CN103512968B - A kind of left nadifloxacin of liquid chromatography for separating and determining L-arginine and the method for optical isomer thereof - Google Patents
A kind of left nadifloxacin of liquid chromatography for separating and determining L-arginine and the method for optical isomer thereof Download PDFInfo
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- CN103512968B CN103512968B CN201210219576.8A CN201210219576A CN103512968B CN 103512968 B CN103512968 B CN 103512968B CN 201210219576 A CN201210219576 A CN 201210219576A CN 103512968 B CN103512968 B CN 103512968B
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Abstract
The invention belongs to drug world, relate to a kind of liquid chromatography for separating and determining left nadifloxacin of L arginine and the method for optical isomer thereof, the method of the present invention is with three (3,5 xylyls) carbamate amylose is the chiral chromatographic column of filler, with normal hexane low-alcohol solution for flowing phase, wherein comprising one or more organic acid in formic acid, acetic acid and trifluoroacetic acid in low-alcohol solution, its concentration volume ratio is 0.1～1%；The method can simply, separate quickly and accurately, detect the left nadifloxacin of L arginine and optical isomer impurity thereof.
Description
Technical field
The invention belongs to drug world, be specifically related to the left nadifloxacin of liquid chromatography for separating and determining L-arginine and light thereof
The method learning isomer.
Background technology
Quinolones had evolved to for four generations now, and the first generation is with nalidixan as representative, and the second filial generation is with pipemidic acid as generation
Table, only effective to gram negative bacteria, the third generation is the peak period of this type of drug development, occurs in that a large amount of new drug, and is wide
Composing antibacterial, among these with norfloxacin, ciprofloxacin etc. is representative.Forth generation quinolone antibiotic is then at third generation wide spectrum
On the basis of further expand antimicrobial spectrum, being allowed to can be to anti-mycoplasma and chlamydia infection.
The research and development of domestic antibiotic are the most popular, and applying most in the market is third generation quinolones.
Nadifloxacin, by the exploitation of great Zhong company of Japan, belongs to third generation quinolone antimicrobial, external curing acne and folliculitis.1993
Listing (trade name: Acuatim) in Japan first, within 2004, list (trade name: Nadixa) in Germany, 2005 in China
City's (trade name: Yi Youning, 1% ointment).
Nadifloxacin structure exists a chiral carbon atom, therefore there is one group of different optical siomerism of spatial configuration
Body, i.e. (R)-nadifloxacin and (S)-nadifloxacin, having the most bioactive is (S)-nadifloxacin, and research shows,
S-type isomer is the composition of main onset, and S-type isomer antibacterial activity is 2 times of raceme, be R-isomer 64～
256 times.Become with aminoacid after salt, add water solublity thus improve bioavailability, enhance stability, reduce blood vessel
The side effect such as zest.The left nadifloxacin of L-arginine is the amidates of wherein S-type isomer, chemical entitled S-()-
9-fluoro-6,7-dihydro-8-(4-hydroxyl-piperidino)-5-methyl isophthalic acid-oxo-1H, 5H-benzo (i, j) quinolizine-2-carboxylic acid essence
Propylhomoserin salt.In addition to left nadifloxacin, its optical isomer is listed in the impurity of the left nadifloxacin of L-arginine.
The optical isomer of nadifloxacin left for L-arginine is impurity, is producing L-arginine left nadifloxacin process
In need to carry out quality control.The difficult point separating always chiral drug quality control of the optical isomer of chiral drug.Cause
This, it is achieved the left nadifloxacin of L-arginine is L-arginine left nadifloxacin quality control with the separation determination of its optical isomer
Aspect processed has realistic meaning.
Summary of the invention
It is an object of the invention to provide the one chiral chromatographic column left nadifloxacin of separation determination L-arginine and optics thereof
The efficient liquid-phase chromatography method of isomer impurities, effectively can divide left for L-arginine nadifloxacin with its optical isomer
From, such that it is able to accurately control the quality of the left nadifloxacin of L-arginine, thus realize the left nadifloxacin of L-arginine and its light
Learn the separation determination of isomer.
