CN110305106B - Trelagliptin succinate related substance, and preparation method, analysis method and application thereof - Google Patents
Trelagliptin succinate related substance, and preparation method, analysis method and application thereof Download PDFInfo
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Abstract
The invention relates to a trelagliptin succinate related substance L which is not reported in documents, and a preparation method, an analysis and detection method and application thereof. The analysis and detection method can detect 10 related substances including the related substance L, and has good separation degree and high sensitivity.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, and particularly relates to a trelagliptin succinate related substance, and a preparation method, an analysis method and application thereof.
Background
Trelagliptin succinate (Trelagliptin succinate) structural formula:
trelagliptin succinate (trade name Zafatek) is a very long acting inhibitor of dipeptidyl peptidase IV (DPP-4) and is used in the treatment of type 2 diabetes mellitus, administered once a week. A new drug application was filed by wutian in japan in 3 months 2014 and was approved for sale in japan in 26 days 3 months 2015.
The drug itself usually comprises the active ingredient of the drug and related substances, the presence of which has a significant impact on the quality and efficacy of the product. There is therefore a need for detection and effective control of the substances of interest in the feedstock.
The related substances are mainly starting materials, intermediates, polymers, side reaction products brought in during the production process, degradation products in the storage process and the like. And because the synthesis process of the product is different, the generated related substances are also different. When the starting materials are a compound N and a compound O, the main related substances of the trelagliptin succinate are shown as follows, wherein the related substance B, C, M, I, K, Q is a process product, the related substance D is an intermediate, the related substance G, J is a degradation product, and L is a new related substance which is not reported in documents.
At present, a great number of trelagliptin-related substances and analytical methods have been disclosed in the prior art. Such as:
CN104237421B discloses a method for detecting related substances in trelagliptin succinate and its preparation, wherein mobile phase a is phosphate buffer, mobile phase B is acetonitrile, and the detection wavelength is 278nm, but the method has the following problems: (1) the patent does not give any known impurities, and the applicability of the method cannot be judged; (2) the wavelength parameter of this analysis method was set at 278nm and could not cover all impurities, some of which had no uv absorption at this wavelength by spectrogram analysis of each known impurity.
CN106290596A discloses a method for separating and analyzing trelagliptin succinate and related substances of its preparation, wherein mobile phase a is phosphate buffer (0.3 vol% of triethylamine is also added), mobile phase B is acetonitrile or methanol, and its preparation is complex, and only 3 impurities are detected, and the applicability of the detection system for various impurities is poor.
CN106526010A discloses a related substance detection method for trelagliptin succinate and a preparation thereof, wherein a mobile phase A is an ammonium chloride buffer solution, a mobile phase B is methanol-acetonitrile (15: 85), and a sample preparation solvent is formic acid water.
CN106896166A is named as an analysis method of related substances of trelagliptin succinate and preparations thereof, which discloses an analysis method of related substances of 11 trelagliptin, wherein the volume ratio of phosphate buffer aqueous solution with the pH value of 3.3-3.7 to acetonitrile is 88-92: 8-12 is used as a mobile phase A, and the volume ratio of phosphate buffer aqueous solution with the pH value of 3.3-3.7 to acetonitrile is 18-22: 78-82 are mobile phase B, and it can be seen from Table 2 and FIG. 13 that the retention time of impurity 11 is 46.276min, and the retention time of 4 impurities exceeds 40 min. The method has the following disadvantages: (1) the mobile phases A and B are binary systems of aqueous solvents and organic solvents, so that the preparation is complex and the organic solvents are difficult to recycle; (2) the elution time is too long, the detection and separation efficiency is low, and the solvent consumption is too much.
CN108680678A is named as a method for determining trelagliptin related substances, 8 related substances are separated, a mobile phase A is a phosphoric acid aqueous solution, a mobile phase B is acetonitrile, the method is actually two-stage isocratic elution and is not suitable for elution and separation of various impurities with large differences in structure and polarity, the method does not give the corresponding situation of each impurity and an HPLC elution peak, and correspondingly, the retention time of each impurity cannot be confirmed, so the reference significance for researching analysis methods of other trelagliptin impurities is not great.
