CN114324638A - Method for simultaneously separating and determining palonosetron hydrochloride and impurities thereof - Google Patents
Method for simultaneously separating and determining palonosetron hydrochloride and impurities thereof Download PDFInfo
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- CN114324638A CN114324638A CN202111571246.0A CN202111571246A CN114324638A CN 114324638 A CN114324638 A CN 114324638A CN 202111571246 A CN202111571246 A CN 202111571246A CN 114324638 A CN114324638 A CN 114324638A
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Abstract
The invention belongs to the field of analytical chemistry, and particularly relates to a method for simultaneously separating and determining palonosetron hydrochloride and impurities thereof. The method adopts a chromatographic column with silica gel coated with amylose-tri (3, 5-xylyl carbamate) on the surface as a filler, and a mixed solution of acetonitrile, n-butyl alcohol and diethylamine as a mobile phase for elution and separation. The method can simultaneously separate and measure and separate the palonosetron hydrochloride, 3 isomer impurities and 1 process impurity at most, has good specificity and excellent separation performance and durability, and achieves good effect on tailing factors and theoretical pedal numbers.
Description
Technical Field
The invention belongs to the field of analytical chemistry, and particularly relates to a method for simultaneously separating and determining palonosetron hydrochloride and impurities thereof.
Background
Palonosetron Hydrochloride (palosetron Hydrochloride) was synthesized by Berger, J et al in 1991, Syntex corporation, USA (Roche bioscience, Switzerland). Then developed successfully by Helsinn Healthcare, switzerland, MGI Pharma bought the drug for marketing in north america, received FDA approval in 2003 and was marketed in the united states in the same year for 9 months. Can be used for preventing acute or delayed nausea and emesis caused by moderate or high-grade vomit chemotherapy. The product is highly selective 5-HT3ReceptorsThe antagonist has obvious effect. Palonosetron hydrochloride chemical name 2- [ 1-azabicyclo (2.2.2) oct-3S-yl]-2,3,3aS,4,5, 6-hexahydro-1H-benzo [ de ]]Isoquinoline-1-one hydrochloride with molecular formula C19H24N2And O.HCl. The structural formula of the palonosetron hydrochloride agar is as follows:
the chemical names and structural formulas of impurity C (diastereomer), impurity D (diastereomer), impurity E (process impurity) and enantiomer are shown in table 1 below.
TABLE 1 Palonosetron hydrochloride journal names and structural formulas
Strict control on the contents of impurities C (diastereoisomer), D (diastereoisomer), E (process impurity) and enantiomer in palonosetron hydrochloride is required in the process of medicine synthesis and preparation. The palonosetron hydrochloride and the impurity F are enantiomers, the impurity C and the impurity D are enantiomers, the palonosetron hydrochloride and the palonosetron hydrochloride are diastereomers, the palonosetron hydrochloride, the impurity C, the impurity D and the enantiomers are isomers, the analysis and separation of the isomers are the difficulty and the key points of quality control in the drug synthesis and preparation processes, and the separation of the 3 isomers and 1 process impurity in the palonosetron hydrochloride has very important social significance and economic benefit in the quality control of the palonosetron hydrochloride drug synthesis and preparation processes.
Strict control is required for isomers produced during the preparation of palonosetron hydrochloride, both in bulk drug substances and in formulations. Currently, the USP contains palonosetron hydrochloride serving as a medicine, and a detection method for impurities C (diastereoisomers), D (diastereoisomers), E (process impurities) and enantiomers is provided, but in the detection method for the palonosetron hydrochloride, the separation degree of the impurities C and D is less than 1.0, the separation degree of the impurities D and the enantiomers is less than 1.5, the separation degree of the enantiomers and the E is less than 1.5, the impurities cannot be effectively separated, and the separation degree cannot meet the requirement of being more than 1.5. The national research shows that the medicine palonosetron hydrochloride exists in the medicine, and in the related substance method, the impurity C and the impurity D are completely superposed and can not be effectively separated.
