CN111239299B - Method for separating and measuring palbociclib and impurities thereof - Google Patents
Method for separating and measuring palbociclib and impurities thereof Download PDFInfo
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Abstract
A method for separating and measuring palbociclib and impurities thereof comprises the following steps of 1) taking palbociclib or a preparation containing palbociclib, adding a diluent for dissolving to obtain a sample solution with the concentration of 0.1-10 mg/ml; 2) taking the sample solution obtained in the step 1), and adding a diluent to dilute the sample solution by 50-1000 times to obtain a control solution; 3) adopting a chromatographic column with octadecylsilane chemically bonded silica as a filler, setting the flow rate of a mobile phase to be 0.8-1.2ml/min, wherein the mobile phase consists of a mobile phase A and a mobile phase B, the mobile phase A is a buffer solution with the concentration of 0.0001-1.0mol/L, the pH value of the buffer solution is adjusted to 1-5 by phosphoric acid, the mobile phase B is methanol, and the mobile phase enters the chromatographic column by adopting a gradient elution mode; 4) injecting equal volumes of the sample solution in the step 1) and the control solution in the step 2) into a high performance liquid chromatograph respectively, wherein the injection amount is 5-100 mu l, detecting by using the wavelength of 200-280 nm, recording a chromatogram, and completing the separation and determination of impurities in the sample solution.
Description
Technical Field
The invention relates to the field of analytical chemistry, in particular to a method for separating and measuring palbociclib and impurities thereof.
Background
Palbociclib is a highly selective reversible antagonist of the cyclin-dependent kinases CDK4 and CDK 6. By inhibiting CDK4/6, the progression of the cell cycle from G1 phase to S phase is blocked, thereby inhibiting DNA synthesis. Preclinical research data show that the palbociclib has the effects of reducing and killing tumor cells and inhibiting cell growth, and is a novel breast cancer medicament. The molecular formula of the palbociclib is C24H29N7O2The chemical name is: 6-acetyl-8-cyclopentyl-5-methyl-2- [ [5- (piperazin-1-yl) pyridin-2-yl]Amino group]-8H-pyrido [2,3-D]The structural formula of the pyrimidine-7-ketone is shown as the formula (a)
In the process of synthesizing the compound, there are several important intermediates and unknown impurities which may affect the purity and quality of the drug due to incomplete removal, and the known intermediates and unknown impurities and the resulting degradation products are known as related substances (i.e., impurities) in the quality control of the drug. Twelve known impurities that are primarily controlled for the synthesis of palbociclib are: impurity SM1, impurity SM2, impurity A1, impurity Z7, impurity Z8, impurity Z12, impurity Z16, impurity Z21, impurity Z23, impurity Z25, impurity Z26 and impurity Z29, wherein the structural formulas are respectively shown as formulas (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l) and (m)
Therefore, the palbociclib has more impurities and similar structure, which brings difficulty to separation. In addition, the polarity of each impurity is different, and on the premise of meeting the separation requirement of the palbociclib and each impurity, the separation requirement of the impurities is also met, so that the detection difficulty is high. The conventional detection method is difficult to realize effective separation of palbociclib from impurities and impurities, and the quality control of palbociclib and the preparation thereof is seriously influenced.
In order to accurately control the quality of palbociclib and its preparation products, it is necessary to research a method for simply, rapidly and accurately separating and detecting palbociclib and its preparation-related substances.
Disclosure of Invention
The invention aims to provide a method for separating and measuring palbociclib and impurities thereof aiming at the defects of the prior art, which is simple and convenient to operate, can effectively separate and measure palbociclib and impurities thereof, and effectively controls the quality of palbociclib and products thereof.
