CN102721775A - High performance liquid chromatography method for separating proparacaine hydrochloride intermediate IV from other intermediates - Google Patents
High performance liquid chromatography method for separating proparacaine hydrochloride intermediate IV from other intermediates Download PDFInfo
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Abstract
The invention discloses a high performance liquid chromatography method for separating a proparacaine hydrochloride intermediate IV from other intermediates. The method comprises the following steps: step 1, acquiring a proparacaine hydrochloride sample, and dissolving the proparacaine hydrochloridesample sample with an organic solvent to prepare a sample solution which contains 0.5 to 1.0 mg of proparacaine hydrochloride per 1 ml; step 2, setting the mobile phase of a liquid chromatograph, with the flow velocity of the mobile phase being 0.6-1.2 mL/min and detection wavelength being 232 plus or minus 3 nm, and setting the column heater of the chromatographic column of the liquid chromatograph at a temperature of 20 DEG C to 40 DEG C; and step 3, acquiring 5-20 microliters of the sample solution of step 1 and injecting the sample solution to the liquid chromatograph set in step 2 to complete the separation of the proparacaine hydrochloridesample intermediate IV from other intermediates.
Description
Technical field
the invention provides a kind of method that proxymetacaine hydrochloride intermedium IV is separated with the high performance liquid chromatography of other intermedium.
Background technology
Advantages such as proxymetacaine hydrochloride is a kind of surface anaesthetic, is used for the surface anesthesia of various ophthalmologic operations and eye examination, compares with other anesthetic, has fast, efficient, and the corneal toxic and side effect is light.Proxymetacaine hydrochloride intermediate compound IV molecular formula: C
13H
17NO
5, chemistry 3-nitro by name-4-propoxy benzoic acid propyl ester, intermediate compound I, II, III, the IV structural formula is distinguished as follows:
Intermediate I
The intermedium II
The intermedium III
Intermediate compound IV
In order to control the quality of proxymetacaine hydrochloride intermedium exactly; Need proxymetacaine hydrochloride intermedium IV be separated with other intermedium effectively, but the high performance liquid chromatogram isocratic elution mode that adopts at present can't realize effectively separating of proxymetacaine hydrochloride intermedium IV and other intermedium.
Summary of the invention
The invention provides
a kind of method that proxymetacaine hydrochloride intermedium IV is separated with the high performance liquid chromatography of other intermedium, it can realize the accurate control of the disintegrate-quality of proxymetacaine hydrochloride intermedium IV and other intermedium.
The present invention has adopted following technical scheme:A kind of
The method that proxymetacaine hydrochloride intermedium IV is separated with the high performance liquid chromatography of other intermedium, may further comprise the steps: step 1, get the proxymetacaine hydrochloride sample, with organic solvent dissolution proxymetacaine hydrochloride sample, be mixed with the sample solution of the hydrochloric proparacaine 0.5～1.0mg of every 1ml; Step 2 is provided with the moving phase of liquid chromatograph, the flow velocity 0.6～1.2mL/min of moving phase, detects wavelength 232 ± 3nm, and 20 ℃～40 ℃ of the column ovens that the liquid chromatograph chromatographic column is set;
Step 3, the sample solution 5-20 μ l that gets in the step 1 injects the liquid chromatograph that is provided with through step 2, and completion proxymetacaine hydrochloride intermedium IV is separated with other intermedium.
The organic solvent of step 1 of the present invention is methyl alcohol or ethanol.