At present, a separation and detection method capable of simultaneously separating impurities C (diastereoisomer), D (diastereoisomer), E (process impurity) and enantiomer in palonosetron hydrochloride does not exist.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for simultaneously separating palonosetron hydrochloride and impurities thereof, wherein the impurities are isomers and process impurities, the method can simultaneously separate and determine at most palonosetron hydrochloride and 3 isomer impurities and 1 process impurity thereof, the method has good specificity and excellent separation performance and durability, and the tailing factor and the theoretical number of pedals can achieve very good effects.
The impurity is one or more of impurity C, impurity D, impurity E and impurity F, wherein palonosetron hydrochloride and impurity F are enantiomers, impurity C and impurity D are enantiomers, and are diastereoisomers with palonosetron hydrochloride, and the palonosetron hydrochloride and impurity C, impurity D and enantiomer are isomers, and the structural formulas of substance C, impurity D, impurity E and impurity F are as follows:
the method comprises the following steps: the method adopts a chromatographic column with silica gel coated with amylose-tri (3, 5-xylyl carbamate) on the surface as a filler, and uses a mixed solution of acetonitrile, n-butyl alcohol and diethylamine as a mobile phase for elution and separation.
Preferably, in certain embodiments, a Chiralpak AD-H chromatography column is selected, with a specification of 250X 4.6mm, 5 μm.
Specifically, for a Chiralpak AD-H analytical column of this specification, the optimum mobile phase flow rate range is 0.6-1.0ml/min, and peak diffusion due to solute transport effects at high flow rates (1.5-3.0ml/min) leads to reduced column efficiency and resolution.
More preferably, the flow rate of the mobile phase is 0.8 ml/min.
Preferably, the concentration of the diethylamine is 0.01mol/L to 0.03 mol/L.
Preferably, in the mobile phase, the volume ratio of acetonitrile, n-butanol and diethylamine is 85: 15: 0.1-95: 5: 0.1.
more preferably, in the mobile phase, the volume ratio of acetonitrile, n-butanol and diethylamine is 90: 10: 0.1.
preferably, the temperature of the chromatography column is set to 30-40 ℃.
Specifically, the binding constant of the solute to silica gel with amylose-tris (3, 5-xylylcarbamate) coated on the surface is greatly affected by temperature, and the binding constant increases at low temperature, but solute transfer becomes poor, so that lowering the column temperature increases the selectivity of the bonding phase of octylsilane-bonded silica gel, and also may decrease the separation degree, but increasing the column temperature improves the separation of the strongly retained solute, so that it was verified by experiments that the temperature range of the column box of the chromatography column was selected to be 30-40 ℃.
Preferably, the temperature of the chromatography column is set at 35 ℃.
Preferably, a mixed solution of acetonitrile, n-butanol and diethylamine is used as the sample to be injected, and the volume ratio of the acetonitrile, n-butanol and diethylamine is 85: 15: 0.1-95: 5: 0.1, more preferably 90: 10: 0.1.
the invention further provides a method for detecting palonosetron hydrochloride and impurities thereof on the basis of the method for simultaneously separating the palonosetron hydrochloride and the impurities thereof, which comprises the following steps: (1) separating palonosetron hydrochloride and impurities thereof using the process of any one of claims 1 to 7; (2) and entering a detector for detection.
Preferably, the wavelength of the detector is 230-240nm, more preferably 235 nm.
Further, after the detection is finished, the contents of the palonosetron hydrochloride and impurities thereof are calculated according to the peak area of the detection.
Furthermore, the detector can be replaced by detection instruments such as a mass spectrum instrument and the like in certain detection environments, and the combination of chromatography and mass spectrum is realized.
