced.
Description
Technical field
The present invention relates to Pharmaceutical Analysis technical field, him is bent more particularly, to one kind high effective liquid chromatography for measuring hydrochloric acid
About the method for material in dimension woods parenteral solution.
Background technology
Drotaverine hydrochloride (Drotaverine hydrochloride), chemical name is:1- { (3,4- diethoxybenzenes
Base) methylene -6,7- diethoxy -1,2,3,4- four hydrogen isoquinoline hydrochloric acid salts, trade name No-SPA (RNO-SPA), be by
A kind of new solution spasm medicine that match Norfin, Inc of France develops in Hungarian co-partnership company Chinoin pharmaceutical factories.The medicine is
Isoquinoline class derivate, with traditional anisodamine, the anticholinergic such as atropine releases spasm medicine difference, and it directly acts on smooth
Myocyte, the mechanism of action of its diastole smooth muscle is:Smooth muscle cells are acted on, changes cell membrane potential and permeability;
Suppress phosphodiesterase, increase adenosine cyclophosphate (cAMP) level in myocyte;Suppress intracellular initial calcium ion reaction, smooth
Flesh diastole, releases spasm.It is characterized in:(1) act on comprehensive, persistently, drotaverine hydrochloride shrinks curative effect to smooth muscle spasmodic
Each link all work, particularly high-tension smooth muscle has special efficacy, and it is 9-11h that it eliminates half-life period, therefore the term of validity is long;
(2) adverse reaction is small, and drotaverine hydrochloride does not influence autonomic nerves system, on the normal smooth muscle of intestines and stomach without influence, does not have M
The adverse reaction of receptor antagonist.The indication of the medicine includes coronary artery insufficiency, endarteritis obliterans, angina pectoris, stomach
Intestinal smooth spasm, IBS, cholecystalgia, renal colic and the urinary tract spasm, hysterotrismus, dysmenorrhoea etc..Its advantage
Be without serious cardiovascular reaction, without parasympathetic blockade, acorea amplification, the acute attack without glaucoma, without urethra wing
The expansion of Guang, rapid-action, adverse reaction is few.
The composition of drotaverine hydrochloride bulk drug is clear and definite, mainly includes drotaverine hydrochloride and 2 kinds of related impurities (second
Base papaverine, Drotaverine ketone), this 2 kinds of materials are thoroughly quickly separated particularly significant.
The relevant material high efficient liquid phase analysis method reference of drotaverine hydrochloride parenteral solution State Bureau standard (YBH17602006)
Drotaverine hydrochloride parenteral solution check standard JX20000051, drotaverine hydrochloride tablet quality standard WS-2127 (X-184)-
2002 formulate.
State Bureau's standard (YBH17602006), washes using phosphate buffer (pH3.3 ± 0.05)-acetonitrile-methanol is isocratic
De-, analysis time period is shorter, about 5~7 minutes appearances of main peak, there is rear conditions of streaking, it is understood that there may be unknown impuritie is with main peak not
Situation about efficiently separating, each known impurities are separated preferably, but drotaverine hydrochloride parenteral solution has 3 through improving sterilization process condition
The degraded of individual unknown impuritie is obvious, separates undesirable, and some impurity are overlapped between retention time about 3~5 minutes, determine not
Accurately, it is impossible to reach Related substances separation requirement, it is unfavorable for actual popularization and application.
Accordingly, it would be desirable to be improved to drotaverine hydrochloride parenteral solution Related substance method, set up one it is quick, have
The detection method of effect, sterilization process by 100 DEG C sterilize 20 minutes, be changed into 121 DEG C sterilizing 15 minutes after, can distinguish and detect
All related substanceses in drotaverine hydrochloride bulk drug, are conducive to improving the product quality of drotaverine hydrochloride parenteral solution, carry
Patient medication security high.
Regarding to the issue above, it is special to propose the present invention.
The content of the invention
The purpose of the present invention is the various conditions for exploring drotaverine hydrochloride about material efficient liquid phase chromatographic analysis, there is provided
One simplicity, the relevant material HPLC analytical method of reliable drotaverine hydrochloride.
In order to solve the above technical problems, the present invention is adopted the following technical scheme that:
About the method for material in a kind of use high effective liquid chromatography for measuring drotaverine hydrochloride parenteral solution, the method includes
Following steps:
(1) test sample solution is prepared:
Take drotaverine hydrochloride solvent and be configured to test sample solution;
(2) reference substance solution is prepared:
Take drotaverine hydrochloride, ethaquin and Drotaverine ketone solvent and be configured to reference substance solution;
(3) compounding system applicability solution:
Take drotaverine hydrochloride, ethaquin and Drotaverine ketone solvent and be configured to system suitability solution;
(4) system suitability experiment is carried out;
(5) detection sensitivity experiment is carried out;
The detection sensitivity of high performance liquid chromatograph is adjusted with reference substance solution, makes the peak height of principal component chromatographic peak be full amount
The 10-25% of journey;
(6) it is measured according to following high-efficient liquid phase chromatogram condition:
Mobile phase:It is mobile phase C with methyl alcohol with acetonitrile as Mobile phase B using phosphate buffer as mobile phase A;It is described
Phosphate buffer is adjusted to pH=3.3 ± 0.05 for 0.1% phosphate aqueous solution triethylamine;
UV-detector:Detection wavelength is 200-400nm;
Chromatographic column:With octadecylsilane chemically bonded silica as filler;
Flow velocity:0.5-2.0mL/min;
Column temperature:20-60℃;
(7) by external standard method, the content about material is calculated.
Preferably, the Detection wavelength of described UV-detector is 200-300nm, more preferably 244nm.
Preferably, the flow velocity is 1.0mL/min;The column temperature is 30-50 DEG C, more preferably 40 DEG C.
Preferably, the phosphate buffer is made after adjusting pH3.3 ± 0.05 with triethylamine by 0.1% phosphate aqueous solution
Into.
