CN111239285B - Method for detecting content of genotoxic impurities in Tenofovir alafenamide - Google Patents
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Abstract
The invention discloses a method for detecting the content of genotoxic impurities in tenofovir alafenamide. The detection method comprises the following steps: preparing a to-be-detected sample solution from the to-be-detected tenofovir alafenamide, and preparing reference substance solutions with different concentrations from the impurity E and the impurity G; respectively carrying out high performance liquid chromatography detection on the reference solution, and respectively taking the chromatographic peak areas of the impurities E and G as vertical coordinates and the concentrations of the impurities E and G in the reference solution as horizontal coordinates to prepare standard curves; and (3) carrying out the high performance liquid chromatography detection on the test solution to obtain peak areas of impurities E and G in the test solution, and obtaining the contents of the impurities E and G in the tenofovir alafenamide according to a standard curve. The method can greatly improve the sensitivity of the detection method, the equipment and instruments are common, the detection cost is low, the operation is extremely simple and convenient, and the detection cost and the detection time are greatly saved.
Description
Technical Field
The invention relates to a method for detecting the content of genotoxic impurities in tenofovir alafenamide, belonging to the technical field of pharmaceutical analysis.
Background
Tenofovir alafenamide (Compound I) is under the trade name Vemlidy, and is the first hepatitis B drug approved by the FDA in 10 years 11 and 10 days 2016, and then marketed in Japan in 2016, 12 and 19 days, and European EMA approval in 2017, 1 and 9 days 1 and 9.
In 2017, 4 and 20 days, the European liver research institute issued 2017 edition of the latest hepatitis B management guidelines, wherein for the first line of preferred nucleoside (acid) analogue treatment regimens for treating patients with chronic hepatitis B initially, the guidelines were supplemented with tenofovir disoproxil fumarate and entecavir, in addition to the original tenofovir disoproxil fumarate and entecavir. For patients with kidney or bone disease and/or at risk of developing the above, particularly those who have been exposed to nucleoside analogs, the guidelines recommend first choice treatment with tenofovir alafenamide.
WO2013052094(A1) and NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS,20(4-7),621-628(2001) disclose the preparation method of tenofovir dipivoxil, the synthetic route is shown as follows:
genotoxic impurities (genotoxic impurities) are substances which can damage DNA directly or indirectly, cause genetic mutations or have a carcinogenic predisposition. It features that at very low concentration, it can cause the damage of human genetic material, and has mutagenicity and carcinogenicity, and in the course of application, it seriously threatens the health of human body.
It was found by analysis that in the tenofovir alafenamide prepared by the above method, there were an impurity E (isopropyl-phenyl ((((R) -1- (6-amino-9H-purin-9-yl) propan-2-yl) oxo) methyl) phosphoric acid) and an impurity G ((R) -diisopropyl (((1- (6-amino-9H-purin-9-yl) propan-2-yl) oxo) methyl) phosphoric acid). According to the analysis of ICH M7, these two impurities have alkyl phosphonate (alkyl esters of phosphonic acids) warning structures, so that they should be studied and controlled according to genotoxic impurities.
An important concept in the control of genotoxicity is the Threshold of Toxicological Concern (TTC), the limit of which (1.5 μ g/d) is an acceptable limit for genotoxic impurities below which no significant toxicological effects can be observed. The specific definition is: the risk of carcinogenesis is acceptable in humans throughout their lifetime (70 years) by ingesting 1.5 μ g of genotoxic impurities per day. According to the principle, the limit of genotoxic impurities of the Tenofovir alafenamide is 60 ppm. Therefore, a method for detecting the content of genotoxic impurities in the tenofovir alafenamide is needed.
Disclosure of Invention
The invention aims to provide a method for detecting the content of genotoxic impurities in tenofovir alafenamide (9- [ (R) -2- [ [ (S) - [ [ (S) -1- (isopropyloxycarbonyl) ethyl ] amino ] phenoxy phosphinyl ] methoxy ] propyl adenine hemifumarate).
