CN113527183A - Tirofiban degradation impurity and preparation method and application thereof - Google Patents
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
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- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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Abstract
The invention relates to the technical field of pharmacy, in particular to a tirofiban degradation impurity I and a preparation method and application thereof. The invention finds a new tirofiban degradation impurity, and determines whether the quality of the tirofiban injection reaches the standard or not by measuring the content of the tirofiban degradation impurity in the tirofiban injection, thereby realizing the quality control of the tirofiban injection.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to a tirofiban degradation impurity and a preparation method and application thereof.
Background
Tirofiban (Tirofiban), otherwise known as Tirofiban, chemical name N- (butylsulfonyl) -O- [4- (4-piperidinyl) butyl]-L-tyrosine, molecular formula C22H36N2O5S，Developed by merck, usa, marketed in the united states in 1998 and approved for marketing in china in 2004 at 8 months. Tirofiban is an antiplatelet drug, and is mainly used for coronary angioplasty or coronary atherectomy of patients with coronary ischemic syndrome clinically so as to prevent and treat related cardiac ischemic complications; also used for unstable angina or non-Q wave type myocardial infarction patients (combined with heparin or aspirin) to prevent the occurrence of cardiac ischemic events. The current clinically used medicine is mainly tirofiban hydrochloride injection, is a reversible non-peptide platelet surface Glycoprotein (GP) IIb/IIa receptor antagonist, and can competitively inhibit the combination of fibrinogen and platelet (GP) IIb/IIa receptors. Intravenous injection can inhibit platelet aggregation in vitro caused by ADP, collagen, arachidonic acid, thromboxane analog U46619 and thrombin, prolong bleeding time, and inhibit thrombosis.
The injection may produce degradation impurity in the preparation and storage process, which not only affects the content of the main drug, but also reduces the curative effect of the drug and may cause toxic and side effects. Therefore, the research on the degradation impurities which can be generated is of great significance. Currently, the standard related to the tirofiban hydrochloride injection is the import registration standard of the tirofiban hydrochloride injection (JX20080265), but the reports on the types of degradation impurities generated due to storage or environmental condition change are less, and meanwhile, the tirofiban and the impurities thereof are not received in domestic and foreign pharmacopoeias. The internationally popular drug registration for human use requires that the international harmonization conference (ICH) require strict limits on drug impurity levels. ICH requires researchers to fully evaluate the objectively present and potentially degradable impurities in the drug during the preparation and storage process, and thus the impurities in the drug should be fully studied with strict control over the content. At present, research on tirofiban degradation impurities is not sufficient, particularly research on degradation impurities with high toxicity and great harm is not sufficient, for example, genotoxic impurities can cause harm to human bodies at very low content, so toxic and side effects can be caused.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, the invention aims to find a new tirofiban degradation impurity in the preparation process of tirofiban and provide a preparation method of the tirofiban degradation impurity. The prepared compound shown in the formula I is used as an impurity standard substance for detecting a tirofiban product, so that the quantification and the qualification of the tirofiban degradation impurities are facilitated, and the quality control of raw material medicaments of the tirofiban product is improved.
To this end, the invention provides in a first aspect a compound. According to an embodiment of the invention, the compound has the structural formula I:
the tirofiban injection can generate degradation impurities in the preparation and storage processes, not only influences the content of the main drug, but also reduces the curative effect of the drug and can cause toxic and side effects. Therefore, the research on the degradation impurities which can be generated is of great significance. However, the types of degradation impurities generated by storage or environmental condition change are less reported at present, and because the injection needs to be subjected to high-temperature sterilization treatment before use, the inventor finds that after the high-temperature treatment, the tirofiban injection is degraded and forms a new impurity, namely the compound shown in the formula I.
The second aspect of the invention provides a quality control method of tirofiban injection. According to an embodiment of the invention, the method comprises:
determining the amount of a compound of the first aspect in a tirofiban injection;
and determining whether the quality of the tirofiban injection reaches the standard or not based on the content of the compound.
The content of impurities shown in the formula I generated by degradation of the tirofiban injection in the storage process or after high-temperature treatment can be determined by measuring the content of the compound shown in the formula I, and the content is compared with a preset impurity content threshold value, so that whether the quality of the tirofiban injection reaches the standard or not is determined.
According to an embodiment of the present invention, the determination is performed using high performance liquid chromatography. Therefore, the detection accuracy and the detection efficiency are improved.
According to the embodiment of the invention, the mobile phase adopted by the high performance liquid chromatography comprises a mobile phase A and a mobile phase B, wherein the mobile phase A is NH4HCO3And the mobile phase B is acetonitrile.
