CN108872405A - A kind of HPLC analyzing detecting method of the lodoxamide tromethamine in relation to substance - Google Patents
A kind of HPLC analyzing detecting method of the lodoxamide tromethamine in relation to substance Download PDFInfo
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- CN108872405A CN108872405A CN201710331008.XA CN201710331008A CN108872405A CN 108872405 A CN108872405 A CN 108872405A CN 201710331008 A CN201710331008 A CN 201710331008A CN 108872405 A CN108872405 A CN 108872405A
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- 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
Abstract
The invention belongs to analysis method technical field, a kind of high efficiency liquid phase chromatographic analysis method of the related substance detection of lodoxamide tromethamine is specifically disclosed, separates and detects 6 impurity in lodoxamide tromethamine bulk pharmaceutical chemicals or preparation.Amine substance is creatively added in the method for the present invention in mobile phase for the first time, thoroughly solves the separation problem between main peak and impurity peaks, impurity peaks and auxiliary material peak, easy to operate, high sensitivity.The specificity of existing method is substantially increased, the research for the safety of the preparation containing lodoxamide tromethamine provides more efficiently foundation.
Description
Technical field
The present invention relates to analysis method technical fields, and in particular to a kind of related substance detection of lodoxamide tromethamine
High efficiency liquid phase chromatographic analysis method separates and detects 6 impurity in lodoxamide tromethamine bulk pharmaceutical chemicals or preparation.
Background technique
Lodoxamide tromethamine, chemical structural formula are：
It is mainly used for ophthalmology disease local treatment, such as spring catarrb keratitis, pinkeye.By Lodoxamide
Eye drops made from tromethamine is in China's approval listing, trade name
Present inventor has found that there are 6 during studying lodoxamide tromethamine bulk pharmaceutical chemicals
The impurity that may be introduced by technical process, starting material or degradation reaction, shown in the following Table A of impurity information.
Table A lodoxamide tromethamine impurity information table
However, being rarely reported about the related object Quality Research of lodoxamide tromethamine.United States Pharmacopeia, Britain's medicine at present
The quality standard of uncharged lodoxamide tromethamine raw material and preparation in allusion quotation, Pharmacopeia of Japan and Chinese Pharmacopoeia in 2015.
Also related substance is not studied in the import registered standard JX19980121 of Lodoxamide eye drops original triturate producer.
Through investigating, only lodoxamide tromethamine bulk pharmaceutical chemicals standard YBH20722004 and Lodoxamide eye drops import registered standard
YBH19932004 studies the related substance in Lodoxamide eye drops, and the method that the two uses is identical.
Present inventor studies discovery using the method in lodoxamide tromethamine bulk pharmaceutical chemicals standard YBH20722004
Baseline separation can not be realized to above-mentioned 6 kinds of known impurities, after being adjusted on the basis of this method to chromatographic parameter, 6 kinds
Know that impurity still can not achieve baseline separation.Simultaneously under the conditions of this method, impurity A appearance is very fast, and auxiliary in Lodoxamide eye drops
Expect natrium adetate, sodium citrate, citric acid (It includes natrium adetate, benzene bundle chlorine that the original of announcement, which grinds auxiliary material in prescription,
Ammonium, mannitol, citric acid, sodium citrate, hydroxypropyl methylcellulose, alevaire) it overlaps, interfere the measurement of impurity A.
Summary of the invention
To solve the above problems, being detected in lodoxamide tromethamine bulk pharmaceutical chemicals or preparation simultaneously the present invention provides a kind of
The high-efficiency liquid chromatography method for detecting of 6 kinds of known impurities.
The method includes：
The filler of reverse-phase chromatographic column is alkyl linked silica gel；Using aqueous solution-organic solvent of amine substance as mobile phase,
The organic solvent is methanol and/or acetonitrile；Using gradient elution, flow velocity is 0.8ml/min~1.2ml/min；Column temperature is 25
~45 DEG C；Detection wavelength is 240~250nm；
The filler of the reverse-phase chromatographic column be octadecylsilane chemically bonded silica or octyl silane group silica gel, it is excellent
It is selected as octadecylsilane chemically bonded silica.
The specification of the reverse-phase chromatographic column be 250 × 4.6mm, 5 μm.
The amine substance is diethylamine and/or triethylamine, preferably triethylamine.
The aqueous solution pH of the triethylamine is 5.0~8.0, preferably 6.0~7.0, and more excellent is 6.8.