CN105738517B discloses a method for determining related substances in trelagliptin tablets, in 3 examples of the patent, mobile phase a is phosphoric acid aqueous solution, mobile phase B is acetonitrile, the proportion of mobile phase B reaches 70% at most, fig. 2 shows that 8 known impurities are tested to be separated from trelagliptin, all impurities are eluted within 23 minutes, the elution speed is very fast, but it is seen from the figure that the retention time of at least five known impurities is concentrated around 20 minutes, and some small peaks exist between the peaks of the known impurities, and it cannot be confirmed whether the peaks of unknown impurities are covered or overlapped by the peaks of the known impurities. Researchers have attempted to apply their method to the separation and detection of the 10 impurities of the present invention and found that peak overlap occurs, affecting separation.
CN105699547A is a method for determining related substances in a succinic acid trelagliptin raw material, and discloses detection of 7 related substances, wherein a mobile phase A and a mobile phase B are both mixed solutions of an acidic aqueous solution and an organic solvent, the acidic aqueous solution is a trifluoroacetic acid or perchloric acid aqueous solution, the pH value of the solution is adjusted to 3.0 by using alkali (triethylamine), the volume percentage of the trifluoroacetic acid or perchloric acid in the acidic aqueous solution is 0.1%, and the mobile phase A is a mixed solution of the acidic aqueous solution and the organic solvent in a volume ratio of 90: 10; the mobile phase B is a mixed solution of an acidic aqueous solution and an organic solvent in a volume ratio of 40: 60. One obvious disadvantage of this method is that: the preparation of the mobile phase is very complicated, on one hand, the mobile phases A and B are a binary system of an aqueous solvent and an organic solvent, and the pH value needs to be adjusted by alkali.
When a sample containing the above-mentioned 10 related substances is tested by the above-mentioned analytical methods reported so far, these methods have various problems in terms of system applicability, ease of use, economy, separation effect, and the like, as described above. Therefore, an analysis method which has high sensitivity, meets the requirement of specificity and has better separation degree of all related substances is urgently needed, and the related substances of the trelagliptin succinate raw material and preparation can be effectively detected.
On the other hand, the substance L which is found to affect the purity of trelagliptin succinate is not reported in the following documents. There is therefore also a need for a synthesis and analysis method which facilitates detailed qualitative, qualitative studies and strict quality control of the substance of interest L
Disclosure of Invention
The first purpose of the invention is to provide a related substance L of trelagliptin succinate.
The second object of the present invention is to provide a process for producing the substance L.
The third purpose of the present invention is to provide a method for analyzing 10 related substances of trelagliptin succinate, including the related substance L.
The fourth purpose of the invention is to provide the application of the related substance L as a related substance reference substance in related substance examination items of the trelagliptin succinate raw material and the preparation thereof.
The above purpose is realized by the following technical scheme:
a related substance L of trelagliptin succinate has a compound structural formula as follows:
a preparation method of the related substance L comprises the following steps: taking trogliptin and 2-cyano-5-fluorobenzyl bromide as raw materials, and reacting under an alkaline condition.
The reaction is carried out in a reaction solvent, the temperature is raised and the stirring is carried out until the reaction is complete, the temperature is reduced to the room temperature, and water is added for crystallization to obtain the related substance L.
Further, the alkaline condition is provided by organic base and/or inorganic base, wherein the organic base is selected from one or more of triethylamine, trimethylamine, N-ethyldiisopropylamine, pyridine, picoline, N-methylmorpholine and DBU, and the inorganic base is selected from one or more of alkali metal hydroxide, alkali metal carbonate and alkali metal bicarbonate, preferably one or more of sodium hydroxide, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
Further, the reaction is carried out in a reaction solvent selected from one or more of N, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, dichloromethane, tetrahydrofuran, preferably N, N-dimethylformamide.
A High Performance Liquid Chromatography (HPLC) analysis method for related substances of trelagliptin succinate comprises the following chromatographic conditions:
a chromatographic column: a chromatographic column with octadecylsilane chemically bonded silica as filler;
mobile phase: a is perchloric acid aqueous solution with volume ratio of 0.04-0.06%, B is acetonitrile;
flow rate: 0.8-1.3 ml/min, preferably 0.8ml/min or 0.9ml/min or 1.0ml/min or 1.1ml/min or 1.2ml/min or 1.3ml/min, more preferably 0.8ml/min or 1.0 ml/min;
detection wavelength: 200-240nm, preferably 200nm or 210nm or 220nm or 230nm or 240 nm;
column temperature: 25 ℃ to 35 ℃, preferably 25 ℃ or 30 ℃ or 35 ℃, more preferably 25 ℃ or 30 ℃.
