CN114965770A - Method for detecting starting material, impurity D and impurity F in ifosfamide bulk drug - Google Patents
Method for detecting starting material, impurity D and impurity F in ifosfamide bulk drug Download PDFInfo
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Abstract
The invention discloses a method for detecting a starting material, an impurity D and an impurity F in an ifosfamide raw material drug, which is used for detecting and recording a solution based on a gas chromatography, wherein the detection step comprises the preparation of the solution, and the gas chromatography is used for detecting and recording a chromatogram map, the invention provides a rapid and convenient gas chromatography method, which is beneficial to the establishment of quality standards of related substances in the ifosfamide raw material drug, has good precision, linear relation, accuracy and the like, can meet the detection requirements of the related substances in the ifosfamide raw material drug, has strong specificity, good linear relation and good precision, can rapidly and accurately detect the starting material, the impurity D and the impurity F in the ifosfamide raw material drug, has reliable and controllable operation in the whole process, and is suitable for practical application and popularization, has wide application prospect.
Description
Technical Field
The invention relates to the technical field of pharmaceutical analysis, in particular to a method for detecting a starting material, an impurity D and an impurity F in an ifosfamide raw material medicine.
Background
Ifosfamide (Ifosfamide) belongs to a nitrogen mustard alkylating agent, is also a latent activating medicament, has no antitumor activity in vitro, needs to enter human body and is firstly converted into aldehyde phosphoramide by microsome functional oxidase in liver, the aldehyde phosphoramide is decomposed into phosphoramide nitrogen mustard and acrolein in tumor, and the phosphoramide nitrogen mustard shows pharmacological activity. Some related substances such as starting materials, actual materials, intermediates, by-products, isomers and the like can be brought in the production of the raw material medicaments, and the substances can reduce the curative effect and influence the stability, and some substances are even harmful to the health of human bodies or generate other adverse reactions. Therefore, the detection of related impurities of ifosfamide is of great importance to control the purity of the drug and the quality of the drug. At present, most of the analysis and detection of ifosfamide are based on liquid chromatography and gas chromatography to determine ifosfamide and organic solvent residues in blood and urine samples, but a reliable quality control standard for effective components and related substances in the production process of ifosfamide bulk drugs is not established. Therefore, the invention provides a method for detecting the starting material 3-aminopropanol, the impurity D and the impurity F in the ifosfamide bulk drug, which has good precision, linear relation and accuracy and can meet the detection requirements of the starting material 3-aminopropanol, the impurity D and the impurity F in the ifosfamide bulk drug.
Disclosure of Invention
The invention provides a rapid and convenient gas chromatography method for detecting starting materials 3-aminopropanol, impurities D and impurities F in an ifosfamide raw material medicine, which is beneficial to establishing quality standards of related substances in the ifosfamide raw material medicine, the detection method has good precision, linear relation, accuracy and the like, can meet the detection requirements of the related substances in the ifosfamide raw material medicine, and the specific technical scheme is as follows:
a method for detecting a starting material, an impurity D and an impurity F in an ifosfamide raw material medicine is characterized in that a solution is detected and recorded based on a gas chromatography, and the structures of the starting material, the impurity D and the impurity F are respectively shown as formulas I, II and III:
further, the method for detecting the starting material, the impurity D and the impurity F in the ifosfamide bulk drug comprises the following steps:
(1) preparing a blank solution, a reference substance stock solution, a reference substance solution and a test solution, wherein:
blank solution: HPLC grade methanol as diluent;
control stock solutions: precisely weighing 3-aminopropanol as an ifosfamide starting material, an impurity D and an impurity F, respectively placing the materials into a 10mL brown volumetric flask, adding a diluent to dilute the materials to a constant volume to a scale, and shaking up to obtain a reference substance stock solution;
control solution: precisely measuring a reference substance stock solution, placing the reference substance stock solution in a 10mL brown volumetric flask, adding a diluent to dilute to a constant volume to a scale, and shaking up to obtain a reference substance solution;
test solution: accurately weighing ifosfamide bulk drugs, placing the ifosfamide bulk drugs in a 10mL brown volumetric flask, adding a diluent to dilute to a constant volume to a scale, and shaking up to obtain a test solution;
(2) detecting the blank solution, the reference solution and the test solution by adopting a gas chromatography and recording chromatograms.