The pH adjusting agent is phosphoric acid, acetic acid and formic acid, preferably phosphoric acid.
The concentration of triethylamine is 0.05v/v%-0.2v/v%, preferably 0.1v/v% in the aqueous solution of the triethylamine.
The organic solvent is preferably methanol.
The gradient elution program is：
Compared with prior art, the advantages of the present invention are as follows：
The related substance detecting method of lodoxamide tromethamine bulk pharmaceutical chemicals and preparation of the invention, is retrieved, for for the first time
Amine substance substance is creatively added in mobile phase, thoroughly solves between main peak and impurity peaks, impurity peaks and auxiliary material peak
Separation problem, easy to operate, high sensitivity.
Detailed description of the invention
Fig. 1 is that reference substance chromatogram is mixed in embodiment 1；
Fig. 2 is that reference substance chromatogram is mixed in embodiment 2；
Fig. 3 is natrium adetate chromatogram in embodiment 2；
Fig. 4 is that reference substance chromatogram is mixed in embodiment 3；
Fig. 5 is that reference substance chromatogram is mixed in embodiment 4.
Specific embodiment
In order to make those skilled in the art more fully understand technical solution of the present invention, disclose further below some non-
The present invention is described in further detail for restricted embodiment.
In embodiment impurity A~E impurity reference substance and lodoxamide tromethamine reference substance used by applicant according to
Prior art self-control, impurity F are provided by Wuhan kino Pharmaceutical Technology Co., Ltd, and impurity F can be obtained by commercialization approach
, other are conventional reagent.
The preparation process flow of lodoxamide tromethamine is as follows, and present inventor is prepared for three batches of Lodoxamides
Tromethamine bulk pharmaceutical chemicals, lot number are respectively 20160501,20160502,20160503.
In above-mentioned synthesis process, impurity A, B, C, D, E are generated in first step reaction, and impurity F is starting material.
Impurity A~E preparation process is as follows：20g lodoxamide tromethamine bulk pharmaceutical chemicals and 200ml purified water are taken to put into
In 500ml there-necked flask, dissolution is stirred at room temperature, tromethamine is added after solid dissolution and adjusts pH to 12~13, adjusting finishes, and rises
Temperature is concentrated to dryness, solid is beaten 30min with 20ml 95wt% ethyl alcohol, filters, and dries after completion of the reaction to 50 DEG C of reaction 3h
It is dry, impurity A, impurity B, impurity C, impurity D, impurity E reference substance are obtained using preparation chromatographic isolation.
The structural identification information of impurity A~F and lodoxamide tromethamine is as shown in following table B-C.
Table B lodoxamide tromethamine STRUCTURE DECOMPOSITION schematic table
Table C impurity A~F and lodoxamide tromethamine structural identification information
1 method 1 of embodiment
This method is to have adjusted mobile phase ratio on the basis of lodoxamide tromethamine bulk pharmaceutical chemicals standard YBH20722004
Example chromatographic condition：Waters e2695 high performance liquid chromatograph, chromatographic column be Kromasil 100-5 C18 chromatographic column (250 ×
4.6mm, 5 μm), mobile phase is 0.025mol/l potassium dihydrogen phosphate (ammonium hydroxide tune pH to 6.8)-methanol, flow velocity 1.0ml/
Min, Detection wavelength 244nm, 20 μ l of sample volume, gradient elution are as shown in table 1 below：
Table 1
Sample preparation：Take impurity A~F, lodoxamide tromethamine reference substance each appropriate, respectively plus 20% (v/v) methanol
It is configured to the single solution of each reference substance concentration about 0.5mg/ml, sample introduction is analyzed under the present embodiment chromatographic condition, records chromatography
Figure, the chromatographic peak for subsequent poly-doped impurity reference substance position.Separately take impurity A~F, lodoxamide tromethamine reference substance suitable
Amount mixing, adds 20% (v/v) methanol to dissolve, is configured to every 1ml about 20 μ g containing each impurity, about containing lodoxamide tromethamine
The solution of 0.5mg, as poly-doped impurity solution, sample introduction is analyzed under the present embodiment chromatographic condition, records chromatogram, as a result sees
The following table 2 and attached drawing 1.
2 impurity location information table of table
Test result shows that impurity C and impurity D are not able to achieve baseline separation.
