CN111766317A - Method for measuring GS-441524 content in preparation by using polyethylene glycol and water - Google Patents
Method for measuring GS-441524 content in preparation by using polyethylene glycol and water Download PDFInfo
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Abstract
The invention discloses a method for measuring the content of GS-441524 in a preparation by using polyethylene glycol and water, which comprises the following steps: a. preparing a test sample, namely precisely measuring a test preparation of the Rudexilvir intermediate, and diluting the test preparation into the test sample by using acetonitrile/water solution; b: preparing a standard solution, namely precisely weighing a reference substance, dissolving the reference substance by using acetonitrile/water solution and quantitatively diluting the reference substance into a series of standard solutions step by step; c: liquid chromatography-mass spectrometry combined method determination: quantitatively measuring the series of standard solutions in the step b to perform liquid chromatography-mass spectrometry combined determination, and calculating a standard curve by using the peak area in the extraction ion flow graph of GS-441524; quantitatively measuring the sample to be tested in the step a for liquid chromatography mass spectrometry; the double peak phenomenon of the sample is avoided; the GS-441524 has good separation degree from polyethylene glycol molecules; the mass spectrum detection limit is better than 0.05 mu g/mL, and the quantification limit is better than 0.1 mu g/mL.
Description
Technical Field
The invention relates to the field of pharmaceutical analysis, in particular to a method for determining the content of a Rudexilvir intermediate GS-441524 in a preparation with polyethylene glycol and water as solvents.
Background
The Ruideciclovir intermediate GS-441524 is a small molecular nucleotide analogue, which is a precursor molecule for synthesizing nucleoside triphosphate with pharmacological activity; GS-441524, also known as a nucleoside triphosphate competitive inhibitor, exhibits potent antiviral activity against many RNA viruses.
CAS registry number of GS-441524: 1191237-69-0, formula: C12H13N5O4 molecular weight: 291.267, respectively; the systematic chemical name is (2R,3R,4S,5R) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile; the chemical name of English is (2R,3R,4S,5R) -2- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3,4-dihydroxy-5- (hydroxymethy) tetrahydrofuran-2-carbonitrile.
GS-441524 has been reported in literature as having strong inhibitory effect on Feline Infectious Peritonitis (FIP) virus, half maximal Effect Concentration (EC)50) 0.78. mu.M; GS-441524 acts pharmacologically as an alternative substrate for viral RNA polymerase, allowing viral RNA strand polymerization to terminate; whether the GS-441524 content is used as a synthetic intermediate or a metabolite of the Reidcisvir or is directly used as a medicine, the GS-441524 content is required to be accurately determined in the field of medicine analysis; at present, no report related to a method for measuring the content of the Ruideciclovir intermediate GS-441524 in a preparation system taking polyethylene glycol and water as solvents is found in domestic and foreign documents.
Disclosure of Invention
The invention aims to solve the problem of providing an analysis method which is simple and rapid to operate and has good accuracy and precision, and the analysis method is used for measuring the content of the Reidesciclovir intermediate GS-441524 in a preparation system taking polyethylene glycol and water as solvents.
In order to solve the technical problems, the invention adopts the technical scheme that: a method for measuring the content of a Reidesciclovir intermediate GS-441524 in a preparation with polyethylene glycol and water as solvents comprises the following steps:
A. preparation of test samples
Precisely measuring a test preparation of polyethylene glycol/water solvent of the Rudexiliwei intermediate GS-441524, putting the test preparation into a volumetric flask, diluting the test preparation with acetonitrile/water solution, and shaking up to prepare a test sample.
B: preparation of Standard solutions
Accurately weighing GS-441524 reference substance (content >99%), dissolving with acetonitrile/water solution, fixing volume, and shaking; then using acetonitrile/water solution to dilute the solution step by step quantitatively to prepare a series of solutions with the concentration of 0.05 mu g/mL-10 mu g/mL, and filtering the solutions by using a 0.22 mu m microporous filter membrane to obtain a series of standard solutions.