The genotoxic impurities according to the invention are the impurities E (isopropyl-phenyl (((((R) -1- (6-amino-9H-purin-9-yl) propan-2-yl) oxo) methyl) phosphate) of formula I and the impurity G ((R) -diisopropyl (((1- (6-amino-9H-purin-9-yl) propan-2-yl) oxo) methyl) phosphate) of formula II):
specifically, the method for detecting the content of genotoxic impurities in the Tenofovir alafenamide provided by the invention comprises the following steps:
(1) preparing a sample solution from the to-be-detected tenofovir alafenamide, and preparing reference substance solutions with different concentrations from the impurity E shown in the formula I and the impurity G shown in the formula II;
(2) respectively carrying out high performance liquid chromatography detection on the reference solution, and respectively taking the chromatographic peak areas of the impurity E shown in the formula I and the impurity G shown in the formula II as vertical coordinates, and respectively taking the concentrations of the impurity E shown in the formula I and the impurity G shown in the formula II as horizontal coordinates to prepare a standard curve;
(3) performing the high performance liquid chromatography detection on the test solution to obtain peak areas of the impurity E shown in the formula I and the impurity G shown in the formula II in the test solution, and obtaining the contents of the impurity E shown in the formula I and the impurity G shown in the formula II in the Tenofuravirenzamide according to the standard curve;
in the detection method, in the step (1), acetonitrile aqueous solution is adopted to prepare the test sample solution and the reference solution;
the volume content of acetonitrile in the acetonitrile water solution is preferably 30%;
in the reference solution, the concentration of the impurity E shown in the formula I is 0-4.0 mu G/ml, preferably 0.1-4.0 mu G/ml, and the concentration of the impurity G shown in the formula II is 0-0.2 mu G/ml, preferably 0.02-0.12 mu G/ml.
At least 3 different concentrations of the control solutions were prepared.
In the above detection method, in steps (2) and (3), the conditions for the high performance liquid chromatography detection are as follows:
stationary phase: the stationary phase is octadecylsilane chemically bonded silica, preferably an Ultimate XB-C184.6X 150mm 5-micron chromatographic column;
a detector: an ultraviolet detector with the detection wavelength of 260 cm;
mobile phase A: a phosphate buffer solution;
mobile phase B: acetonitrile;
and (3) an elution mode: gradient elution;
flow rate: 1.0 plus or minus 0.1 mL/mim;
temperature of the column oven: 35 +/-5 ℃.
In the detection method, the elution gradient program comprises:
0-10 min, wherein the volume fraction of the mobile phase A is 75%;
10-15 mim, the volume fraction of the mobile phase A is reduced to 70% from 75%;
15-25 mim, the volume fraction of the mobile phase A is kept at 70%;
25-25.1 mim, the volume fraction of the mobile phase A is increased from 70% to 75%;
25.1-40 mim, the volume fraction of the mobile phase A is kept at 75%.
In the detection method, the concentration of the phosphate buffer solution is 0.01-0.03 mol/L, preferably 0.02 mol/L;
the phosphate buffer solution is potassium dihydrogen phosphate aqueous solution or sodium dihydrogen phosphate aqueous solution, and phosphoric acid is adopted to adjust the pH value.
Since impurity E of formula I is a pair of diastereomers, 2 peaks elute on the chromatogram (FIG. 1).
The contents of the impurity E and the impurity G are not more than 60ppm calculated by an external standard method.
Shown by methodological research, the detection method has good system applicability; the specificity test shows that the blank solvent has no influence on the detection of impurities and has strong specificity; the method has high sensitivity and good accuracy for detecting the two impurities; the solution stability test shows that the test solution adopted by the method is placed at room temperature, and the solution stability is good.
The method can greatly improve the sensitivity of the detection method, the equipment and instruments are common, the detection cost is low, the operation is extremely simple and convenient, and the detection cost and the detection time are greatly saved.
Drawings
FIG. 1 is a system adaptive chromatogram for detecting toxic impurities in a Tenofovir alafenamide gene.
FIG. 2 is a standard curve for impurity E in the control solution.
FIG. 3 is a standard curve of impurity G in the control solution.
FIG. 4 is a chromatogram of a blank solvent, a control solution and a test solution.
FIG. 5 is a graph showing the stability trend of the control solutions.
FIG. 6 is a graph showing the tendency of stability of the test solution.
Detailed Description
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Examples 1,
Taking a proper amount of the Tenofovir alafenamide, adding a diluent (30% acetonitrile aqueous solution, v/v), ultrasonically dissolving, and quantitatively diluting to prepare a solution containing 1.5mg in each 1ml, wherein the solution is used as a test solution.
An appropriate amount of the impurity E and the impurity G were precisely weighed, and quantitatively diluted with a diluent (30% acetonitrile aqueous solution, v/v) to prepare solutions containing 0.091 and 0.089. mu.g of the impurity G and the impurity E, respectively, per 1ml as control solutions.
The detection conditions of the high performance liquid chromatography are as follows:
a chromatographic column: ultimate XB-C184.6X 150mm, 5 μm chromatography column;
a detector: an ultraviolet detector with the detection wavelength of 260 nm;
mobile phase A: 0.02mol/L dipotassium hydrogen phosphate solution (pH value is adjusted to 5.5 by phosphoric acid);
mobile phase B: acetonitrile;
temperature of the column oven: 35 ℃;
flow rate: 1.0 ml/min;
elution gradient, elution program as shown in table 1:
TABLE 1 gradient elution procedure
| Time (min) | Mobile phase A% | Mobile |
| 0 | 75 | 25 |
| 10 | 75 | 25 |
| 15 | 70 | 30 |
| 25 | 70 | 30 |
| 25.1 | 75 | 25 |
| 40 | 75 | 25 |
Precisely measuring 20 μ l of each of the test solution and the reference solution, and injecting into a liquid chromatograph for detection to obtain a chromatogram.