2 method 2 of embodiment
Chromatographic condition：Waters e2695 high performance liquid chromatograph, chromatographic column are Kromasil 100-5 C18 chromatographic column
(250 × 4.6mm, 5 μm), mobile phase are that phosphate buffer [takes disodium hydrogen phosphate (Na2HPO4.12H2O) 5.7g and di(2-ethylhexyl)phosphate
Hydrogen sodium (NaHPO4.2H2O) 1.43g is dissolved in water into 2000ml, and the pH value of this solution is 7.0]-methanol (9:1), flow velocity
1.0ml/min, Detection wavelength 244nm, 20 μ l of sample volume.
Sample preparation：Take impurity A~F, lodoxamide tromethamine reference substance appropriate, respectively plus 20% (v/v) methanol is matched
The single reference substance solution of 0.5mg/ml is restricted, sample introduction is analyzed under the present embodiment chromatographic condition, records chromatogram.Take impurity A
~F, lodoxamide tromethamine reference substance mix in right amount, and 20% (v/v) methanol is added to dissolve, and are configured to every 1ml and contain each impurity about
The solution of 20 μ g, the about 0.5mg containing lodoxamide tromethamine, as poly-doped impurity solution, under the present embodiment chromatographic condition into
Sample analysis, records chromatogram, as a result see the table below 3 and attached drawing 2；It is clearly write exactly in Lodoxamide eye drops original triturate specification
Auxiliary material natrium adetate dosage is 0.01% (w/v, g/mL), is the specificity for further investigating method, takes edetic acid(EDTA) in experiment
Appropriate disodium adds the dissolution of 20% (v/v) methanol to be configured to the solution of every 1ml about 0.05mg containing natrium adetate, in the present embodiment
Sample introduction is analyzed under chromatographic condition, records chromatogram, as a result see the table below 3 and attached drawing 3.
3 impurity location information table of table
| Chromatographic peak | Retention time (min) | Separating degree |
| Natrium adetate | 2.633 | / |
| Impurity A | 2.579 | / |
| Impurity B | 33.488 | 16.44 |
| Impurity C | 5.633 | 3.18 |
| Impurity D | 4.912 | 9.43 |
| Impurity E | 11.583 | 6.70 |
| Impurity F | 43.561 | 7.86 |
| Lodoxamide tromethamine | 17.989 | 11.02 |
Test result shows impurity A~F and lodoxamide tromethamine is able to achieve baseline separation, but Lodoxamide eye drip
Auxiliary material natrium adetate and impurity A appearance near the dead time in liquid, natrium adetate interfere the measurement of impurity A.
3 method 3 of embodiment
Chromatographic condition：Waters e2695 high performance liquid chromatograph, chromatographic column are Kromasil 100-5 C18 chromatographic column
(250 × 4.6mm, 5 μm), mobile phase are 20mmol/l ammonium acetate solution (adding phosphoric acid tune pH to 6.8)-methanol, flow velocity 1.0ml/
Min, Detection wavelength 244nm, 20 μ l of sample volume, gradient elution：
Sample preparation：With embodiment 1, it as a result see the table below 4 and attached drawing 4.
4 impurity location information table of table
Test result shows that impurity C and impurity D are not able to achieve baseline separation.
4 method 4 of embodiment
Chromatographic condition：Waters e2695 high performance liquid chromatograph, chromatographic column are Kromasil 100-5 C18 chromatographic column
(250 × 4.6mm, 5 μm), mobile phase are 0.1v/v% triethylamine solution (adding phosphoric acid tune pH to 6.8)-methanol, flow velocity 1.0ml/
Min, Detection wavelength 244nm, 20 μ l of sample volume, gradient elution：
Sample preparation：Take impurity A~F, lodoxamide tromethamine reference substance appropriate, respectively plus 20% (v/v) methanol is matched
The single solution containing 0.5mg/ml is restricted, sample introduction is analyzed under the present embodiment chromatographic condition, records chromatogram.Take impurity A~F,
Lodoxamide tromethamine mixes in right amount, adds 20% (v/v) methanol to dissolve, is configured to every 1ml about 20 μ g containing each impurity, contains Lip river
The solution of husky amine tromethamine about 0.5mg is spent, as poly-doped impurity solution, sample introduction is analyzed under the present embodiment chromatographic condition, note
Chromatogram is recorded, as a result see the table below 5 and attached drawing 5；Auxiliary material edetic acid(EDTA) is clearly write exactly in Lodoxamide eye drops original triturate specification
Disodium dosage is 0.01% (w/v, g/mL), and Citric Acid Dosage is 0.0175% (w/v, g/mL), and sodium citrate dosage is
0.0415% (w/v, g/mL) is the specificity for further investigating method, takes natrium adetate appropriate in experiment, add 20% (v/
V) methanol dissolution is configured to the solution of every 1ml about 0.05mg containing natrium adetate；It takes citric acid appropriate, adds 20% (v/v) methanol
Dissolution is configured to the solution of every 1ml about 0.10mg containing citric acid；It takes sodium citrate appropriate, the dissolution of 20% (v/v) methanol is added to prepare
At the solution of every 1ml about 0.5mg containing sodium citrate.Sample introduction is analyzed under the present embodiment chromatographic condition, records these three solution
As a result chromatogram see the table below 5.
