CN112684022B - Vitamin B 1 Injection impurity and preparation and detection method thereof - Google Patents
Vitamin B 1 Injection impurity and preparation and detection method thereof Download PDFInfo
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Abstract
The invention provides vitamin B 1 Injection impurities and 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. Vitamin B of the invention 1 And (3) when the injection is subjected to high-temperature damage and alkali damage, preparing impurities shown in the formula I. The invention can separate and prepare the impurity shown in the formula I, namely vitamin B 1 The impurity detection of the injection provides a new reference substance, and is more beneficial to vitamin B 1 The development of a method for detecting related substances in the injection can control the quality of the product.
Description
Technical Field
The invention belongs to the technical field of pharmacy, and particularly relates to vitamin B 1 Injection impurity, and its preparation method and detection method are provided.
Background
Vitamin B 1 The injection is sold under the trade name of LYMPHAZURIN, developed by FRESENIUS KABI USA LLC, and is approved by the FDA for marketing in the United states in 1982. Vitamin B 1 The injection is suitable for vitamin B 1 Lack of treatment for the resulting beriberi or Wernicke's encephalopathy. Can also be used for vitamin B 1 The adjuvant treatment of peripheral neuritis and dyspepsia caused by deficiency. Has been used in the united states for nearly 40 years, safe and effective.
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.
Vitamin B 1 The injection can be gradually degraded during the stability period to generate impurities, and if the impurities are not determined by structure, vitamin B can be given 1 The quality control of the injection brings about a great risk; vitamin B can be ensured only by determining the chemical structure of the impurity, knowing the generation mechanism of the impurity and then effectively controlling the reaction operation 1 The injection meets the quality requirement.
ChP contains crude drug and injection, EP and USP contain crude drug. Comparison of vitamin B in ChP and USP methods 1 The time to peak is too early and the number of impurities is less than that of the EP method; vitamin B in EP Process 1 The time of peak emergence was too late.
Disclosure of Invention
The invention aims to provide vitamin B based on the prior art 1 Impurities of the injection.
Another object of the present invention is to provide the above-mentioned vitamin B 1 A preparation method of impurities of injection.
It is a third object of the present invention to provide vitamin B 1 A method for detecting the impurities in the injection.
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:
vitamin B 1 The 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 inventionIn vitamin B 1 The impurities shown in the formula I are found in the injection, the content of the impurities exceeds the identification threshold value by 0.2% along with the prolonging of the stable standing time, and no vitamin B is reported in the literature at present 1 The injection contains the unknown impurities. According to the ICH guiding principle, the generation mechanism of the unknown impurity is necessary to be understood, the unknown impurity is further prepared and separated, and the structure of the impurity is determined by characterization means such as LC-MS and NMR, so that the vitamin B can be effectively controlled 1 Product quality of the injection.
Based on para-vitamin B 1 The inventors of the present invention used destructive conditions such as high temperature, acid, alkali, oxidation, etc. to treat vitamin B 1 Injection and vitamin B 1 The aqueous solution of the drug substance was subjected to a destruction study to investigate the degradation pathway of the unknown impurity. The inventors detected this unknown impurity in both the high temperature and base-destruct samples, and the impurity degraded significantly under base-destruct conditions. Therefore, the degradation pathways of the unknown impurities are mainly high temperature destruction and alkali destruction.
The invention converts vitamin B into vitamin B 1 Injection and vitamin B 1 When the aqueous solution of the raw material medicine is damaged at high temperature, the high temperature generally refers to 75-100 ℃.
In a preferred embodiment, the present inventors compound vitamin B 1 When the injection is damaged at high temperature, the method comprises the following steps: vitamin B 1 The injection is subjected to chemical reaction at 75-85 ℃ to prepare the impurity shown in the formula I.
In a more preferred embodiment, vitamin B 1 When the injection is destroyed at high temperature, the reaction temperature is 80 ℃, and the reaction time is 18 to 30 hours, preferably 24 hours.
In one embodiment, the present invention employs vitamin B 1 When the injection is subjected to alkali destruction, the method comprises the following steps: mixing vitamin B 1 The injection and the alkali solution are subjected to chemical reaction at the temperature of 25-60 ℃ to prepare the impurity shown in the formula I.
For the purposes of the present invention, vitamin B 1 When the injection is subjected to alkali destruction, the adopted alkali is inorganic alkali, and can beBut is not limited to, one of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate or ammonia, for example, sodium hydroxide may be selected.