C: liquid chromatography-mass spectrometry combined method for determination
Quantitatively measuring the series of standard solutions in the step B, measuring by a liquid chromatography-mass spectrometry combined method, and calculating a standard curve; quantitatively measuring the sample to be tested in the step A, and measuring by a liquid chromatography-mass spectrometry combination method under the same conditions; the content of GS-441524 in the test sample was calculated as the peak area by the external standard method.
Further, the diluent used in the step A is an organic-inorganic mixed solution of acetonitrile/water (1: 9, v/v).
Further, the diluent used in the step B is an organic-inorganic mixed solution of acetonitrile/water (1: 9, v/v).
Further, the chromatographic column packing used in the step C is Octadecylsilane (ODS) bonded silica gel packing.
Further, the specification of the chromatographic column used in the step C is as follows: the inner diameter is 2.1mm, the length is 50-150 mm, and the grain diameter of the filler is 1.7-1.8 μm.
Further, the mass spectrometer used in step C is equipped with an atmospheric pressure interface for liquid mass spectrometry.
Further, the mass spectrometer used in the step C works in a positive ion mode, and the mass detection range is 100-1000 Dalton.
Further, the chromatographic conditions used in step C were: the column temperature is 25-38 ℃; the flow rate is 0.2-0.3 mL/min; taking acetonitrile and water as two phases of mobile phases, and performing gradient elution; the sample injection amount is 1-5 mu L.
Further, the peak area used in the quantitative calculation in the step C is the peak area in the extracted ion flow graph of GS-441524.
Furthermore, formic acid with the same concentration is added into both acetonitrile and water phase to be used as a modifier, and the addition concentration is 0.2-0.3% (v/v).
Further, according to fig. 5, wherein a is an aqueous phase and B is an acetonitrile phase:
further, the proton adduct ion of GS-441524 was extracted from the total ion flow diagram, and its mass/charge ratio was m/z 292.1.
Adopt the produced beneficial effect of above-mentioned technical scheme to lie in: the method adopts an external standard method to simply, quickly and accurately measure the content of GS-441524 in a preparation taking polyethylene glycol and water as solvents; for the solvent used in the sample preparation process, the inventor adopts the initial proportion of the mobile phase to prepare the diluent for the sample, thereby effectively avoiding the solvent elution phenomenon in the liquid chromatogram, avoiding the bimodal phenomenon of sample substances and avoiding the retention time drift phenomenon; through development and test, the inventor finally determines two phases using acetonitrile and water as mobile phases, adds modifier formic acid with the same proportion in the two phases, and performs gradient elution, thereby ensuring good separation degree of a sample and polyethylene glycol and ensuring a rapid analysis process; the formic acid modifier not only ensures that the peak shape of GS-441524 in a result spectrogram is symmetrical, but also ensures the ionization efficiency of a sample in the process of entering a mass spectrometer, and avoids the phenomenon of ion inhibition; the peak area of GS-441514 in an ion flow graph extracted from a mass spectrum detection result is aimed at in the calculation of the external standard method, and the method is high in specificity.
Drawings
The present invention will be described in further detail with reference to the accompanying drawings and specific embodiments.
FIG. 1 is a graph of Total Ion Current (TIC) and extract ion current (XIC) of a test sample according to a first embodiment of the present invention,
FIG. 2 is a second graph of Total Ion Current (TIC) and extract ion current (XIC) of the test sample according to the first embodiment of the present invention,
figure 3 is a linear relationship diagram of a first embodiment of the invention,
FIG. 4 is a mass spectrometry scan at a retention time of 0.91min according to a first embodiment of the present invention,
FIG. 5 is a schematic diagram of a gradient elution procedure,
figure 6 shows the results of the precision test,
figure 7 is a graph of the results of normalized recovery,
FIG. 8 shows the results of the sample stability test.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments; all other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those specifically described and will be readily apparent to those of ordinary skill in the art without departing from the spirit of the present invention, and therefore the present invention is not limited to the specific embodiments disclosed below.
