CN104359992B - Adopt the method for high-efficient liquid phase chromatogram technique analysis injection ACV - Google Patents
Adopt the method for high-efficient liquid phase chromatogram technique analysis injection ACV Download PDFInfo
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- CN104359992B CN104359992B CN201410721144.6A CN201410721144A CN104359992B CN 104359992 B CN104359992 B CN 104359992B CN 201410721144 A CN201410721144 A CN 201410721144A CN 104359992 B CN104359992 B CN 104359992B
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Abstract
The invention discloses a kind of method that adopts high-efficient liquid phase chromatogram technique analysis injection ACV, the analysis condition of high performance liquid chromatography is: chromatographic column adopting octadecylsilane chemically bonded silica post; The mixed solution that employing contains 0.1-0.3 % by weight acetate buffer and the first organic solvent is as mobile phase A; And adopt the second organic solvent as Mobile phase B, and wherein, described the first organic solvent is acetonitrile and/or methyl alcohol, described the second organic solvent is acetonitrile and/or methyl alcohol. Adopt the method the impurity existing in injection ACV bulk drug and preparation can be carried out under same chromatographic condition to separation rapidly and efficiently, effectively control the quality of bulk drug and preparation. This detection method is highly sensitive, specificity is strong, precision is high, accuracy is strong, easy to operate, can comprehensively, effectively control product quality.
Description
Technical field
The invention belongs to Pharmaceutical Analysis technical field, particularly, the present invention relates to a kind of high performance liquid chromatography that adoptsAnalyze the method for injection ACV.
Background technology
Injection ACV main component is ACV (chemical name: 9-(2-hydroxyl ethoxymethyl) guanine, 1 of formulaShow compound). It is purines nucleoside analog, is a kind of antiviral agent of high-efficiency broad spectrum, the huge market demand. Be mainly used inVarious infection due to herpes simplex virus (HSV), can be used for onset or recurrent skin, mucous membrane, and external genital organs infects and exempts fromThe HSV that epidemic disease handicapped occurs infects. For the choice drug for the treatment of HSV encephalitis, reduce the incidence of disease and reduce the death rate be all better than AhSugar adenosine. Also can be used for herpes zoster, ebb virus's (Epstein-Barr virus), and the infection such as the concurrent varicella of immune deficiency person.
Synthetic route: N-2, the 9-diacetylguanine+Isosorbide-5-Nitrae-diacetoxy-2-oxa-of adopting of ACV bulk drug, in this process, easily there is compound shown in side reaction production 3, compound warp shown in formula 3 in butane → diacetyl group ACVCross compound shown in hydrolysis meeting production 4. ACV bulk drug hydro-oxidation sodium salify, obtained aqueous solution, through degermingFiltration is also filling under gnotobasis, obtains injection ACV after freeze-drying. In quality control, remove and need to control guanine (formula 2Shown in compound) outside, also need, to issuable impurity in building-up process, strictly to control, to ensure product matter comprehensivelyAmount and safety.
At present, the method for analysis injection Acyclovir formulations still haves much room for improvement.
Summary of the invention
The present invention is intended to solve at least to a certain extent one of technical problem in correlation technique. For this reason, of the present inventionAn object is to propose a kind of method that adopts high-efficient liquid phase chromatogram technique analysis injection ACV, and the method can be simultaneouslyMeasure the content of compound shown in the formula 1 that exists in injection ACV, formula 2, formula 3, formula 4. By at same chromatographic conditionLower quick compartment analysis main ingredient and related substance, realize the quality control of injection ACV.
In one aspect of the invention, the invention provides a kind of high-efficient liquid phase chromatogram technique analysis injection Ah former times Lip river that adoptsThe method of Wei. It is characterized in that: the analysis condition of described high performance liquid chromatography is:
Chromatographic column adopting octadecylsilane chemically bonded silica post;
The mixed solution that employing contains 0.1-0.3 % by weight acetate buffer and the first organic solvent is as mobile phaseA; And
Adopt the second organic solvent as Mobile phase B,
Wherein, described the first organic solvent is acetonitrile and/or methyl alcohol, and described the second organic solvent is acetonitrile and/or methyl alcohol.
Can be effective according to the method for the employing high-efficient liquid phase chromatogram technique analysis injection ACV of the embodiment of the present inventionCompound shown in compound shown in compound shown in main ingredient ACV in product and formula 2, formula 3, formula 4 is detected, itsTesting result has significant sensitivity, stability and repeatability. By adding 0.1-0.3 % by weight ammonium acetate, can increaseThe reservation of compound shown in formula 2, formula 3, formula 4, thus peak shape improved, avoid hangover, and can increase separating degree. Accuracy is strong, behaviourFacilitate, can effective control for product quality.