The use liquid-phase chromatography method left nadifloxacin of separation determination L-arginine and optical isomer thereof described in the present invention are miscellaneous
The method of matter, is with three (3,5-xylyl)-carbamate amylose [Amylose tris (3,5-
Dimethylphenyl carbamate)] it is the chiral chromatographic column of filler, with normal hexane-low-alcohol solution for flowing phase, wherein
Low-alcohol solution comprises organic acid.Liquid chromatography mentioned here includes high performance liquid chromatography or high performance liquid chromatography
Method-mass spectrography combination.
Above-mentioned described chiral chromatographic column is CHIRALPAK AD and the chromatographic column of CHIRALPAK AD-H selected from the trade mark.
The lower alcohol of the present invention is selected from following solvent: methanol, ethanol, propanol or isopropanol, or its mixture, preferably second
Alcohol or isopropanol.
Method of the present invention, the volume ratio of its flowing phase normal hexane-low-alcohol solution is 80:20～50:50.
The organic acid comprised in above-mentioned described low-alcohol solution selected from formic acid, acetic acid and trifluoroacetic acid, organic acid dense
It is 0.1～1% that degree accounts for the percent by volume (V/V) of low-alcohol solution.
Method of separating and assaying of the present invention, can realize by the following method:
1) take the left nadifloxacin of L-arginine or the preparation containing the left nadifloxacin of L-arginine is appropriate, molten with ethanol or methanol
Solve sample, and be configured in every 1ml the sample solution containing left nadifloxacin 0.2～5mg；
2) flow velocity arranging flowing phase is 0.5～1.5ml/min, and the flow velocity of flowing phase is preferably 1.0ml/min；Detection ripple
A length of 215～250nm, best detection wavelength is 235nm；Chromatographic column column oven temperature is 20～50 DEG C, and optimum column temperature is 30 DEG C；
3) take 1) sample solution 2～50 μ l, inject high performance liquid chromatograph, complete the left nadifloxacin of L-arginine and light
Learn the separation determination of isomer.
Wherein:
High performance liquid chromatograph: wear peace P680 type high performance liquid chromatograph；
Chromatographic column: CHIRALPAK AD-H chiral chromatographic column (250mm × 4.6mm)；
Column temperature: 30 DEG C；
Flowing phase: normal hexane-ethanol (trifluoroacetic acid containing 0.1%)=(65:35)；
Flow: 1.0ml/min；
Detection wavelength: 235nm；
Sampling volume: 20 μ l；
Described method of separating and assaying, measures according to high performance liquid chromatography (Chinese Pharmacopoeia two annex V D of version in 2010).
The most preferably method of the left nadifloxacin of liquid chromatography for separating and determining L-arginine and optical isomer thereof is: take
The left nadifloxacin of L-arginine is appropriate, adds ethanol and dissolves and dilute the solution made in every 1ml containing about left nadifloxacin 0.5mg,
As need testing solution, precision measures in right amount, makes in every 1ml the solution containing about left nadifloxacin 5 μ g with ethanol dilution, as
Contrast solution；Measure according to high performance liquid chromatography (Chinese Pharmacopoeia two annex V D of version in 2010).With DAICEL AD-H(
4.6 × 250mm) chromatographic column；With normal hexane-ethanol (trifluoroacetic acid containing 0.1%) (35:65) for flowing phase, column temperature 30 DEG C, stream
Speed 1.0ml/min；Detection wavelength 235nm；Take the left nadifloxacin of L-arginine and right nadifloxacin is each in right amount, add ethanol and dissolve also
Each solution containing about 0.1mg in every 1ml is made in dilution, as system suitability solution.Precision measures system suitability examination
Testing solution 20 μ l, inject chromatograph of liquid, record chromatogram, the left nadifloxacin of arginine and right nadifloxacin go out peak successively, and two
The separating degree of person should meet the requirements.Take contrast solution 20 μ l and inject chromatograph of liquid, regulate detection sensitivity, make main constituent chromatograph
The peak height at peak is about the 25% of full scale；Precision measures need testing solution and each 20 μ l of contrast solution again, is injected separately into liquid phase color
Spectrometer, 3 times of record chromatogram to main constituent peak retention time, in need testing solution chromatogram, right nadifloxacin peak cannot be greater than
0.2 times (0.2%) of contrast solution main peak area.
