CN112557523B - Impurities of isoshu pang blue injection, preparation method and detection method thereof - Google Patents
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Abstract
The invention provides an impurity of isosulindachene injection, a preparation method and a detection method thereof, belonging to the technical field of pharmacy. The structural formula of the impurity shown in the formula I is shown as follows. The impurities shown in the formula I are prepared when the isosulindac blue injection is subjected to high-temperature damage and alkali damage. The invention can separate and prepare the impurities shown in the formula I, provides a new reference substance for impurity detection of the isosulubicin injection, and is more beneficial to development of a method for detecting related substances in the isosulubicin injection, thereby controlling the product quality.
Description
Technical Field
The invention belongs to the technical field of pharmacy, and particularly relates to impurities of an isoshu panoxan injection, and a preparation method and a detection method thereof.
Background
The ISHUFULAN injection is available under the trade name LYMPHAZURIN, developed by Hirsch Industries in 1981, and approved by FDA at 29 days 07/1981 for marketing in the United states. The isoshu blue injection belongs to a lymphatic vessel developer, has been used in the United states for nearly 40 years, and is safe and effective. It is an assisted lymphatic contrast agent: primary and secondary lymphedema of the extremities; chyluria, chylomicronemia ascites or chylomicron; lymph node invasion of primary or secondary tumors; and lymph node response to treatment modalities. At present, no original grinding product of the isoshu pang blue injection exists on the market in China, and no similar product exists on the market.
On 14 days 05 and 2020, the national drug administration issued "a notice on the development of evaluation work on the quality and efficacy consistency of imitation drugs for chemical injections (62: 2020), and required the consistency of the quality and efficacy of imitation drugs for injections and the original drugs, wherein an important aspect is the consistency study of the impurity spectrum.
The isoshu bluing injection can be gradually degraded to generate impurities during the stability period, and if the structure of the impurities is not determined, the impurities bring a greater risk to the quality control of the isoshu bluing injection; only by determining the chemical structure of the impurities, the generation mechanism of the impurities is known, and then the reaction operation in the step is effectively controlled, so that the quality requirement of the isoshu bluing injection can be met.
Disclosure of Invention
The invention aims to provide impurities of isosulbactam blue injection on the basis of the prior art.
The invention also aims to provide a preparation method of the impurities of the isosulubine injection.
The third purpose of the invention is to provide a method for detecting the impurities in the isosulubine injection.
A fourth object of the invention is the use of the impurity for the quality testing of an injection solution of isosulubine.
The technical scheme of the invention is as follows:
an impurity of formula I, having the formula:
the invention also provides a preparation method of the impurity shown in the formula I, which comprises the following steps:
the isosulindacene injection can be gradually degraded to generate impurities in the stability period, and the degradation amount of the impurities is continuously increased along with the extension of the stability lofting time. The inventor of the invention finds the impurity shown in the formula I in the isosulindac blue injection, and the content of the impurity exceeds the identification threshold value by 0.2% along with the prolonging of the stable standing time, so that no literature reports that the isosulindac blue injection contains the unknown impurity at present. According to ICH guiding principle, it is necessary to know the generation mechanism of the unknown impurity, further prepare and separate the unknown impurity, and determine the structure of the unknown impurity by means of characterization means such as LC-MS and NMR, so as to effectively control the product quality of the ISHUFUPANLAN injection.
Based on the structural analysis of the isosulbactam blue, the inventor of the invention respectively adopts the destructive conditions of high temperature, acid, alkali, oxidation and the like to carry out destructive research on the isosulbactam blue injection and the aqueous solution of the isosulbactam blue raw material medicine, and inspects the degradation path of the unknown impurities. The inventors detected this unknown impurity in both the high temperature and alkaline breakdown samples, and the impurity degraded significantly under alkaline breakdown conditions. Therefore, the degradation pathways of the unknown impurities are mainly high temperature destruction and alkali destruction.
When the isoshupeng blue injection and the aqueous solution of the isoshupeng blue raw material medicine are damaged at high temperature, the high temperature generally refers to 50-100 ℃.