In a preferred embodiment, vitamin B 1 When the injection is subjected to alkali destruction, the concentration of the alkali solution is 1 to 3mol/L, preferably 1 to 2mol/L, and more preferably 2mol/L.
Vitamin B as mentioned in the invention 1 Vitamin B in injection 1 The concentration of (B) is 100mg/mL to 200mg/mL, preferably 200mg/mL.
In a preferred embodiment, vitamin B 1 Vitamin B in the case of alkali destruction of injection 1 The volume ratio of the injection to the alkali solution is 1-3; preferably 1; for example, 1.
In a preferred embodiment, vitamin B 1 When the injection is subjected to alkali destruction, the reaction temperature is 30-40 ℃.
Further, the reaction time is 0.5 to 2 hours, preferably 1 hour.
For vitamin B 1 The inventors tried to separate the impurities represented by formula I prepared when the injection solution was subjected to alkali destruction by using high performance liquid chromatography under conditions including: 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 0.05-0.5% trifluoroacetic acid solution, and the mobile phase B1 is methanol; the gradient elution comprises the following steps: (1) The volume ratio of mobile phase A1 to mobile phase B1 was kept constant at 95; (2) In 16-16.2 minutes, the volume ratio of the mobile phase A1 to the mobile phase B1 is uniformly graded from 95; (3) The volume ratio of the mobile phase A1 to the mobile phase B1 is kept constant at 5; (4) In 18-18.2 minutes, the volume ratio of the mobile phase A1 to the mobile phase B1 is uniformly graded from 5; (5) The volume ratio of mobile phase A1 to mobile phase B1 was kept constant at 95. 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 30mm x 250mm,5 μm.
In a preferred embodiment, the mobile phase A1 is a 0.1% trifluoroacetic acid solution.
Further, the detection wavelength is 245 to 250nm, preferably 248nm.
Further, the flow rate is 10 to 50ml/min, preferably 30ml/min.
Further, the column temperature is 15 to 35 ℃, preferably 25 ℃.
Further, the amount of sample is 1000 to 5000. Mu.L, preferably 4000. Mu.L.
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 vitamin B 1 The detection method of the impurity shown in the formula I in the injection adopts high performance liquid chromatography for detection, carries out qualitative or quantitative detection on the impurity, and the high performance liquid chromatography conditions comprise that: performing gradient elution by using an octadecylsilane bonded silica gel column as a chromatographic column and adopting a mobile phase A2 and a mobile phase B2 as a mixed mobile phase, wherein the mobile phase A2 is an ammonium hexanesulfonate solution, and the mobile phase B2 is methanol; the gradient elution comprises the following steps: (1) The volume ratio of mobile phase A2 to mobile phase B2 was kept constant at 95; (2) The volume ratio of the mobile phase A2 to the mobile phase B2 is uniformly graded from 95; (3) The volume ratio of the mobile phase A2 to the mobile phase B2 is kept constant at 50; (4) The volume ratio of the mobile phase A2 to the mobile phase B2 is uniformly graded from 50; (5) The volume ratio of mobile phase A2 to mobile phase B2 was kept constant at 95. The detailed elution procedure is shown in table 2 below.
TABLE 2 gradient elution procedure
In the detection method, an octadecylsilane chemically bonded silica gel column is used as a chromatographic column, and the model of the chromatographic column is Shimadzu Inertsil ODS-3, 250mm multiplied by 4.6mm, and 5.0 mu m.
For the purposes of the present invention, mobile phase A2 is a solution of ammonium hexanesulfonate, in a preferred embodiment the concentration of ammonium hexanesulfonate in mobile phase A2 is between 0.5% and 2% by weight, for example 1% by weight.
In the detection of vitamin B 1 When the impurities shown in the formula I in the injection are impurities, the following solutions are prepared:
control solution: with vitamin B 1 The impurities represented by formula I prepared by alkali destruction of injection are used as reference substance, precisely weighed, and diluted with [0.75% glacial acetic acid ]]Dissolving and diluting to obtain control solution containing 0.01mg per 1 mL.
Test solution: taking vitamin B destroyed by alkali solution 1 Injection, with diluent [0.75% glacial acetic acid ]]Diluting to 1mL of vitamin B 1 As a test solution.
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 a conventional method for calculation; however, in qualitative analysis, it is not necessary to prepare a standard curve, and the determination can be made by 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 248nm.