The present invention uses CHIRALPAK AD-H chiral chromatographic column, it is possible to efficiently separate the mensuration left nadifloxacin of L-arginine
Optical isomer；Select ethanol or methanol sample dissolution, it is ensured that the stability of solution；Selecting sampling volume is 20 μ l, post
Temperature is 30 DEG C, improves the symmetry of chromatographic peak.The optics that the present invention solves the left nadifloxacin of separation determination L-arginine is different
The mensuration problem of structure body, can simply, separate quickly and accurately, detect the left nadifloxacin of L-arginine and optical isomer thereof
Impurity, thus ensure that the quality controllable of the left nadifloxacin of L-arginine and preparation thereof.
Accompanying drawing explanation
The high-efficient liquid phase chromatogram of Fig. 1 blank solvent；
The high-efficient liquid phase chromatogram of Fig. 2 nadifloxacin raceme；
The high-efficient liquid phase chromatogram of the left nadifloxacin of Fig. 3 L-arginine；
The high-efficient liquid phase chromatogram of Fig. 4 blank auxiliary；
The high-efficient liquid phase chromatogram of Fig. 5 L-arginine left nadifloxacin sheet.
Detailed description of the invention
Embodiment 1
Test apparatus:
The U.S. wears peace P680 type highly effective liquid phase chromatographic system and work station；Auto injection；With CHIRALPAK AD-H chirality
Chromatographic column (250mm × 4.6mm) is detached dowel；
Testing conditions:
Ultraviolet detection wavelength: 235nm；Flowing phase: normal hexane-ethanol (trifluoroacetic acid containing 0.1%)=(65:35)；Column temperature
30℃；Sampling volume is 20 μ l.
Test procedure:
Take nadifloxacin raceme about 10mg, put in 100ml volumetric flask, add ethanol and dissolve and be diluted to scale, shake up, make
For need testing solution (1).Take ethanol blank solution and need testing solution (1) respectively, enter by above-mentioned test apparatus and testing conditions
Row efficient liquid phase chromatographic analysis, records chromatogram, and result is shown in Fig. 1, Fig. 2.In Fig. 2, retention time is the chromatographic peak of 6.805 minutes
Chromatographic peak for left nadifloxacin；The chromatographic peak of 11.640 minutes is the chromatographic peak of left nadifloxacin optical isomer.
Take L-arginine left nadifloxacin about 42mg(and be approximately equivalent to left nadifloxacin 25mg), put in 50ml volumetric flask, add
Ethanol dissolves and is diluted to scale, shakes up, as need testing solution (2).Take need testing solution (2), by above-mentioned test apparatus and
Testing conditions carries out efficient liquid phase chromatographic analysis, records chromatogram, and result is shown in Fig. 3.Fig. 3 proves, the left nadifloxacin of L-arginine
Optical purity reach medicine crude drug requirement, this law may be used for the quality-monitoring of the left nadifloxacin of L-arginine.
Take L-arginine left nadifloxacin sheet (adjuvant is sodium carboxymethyl cellulose, L-arginine) appropriate, be approximately equivalent to a left side
Nadifloxacin 25mg, puts in 50ml volumetric flask, adds ethanol and dissolves and be diluted to scale, shakes up, and filters, and takes subsequent filtrate as examination
Product solution (3).Take blank auxiliary (adjuvant is sodium carboxymethyl cellulose, L-arginine) solution respectively and take need testing solution (3),
Testing instrument and testing conditions carries out efficient liquid phase chromatographic analysis by above-mentioned, record chromatogram, result is shown in Fig. 4, Fig. 5.Fig. 4 proves,
Blank auxiliary not interference measurement, Fig. 5 shows that this law may be used for the quality-monitoring of L-arginine left nadifloxacin preparation.
Embodiment 2
Test apparatus:
The U.S. wears peace P680 type highly effective liquid phase chromatographic system and work station；Auto injection；With CHIRALPAK AD-H chirality
Chromatographic column (250mm × 4.6mm) is detached dowel；
Testing conditions:
Ultraviolet detection wavelength: 235nm；Flowing phase: normal hexane-methanol (trifluoroacetic acid containing 0.1%)=(65:35)；Column temperature
30℃；Sampling volume is 20 μ l.