Preferably, the preparation of the test sample solution is specifically included and prepares the molten of hydrochloric Drotaverine 0.8mg/mL
Liquid, the solvent of the solution is the mixed solvent that mobile phase A, methyl alcohol and acetonitrile are formed, and the mixed solvent is by methyl alcohol and second
Nitrile by volume 2:1 mixed mixed liquor again with mobile phase A by volume 1:9 mixing.
Preferably, the preparation of the reference substance solution specifically includes the hydrochloric Drotaverine of preparation, ethaquin and bends
The solution of Ta Weilin ketone, the concentration of drotaverine hydrochloride is 4.0 μ g/mL in the solution;The concentration of ethaquin is 1.6 μ
g/mL;The concentration of Drotaverine ketone is 4.0 μ g/mL;Drotaverine hydrochloride, ethaquin and Drotaverine ketone are first used into methyl alcohol
It is 2 with acetonitrile volume ratio:1 mixed liquor dissolving, is subsequently adding the mixed solvent that mobile phase A, methyl alcohol and acetonitrile are formed, described mixed
Bonding solvent is by methyl alcohol and acetonitrile by volume 2:1 mixed mixed liquor again with mobile phase A by volume 1:9 mixing.
Preferably, the preparation of the system suitability solution specifically includes the hydrochloric Drotaverine of preparation, ethaquin
With the solution of Drotaverine ketone, the concentration of drotaverine hydrochloride is 0.8mg/mL in the solution;The concentration of ethaquin is
1.6μg/mL;The concentration of Drotaverine ketone is 4.0 μ g/mL;Drotaverine hydrochloride, ethaquin and Drotaverine ketone are first used
Methyl alcohol is 2 with acetonitrile volume ratio:1 mixed liquor dissolving, is subsequently adding the mixed solvent that mobile phase A, methyl alcohol and acetonitrile are formed, institute
It is by methyl alcohol and acetonitrile by volume 2 to state mixed solvent:1 mixed mixed liquor again with mobile phase A by volume 1:9 mixing.
Preferably, the system suitability refers to take the μ L of system suitability solution 20 injection liquid chromatographs, hydrochloric acid
Drotaverine is more than 3.0 with the separating degree of ethaquin, and separating degree meets the requirements between each impurity peaks, and theoretical cam curve presses salt
Sour Drotaverine is calculated, and is not less than 3000.
Preferably, gradient elution is carried out with mobile phase A, Mobile phase B and mobile phase C;Described gradient is:
Beneficial effects of the present invention are as follows:
The present invention based on HPLC analytical method, do not drag for the separation existed for prior art by thorough, peak shape
Tail is serious, bag peak the shortcomings of, using new buffer solution system and mobile phase ratio, impurity is kept completely separate, solve
The relevant issues of prior art;And the method that the present invention is provided is through the methodological studies such as specificity, sensitivity and checking, its checking
Result is in tolerance interval;The present invention carries out specificity comparative study with current standard, it was demonstrated that its method more can be controlled effectively
The relevant material of drotaverine hydrochloride parenteral solution processed;The inventive method also has following beneficial effects,
1. mobile phase is prepared relatively simple easy to operate;
2. impurity can be efficiently separated, and principal component is above State Bureau's standard without hangover, the dopant species of detection, quantity
(YBH17602006) method, accuracy in detection is high, improves the security of product, and methodological science, reliability are controllable;
3. easy to operate, it is suitable to practical application and popularization.
Brief description of the drawings
Fig. 1 shows the HPLC collection of illustrative plates of the testing result that the application comparative example 1 is provided;
Fig. 2 shows the HPLC collection of illustrative plates of the testing result that the application comparative example 2 is provided;
Fig. 3 shows the HPLC collection of illustrative plates of the testing result that the embodiment of the present application 1 is provided;
Fig. 4 shows the HPLC collection of illustrative plates of the testing result that the embodiment of the present application 2 is provided;
Fig. 5 shows the HPLC collection of illustrative plates of the testing result that the embodiment of the present application 3 is provided;
Fig. 6 A show the HPLC collection of illustrative plates of the testing result that the application comparative example 3 is provided;
Fig. 6 B show the HPLC collection of illustrative plates of the testing result that the embodiment of the present application 4 is provided;
Fig. 7 A show the HPLC collection of illustrative plates of the testing result that the application comparative example 4 is provided;
Fig. 7 B show the HPLC collection of illustrative plates of the testing result that the embodiment of the present application 5 is provided;
Fig. 8 A show the HPLC collection of illustrative plates of the testing result that the application comparative example 5 is provided;
Fig. 8 B show the HPLC collection of illustrative plates of the testing result that the embodiment of the present application 6 is provided;
Fig. 9 A show the HPLC collection of illustrative plates of the testing result that the application comparative example 6 is provided;
Fig. 9 B show the HPLC collection of illustrative plates of the testing result that the embodiment of the present application 7 is provided;
Figure 10 A show the HPLC collection of illustrative plates of the testing result that the application comparative example 7 is provided;
Figure 10 B show the HPLC collection of illustrative plates of the testing result that the embodiment of the present application 8 is provided;
Figure 11 shows the HPLC collection of illustrative plates of the testing result that the embodiment of the present application 14 is provided;
Figure 12 shows the HPLC collection of illustrative plates of the testing result that the embodiment of the present application 14 is provided;
Figure 13 shows the HPLC collection of illustrative plates of the testing result that the embodiment of the present application 14 is provided;
Figure 14 shows the HPLC collection of illustrative plates of the testing result that the embodiment of the present application 14 is provided.
Specific embodiment
Technical scheme is clearly and completely described below in conjunction with accompanying drawing, it is clear that described implementation
Example is a part of embodiment of the invention, rather than whole embodiments.Based on the embodiment in the present invention, ordinary skill
The every other embodiment that personnel are obtained under the premise of creative work is not made, belongs to the scope of protection of the invention.