The technical scheme of the invention is as follows: a method for separating and measuring palbociclib and impurities thereof comprises the following steps,
1) preparation of sample solution
Dissolving palbociclib or a preparation containing palbociclib by adding a diluent to obtain a sample solution with the concentration of 0.1-10 mg/ml;
2) preparation of control solutions
Taking the sample solution obtained in the step 1), and adding a diluent to dilute the sample solution by 50-1000 times to obtain a control solution;
3) the method comprises the following steps of (1) adopting a chromatographic column with octadecylsilane chemically bonded silica as a filler, setting the flow rate of a mobile phase to be 0.8-1.2ml/min, wherein the mobile phase consists of a mobile phase A and a mobile phase B, the mobile phase A is a buffer solution with the concentration of 0.0001-1.0mol/L, adding phosphoric acid into the buffer solution to adjust the pH value to be 1-5, the mobile phase B is methanol, the mobile phase enters the chromatographic column by adopting a gradient elution mode for 0 min, the volume percentage of the mobile phase A is 88-92%, and the volume percentage of the mobile phase B is 8-12%; 0 minute to 5 minutes, the volume percentage of the mobile phase A is 88 percent to 92 percent, and the volume percentage of the mobile phase B is 8 percent to 12 percent; from 5 minutes to 10 minutes, the volume percent of mobile phase a decreased linearly to 58% -62%, and the volume percent of mobile phase B increased linearly to 38% -42%; from 10 minutes to 40 minutes, the volume percentage of mobile phase a decreased linearly to 23% to 27%, and the volume percentage of mobile phase B increased linearly to 73% to 77%; from 40 minutes to 45 minutes, the volume percentage of mobile phase a decreased linearly to 8% -12%, and the volume percentage of mobile phase B increased linearly to 88% -92%; 45 to 65 minutes, 8 to 12 volume percent of mobile phase a, 88 to 92 volume percent of mobile phase B, 65 to 66 minutes, linear increase to 88 to 92 volume percent of mobile phase a, linear decrease to 8 to 12 volume percent of mobile phase B, 66 to 75 minutes, 88 to 92 volume percent of mobile phase a, 8 to 12 volume percent of mobile phase B;
4) injecting equal volumes of the sample solution in the step 1) and the control solution in the step 2) into a high performance liquid chromatograph respectively, wherein the injection amount is 5-100 mu l, detecting by using the wavelength of 200-280 nm, recording a chromatogram, and completing the separation and determination of impurities in the sample solution.
Further, in the step 1) and the step 2), the diluent is a mixture of methanol and a buffer solution, and the volume ratio of the methanol to the buffer solution is 25-55: 45-75.
Preferably, the volume ratio of methanol to buffer solution is 40: 60.
further, the buffer solution is phosphoric acid, or a phosphate solution or a mixture of the phosphoric acid and the phosphate, and the phosphate is potassium dihydrogen phosphate, sodium dihydrogen phosphate, ammonium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, diamine hydrogen phosphate or a mixture of any of the phosphoric acid, the sodium dihydrogen phosphate, the ammonium dihydrogen phosphate, the dipotassium hydrogen phosphate, the disodium hydrogen phosphate and the diamine hydrogen phosphate.
The concentration of the mobile phase A in the step 3) is 0.001-0.01 mol/L.
The buffer solution in the step 3) is phosphoric acid, or a phosphate solution or a mixture of the phosphoric acid and the phosphate solution, the phosphate is potassium dihydrogen phosphate, sodium dihydrogen phosphate, ammonium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, diammonium hydrogen phosphate or any mixture, and the pH value of the buffer solution is 2.0-3.5.
Step 3), the mobile phase enters a chromatographic column by adopting a gradient elution mode for 0 minute, wherein the volume percentage of the mobile phase A is 90 percent, and the volume percentage of the mobile phase B is 10 percent; from 0 minute to 5 minutes, the volume percent of mobile phase a is 90%, and the volume percent of mobile phase B is 10%; from 5 minutes to 10 minutes, the volume percent of mobile phase a decreased linearly to 60%, and the volume percent of mobile phase B increased linearly to 40%; from 10 minutes to 40 minutes, the volume percent of mobile phase a decreased linearly to 25%, and the volume percent of mobile phase B increased linearly to 75%; from 40 minutes to 45 minutes, the volume percent of mobile phase a decreased linearly to 10%, and the volume percent of mobile phase B increased linearly to 90%; 45 minutes to 65 minutes, 10% by volume of mobile phase a, 90% by volume of mobile phase B, 65 minutes to 66 minutes, a linear increase to 90% by volume of mobile phase a, a linear decrease to 10% by volume of mobile phase B, 66 minutes to 75 minutes, 90% by volume of mobile phase a, 10% by volume of mobile phase B.
