CN113979924A - Method for separating and purifying bupivacaine nitrogen oxide impurities and preparing single crystal - Google Patents

Method for separating and purifying bupivacaine nitrogen oxide impurities and preparing single crystal Download PDF

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CN113979924A
CN113979924A CN202111203457.9A CN202111203457A CN113979924A CN 113979924 A CN113979924 A CN 113979924A CN 202111203457 A CN202111203457 A CN 202111203457A CN 113979924 A CN113979924 A CN 113979924A
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bupivacaine
impurity
soluble solvent
solvent
single crystal
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周虎
蔡鹏俊
李悦
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Shanghai Institute of Materia Medica of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/94—Oxygen atom, e.g. piperidine N-oxide
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Abstract

The invention discloses a method for separating, purifying and preparing monocrystals of bupivacaine nitric oxide impurities, which is characterized in that bupivacaine raw material medicines are dissolved in hydrogen peroxide to obtain solution; then, preparing impurity components by adopting a preparation liquid phase or a semi-preparation liquid phase and mass spectrometry; then concentrating the impurity components under reduced pressure to dryness to obtain the impurity of bupivacaine. Dissolving the impurities in a soluble solvent, adding an insoluble solvent, standing, and naturally volatilizing the solvent to obtain the impurity single crystal of the bupivacaine. The invention discloses a method for separating and purifying bupivacaine nitrogen oxide impurities and a single crystal preparation method, which provide a basis for the structural representation of the bupivacaine nitrogen oxide impurities and can provide an impurity standard substance for the quality research of bupivacaine bulk drugs.

