CN102207492B - Quantitative analysis method for biapenem dimer in biapenem - Google Patents
Quantitative analysis method for biapenem dimer in biapenem Download PDFInfo
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- CN102207492B CN102207492B CN2011100650985A CN201110065098A CN102207492B CN 102207492 B CN102207492 B CN 102207492B CN 2011100650985 A CN2011100650985 A CN 2011100650985A CN 201110065098 A CN201110065098 A CN 201110065098A CN 102207492 B CN102207492 B CN 102207492B
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Abstract
The invention relates to a quantitative analysis method for a biapenem dimer in biapenem. The quantitative analysis method is characterized in that: the quantitative analysis method comprises the following steps: 1) adding water to biapenem sample to dissolve and dilute the biapenem sample; 2) separating and positioning the resulting solution from the step 1) through a isocratic elution according to the following chromatographic conditions: mobile phase: a trifluoroacetic acid-methyl cyanides solution having a volume concentration of 0.05%, flow rate: 0.8-1.2 ml/min, chromatographic column: C18, detection wavelength: 318nm; 3) obtaining a content of the biapenem dimer in the biapenem through a ratio of a peak area of the biapenem dimmer to a total peak area in a chromatogram. The method has advantages of strong specificity and high sensitivity, can rapid determine the biapenem dimmer A and the biapenem dimmer B in the biapenem, such that safety of the biapenem is ensured.
Description
[technical field]
The present invention relates to the Pharmaceutical Analysis field, particularly a kind of quantitative analysis method of biapenem dimer in biapenem.
[background technology]
As shown in Figure 1, Biapenem is a kind of novel 1 Beta-methyl carbapenem antibiotic, for atypical beta-lactam, the synthetic antibacterial action that produces by the anti-bacteria cell membrane, can tolerate the hydrolytic action of multiple beta-lactamase, have stronger stability, its specific activity Imipenem that suppresses Pseudomonas aeruginosa and anaerobion is strong 2～4 times, suppress drug-resistant pseudomonas aeruginosa specific activity Meropenem strong 4～8 times, more effective than cefotaxime to acinetobacter calcoaceticus, anaerobion.Its preparation is the injection Biapenem, 2003 in Japan's approval listing, the clinical superinfection that septicemia, pneumonia, lung's abscess, chronic respiratory disease that treatment causes by sensitive bacterial cause, intractable cystitis, pyelonephritis, peritonitis, the gynaecologic accessory inflammation etc. of being applicable to; Use said preparation bad reaction to occur sometimes: allergic reaction, these bad reactions are relevant with the Biapenem polymkeric substance existed in the injection Biapenem, in order to reduce the user, allergic reaction appears, need to reduce and use the Biapenem product that contains excessive Biapenem polymkeric substance, how to judge that it is exactly purpose of the present invention that the Biapenem product contains how many Biapenem polymkeric substance.
Because Biapenem is full synthetic antibiotic series products, due to space steric effect, the Biapenem polymkeric substance mostly is dipolymer; As shown in Figure 2 A and 2 B, biapenem dimer comprises biapenem dimer A and biapenem dimer B.
[summary of the invention]
The technical problem to be solved in the present invention is to provide a kind of quantitative analysis method of biapenem dimer in biapenem, can judge fast the amount that contains biapenem dimer in the Biapenem raw material.
Above-mentioned technical matters solves by the following technical programs:
A kind of quantitative analysis method of biapenem dimer in biapenem, is characterized in that, comprises the following steps:
1) get the Biapenem sample, dilution is dissolved in water;
2) according to following chromatographic condition, above-mentioned solution is separated to location:
Mobile phase: trifluoroacetic acid-acetonitrile solution that volumetric concentration is 0.05%, flow velocity 0.8-1.2ml/min, chromatographic column: C18, detect wavelength: 318nm, isocratic elution;
3) the material peak area of biapenem dimer in chromatogram and the ratio of the peak total area are drawn to the content of biapenem dimer in biapenem.
In described trifluoroacetic acid-acetonitrile solution, the volume ratio of trifluoroacetic acid and acetonitrile=92: 8.
Described flow velocity is 1ml/min.
This method specificity is strong, highly sensitive, and biapenem dimer A and the biapenem dimer B of Biapenem in rapid judgement Biapenem can be arranged, and guarantees the security of Biapenem.
The present invention also provides a kind of preparation method of biapenem dimer simultaneously, comprises the following steps:
1) get the Biapenem sample, adding volumetric concentration is 0.05% trifluoroacetic acid solution dissolved dilution, in room temperature, places 1-2 hour;
2) according to following chromatographic condition, above-mentioned solution is separated to location:
Mobile phase: trifluoroacetic acid-acetonitrile solution that volumetric concentration is 0.05%, flow velocity 0.8-1.2ml/min, chromatographic column: C18, detect wavelength: 318nm, isocratic elution;
3) collect the biapenem dimer in above-mentioned separator.