In addition, according to the method for the employing high-efficient liquid phase chromatogram technique analysis injection ACV of the embodiment of the present invention, alsoCan there is following additional technical feature:
In some embodiments of the invention, adopt phosphoric acid to regulate described acetate buffer in described mobile phase APH is 2.6-3.0, preferably 2.8. Thus, can further improve separating of main ingredient and related substance in injection ACVDegree.
In some embodiments of the invention, the acetate buffer in described mobile phase A and described the first organic solventVolume ratio be (60%-90%): (10%-40%). Thus, can further improve in injection ACV main ingredient and haveThe separating degree of related substance. In specific embodiments of the invention, the acetate buffer in described mobile phase A and described first hasThe volume ratio of machine solvent is (70%～80%): (20%～30%), is preferably 80%:20%. Thus, can further improveSeparating degree.
In some embodiments of the invention, detection wavelength is 250-260nm, preferably 254nm. Thus, can significantly carryHigh detection sensitivity.
In some embodiments of the invention, the column temperature of described chromatographic column is 30-40 degree Celsius, preferably 35 degrees Celsius. ByThis, can further improve the separating degree of each component in injection ACV.
In some embodiments of the invention, in described chromatographic column, the particle diameter of filler is 2-5 μ m. Thus, can be furtherImprove the separating degree of each component in injection ACV.
In some embodiments of the invention, described high-efficient liquid phase chromatogram technique analysis adopts 4.6 × 150mm, 5 μ m'sAgilentSB-C18 chromatographic column, 0.1 volume % ammonium acetate buffer (with phosphorus acid for adjusting pH value to 2.8): acetonitrile=80:20 (v/V) as mobile phase A, acetonitrile, as Mobile phase B, carries out gradient elution, and condition of gradient elution is:
| Time/minute | Mobile phase A/% | Mobile phase B/% |
| 0 | 95 | 5 |
| 15 | 80 | 20 |
| 25 | 60 | 40 |
| 28 | 80 | 20 |
| 30 | 95 | 5 |
Wherein, column temperature is 35 degrees Celsius, and detection wavelength is 254nm, and flow velocity is 1.2 ml/min, and sampling volume is 10 μL. Thus, when can effectively realizing compound shown in compound, formula 4 shown in compound, formula 3 shown in ACV and formula 2Detect.
In some embodiments of the invention, described high-efficient liquid phase chromatogram technique analysis adopts 4.6 × 150mm, 5 μ m'sDikmaC18Chromatographic column, 0.3 volume % ammonium acetate buffer (with phosphorus acid for adjusting pH value to 2.8): acetonitrile=80:20 (v/v) doesFor mobile phase A, acetonitrile, as Mobile phase B, carries out gradient elution, and condition of gradient elution is:
| Time/minute | Mobile phase A/% | Mobile phase B/% |
| 0 | 95 | 5 |
| 15 | 80 | 20 |
| 25 | 60 | 40 |
| 28 | 80 | 20 |
| 30 | 95 | 5 |
Wherein, column temperature is 40 degrees Celsius, and detection wavelength is 260nm, and flow velocity is 1 ml/min, and sampling volume is 10 μ L.Thus, inspection when can effectively realizing compound shown in compound, formula 4 shown in compound, formula 3 shown in ACV and formula 2Survey.
According to the embodiment of the present invention, described injection ACV adopts 0.4 quality % sodium hydroxide solution to be mixed with and treatsSurvey liquid.
In some embodiments of the invention, contrast solution is chemical combination shown in compound, formula 3 shown in ACV and formula 2The mixed solution of compound shown in thing, formula 4, wherein, compound concentration shown in compound, formula 4 shown in compound shown in formula 2, formula 3Be 25ppm. Thus, can be in reducing sample size as far as possible, make response meet the needs of measuring, avoid continuous heightConcentration sample introduction, extends the service life of chromatographic column, and under this concentration, complete between main component ACV and other peaksSeparate.
The wash-out separating effect of the inventive method is better, can make three impurity in sample effectively separate. Only need detection time30min. Can separate fast, accurately, reliably ACV and adjacent impurity.
Additional aspect of the present invention and advantage in the following description part provide, and part will become from the following descriptionObtain obviously, or recognize by practice of the present invention.