Further, the flow rate is 0.6 to 1.2mL/min, preferably 0.8mL/min.
Further, the column temperature is 20 to 40 ℃, preferably 30 ℃.
Further, the amount of the sample is 20 to 50. Mu.L, preferably 25. Mu.L.
By adopting the technical scheme of the invention, the advantages are as follows:
(1) The present invention provides vitamin B 1 The new impurities generated in the injection define the degradation path of the impurities and are beneficial to vitamin B 1 And (5) controlling the quality of the product.
(2) The invention provides a method for synthesizing impurities shown in a formula I.
(3) The invention provides vitamin B after alkali destruction 1 The method for separating and preparing the impurities shown in the formula I in the injection does not need to use excessive chemical reagents and post-treatment, has high reaction conversion rate and is easy to separate and prepare.
(4) The invention prepares the impurity shown in the formula I, namely vitamin B through separation 1 The impurity detection of the injection provides a new reference substance, and is more beneficial to vitamin B 1 The development of a method for detecting related substances in the injection so as to control the quality of products.
Drawings
FIG. 1 is vitamin B prepared in example 6 1 Of impurities in the injection 1 H NMR chart;
FIG. 2 is an enlarged view of a portion of FIG. 1;
FIG. 3 is vitamin B prepared in example 6 1 Of impurities in the injection 13 C NMR chart;
FIG. 4 is vitamin B prepared in example 6 1 DEPT90 plot of injection impurities;
FIG. 5 is vitamin B prepared in example 6 1 DEPT135 plot of injection impurities;
FIG. 6 is vitamin B prepared in example 6 1 COSY plot of injection impurities;
FIG. 7 is vitamin B prepared in example 6 1 HSQC plot of injection impurities;
FIG. 8 is vitamin B prepared in example 6 1 HMBC picture-1/3 of injection impurities;
FIG. 9 is vitamin B prepared in example 6 1 HMBC picture-2/3 of injection impurities;
FIG. 10 is vitamin B prepared in example 6 1 HMBC picture-3/3 of injection impurities;
FIG. 11 is vitamin B prepared in example 6 1 LC-MS (positive ion) profile of injection impurities;
FIG. 12 is an HPLC chart of the control solution in example 7;
FIG. 13 is a HPLC chart of the test solution in example 7.
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 intended to illustrate 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
Taking 5mL 200mg/mL vitamin B 1 The injection was analyzed by HPLC, and no impurity represented by formula I was detected, and then 5mL of a 2mol/L hydrochloric acid solution was added thereto, and reacted at 25 ℃ for 24 hours, and the impurity represented by formula I was still not detected by HPLC.
Comparative example 2
Taking 5mL 200mg/mL vitamin B 1 The injection was analyzed by HPLC, and no impurity represented by formula I was detected, and 5ml of a 3% hydrogen peroxide solution was added thereto, and reacted at 25 ℃ for 24 hours, and the impurity represented by formula I was still not detected by HPLC.
Example 1
Taking 5mL of 200mg/mL vitamin B 1 The injection is analyzed by HPLC, the impurities shown in the formula I are not detected, the injection is placed in an oven at the temperature of 80 ℃ for reaction for 24 hours, and the content of the impurities shown in the formula I is about 0.5% by HPLC analysis.
Example 2
Taking 5mL of 200mg/mL vitamin B 1 The injection, through HPLC analysis, does not detect the impurity shown in formula I, to which is added 5mL 1mol/L sodium hydroxide solution, 25 ℃ reaction for 1h, through HPLC analysis, the impurity content shown in formula I is about 0.5%.
Example 3
Taking 5mL 200mg/mL vitamin B 1 The injection is analyzed by HPLC, impurities shown in the formula I are not detected, 5mL of 2mol/L sodium hydroxide solution is added into the injection, the reaction lasts for 1h at the temperature of 25 ℃, and the content of the impurities shown in the formula I is about 1.0% by HPLC analysis.
Example 4
Taking 5mL 200mg/mL vitamin B 1 The injection is analyzed by HPLC, the impurities shown in the formula I are not detected, a 5 mL/3 mol/L sodium hydroxide solution is added into the injection to react for 1h at the temperature of 25 ℃, and the impurities shown in the formula I are not effectively separated from peripheral peaks by the analysis of HPLC.