Description

Method for separating and purifying bupivacaine nitrogen oxide impurities and preparing single crystal
Technical Field
The invention relates to a method for separating and purifying bupivacaine nitrogen oxide impurities and preparing single crystals.
Background
Bupivacaine is an amide local anesthetic and can be used for infiltration anesthesia, nerve block and intraspinal block anesthesia. The hydrochloride which is commonly used clinically is white crystalline powder, is odorless, is easily dissolved in ethanol, is dissolved in water, and the pH value of an aqueous solution of the hydrochloride is 4.5-6.0. Bupivacaine increases the threshold value of nerve action potential, reduces the speed of the increase of the action potential and delays the expansion of nerve impulse by inhibiting the sodium ion channel of nerve cells, thereby blocking the generation and the conduction of the nerve impulse and realizing the anesthesia effect. The long-acting local anesthetic liposome suspension (EXPAREL) developed by Pacira pharmaceutical company Limited in the United states is used for injection of bupivacaine, the release of the drug is controlled in an ideal time range, and the single administration has the effect time of up to 72 hours, so that the postoperative pain of a patient can be relieved. Due to the special formulation, complex preparation process and high technical difficulty of the liposome, although the EXPAREL is imitated by the existing enterprises in China, the liposome dosage is not approved at present. Currently, the pharmacopoeia does not record bupivacaine raw material medicines.
When researchers study the stability of bupivacaine bulk drug, the researchers found that bupivacaine is unstable under oxidation conditions and can degrade to generate two impurities with the same molecular weight, and the high-resolution element composition of the mass spectrum shows that the two impurities have the same element composition. The two impurities are subjected to secondary mass spectrometry, the fragment ions of the two impurities are basically the same, and the structures cannot be determined according to the mass spectrometry. Research on impurities related to bupivacaine bulk drugs needs to be carried out.
Disclosure of Invention
The invention provides a preparation method and a single crystal preparation method of bupivacaine oxynitride impurities and aims to overcome the defect that the existing research on the structural characterization of bupivacaine oxynitride impurities is less.
In a first aspect of the present invention, there is provided a method for separating and purifying impurities of bupivacaine, the method comprising the steps of:
i) dissolving a bupivacaine raw material medicament in hydrogen peroxide to obtain a solution;
ii) collecting and preparing impurity components by combining a preparation liquid phase or a semi-preparation liquid phase with mass spectrometry;
iii) concentrating the impurity components under reduced pressure to dryness to obtain the impurity of bupivacaine.
In another preferred embodiment, the parameters used for preparing the liquid phase or semi-prepared liquid phase in step ii) are:
mobile phase: h2O：MeOH＝40-60:60-40
Flow rate: 15-50ml/min
Sample introduction volume: 10 to 800. mu.l.
In another preferred embodiment, the parameters used for preparing the liquid phase or semi-prepared liquid phase in step ii) are:
mobile phase: h2O：MeOH＝50-60:50-40
Flow rate: 15-40ml/min
Sample introduction volume: 10 to 800. mu.l.
In another preferred embodiment, the parameters used for preparing the liquid phase or semi-prepared liquid phase in step ii) are:
mobile phase: h2O：MeOH＝50-55:50-45
Flow rate: 15-35ml/min
Sample introduction volume: 10 to 800. mu.l.
In another preferred embodiment, the parameters used for preparing the liquid phase or semi-prepared liquid phase in step ii) are:
mobile phase: h2O：MeOH＝50-55:50-45
Flow rate: 15-30ml/min
Sample introduction volume: 10 to 800. mu.l.
In another preferred example, the parameters used for mass spectrometry in step ii) are:
the split ratio is as follows: 1000:1
Detection wavelength: 210nm
An ionization mode: ESI source, positive ion mode.
In a second aspect of the present invention, there is provided a method for producing a single crystal of impurities of bupivacaine, the method comprising the steps of:
a) dissolving impurities of bupivacaine in a soluble solvent to obtain a solution;
b) adding a sparingly soluble solvent to the solution obtained in step a to reach or approach saturation;
c) standing, naturally volatilizing the solvent until obtaining the impurity single crystal of the bupivacaine,
wherein the easily soluble solvent is dichloromethane, trichloromethane, tetrahydrofuran, 1, 2-dichloroethane or a mixed solvent of more than two solvents; the indissolvable solvent is petroleum ether, n-hexane, cyclohexane, methyl tert-butyl ether or a mixed solvent of more than two of the petroleum ether, the n-hexane, the cyclohexane and the methyl tert-butyl ether.
In another preferred embodiment, the easily soluble solvent is dichloromethane, tetrahydrofuran or a mixed solvent of the two.
In another preferred example, the poorly soluble solvent is n-hexane, cyclohexane or a mixed solvent of the two.
In another preferred embodiment, the volume ratio of the easily soluble solvent to the hardly soluble solvent is 1:1 to 1: 4.
In another preferred embodiment, the easily soluble solvent is tetrahydrofuran, the difficultly soluble solvent is cyclohexane, and the volume ratio of the easily soluble solvent to the difficultly soluble solvent is 1:1-1: 2.
In a third aspect of the present invention, there is provided a single crystal of impurities of bupivacaine, which is produced by the production method of the second aspect.
The fourth aspect of the invention provides the use of the impurity single crystal of bupivacaine described in the third aspect, and the impurity single crystal is used as an impurity standard substance for quality research of bupivacaine bulk drug and compound preparation thereof.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 shows the LC profile (flow rate: 30ml/min) of nitrogen oxide impurity 1.