In a preferred embodiment, when the inventor of the present invention destroys an isosulubine injection at high temperature, it comprises the following steps: the isosulubicin blue injection is subjected to chemical reaction at the temperature of 50-70 ℃ to prepare the impurity shown in the formula I.
In a more preferable scheme, when the ISHUFULAN injection is subjected to high-temperature destruction, the reaction temperature is 60 ℃, and the reaction time is 36 to 60 hours, preferably 48 hours.
In one embodiment, the method for performing alkali destruction on the isosulbactam blue injection comprises the following steps: the isosulindacene injection and an alkali solution are subjected to chemical reaction at the temperature of 10-65 ℃ to prepare the impurities shown in the formula I.
For the present invention, when the alkali destruction is performed on the isosulindac blue injection, the used alkali is an inorganic alkali, which can be, but not limited to, one of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate or ammonia water, and for example, sodium hydroxide can be selected.
In a preferred embodiment, when the alkali destruction is performed on the isosulubine injection, the concentration of the alkali solution is 1 to 3mol/L, preferably 1 to 2mol/L, and more preferably 2mol/L.
The concentration of the isosulbactam blue in the isosulbactam blue injection is 6-10 mg/mL, and is preferably 10mg/mL.
In a preferred scheme, when the isosulubicin injection is subjected to alkali destruction, the volume ratio of the isosulubicin injection to the alkali solution is 1-3; preferably 1; for example, 1.
In a preferred embodiment, the alkali-labile ISHUFULAN injection is subjected to a reaction temperature of 30 deg.C to 50 deg.C, such as, but not limited to, 30 deg.C, 35 deg.C, 40 deg.C, 45 deg.C, or 50 deg.C.
Further, the reaction time is 1 to 3 hours, preferably 2 hours.
For the impurities represented by formula I prepared when the isoshu pan blue injection is subjected to alkali destruction, the inventors tried to separate the impurities by using high performance liquid chromatography, wherein the conditions of the high performance liquid chromatography comprise: the chromatographic column is Welch Ultimate AQ, and gradient elution is carried out by adopting a mobile phase A1 and a mobile phase B1 as a mixed mobile phase, wherein the mobile phase A1 is an ammonium acetate solution, and the mobile phase B1 is acetonitrile; the gradient elution comprises the steps of: (1) The volume ratio of the mobile phase A1 to the mobile phase B1 is kept constant at 90; (2) In 2-12 minutes, the volume ratio of the mobile phase A1 to the mobile phase B1 is uniformly graded from 90; (2) In 12-12.2 minutes, the volume ratio of the mobile phase A1 to the mobile phase B1 is uniformly graded from 50; (4) The volume ratio of the mobile phase A1 to the mobile phase B1 is kept constant at 5; (5) In 15-15.2 minutes, the volume ratio of the mobile phase A1 to the mobile phase B1 is uniformly graded from 5; (6) The volume ratio of mobile phase A1 to mobile phase B1 was kept constant at 90. The detailed elution procedure is shown in table 1 below.
TABLE 1 gradient elution procedure
In a preferred embodiment, the impurities are separated by HPLC using a column of Welch Ultimate AQ 30 mm. Times.250mm, 5 μm pore size 100A.
In a preferred embodiment, the mobile phase A1 is a 15 to 25mmol/L ammonium acetate solution, adjusted with acetic acid pH =4. In a more preferred embodiment, the mobile phase A1 is a 20mmol/L ammonium acetate solution, adjusted with acetic acid pH =4.
Further, the detection wavelength is 350 to 370nm, preferably 360nm.
Further, the flow rate is 30 to 40mL/min, preferably 35mL/min
Further, the column temperature is 20 to 40 ℃, preferably 30 ℃.
And collecting the preparation liquid of the target peak, pre-freezing the preparation liquid by using dry ice and ethanol, and freeze-drying the preparation liquid in a dark place to obtain a target impurity solid shown in the formula I.