Further, the analysis method can detect one or more of the following 10 related substances of the trelagliptin succinate, preferably 5 or more, or 6 or more, or 7 or more, or 8 or more, or 9 or more, or 10 substances simultaneously,
further, the analytical method column was Agilent Pursuit 3C18, 150mm in length, 4.6mm in diameter, and 3 μm in filler particle size.
Further, the linear gradient elution procedure of the analytical method is: 0min, wherein A is 88-95%; 5min, wherein A is 88-95%; 15min, wherein A is 82-86%; for 40min, A is 51-57%; 50min, wherein A is 51-59%; 52min, wherein A is 88-95%; 57min, wherein A is 88-95%.
Further, the linear gradient elution procedure of the analytical method is: 0min, wherein A is 93%; 5min, wherein A is 93%; 15min, wherein A is 84-86%; for 40min, A is 51-55%; 50min, wherein A is 55%; 52min, wherein A is 93%; 57min, A93%.
The use of the trelagliptin succinate related substance L as a related substance reference substance in related substance examination items of trelagliptin succinate and preparations thereof. The related substance L is easily obtained and has high purity (more than 99.0%), and can be used as reference substance for quality control.
The invention has the beneficial effects that:
(1) the invention discloses a related substance L of trelagliptin succinate, which is not reported in documents at present;
(2) the preparation method of the related substance L provided by the invention is simple and feasible, and can be used for large-scale preparation;
(3) the liquid phase analysis method provided by the invention can quickly detect 10 related substances including the related substance L, has good separation effect and low detection limit, and has good linearity in the concentration level range of detection limit to 1.0%;
(4) the related substance L provided by the invention can be used for checking related substances of the trelagliptin succinate and the preparation thereof, so that the quality standard of the trelagliptin succinate and the preparation thereof is further improved, and the safety and controllability of the trelagliptin succinate and the preparation thereof are improved.
Drawings
Figure 1 HPLC profile of trelagliptin succinate related substance I.
Figure 2 HPLC profile of trelagliptin succinate related substance Q.
Figure 3 HPLC profile of trelagliptin.
Figure 4 HPLC profile of trelagliptin succinate related substance K.
Figure 5 HPLC profile of trelagliptin succinate related substance G.
Figure 6 HPLC profile of trelagliptin succinate related substance B.
Figure 7 HPLC profile of trelagliptin succinate related substance L.
Figure 8 HPLC profile of trelagliptin succinate related substance D.
Figure 9 HPLC profile of trelagliptin succinate related substance C.
Figure 10 HPLC profile of trelagliptin succinate related substance J.
Figure 11 HPLC profile of trelagliptin succinate related substance M.
FIG. 12 HPLC chromatogram of mixed solution of related substances and Trelagliptin succinate.
Figure 13 HPLC profile of blank solvent.
Detailed Description
Since some related substances have been reported and studied in the prior art, and related substance L was first isolated and identified during the research of the preparation method of trelagliptin succinate, only the synthesis method of related substance L will be described in detail below. The synthesis method and the analysis method are exemplified by the following examples, but the present invention is not limited to the following examples. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
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 exemplary only.
Example 1: preparation of trelagliptin succinate related substance L
Trelagliptin (1.0g, 2.8mmol), 2-cyano-5-fluorobenzyl bromide (0.63g, 2.9mmol), potassium carbonate (0.39g, 2.8mmol) and DMF (20mL) were added sequentially to a 100mL three-necked flask, and after the addition was complete, the system was warmed to 60 ℃ and stirred at that temperature for 4h, with TLC detection showing substantial completion of the reaction. Slowly dripping water (20mL) into the system at room temperature, continuously stirring for 1h after dripping, performing suction filtration, washing a filter cake with water and methanol respectively, and performing vacuum drying to obtain 1.0g of white solid, namely the related substance L, wherein the yield is 73.0%, and the purity is 99.12%.