The moving phase of step 2 kind liquid chromatograph of the present invention is: the A pump is an organic modifiers, and the B pump is a buffer salt solution, and it is following that the gradient elution program of liquid chromatograph is set:
Time (min) A pump moving phase (%) B pump moving phase (%)
5-10 0-30 100-70
10-20 30-60 70-40
20-30 60 40
30-50 60-0 40-100
50-60 0 100，
The volume ratio of organic modifiers and buffer solution changes in time and changes, and 5 minutes to 10 minutes, the volume of mobile phase A pump changed to 30% from 0% gradually, and the volume of Mobile phase B pump changes to 70% from 100% gradually simultaneously,
A pump moving phase: B pump moving phase does0-30: 100-70; 10 minutes to 20 minutes, the volume of mobile phase A pump changed to 60% from 30% gradually, and the volume of Mobile phase B pump changes to 40% from 70% gradually simultaneously
, A pump moving phase: B pump moving phase does30-60: 70-40; 20 minutes to 30 minutes, it is 60% constant that the volume of mobile phase A pump keeps, and the volume of Mobile phase B pump keeps 40% constant simultaneously,
A pump moving phase: B pump moving phase does60: 40; 30 minutes to 50 minutes, the volume of mobile phase A pump changed to 0% from 60% gradually, and the volume of Mobile phase B pump changes to 100% from 40% gradually simultaneously,
A pump moving phase: B pump moving phase does60-0:40-100; 50 minutes to 60 minutes, it is 0% constant that the volume of mobile phase A pump keeps, and the volume of Mobile phase B pump keeps 100% constant simultaneously,
A pump moving phase: B pump moving phase does0:100.
It is the chromatographic column of filling agent that liquid chromatograph in the step 2 of the present invention adopts carbon octadecane silane key and silica gel, and the specification of chromatographic column is length 250mm, internal diameter 4.6mm, granularity 5 μ m.
Described organic modifiers is acetonitrile or methyl alcohol.Described buffer salt solution is 90% phosphate solution, and 90% phosphate solution is after 0.05M potassium dihydrogen phosphate and 0.02M sodium heptanesulfonate are dissolved in water, add triethylamine again and transfer PH to 5.2.
The present invention has following technique effect: it is the chromatographic column of filling agent that the present invention adopts carbon octadecane silane key and silica gel, can effectively separate proxymetacaine hydrochloride intermedium IV and other intermedium; Selection methyl alcohol is solvent, guarantees that sample can dissolve fully; Select sampling volume 10 μ L, column temperature is 25 ℃ of room temperatures, has improved the symmetry of chromatographic peak; Select flow velocity 1.0mL/min, can improve degree of separation; Selecting the A pump is organic modifiers; Organic modifiers is a methyl alcohol, and B pump buffer salt solution is 90% phosphate (0.05M potassium dihydrogen phosphate, 0.02M sodium heptanesulfonate; Triethylamine is transferred PH to 5.2); Adopt gradient elution to realize separating fully of proxymetacaine hydrochloride intermedium IV and other intermedium, realized the detection of proxymetacaine hydrochloride intermedium purity, aspect the quality control that realizes proxymetacaine hydrochloride intermedium and preparation production run synthetic, have realistic meaning at the proxymetacaine hydrochloride medicine.
Description of drawings
Fig. 1 is the high-efficient liquid phase chromatogram of embodiment one.
Fig. 2 is the high-efficient liquid phase chromatogram of embodiment two.
Fig. 3 is the high-efficient liquid phase chromatogram of embodiment three.
Embodiment
Further specify the present invention through following examples.
Embodiment one
Adopting Agilent LC-1200 model high performance liquid chromatograph, Apollo brand carbon 18 silane keys and silica gel is the chromatographic column of filling agent, and the specification of chromatographic column is length 250mm, internal diameter 4.6mm, granularity 5 μ m.