In certain embodiments, the method for simultaneously separating and detecting palonosetron hydrochloride and impurities thereof comprises the following steps:
(1) respectively taking a reference substance of palonosetron hydrochloride, impurity C (diastereoisomer), impurity D (diastereoisomer), impurity E (process impurity) and impurity F (enantiomer), dissolving with a diluent to prepare a sample to be detected, impurity C (diastereoisomer) and impurity D (diastereoisomer), respectively sampling reference substance solutions of impurities E (process impurities) and F (enantiomers) of palonosetron hydrochloride and impurities C (diastereoisomers), D (diastereoisomers), E (process impurities) and F (enantiomers) of samples to be detected, performing high performance liquid chromatography, and determining retention time of palonosetron hydrochloride and impurities C (diastereoisomers), D (diastereoisomers), E (process impurities) and F (enantiomers);
(2) taking a palonosetron hydrochloride test sample and adding a diluent (mixing acetonitrile, n-butyl alcohol and diethylamine in a ratio of 90: 10: 0.1) to prepare a test sample solution, taking the diluent as a blank solution, respectively taking the test sample solution and the blank solution for sample injection, performing high performance liquid chromatography analysis, recording a chromatogram, and completing the separation and determination of impurities C (diastereoisomer), D (diastereoisomer), E (process impurity) and enantiomer in palonosetron hydrochloride.
In certain embodiments, the specific steps are as follows:
(1) taking a proper amount of palonosetron hydrochloride, dissolving a sample by using a diluent (acetonitrile: n-butyl alcohol: diethylamine ═ 90: 10: 0.1) to prepare a sample solution containing 1.5-2.5mg of palonosetron hydrochloride per 1 ml;
(2) selecting a chromatograph with the model of Shimadzu LC-20AT, the model of a chromatographic column of Chiralpak AD-H, (250 multiplied by 4.6mm, 5 mu m), and a mobile phase of acetonitrile: n-butanol: the ratio of diethylamine is 90: 10: and (2) 0.1, injecting 10 mu l of the sample solution obtained in the step (1) into a liquid chromatograph, setting the flow rate of a mobile phase to be 0.8ml/min, the detection wavelength to be 235nm and the temperature of a chromatographic column box to be 35 ℃, and completing the separation and determination of the impurity C (diastereoisomer), the impurity D (diastereoisomer), the impurity E (process impurity) and the impurity F (enantiomer) in the palonosetron hydrochloride.
The invention has the beneficial effects that
(1) The method for simultaneously separating the palonosetron hydrochloride and the impurities thereof provided by the invention has the advantages that the impurities are isomers and process impurities, the method can simultaneously separate and determine the palonosetron hydrochloride and 3 isomer impurities (impurity C, D, F) and 1 process impurity (impurity E) within 30 minutes at most, the specificity is good, the sensitivity is high, the reproducibility is good, the separation performance and the durability are excellent, and the tailing factor and the theoretical pedal number can achieve a very good effect.
(2) The method for simultaneously separating palonosetron hydrochloride and impurities thereof uses silica gel coated with amylose-tri (3, 5-xylyl carbamate) on the surface as a filler, and the filler is durable, environment-friendly and low in toxicity, and can be used for quickly separating palonosetron hydrochloride, impurities C (diastereoisomer), impurities D (diastereoisomer), impurities E (process impurities) and enantiomers, and is very meaningful work for health of pharmaceutical analysts and quality control research of products thereof.
Drawings
FIG. 1 is a high performance liquid chromatogram of a blank solvent.
FIG. 2 is a high performance liquid chromatogram of an enantiomer positioning solution.
FIG. 3 is a high performance liquid chromatogram of an impurity D localization solution.
FIG. 4 is a high performance liquid chromatogram of an impurity C localization solution.
FIG. 5 is a high performance liquid chromatogram of an impurity E localization solution.
FIG. 6 is a high performance liquid chromatogram of the test solution.
Fig. 7 is a high performance liquid chromatogram of a mixed solution (a mixed solution of palonosetron hydrochloride and its impurity C, impurity D, impurity E, and impurity F (enantiomer)).
FIG. 8 is a limit chromatogram.
FIG. 9 is a detection-limited activity chromatogram.