The structure of the substance L is confirmed, and the result is as follows:
a related substance L: m/z 491.3[ M + H]+。
1H-NMR(DMSO-d6,600MHz),δ:1.27(s,1H,-CH 2-)；1.46(s,1H,-CH 2-)；1.73(s,1H,-CH 2-)；1.85(s,1H,-CH 2-)；2.39(s,1H,-CH 2-)；2.53(s,1H,-CH-NH)；2.68(s,1H,-CH 2-)；2.93(s,1H,-CH 2-)；3.10(s,4H,-CH 2-,-CH 3)；3.79-3.66(m,2H,-CH 2-)；5.16(s,2H,-CH 2-)；5.36(s,1H,＝CH-)；7.21-7.19(d,1H,Ar-H)；7.30-7.26(m,2H,Ar-H)；7.37-7.36(d,1H,Ar-H)；7.89-7.86(m,2H,Ar-H)。
Example 2: trelagliptin succinate related substance analysis method-influence of mobile phase
Preparing a blank solvent: 80 percent of water and 20 percent of methanol (volume ratio)
Preparing a mixed solution:
the related substance I, Q, K, G, B, L, D, C, J, M and the trelagliptin succinate are weighed respectively, and blank solvents are added respectively to dissolve and quantitatively dilute into solution containing 0.5mg per 1ml to serve as positioning solution. Respectively measuring 20 mu l of the related substance positioning solution and 1ml of trelagliptin succinate positioning solution, and uniformly mixing to obtain a mixed solution of the related substances and the trelagliptin succinate.
Chromatographic conditions are as follows:
a chromatographic column: agilent Pursuit 3C18 (4.6X 150mm, 3 μm)
Detection wavelength: 220nm
Column temperature: 30 deg.C
Flow rate: 1.0ml/min
Mobile phase: taking perchloric acid aqueous solution with the volume ratio of 0.05% as a mobile phase A and acetonitrile as a mobile phase B; the different linear gradients eluted are shown in tables 1-4.
TABLE 1 gradient elution procedure
| Experiment number | 1 | 2 | 3 | 4 |
| Time (min) | A(％) | A(％) | A(％) | A(％) |
| 0 | 88 | 90 | 93 | 95 |
| 5 | 88 | 90 | 93 | 95 |
| 15 | 84 | 84 | 84 | 84 |
| 40 | 55 | 55 | 55 | 55 |
| 50 | 55 | 55 | 55 | 55 |
| 52 | 88 | 90 | 93 | 95 |
| 57 | 88 | 90 | 93 | 95 |
TABLE 2 gradient elution procedure
| Experiment number | 5 | 6 | 7 |
| Time (min) | A(％) | A(％) | A(％) |
| 0 | 93 | 93 | 93 |
| 5 | 93 | 93 | 93 |
| 15 | 80 | 82 | 86 |
| 40 | 55 | 55 | 55 |
| 50 | 55 | 55 | 55 |
| 52 | 93 | 93 | 93 |
| 57 | 93 | 93 | 93 |
TABLE 3 gradient elution procedure
TABLE 4 gradient elution procedure
| Experiment number | 12 | 13 | 14 | 15 |
| Time (min) | A(％) | A(％) | A(％) | A(％) |
| 0 | 93 | 93 | 93 | 93 |
| 5 | 93 | 93 | 93 | 93 |
| 15 | 84 | 84 | 84 | 84 |
| 40 | 55 | 55 | 55 | 55 |
| 50 | 51 | 53 | 57 | 59 |
| 52 | 93 | 93 | 93 | 93 |
| 57 | 93 | 93 | 93 | 93 |
Measuring 20 mu l of each positioning solution and each mixed solution, respectively injecting the positioning solutions and the mixed solutions into a liquid chromatograph, recording corresponding chromatograms according to different elution programs, measuring the chromatograms of the positioning solutions and the mixed solutions according to the linear gradient elution conditions of experiment 3 and showing in the figures 1-12, and observing the separation degree results of related substances under each experiment condition and showing in the following tables 5-8.