According to drotaverine hydrochloride Material synthesis process route and experiment, it may be determined that possible relevant material is:
(1) starting material:3,4- diethoxy phenylacetic acids and 3,4- diethoxy phenyl ethylamine;
(2) synthetic intermediate (condensation product):N- (3,4- diethoxy phenylacetyl)-β-(3,4- diethoxybenzene) ethamine;
(3) catabolite:Ethaquin, Drotaverine ketone.
Starting material and intermediate have been controlled by feed preparation process, and formulate inner quality standard.This method weight
Degraded becomes 3 big unknown impurities in point concern 2 known catabolite ethaquins, Drotaverine ketone and sterilization process.
Step 1. prepares test sample solution:Precision measures drotaverine hydrochloride parenteral solution in right amount, and solubilizer 2 quantitatively dilutes
Solution containing about drotaverine hydrochloride 0.8mg is made in every 1mL, as need testing solution;
Step 2. prepares reference substance solution:It is each suitable that precision weighs drotaverine hydrochloride, ethaquin and Drotaverine ketone
Amount, solubilizer 1 dissolves in right amount, then is made every 1mL containing about the μ g of drotaverine hydrochloride 4.0, the μ of ethaquin 1.6 with the dilution of solvent 2
The mixed solution of the g and μ g of Drotaverine ketone 4.0, as reference substance solution;
Step 3. compounding system applicability solution:Precision weighs drotaverine hydrochloride, ethaquin and Drotaverine ketone
Each appropriate, solubilizer 1 dissolves in right amount, then is diluted to every 1mL containing about the μ g of ethaquin 1.6, the μ of Drotaverine ketone 4.0 with solvent 2
The mixed solution of g and drotaverine hydrochloride 0.8mg, as system suitability solution;
Step 4. is detected:Using octadecylsilane chemically bonded silica as chromatographic column filler, with phosphate buffer (0.1%
Phosphate aqueous solution triethylamine adjusts pH3.3 ± 0.05) as mobile phase A, using acetonitrile as Mobile phase B, using methyl alcohol as stream
Dynamic phase C, using linear gradient elution method, detects the test sample solution, and Detection wavelength is 244nm;Column temperature is 40 DEG C, and flow velocity is
1.0mL/ minutes.Gradient condition is shown in Table 1;
Table 1
Step 5. precision measures the μ L of system suitability solution 20 injection liquid chromatographs, records chromatogram.Number of theoretical plate is pressed
Drotaverine hydrochloride is calculated, and should be not less than 3000, and drotaverine hydrochloride peak should be greater than 3.0 with the separating degree of ethaquin, respectively
Separating degree meets the requirements between impurity peaks;
Step 6. precision measures the μ L of reference substance solution 20, injects liquid chromatograph, adjusts detection sensitivity, makes principal component color
The peak height of spectral peak is the 10%-25% of full scale;
Step 7. presses external standard method, calculates ethaquin, Drotaverine ketone, the content of other single impurity;
In above-mentioned steps 1,2 and 3, the solvent 1 is methanol acetonitrile mixed solution (Jia Chun ︰ acetonitrile=2 ︰ 1);Solvent 2 is
Mobile phase A ︰ methanol acetonitrile mixed solution (Jia Chun ︰ acetonitrile=2 ︰ 1)=9 ︰ 1.
The laboratory apparatus used in following examples and comparative example is Agilent high performance liquid chromatograph;
The chromatographic column for using is COSMOSIL 5C18-MS-Ⅱ250mm×4.6mm 5μm;In each embodiment, with phosphate
Buffer solution (0.1% phosphate aqueous solution with triethylamine adjust pH3.3 ± 0.05) as mobile phase A, using acetonitrile as Mobile phase B,
Using methyl alcohol as mobile phase C, solvent 1 is methanol acetonitrile mixed solution (Jia Chun ︰ acetonitrile=2 ︰ 1);Solvent 2 is mobile phase A ︰ methyl alcohol
Acetonitrile mixed solution (Jia Chun ︰ acetonitrile=2 ︰ 1)=9 ︰ 1;The test sample solution is detected, Detection wavelength is 244nm;Column temperature is
40 DEG C, flow velocity is 1.0mL/ minutes, sample size:20μL.Gradient elution carries out linear elution according to table 2:
Table 2
Impurity information see the table below 3:
The impurity information of table 3 collects
Embodiment 1-3
System suitability
Embodiment 1, system suitability solution is prepared:
Drotaverine hydrochloride, known impurities Drotaverine ketone, known impurities ethaquin are taken respectively each appropriate, solubilizer
1 appropriate dissolving, every 1mL is made containing about the μ g (0.5%) of Drotaverine ketone 4.0, the μ g of ethaquin 1.6 being diluted with solvent 2
(0.2%), the mixed solution of drotaverine hydrochloride 0.8mg, as system suitability solution;
Embodiment 2, need testing solution is prepared:
It is appropriate that precision measures drotaverine hydrochloride parenteral solution, and quantitatively dilution is made and about hydrochloric in every 1mL bends him solubilizer 2
The solution of dimension woods 0.8mg, as need testing solution;
Embodiment 3, selective solution is prepared:
Drotaverine hydrochloride, known impurities Drotaverine ketone, known impurities ethaquin, Drotaverine condensation are taken respectively
Thing (intermediate), starting material 3,4- diethoxies phenylacetic acid and each appropriate solubilizer 1 of 3,4- diethoxy phenyl ethylamine are appropriate molten
Solution, then every 1mL is made containing about Drotaverine ketone, Drotaverine condensation product, 3,4- diethoxies phenylacetic acid, 3 with the dilution of solvent 2,
Each 4.0 μ g (0.5%) of 4- diethoxy phenyl ethylamines, the μ g (0.2%) of ethaquin 1.6, the mixing of drotaverine hydrochloride 0.8mg
Solution, it is alternatively that property solution;Sample introduction simultaneously records chromatogram.