In described trifluoroacetic acid-acetonitrile solution, the volume ratio of trifluoroacetic acid and acetonitrile=92: 8.
Described flow velocity is 1ml/min.
The present invention has advantage: between each peak, degree of separation is good, and noiseless impurity produces, and the failure condition gentleness is convenient to collection and is prepared biapenem dimer.
[accompanying drawing explanation]
The molecular structural formula figure that Fig. 1 is Biapenem;
The molecular structural formula figure that Fig. 2 A is biapenem dimer A;
The molecular structural formula figure that Fig. 2 B is biapenem dimer B;
The chromatogram that Fig. 3 is Biapenem solution;
The ultraviolet spectrogram that Fig. 4 A is biapenem dimer A;
The ultraviolet spectrogram that Fig. 4 B is biapenem dimer B.
[embodiment]
Embodiment mono-
Before the amount that contains biapenem dimer in judgement Biapenem raw material, the design people prepares biapenem dimer A and biapenem dimer B and confirmation by the following method in Biapenem solution:
1) preparation system employment and suitability test (E & ST) solution: get the about 0.1g of Biapenem sample, after the trifluoroacetic acid solution that to add the 10ml volumetric concentration be 0.05% is dissolved, place 2 hours (now in room temperature, there have been biapenem dimer A and biapenem dimer B in solution), get again the above-mentioned solution of 3ml to the 20ml measuring bottle, be diluted with water to the 20ml scale, shake up, standby; [select 0.05% trifluoroacetic acid solution for destroying solvent (the pH value is about 2.4), with this understanding, Biapenem is easier to polymerization, can form biapenem dimer A and biapenem dimer B; Be chosen under room temperature condition and place, do not produce and disturb impurity, between each peak, degree of separation is good; Time is controlled at the dipolymer amount produced in 1～2 hour and all meets positioning requirements, and standing time is long, and one of them dipolymer is unstable, and content reduces.]
2) confirm:
As shown in Figure 3, adopt Shimadzu 20A type high performance liquid chromatograph, system suitability solution is separated, concrete chromatographic condition is: filling agent: octadecyl silane, mobile phase: trifluoroacetic acid-acetonitrile solution that volumetric concentration is 0.05% (volume ratio of trifluoroacetic acid and acetonitrile=92: 8), flow velocity 1.0ml/min, chromatographic column: C18, detect wavelength: 318nm, isocratic elution;
By mass spectrometer, above-mentioned separator being detected to confirmation again, exist two m/z to be 701 material, is respectively biapenem dimer A and biapenem dimer B.
Therefore, we can prepare biapenem dimer A and biapenem dimer B by the following method:
1) get the Biapenem sample, after the trifluoroacetic acid solution that to add volumetric concentration be 0.05% is dissolved, in room temperature place 2 hours standby;
2) according to following chromatographic condition, above-mentioned solution is separated to location:
Mobile phase: trifluoroacetic acid-acetonitrile solution that volumetric concentration is 0.05%, flow velocity 1.0ml/min, chromatographic column: C18, detect wavelength: 318nm, isocratic elution;
3) collect biapenem dimer A and the biapenem dimer B in above-mentioned separator.
Simultaneously, by mass spectrometric confirmation, we can know by above-mentioned chromatographic condition and undertaken in detachment process, and the material peak of those two time periods is biapenem dimer A and biapenem dimer B; And as shown in Figure 3, separated by above-mentioned chromatographic condition, between each peak, degree of separation is good, and analysis time is short, noiseless impurity produces, and the failure condition gentleness meets and measures needs.Therefore, by above-mentioned chromatographic condition, Biapenem solution is separated, as long as the material peak occurs in the corresponding time, just think that there is corresponding biapenem dimer in Biapenem solution, then calculates in Biapenem according to the peak-to-peak area amount that contains biapenem dimer.
The amount that contains biapenem dimer in judgement Biapenem raw material:
Need testing solution: get the about 15mg of Biapenem sample, put in the 10ml measuring bottle, be dissolved in water and be diluted to the 10ml scale, shake up, standby; The effect of this need testing solution is the existence of reaffirming biapenem dimer A and biapenem dimer B.
Contrast solution: get above-mentioned need testing solution 2ml, put in 100ml bottle amount, be dissolved in water and be diluted to the 100ml scale, shake up, standby; The effect of this solution is for calculating the content of biapenem dimer.