Therefore, the compound (impurity A for short) can be separated from the tirofiban and other impurities (such as 3-chloro-tirofiban), and the detection accuracy is improved.
According to the embodiment of the invention, the high performance liquid chromatography adopts a gradient elution mode, and the conditions are as follows:
| time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0.01 | 85 | 15 |
| 11.0 | 55 | 45 |
| 11.2 | 0 | 100 |
| 13.2 | 0 | 100 |
| 13.4 | 85 | 15 |
| 14.4 | 85 | 15 |
。
Therefore, the compound (impurity A for short) can be separated from the tirofiban and other impurities (such as 3-chloro-tirofiban), and the detection accuracy is improved.
According to an embodiment of the invention, the NH4HCO3The concentration of the solution is 5-15 mM.
According to the embodiment of the invention, when the high performance liquid chromatography detection is carried out, the filler of the chromatographic column is octadecylsilane chemically bonded silica.
According to an embodiment of the invention, the column temperature of the chromatography column is 25-35 ℃.
According to an embodiment of the invention, the flow rate of the mobile phase is 20-30 ml/min.
According to the embodiment of the invention, the detection wavelength in the high performance liquid chromatography is 200-280 nm.
In a third aspect, the present invention provides a process for the preparation of a compound according to the first aspect. According to an embodiment of the invention, the method comprises:
(1) mixing tirofiban hydrochloride with hydrochloric acid to obtain a degradation solution;
(2) heating the degradation solution to obtain a solution containing the compound of the first aspect;
(3) separating the solution containing the compound of the first aspect by high performance liquid chromatography and collecting fractions containing the compound of the first aspect.
The tirofiban injection can generate degradation impurities in the preparation and storage processes, not only influences the content of the main drug, but also reduces the curative effect of the drug and can cause toxic and side effects. Therefore, after the tirofiban hydrochloride is mixed with the hydrochloric acid, the tirofiban hydrochloride is conveniently and forcibly degraded, so that the influence of degraded impurities on a medicine system is conveniently researched. Further, since the injection solution needs to be sterilized at high temperature before use, the compound represented by formula I can be obtained by subjecting the first degradation solution to a corresponding heat treatment.
According to the embodiment of the invention, the temperature of the heating treatment is 80-100 ℃, and the time is 180-360 min.
Therefore, the harmful bacteria can be killed sufficiently, the use safety of the medicine is improved, and the shelf life is prolonged.
According to the embodiment of the invention, the mobile phase adopted by the high performance liquid chromatography comprises a mobile phase A and a mobile phase B, wherein the mobile phase A is NH4HCO3And the mobile phase B is acetonitrile.
According to the embodiment of the invention, the high performance liquid chromatography adopts a gradient elution mode, and the conditions are as follows:
| time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0.01 | 85 | 15 |
| 11.0 | 55 | 45 |
| 11.2 | 0 | 100 |
| 13.2 | 0 | 100 |
| 13.4 | 85 | 15 |
| 14.4 | 85 | 15 |
。
According to an embodiment of the invention, the NH4HCO3The concentration of the solution is 5-15 mM;
according to the embodiment of the invention, when the high performance liquid chromatography detection is carried out, the filler of the chromatographic column is octadecylsilane chemically bonded silica.
According to an embodiment of the invention, the column temperature of the chromatography column is 25-35 ℃.
According to an embodiment of the invention, the flow rate of the mobile phase is 20-30 ml/min.
According to the embodiment of the invention, the detection wavelength in the high performance liquid chromatography is 200-280 nm.
According to an embodiment of the present invention, the degradation solution is subjected to a concentration treatment before the heat treatment. Thereby, the impurity content is increased.
According to an embodiment of the invention, prior to separation by high performance liquid chromatography, the solution containing the compound of the first aspect is subjected to:
adjusting the pH value of the solution containing the compound of the first aspect to 6-8, and performing extraction treatment by using ethyl acetate to obtain an ethyl acetate layer and a water layer;
concentrating the ethyl acetate layer to obtain a concentrate, and dissolving the concentrate by using acetonitrile aqueous solution to obtain a sample solution;
and respectively carrying out high performance liquid chromatography separation on the sample loading liquid and the water layer, and collecting fractions containing the compound.
According to an embodiment of the present invention, the volume ratio of tirofiban hydrochloride to hydrochloric acid is 1: 0.5-1: 2.
according to an embodiment of the invention, the concentration of the hydrochloric acid is 1-3M.
According to an embodiment of the invention, the concentration of tirofiban hydrochloride is between 0.05 and 0.3 mg/ml.