Further, 100mg of ifosfamide starting material 3-aminopropanol, 100mg of impurity D and 10mg of impurity F are precisely weighed in the reference substance stock solution to prepare a reference substance stock solution of 10.0mg/mL of starting material 3-aminopropanol, 10.0mg/mL of impurity D and 1.0mg/mL of impurity F.
Further, 0.1mL of ifosfamide starting material 3-aminopropanol, impurity D and impurity F reference stock solution is precisely measured from the reference solution to prepare a reference solution of 100.00 μ g/mL of starting material 3-aminopropanol, 100.00 μ g/mL of impurity D and 10.00 μ g/mL of impurity F.
Further, 1.0g of ifosfamide raw material medicine is precisely weighed in the test solution, and the test solution of ifosfamide with 100.0mg/mL is prepared.
Further, the column: HP-530 m.times.320. mu.m.times.0.25. mu.m, detector: FID, flow rate: 2 mL/min; the split ratio is as follows: 5:1, sample injection volume: 1 μ L, run time: 36min, column temperature: temperature programming: 50 ℃, 5 ℃/min, 2min → 180 ℃, 20 ℃/min, 1min → 260 ℃, 3min, injection port temperature: 380 ℃; detector temperature: at 380 ℃.
Compared with the prior art, the invention has the following beneficial effects:
the method for detecting the starting material 3-aminopropanol, the impurity D and the impurity F in the ifosfamide bulk drug provided by the invention realizes qualitative and quantitative analysis of the 3-aminopropanol, the impurity D and the impurity F in the ifosfamide bulk drug, has strong specificity, good linear relation and good precision, can quickly and accurately detect the starting material, the impurity D and the impurity F in the ifosfamide bulk drug, is reliable and controllable in operation in the whole process, is suitable for practical application and popularization, and has wide application prospect.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the technical descriptions of the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without creative efforts.
FIG. 1 is a gas chromatogram of a blank solution.
FIG. 2 is a gas chromatogram of the starting material and impurity D.
Fig. 3 is a gas chromatogram of impurity F.
FIG. 4 is a gas chromatogram of a sample solution.
FIG. 5 is a linear regression plot of the starting material.
FIG. 6 is a linear regression plot of impurity D.
FIG. 7 is a linear regression plot of impurity F.
Detailed Description
The technical solutions in the embodiments of the present invention will be described clearly and completely 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, but not all the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without any inventive step, are within the scope of the present invention.
A method for detecting a starting material, an impurity D and an impurity F in an ifosfamide raw material medicine is characterized in that a solution is detected and recorded based on a gas chromatography, and the structures of the starting material, the impurity D and the impurity F are respectively shown as formulas I, II and III:
as a preferred scheme, the detection method of the starting material, the impurity D and the impurity F in the ifosfamide bulk drug comprises the following steps:
(1) preparing a blank solution, a reference substance stock solution, a reference substance solution and a test solution, wherein:
blank solution: HPLC grade methanol as diluent;
control stock solutions: precisely weighing 100mg of ifosfamide starting material 3-aminopropanol, 100mg of impurity D and 10mg of impurity F, respectively placing the materials in a 10mL brown volumetric flask, adding a diluent to dilute to a constant volume to scale, and shaking up to obtain reference stock solutions of 10.0mg/mL of starting material 3-aminopropanol, 10.0mg/mL of impurity D and 1.0mg/mL of impurity F;
control solution: precisely measuring 0.1mL of ifosfamide starting material 3-aminopropanol, impurity D and impurity F in the reference substance stock solution, placing the reference substance stock solution in a 10mL brown volumetric flask, adding a diluent to dilute to a constant volume to scale, and shaking up to obtain a reference substance solution of 100.00 mu g/mL of starting material 3-aminopropanol, 100.00 mu g/mL of impurity D and 10.00 mu g/mL of impurity F;
test solution: accurately weighing 1.0g of ifosfamide raw material medicine, placing the ifosfamide raw material medicine in a 10mL brown volumetric flask, adding a diluent to dilute to a constant volume to a scale, and shaking up to prepare a 100.0mg/mL ifosfamide test solution.