Test procedure:
Take nadifloxacin raceme about 10mg, put in 100ml volumetric flask, add methanol and dissolve and be diluted to scale, shake up, make
For need testing solution (1).Take methanol blank solution and need testing solution (1) respectively, enter by above-mentioned test apparatus and testing conditions
Row efficient liquid phase chromatographic analysis, records chromatogram, and result is shown in Fig. 1, Fig. 2.In Fig. 2, retention time is the chromatographic peak of 6.805 minutes
Chromatographic peak for left nadifloxacin；The chromatographic peak of 11.640 minutes is the chromatographic peak of left nadifloxacin optical isomer.
Take L-arginine left nadifloxacin about 42mg(and be approximately equivalent to left nadifloxacin 25mg), put in 50ml volumetric flask, add
Ethanol dissolves and is diluted to scale, shakes up, as need testing solution (2).Take need testing solution (2), by above-mentioned test apparatus and
Testing conditions carries out efficient liquid phase chromatographic analysis, records chromatogram, and result is shown in Fig. 3.Fig. 3 proves, the left nadifloxacin of L-arginine
Optical purity reach medicine crude drug requirement, this law may be used for the quality-monitoring of the left nadifloxacin of L-arginine.
Take L-arginine left nadifloxacin sheet (adjuvant is sodium carboxymethyl cellulose, L-arginine) appropriate, be approximately equivalent to a left side
Nadifloxacin 25mg, puts in 50ml volumetric flask, adds ethanol and dissolves and be diluted to scale, shakes up, and filters, and takes subsequent filtrate as examination
Product solution (3).Take blank auxiliary (adjuvant is sodium carboxymethyl cellulose, L-arginine) solution respectively and take need testing solution (3),
Testing instrument and testing conditions carries out efficient liquid phase chromatographic analysis by above-mentioned, record chromatogram, result is shown in Fig. 4, Fig. 5.Fig. 4 proves,
Blank auxiliary not interference measurement, Fig. 5 shows that this law may be used for the quality-monitoring of L-arginine left nadifloxacin preparation.
Embodiment 3
Testing conditions: ultraviolet detection wavelength: 215nm；Flowing phase: normal hexane-ethanol (trifluoroacetic acid containing 0.5%)=
(60:40)；Column temperature 20 DEG C；Sampling volume is 20 μ l.
Detecting instrument and test determination method are with embodiment 1.
Embodiment 4:
Testing conditions: ultraviolet detection wavelength: 250nm；Flowing phase: normal hexane-ethanol (formic acid containing 0.2%)=(80:
20)；Column temperature 50 DEG C；Sampling volume is 20 μ l.
Detecting instrument and test determination method are with embodiment 1.
Embodiment 5:
Testing conditions: ultraviolet detection wavelength: 220nm；Flowing phase: normal hexane-ethanol (trifluoroacetic acid containing 1%)=(50:
50)；Column temperature 40 DEG C；Sampling volume is 20 μ l.
Detecting instrument and test determination method are with embodiment 1.
Embodiment 6
Testing conditions: ultraviolet detection wavelength: 235nm；Flowing phase: normal hexane-isopropanol (formic acid containing 0.1%)=(65:
35)；Column temperature 30 DEG C；Sampling volume is 20 μ l.
Detecting instrument and test determination method are with embodiment 1.
Embodiment 7
Testing conditions: ultraviolet detection wavelength: 250nm；Flowing phase: normal hexane-isopropanol (trifluoroacetic acid containing 0. 5%)=
(60:40)；Column temperature 20 DEG C；Sampling volume is 20 μ l.
Detecting instrument and test determination method are with embodiment 1.
Embodiment 8
Testing conditions: ultraviolet detection wavelength: 235nm；Flowing phase: normal hexane-methanol (acetic acid containing 0.1%)=(65:
35)；Column temperature 30 DEG C；Sampling volume is 20 μ l.
Detecting instrument and test determination method are with embodiment 1.
Embodiment 9
Testing conditions: ultraviolet detection wavelength: 215nm；Flowing phase: normal hexane-methanol (trifluoroacetic acid containing 1%)=(70:
30)；Column temperature 20 DEG C；Sampling volume is 20 μ l.
Detecting instrument and test determination method are with embodiment 1.
Embodiment 10
Testing conditions: ultraviolet detection wavelength: 215nm；Flowing phase: normal hexane-methanol (formic acid containing 0.1% and 0.1%
Acetic acid)=(70:30)；Column temperature 20 DEG C；Sampling volume is 20 μ l.