Step 1 is got the proxymetacaine hydrochloride sample respectively, intermedium IV in the sample and intermediate I, II, each 5mg of III; Place the 10mL volumetric flask, add dissolve with methanol and be diluted to scale, shake up; Be mixed with the sample solution of the hydrochloric proparacaine 0.5～1.0mg of every 1ml, as need testing solution;
Step 2 is provided with the moving phase of liquid chromatograph, and promptly the A pump is an organic modifiers, and the B pump is a buffer salt solution, and it is following that the gradient elution program of liquid chromatograph is set:
Gradient one: time (min) A pump moving phase (%) B pump moving phase (%)
5-10 10 90
10-20 40 60
20-40 60 40
40-60 70 30
60 10 90，
In the time of 5-10 minute,
A pump moving phase: B pump moving phase is 10:90, whenIn the time of 10-20 minute,
A pump moving phase: B pump moving phase is 40:60, in the time of 20-40 minute,
A pump moving phase: B pump moving phase is 60:40,In the time of 40-60 minute,
A pump moving phase: B pump moving phase does70: 30, in the time of 60 minutes,
A pump moving phase: B pump moving phase does10:90, be provided with liquid chromatograph flow rate of mobile phase 0.6mL/min, detect wavelength 230nm, and 20 ℃ of column ovens that the liquid chromatograph chromatographic column is set;
Step 3, the need testing solution 20 μ l that get step 1 inject the liquid chromatograph that is provided with through step 2, and completion proxymetacaine hydrochloride intermedium IV is separated with other intermedium, the record chromatogram, the result sees accompanying drawing 1.
In Fig. 1, retention time is the chromatographic peak that the chromatographic peak of 5.577min, 21.500min, 29.475min is respectively intermedium II, I, III, and retention time is that 33.798min is the chromatographic peak of proxymetacaine hydrochloride intermedium IV.The degree of separation of intermedium III and intermedium IV reaches 25.69, meets fully that " 2005 editions Chinese pharmacopoeia degree of separation are not less than 1.5 regulation, show that proxymetacaine hydrochloride intermedium IV can be issued to well at same chromatographic condition with other intermedium to separate.
Embodiment two
Adopting Agilent LC-1200 model high performance liquid chromatograph, Apollo brand carbon octadecane silane key and silica gel is the chromatographic column of filling agent, and the specification of chromatographic column is length 250mm, internal diameter 4.6mm, granularity 5 μ m.
Step 1; Get the proxymetacaine hydrochloride sample respectively, intermedium IV in the sample and intermediate I, II, each 10mg of III place the 10mL volumetric flask; Add dissolve with methanol and be diluted to scale; Shake up, be mixed with the sample solution of the hydrochloric proparacaine 0.5～1.0mg of every 1ml, as need testing solution;
Step 2 is provided with the moving phase of liquid chromatograph, and promptly the A pump is an organic modifiers, and the B pump is a buffer solution, and it is following that the gradient elution program of liquid chromatograph is set:
Gradient two: time (min) A pump moving phase (%) B pump moving phase (%)
5-10 0 100
10-20 30 70
20 -30 70 30
30 -50 70 30
50 -60 10 90
60 10 90，
In the time of 5-10 minute,
A pump moving phase: B pump moving phase is 0:100, whenIn the time of 10-20 minute,
A pump moving phase: B pump moving phase is 30:70, in the time of 20-30 minute,
A pump moving phase: B pump moving phase is 70:30,In the time of 30-50 minute,
A pump moving phase: B pump moving phase does70: 30, in the time of 50-60 minutes,
A pump moving phase: B pump moving phase does10:90, when 60 minutes,
A pump moving phase: B pump moving phase does10: 90, be provided with liquid chromatograph flow rate of mobile phase 1.2mL/min, detect wavelength 237nm, and 40 ℃ of column ovens that the liquid chromatograph chromatographic column is set;
Step 3, the need testing solution 5 μ l that get step 1 inject the liquid chromatograph that is provided with through step 2, and completion proxymetacaine hydrochloride intermedium IV is separated with other intermedium, and the record chromatogram is seen Fig. 2.
In Fig. 2; Retention time is the chromatographic peak that the chromatographic peak of 5.667min, 16.374 min, 22.059min is respectively intermedium II, I, III; Retention time is that 28.384min is the chromatographic peak of proxymetacaine hydrochloride intermedium IV; The degree of separation of intermedium III and intermedium IV reaches 25.78, meets fully that " 2005 editions Chinese pharmacopoeia degree of separation are not less than 1.5 regulation, show that proxymetacaine hydrochloride intermedium IV can be issued to well at same chromatographic condition with other intermedium to separate.