(2) Detecting the blank solution, the reference solution and the test solution by adopting a gas chromatography and recording a chromatogram, wherein the chromatographic column comprises: HP-530 m.times.320. mu.m.times.0.25. mu.m, detector: FID, flow rate: 2 mL/min; the split ratio is as follows: 5:1, sample injection volume: 1 μ L, run time: 36min, column temperature: temperature programming: 50 ℃, 5 ℃/min, hold for 2min → 180 ℃, 20 ℃/min, hold for 1min → 260 ℃, hold for 3min, injection port temperature: 380 ℃; detector temperature: at 380 ℃.
Example 1:
firstly, preparing a solution:
(1) preparing a blank solution: HPLC grade methanol as diluent;
(2) control stock solutions: accurately weighing 100mg of an isocyclophosphamide impurity starting material 3-aminopropanol, an impurity D reference substance and 10mg of an impurity F reference substance, respectively placing the starting material and the impurity D reference substance in 10mL volumetric flasks, dissolving the starting material and the impurity D reference substance by using a diluent, diluting the starting material and the impurity D reference substance to scales, and uniformly mixing the starting material and the impurity D reference substance to obtain a reference substance stock solution with the concentration of the impurity D of 10.0mg/mL and the concentration of the impurity F of 1.0 mg/mL;
(3) control solution: precisely measuring 0.1mL of each impurity reference substance stock solution, respectively placing the stock solutions in 10mL volumetric flasks, adding a diluent to dissolve and dilute the stock solutions to a scale, and uniformly mixing to obtain a starting material and each impurity reference substance solution with the impurity D concentration of 100.00 mu g/mL and the impurity F concentration of 10.00 mu g/mL;
(4) test solution: 1.0g of raw material medicine of ifosfamide is precisely weighed and placed in a 10mL volumetric flask, dissolved and diluted to scale by diluent, and mixed evenly to prepare a test solution with ifosfamide concentration of 100.0 mg/mL.
Secondly, gas chromatography detection:
detecting blank solution, reference solution and test solution by gas chromatography, and recording chromatograms which are shown in figures 1-4. The gas chromatography conditions were: a chromatographic column: HP-530 m.times.320 μm.times.0.25 μm; a detector: FID; flow rate: 2 mL/min; the split ratio is as follows: 5: 1; sample introduction volume: 1 mu L of the solution; operating time: 36 min; column temperature: temperature programming (50 ℃, 5 ℃/min, 2min → 180 ℃, 20 ℃/min, 1min → 260 ℃, 3 min); sample inlet temperature: 380 ℃; detector temperature: at 380 ℃.
As shown in FIGS. 1 to 4, the blank solvent has an interference effect on the detected substance, and the separation degree between the chromatographic peaks of all components is more than 1.5, which indicates that the specificity of the method of the invention is good.
Example 2:
firstly, a quantitative limit:
the reference stock solution prepared in example 1 and having the impurity F concentration of 1.0mg/mL, the starting material 3-aminopropanol and the impurity D concentration of 10.0mg/mL is diluted by a diluent in a stepwise quantitative manner, and then detected by a gas chromatography, wherein the specific conditions of the gas chromatography are as described in example 1, a chromatogram is recorded, and the signal-to-noise ratio is not lower than 10: 1, the limit of quantitation was obtained and the results are shown in table 1.
TABLE 1
As can be seen from Table 1, in the quantitative limiting solution, the chromatographic peaks S/N of the starting material, the impurity D and the impurity F are all more than 10; the retention time RSD of the starting material, the impurity D and the impurity F is less than or equal to 2.0 percent; the peak areas RSD of the starting material, the impurity D and the impurity F are all less than or equal to 15 percent.
II, linear relation:
the stock solutions of the impurity F prepared in example 1 at a concentration of 1.0mg/mL and the starting material and the reference substance at an impurity D concentration of 10.0mg/mL were diluted with a diluent to prepare linear solutions of different concentrations.