Adopt Shimadzu 20A type high performance liquid chromatograph, need testing solution is separated respectively to location with contrast solution, concrete chromatographic condition is: filling agent: octadecyl silane, mobile phase: trifluoroacetic acid-acetonitrile solution that volumetric concentration is 0.05% (volume ratio of trifluoroacetic acid and acetonitrile=92: 8), flow velocity 1.0ml/min, chromatographic column: C18, detect wavelength: 318nm, isocratic elution.
After testing, the material peak of biapenem dimer A and the material peak of biapenem dimer B do not appear in the corresponding time period in chromatographic process; Therefore, we think that this batch of Biapenem sample do not contain biapenem dimer A and biapenem dimer B.
Selection for the detection wavelength:
As shown in Figure 4 A and 4 B shown in FIG., the biapenem dimer A detected by the employing diode array detector and the ultraviolet spectrogram of biapenem dimer B are known, biapenem dimer A has absorption maximum about the wavelength place of 318nm, biapenem dimer B has absorption maximum about the wavelength place of 367nm, and at the 318nm wavelength, also there is larger absorption at place.And under the 318nm wavelength, the response maximum of biapenem dimer A and biapenem dimer B, sensitivity is the highest.Consider the maximum absorption wavelength of biapenem dimer and the sensitivity of detection, select 318nm for detecting wavelength.
Embodiment bis-
Get the about 2g of Biapenem sample, after the trifluoroacetic acid solution that the volumetric concentration that adds 2ml is 0.05% is moistening, dry in 80 ℃ of baking ovens, standby.
Need testing solution: get the about 15mg of above-mentioned oven dry thing, put in the 10ml measuring bottle, be dissolved in water and be diluted to the 10ml scale, shake up, standby.
Contrast solution: get above-mentioned need testing solution 2ml, put in 100ml bottle amount, be dissolved in water and be diluted to the 100ml scale, shake up, standby.
Adopt Shimadzu 20A type high performance liquid chromatograph, above-mentioned need testing solution and contrast solution are carried out to separation determination, concrete chromatographic condition is: filling agent: octadecyl silane, mobile phase: trifluoroacetic acid-acetonitrile solution that volumetric concentration is 0.05% (volume ratio of trifluoroacetic acid and acetonitrile=92: 8), flow velocity 1.0ml/min, chromatographic column: C18, detect wavelength: 318nm, isocratic elution.
After testing, the material peak of biapenem dimer A and the material peak of biapenem dimer B all occur in the corresponding time period of chromatographic process, calculate according to the peak-to-peak Area Ratio, in drying thing, the content of A Peinan dipolymer A is 0.05%, and the content of biapenem dimer B is 0.35%.
The present invention is not limited to above-described embodiment, based on above-described embodiment, simple replacement that do not make creative work, should belong to the scope that the present invention discloses.
Claims (6)
1. the quantitative analysis method of a biapenem dimer in biapenem, is characterized in that, comprises the following steps:
1) get the Biapenem sample, dilution is dissolved in water;
2) according to following chromatographic condition, above-mentioned solution is separated to location:
Mobile phase: trifluoroacetic acid-acetonitrile solution that volumetric concentration is 0.05%, flow velocity: 0.8-1.2ml/min, chromatographic column: C18, detect wavelength: 318nm, isocratic elution;
3) the material peak area of biapenem dimer in chromatogram and the ratio of the peak total area are drawn to the content of biapenem dimer in biapenem;
Described biapenem dimer is biapenem dimer A (I) and biapenem dimer B (II),
2. quantitative analysis method according to claim 1, is characterized in that, in described trifluoroacetic acid-acetonitrile solution, and the volume ratio of trifluoroacetic acid and acetonitrile=92: 8.
3. quantitative analysis method according to claim 1, is characterized in that described flow velocity is 1ml/min.
4. the preparation method of a biapenem dimer, is characterized in that, comprises the following steps:
1) get the Biapenem sample, adding volumetric concentration is 0.05% trifluoroacetic acid solution dissolved dilution, in room temperature, places 1-2 hour;
2) according to following chromatographic condition, above-mentioned solution is separated to location:
Mobile phase: trifluoroacetic acid-acetonitrile solution that volumetric concentration is 0.05%, flow velocity: 0.8-1.2ml/min, chromatographic column: C18, detect wavelength: 318nm, isocratic elution;
3) collect the biapenem dimer in the above-mentioned separator of preparation;
Described biapenem dimer is biapenem dimer A (I) and biapenem dimer B (II),
5. preparation method according to claim 4, is characterized in that, in described trifluoroacetic acid-acetonitrile solution, and the volume ratio of trifluoroacetic acid and acetonitrile=92: 8.
6. preparation method according to claim 4, is characterized in that, described flow velocity is 1ml/min.
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