5 impurity location information table of table
| Chromatographic peak | Retention time (min) | Separating degree |
| Natrium adetate | 3.268 | / |
| Citric acid | 3.522 | / |
| Sodium citrate | 3.527 | / |
| Impurity A | 5.762 | / |
| Impurity B | 18.330 | 7.62 |
| Impurity C | 9.295 | 12.99 |
| Impurity D | 6.999 | 5.36 |
| Impurity E | 10.130 | 4.48 |
| Impurity F | 20.453 | 6.25 |
| Lodoxamide tromethamine | 14.994 | 4.72 |
Test result shows that under this liquid phase chromatogram condition, each impurity can be kept completely separate with main peak, and between each impurity
Separating degree is good, and natrium adetate, sodium citrate, citric acid do not interfere the measurement of principal component and each impurity.
5 methodology validation of embodiment
Chromatographic condition is the same as embodiment 4.
The preparation of sample solution：
(1) preparation of Lodoxamide eye drops is made by oneself：Referring to Lodoxamide eye drops original triturate composition and ratio：
Lodoxamide 0.1% (w/v) (lot number 20160501), benzalkonium chloride 0.007% (w/v), mannitol 4.7% (w/v), hydroxypropyl
Methylcellulose 0.38% (w/v), sodium citrate 0.0415% (w/v), citric acid 0.0175% (w/v), natrium adetate
0.01% (w/v), alevaire 0.025% (w/v) are prepared according to eye drops common process.
(2) preparation of linear solvent：It takes impurity A~F, lodoxamide tromethamine reference substance appropriate respectively, adds 20% (v/
V) methanol prepares the serial mixed standard solution of impure A~F, lodoxamide tromethamine, as a result as shown in the table, with peak
Area is as ordinate Y, using concentration as abscissa X.
(3) precision solution is prepared：6 parts of lodoxamide tromethamine bulk pharmaceutical chemicals are taken, impurity A~F reference substance is separately added into,
Add 20% (v/v) methanol to dissolve and dilute and every 1ml 5 μ g, containing lodoxamide tromethamine 0.5mg each containing about impurity A~F is made
Solution, as test solution.It takes test solution appropriate, adds 20% (v/v) methanol dilution that every 1ml is made containing about Lip river degree
The solution of husky 5 μ g of amine tromethamine, as own control solution, as a result as shown in table 6 below.
It is appropriate to be derived from Lodoxamide eye drops processed, is separately added into impurity A~F reference substance, adds the dissolution of 20% (v/v) methanol simultaneously
The solution of every 1ml 5 μ g, containing lodoxamide tromethamine 0.5mg each containing about impurity A~F is made in dilution, as test solution.
It takes test solution appropriate, adds 20% (v/v) methanol dilution that solution of every 1ml containing about 5 μ g of lodoxamide tromethamine is made,
As own control solution, as a result as shown in table 6 below.
(4) preparation of rate of recovery solution：Lodoxamide tromethamine bulk pharmaceutical chemicals are taken, impurity A~F reference substance system is separately added into
At the solution containing about each 4 μ g/ml of impurity A~F, 5 μ g/ml, 6 μ g/ml, the 0.5mg/ml containing lodoxamide tromethamine, Mei Genong
Degree is parallel to prepare three parts, as a result as shown in table 6 below.
It is appropriate to be derived from Lodoxamide eye drops processed, be separately added into impurity A~F reference substance be made in right amount it is each containing about impurity A~F
The solution of 4 μ g/ml, 5 μ g/ml, 6 μ g/ml, the 0.5mg/ml containing lodoxamide tromethamine, each concentration prepare three parts in parallel.