The linear solution prepared above was examined by gas chromatography under the conditions as in example 1, and a chromatogram was recorded. The concentrations of the components are used as an X axis, the response is used as a Y axis to draw a linear curve, the correlation coefficient R, the slope and the linear equation are calculated, the result is shown in a table 2, and the linear graph is shown in figures 5-7.
TABLE 2
As can be seen from table 2, the linear equation of the starting material in the range of 39.80 μ g/mL to 199.00 μ g/mL (corresponding to 0.04% to 0.2% of the test solution, corresponding to 40% to 200% of the limit concentration of the starting material) is 3.1581x-108.55, and the correlation coefficient is 0.9991, > 0.990; the impurity D is in the range of 39.48-197.40 mug/mL (equivalent to 0.04-0.2% of the sample solution and equivalent to 40-200% of the limit concentration of the starting material), the linear equation is that y is 3.5951x-45.912, the correlation coefficient is 0.9997 and is more than 0.990; the impurity F is in the range of 2 mu g/mL-20 mu g/mL (equivalent to 0.02% -0.2% of the test solution and equivalent to 20% -200% of the limit concentration of the initial material), the linear equation is that y is 18.762x +5.4378, and the correlation coefficient is 0.9999 and is more than 0.990. The detection method disclosed by the invention is proved to have good linear relation.
Thirdly, precision:
6 parts of 100% concentration starting material, a reference solution of impurity F and a 100% standard sample solution are prepared in parallel, and the starting material, impurity D and impurity F in the ifosfamide bulk drug are detected by gas chromatography according to the detection method of the starting material, impurity D and impurity F in the ifosfamide bulk drug described in example 1, wherein the specific conditions of the gas chromatography are as described in example 1, and the results are shown in Table 3.
TABLE 3
As can be seen from Table 3, the starting material peak area RSD was 7.4%; the impurity D peak area RSD is 7.0%; the impurity F peak area RSD is 7.9%, which shows that the detection method of the invention has good precision.
Fourthly, accuracy:
accuracy tests of the starting material, impurity D, impurity F are expressed in recovery (%).
Preparing a standard sample solution with 100% of impurity D: precisely weighing about 1.0g of ifosfamide, precisely weighing 0.1mL of impurity D reference substance stock solution, placing the stock solution in the same 10mL volumetric flask, adding a diluent to dilute to a constant volume to scale, and shaking up to obtain a standard sample solution with ifosfamide content of 0.1g/mL and impurity D100 mu g/mL.
Taking 100% of impurity D, adding a standard sample solution, a starting material and a reference substance solution of impurity F, and detecting by adopting a high gas chromatography according to the detection method of the starting material, the impurity D and the impurity F in the ifosfamide bulk drug described in the embodiment 1, wherein the specific conditions of the gas chromatography are as described in the embodiment 1, and the results are shown in Table 4.
TABLE 4
As can be seen from Table 4, the recovery rate of the starting material is in the range of 90.09% -103.31%, the RSD is 4.8%, < 10%; the recovery rate of the impurity D is within the range of 92.95-98.26 percent, and the RSD is 2.3 percent and less than 10 percent; the recovery rate of the impurity F is in the range of 95.95-115.90%, the RSD is 7.2% < 10%, and the table 4 shows that the detection method of the invention has good accuracy.
Fifthly, solution stability:
stability of starting material, impurity D, impurity F solution: the reference substance solutions were taken and left at room temperature for different periods of time, and RSD of the chromatographic peak areas of the starting material, impurity D, and impurity F were calculated, and the results are shown in table 5.
TABLE 5
As can be seen from Table 5, the starting material, impurity D, was stable over 8h and impurity F was stable over 9 h. The detection method disclosed by the invention is proved to be good in solution stability.
Example 3:
firstly, sample determination:
according to the method for detecting the starting material, the impurity D and the impurity F in the ifosfamide raw material provided in example 1, the contents of the starting material, the impurity D and the impurity F in 3 batches of ifosfamide raw material samples are detected, and the results are shown in table 6:
TABLE 6
As can be seen from table 6, all of impurity D was detected in 3 batches of ifosfamide bulk drug, and the starting material and impurity F were not detected.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.