Detecting instrument and test determination method are with embodiment 1.
Claims (5)
1. the left nadifloxacin of liquid chromatography for separating and determining L-arginine and a method for optical isomer thereof, its feature exists
In: it is the chiral chromatographic column of filler with three (3,5-xylyl)-carbamate amylosies, with normal hexane-rudimentary
Alcoholic solution is flowing phase, wherein comprises one or more in formic acid, acetic acid and trifluoroacetic acid in low-alcohol solution organic
Acid, its concentration volume ratio is 0.1～1%.
2. the method described in claim 1, it is characterised in that described lower alcohol is selected from one or more of following compound: first
Alcohol, ethanol, propanol or isopropanol.
3. the method described in claim 1, it is characterised in that the volume ratio of described normal hexane-low-alcohol solution is 80:20～50:
50。
4. the method according to any one of claim 1-3, it is characterised in that comprise the steps of
1) take the left nadifloxacin of L-arginine or the preparation containing the left nadifloxacin of L-arginine is appropriate, dissolve sample with ethanol or methanol
Product, and it is configured in every 1ml the sample solution containing left nadifloxacin 0.2～5mg；
2) arranging flow rate of mobile phase is 0.5～1.5ml/min；Detection wavelength is 215～250nm；Chromatographic column column oven temperature is
20～50 DEG C；
3) 1 is taken) the sample solution 2～50 μ l of step, injects high performance liquid chromatograph, completes the left nadifloxacin of L-arginine and light
Learn the separation determination of isomer.
5. the method described in claim 1, it is characterised in that comprise the steps of and take the left nadifloxacin of L-arginine in right amount, add
Ethanol dissolves and dilutes the solution made in every 1ml containing about left nadifloxacin 0.5mg, and as need testing solution, precision measures confession
Test sample solution is appropriate, makes in every 1ml the solution containing about left nadifloxacin 5 μ g with ethanol dilution, as contrast solution；With color
Spectrum post specification is the DAICEL AD-H of 4.6 × 250mm；With the normal hexane-ethanol of 65:35 for flowing phase, described ethanol contains
The trifluoroacetic acid of 0.1%, column temperature 30 DEG C, flow velocity 1.0ml/min；Detection wavelength 235nm；Take the left nadifloxacin of L-arginine and the right side
Nadifloxacin is each in right amount, adds ethanol and dissolves and dilute and make in every 1ml each solution containing about 0.1mg, tries as system suitability
Test solution；Precision measures system suitability solution 20 μ l, injects chromatograph of liquid, records chromatogram；Take contrast solution 20 μ
L injects chromatograph of liquid, regulates detection sensitivity, makes the peak height of main constituent chromatographic peak be about the 25% of full scale；Accurate amount again
Taking need testing solution and each 20 μ l of contrast solution, be injected separately into chromatograph of liquid, record chromatogram is to main constituent peak retention time
3 times, in need testing solution chromatogram, right nadifloxacin peak cannot be greater than 0.2 times of contrast solution main peak area.
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| CN109387587B (en) * | 2018-12-28 | 2021-07-20 | 广东盛泰华生物制药有限公司 | Detection method of L-2-amino-5-guanidino valeric acid enantiomer |
| CN111426769B (en) * | 2020-04-22 | 2022-10-28 | 江西省药品检验检测研究院 | Chiral mobile phase additive HPLC resolution method of nadifloxacin enantiomer |
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| WO2003099815A1 (en) * | 2002-05-28 | 2003-12-04 | Wockhardt Limited | Crystalline fluoroquinolone arginine salt form |
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Non-Patent Citations (3)
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| Validated chiral high-performance liquid chromatography method for a novel anti-methicillin-resistant staphylococcus aureus fluoroquinolone;R.D. Yeole,et al;《Journal of Chromatography A》;20060119;第1108卷(第1期);38－42 * |
| 用Chiralcel OD 和Chiralpak AD 拆分手性药物的研究进展;余露山等;《中国药学杂质》;20030930;第38卷(第9期);641－643 * |
| 那氟沙星含量测定方法研究;王启帅等;《中国药业》;20071231;第16卷(第23期);29－30 * |
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