Brief description of the drawings
Fig. 1 has shown according to embodiments of the invention 1, the high-efficient liquid phase chromatogram of three impurity location of gained;
Fig. 2 has shown according to embodiments of the invention 2, the high efficiency liquid phase of gained injection ACV bulk drug and impurityChromatogram;
Fig. 3 has shown according to embodiments of the invention 3, the high-efficient liquid phase color of gained injection Acyclovir formulations and impuritySpectrogram;
Fig. 4 has shown according to comparative example 1 of the present invention, the high performance liquid chromatography of gained injection ACV and impurityFigure.
Detailed description of the invention
Describe embodiments of the invention below in detail. Embodiment described below is exemplary, only for explaining thisBright, and can not be interpreted as limitation of the present invention. Unreceipted concrete technology or condition in embodiment, according to the literary composition in this areaOffer described technology or condition or carry out according to product description. The unreceipted person of production firm of agents useful for same or instrument, allFor can be by the conventional products of commercial acquisition.
ACV bulk drug and injection ACV used in the embodiment of the present invention are applicant's self-control.
ACV bulk drug is through N-2,9-diacetylguanine+Isosorbide-5-Nitrae-diacetoxy-2-oxa-butane → bis-secondAcyl group ACV is synthetic to be obtained.
Injection ACV preparation technology: carry out salt-forming reaction with ACV in the aqueous solution of NaOH, joinThe aqueous solution processed, through aseptic filtration, freeze drying, then carry out vacuum tamponade, roll lid, lamp inspection, packaging, obtain injection ACVProduct.
Embodiment 1
Instrument: Agilent1100 high performance liquid chromatograph, 1100 UV-detectors
Chromatographic column: AgilentSB-C18 chromatographic column (150 × 4.6mm, 5 μ are m);
Mobile phase A: 0.1 volume % ammonium acetate buffer (with phosphorus acid for adjusting pH value to 2.8): acetonitrile=80:20 (v/v)
Mobile phase B: acetonitrile
Gradient elution sees the following form:
| Time/minute | Mobile phase A/% | Mobile phase B/% |
| 0 | 95 | 5 |
| 15 | 80 | 20 |
| 25 | 60 | 40 |
| 28 | 80 | 20 |
| 30 | 95 | 5 |
Flow velocity: 1.2mL/min
Detect wavelength: 254nm
Column temperature: 35 DEG C
Sampling volume: 10 μ L
Diluent: 0.4 quality % sodium hydroxide solution
Running time: 30 minutes
Experimental procedure:
Impurity location solution preparation: precision takes compound pair shown in compound, formula 4 shown in compound shown in formula 2, formula 3According to the each 25mg of product, be placed in same 100ml volumetric flask, add 0.4 quality % sodium hydroxide solution and dissolve also rare as dilutionRelease to scale, shake up, precision measures 1ml and puts in 10ml volumetric flask, adds diluted to scale, shake up, then precision measures 1mlPut in 100ml volumetric flask, add diluted to scale, shake up, to obtain final product, obtain the solution of 25ppm concentration.
Conclusion: under this chromatographic condition, three impurity can be issued to good separation at same chromatographic condition, protect in Fig. 1Stay time 7.050min, 9.8697min, the chromatographic peak of 17.675min be respectively compound shown in compound shown in formula 2, formula 3,The chromatographic peak of compound shown in formula 4.
Chromatogram shows that three impurity are in the time that content is 25ppm, and carrying out efficient liquid phase chromatographic analysis is to do qualitative pointAnalyse, be quantitatively limited to 25ppm.
Embodiment 2
Instrument: Agilent1100 high performance liquid chromatograph, 1100 UV-detectors
Chromatographic column: DikmaC18(250×4.6mm,5μm)；
Mobile phase A: 0.3 volume % ammonium acetate buffer (with phosphorus acid for adjusting pH value to 2.8): acetonitrile=80:20 (v/v)
Mobile phase B: acetonitrile
Gradient elution sees the following form:
| Time/minute | Mobile phase A/% | Mobile phase B/% |
| 0 | 95 | 5 |
| 15 | 80 | 20 |
| 25 | 60 | 40 |
| 28 | 80 | 20 |
| 30 | 95 | 5 |
Flow velocity: 1mL/min
Detect wavelength: 260nm
Column temperature: 40 DEG C
Sampling volume: 10 μ L
Diluent: 0.4 quality % sodium hydroxide solution
Running time: 30 minutes
Experimental procedure: precision takes ACV bulk drug 100mg, puts in same 10ml volumetric flask, adds embodiment 1 and joinsThe impurity location solution of system dissolves and is diluted to scale, shakes up, and obtains the solution of 10mg/ml.