Detailed Description
The examples are given for the purpose of better illustration of the invention, but the invention is not limited to the examples. Therefore, those skilled in the art should make insubstantial modifications and adaptations to the embodiments of the present invention in light of the above teachings and remain within the scope of the invention.
In the embodiment of the invention, the adopted instruments and chromatographic conditions are as follows: high performance liquid chromatograph: shimadzu LC-20 AT; a chromatographic column: chiralpak AD-H, (250X 4.6mm, 5 μm); mobile phase: acetonitrile: n-butanol: diethylamine-90: 10: 0.1; the detector detects the wavelength: 235 nm; flow rate of mobile phase: 0.8 ml/min; column temperature of chromatographic column box: 35 ℃; sample introduction amount: 10 mu l of the mixture; diluent (acetonitrile: n-butanol: diethylamine ═ 90: 10: 0.1).
In the embodiment of the invention, the preparation of the impurity C positioning solution comprises the following steps: precisely weighing 49.33mg of impurity C, placing the impurity C in a 25ml measuring flask, adding a diluent to dissolve and dilute the impurity C to a scale, and shaking up to obtain an impurity C stock solution; precisely transferring 0.5ml of the solution, placing the solution into a 50ml measuring flask, adding a diluent to dilute the solution to a scale, and shaking up the solution to obtain the liquid.
In the embodiment of the invention, the preparation of the impurity D positioning solution comprises the following steps: accurately weighing 50.02mg of impurity D, placing the impurity D in a 25ml measuring flask, adding a diluent to dissolve and dilute the impurity D to a scale, and shaking up to obtain an impurity D stock solution; precisely transferring 0.5ml of the solution, placing the solution into a 50ml measuring flask, adding a diluent to dilute the solution to a scale, and shaking up the solution to obtain the liquid.
In the embodiment of the invention, the preparation of the impurity E positioning solution is as follows: precisely weighing the impurity E50.43 mg, placing the impurity E50.43 mg in a 25ml measuring flask, adding a diluent to dissolve and dilute the impurity E to a scale, and shaking up to obtain an impurity E stock solution; precisely transferring 0.5ml of the solution, placing the solution into a 50ml measuring flask, adding a diluent to dilute the solution to a scale, and shaking up the solution to obtain the liquid.
In the examples of the present invention, the enantiomer localization solution was prepared as follows: accurately weighing 50.10mg of enantiomer, placing in a 25ml measuring flask, adding a diluent to dissolve and dilute to scale, and shaking up to obtain impurity enantiomer stock solution; precisely transferring 0.5ml of the solution, placing the solution into a 50ml measuring flask, adding a diluent to dilute the solution to a scale, and shaking up the solution to obtain the liquid.
In the embodiment of the invention, the preparation of the test solution is as follows: precisely weighing 51.08mg of test sample, placing in a 25ml measuring flask, adding diluent to dissolve and dilute to scale, and shaking.
In the embodiment of the invention, the preparation of the mixed solution is as follows: precisely weighing 100.68mg of sample, placing in a 50ml measuring flask, precisely transferring 0.5ml of the impurity C, the impurity D, the impurity E and the enantiomer stock solution respectively, placing in the same 50ml measuring flask, adding a diluent to dissolve and dilute to scale, and shaking uniformly to obtain the final product.
In the embodiment of the invention, the preparation of the quantitative limiting solution comprises the following steps: precisely weighing the sample and the impurity C reference, preparing a solution with a certain concentration, and diluting step by step to obtain a quantitative limit solution.
In the embodiment of the invention, the preparation of the detection limit solution is as follows: precisely transferring 7.0ml of the quantitative limiting solution, putting the quantitative limiting solution into a 20ml measuring flask, adding a diluent to dilute the quantitative limiting solution to a scale, and shaking up to obtain the detection limiting solution.