Embodiment three
Adopting Agilent LC-1200 model high performance liquid chromatograph, Apollo brand carbon octadecane silane key and silica gel is the chromatographic column of filling agent, and the specification of chromatographic column is length 250mm, internal diameter 4.6mm, granularity 5 μ m.
Step 1; Get the proxymetacaine hydrochloride sample respectively, intermedium IV in the sample and intermediate I, II, III, each 8mg of IV place the 10mL volumetric flask; Add dissolve with methanol and be diluted to scale; Shake up, be mixed with the sample solution of the hydrochloric proparacaine 0.5～1.0mg of every 1ml, as need testing solution;
Step 2 is provided with the moving phase of liquid chromatograph, and promptly the A pump is an organic modifiers, and the B pump is a buffer solution, and it is following that the gradient elution program of liquid chromatograph is set:
Gradient three: time (min) A pump moving phase (%) B pump moving phase (%)
5-10 0 100
10-20 30 70
20 -30 60 40
30 -50 60 40
50 -60 0 100
60 0 100，
In the time of 5-10 minute,
A pump moving phase: B pump moving phase is 0:100, whenIn the time of 10-20 minute,
A pump moving phase: B pump moving phase is 30:70, in the time of 20-30 minute,
A pump moving phase: B pump moving phase is 60:40,In the time of 30-50 minute,
A pump moving phase: B pump moving phase does60: 40, in the time of 50-60 minutes,
A pump moving phase: B pump moving phase does0:100, when 60 minutes,
A pump moving phase: B pump moving phase does0: 100, be provided with liquid chromatograph flow rate of mobile phase 1.0mL/min, detect wavelength 232nm, and 25 ℃ of column ovens that the liquid chromatograph chromatographic column is set;
Step 3, the need testing solution 10 μ l that get step 1 inject the liquid chromatograph that is provided with through step 2, and completion proxymetacaine hydrochloride intermedium IV is separated with other intermedium, the record chromatogram, the result sees accompanying drawing 3.
In Fig. 3; Retention time is the chromatographic peak that the chromatographic peak of 3.580min, 12.858 min, 21.715min is respectively intermedium II, I, III; Retention time is that 27.501min is the chromatographic peak of proxymetacaine hydrochloride intermedium IV; The degree of separation of intermedium III and intermedium IV reaches 27.26, meets fully that " 2005 editions Chinese pharmacopoeia degree of separation are not less than 1.5 regulation, show that proxymetacaine hydrochloride intermedium IV can be issued to well at same chromatographic condition with other intermedium to separate.
Claims (6)
1. one kind with proxymetacaine hydrochloride intermedium IV and the method that the high performance liquid chromatography of other intermedium separates, and may further comprise the steps:
Step 1 is got the proxymetacaine hydrochloride sample, with organic solvent dissolution proxymetacaine hydrochloride sample, is mixed with the sample solution of the hydrochloric proparacaine 0.5～1.0mg of every 1ml;
Step 2 is provided with the moving phase of liquid chromatograph, the flow velocity 0.6～1.2mL/min of moving phase, detects wavelength 232 ± 3nm, and 20 ℃～40 ℃ of the column ovens that the liquid chromatograph chromatographic column is set;
Step 3, the sample solution 5-20 μ l that gets in the step 1 injects in the liquid chromatograph that step 2 is provided with, and completion proxymetacaine hydrochloride intermedium IV is separated with other intermedium.