Example one
1. Instruments and reagents
High performance liquid chromatography (Agilent-1290, USA with DAD detector); mass spectrometer (abciex 5600+, usa); analytical balance (sartorius bsa224S, sartorius scientific instruments (beijing) ltd.); an ultrasonic cleaning apparatus (KQ-100DE type, ultrasonic instruments Co., Ltd., Kunshan city); GS-441524 control (commercially available, content > 99%); acetonitrile was chromatographically pure water prepared by a water purifier (Milli-Qdirect 8, Millipore, France) and the other reagents were analytically pure reagents.
2. Content detection of GS-441524 in sample
A. Preparation of test samples
Precisely measuring 100 mu L of the sample preparation, diluting 10000 times by acetonitrile/water (1: 9, v/v) solution step by step to prepare the sample solution, and filtering the sample solution through a 0.22 mu m microporous filter membrane to be detected.
B. Preparing standard solution
Accurately weighing 50mg of GS-441524 reference substance, ultrasonically dissolving with acetonitrile/water (1: 9, v/v), and diluting to 250mL to obtain mother liquor; the mother liquor is diluted by acetonitrile/water (1: 9, v/v) solution step by step to obtain a series of standard solutions with the concentrations of 0.05 mu g/mL, 0.1 mu g/mL, 2.0 mu g/mL, 4.0 mu g/mL, 6.0 mu g/mL, 8.0 mu g/mL and 10 mu g/mL, and the standard solutions are filtered by a 0.22 mu m microporous filter membrane to be tested.
3. Chromatographic-mass spectrometry combined analysis condition
A chromatographic part: the chromatographic column was ACQUITYUPLCBEHC18 (2.1X 50mm, 1.7 μm) from Waters (USA); mobile phase a was water (0.2% formic acid), mobile phase B was acetonitrile (0.2% formic acid), both ultrasonically degassed for 30 minutes prior to use to remove air bubbles in the mobile phase; the elution speed of the mobile phase is 0.2mL/min, the column temperature is 38 ℃, the detection wavelength of DAD is 190-400 nm, and the sample injection amount is 2 mu L.
And mass spectrum part: the ion source working mode is an electrospray ionization (ESI) positive ion mode; atomizing air flow 55 psi; auxiliary gas 55 psi; air curtain air 35 psi; the temperature is 550 ℃; ionization voltage + 5000V; mass spectrometry scanning mode primary mass spectrometry scanning; and scanning the mass by 100-1000 Dalton.
For the type selection and proportion of the mobile phase, development tests are carried out; as a result, 0.2% formic acid acetonitrile solution is selected as an organic phase, 0.2% formic acid water is selected as an inorganic phase, the gradient program of the method is used for elution, and the chromatographic separation process is completed within 6 min; in the obtained spectrogram, GS-441524 and polyethylene glycol each mass component and other impurities realize separation above base line, GS-441524 retention time is about 0.91min, and peak shape is symmetrical, as shown in the upper part of figure 1; extracting m/z292.1 ion signals from the total ion flow diagram to obtain a GS-441524 proton addition ion flow diagram which is listed at the lower part of the figure 1; from the figure, it can be seen that GS-441524 has high signal-to-noise ratio (S/N), indicating that the method has high specificity and the test result is satisfactory.
4. Linear range investigation
Taking 0.1 mu g/mL, 2.0 mu g/mL, 4.0 mu g/mL, 6.0 mu g/mL, 8.0 mu g/mL and 10 mu g/mL series of standard solutions for sequential analysis; measuring each standard solution by using a2 mu L injection liquid mass spectrometer according to the method of the invention, and recording a total ion flow diagram; drawing a standard curve graph by taking the concentration C (mu g/mL) of the standard solution as an abscissa and taking the peak area A in a GS-441524 extraction ion flow (m/z 292.1) graph as an ordinate, as shown in FIG. 3; through standard curve data calculation, a linear regression equation y =10.837x +0.4433 and a linear correlation coefficient R =0.9970 are obtained, which shows that the GS-441524 has a good linear relation in a range of 0.1-10 μ g/mL.