TABLE 5 results of the resolution study of trelagliptin from known related substances
| Experiment number | 1 | 2 | 3 | 4 |
| Sample name | Degree of separation | Degree of separation | Degree of separation | Degree of separation |
| Related substances I | --- | --- | --- | --- |
| Related substance Q | 46.8 | 58.5 | 51.2 | 43.7 |
| Trelagliptin | 3.2 | 2.9 | 2.9 | 2.9 |
| Related substance K | 9.8 | 9.8 | 9.2 | 8.9 |
| Related substance G | 9.2 | 8.9 | 8.6 | 8.6 |
| Related substance B | 8.6 | 9.2 | 10.0 | 10.4 |
| Related substance L | 12.5 | 11.7 | 9.6 | 10.5 |
| Related substance D | 3.6 | 4.2 | 6.5 | 5.5 |
| Related substance C | 12.3 | 11.9 | 11.4 | 11.2 |
| Related substance J | 6.4 | 6.1 | 5.7 | 5.5 |
| Related substance M | 1.2 | 1.3 | 1.5 | 1.3 |
TABLE 6 results of the resolution study of trelagliptin from known related substances
TABLE 7 results of the resolution study of trelagliptin from known related substances
| Experiment number | 8 | 9 | 10 | 11 |
| Sample name | Degree of separation | Degree of separation | Degree of separation | Degree of separation |
| Related substances I | --- | --- | --- | --- |
| Related substance Q | 52.6 | 52.3 | 51.8 | 51.5 |
| Trelagliptin | 2.8 | 2.8 | 2.9 | 2.9 |
| Related substance K | 8.9 | 9.0 | 9.4 | 9.7 |
| Related substance G | 8.4 | 8.5 | 8.8 | 9.0 |
| Related substance B | 10.2 | 10.1 | 9.9 | 9.8 |
| Related substance L | 8.8 | 10.6 | 11.3 | 11.9 |
| Related substance D | 7.0 | 5.2 | 4.7 | 4.4 |
| Related substance C | 10.8 | 11.1 | 11.8 | 12.2 |
| Related substance J | 4.4 | 5.0 | 6.4 | 6.9 |
| Related substance M | 1.6 | 1.5 | 1.1 | 0.8 |
TABLE 8 results of the resolution study of trelagliptin from known related substances
| Experiment number | 12 | 13 | 14 | 15 |
| Sample name | Degree of separation | Degree of separation | Degree of separation | Degree of separation |
| Related substances I | --- | --- | --- | --- |
| Related substance Q | 52.2 | 52.0 | 52.2 | 51.5 |
| Trelagliptin | 2.8 | 2.9 | 2.9 | 2.8 |
| Related substance K | 9.2 | 9.2 | 9.2 | 9.2 |
| Related substance G | 8.7 | 8.7 | 8.7 | 8.6 |
| Related substance B | 10.0 | 10.0 | 10.0 | 10.0 |
| Related substance L | 11.0 | 10.9 | 10.9 | 10.9 |
| Related substance D | 5.0 | 5.0 | 5.0 | 5.0 |
| Related substance C | 11.5 | 11.4 | 11.4 | 11.5 |
| Related substance J | 5.7 | 5.7 | 5.7 | 5.7 |
| Related substance M | 1.3 | 1.3 | 1.3 | 1.3 |
From the results of the degrees of separation in tables 5-8, it can be seen that when the gradient elution procedure is in the following range: when 0min is needed, A is 88% -95%; when the time is 5min, A is 88% -95%; when 15min is needed, A is 82% -86%; at 40min, A is 51-57%; when the time is 50min, A is 53-59 percent; when the time is 52min, A is 88 to 95 percent; when the time is 57min, A is 88% -95%; the 10 related substances can be separated, and the lowest separation degree can also reach more than 1.0.
When 15min is needed: 84-86% of A, and 51-55% of A at 40min, the separation degree of related substances J and M can reach more than 1.2.
Under the gradient elution conditions of experiments 3, 7, 8 and 9, the separation degree of related substances J and M can reach more than 1.5.
Example 3: trelagliptin succinate related substance analysis method-flow rate influence experiment
Chromatographic conditions were the same as those in experiment 3 of example 2, and only the flow rate was changed, and 20. mu.l of the mixed solution of example 2 was taken, injected into a liquid chromatograph, and chromatograms were recorded, and the results of examining the degree of separation between the respective substances are shown in Table 9 below.
TABLE 9 results of the resolution study of trelagliptin from known related substances
Note: "/" is no degree of separation and "- -" is no degree of separation calculated.
Example 4: influence experiment of column temperature on related substance analysis method of trelagliptin succinate
Chromatographic conditions were the same as those in experiment 3 of example 2, only the column temperature was changed, 20. mu.l of the mixed solution of example 2 was taken, injected into a liquid chromatograph, chromatograms were recorded, and the results of examining the degrees of separation between the respective substances are shown in Table 10 below.
TABLE 10 results of the resolution study of trelagliptin from known related substances
Note: "/" is no degree of separation and "- -" is no degree of separation calculated.
Example 5: trelagliptin succinate related substance analysis method-mobile phase influence experiment
Chromatographic conditions were the same as those in experiment 3 of example 2, and only the preparation ratio of the perchloric acid aqueous solution of mobile phase a was changed, and 20 μ l of the mixed solution of example 2 was taken, injected into a liquid chromatograph, and a chromatogram was recorded, and the results of examining the degree of separation between the respective substances are shown in table 11 below.