Under the detection conditions, as shown in fig. 1 and table 2, the impurity E is a pair of diastereoisomers, so 2 absorption peaks (6.402min and 6.950min) are eluted on a chromatogram, and the absorption peak of the impurity G appears at 3.737min, and as can be seen from fig. 1, under the detection conditions provided by the invention, the impurities E and G can be effectively separated from the tenofovir alafenamide, and the two impurities can be well separated.
TABLE 2 chromatographic peak results of the chromatogram in FIG. 1
| Retention time | Area of | Number of theoretical plates of USP | Degree of separation of | Peak height | ||
| 1 | 3.737 | 2295 | 3651 | 302 | ||
| 2 | 6.402 | 24656 | 15006 | 11.79 | 3083 | |
| 3 | 6.950 | 28608 | 15672 | 2.49 | 3308 |
Respectively taking the concentrations of the impurity E and the impurity G in the reference substance solution as abscissa and taking the chromatographic peak areas of the impurity E and the impurity G as ordinate, and preparing a standard curve: standard curve for impurity E: concentration range: 0.11-4.04 mu g/ml, and the linear equation y is 26426.3793x-434.7637, r20.9999; standard curve for impurity G: concentration range: 0.02-0.11 mu g/ml, linear equation y is 30823.5294x +114.2132, r20.9985. The results show that the linearity of impurity E and impurity G is good, and the standard graphs are shown in fig. 2 and 3, respectively.
The specificity test shows that the blank solvent has no influence on the detection of impurities, and the method has strong specificity:
blank solvent: acetonitrile-water (30:70, v/v).
Weighing about 2mg of impurity G, placing the impurity G into a 10ml volumetric flask, adding a diluent (30% acetonitrile aqueous solution, v/v) to dissolve and dilute the impurity G to a scale, shaking up, then transferring the solution 1ml into a 100ml volumetric flask, adding the diluent to dilute the solution to the scale, shaking up to obtain an impurity G stock solution, weighing about 2mg of impurity E, placing the impurity E into the 10ml volumetric flask, adding the diluent (30% acetonitrile aqueous solution, v/v) to dissolve and dilute the solution to the scale, shaking up to obtain an impurity E stock solution, transferring 5ml of impurity G stock solution and 1.5ml of impurity E stock solution respectively, placing the impurity G stock solution and the impurity E stock solution into the same 100ml volumetric flask, adding the diluent to the scale, shaking up to obtain an impurity reference product stock solution, transferring 5ml of the impurity reference product stock solution into the 10ml volumetric flask, adding the diluent to dilute the scale, shaking up to obtain two parts in parallel as a reference product solution.
Taking about 10mg of Tenofovir alafenamide, putting the Tenofovir alafenamide into a 10ml measuring flask, adding a diluent (30% acetonitrile aqueous solution, v/v) to dilute to a scale, and shaking up to obtain a sample solution.
Precisely measuring 20 μ l of each sample solution, injecting into a liquid chromatograph for detection, and recording chromatogram, wherein the absorption peaks of the reference solution, the sample solution and the blank solvent are sequentially from top to bottom in the chromatogram as shown in FIG. 4, and it can be seen that the blank solvent does not interfere with the detection of impurities.
The method has high sensitivity and good accuracy in detecting two impurities:
taking a proper amount of an impurity G and an impurity E reference substance, precisely weighing, adding a diluent (30% acetonitrile aqueous solution, v/v) to dissolve and quantitatively dilute to prepare a solution with a certain concentration, gradually diluting the solution to the proper concentration by using a solvent, and performing chromatographic analysis on the solution under the conditions that the signal-to-noise ratio is 3: the amount of the sample injected into the chromatograph at 1 hour was used to determine the detection limit, and the results are shown in Table 3.
TABLE 3 detection limits for impurities G and E
| Name (R) | Concentration (μ g/ml) | S/N | Corresponding to the percentage of the main component (%) |
| Impurity G | 0.006 | 2.66 | 0.001 |
| Impurity E1 | 0.01 | 2.78 | 0.001 |
| Impurity E2 | 0.01 | 2.75 | 0.001 |
As can be seen from Table 3, the signal-to-noise ratios of the impurity G, the impurity E1 and the impurity E2 are all about 3, the detection limit concentrations are respectively 0.006 μ G/ml, 0.01 μ G/ml and 0.01 μ G/ml, which are respectively equivalent to 0.001%, 0.001% and 0.001% of the main component, and the experimental results show that the chromatographic condition of the invention has high sensitivity and is suitable for detecting two impurities.
