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Method for measuring Doripenem and/or relevant substances by utilizing high performance liquid chromatography

A technology of high performance liquid chromatography and related substances, applied in the field of drug analysis, can solve the problem of unstable doripenem peak time, unfavorable impurity research, poor reproducibility between batches and between columns and columns, etc. question

Active Publication Date: 2013-11-13
SHENZHEN HAIBIN PHARMA
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  • Summary
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  • Claims
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AI Technical Summary

Problems solved by technology

[0007] The shortcomings of the above two methods are: 1) The L-columnODS and ZorbaxSB-C18 chromatographic columns used are all general-purpose octadecylsilane bonded silica gel fillers (Octadecylsilyl, ODS for short)
The disadvantages of this method are: 1) good baseline separation between the main peak and impurity peaks, and between impurities and impurities cannot be achieved, and the measurement results are not accurate; 2) the peak eluting time of doripenem is unstable, with a difference of about 5 minutes between batches, Not conducive to impurity research
3) This method is not suitable for the determination of related substances of doripenem
[0009]Therefore, in the prior art, the method for determining doripenem by high performance liquid chromatography has the main peak and the impurity peak, and the impurity and the impurity can not achieve a good balance. Baseline separation, unstable doripenem peak elution time between batches, poor reproducibility between batches and columns, inaccurate determination results, and lack of methods for the determination of related substances

Method used

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  • Method for measuring Doripenem and/or relevant substances by utilizing high performance liquid chromatography
  • Method for measuring Doripenem and/or relevant substances by utilizing high performance liquid chromatography
  • Method for measuring Doripenem and/or relevant substances by utilizing high performance liquid chromatography

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] Example 1 Selection of mobile phase-stationary phase system

[0098] Referring to the prior art, the effects of different mobile phase-stationary phase systems on the detection of doripenem and related substances were investigated

[0099] 1.1 MOPS (3-(N-morpholino)propanesulfonic acid)

[0100] Chromatographic column: general-purpose C18 column (4.6×250, 5 μm); column temperature: 25°C; mobile phase: 10mmol / L MOPS (adjust pH=5.7 with acetic acid) as mobile phase A, acetonitrile as mobile phase B; flow rate : 1.0ml / min, detection wavelength: 230nm; using the gradient elution program in Table 1, see the detection results figure 1 A and Table 4.

[0101] Table 1 MOPS gradient elution program

[0102] t (min)

0

15

30

35

45

50

51

56

A（%）

96

96

90

90

85

85

96

96

B（%）

4

4

10

10

15

15

4

4

[0103] 1.2 Ammonium acetate

[0104] Chromatographic col...

Embodiment 2

[0115] Example 2 Validation of mobile phase-stationary phase systems

[0116] In order to exclude the influence of the mobile phase on the separation effect, phosphate solution-acetonitrile was used as the mobile phase uniformly to investigate the separation effect of different immobilized phases on doripenem and related substances.

[0117] 2.1 Test object

[0118] Universal C8 column: Agilent ZORBAX Eclipse plus C8 (4.6×250mm, 5μm);

[0119] Universal C18 column: Merck LP C18 (4.6×250mm, 5μm);

[0120] Octadecylsilane bonded silica gel column with polar groups (aqueous C18 column): Welch Polar-RP (4.6×250mm, 5μm).

[0121] 2.2 Experimental method

[0122] A 0.02 mol / L potassium dihydrogen phosphate buffer solution adjusted to pH=5.7 with freshly prepared KOH was used as the mobile phase A, and acetonitrile was used as the mobile phase B; the gradient elution program shown in Table 5 was used. Column temperature: 25°C, flow rate: 1ml / min, detection wavelength: 230nm.

...

Embodiment 3

[0135] Example 3 Choice of detection wavelength

[0136] Chromatographic column: Octadecylsilane bonded silica gel chromatographic column Welch Polar-RP (5μm, φ4.6×250mm) with bonded polar groups;

[0137] Sample: 2.5mg / mL doripenem aqueous solution;

[0138] Injection volume: 10μl;

[0139] Flow rate: 1.0ml / min;

[0140] Column temperature: 25°C;

[0141] Mobile phase A is KH 2 PO 4 Aqueous solution (0.02mol / L, adjusted to pH 5.7 with KOH), mobile phase B is acetonitrile, gradient elution according to Table 5;

[0142] The same sample was detected at wavelengths of 210nm, 220nm, 230nm, 240nm, 250nm and 298nm.

[0143] Experimental results: see Figure 5 . The peak area of ​​each impurity peak in the spectrum was integrated, and the percentage content of each impurity was calculated using the normalization method. The results are shown in Table 8.

[0144] Table 8 The status of impurities detected at different wavelengths

[0145]

[0146] The maximum ultraviole...

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Abstract

The invention provides a method for measuring Doripenem and / or relevant substances by utilizing a high performance liquid chromatography. The method comprises the following steps of: measuring by utilizing an ultraviolet detector with the detection wavelength of 230nm; with silane-bonded silica gel bonded with polar groups as a stationary phase, with a mixture compounded of a sodium salt or sylvite aqueous solution of phosphoric acid with the pH of 4.7-6.0 and the concentration of 0.01-0.2mol / L and acetonitrile as a mobile phase, carrying out isocratic or gradient elution. Compared with the prior art, the method provided by the invention has the advantages that more impurities can be detected, good separation degree and peak shape of the Doripenem and / or relevant substances can be realized, and good base line separation can be realized between the Doripenem and the impurities as well as between the impurities and the impurities; and the method has good reproducibility between batches and between columns and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of drug analysis, in particular to a method for determining doripenem and / or related substances by high performance liquid chromatography. Background technique [0002] Doripenem, chemical name: (+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl 7-oxo-3-[[ (3S,5S)-5-[(Aminosulfonylamino)-methyl]-3-pyrrolidinyl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, structure As shown in (I), it was developed by Japan's Shionogi Company (Shionogi), and it was first listed in Japan in 2005. The trade name is "Finibax", which belongs to 1-beta methyl carbapenem antibiotics and has a broad spectrum. antibacterial activity. [0003] [0004] Related substances, also known as impurities, are mainly starting materials, intermediates, polymers, side reaction products, and degradation products during storage brought in during the production process. Ring-opening degradation products, acid hydrolysis products, polymers and ot...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N30/02
Inventor 张验军张燕张利香王金玲任鹏
Owner SHENZHEN HAIBIN PHARMA
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