FIG. 2 shows the LC spectrum (flow rate: 17ml/min) of nitrogen oxide impurity 1
FIG. 3 shows the LC spectrum (H) of nitrogen oxide impurity 12O：MeOH＝52：48)
Figure 4 shows a block diagram of bupivacaine nitroxide impurity 1.
Detailed Description
The inventors of the present application have extensively and intensively studied to develop a method for separating and purifying bupivacaine impurities to obtain pure impurities, and have performed nuclear magnetic hydrogen spectrometry, carbon spectrometry and circular dichroism spectrometry. Because the absolute structure of the impurity cannot be determined by mass spectrometry and nuclear magnetism, a single crystal preparation method is further developed to obtain a single crystal form, and the three-dimensional structure of bupivacaine impurity 1 is determined. The invention discloses a method for separating and purifying bupivacaine nitrogen oxide impurities and a single crystal preparation method, which provide a basis for the structural representation of the bupivacaine nitrogen oxide impurities and provide an impurity standard substance for the quality research of bupivacaine bulk drugs. On the basis of this, the present invention has been completed.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
Example 1 preparation of bupivacaine nitroxide impurity
1.1 instruments and parameters
Waters 2767/2545/2789-3100 Mass Spectrometry guided purification System, equipped with MassLynx4.0 data processing System.
A chromatographic column: xbridge prep C185 μm 30 x 100mm
Mobile phase: h2O：MeOH＝55:45
Flow rate: 30ml/min
The split ratio is as follows: 1000:1
Sample introduction volume: 10 to 800. mu.l
Detection wavelength: 210nm
An ionization mode: ESI source, positive ion mode
1.2 Experimental content and results
Taking a proper amount of bupivacaine raw material medicine, adding 3% hydrogen peroxide solution, and standing for 1 hour at room temperature. The oxidative destruction solution was prepared by collection of the nitrogen oxide impurity component (impurity 1) using the instrumentation and technical parameters under item 1.1. Concentrating under reduced pressure at 40 deg.C until the solvent is completely evaporated to dryness to obtain pale yellow viscous solid. Taking a proper amount of solid, dissolving and diluting the solid by using methanol, and analyzing the purity of the nitrogen oxide impurities by using an LC-MS method to be 98.99 percent.
The LC profile of nitrogen oxide impurity 1 obtained under the above test conditions is shown in fig. 1.
The LC profile of the nitrogen oxide impurity 1 obtained at a flow rate of 17ml/min is shown in FIG. 2, with other parameters being unchanged, indicating that the change in flow rate has little effect on sample separation.
Other parameters were unchanged, the mobile phase ratio was H2O: MeOH 52: 48, the LC profile of the nitrogen oxide impurity 1 obtained is shown in FIG. 3 of the drawings, which illustrates a slight change in mobile phase ratio, without affecting the separation.
Example 2 structural analysis of bupivacaine nitroxide impurities
And analyzing the destruction solution by adopting LC-MS detection and ESI source positive ion detection, and detecting two impurity peaks with relative retention time of 2.87 and 3.32 respectively. The excimer peaks of both components are [ M + H]+305, relative molecular weight 304, high resolution data indicates that the elemental composition of the two components is the same, both C18H29N2O2The two isomers are isomers of each other. The two components of the secondary mass spectrum obtain basically same fragment ions with mass-to-charge ratios of 287, 249, 231, 148, 140, 120, 100 and the like, wherein the important fragment peak has the mass-to-charge ratio of m/z100, and the high-resolution element is formed to obtain the fragment ions with the structure possibly of m/z100
Figure BDA0003305948020000061
Suggesting that oxidative degradation occurs at the nitrogen atom of the heterocycle.
Further performing nuclear magnetic resonance on bupivacaine oxynitride impurity 1 by nuclear magnetic resonance spectroscopy1H spectrum and13and C spectrum detection.
1HNMR(500MHz,CD3OD)δppm 1.032(t，J＝7.5Hz，3H)1.404(m，2H)1.554(m，1H)1.696(m，1H)1.780(m，1H)1.857(m，1H)2.042(m，1H)2.229(s，6H)2.308(m，1H)2.524(m，1H)3.318(m，3H)3.567(m，2H)3.859(dd，J＝12Hz，2.5Hz，1H)7.084(m，3H)。
13CNMR(500MHz,CD3OD)δppm14.65(CH3)19.60(CH3)21.74(CH2)21.78(CH2)23.42(CH2)26.36(CH2)28.47(CH2)65.51(CH2)71.28(CH2)76.15(CH)128.79(CH)129.82(CH)135.00(C)136.40(C)169.76(-C＝O)。
The nuclear magnetic results show that the hydrogen spectrum of bupivacaine oxynitride impurity 1 is basically consistent with that of bupivacaine oxynitride reported in patent WO2014152737A1, and the structure in WO2014152737A1 is as follows:
Figure BDA0003305948020000071
circular dichroism of the bupivacaine nitroxide impurity 1 obtained from the preparation suggests that the impurity 1 has no chirality. The chiral isomerism on the asymmetric carbon of the two oxidized impurity isomers is shown, and in order to further characterize the three-dimensional structure of the nitrogen oxide impurity 1, a single crystal preparation method is developed to obtain a single crystal form.
Example 3 preparation and structural characterization of bupivacaine oxynitride impurity 1 single crystal
3.1 Single Crystal production method
Taking a proper amount of bupivacaine nitrogen oxide impurity 1, adding a proper amount of soluble solvent for dissolving, then adding a proper amount of insoluble solvent to enable the sample solution to reach or approach saturation, sealing, standing at room temperature to enable the solvent to naturally volatilize until obtaining a crystal form capable of being detected on a computer. Wherein the easily soluble solvent is one of dichloromethane, trichloromethane, tetrahydrofuran, 1, 2-dichloroethane and mixed solvent thereof; the insoluble solvent is one of petroleum ether, n-hexane, cyclohexane, methyl tert-butyl ether and their mixture.