And 4) during sample injection, the sample injection amount is 10 mu l, the detection is carried out by utilizing the wavelength of 220nm, and the column temperature of the chromatographic column is 20-40 ℃.
The column temperature of the column was 30 ℃.
Adopt above-mentioned technical scheme to have following beneficial effect:
1. the separation and determination method adopts a chromatographic column with octadecylsilane chemically bonded silica as a filler, and adopts a gradient elution mode to ensure that the palbociclib can be effectively separated from impurities and impurities; the pH value of the mobile phase A is adjusted to 1-5 by phosphoric acid, so that the peak shape of impurities is effectively improved, the retention can be enhanced, the separation degree is improved, and the good symmetry and the higher column efficiency of chromatographic peaks are ensured. The mixed solution of methanol and buffer solution is selected as a diluent to dissolve the sample, so that the interference of a solvent peak and the solvent effect are eliminated.
2. The separation and determination method of the invention adopts a mobile phase A (buffer solution + phosphoric acid to adjust pH) and a mobile phase B (methanol) gradient elution mode to determine the impurities of the palbociclib and the preparation thereof, avoids the problem that the conventional mobile phase adopts an organic phase which can not completely separate impurities with similar polarity, can effectively separate and determine the palbociclib from known impurities and unknown impurities, solves the problem that the palbociclib and the impurities thereof are difficult to separate during separation and determination, and ensures the controllable quality of the palbociclib and the preparation thereof.
3. The diluent used in the separation and determination method does not interfere with the determination of impurities and has strong specificity; the sensitivity of each impurity meets the requirement. The impurity content is calculated according to a self-comparison method of adding a correction factor, and the separation degree of the main peak, adjacent impurities and adjacent impurities meets the requirement. The minimum detection limit of the product and each impurity is 0.0013%, which shows that more than 0.0013% of the impurities can be detected, and the accuracy is high.
The following further description is made with reference to the accompanying drawings and detailed description.
Drawings
FIG. 1 is a liquid chromatogram of a methanol-buffer mixture according to example;
FIG. 2 is a liquid chromatogram of a mixed control solution of example one;
FIG. 3 is a liquid chromatogram of a sample solution of example two;
FIG. 4 is a liquid chromatogram of the control solution of the example;
FIG. 5 is a liquid chromatogram of a sample solution of the third example;
FIG. 6 is a liquid chromatogram of a control solution of the third example;
FIG. 7 is a liquid chromatogram of a test solution of the third blank adjuvant of the example.
Detailed Description
Apparatus and conditions
The high performance liquid chromatograph selects Agilent 1260 type liquid chromatograph and chemical workstation, and is set as automatic sample introduction. A ZORBAX Eclipse Plus C18 column (5 μm, 250X 4.6mm) was used as a separation column. Wavelength of ultraviolet detector: 220 nm. Mobile phase: gradient elution was carried out using 0.025mol/L potassium dihydrogen phosphate solution (1000ml potassium dihydrogen phosphate solution adjusted to pH 3.0 with phosphoric acid) as mobile phase A and methanol as mobile phase B: 0 minute, the volume percent of mobile phase a is 90%, and the volume percent of mobile phase B is 10%; from 0 minute to 5 minutes, the volume percent of mobile phase a is 90%, and the volume percent of mobile phase B is 10%; from 5 minutes to 10 minutes, the volume percent of mobile phase a decreased linearly to 60%, and the volume percent of mobile phase B increased linearly to 40%; from 10 minutes to 40 minutes, the volume percent of mobile phase a decreased linearly to 25%, and the volume percent of mobile phase B increased linearly to 75%; from 40 minutes to 45 minutes, the volume percent of mobile phase a decreased linearly to 10%, and the volume percent of mobile phase B increased linearly to 90%; 45 to 65 minutes, 10 volume percent mobile phase a and 90 volume percent mobile phase B; from 65 minutes to 66 minutes, the volume percent of mobile phase a increased linearly to 90%, and the volume percent of mobile phase B decreased linearly to 10%; from 66 minutes to 75 minutes, the volume percentage of mobile phase a is 90% and the volume percentage of mobile phase B is 10%. Column temperature 30 ℃, flow rate: 1.0 ml/min. The injection volume was 10. mu.l.