TABLE 11 results of the resolution study of trelagliptin from known related substances
Example 6: specific experiment as related substance analysis method of trelagliptin succinate
The blank solvent described in example 2 was measured in an amount of 20. mu.l, injected into a liquid chromatograph, measured under the chromatographic conditions of experiment 3 in example 2, and the chromatogram was recorded, as shown in FIG. 13. Each of the mapping solution chromatograms and the mixed solution chromatograms are shown in FIGS. 1-12, and the results of examining the degree of separation between the respective substances of interest are shown in Table 1 in example 2.
The results show that the separation degree of the main peak and the adjacent related substances and the separation degree between other related substances are in accordance with the regulations. Therefore, the method can meet the requirement of related substance measurement.
Example 7: trelagliptin succinate related substance analysis method-detection limit experiment
The appropriate amount of each positioning solution in the preparation process of the mixed solution in the embodiment 2 is precisely measured, diluted step by step, 20 mul is taken and injected into a liquid chromatograph, the chromatographic conditions are measured according to the experiment 3 in the embodiment 2, and the chromatogram is recorded until the peak height of each related substance peak is about three times of the baseline noise signal (S/N is 3). The detection limits of trelagliptin succinate and related substances were calculated, and the minimum detection limit of related substances was calculated when the concentration of trelagliptin succinate was 0.5mg/ml, and the results are shown in Table 12. The result shows that the detection limit of each related substance is lower than the minimum control limit of 0.1 percent, and the detection sensitivity of the method meets the detection requirement of the related substance.
TABLE 12 results of detection limits of respective substances
Example 8: linear experiment-related substance analysis method of trelagliptin succinate
Accurately measuring the trelagliptin succinate and the positioning solution of each related substance and adding a blank solvent to gradually dilute into solutions with concentration levels of 1.0%, 0.5%, 0.2%, 0.1%, 0.05%, 0.02%, 0.01% and 0.005% as linear solutions. And (3) injecting 20 mu l of each solution into a liquid chromatograph, measuring according to the chromatographic conditions of experiment 3 in example 2, selecting 8 concentration levels including the detection limit, and drawing a standard curve by taking the concentration as a horizontal coordinate and taking the peak area as a vertical coordinate. The results are shown in Table 13, which shows that the linear relation between the concentration levels of the trelagliptin succinate and the solutions of various related substances is good between the detection limit and 1.0 percent.
TABLE 13 Linear equations for Trelagliptin succinate and related substances
| Name (R) | Slope of standard curve | Linear equation of equations |
| Trelagliptin | 727598 | y＝727598x+4626,R＝1.0000 |
| Related substances I | 447462 | y＝447462x–11300,R＝1.0000 |
| Related substance Q | 752272 | y＝752272x-7221,R＝1.0000 |
| Related substance K | 779092 | y＝779092x–7173,R＝1.0000 |
| Related substance G | 711676 | y＝711676x-8403,R＝1.0000 |
| Related substance B | 787619 | y＝787619x–6522,R＝1.0000 |
| Related substance L | 755801 | y＝755801x+10310,R＝1.0000 |
| Related substance D | 856982 | y＝856982x+2431,R＝1.0000 |
| Related substance C | 724211 | y＝724211x-6513,R＝1.0000 |
| Related substance J | 713271 | y＝713271x-2220,R＝1.0000 |
| Related substance M | 834800 | y＝834800x-16740,R＝0.9996 |
Claims (9)
1. A high performance liquid phase analysis method for related substances of trelagliptin succinate is characterized by comprising the following steps:
a chromatographic column: a chromatographic column with octadecylsilane chemically bonded silica as filler;
mobile phase: a is perchloric acid aqueous solution with volume ratio of 0.04-0.06%, B is acetonitrile;
flow rate: 0.8 to 1.3ml/min,
detection wavelength: 200-240nm of the wavelength of the light,
column temperature: at the temperature of between 25 and 35 ℃,
the following linear gradient elution procedure was used: 0min, wherein A is 88-95%; 5min, wherein A is 88-95%; 15min, wherein A is 82-86%; for 40min, A is 51-57%; 50min, wherein A is 51-59%; 52min, wherein A is 88-95%; 57min, wherein A is 88-95%.