Conclusion: under this chromatographic condition, retention time 7.073min in Fig. 2,9.987min, 11.820min, 17.707minChromatographic peak be respectively the chromatographic peak of compound shown in compound, ACV, formula 4 shown in compound shown in formula 2, formula 3.
Chromatogram shows in injection ACV shown in three impurity formulas 2 shown in compound, formula 3 shown in compound, formula 4Compound can be issued to good separation at same chromatographic condition. Result also shows that the method can be used for ACV bulk drugQuality testing.
Embodiment 3
Instrument: Agilent1100 high performance liquid chromatograph, 1100 UV-detectors
Chromatographic column: chromatographic column that octadecylsilane chemically bonded silica is filler (150 × 4.6mm, 5 μ are m);
Mobile phase A: 0.1 volume % ammonium acetate buffer (with phosphorus acid for adjusting pH value to 3.0): acetonitrile=70:30 (v/v)
Mobile phase B: methyl alcohol
Gradient elution sees the following form:
| Time/minute | Mobile phase A/% | Mobile phase B/% |
| 0 | 95 | 5 |
| 15 | 80 | 20 |
| 25 | 60 | 40 |
| 28 | 80 | 20 |
| 30 | 95 | 5 |
Flow velocity: 1.0mL/min
Detect wavelength: 250nm
Column temperature: 30 DEG C
Sampling volume: 10 μ L
Diluent: 0.4 quality % sodium hydroxide solution
Running time: 30 minutes
Experimental procedure: precision takes injection ACV product 100mg, puts in same 10ml volumetric flask, adds enforcementThe impurity location solution that example 1 is prepared dissolves and is diluted to scale, shakes up, and to obtain final product.
Conclusion: under this chromatographic condition, in Fig. 3, retention time is respectively 7.152min, 10.073min, 12.028min,The chromatographic peak of 17.916min is respectively the look of compound shown in compound, ACV, formula 4 shown in compound shown in formula 2, formula 3Spectrum peak.
Chromatogram shows that in preparation, compound shown in compound, formula 4 shown in compound, formula 3 shown in three impurity formulas 2 is passableBe issued to good separating with main ingredient ACV at same chromatographic condition. Result shows that the method can be used for injection Ah former times Lip riverThe quality testing of Wei.
Comparative example 1
Instrument: Agilent1100 high performance liquid chromatograph, 1100 UV-detectors
Chromatographic column: chromatographic column that octadecylsilane chemically bonded silica is filler (250 × 4.6mm, 5 μ are m);
Mobile phase A: 0.1 volume % ammonium acetate buffer (with phosphorus acid for adjusting pH value to 3.5): acetonitrile=50:50 (v/v)
Mobile phase B: methyl alcohol
Gradient elution sees the following form:
| Time/minute | Mobile phase A/% | Mobile phase B/% |
| 0 | 95 | 5 |
| 15 | 80 | 20 |
| 25 | 60 | 40 |
| 28 | 80 | 20 |
| 30 | 95 | 5 |
Flow velocity: 1.0ml/min
Detect wavelength: 254nm
Column temperature: 35 DEG C
Sampling volume: 10 μ L
Diluent: 0.4 quality % sodium hydroxide solution
Running time: 30 minutes
Experimental procedure: precision takes injection ACV product 100mg, puts in same 10ml volumetric flask, adds enforcementThe impurity location solution that example 1 is prepared dissolves and is diluted to scale, shakes up, and to obtain final product.
Conclusion: compound shown in compound, formula 4 shown in compound shown in formula 2, formula 3 is peak hangover under this chromatographic condition, andSeparating effect is bad, and shown in formula 3, compound and ACV are inseparable.
In description of the invention, it will be appreciated that, term " first ", " second " be only for describing object, and can notBe interpreted as instruction or hint relative importance or the implicit quantity that indicates indicated technical characterictic. Be limited with thus, " theOne ", one or more these features can be expressed or impliedly be comprised to the feature of " second ". In description of the invention,The implication of " multiple " is two or more, unless otherwise expressly limited specifically.
In the description of this description, reference term " embodiment ", " some embodiment ", " example ", " specifically showExample " or the description of " some examples " etc. mean the specific features, structure, material or the spy that describe in conjunction with this embodiment or examplePoint is contained at least one embodiment of the present invention or example. In this manual, to the schematic statement of above-mentioned term notMust for be identical embodiment or example. And specific features, structure, material or the feature of description can be in officeIn one or more embodiment or example with suitable mode combination. In addition, not conflicting in the situation that, the skill of this areaArt personnel can tie the feature of the different embodiment that describe in this description or example and different embodiment or exampleClose and combine.