The first embodiment is as follows:
respectively taking 25mg of impurities SM1, SM2, A1, Z7, Z8, Z12, Z16, Z21, Z23, Z25, Z26 and Z29 (the purity of each impurity is more than 95%), precisely weighing, placing in a 25ml measuring flask, adding a methanol-buffer solution (the volume ratio is 40: 60) for dissolving and diluting to a scale, and shaking uniformly to obtain an impurity stock solution; taking Pabociclib with the weight of about 20mg, accurately weighing, placing in a 25ml measuring flask, accurately adding 0.25ml of impurity stock solution, adding methanol-buffer solution (volume ratio of 40: 60) for dissolving and diluting to a scale, and shaking up to obtain a mixed control solution.
The diluent methanol-buffer solution (volume ratio 40: 60) and the mixed control solution were respectively taken, liquid chromatography analysis was performed under the above-mentioned chromatographic conditions, and chromatograms were recorded, and the results are shown in fig. 1 and fig. 2.
Figure 1 shows that the methanol-buffer mixture and the chromatographic system do not interfere with the assay.
In fig. 2, the order of successive peaks is impurity Z8, impurity Z16, impurity Z12, impurity SM2, impurity Z26, impurity Z21, palbociclib, impurity Z23, impurity Z29, impurity Z7, impurity SM1, impurity Z25, and impurity a 1. Fig. 2 shows that the separation and determination method of the present invention can effectively separate impurities with unknown structures and impurities with known structures which may exist in palbociclib, and the detection sensitivity of each impurity can meet the requirement, and the separation degree between the main peak and the adjacent impurities and among the impurities can meet the requirement, i.e., the method can be used for the determination of impurities in palbociclib and its preparation.
Examples determination of diprobuxinib drug substance (supplied by Chongqing san Sheng industries, Ltd.)
Taking 20mg of palbociclib, precisely weighing, placing in a 25ml measuring flask, adding a methanol-buffer solution (volume ratio is 40: 60), ultrasonically treating, dissolving and diluting to a scale, and shaking uniformly to obtain a sample solution; precisely measuring 1.0ml of sample solution, placing in a 100ml measuring flask, diluting with methanol-buffer solution (volume ratio of 40: 60) to scale, and shaking to obtain control solution; liquid chromatography was performed under the chromatographic conditions of example one and chromatograms were recorded. If an impurity peak (except a solvent peak) exists in a chromatogram of the sample solution, the content of the impurity is calculated according to a self-contrast method of adding a correction factor. The results are shown in FIGS. 3 and 4. The detection results are shown in table 1:
TABLE 1 Pabociclib-related substance assay results
Examples determination of the triple Pabociclib capsules (supplied by Chongqing Sansheng industries Co., Ltd.)
Taking a proper amount of palbociclib capsules (about equal to 20mg of palbociclib), placing the palbociclib capsules into a 25ml measuring flask, adding methanol-buffer solution (the volume ratio is 40: 60) for ultrasonic treatment, dissolving and diluting the palbociclib capsules to a scale, shaking up, filtering, and taking filtrate as sample solution; precisely measuring 1.0ml of sample solution, placing in a 100ml measuring flask, diluting with methanol-buffer solution (volume ratio of 40: 60) to scale, and shaking to obtain control solution; taking a proper amount of blank auxiliary materials according to the proportion of the formula of the palbociclib capsule, and preparing a blank auxiliary material test solution according to the same method of the sample solution; liquid chromatography was performed according to the chromatographic conditions of example one. The chromatograms were recorded, and the results are shown in fig. 5, 6, and 7. Calculating the impurity content of each isomer in the test sample by adopting a self-comparison method with correction factors, wherein the detection results are shown in a table 2:
TABLE 2 detection results of related substances in Pabociclib capsules
Claims (8)
1. A method for separating and measuring palbociclib and impurities thereof is characterized by comprising the following steps,
1) preparation of sample solution