2. The assay of claim 1, wherein the flow rate is selected from 0.8ml/min or 0.9ml/min or 1.0ml/min or 1.1ml/min or 1.2ml/min or 1.3 ml/min.
3. The assay of claim 2, wherein the flow rate is selected from 0.8ml/min or 1.0 ml/min.
4. The assay of claim 1, wherein the detection wavelength is selected from one of 200nm or 210nm or 220nm or 230nm or 240 nm.
5. The assay of claim 1, wherein the column temperature is selected from 25 ℃ or 30 ℃ or 35 ℃.
6. The assay of claim 5, wherein the column temperature is selected from 25 ℃ or 30 ℃.
7. The assay of any one of claims 1 to 6, wherein the assay is capable of detecting one or more of the 10 Trelagliptin succinate related substances shown below,
8. the method of claim 1, wherein the analytical column is Agilent Pursuit 3C18, 150mm in length, 4.6mm in diameter, and 3 μm in filler particle size.
9. The method for analyzing substances according to claim 1, wherein the method employs the following linear gradient elution procedure: 0min, wherein A is 93%; 5min, wherein A is 93%; 15min, wherein A is 84-86%; for 40min, A is 51-55%; 50min, wherein A is 55%; 52min, wherein A is 93%; 57min, A93%.
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| CN111253372A (en) * | 2020-02-23 | 2020-06-09 | 北京鑫开元医药科技有限公司 | Preparation method and application of trelagliptin succinate dimer |
| CN114235972B (en) * | 2021-10-28 | 2023-08-22 | 乳源东阳光药业有限公司 | Method for determining content of linagliptin impurity RBP-1 |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105524044A (en) * | 2014-10-22 | 2016-04-27 | 重庆医药工业研究院有限责任公司 | Trelagliptin impurity and its composition |
| CN105699547A (en) * | 2016-04-22 | 2016-06-22 | 中山万汉医药科技有限公司 | Method for measuring related substances in succinic acid Trelagliptin raw materials |
| CN105738517A (en) * | 2016-02-24 | 2016-07-06 | 中山万汉医药科技有限公司 | Method for determining related substances in Trelagliptin tablets |
| CN106432184A (en) * | 2016-08-22 | 2017-02-22 | 南京华威医药科技开发有限公司 | Trelagliptin derivative and application tereof |
| CN106526010A (en) * | 2016-10-26 | 2017-03-22 | 北京蓝贝望生物医药科技股份有限公司 | Related substance detection method for trelagliptin succinate preparation |
| CN106896166A (en) * | 2017-01-22 | 2017-06-27 | 合肥拓锐生物科技有限公司 | About the analysis method of material in a kind of amber love song Ge Lieting raw materials and its preparation |
| CN108680678A (en) * | 2018-06-20 | 2018-10-19 | 江苏万川医疗健康产业集团有限公司 | Measure methods of the song Ge Lieting in relation to substance |
-
2019
- 2019-06-20 CN CN201910535170.2A patent/CN110305106B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105524044A (en) * | 2014-10-22 | 2016-04-27 | 重庆医药工业研究院有限责任公司 | Trelagliptin impurity and its composition |
| CN105738517A (en) * | 2016-02-24 | 2016-07-06 | 中山万汉医药科技有限公司 | Method for determining related substances in Trelagliptin tablets |
| CN105699547A (en) * | 2016-04-22 | 2016-06-22 | 中山万汉医药科技有限公司 | Method for measuring related substances in succinic acid Trelagliptin raw materials |
| CN106432184A (en) * | 2016-08-22 | 2017-02-22 | 南京华威医药科技开发有限公司 | Trelagliptin derivative and application tereof |
| CN106526010A (en) * | 2016-10-26 | 2017-03-22 | 北京蓝贝望生物医药科技股份有限公司 | Related substance detection method for trelagliptin succinate preparation |
| CN106896166A (en) * | 2017-01-22 | 2017-06-27 | 合肥拓锐生物科技有限公司 | About the analysis method of material in a kind of amber love song Ge Lieting raw materials and its preparation |
| CN108680678A (en) * | 2018-06-20 | 2018-10-19 | 江苏万川医疗健康产业集团有限公司 | Measure methods of the song Ge Lieting in relation to substance |
Non-Patent Citations (1)
| Title |
|---|
| Synthesis of Trelagliptin Succinate;Shenghui Xu等;《Org. Process Res. Dev.》;20170309;第585-589页 * |
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