Claims (6)
1. A method for detecting starting materials, impurities D and impurities F in ifosfamide bulk drugs is characterized by comprising the following steps: the detection method is to detect and record a solution based on a gas chromatography, and the structures of the starting material, the impurity D and the impurity F are respectively shown as formulas I, II and III:
2. the method for detecting the starting material, the impurity D and the impurity F in the ifosfamide bulk drug according to claim 1, is characterized in that: the detection steps are as follows:
(1) preparing a blank solution, a reference substance stock solution, a reference substance solution and a test solution, wherein the method comprises the following steps:
blank solution: HPLC grade methanol as diluent;
control stock solutions: accurately weighing an ifosfamide starting material 3-aminopropanol, an impurity D and an impurity F, respectively placing the starting material, the impurity D and the impurity F into 10mL brown volumetric flasks, adding a diluent to dilute to a constant volume to a scale, and shaking up to obtain a reference substance stock solution;
control solution: precisely measuring a reference substance stock solution, placing the reference substance stock solution in a 10mL brown volumetric flask, adding a diluent to dilute to a constant volume to a scale, and shaking up to obtain a reference substance solution;
test solution: accurately weighing ifosfamide bulk drugs, placing the ifosfamide bulk drugs in a 10mL brown volumetric flask, adding a diluent to dilute to a constant volume to a scale, and shaking up to obtain a test solution;
(2) detecting the blank solution, the reference solution and the test solution by adopting a gas chromatography and recording chromatograms.
3. The method for detecting the starting material, the impurity D and the impurity F in the ifosfamide bulk drug according to claim 2, is characterized in that: precisely weighing 100mg of ifosfamide starting material 3-aminopropanol, 100mg of impurity D and 10mg of impurity F in the reference substance stock solution to prepare the reference substance stock solution of starting material 3-aminopropanol, 10.0mg/mL of impurity D and 1.0mg/mL of impurity F, wherein the starting material 3-aminopropanol, the impurity D and the impurity F are 10.0 mg/mL.
4. The method for detecting the starting material, the impurity D and the impurity F in the ifosfamide bulk drug according to claim 2, is characterized in that: the control solution is prepared by precisely measuring 0.1mL of ifosfamide starting material 3-aminopropanol, impurity D and impurity F control stock solution, and obtaining the control solution of 100.00 mu g/mL of starting material 3-aminopropanol, 100.00 mu g/mL of impurity D and 10.00 mu g/mL of impurity F.
5. The method for detecting the starting material, the impurity D and the impurity F in the ifosfamide bulk drug according to claim 2, is characterized in that: 1.0g of ifosfamide raw material medicine is precisely weighed in the test solution to prepare the test solution of ifosfamide of 100.0 mg/mL.
6. The method for detecting the starting material, the impurity D and the impurity F in the ifosfamide bulk drug according to claim 2, is characterized in that: the chromatographic column comprises: HP-530 m.times.320. mu.m.times.0.25. mu.m, detector: FID, flow rate: 2 mL/min; the split ratio is as follows: 5:1, sample injection volume: 1 μ L, run time: 36min, column temperature: temperature programming: 50 ℃, 5 ℃/min, 2min → 180 ℃, 20 ℃/min, 1min → 260 ℃, 3min, injection port temperature: 380 ℃; detector temperature: at 380 ℃.
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| FR2125595A1 (en) * | 1971-02-19 | 1972-09-29 | Asta Werke Ag Chem Fab | |
| WO1997022614A1 (en) * | 1995-12-19 | 1997-06-26 | Darwin Discovery Limited | Ifosfamide, analogues thereof and their preparation |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2125595A1 (en) * | 1971-02-19 | 1972-09-29 | Asta Werke Ag Chem Fab | |
| WO1997022614A1 (en) * | 1995-12-19 | 1997-06-26 | Darwin Discovery Limited | Ifosfamide, analogues thereof and their preparation |
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| IMANUEL YÜCE 等: "All on one high-performance thin-layer chromatography plate:solvent-free nanomole-scaled on-surface synthesis, workup andonline high-resolution mass spectrometry for elucidation of two newdegradation products in an ifosfamide formulation", 《JOURNAL OF CHROMATOGRAPHY A》 * |
| MISIURA, K 等: "Stereospecific synthesis of chiral metabolites of ifosfamide and their determination in the urine", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
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