(5) preparation of stability sample：Lodoxamide tromethamine bulk pharmaceutical chemicals are taken, impurity A~F reference substance system is separately added into
At the solution containing about impurity A~F each 5 μ g/ml, the 0.5mg/ml containing lodoxamide tromethamine, room temperature avoid light place, in difference
Time point investigates each impurity content situation of change.
It is derived from Lodoxamide eye drops processed, impurity A~F reference substance is separately added into and each 5 μ g/ml of impure A~F is made, about
The solution of the 0.5mg/ml containing lodoxamide tromethamine, room temperature avoid light place investigate each impurity content variation in different time points
Situation.Test result is as shown in table 6 below：
6 methodology validation test result of table
Upper table the result shows that, the linear relationship of this method is good, accurate, accurate.
6 pattern detection of embodiment
Chromatographic condition is the same as embodiment 5.
The preparation of sample solution：
Take 160501 batches, 160502 batches, 160503 batches of bulk pharmaceutical chemicals it is appropriate, respectively plus every 1ml is made in 20v/v% methanol dilution
It takes test solution appropriate as test solution containing about the solution of lodoxamide tromethamine 0.5mg, adds 20v/v% first
Solution of every 1ml containing about 5 μ g of lodoxamide tromethamine is made in alcohol dilution, as own control solution, experimental result such as following table
Shown in 7.
It is derived from Lodoxamide eye drops processed and former triturate A Lemai, takes respectively in right amount, 20v/v% methanol dilution is added to be made
Solution of every 1ml containing about lodoxamide tromethamine 0.5mg takes test solution appropriate, adds 20v/ as test solution
Solution of every 1ml containing about 5 μ g of lodoxamide tromethamine is made in v% methanol dilution, as own control solution, experimental result
As shown in table 8 below：
The related substance testing result of 7 three batches of bulk pharmaceutical chemicals of table
Table 8 makes Lodoxamide eye drops substance testing result related with former triturate by oneself
Test result shows accurately detect lodoxamide tromethamine raw material using analysis method of the invention
With the major impurity B in preparation, while impurity A and impurity C~F can be detected, substantially increase the specificity of existing method,
Research for the safety of the preparation containing lodoxamide tromethamine provides more efficiently foundation.
Claims (10)
1. the high-efficiency liquid chromatography method for detecting of impurity, feature exist in a kind of lodoxamide tromethamine bulk pharmaceutical chemicals or preparation
In chromatographic condition is：
Reverse-phase chromatographic column, filler are octadecylsilane chemically bonded silica or octyl silane group silica gel；
Using aqueous solution-organic solvent of amine substance as mobile phase, the organic solvent is methanol and/or acetonitrile；Using gradient
Elution, flow velocity are 0.8ml/min~1.2ml/min；Column temperature is 25~45 DEG C；Detection wavelength is 240~250nm；
The amine substance is diethylamine and/or triethylamine；
The aqueous solution pH of the amine substance is 6.0~7.0, and contained pH adjusting agent is phosphoric acid, vinegar in the aqueous solution of amine substance
Acid or formic acid；
The concentration of amine substance is 0.05v/v%-0.2v/v% in the aqueous solution of the amine substance.
2. high-efficiency liquid chromatography method for detecting according to claim 1, it is characterised in that：20 μ l of sample volume.
3. high-efficiency liquid chromatography method for detecting according to claim 1, it is characterised in that：The amine substance is three second
Amine.
4. high-efficiency liquid chromatography method for detecting according to claim 3, it is characterised in that：In the aqueous solution of the triethylamine
Triethylamine concentration is 0.1v/v%.
5. high-efficiency liquid chromatography method for detecting according to claim 4, it is characterised in that：The aqueous solution pH of the triethylamine
It is 6.8.
6. high-efficiency liquid chromatography method for detecting according to claim 5, it is characterised in that：The organic solvent is methanol.
7. high-efficiency liquid chromatography method for detecting according to claim 6, it is characterised in that：The gradient elution program is：
8. any high-efficiency liquid chromatography method for detecting in -7 according to claim 1, it is characterised in that：The impurity includes In
More than one.
9. high-efficiency liquid chromatography method for detecting according to claim 8, it is characterised in that：The impurity includes
10. high-efficiency liquid chromatography method for detecting according to claim 8, it is characterised in that：The impurity includes
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| CN114034782B (en) * | 2021-09-23 | 2024-01-30 | 安徽四环科宝制药有限公司 | Detection method of salbutamol sulfate related substances |
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