In the embodiment of the invention, the calculation formula of the quantitative limit and the detection limit is as follows:
example 1 separation and determination of Palonosetron hydrochloride and impurities C (diastereomer), D (diastereomer), E (process impurity) and enantiomer
Blank solvent (diluent), each impurity positioning solution, test solution and mixed solution are respectively taken, 10 mu l of each solution is injected according to the method, and chromatogram is recorded, wherein, the chromatogram of the blank solvent is shown in figure 1, the chromatogram of the enantiomer positioning solution is shown in figure 2, the chromatogram of the impurity D positioning solution is shown in figure 3, the chromatogram of the impurity C positioning solution is shown in figure 4, the chromatogram of the impurity E positioning solution is shown in figure 5, the chromatogram of the test solution is shown in figure 6, and the chromatogram of the mixed solution is shown in figure 7.
The measurement results of each component are tabulated in table 2 below.
TABLE 2 results of the specificity test
And (4) conclusion: blank diluent does not interfere with sample determination; the separation degree of the palonosetron hydrochloride peak and the impurity C peak is 2.51 and is more than 1.5, the separation degree of the impurity C peak and the impurity D peak is 2.91 and is more than 1.5, the separation degree between each known impurity and the palonosetron hydrochloride peak is more than 1.5, the separation is good, and the specificity is strong.
Example 2 detection limit, quantitation limit test of chromatographic systems for impurity C (diastereomer) and palonosetron hydrochloride
(1) Quantitative limit test
And taking the quantitative limiting solution for continuous sample introduction for 3 times, and calculating the ratio (signal-to-noise ratio) of the main peak height to the noise. And recording the chromatogram. The chromatogram of one sample injection is shown in FIG. 8, and the test results are shown in Table 3 below.
TABLE 3 quantitative Limit determination results
(2) Detection limit test
Taking the detection limit solution for continuous sampling for 3 times, calculating the ratio (signal-to-noise ratio) of the main peak height to the noise, recording the chromatogram, wherein the chromatogram of one sampling is shown in FIG. 9, and the test results are shown in Table 4 below.
TABLE 4 measurement results of detection limits
And (4) conclusion: as can be seen from the test data in table 3 and table 4 above, the detection limit and the quantitative limit of the impurity C in the present chromatography system satisfy S/N ═ 3 (10): 1, in the presence of a catalyst.
Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.
Claims (10)
1. The method for simultaneously separating palonosetron hydrochloride and impurities thereof is characterized in that the impurities are one or more of impurities C, impurities D, impurities E and impurities F, and the structural formulas of the impurities C, the impurities D, the impurities E and the impurities F are as follows:
the method comprises the following steps: the method adopts a chromatographic column with silica gel coated with amylose-tri (3, 5-xylyl carbamate) on the surface as a filler, and uses a mixed solution of acetonitrile, n-butyl alcohol and diethylamine as a mobile phase for elution and separation.
2. The method according to claim 1, wherein the concentration of diethylamine is 0.01-0.03 mol/L.
3. The process according to claim 2, characterized in that the volume ratio of acetonitrile, n-butanol and diethylamine in the mobile phase is 85: 15: 0.1-95: 5: 0.1.
4. the process according to claim 2, characterized in that the volume ratio of acetonitrile, n-butanol and diethylamine in the mobile phase is 90: 10: 0.1.
5. the method of claim 1, wherein the flow rate of the mobile phase is 0.6-1.0 ml/min.
6. The method of claim 1, wherein the temperature of the chromatography column is set at 30-40 ℃.
7. The method according to claim 1, wherein a mixed solution of acetonitrile, n-butanol and diethylamine is used as the sample for injection, and the volume ratio of the acetonitrile, n-butanol and diethylamine is 85: 15: 0.1-95: 5: 0.1.
8. a method for detecting palonosetron hydrochloride and impurities thereof is characterized by comprising the following steps: (1) separating palonosetron hydrochloride and impurities thereof using the process of any one of claims 1 to 7; (2) and entering a detector for detection.
9. The method as claimed in claim 8, wherein the wavelength of the detector is 230-240 nm.
10. The method according to claim 8 or 9, wherein the contents of palonosetron hydrochloride and impurities thereof are calculated according to the peak area of the detection after the detection is finished.
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