Comparative example 1-2
System suitability
Tested by drotaverine hydrochloride parenteral solution quality standard YBH17602006;
Chromatographic condition:
Chromatographic column:Octadecylsilane chemically bonded silica is filler;
Mobile phase:Phosphate buffer (takes diammonium hydrogen phosphate 13.2g, the 200mL that adds water makes dissolving, the phosphoric acid for plus 85%
7.6mL, is diluted with water to 1000mL, regulation ± the 0.05)-acetonitrile-methanols of pH to 3.3 (800: 400: 800);
Solvent:0.1mol/LHCl- methanol-acetonitriles (8: 1: 1);
Flow velocity:1.0mL/min;Wavelength:244nm;Column temperature:40℃;Sample size:20μL;
Comparative example 1, system suitability solution is prepared:Drotaverine hydrochloride, known impurities Drotaverine ketone, known is taken respectively
Each appropriate solubilizer dissolved dilution of impurity ethaquin is made every 1mL containing about the μ g (0.5%) of Drotaverine ketone 4.0, ethyl small-mouthed jar
The μ g (0.2%) of pavine 1.6, the mixed solution of drotaverine hydrochloride 0.8mg, as system suitability solution;
Compare 2, need testing solution is prepared:Precision measures drotaverine hydrochloride parenteral solution in right amount, and solubilizer quantitatively dilutes system
Solution into every 1mL containing about drotaverine hydrochloride 0.8mg, as need testing solution;
Sample introduction simultaneously records chromatogram.
Conclusion:
Comparative example 1 and comparative example 2 are shown in Fig. 1, shown in Fig. 2:In system suitability solution, ethaquin, Drotaverine ketone
With principal component separating degree preferably, but main peak retention time is shorter, there is conditions of streaking, there is that unknown impuritie is not yet in effect with main peak to be separated
Situation;In addition, solvent peak rear impurity appearance time is very fast, and unknown impuritie separate it is undesirable, in about 3~5 points of retention time
Partial impurities are overlapped between clock, and separating effect can not reach Related substances separation requirement.
Embodiment 1-3 results are as shown in Fig. 3, Fig. 4:Ethaquin, Drotaverine ketone and principal component separating degree are preferable, and
Principal component retention time is moderate, without conditions of streaking;In addition, each unknown impuritie separating effect is preferable after solvent peak;Shown in Fig. 5:Choosing
In selecting property solution, add starting material, intermediate, known impurities to investigate separating degree, as a result show, drotaverine hydrochloride and 3,4-
Diethoxy phenylacetic acid, 3,4- diethoxies phenyl ethylamine, Drotaverine condensation product, ethaquin, 5 impurity of Drotaverine ketone
Separating degree be all higher than 3.0, separating effect can reach Related substances separation requirement.
Embodiment 4-8
Destructive testing
It is prepared by need testing solution
Embodiment 4, solution before destruction:Take drotaverine hydrochloride parenteral solution 1mL (being approximately equivalent to drotaverine hydrochloride 20mg)
It is placed in 25mL volumetric flasks, solubilizer 2 is diluted to scale, shakes up, as not destroying solution.
Embodiment 5, high temperature solution:Take drotaverine hydrochloride parenteral solution 1mL and (be approximately equivalent to drotaverine hydrochloride
20mg) it is placed in 25mL volumetric flasks, 100 DEG C of heating 8h are cooled to room temperature, and solvent 2 is diluted to scale, shakes up, broken as high temperature
Bad solution.
Embodiment 6, illumination destruction solution:Take drotaverine hydrochloride parenteral solution 1mL and (be approximately equivalent to drotaverine hydrochloride
20mg), it is placed in 25mL volumetric flasks, illumination 15h under uviol lamp, solvent 2 is diluted to scale, solution is destroyed as illumination.
Embodiment 7, alkali destruction solution:Drotaverine hydrochloride parenteral solution 1mL (equivalent to drotaverine hydrochloride about 20mg) is taken,
It is placed in 25mL volumetric flasks, plus 1mol/L NaOH 1mL, after 60 DEG C of destruction 1.5h, plus 1mol/L hydrochloric acid 1mL is neutralized, solvent 2
Scale is diluted to, is shaken up, solution is destroyed as alkali.
Embodiment 8, Oxidative demage solution:Take drotaverine hydrochloride parenteral solution 1mL and (be approximately equivalent to drotaverine hydrochloride
20mg), it is placed in 25mL volumetric flasks, the hydrogen peroxide 2mL for plus 30%, 60 DEG C of destruction 8h, solvent 2 is diluted to scale, shakes up, as
Oxidative demage solution.
Sample introduction simultaneously records chromatogram.
Comparative example 3-7
Destructive testing
Tested by drotaverine hydrochloride parenteral solution quality standard YBH17602006,
Chromatographic condition:
Chromatographic column:Octadecylsilane chemically bonded silica is filler;
Mobile phase:Phosphate buffer (takes diammonium hydrogen phosphate 13.2g, the 200mL that adds water makes dissolving, the phosphoric acid for plus 85%
7.6mL, is diluted with water to 1000mL, regulation ± the 0.05)-acetonitrile-methanols of pH to 3.3 (800: 400: 800);
Solvent:0.1mol/LHCl solution-methyl alcohols-acetonitrile (8: 1: 1);Flow velocity:1.0mL/min;Wavelength:244nm;Column temperature:
40℃;Sample size:20μL;
It is prepared by need testing solution:
Comparative example 3, solution before destruction:Take drotaverine hydrochloride parenteral solution 1mL (being approximately equivalent to drotaverine hydrochloride 20mg)
It is placed in 25mL volumetric flasks, solubilizer is diluted to scale, shakes up, as does not destroy solution;
Comparative example 4, high temperature solution:Take drotaverine hydrochloride parenteral solution 1mL and (be approximately equivalent to drotaverine hydrochloride
20mg) it is placed in 25mL volumetric flasks, 100 DEG C of heating 8h are cooled to room temperature, and solvent is diluted to scale, shakes up, used as high temperature
Solution.
