CN114014797A - Single crystal preparation method of bupivacaine nitrogen oxide impurity and characterization thereof - Google Patents

Single crystal preparation method of bupivacaine nitrogen oxide impurity and characterization thereof Download PDF

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CN114014797A
CN114014797A CN202111530275.2A CN202111530275A CN114014797A CN 114014797 A CN114014797 A CN 114014797A CN 202111530275 A CN202111530275 A CN 202111530275A CN 114014797 A CN114014797 A CN 114014797A
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bupivacaine
solvent
single crystal
impurities
impurity
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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
    • C—CHEMISTRY; METALLURGY
    • C30—CRYSTAL GROWTH
    • C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
    • C30B29/00—Single crystals or homogeneous polycrystalline material with defined structure characterised by the material or by their shape
    • C30B29/54—Organic compounds
    • C—CHEMISTRY; METALLURGY
    • C30—CRYSTAL GROWTH
    • C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
    • C30B7/00—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions
    • C30B7/14—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions the crystallising materials being formed by chemical reactions in the solution
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N2030/022—Column chromatography characterised by the kind of separation mechanism
    • G01N2030/027—Liquid chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N2030/042—Standards
    • G01N2030/047—Standards external

Abstract

The invention provides a bupivacaine impurity single crystal. The method comprises the steps of firstly dissolving impurities of bupivacaine in a soluble solvent to obtain a solution; then optionally adding a slightly soluble solvent to the solution obtained in the above step to reach or approach saturation, standing, and naturally volatilizing the solvent until obtaining the single crystal of impurities of bupivacaine. The single crystal preparation method of the bupivacaine nitrogen oxide impurity disclosed by the invention provides a basis for the structural representation of the bupivacaine nitrogen oxide impurity, and can provide an impurity standard substance for the quality research of bupivacaine bulk drug.