On the basis of providing an impurity separation preparation method, the invention also provides a detection method of the impurity shown in the formula I in the isoshu pan-blue injection, the detection method adopts a high performance liquid chromatography to carry out detection, and carries out qualitative or quantitative detection on the impurity, and the high performance liquid chromatography conditions comprise: performing gradient elution by taking an octadecylsilane bonded silica gel column as a chromatographic column and taking a mobile phase A2 and a mobile phase B2 as mixed mobile phases, wherein the mobile phase A2 is an ammonium acetate solution, and the mobile phase B2 is an acetonitrile and ammonia water mixed solution; the gradient elution comprises the following steps: (1) The volume ratio of the mobile phase A2 to the mobile phase B2 is kept constant at 90; (2) The volume ratio of the mobile phase A2 to the mobile phase B2 is uniformly graded from 90 to 10 to 20 in 5 to 25 minutes; (3) The volume ratio of mobile phase A2 to mobile phase B2 was kept constant at 20; (4) The volume ratio of the mobile phase A2 to the mobile phase B2 is uniformly graded from 20; (5) The volume ratio of mobile phase A2 to mobile phase B2 was kept constant at 90. The detailed elution procedure is shown in table 2 below.
TABLE 2 gradient elution procedure
In the detection method, an octadecylsilane bonded silica gel column is used as a chromatographic column, the model of the chromatographic column is 250mm multiplied by 4.6mm, and the model is 5.0 μm, and the detection method comprises the following steps: zorbax Eclipse XDB-C18 column or Luna C18.
For the purposes of the present invention, the mobile phase A2 is an ammonium acetate solution, and in a preferred embodiment the concentration of ammonium acetate in the mobile phase A2 is from 1% to 3% by weight, for example 1% by weight.
For the purposes of the present invention, the mobile phase B2 is a mixed solution of acetonitrile and ammonia, and in a preferred embodiment, the volume concentration of ammonia in the mobile phase B2 is 3-10%. In a more preferred embodiment, the concentration of ammonia in mobile phase B2 is 5% by volume.
When detecting impurities shown in formula I in the isoshuVanilla injection, the method comprises the following steps of:
control solution: an impurity represented by formula I prepared when alkali destruction is performed with an isosulubine blue injection is precisely weighed as a control, and dissolved and diluted with a diluent [ the volume ratio of mobile phase A2 to acetonitrile is 9 ] to prepare a control solution containing 0.01mg per 1mL as a control solution.
Test solution: taking the isosulubine injection destroyed by the alkali solution, diluting the isosulubine injection by using a diluent (the volume ratio of the mobile phase A2 to the acetonitrile is 9).
The invention also provides application of the impurity shown in the formula I in detecting the quality of the isosulubicin injection, for example, the impurity is used as a reference substance, and the high performance liquid chromatography is used for detecting the impurity in the isosulubicin injection, so that the quality of the isosulubicin injection is controlled.
The qualitative detection in the present invention can be performed by using conventional methods, for example, corresponding analysis is performed by using external standard method with reference substance, or after separating each component by HPLC, qualitative analysis is performed by using conventional identification means, such as mass spectrum, thin layer, ultraviolet, etc.
In the quantitative detection of the invention, the content can be calculated by using the conventional methods such as an external standard method, an area normalization method and the like.
During quantitative analysis, if an external standard method is used, a standard curve is manufactured by adopting a conventional method for calculation; however, in the qualitative analysis, a standard curve is not required to be prepared, and the determination can be made by the retention time.
In the invention, the parameters such as column temperature, flow rate, sample injection amount and the like can be selected in a common range.
In a preferred embodiment, the detection wavelength is from 210 to 400nm, preferably from 210 to 300nm, for example 225nm.
Further, the flow rate is 0.6 to 1.2mL/min, preferably 1.0mL/min.
Further, the column temperature is 20 to 40 ℃, preferably 30 ℃.
Further, the amount of the sample is 12 to 30. Mu.L, preferably 20. Mu.L.
By adopting the technical scheme of the invention, the advantages are as follows:
(1) The invention provides a new impurity generated in the isosulindblue injection, defines the degradation path of the impurity and is beneficial to the quality control of the isosulindblue product.