Comparative example 5, illumination destruction solution:Take drotaverine hydrochloride parenteral solution 1mL and (be approximately equivalent to drotaverine hydrochloride
20mg), it is placed in 25mL volumetric flasks, illumination 15h under uviol lamp, solvent is diluted to scale, solution is destroyed as illumination.
Comparative example 6, alkali destruction solution:Drotaverine hydrochloride parenteral solution 1mL (equivalent to drotaverine hydrochloride about 20mg) is taken,
It is placed in 25mL volumetric flasks, plus 1mol/L NaOH 1mL, after 60 DEG C of destruction 1.5h, plus 1mol/L hydrochloric acid 1mL is neutralized, solvent
Scale is diluted to, is shaken up, solution is destroyed as alkali.
Comparative example 7, Oxidative demage solution:Take drotaverine hydrochloride parenteral solution 1mL and (be approximately equivalent to drotaverine hydrochloride
20mg), it is placed in 25mL volumetric flasks, the hydrogen peroxide 2mL for plus 30%, 60 DEG C of destruction 8h, solvent is diluted to scale, shakes up, as
Oxidative demage solution.
Conclusion:
Comparative example 3-7 results are shown in Fig. 6 A, 7A, 8A, 9A, shown in 10A:Under each degradation condition, except known impurities Harverine
Outside alkali and Drotaverine ketone, other degradation impurities before main peak appearance time (RT=6.1), and in retention time about 3~5
There is overlap between minute, separating degree is poor, influence testing result.
Embodiment 4-8 results are shown in Fig. 6 B, 7B, 8B, 9B, shown in 10B:(1) test sample can be learnt in various failure conditions
Under catabolite retention time be all higher than 3.0 minutes, each destruction catabolite can be separated very well with solvent peak and main peak, molten
Relevant substance-measuring is not disturbed in agent;Each impurity peaks separating degree is all higher than 3.0;
(2) drotaverine hydrochloride parenteral solution compares through destructive testing with not destroying, ethaquin:High temperature, alkali and
Changes of contents is larger under the conditions of Oxidative demage, and illumination destruction has no significant change;Drotaverine ketone:Alkali destruction changes of contents is bright
Aobvious, high temperature and illumination destruction changes of contents are larger, and Oxidative demage has no significant change;Unknown impuritie:Have in various degree
Degraded is produced, and illumination, oxidation are more obvious;
(3) in addition to high temperature solution, solution impurity number is than State Bureau standard before other destruction solution and destruction
(YBH17602006) method checks that impurity number is more, and Drotaverine ketone content, maximum single miscellaneous content and total impurities are above country
Office's standard inspection method result.
In sum, Related substances separation method of the present invention measures solution and destruction solution impurity number before destruction, bends him and ties up
Woods ketone content, other maximum single miscellaneous contents and total impurities are above State Bureau's standard (YBH17602006) inspection method result.
Therefore, the specificity and separation efficiency of Related substances separation method are better than existing standard inspection method after modification.
It is below drotaverine hydrochloride parenteral solution Related substances separation method validation of the present invention:
Embodiment 9
Test limit and quantitative limit
Take the lower drotaverine hydrochloride (concentration of specificity:4 μ g/mL), ethaquin (concentration:1.6 μ g/mL), bend he
Dimension woods ketone (concentration:4 μ g/mL) single positioning solution, survey its quantitative limit (S/N >=10), test limit (S/N >=3) with dilution method,
The results are shown in Table 4
The test limit of table 4 and quantitative limit
Conclusion:Under this chromatographic condition, the quantitative limit and test limit of drotaverine hydrochloride, ethaquin and Drotaverine ketone
Meet and receive limit.
Embodiment 10
Standard curve and the range of linearity
Precision weighs drotaverine hydrochloride, each 10mg of Drotaverine ketone standard items, is respectively placed in 100mL volumetric flasks, plus
The dissolving solvent 2 of solvent 1 is diluted to scale, shakes up, used as drotaverine hydrochloride, Drotaverine ketone storing solution;Precision weighs second
Base papaverine standard items 20mg, puts in 50mL volumetric flasks, and the dissolving solvent 2 of solubilizer 1 is diluted to scale, shakes up, and precision is measured
Above-mentioned solution 5mL is put in 50mL volumetric flasks, and solubilizer 2 is diluted to scale, shakes up, used as ethaquin storing solution.Precision amount
Take appropriate hydrochloric acid Drotaverine, ethaquin, Drotaverine ketone storing solution, solubilizer 2 is made hydrochloric in every 1mL bend his and tie up
The μ g of woods 0.16,1.0,2.0,4.0,5.0,6.0;The μ g of ethaquin 0.048,0.8,1.2,1.6,2.0,2.4;Drotaverine ketone
0.32nd, 6 parts of solution of 1.0,2.0,4.0,5.0,6.0 μ g.Precision measures each 20 μ L of above-mentioned solution and is injected separately into high-efficient liquid phase color
Spectrometer, records chromatogram, determines peak area, with peak area A as ordinate, concentration C make linear regression for abscissa.The results are shown in Table
5,
The HPLC of the drotaverine hydrochloride of table 5 and known impurities is linear
Title | Linear equation | Coefficient correlation | Range of linearity μ g/mL |
Drotaverine hydrochloride | A=29.120C+0.5168 | R2=0.9993 | 0.16~6.0 |
Ethaquin | A=107.38C+0.8246 | R2=0.9999 | 0.048~2.4 |
Drotaverine ketone | A=23.756C+0.0453 | R2=0.9996 | 0.32~6.0 |
Conclusion:Result shows that drotaverine hydrochloride is in 0.16~6.0 μ g/mL, ethaquin in 0.048~2.4 μ g/
In the range of 0.32~6.0 μ g/mL, peak area is in good linear relation with concentration is determined for mL, Drotaverine ketone.