Example 5
Taking 5mL 200mg/mL vitamin B 1 The injection was analyzed by HPLC, and no impurity represented by formula I was detected, and 10mL of 2mol/L sodium hydroxide solution was added thereto, and the reaction was carried out at 25 ℃ for 1 hour, and the content of the impurity represented by formula I was about 5.0% by HPLC.
Example 6
Taking 5mL 200mg/mL vitamin B 1 The injection was analyzed by HPLC, and no impurity represented by formula I was detected, and 10mL of 2mol/L sodium hydroxide solution was added thereto, and reacted at 40 ℃ for 1 hour, and the content of the degradation impurity was about 10.0% by HPLC.
For vitamin B after alkali destruction of this example 1 The impurities shown in formula I generated by the injection can be separated by adopting high performance liquid chromatography, and the high performance liquid chromatography conditions comprise that:
a chromatographic column: welch Ultimate AQ,30 mm. Times.250mm, 5 μm; detection wavelength: 248nm; the mobile phase comprises a mobile phase A1 and a mobile phase B1, wherein the ratio of the mobile phase A1:0.1% trifluoroacetic acid solution; mobile phase B1: methanol; flow rate: 30ml/min; column temperature: 25 ℃; sample introduction amount: 4000l; the mixed mobile phase is eluted by a gradient elution method, and the elution procedure is as follows in the following table 1:
TABLE 1 gradient elution procedure
Collecting the preparation liquid of the target peak, pre-freezing the preparation liquid by using dry ice and ethanol, and then freeze-drying the preparation liquid in a dark place to obtain 35mg of target impurity solid shown in the formula I, wherein the yield is 35%. LC-MS (M + H +): ESI m/z =230.09592, hplc purity: 93.4 percent.
TABLE 3 1 H NMR (DMSO-d 6) data
* The hydrogen spectrum chemical shift delta (ppm) of the peak shape m and dp is averaged.
TABLE 4 13 C NMR (DMSO-d 6) data
Example 7
Vitamin B 1 The method for detecting the impurities shown in the formula I in the injection comprises the following steps:
a chromatographic column: octadecylsilane chemically bonded silica gel column, the model of the chromatographic column is Shimadzu Inertsil ODS-3, 250mm multiplied by 4.6mm,5.0 μm; the mobile phase comprises a mobile phase A2 and a mobile phase B2, wherein the ratio of the mobile phase A2:1wt% ammonium hexane sulfonate solution; mobile phase B: methanol; 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 0.8mL per minute; the sample size is 25 mu L; the detection wavelength was 248nm.
The impurity of formula I prepared in example 6 was used as a control, precisely weighed, and diluted with [0.75% glacial acetic acid ]]Dissolving and diluting to obtain a reference substance containing 0.01mg per 1mL as a reference solution; harvesting the fruitExample 6 vitamin B after destruction by alkaline solution 1 Injection, with diluent [0.75% glacial acetic acid ]]Diluting to 1mL of vitamin B 1 As a test solution.
Precisely measuring 25 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 13.020min, and the content of the impurities is 95.4% by an area normalization method (see fig. 12); the absolute retention time of the impurity of the present invention in the test solution was 13.025min, and the content thereof was about 9% as measured by the area normalization method (see fig. 13).
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 will be understood by those of ordinary skill in the art that: modifications of the technical solutions described in the foregoing embodiments are still possible, or some technical features may be equivalently replaced; and these modifications or substitutions do not depart from the spirit of the corresponding technical solutions of the embodiments of the present invention.
Claims (9)
1. A preparation method of vitamin B1 injection impurities is characterized in that the structural formula of the impurities is shown as formula I,
the preparation method comprises the following steps:
mixing vitamin B 1 Carrying out chemical reaction on the injection and an alkali solution at the temperature of 25-40 ℃ to prepare impurities shown in a formula I; the impurities are separated by adopting high performance liquid chromatography, and the conditions of the high performance liquid chromatography comprise: the chromatographic column is Welch Ultimate AQ 30mm × 250mm,5 μm, and gradient elution is carried out by adopting mobile phase A1 and mobile phase B1 as mixed mobile phase, and the flow rate is 30mL/min; the mobile phase A1 is 0.05 to 0.5 percent trifluoroacetic acid solution, and the mobile phase B1 is methanol; the gradient elution comprises the following steps: (1) In 0-16 min, mobile phase A1 and the volume ratio of the mobile phase B1 is kept constant at 95; (2) In 16-16.2 minutes, the volume ratio of the mobile phase A1 to the mobile phase B1 is uniformly graded from 95; (3) The volume ratio of the mobile phase A1 to the mobile phase B1 is kept constant at 5; (4) In 18-18.2 minutes, the volume ratio of the mobile phase A1 to the mobile phase B1 is uniformly graded from 5; (5) The volume ratio of mobile phase A1 to mobile phase B1 was kept constant at 95.