Dissolving palbociclib or palbociclib-containing preparation in a diluent to obtain a sample solution with a concentration of 0.1-10mg/ml, wherein the palbociclib or palbociclib-containing preparation contains impurities (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l) and (m) having the following structural formula,
2) preparation of control solutions
Taking the sample solution obtained in the step 1), and adding a diluent to dilute the sample solution by 50-1000 times to obtain a control solution;
3) the method comprises the following steps of (1) adopting a chromatographic column with octadecylsilane chemically bonded silica as a filler, setting the flow rate of a mobile phase to be 0.8-1.2ml/min, wherein the mobile phase consists of a mobile phase A and a mobile phase B, the mobile phase A is a buffer solution with the concentration of 0.0001-1.0mol/L, the buffer solution is phosphoric acid or a phosphate solution or a mixture of the phosphoric acid and the phosphate solution, phosphoric acid is added into the buffer solution to adjust the pH value to be 1-5, the mobile phase B is methanol, the mobile phase enters the chromatographic column in a gradient elution mode for 0 minute, the volume percentage of the mobile phase A is 90%, and the volume percentage of the mobile phase B is 10%; from 0 minute to 5 minutes, the volume percent of mobile phase a is 90%, and the volume percent of mobile phase B is 10%; from 5 minutes to 10 minutes, the volume percent of mobile phase a decreased linearly to 60%, and the volume percent of mobile phase B increased linearly to 40%; from 10 minutes to 40 minutes, the volume percent of mobile phase a decreased linearly to 25%, and the volume percent of mobile phase B increased linearly to 75%; from 40 minutes to 45 minutes, the volume percent of mobile phase a decreased linearly to 10%, and the volume percent of mobile phase B increased linearly to 90%; 45 to 65 minutes, 10% by volume of mobile phase a, 90% by volume of mobile phase B, 65 to 66 minutes, a linear increase to 90% by volume of mobile phase a, a linear decrease to 10% by volume of mobile phase B, 66 to 75 minutes, 90% by volume of mobile phase a, 10% by volume of mobile phase B;
4) injecting equal volumes of the sample solution in the step 1) and the control solution in the step 2) into a high performance liquid chromatograph respectively, wherein the injection amount is 5-100 mu l, detecting by using the wavelength of 200-280 nm, recording a chromatogram, and completing the separation and determination of impurities in the sample solution.
2. The method as claimed in claim 1, wherein the diluent in step 1) and step 2) is a mixture of methanol and a buffer solution, and the volume ratio of the methanol to the buffer solution is 25-55: 45-75.
3. The method of claim 2, wherein the volume ratio of methanol to buffer solution is 40: 60.
4. the method according to claim 2 or 3, wherein the buffer solution is phosphoric acid, or a phosphate solution, or a mixture of both, and the phosphate is potassium dihydrogen phosphate, sodium dihydrogen phosphate, ammonium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, diamine hydrogen phosphate, or any mixture thereof.
5. The method according to claim 1, wherein the concentration of mobile phase A in step 3) is 0.001-0.01 mol/L.
6. The method according to claim 1, wherein the phosphate in step 3) is potassium dihydrogen phosphate, sodium dihydrogen phosphate, ammonium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, diamine hydrogen phosphate, or any mixture thereof, and the pH value of the buffer solution is 2.0 to 3.5.
7. The method according to claim 1, wherein the sample is injected in step 4), the sample injection amount is 10 μ l, the detection is carried out by using a wavelength of 220nm, and the column temperature of the chromatographic column is 20-40 ℃.
8. The method of claim 7, wherein the column temperature of the chromatography column is 30 ℃.
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| WO2019056163A1 (en) * | 2017-09-19 | 2019-03-28 | 浙江华海药业股份有限公司 | N-formyl palbociclib and preparation method therefor and use thereof, and palbociclib preparation and quality control method therefor |
| CN114544847B (en) * | 2022-03-09 | 2023-11-03 | 上海皓元医药股份有限公司 | Method for detecting genotoxic impurities in starting raw material for synthesizing piperaquine Bai Xi |
| CN116735746B (en) * | 2023-06-16 | 2024-06-18 | 辽源市百康药业有限责任公司 | Method for separating and measuring clopidodine hydrochloride and impurities thereof |
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