5. Detection of GS-441524 content in sample
Taking a sample solution to be tested, injecting 2.0 mu L of the sample solution into a liquid chromatograph, developing according to the method of the invention, recording a total ion flow diagram, and repeating for 3 times; extracting an extraction ion flow diagram of m/z292.1 from the total ion flow diagram; and substituting the average value of the peak area corresponding to RT =0.91min for 3 times in the extraction ion flow graph into a linear regression equation to calculate that the content of GS-441524 in the sample to be tested is 15.12 mg/mL.
The result shows that the detection method of the invention can well separate GS-441524, polyethylene glycol series components in the preparation and other impurities; when the retention time RT =0.91min, only the proton-plus-ion peak m/z292.1 of GS-441524 is visible from the mass scan FIG. 4, which shows that the specificity of the invention is high.
6. Precision survey
Taking a sample solution to be tested, carrying out continuous sample introduction for 9 times according to the sample introduction amount of 2 mu L, and determining according to the method of the invention; the peak area of the extracted ion flow diagram of m/z292.1 is used for calculating the average value and the Relative Standard Deviation (RSD), and according to the graph 6, the method for determining the GS-441524 content is shown to have high precision, good reproducibility and small relative standard deviation.
7. Spiking recovery survey
Adding a reference substance into the test sample solution to prepare a standard sample; the additive amount is 0.50 mu g/mL; according to the method of the invention, 5 determinations are performed in parallel; the measurement result is expressed by the formula:
standard recovery rate = (standard sample measured concentration-test sample measured concentration)/standard addition amount x 100%
Calculating the recovery rate; the recovery of spiked 5 times, the average spiked recovery and the RSD value in parallel, are shown in FIG. 7.
8. Stability testing of solutions
Taking the prepared sample solution as a stability investigation sample, sealing and storing at 4 ℃; sampling and measuring at 0, 6, 12, 24 and 48 hours respectively; according to the method, the standard curve is determined again for each batch, and then the stability investigation sample is determined and the content of GS-441524 is calculated according to the figure 8; according to the relative standard deviation value RSD =1.06% of the content result, the solution stability of the test article is good after the test article is placed under a 4 ℃ sealing condition for 48 hours in the method.
9. Determination of detection and quantitation limits
The ratio (signal-to-noise ratio, S/N) of the peak height to the baseline noise in an extraction ion current (m/z 292.1) diagram of GS-441524 is greater than 3, and experiments show that the detection limit of the method is better than 0.05 mu g/mL; experiments show that the quantitative limit of the method is better than 0.1 mu g/mL by taking the signal-to-noise ratio (S/N) of more than 10 as the quantitative limit standard.
The 4-9 methodological investigation test results show that the method has good specificity, the results show that GS-441524 in a preparation taking polyethylene glycol and water as solvents presents a good linear relationship in the range of 0.1-10 mug/mL, the precision, the stability and the recoverability are good, the average recovery rate is 98.5 percent, the method is simple and rapid, the content measurement is accurate and reliable, and no interference peak exists; the separation degree, the tailing factor and the symmetry factor all accord with the general requirements of Chinese pharmacopoeia, the detection result is good, and the method can be used for the inspection control of the content item.