(2) The invention provides a method for separating and preparing impurities shown in the formula I from an isosulubine injection damaged by alkali, which does not need to use excessive chemical reagents and post-treatment, has high reaction conversion rate and is easy to separate and prepare.
(3) According to the invention, the impurities shown in the formula I are separated and prepared, so that a new reference substance is provided for impurity detection of the isosulindacene injection, and development of a detection method for related substances in the isosulindacene injection is facilitated, so that the product quality is controlled.
Drawings
FIG. 1 is a graph of impurities in the isosulubicin injection prepared in example 4 1 H NMR chart;
FIG. 2 shows the impurities in the isosulubine injection prepared in example 4 13 C NMR chart;
FIG. 3 is a DEPT90 plot of the impurities of the isosulubine injection prepared in example 4;
FIG. 4 is a DEPT135 plot of the impurities of the isosulubine injection prepared in example 4;
FIG. 5 is a COSY plot of the impurities of the isosulubine injection prepared in example 4;
FIG. 6 is a HSQC plot of the impurities of the isosulbactam blue injection prepared in example 4;
FIG. 7 is a HMBC plot of the impurities of the isosulubine injection prepared in example 4;
FIG. 8 is a LC-MS (positive ion) plot of the impurities of the isosulubine blue injection prepared in example 4;
FIG. 9 is a LC-MS (negative ion) profile of the impurities of the isosulubine injection prepared in example 4;
FIG. 10 is an HPLC chart of the control solution in example 5;
FIG. 11 is a HPLC chart of the test solution in example 5.
Detailed Description
Terms used in the present invention generally have meanings commonly understood by those of ordinary skill in the art, unless otherwise specified.
The present invention will be described in further detail with reference to specific examples. It will be understood that these examples are for the purpose of illustrating the invention and are not intended to limit the scope of the invention in any way.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
Comparative example 1
10mL of 10mg/mL of isoshu panblue injection is taken, HPLC analysis shows that the impurity shown in the formula I is not detected, 20mL of 1mol/L hydrochloric acid solution is added into the injection, reaction is carried out at 30 ℃ for 24 hours, and HPLC analysis shows that the impurity shown in the formula I is still not detected.
Comparative example 2
10mL of 10mg/mL of isoshu bluish injection was taken, and subjected to HPLC analysis, whereby the impurities represented by the formula I were not detected, and then, 20mL of 10% hydrogen peroxide solution was added thereto, reacted at 30 ℃ for 24 hours, and subjected to HPLC analysis, whereby the impurities represented by the formula I were not detected.
Example 1
10mL of 10mg/mL of isoshu pan-blue injection is taken, HPLC analysis shows that the impurity shown in the formula I is not detected, the mixture is placed in a 60-DEG C oven to react for 48 hours, and HPLC analysis shows that the content of the impurity shown in the formula I is 0.5%.
Example 2
10mL of 10mg/mL of isoshu pan-blue injection is taken, HPLC analysis shows that the impurity shown in the formula I is not detected, 30mL of 1mol/L sodium hydroxide aqueous solution is added into the injection, the reaction is carried out at 40 ℃ for 2 hours, and HPLC analysis shows that the content of the impurity shown in the formula I is 8%.
Example 3
10mL of 10mg/mL of isoshu pan-blue injection is taken, HPLC analysis shows that the impurity shown in the formula I is not detected, 10mL of 3mol/L of sodium hydroxide aqueous solution is added into the injection, reaction is carried out at 30 ℃ for 2 hours, and HPLC analysis shows that the content of the impurity shown in the formula I is 15%.
Example 4
10mL of 10mg/mL of isoshu blue injection is taken, HPLC analysis is carried out, no impurity shown in the formula I is detected, 20mL of 2mol/L sodium hydroxide aqueous solution is added into the injection, reaction is carried out at 50 ℃ for 2 hours, and HPLC analysis is carried out, so that the content of the impurity shown in the formula I is 40%.