Although illustrated and described embodiments of the invention above, be understandable that, above-described embodiment is exampleProperty, can not be interpreted as limitation of the present invention, those of ordinary skill in the art within the scope of the invention can be to above-mentionedEmbodiment changes, amendment, replacement and modification.
Claims (9)
1. a method that adopts high-efficient liquid phase chromatogram technique analysis injection ACV and related substance thereof, is characterized in that,The analysis condition of described high performance liquid chromatography is:
Chromatographic column adopting octadecylsilane chemically bonded silica post, chromatographic column is 4.6 × 150mm, in chromatographic column, the particle diameter of filler is2-5 μ m; The mixed solution that employing contains 0.1-0.3 volume % acetate buffer and the first organic solvent is as mobile phase A,And
Adopt the second organic solvent as Mobile phase B, carry out gradient elution, condition of gradient elution is:
Wherein, described related substance is compound shown in formula 2, formula 3 and formula 4;
Adopting phosphoric acid to regulate the pH of the described acetate buffer in described mobile phase A is 2.6-3.0;
Described the first organic solvent is acetonitrile and/or methyl alcohol, and described the second organic solvent is acetonitrile and/or methyl alcohol;
The volume ratio of the acetate buffer in described mobile phase A and described the first organic solvent is (60%-90%): (10%-40％)；
Detection wavelength is 250-260nm;
Flow velocity is 1.0 ml/min-1.2 ml/min;
The column temperature of chromatographic column is 30-40 degree Celsius;
Sampling volume is 10 μ L.
2. method according to claim 1, is characterized in that, adopts phosphoric acid to regulate the described acetic acid in described mobile phase AThe pH of salt buffer is 2.8.
3. method according to claim 1, is characterized in that: the acetate buffer in described mobile phase A and describedThe volume ratio of one organic solvent is (70%～80%): (20%～30%).
4. method according to claim 3, is characterized in that, the acetate buffer in described mobile phase A and describedThe volume ratio of one organic solvent is 80%:20%.
5. method according to claim 1, is characterized in that, described detection wavelength is 254nm.
6. method according to claim 1, is characterized in that, the column temperature of described chromatographic column is 35 degrees Celsius.
7. method according to claim 1, is characterized in that, described high-efficient liquid phase chromatogram technique analysis employing 4.6 ×150mm, the AgilentSB-C18 chromatographic column of 5 μ m, 0.1 volume % ammonium acetate buffer and acetonitrile are that 80:20 is mixed according to volume ratioCooperation is mobile phase A, regulates the pH value to 2.8 of ammonium acetate buffer with phosphoric acid, and acetonitrile, as Mobile phase B, carries out gradient elution,Condition of gradient elution is:
Wherein, column temperature is 35 degrees Celsius, and detection wavelength is 254nm, and flow velocity is 1.2 ml/min, and sampling volume is 10 μ L.
8. method according to claim 1, is characterized in that, described high-efficient liquid phase chromatogram technique analysis employing 4.6 ×150mm, the DikmaC of 5 μ m18Chromatographic column, 0.3 volume % ammonium acetate buffer is that 80:20 mixes work with acetonitrile according to volume ratioFor mobile phase A, regulate the pH value to 2.8 of ammonium acetate buffer with phosphoric acid, acetonitrile, as Mobile phase B, carries out gradient elution, gradientElution requirement is:
Wherein, column temperature is 40 degrees Celsius, and detection wavelength is 260nm, and flow velocity is 1 ml/min, and sampling volume is 10 μ L.
9. method according to claim 1, is characterized in that, described injection ACV adopts 0.4 quality % hydrogen-oxygenChange sodium solution and be mixed with liquid to be measured.
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| CN107543884A (en) * | 2017-08-31 | 2018-01-05 | 中国农业科学院农业质量标准与检测技术研究所 | ACV purity rubric material and preparation method and application |
| CN110702669A (en) * | 2019-09-19 | 2020-01-17 | 湖北科益药业股份有限公司 | Method for rapidly determining content of acyclovir gel |
| CN114441659B (en) * | 2020-11-03 | 2024-10-01 | 沈阳兴齐眼药股份有限公司 | Method for detecting ganciclovir and related substances in ganciclovir ophthalmic gel |
| CN114047262A (en) * | 2021-10-14 | 2022-02-15 | 湖北省宏源药业科技股份有限公司 | Method for separating and measuring easily hydrolyzed large-polarity compound |
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| CN101105478A (en) * | 2007-07-31 | 2008-01-16 | 复旦大学附属华山医院 | Method for determining human plasma antiviral drug concentration |
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