2. the method that proxymetacaine hydrochloride intermedium IV is separated with the high performance liquid chromatography of other intermedium according to claim 1; The moving phase that it is characterized in that step 2 kind liquid chromatograph is: the A pump is an organic modifiers; The B pump is a buffer salt solution, and it is following that the gradient elution program of liquid chromatograph is set:
Time (min) A pump moving phase (%) B pump moving phase (%)
5-10 0-30 100-70
10-20 30-60 70-40
20-30 60 40
30-50 60-0 40-100
50-60 0 100，
The volume ratio of organic modifiers and buffer solution changes in time and changes; 5 minutes to 10 minutes; The volume of mobile phase A pump changes to 30% from 0% gradually, and the volume of Mobile phase B pump changes to 70%, A pump moving phase from 100% gradually simultaneously: B pump moving phase is 0-30: 100-70; 10 minutes to 20 minutes, the volume of mobile phase A pump changed to 60% from 30% gradually, and the volume of Mobile phase B pump changes to 40%, A pump moving phase from 70% gradually simultaneously: B pump moving phase is 30-60: 70-40; 20 minutes to 30 minutes, it is 60% constant that the volume of mobile phase A pump keeps, and the volume of Mobile phase B pump keeps 40% constant simultaneously, and A pump moving phase: B pump moving phase is 60: 40; 30 minutes to 50 minutes, the volume of mobile phase A pump changed to 0% from 60% gradually, and the volume of Mobile phase B pump changes to 100%, A pump moving phase from 40% gradually simultaneously: B pump moving phase is 60-0:40-100; 50 minutes to 60 minutes, it is 0% constant that the volume of mobile phase A pump keeps, and the volume of Mobile phase B pump keeps 100% constant simultaneously, and A pump moving phase: B pump moving phase is 0:100.
3. according to claim 1 with proxymetacaine hydrochloride intermedium IV and the method that the high performance liquid chromatography of other intermedium separates, the organic solvent that it is characterized in that said step 1 is methyl alcohol or ethanol.
4. the method that proxymetacaine hydrochloride intermedium IV is separated with the high performance liquid chromatography of other intermedium according to claim 1; It is characterized in that liquid chromatograph employing carbon octadecane silane key and silica gel in the described step 2 are the chromatographic column of filling agent, the specification of chromatographic column is length 250mm, internal diameter 4.6mm, granularity 5 μ m.
5. according to claim 2 with proxymetacaine hydrochloride intermedium IV and the method that the high performance liquid chromatography of other intermedium separates, it is characterized in that described organic modifiers is acetonitrile or methyl alcohol.
6. the method that proxymetacaine hydrochloride intermedium IV is separated with the high performance liquid chromatography of other intermedium according to claim 2; It is characterized in that described buffer salt solution is 90% phosphate solution; 90% phosphate solution is after 0.05M potassium dihydrogen phosphate and 0.02M sodium heptanesulfonate are dissolved in water, add triethylamine again and transfer PH to 5.2.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US1317250A (en) * | 1919-09-30 | A cobporatiojet | ||
| US3775464A (en) * | 1970-04-22 | 1973-11-27 | Isf Spa | Process for preparing 2-dialkylaminoethyl 4-alkoxy-3-aminobenzoates |
| CN101104591A (en) * | 2006-07-14 | 2008-01-16 | 海南盛科生命科学研究院 | Polymorph of proparacaine hydrochloride and preparation method thereof |
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2012
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US1317250A (en) * | 1919-09-30 | A cobporatiojet | ||
| US3775464A (en) * | 1970-04-22 | 1973-11-27 | Isf Spa | Process for preparing 2-dialkylaminoethyl 4-alkoxy-3-aminobenzoates |
| CN101104591A (en) * | 2006-07-14 | 2008-01-16 | 海南盛科生命科学研究院 | Polymorph of proparacaine hydrochloride and preparation method thereof |
Non-Patent Citations (5)
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| A. DINCEL ET AL: "An Experimental Design Approach to Selecting the Optimum LC Conditions for the Determination of Local Anaesthetics", 《CHROMATOGRAPHIA 》 * |
| DINCEL A ET AL: "Development and Validation of an HPLC–UV–Vis Method for the Determination of Proparacaine in Human Aqueous Humour", 《CHROMATOGRAPHIA》 * |
| R. O. CLINTON ET AL: "Derivatives of 4-Amino-2-hydroxybenzoic Acid. II", 《J. AM. CHEM. SOC》 * |
| 孙化中 等: "盐酸丙美卡因对于混合痔术后创面肉芽组织的影响", 《中国药物与临床》 * |
| 王正玲 等: "爱尔卡因滴眼液开启时间与菌落数及表麻后房水浓度影响的研究", 《中国医药指南》 * |
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