For the impurities shown in formula I produced by the alkali-destroyed isoshu blue injection of the embodiment, the impurities can be separated by high performance liquid chromatography, and the conditions of the high performance liquid chromatography include:
a chromatographic column: welch Ultimate AQ,30 mm. Times.250mm, 5 μm, pore size 100A; detection wavelength: 360nm; flow rate: 35mL/min; column temperature: 30 ℃; the mobile phase comprises a mobile phase A1 and a mobile phase B1, wherein the ratio of the mobile phase A1:20mmol/L ammonium acetate solution (acetic acid adjusted pH = 4); mobile phase B1: acetonitrile; the mobile phase was eluted by gradient elution, according to the following procedure in table 1:
TABLE 1 gradient elution procedure
The target peak preparation was collected, prefreezed with dry ice and ethanol, and lyophilized in the dark to obtain 38mg of the target impurity solid with a yield of 38%. LC-MS (M + H) + )：ESI m/z＝414.06761。LC-MS(M+H - ): ESI m/z =412.05231.HPLC purity: 98.4 percent.
TABLE 3 1 H NMR (DMSO-d 6) data
* The chemical shifts delta (ppm) of the d, t, q and m peaks in the nuclear magnetic hydrogen spectrum are averaged.
TABLE 4 13 C NMR (DMSO-d 6) data
Example 5
The method for detecting the impurities shown in the formula I in the isosulubine injection comprises the following steps:
and (3) chromatographic column: zorbax Eclipse XDB C18, 250 mm. Times.4.6 mm, 5.0. Mu.m; the mobile phase comprises a mobile phase A2 and a mobile phase B2, wherein the ratio of the mobile phase A2:1wt% ammonium acetate solution; and (3) mobile phase B: a mixed solution of ammonia water and acetonitrile (the volume concentration of the ammonia water is 5%); the mobile phase was eluted by gradient elution according to the following procedure in table 2:
TABLE 2 gradient elution procedure
The column temperature is 30 ℃; the flow rate was 1.0mL per minute; the sample size is 20 mu L; the detection wavelength was 225nm.
Taking the impurity shown in the formula I prepared in the example 4 as a reference substance, precisely weighing, dissolving and diluting by using a diluent [ the volume ratio of the mobile phase A2 to the acetonitrile is 9 ]; the isosumatriptan injection destroyed by the alkali solution in example 2 was diluted with a diluent [ volume ratio of mobile phase A2 to acetonitrile 9 ] to prepare an isosumatriptan containing 2mg per 1mL, which was used as a test solution.
Precisely measuring 20 μ L of each of the test solution and the reference solution, injecting into a liquid chromatograph, and recording chromatogram; according to the detection result, the absolute retention time of the impurities in the reference solution is 12.752min, and the content of the impurities is 98.4% by an area normalization method (see fig. 10); the absolute retention time of the impurity of the present invention in the test solution was 12.669min, and its content was 8% by area normalization (see fig. 11).
The above examples are only intended to illustrate the technical solution of the present invention, and not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it should be understood by those of ordinary skill in the art that: modifications may be made to the technical solutions described in the foregoing embodiments, or equivalents may be substituted for some of the technical features; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (9)
1. A method for preparing impurities of isosulindachene injection is characterized in that the structural formula of the impurities is shown as a formula I,
the preparation method comprises the following steps:
carrying out chemical reaction on the isosulindblue injection and an alkali solution at the temperature of 10-65 ℃ to prepare impurities shown in the formula I; the impurities are separated by adopting high performance liquid chromatography, and the high performance liquid chromatography conditions comprise: the chromatographic column is Welch Ultimate AQ,30mm X250mm, 5 μm; the detection wavelength is 360nm; the flow rate is 35mL/min; performing gradient elution by adopting a mixed mobile phase of a mobile phase A1 and a mobile phase B1, wherein the mobile phase A1 is an ammonium acetate solution, and the mobile phase B1 is acetonitrile; the gradient elution comprises the steps of: (1) The volume ratio of the mobile phase A1 to the mobile phase B1 is kept constant at 90; (2) In 2-12 minutes, the volume ratio of the mobile phase A1 to the mobile phase B1 is uniformly graded from 90; (2) In 12-12.2 minutes, the volume ratio of the mobile phase A1 to the mobile phase B1 is uniformly graded from 50; (4) The volume ratio of the mobile phase A1 to the mobile phase B1 is kept constant at 5; (5) The volume ratio of the mobile phase A1 to the mobile phase B1 is uniformly graded from 5; (6) The volume ratio of mobile phase A1 to mobile phase B1 was kept constant at 90.