Description

Single crystal preparation method of bupivacaine nitrogen oxide impurity and characterization thereof
Technical Field
The invention relates to a single crystal preparation method of bupivacaine nitrogen oxide impurities and characterization thereof.
Background
Bupivacaine is an amide long-acting local anesthetic which blocks nerve excitation and conduction mainly by inhibiting a sodium ion channel of a nerve cell membrane. Is suitable for local infiltration anesthesia, sacral canal block, peripheral nerve block, epidural block and subarachnoid space block. The hydrochloride which is commonly used clinically is white crystalline powder, is easy to dissolve in ethanol and is dissolved in water. Bupivacaine hydrochloride and preparations thereof are recorded in pharmacopoeias of various countries, but bupivacaine is not recorded.
When researchers study the stability of bupivacaine bulk drug, the researchers find that bupivacaine can be degraded in the process of being placed to generate two impurities with the same molecular weight, and the mass spectrum high resolution result shows that the two impurities have the same element composition and are both products of oxidative degradation. For secondary mass spectrometry, the fragment ions of the two impurities are essentially identical and the structure cannot be determined from the mass spectrum. At present, no literature reports about the impurities exist, and research on impurities related to bupivacaine bulk drugs needs to be carried out.
Disclosure of Invention
The invention aims to overcome the defect that the existing characterization research on the structure of the bupivacaine nitrogen oxide impurity is less, provide a novel three-dimensional structure of the bupivacaine nitrogen oxide impurity, provide a single crystal preparation method of the bupivacaine nitrogen oxide impurity and characterize the structure of the impurity.
In a first 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:
(s1) dissolving impurities of bupivacaine in a readily soluble solvent to obtain a solution;
optionally (s2) adding a sparingly soluble solvent to the solution obtained in step s1 at or near saturation; and
(s3) standing to allow the solvent to naturally volatilize until obtaining the impurity single crystal of bupivacaine,
wherein the easily soluble solvent is diethyl ether, dichloromethane, chloroform, 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 example, the easily soluble solvent is diethyl ether, dichloromethane, tetrahydrofuran or a mixed solvent of two or more.
In another preferred embodiment, the easily soluble solvent is diethyl ether.
In another preferred example, the mass-to-volume ratio of the impurities of bupivacaine to the easily soluble solvent is 8-15g/L, such as 10g/L and 12 g/L.
In another preferred example, the poorly soluble solvent is petroleum ether, n-hexane, cyclohexane, or a mixed solvent of two or more kinds.
In another preferred embodiment, the volume ratio of the easily soluble solvent to the hardly soluble solvent is 1:1 to 1:4, such as 1:1, 1:2, 1: 4.
In another preferred embodiment, the preparation process is carried out at 25 ± 10 ℃.
In another preferred example, the impurities of bupivacaine are prepared by separation by a preparation liquid phase method.
In a second aspect of the present invention, there is provided a single crystal of impurities of bupivacaine, which is produced by the production method according to the first aspect of the present invention.
In the third aspect of the invention, the use of the single crystal of the impurity of bupivacaine as described in the second aspect of the invention is provided, and the 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. Not to be reiterated herein, but to the extent of space.
Drawings
Figure 1 shows a liquid chromatogram of bupivacaine nitroxide impurity.
Figure 2 shows a block diagram of bupivacaine nitroxide impurity 2.
Detailed Description
The inventor of the invention has extensively and deeply researched, and as the absolute structure of impurities can not be determined by mass spectrum, nuclear magnetism and the like, a single crystal preparation method of bupivacaine impurities is firstly developed, a single crystal form is obtained, and the three-dimensional structure of the bupivacaine impurities is determined. The invention discloses a single crystal preparation method of bupivacaine nitrogen oxide impurities, which provides a basis for the structural representation of the bupivacaine nitrogen oxide impurities and provides an impurity standard substance for the quality research of bupivacaine bulk drugs. On the basis of this, the present invention has been completed.
Term(s) for
As used herein, the term "optionally" means optional or optional.
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 under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
Example 1 preparation and structural characterization of bupivacaine oxynitride impurity 2 single crystal
1.1 preparation of impurity 2
Bupivacaine can be degraded in the process of standing to generate two impurities with the same molecular weight, and a liquid chromatogram is shown in figure 1.
And (3) separating and preparing the impurity 2 by adopting a preparation liquid phase method to obtain a pure product of the impurity 2.
The nmr data and assignments for impurity 2 are as follows:1HNMR(500MHz,CD3OD)δppm 1.001(t，J＝7.5Hz，3H)1.383(m，2H)1.723(m，3H)1.894(m，1H)2.016(m，2H)2.209(s，6H)2.240(m，1H)2.690(m，1H)3.098(brd，J＝12Hz，1H)3.231(m，1H)3.534(m，1H)4.132(brt，J＝4.5Hz，1H)4.252(m，1H)7.110(m，3H)；
13CNMR(500MHz,CD3OD)δppm 14.70(CH3)18.98(CH3)19.78(CH2)21.56(CH2)22.08(CH2)25.42(CH2)27.06(CH2)64.59(CH2)69.05(CH2)74.19(CH)129.30(CH)129.84(CH)134.98(C)137.10(C)169.33(-C＝O)。
1.2 Single Crystal production method
Taking 1mg of bupivacaine nitrogen oxide impurity 2, adding about 0.1ml of soluble solvent to dissolve, sealing, or 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 be naturally volatilized until a crystal form capable of being detected on a computer is obtained. Wherein the easily soluble solvent is one of diethyl ether, dichloromethane, tetrahydrofuran and their mixture; the insoluble solvent is one of petroleum ether, n-hexane, cyclohexane and their mixture.
1.3 list of Single Crystal production results
Conditions and results for production of single crystals of nitrogen oxide impurity 2
Solvent(s) Volume ratio Results
Methylene dichloride
1 No crystal generation
Ether (A) 1 Granular crystal, detection on machine
Dichloromethane: petroleum ether 1:1，1:2 Bulk crystals of poor quality
Dichloromethane: n-hexane 1:2，1:4 Bulk crystal
Tetrahydrofuran: cyclohexane 1:1 Bulk crystal
1.4 diffraction results on single crystals
Figure BDA0003410413670000044
Crystal data
Figure BDA0003410413670000043
Atomic fraction coordinates and isotropic or equivalent isotropic displacement parameters
Figure BDA0003410413670000051
Figure BDA0003410413670000052
Figure BDA0003410413670000061
Figure BDA0003410413670000071
Figure BDA0003410413670000081
Figure BDA0003410413670000091
Figure BDA0003410413670000101
Figure BDA0003410413670000111
Atomic displacement parameter
Figure BDA0003410413670000112
Figure BDA0003410413670000113
Figure BDA0003410413670000121
Figure BDA0003410413670000131
Figure BDA0003410413670000141
Figure BDA0003410413670000151
Geometric parameters
Figure BDA0003410413670000152
Figure BDA0003410413670000153
Figure BDA0003410413670000161
Figure BDA0003410413670000171
Figure BDA0003410413670000181
Based on the above analysis data, it was confirmed that the structure of bupivacaine nitroxide impurity 2 is shown in fig. 2.
The single crystal preparation method of the bupivacaine nitrogen oxide impurity disclosed by the invention provides a basis for the structural representation of the bupivacaine nitrogen oxide impurity, and can provide an impurity standard substance for the quality research of bupivacaine bulk drug.
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 producing a single crystal of impurities of bupivacaine, characterized by comprising the steps of:
(s1) dissolving impurities of bupivacaine in a readily soluble solvent to obtain a solution;
optionally (s2) adding a sparingly soluble solvent to the solution obtained in step s1 at or near saturation; and
(s3) standing to allow the solvent to naturally volatilize until obtaining the impurity single crystal of bupivacaine,
wherein the easily soluble solvent is diethyl ether, dichloromethane, chloroform, 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.
2. The method according to claim 1, wherein the easily soluble solvent is diethyl ether, dichloromethane, tetrahydrofuran or a mixed solvent of two or more thereof.
3. The method of claim 1, wherein the lyotropic solvent is diethyl ether.
4. The preparation method according to claim 1, wherein the mass-to-volume ratio of the impurities of bupivacaine to the easily soluble solvent is 8-15 g/L.
5. The process according to claim 1, wherein the sparingly soluble solvent is petroleum ether, n-hexane, cyclohexane or a mixed solvent of two or more thereof.
6. The method according to claim 1, wherein the volume ratio of the easily soluble solvent to the poorly soluble solvent is 1:1 to 1: 4.
7. The method of claim 1, wherein the method is performed at 25 ± 10 ℃.
8. The method of claim 1, wherein the impurities of bupivacaine are separated by a preparative liquid phase method.
9. A single crystal of impurities of bupivacaine, characterized in that it is produced by the production method of claims 1 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
CN111548303A (en) * 2020-06-28 2020-08-18 山东美泰医药有限公司 Levobupivacaine hydrochloride impurity and preparation and analysis method thereof
WO2021146215A1 (en) * 2020-01-13 2021-07-22 Durect Corporation Sustained release drug delivery systems with reduced impurities and related methods

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
CN111548303A (en) * 2020-06-28 2020-08-18 山东美泰医药有限公司 Levobupivacaine hydrochloride impurity and preparation and analysis method thereof

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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