3.2 list of Single Crystal production results
Conditions and results for single crystal production of nitrogen oxide impurity 1
Figure BDA0003305948020000072
Figure BDA0003305948020000081
3.3 diffraction results on single crystals
The instrument model is as follows: d8 Venture
The instrument parameters are as follows:
light source: cu target X-ray:
Figure BDA0003305948020000083
a detector: resolution of the CMOS area detector:
Figure BDA0003305948020000084
current and voltage: 50kV, 1.2mA exposure time: 10s
Face probe-to-sample distance: 40mm test temperature: 170(2) K
Crystal data
Figure BDA0003305948020000082
Atomic fraction coordinates and isotropic or equivalent isotropic displacement parameters
Figure BDA0003305948020000091
Figure BDA0003305948020000092
Figure BDA0003305948020000101
Figure BDA0003305948020000111
Atomic displacement parameter
Figure BDA0003305948020000121
Figure BDA0003305948020000122
Figure BDA0003305948020000131
Figure BDA0003305948020000141
Geometric parameters
Figure BDA0003305948020000142
Figure BDA0003305948020000143
Figure BDA0003305948020000151
Figure BDA0003305948020000161
Figure BDA0003305948020000171
Figure BDA0003305948020000181
Based on the above analysis data, it was confirmed that the structure of bupivacaine nitroxide impurity 1 is shown in fig. 4.
The invention discloses a method for separating and purifying bupivacaine nitrogen oxide impurities and a single crystal preparation method, which provide a basis for the structural representation of the bupivacaine nitrogen oxide impurities and can provide an impurity standard substance for the quality research of bupivacaine bulk drugs.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. A method for separating and purifying impurities of bupivacaine is characterized by comprising the following steps:
i) dissolving a bupivacaine raw material medicament in hydrogen peroxide to obtain a solution;
ii) collecting and preparing impurity components by combining a preparation liquid phase or a semi-preparation liquid phase with mass spectrometry;
iii) concentrating the impurity components under reduced pressure to dryness to obtain the impurity of bupivacaine.
2. The separation and purification process according to claim 1, wherein the use parameters for the preparation of the liquid phase or the semi-preparation of the liquid phase in step ii) are:
mobile phase: h2O：MeOH＝40-60:60-40
Flow rate: 15-50ml/min
Sample introduction volume: 10 to 800. mu.l.
3. The separation and purification method according to claim 1, wherein the parameters used in the mass spectrometry in the step ii) are:
the split ratio is as follows: 1000:1
Detection wavelength: 210nm
An ionization mode: ESI source, positive ion mode.
4. A method for producing a single crystal of impurities of bupivacaine, characterized by comprising the steps of:
a) dissolving impurities of bupivacaine in a soluble solvent to obtain a solution;
b) adding a sparingly soluble solvent to the solution obtained in step a to reach or approach saturation;
c) standing, naturally volatilizing the solvent until obtaining the impurity single crystal of the bupivacaine,
wherein the easily soluble solvent is dichloromethane, trichloromethane, tetrahydrofuran, 1, 2-dichloroethane or a mixed solvent of more than two solvents; the indissolvable solvent is petroleum ether, n-hexane, cyclohexane, methyl tert-butyl ether or a mixed solvent of more than two of the petroleum ether, the n-hexane, the cyclohexane and the methyl tert-butyl ether.
5. The method according to claim 4, wherein the easily soluble solvent is dichloromethane, tetrahydrofuran or a mixture thereof.
6. The process according to claim 4, wherein the sparingly soluble solvent is n-hexane, cyclohexane or a mixed solvent of both.
7. The method according to claim 4, wherein the volume ratio of the easily soluble solvent to the poorly soluble solvent is 1:1 to 1: 4.
8. The method according to claim 4, wherein the easily soluble solvent is tetrahydrofuran, the poorly soluble solvent is cyclohexane, and the volume ratio of the easily soluble solvent to the poorly soluble solvent is 1:1 to 1: 2.
9. A single crystal of impurities of bupivacaine, which is produced by the production method described in any one of claims 4 to 8.
10. The use of the impurity single crystal of bupivacaine according to claim 9, which is used as an impurity standard substance for quality research of bupivacaine bulk drug and compound preparation thereof.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014152737A1 (en) * 2013-03-14 2014-09-25 Hepatochem Selective modification of organic compounds in the presence of amines and/or sulfides
CN108663444A (en) * 2018-03-02 2018-10-16 珠海润都制药股份有限公司 The detection method of dextroisomer in a kind of Levobupivacaine HCL
WO2021146215A1 (en) * 2020-01-13 2021-07-22 Durect Corporation Sustained release drug delivery systems with reduced impurities and related methods
CN115483030A (en) * 2021-06-16 2022-12-16 株式会社村田制作所 Laminated ceramic electronic component

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014152737A1 (en) * 2013-03-14 2014-09-25 Hepatochem Selective modification of organic compounds in the presence of amines and/or sulfides
CN108663444A (en) * 2018-03-02 2018-10-16 珠海润都制药股份有限公司 The detection method of dextroisomer in a kind of Levobupivacaine HCL
WO2021146215A1 (en) * 2020-01-13 2021-07-22 Durect Corporation Sustained release drug delivery systems with reduced impurities and related methods
CN115483030A (en) * 2021-06-16 2022-12-16 株式会社村田制作所 Laminated ceramic electronic component

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
AXEL RYDEVIK ET AL.: "Structural elucidation of phase I and II metabolites of bupivacaine in horse urine and fungi of the Cunninghamella species using liquid chromatography/multi-stage mass spectrometry", 《RAPID COMMUN. MASS SPECTROM.》 *
刘新泳等: "《实验室有机化合物制备与分离纯化技术》", 31 January 2011, 人民卫生出版社 *

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