2. The method of preparing impurities of isosuzublue injection according to claim 1, wherein the base is an inorganic base; the concentration of the alkali solution is 1-3 mol/L.
3. The method for preparing impurities of isosulbactam blue injection according to claim 2, wherein the alkali is sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate or ammonia water; the concentration of the alkali solution is 1-2 mol/L.
4. The method of preparing impurities of isosulbactam blue injection according to claim 3, wherein the base is sodium hydroxide; the concentration of the alkali solution is 2mol/L.
5. The method for preparing impurities of isosulbactam blue injection according to claim 1, wherein the concentration of isosulbactam blue in the isosulbactam blue injection is 6-10 mg/mL; the reaction temperature is 30-50 ℃; the reaction time is 1 to 3 hours; the volume ratio of the isosulbactam blue injection to the alkali solution is 1.
6. The method of preparing an impurity in an isosulubine injection according to claim 5, wherein the concentration of isosulubine in said isosulubine injection is 10mg/mL; the volume ratio of the isosulubicin injection to the alkali solution is 1-2.
7. The method for preparing impurities of isosulbactam blue injection according to claim 6, wherein the volume ratio of the isosulbactam blue injection to the alkali solution is 1.
8. A method for detecting impurities in an isosulubin injection is characterized in that the structural formula of the impurities is shown as a formula I,
the detection method adopts high performance liquid chromatography to detect the impurities in the isosulindachene injection, and the conditions of the high performance liquid chromatography comprise: the chromatographic column is Zorbax Eclipse XDB C18, 250mm multiplied by 4.6mm,5.0 μm; the detection wavelength is 225nm; the flow rate was 1.0mL per minute; carrying out gradient elution by adopting a mobile phase A2 and a mobile phase B2 as mixed mobile phases, wherein the mobile phase A2 is an ammonium acetate solution, and the mobile phase B2 is an acetonitrile and ammonia water mixed solution; the gradient elution comprises the steps of: (1) The volume ratio of the mobile phase A2 to the mobile phase B2 is kept constant at 90; (2) The volume ratio of the mobile phase A2 to the mobile phase B2 is uniformly graded from 90 to 10 to 20 in 5 to 25 minutes; (3) The volume ratio of mobile phase A2 to mobile phase B2 was kept constant at 20; (4) The volume ratio of the mobile phase A2 to the mobile phase B2 is uniformly graded from 20; (5) The volume ratio of mobile phase A2 to mobile phase B2 was kept constant at 90.
9. An application of impurities of isosulindachene blue injection in detecting the quality of the isosulindachene blue injection is characterized in that the structural formula of the impurities is shown as a formula I,
the high performance liquid chromatography is adopted to detect the impurities in the isosulindac blue injection, and the high performance liquid chromatography conditions comprise: performing gradient elution by taking an octadecylsilane bonded silica gel column as a chromatographic column and taking a mobile phase A2 and a mobile phase B2 as mixed mobile phases, wherein the mobile phase A2 is an ammonium acetate solution, and the mobile phase B2 is an acetonitrile and ammonia water mixed solution; the gradient elution comprises the following steps: (1) The volume ratio of mobile phase A2 to mobile phase B2 was kept constant at 90; (2) The volume ratio of the mobile phase A2 to the mobile phase B2 is uniformly graded from 90 to 10 to 20 in 5 to 25 minutes; (3) The volume ratio of the mobile phase A2 to the mobile phase B2 is kept constant at 20; (4) The volume ratio of the mobile phase A2 to the mobile phase B2 is uniformly graded from 20; (5) The volume ratio of mobile phase A2 to mobile phase B2 was kept constant at 90.
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