Embodiment 11
Need testing solution stability test
Drotaverine hydrochloride parenteral solution is taken according to Related substances separation method, need testing solution is prepared, respectively at 0,2,4,6,
8th, 10,12h sample introductions, investigate ethaquin, Drotaverine ketone peak area, other maximum single miscellaneous and total impurities changes.Knot
Fruit is shown in Table 6,
The need testing solution stability test result of table 6
Conclusion:In 12h, Harverine alkali content RSD is 0.89%, and Drotaverine ketone content RSD is 5.43%, and other are most
Big single miscellaneous content RSD is 1.78%, and total miscellaneous content RSD is 2.51%.Need testing solution is can be seen that from above determination data to exist
Each impurity is miscellaneous without significant change with total in 12h, has good stability.
Embodiment 12
Replica test
Drotaverine hydrochloride parenteral solution is taken, according to Related substances separation method, 6 parts of need testing solutions of parallel preparation, every part each
Determine 1 time, calculate each impurity content.The results are shown in Table 7,
The replica test result of table 7
Conclusion:6 parts of need testing solution measurement results meet the requirements, and repeatability is good.
Embodiment 13
Accuracy test
Drotaverine hydrochloride parenteral solution 1mL being taken respectively, being put in 25mL volumetric flasks, totally 9 parts, every 3 parts is one group, accurate respectively
Add ethaquin, Drotaverine each 0.5mL of ketone impurity storing solution (limit 50%), 1.0mL (limit 100%), 1.5mL
(limit 150%), solubilizer 2 is diluted to scale, as basic, normal, high three groups of concentration need testing solutions, determines in accordance with the law, calculates back
Yield and RSD.8 and table 9 are the results are shown in Table,
The ethaquin accuracy test result of table 8
The Drotaverine ketone accuracy test result of table 9
Embodiment 14
Serviceability test
It is main from mobile phase difference phosphoric acid concentration, difference pH, chromatographic column different in flow rate and different etc. about material durability
Several aspect checkings.The results are shown in Table 10,
The serviceability test result of table 10
Serviceability test conditions correlation collection of illustrative plates is shown in Figure 11-14,
Conclusion:To sum up serviceability test result shows that this method chromatographic condition parameter has to drotaverine hydrochloride parenteral solution
Material impurities separation is closed to be had not significant impact with inspection.
Embodiment 15
Related substances separation
Each three batches of the change forward and backward sample of sterilization process is taken respectively and original grinds product, according to national standard and the inventive method
Related substances separation is carried out, and carries out comparative study, the impurity change of sample, Xin Laofang before and after comprehensive assessment change sterilization process
The detection performance of method.The results are shown in Table 11,
The sterilization process of table 11 before changing after drotaverine hydrochloride parenteral solution and original grind the relevant material impurities of product and compare
Conclusion:
1st, sterilization process before changing after each three batches of samples and original grind the relevant material contrast of product:
(1) there is 1 impurity not occur in original grinds product in the drotaverine hydrochloride parenteral solution after sterilization process change, contain
Amount is 0.02% or so;Original has 3 impurity not occur in sample is made by oneself in grinding product;
(2) dopant species and impurity number grind product less than original in the drotaverine hydrochloride parenteral solution after sterilization process change
Product, self-control sample and original are ground containing ethaquin and Drotaverine ketone in product, ethaquin and are bent in self-control sample
Ta Weilin ketone content is not higher than original and grinds product, and other maximum single miscellaneous contents and total impurities are not higher than original and grind in self-control sample
Product, identical unknown impuritie is respectively less than original and grinds product.Other maximum simple substance are respectively less than 0.1%.Self-control quality is not less than original and grinds
Product.
2nd, three batches of samples and three batches of sample contrasts before changing after sterilization process change, dopant species are consistent with number, second
, without significant change, other maximum single miscellaneous and total impurities are without significant change for base papaverine and Drotaverine ketone content.
The inventive method and the contrast of State Bureau's standard (YBH17602006) method are as shown in table 12 below:
The inventive method of table 12 and State Bureau's Comparison of standards result
Using bulk drug drotaverine hydrochloride of the invention about material HPLC analytical method, gradient washes
It is de-, the impurity of drotaverine hydrochloride parenteral solution is fully disclosed, improve the security of product, methodological science, reliability, operation letter
Just, it is controllable, it is suitable to practical application and popularization.
Finally it should be noted that:Various embodiments above is merely illustrative of the technical solution of the present invention, rather than its limitations;To the greatest extent
Pipe has been described in detail with reference to foregoing embodiments to the present invention, it will be understood by those within the art that:Its according to
The technical scheme described in foregoing embodiments can so be modified, or which part or all technical characteristic are entered
Row equivalent;And these modifications or replacement, the essence of appropriate technical solution is departed from various embodiments of the present invention technology
The scope of scheme.
Claims (9)
1. about the method for material in a kind of use high effective liquid chromatography for measuring drotaverine hydrochloride parenteral solution, it is characterised in that
The method comprises the following steps:
(1) test sample solution is prepared:
Take drotaverine hydrochloride parenteral solution solvent and be configured to test sample solution;
(2) reference substance solution is prepared:
Take drotaverine hydrochloride, ethaquin and Drotaverine ketone solvent and be configured to reference substance solution;
(3) compounding system applicability solution:
Take drotaverine hydrochloride, ethaquin and Drotaverine ketone solvent and be configured to system suitability solution;
(4) system suitability experiment is carried out;
(5) detection sensitivity experiment is carried out;
The detection sensitivity of high performance liquid chromatograph is adjusted with reference substance solution, makes the peak height of principal component chromatographic peak be full scale
10-25%;
(6) it is measured according to following high-efficient liquid phase chromatogram condition:
Mobile phase:It is mobile phase C with methyl alcohol with acetonitrile as Mobile phase B using phosphate buffer as mobile phase A;The phosphoric acid
Salt buffer is adjusted to pH=3.3 ± 0.05 for 0.1% phosphate aqueous solution triethylamine;
UV-detector:Detection wavelength is 200-400nm;
Chromatographic column:With octadecylsilane chemically bonded silica as filler;
Flow velocity:0.5-2.0mL/min;
Column temperature:20-60℃;
(7) by external standard method, the content about material is calculated.