The fourth aspect of the present invention provides the use of the compound of the first aspect and/or the compound prepared by the method of the third aspect for quality control of a tirofiban hydrochloride bulk drug or an injection. According to the embodiment of the invention, the compound shown in the formula I in the tirofiban raw material medicine or the injection is analyzed by using the compound as a standard substance so as to control the quality of the tirofiban raw material medicine and the injection.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:
FIG. 1 shows the HPLC results for the impurity of example 1, wherein MS262 preparative samples were obtained by both method (1) and method (2) of example 1;
figure 2 shows HRMS results for the impurities in example 1.
Detailed Description
According to a particular embodiment of the invention, there is provided a process for the preparation of a compound of formula I, comprising:
(1) mixing tirofiban hydrochloride with hydrochloric acid to obtain a degradation solution;
(2) heating the degradation solution to obtain a solution containing a compound shown as a formula I;
(3) separating the solution containing the compound of formula I by high performance liquid chromatography and collecting fractions containing the compound of claim 1.
According to a specific embodiment of the present invention, the temperature of the heat treatment is 80-100 ℃ for 180-360 min.
According to a specific embodiment of the present invention, the detection conditions of high performance liquid chromatography are as follows:
the compound shown in the formula I has the following structure:
according to a particular embodiment of the invention, before the separation by high performance liquid chromatography, the solution containing the compound of formula i is subjected to the following treatment:
adjusting the pH value of the solution containing the compound shown in the formula I to 6-8, and extracting with ethyl acetate to obtain an ethyl acetate layer and a water layer;
concentrating the ethyl acetate layer to obtain a concentrate, and dissolving the concentrate by using acetonitrile aqueous solution to obtain a sample solution;
and respectively carrying out high performance liquid chromatography separation on the sample loading liquid and the water layer, and collecting fractions containing the compound.
According to a specific embodiment of the present invention, the volume ratio of tirofiban hydrochloride to hydrochloric acid is 1: 0.5-1: 2;
the concentration of the hydrochloric acid is 1-3M;
the concentration of the tirofiban hydrochloride is 0.05-0.3 mg/ml.
In the invention, MS262, impurity A and tirofiban degradation impurity all refer to compounds with structural formula I.
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention.
The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Example 1 acquisition of impurities
Preparing a degradation solution: weighing tirofiban hydrochloride sample (crude drug, Wuhanwu Wu drug of production unit) about 250mg, placing in a 1L volumetric flask, adding water to completely dissolve and dilute to scale, and shaking up. 5ml of the solution was taken and placed in a 20ml headspace bottle, 5ml of 2M HCl solution was added, shaken well and sealed with a gland. The prepared 1L solution was dispensed into 200 20ml headspace bottles in this manner. And (4) placing the headspace bottle in an oven at 90 ℃ for 4h, taking out, and cooling to room temperature. All solutions were then transferred to a 2L vessel as a preparative degradation solution. The degradation solution is divided into two parts and is respectively treated by the following modes (1) and (2):
(1) and (3) carrying out rotary evaporation on part of the degradation solution under reduced pressure to remove part of water and hydrochloric acid in the solution. A part of the concentrated solution was taken, separation conditions were prepared as in table 1 below, and a part of the objective fraction was collected. Fractions from preparative separations were then lyophilized to obtain a small sample of impurities.
TABLE 1 HPLC detection conditions
(2) And (4) adjusting the pH of the residual concentrated solution to be neutral by adopting NaOH, and then extracting by using ethyl acetate. Collecting the water layer and the ethyl acetate layer respectively. And (3) carrying out reduced pressure rotary evaporation on the ethyl acetate layer, evaporating to dryness, and dissolving residues with a proper amount of water and acetonitrile for impurity preparation. The aqueous layer and the ethyl acetate layer were concentrated to give a solution, which was separated and purified according to the following table 2, and the target fraction was collected. Fractions were lyophilized to obtain a small sample of impurities.
TABLE 2 HPLC detection conditions
And comparing the prepared degradation impurities with a degradation sample HPLC spectrogram to determine whether the preparation of the degradation impurities is successful.
Example 2 structural characterization of impurities
The impurities obtained in example 1 were structurally characterized by HPLC, HRMS and NMR.
The HPLC detection conditions are shown in Table 3 below:
TABLE 3
FIG. 1 shows the results of HPLC measurements, which indicate that under the degradation conditions of example 1, two degradation impurities MS475 (3-chloro-tirofiban) and MS262 are produced, with retention times of 27.1min and 26.6min, respectively. It can be seen that tirofiban and 3-chloro-tirofiban can be separated efficiently using this method.
The structure of the impurity was identified by HRMS and NMR.