Claims (12)
1. A method for measuring the content of GS-441524 in a preparation by using polyethylene glycol and water is characterized by comprising the following steps:
a. preparation of test samples
Precisely measuring a test preparation of polyethylene glycol/water solvent of a Rudexiliwei intermediate GS-441524, placing the test preparation into a volumetric flask, diluting the test preparation with acetonitrile/water solution, and shaking up to prepare a test sample;
b: preparation of Standard solutions
Accurately weighing GS-441524 reference substance (content >99%), dissolving with acetonitrile/water solution, fixing volume, and shaking; then using acetonitrile/water solution to dilute quantitatively step by step to prepare solution with the concentration of 0.05 mu g/mL-10 mu g/mL, and filtering by using a 0.22 mu m microporous filter membrane to obtain standard solution;
c: liquid chromatography-mass spectrometry combined method for determination
Quantitatively measuring the series of standard solutions in the step b to perform liquid chromatography-mass spectrometry combined determination, and calculating a standard curve by using the peak area in the extraction ion flow graph of GS-441524; quantitatively measuring the sample to be tested in the step a, and measuring by a liquid chromatography-mass spectrometry combination method under the same conditions; and calculating the content of GS-441524 in the sample to be tested according to the peak area in the extracted ion flow graph of GS-441524 by an external standard method.
2. The method according to claim 1, wherein the preparation of a sample is characterized in that: the diluent used in the step a is an organic-inorganic mixed solution of acetonitrile/water (1: 9, v/v).
3. The method for measuring a content according to claim 1, wherein the preparation of the standard solution comprises: the diluent used in the step b is an organic-inorganic mixed solution of acetonitrile/water (1: 9, v/v).
4. The method for measuring the content of claim 1, wherein the method comprises the following steps: and c, the chromatographic column packing used in the step c is Octadecylsilane (ODS) bonded silica gel packing.
5. The method for measuring the content of claim 1, wherein the method comprises the following steps: the specification of the chromatographic column used in step c is: the inner diameter is 2.1mm, the length is 50-150 mm, and the grain diameter of the filler is 1.7-1.8 μm.
6. The method for measuring the content of claim 1, wherein the method comprises the following steps: the mass spectrometer used in step c is equipped with an atmospheric pressure LC-MS interface.
7. The method for measuring the content of claim 1, wherein the method comprises the following steps: and c, operating the mass spectrometer used in the step c in a positive ion mode, wherein the mass detection range is 100-1000 Dalton.
8. The method for measuring the content of claim 1, wherein the method comprises the following steps: the chromatographic conditions used in step c were: the column temperature is 25-38 ℃; the flow rate is 0.2-0.3 mL/min; taking acetonitrile and water as two phases of mobile phases, and performing gradient elution; the sample injection amount is 1-5 mu L.
9. The method for measuring the content of claim 1, wherein the method comprises the following steps: and c, the peak area used in the quantitative calculation in the step c is the peak area in the extracted ion flow graph of GS-441524.
10. A biphasic eluent according to claim 8 characterised in that: formic acid with the same concentration is added into both acetonitrile and water phases to be used as a modifier, and the addition concentration is 0.2-0.3% (v/v).
11. Gradient elution according to claim 8, characterized in that: the gradient elution procedure is described below, where a is the aqueous phase and B is the organic phase: 0 min: (A90% -B10%) to 0.8 min (A90% -B10%) to 0.9 min (A85% -B15%) to 3.0 min (A85% -B15%) to 5.0 min (A0% -B100%) to 5.2min (A0% -B100%) to 5.3 min (A90% -B10%) to 6.0 min (A90% -B10%).
12. The extracted ion flow graph of claim 9, wherein: and extracting the proton adducted ions of GS-441524 from the total ion flow diagram, wherein the mass-to-charge ratio of the extracted proton adducted ions is m/z 292.1.
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| CN112495328A (en) * | 2020-11-12 | 2021-03-16 | 天津全和诚科技有限责任公司 | Synthesis method of nucleoside triphosphate competitive inhibitor |
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| CN113092624A (en) * | 2021-04-07 | 2021-07-09 | 河南泰丰生物科技有限公司 | Ruidexiwei-related substance and content determination method |
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| CN112495328A (en) * | 2020-11-12 | 2021-03-16 | 天津全和诚科技有限责任公司 | Synthesis method of nucleoside triphosphate competitive inhibitor |
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| CN113092624A (en) * | 2021-04-07 | 2021-07-09 | 河南泰丰生物科技有限公司 | Ruidexiwei-related substance and content determination method |
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