2. method according to claim 1, it is characterised in that the Detection wavelength of described UV-detector is 200-
300nm, more preferably 244nm.
3. method according to claim 1, it is characterised in that the flow velocity is 1.0mL/min;;The column temperature is 30-50
DEG C, more preferably 40 DEG C.
4. method according to claim 1, it is characterised in that the phosphate buffer is used by 0.1% phosphate aqueous solution
Triethylamine regulation is made behind pH3.3 ± 0.05.
5. method according to claim 1, it is characterised in that the preparation of the test sample solution specifically includes preparation and contains
The solution of drotaverine hydrochloride 0.8mg/mL, the solvent of the solution is the mixed solvent that mobile phase A, methyl alcohol and acetonitrile are formed,
The mixed solvent is by methyl alcohol and acetonitrile by volume 2:1 mixed mixed liquor again with mobile phase A by volume 1:9 mix
Close.
6. method according to claim 1, it is characterised in that the preparation of the reference substance solution specifically includes preparation saliferous
The solution of sour Drotaverine, ethaquin and Drotaverine ketone, the concentration of drotaverine hydrochloride is 4.0 μ g/ in the solution
mL;The concentration of ethaquin is 1.6 μ g/mL;The concentration of Drotaverine ketone is 4.0 μ g/mL;By drotaverine hydrochloride, ethyl
Papaverine and Drotaverine ketone are first 2 with methyl alcohol and acetonitrile volume ratio:1 mixed liquor dissolving, is subsequently adding mobile phase A, methyl alcohol
The mixed solvent formed with acetonitrile, the mixed solvent is by methyl alcohol and acetonitrile by volume 2:1 mixed mixed liquor again with
Mobile phase A by volume 1:9 mixing.
7. method according to claim 1, it is characterised in that the preparation of the system suitability solution specifically includes preparation
The solution of hydrochloric Drotaverine, ethaquin and Drotaverine ketone, the concentration of drotaverine hydrochloride is in the solution
0.8mg/mL;The concentration of ethaquin is 1.6 μ g/mL;The concentration of Drotaverine ketone is 4.0 μ g/mL;Hydrochloric acid is bent into he to tie up
Woods, ethaquin and Drotaverine ketone are first 2 with methyl alcohol and acetonitrile volume ratio:1 mixed liquor dissolving, is subsequently adding mobile phase
The mixed solvent that A, methyl alcohol and acetonitrile are formed, the mixed solvent is by methyl alcohol and acetonitrile by volume 2:1 mixed mixing
Liquid again with mobile phase A by volume 1:9 mixing.
8. method according to claim 1, it is characterised in that the system suitability refers to that to take system suitability molten
The μ L of liquid 20 inject liquid chromatograph, and drotaverine hydrochloride is more than 3.0, is separated between each impurity peaks with the separating degree of ethaquin
Degree is met the requirements, and theoretical cam curve is calculated by drotaverine hydrochloride, is not less than 3000.
9. method according to claim 1, it is characterised in that gradient is carried out with mobile phase A, Mobile phase B and mobile phase C and is washed
It is de-;Described gradient is:
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201611221591.0A CN106706789B (en) | 2016-12-26 | 2016-12-26 | With the method in relation to substance in high effective liquid chromatography for measuring drotaverine hydrochloride injection |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201611221591.0A CN106706789B (en) | 2016-12-26 | 2016-12-26 | With the method in relation to substance in high effective liquid chromatography for measuring drotaverine hydrochloride injection |
Publications (2)
Publication Number | Publication Date |
---|---|
CN106706789A true CN106706789A (en) | 2017-05-24 |
CN106706789B CN106706789B (en) | 2019-02-01 |
Family
ID=58902765
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201611221591.0A Active CN106706789B (en) | 2016-12-26 | 2016-12-26 | With the method in relation to substance in high effective liquid chromatography for measuring drotaverine hydrochloride injection |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN106706789B (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108195962A (en) * | 2017-12-27 | 2018-06-22 | 江苏联环药业股份有限公司 | A kind of inspection separation method of RMI 9918 in relation to substance |
CN111796043A (en) * | 2020-08-15 | 2020-10-20 | 山东北大高科华泰制药有限公司 | Papaverine hydrochloride powder injection for injection and quality detection method thereof |
CN114113375A (en) * | 2021-11-10 | 2022-03-01 | 湖北大学 | Method for detecting content of drotaverine hydrochloride raw material medicine by HPLC |
CN115166104A (en) * | 2022-09-08 | 2022-10-11 | 康瑞鑫(天津)药物研究院有限公司 | Method for separating pitavastatin calcium starting material and impurities thereof and application |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SU789713A1 (en) * | 1978-07-12 | 1980-12-23 | Читинский Медицинский Институт | Method of quantitative determination of drotaverin hydrochloride |
RU2012129609A (en) * | 2012-07-12 | 2014-01-20 | Государственное бюджетное образовательное учреждение высшего профессионального образования Иркутский государственный медицинский университет Министерства здравоохранения и социального развития Российской Федерации | METHOD FOR DETERMINING DROTAVERIN |
CN103664781A (en) * | 2013-12-13 | 2014-03-26 | 浙江普洛康裕制药有限公司 | Drotaverine hydrochloride crystal form I and crystal form II and preparation method |
-
2016
- 2016-12-26 CN CN201611221591.0A patent/CN106706789B/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SU789713A1 (en) * | 1978-07-12 | 1980-12-23 | Читинский Медицинский Институт | Method of quantitative determination of drotaverin hydrochloride |