HRMS test conditions are as follows in table 4:
TABLE 4
FIG. 2 shows the result of HRMS detection, which indicates that the molecular weight of the impurity is 261.1738 and the molecular formula C is in high-resolution mass spectrum16H23NO2。
The NMR measurement conditions are shown in tables 5 to 7 below, and Table 8 shows the results of measurement:
TABLE 5
| Instrumentation and equipment | Model number | Manufacturer of the product |
| Nuclear magnetic resonance apparatus | Bruker AVANCE NEO 400MHz | Bruker |
| Probe head | 5mm BBO Probe | Bruker |
TABLE 6
| Name of reagent | Manufacturer of the product | Batch number | Period of validity |
| DMSO-d6 | Sigma | STBJ7890 | 21-Feb-2022 |
TABLE 7
TABLE 8
The impurities were resolved by nuclear magnetic resonance 1D/2D NMR and were in accordance with the following structures:
in the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (11)
1. A compound having the formula I:
2. a quality control method of tirofiban injection is characterized by comprising the following steps:
determining the amount of the compound of claim 1 in a tirofiban injection;
and determining whether the quality of the tirofiban injection reaches the standard or not based on the content of the compound.
3. The quality control method according to claim 2, wherein the measurement is performed by high performance liquid chromatography.
4. The quality control method according to claim 3, wherein the mobile phase used in the high performance liquid chromatography comprises mobile phase A and mobile phase B, and the mobile phase A is NH4HCO3And the mobile phase B is acetonitrile.
5. The quality control method according to claim 4, wherein the high performance liquid chromatography adopts gradient elution method, and the conditions are as follows:
。
6. The quality control method of claim 4, wherein the NH is4HCO3The concentration of the solution is 5-15 mM;
optionally, when the high performance liquid chromatography detection is carried out, the adopted filler of the chromatographic column is octadecylsilane chemically bonded silica;
optionally, the column temperature of the chromatography column is 25-35 ℃;
optionally, the flow rate of the mobile phase is 20-30 ml/min;
optionally, the detection wavelength in the high performance liquid chromatography is 200-280 nm.
7. A process for preparing the compound of claim 1, comprising:
(1) mixing tirofiban hydrochloride with hydrochloric acid to obtain a degradation solution;
(2) subjecting said degraded solution to a heat treatment to obtain a solution containing a compound of claim 1;
(3) separating the solution containing the compound of claim 1 by high performance liquid chromatography, and collecting fractions containing the compound of claim 1.
8. The method as claimed in claim 7, wherein the temperature of the heat treatment is 80-100 ℃ for 360 min;
optionally, the mobile phase adopted by the high performance liquid chromatography comprises a mobile phase A and a mobile phase B, wherein the mobile phase A is NH4HCO3The mobile phase B is acetonitrile;
optionally, the high performance liquid chromatography employs a gradient elution mode, and the conditions are as follows:
；
Optionally, the NH4HCO3The concentration of the solution is 5-15 mM;
optionally, when the high performance liquid chromatography detection is carried out, the adopted filler of the chromatographic column is octadecylsilane chemically bonded silica;
optionally, the column temperature of the chromatography column is 25-35 ℃;
optionally, the flow rate of the mobile phase is 20-30 ml/min;
optionally, the detection wavelength in the high performance liquid chromatography is 200-280 nm;
optionally, the degradation solution is subjected to a concentration treatment before the heat treatment.
9. The method of claim 8, wherein prior to separation by high performance liquid chromatography, the solution containing the compound of claim 1 is subjected to:
adjusting the pH of the solution containing the compound of claim 1 to 6-8, and performing an extraction treatment with ethyl acetate to obtain an ethyl acetate layer and an aqueous layer;
concentrating the ethyl acetate layer to obtain a concentrate, and dissolving the concentrate by using acetonitrile aqueous solution to obtain a sample solution;
and respectively carrying out high performance liquid chromatography separation on the sample loading liquid and the water layer, and collecting fractions containing the compound.
10. The method of claim 7, wherein the volume ratio of tirofiban hydrochloride to hydrochloric acid is 1: 0.5-1: 2;
optionally, the concentration of the hydrochloric acid is 1-3M;
optionally, the concentration of tirofiban hydrochloride is 0.05-0.3 mg/ml.
11. Use of the compound of claim 1 and/or the compound prepared by the method of any one of claims 7 to 10 for quality control of a tirofiban hydrochloride drug substance or injection, wherein the compound of formula i in the tirofiban drug substance or injection is analyzed by using the compound as a standard substance so as to perform quality control on the tirofiban drug substance and injection.
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Application publication date: 20211022 |