The solution stability test shows that the test solution and the reference solution are placed at room temperature, and the solution stability is good:
weighing about 2mg of impurity G, placing the impurity G into a 10ml volumetric flask, adding a diluent (30% acetonitrile aqueous solution, v/v) to dissolve and dilute the impurity G to a scale, shaking up, then transferring the solution 1ml into a 100ml volumetric flask, adding the diluent to dilute the solution to the scale, shaking up to obtain an impurity G stock solution, weighing about 2mg of impurity E, placing the impurity E into the 10ml volumetric flask, adding the diluent (30% acetonitrile aqueous solution, v/v) to dissolve and dilute the solution to the scale, shaking up to obtain an impurity E stock solution, transferring 5ml of impurity G stock solution and 1.5ml of impurity E stock solution respectively, placing the impurity G stock solution and the impurity E stock solution into the same 100ml volumetric flask, adding the diluent to the scale, shaking up to obtain an impurity reference product stock solution, transferring 5ml of the impurity reference product stock solution into the 10ml volumetric flask, adding the diluent to dilute the scale, shaking up to obtain two parts in parallel as a reference product solution.
Taking about 10mg of Tenofovir alafenamide, putting the Tenofovir alafenamide into a 10ml measuring flask, adding a diluent (30% acetonitrile aqueous solution, v/v) to dilute to a scale, and shaking up to obtain a sample solution.
Respectively injecting 20 μ l of the test solution and the reference solution at room temperature into a liquid chromatograph at 0min, 140min, 220min, 340min, 500min, 600min, 640min, 680min, 720min, 760min, 800min, 840min, 880min, 920min, 960min and 1000min, and recording chromatogram, wherein the test results are shown in tables 4 and 5, and fig. 5 and 6.
TABLE 4 stability test results for control solutions
TABLE 5 stability test results of test solutions
As can be seen from tables 4 and 5 and fig. 5 and 6, the peak areas of the reference samples of impurity G and impurity E were not greatly changed within 16.6 hours at room temperature; adding an impurity G and an impurity E into a sample solution, wherein the peak areas RSD of the impurities are respectively 1.2 percent and 0.2 percent, and are both less than 5.0 percent, and the impurities do not change greatly; the test solution was stable for 16.6 hours of the time examined.
Claims (4)
1. A method for detecting the content of genotoxic impurities in Tenofovir alafenamide comprises the following steps:
(1) preparing a sample solution from the to-be-detected tenofovir alafenamide, and preparing reference substance solutions with different concentrations from the impurity E shown in the formula I and the impurity G shown in the formula II;
(2) respectively carrying out high performance liquid chromatography detection on the reference solution, and respectively taking the chromatographic peak areas of the impurity E shown in the formula I and the impurity G shown in the formula II as vertical coordinates, and respectively taking the concentrations of the impurity E shown in the formula I and the impurity G shown in the formula II as horizontal coordinates to prepare a standard curve;
(3) performing the high performance liquid chromatography detection on the test solution to obtain peak areas of the impurity E shown in the formula I and the impurity G shown in the formula II in the test solution, and obtaining the contents of the impurity E shown in the formula I and the impurity G shown in the formula II in the Tenofuravirenzamide according to the standard curve;
the detection conditions of the high performance liquid chromatography are as follows:
stationary phase: the stationary phase is octadecylsilane chemically bonded silica;
a detector: an ultraviolet detector with the detection wavelength of 260 nm;
mobile phase A: a phosphate buffer solution;
mobile phase B: acetonitrile;
and (3) an elution mode: gradient elution;
the procedure for the elution gradient was:
0-10 min, wherein the volume fraction of the mobile phase A is 75%;
reducing the volume fraction of the mobile phase A from 75% to 70% in 10-15 min;
15-25 min, keeping the volume fraction of the mobile phase A at 70%;
the volume fraction of the mobile phase A is increased from 70% to 75% in 25-25.1 min;
and (3) keeping the volume fraction of the mobile phase A at 75% for 25.1-40 min.
Flow rate: 1.0 plus or minus 0.1 mL/min;
temperature of the column oven: 35 +/-5 ℃;
2. the content detection method according to claim 1, characterized in that: in the step (1), preparing the sample solution and the reference solution by using acetonitrile aqueous solution;
in the reference solution, the concentration of the impurity E shown in the formula I is 0-4.0 mu G/ml, and the concentration of the impurity G shown in the formula II is 0-0.2 mu G/ml.
3. The content detection method according to claim 1 or 2, characterized in that: the concentration of the phosphate buffer solution is 0.01-0.03 mol/L;
the phosphate buffer solution is potassium dihydrogen phosphate aqueous solution or sodium dihydrogen phosphate aqueous solution, and phosphoric acid is adopted to adjust the pH value.
4. The content detection method according to claim 3, characterized in that: the stationary phase is Ultimate XB-C18.
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