2. The method for preparing vitamin B1 injection impurities as claimed in claim 1, wherein the base is an inorganic base; the concentration of the alkali solution is 1 to 3mol/L.
3. The method for preparing vitamin B1 injection impurities 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 to 2mol/L.
4. The method for preparing vitamin B1 injection impurity according to claim 2, wherein the base is sodium hydroxide; the concentration of the alkali solution is 2mol/L.
5. The method for preparing vitamin B1 injectable solution impurities as claimed in claim 1, wherein the vitamin B is 1 Vitamin B in injection 1 The concentration of (a) is 100 mg/mL-200 mg/mL; the reaction temperature is 30-40 ℃; the reaction time is 0.5 to 2 hours; the vitamin B 1 The volume ratio of the injection to the alkali solution is 1 to 3.
6. The method for preparing vitamin B1 injectable solution impurities as claimed in claim 5, wherein the vitamin B 1 Vitamin B in injection 1 The concentration of (A) is 200mg/mL; the vitamin B 1 The volume ratio of the injection to the alkali solution is 1:1 to 2.
7. The vitamin of claim 6B1 The preparation method of impurities of the injection is characterized in that the vitamin B 1 The volume ratio of the injection to the alkali solution is 1.
8. A method for detecting impurities in vitamin B1 injection is characterized in that the structural formula of the impurities is shown as formula I,
the detection method adopts high performance liquid chromatography to detect vitamin B 1 The impurities in the injection are detected, and the high performance liquid chromatography conditions comprise: performing gradient elution by using an octadecylsilane bonded silica gel column as a chromatographic column and adopting a mobile phase A2 and a mobile phase B2 as a mixed mobile phase, wherein the mobile phase A2 is an ammonium hexanesulfonate solution, and the mobile phase B2 is methanol; the gradient elution comprises the steps of: (1) The volume ratio of mobile phase A2 to mobile phase B2 was kept constant at 95; (2) The volume ratio of the mobile phase A2 to the mobile phase B2 is uniformly graded from 95; (3) The volume ratio of the mobile phase A2 to the mobile phase B2 is kept constant at 50; (4) The volume ratio of the mobile phase A2 to the mobile phase B2 is uniformly graded from 50; (5) The volume ratio of mobile phase A2 to mobile phase B2 was kept constant at 95.
9. Vitamin B1 injection impurity in vitamin B detection 1 The application of the injection in quality is characterized in that the structural formula of the impurity is shown as formula I,
high performance liquid chromatography is adopted to detect vitamin B 1 The impurities in the injection are detected, and the high performance liquid chromatography conditions comprise: using octadecylsilane bonded silica gel column as chromatographic column, and adopting mobile phase A2 and flowPerforming gradient elution on the mobile phase B2 which is a mixed mobile phase, wherein the mobile phase A2 is a hexane ammonium sulfonate solution, and the mobile phase B2 is methanol; the gradient elution comprises the following steps: (1) The volume ratio of mobile phase A2 to mobile phase B2 was kept constant at 95; (2) The volume ratio of the mobile phase A2 to the mobile phase B2 is uniformly graded from 95; (3) The volume ratio of the mobile phase A2 to the mobile phase B2 is kept constant at 50; (4) The volume ratio of the mobile phase A2 to the mobile phase B2 is uniformly graded from 50 to 95 in 35-36 minutes; (5) The volume ratio of mobile phase A2 to mobile phase B2 was kept constant at 95.
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| RP-HPLC法测定复合维生素BC注射液中维生素B_1的有关物质;李文倩 等;《药物分析杂志》;20101231(第08期);第1520-1523页 * |
| THE GENES AND ENZYMES INVOLVED IN THE BIOSYNTHESIS OF THIAMIN AND THIAMIN DIPHOSPHATE IN YEASTS;EWA KOWALSKA et al.;《CELLULAR & MOLECULAR BIOLOGY LETTERS》;20071228;第271-282页 * |
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