RU2012129609A (en) * | 2012-07-12 | 2014-01-20 | Государственное бюджетное образовательное учреждение высшего профессионального образования Иркутский государственный медицинский университет Министерства здравоохранения и социального развития Российской Федерации | METHOD FOR DETERMINING DROTAVERIN |
CN103664781A (en) * | 2013-12-13 | 2014-03-26 | 浙江普洛康裕制药有限公司 | Drotaverine hydrochloride crystal form I and crystal form II and preparation method |
Non-Patent Citations (3)
Title |
---|
JYOTESH R JAIN 等: "RP-HPLC method for simultaneous estimation of Drotaverine hydrochloride and Aceclofenac in their combined tablet dosage form", 《DER PHARMA CHEMICA》 * |
M.S.CHARDE 等: "DEVELOPMENT AND VALIDATION OF RP-HPLC METHOD FOR SIMULTANEOUS ESTIMATION OF DROTAVERINE HCL AND NIMESULIDE FROM TABLET DOSAGE FORM", 《INTERNATIONAL JOURNAL OF PHARMACEUTICAL CHEMISTRY》 * |
黄坤 等: "屈他维林有关物质的合成", 《中国医药工业杂志》 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108195962A (en) * | 2017-12-27 | 2018-06-22 | 江苏联环药业股份有限公司 | A kind of inspection separation method of RMI 9918 in relation to substance |
CN108195962B (en) * | 2017-12-27 | 2020-08-11 | 江苏联环药业股份有限公司 | Method for detecting and separating related substances of terfenadine |
CN111796043A (en) * | 2020-08-15 | 2020-10-20 | 山东北大高科华泰制药有限公司 | Papaverine hydrochloride powder injection for injection and quality detection method thereof |
CN111796043B (en) * | 2020-08-15 | 2022-02-22 | 山东北大高科华泰制药有限公司 | Papaverine hydrochloride powder injection for injection and quality detection method thereof |
CN114113375A (en) * | 2021-11-10 | 2022-03-01 | 湖北大学 | Method for detecting content of drotaverine hydrochloride raw material medicine by HPLC |
CN115166104A (en) * | 2022-09-08 | 2022-10-11 | 康瑞鑫(天津)药物研究院有限公司 | Method for separating pitavastatin calcium starting material and impurities thereof and application |
Also Published As
Publication number | Publication date |
---|---|
CN106706789B (en) | 2019-02-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN106706789B (en) | With the method in relation to substance in high effective liquid chromatography for measuring drotaverine hydrochloride injection | |
CN103344733B (en) | High performance liquid chromatographic separation detection method for bortezomib enantiomers | |
CN105092741B (en) | A kind of method that high performance liquid chromatography detects the caprolactam of 3 amino 2 | |
CN102072942A (en) | Analysis method for measuring pyrroloquinoline quinine content through ion pair chromatography | |
CN103076409B (en) | Analysis and detection method for oxiracetam and impurities thereof | |
CN104122363A (en) | Measuring method of mecobalamin tablet related substance | |
CN108663448A (en) | Detection method in relation to substance in a kind of Amino Acid Compound Injection | |
CN110398555A (en) | A kind of detection method of the capecitabine in relation to substance | |
CN107991415B (en) | Method for simultaneously separating and measuring pyroglutamic acid and methionine sulfoxide impurities in compound amino acid injection 18AA by liquid chromatography | |
CN106053625A (en) | Method utilizing HPLC to measure higenamine hydrochloride related substances | |
CN105301157A (en) | Quality control method of related substances of methanesulfonic acid kukoamine B | |
CN108614052A (en) | The method for detecting gelsemine in biological sample, koumine and hexa-gelsemicine simultaneously based on two-dimensional liquid chromatography | |
CN105004803B (en) | The liquid-phase chromatography method of multiple impurity in a kind of separation determination tolvaptan | |
CN106525994A (en) | Method for determination of related substances of paracetamol and tramadol hydrochloride capsules | |
CN108931586A (en) | A kind of compound codeine phosphate oral administration solution measuring method | |
CN106338564B (en) | A method of for detecting enantiomter in vildagliptin intermediate | |
CN110441424A (en) | Method in relation to substance in a kind of liquid chromatography analysis measurement pyrazinamide | |
CN109521117A (en) | A kind of detection method of the ibuprofen injection in relation to substance | |
CN1790013B (en) | Method for simultaneous determination of protocatechuic acid content and 5-hydroxymethyl furfural content in pulse-activating injection | |
CN109580834A (en) | Detection method in relation to substance in a kind of pharmaceutical preparation containing C14H25N4NaO11P2 | |
CN102636582B (en) | Method for determining content of diminazene and antipyrine in diminazene particle | |
CN115356420A (en) | Pudilan anti-inflammatory tablet quality evaluation method based on one-test-multiple evaluation | |
CN106950314A (en) | A kind of method for detecting allyl bromide, bromoallylene content in rocuronium or its parenteral solution | |
CN108872406A (en) | HPLC analyzing detecting method in relation to substance in a kind of L-aminobutanedioic acid bulk pharmaceutical chemicals | |
CN103149314A (en) | Method for identification and content determination of 1, 2-propanediol in isosorbide mononitrate injection |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CP02 | Change in the address of a patent holder |
Address after: 225000 No.9, Jiankang 1st Road, biological health industrial park, Hanjiang District, Yangzhou City, Jiangsu Province Patentee after: JIANGSU LIANHUAN PHARMACEUTICAL Co.,Ltd. Address before: 225000 No.21 Wenfeng Road, Guangling District, Yangzhou City, Jiangsu Province Patentee before: JIANGSU LIANHUAN PHARMACEUTICAL Co.,Ltd. |
|
CP02 | Change in the address of a patent holder |