CN113801101A - AZD 9291-2-ketoglutarate and preparation method thereof - Google Patents
AZD 9291-2-ketoglutarate and preparation method thereof Download PDFInfo
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- CN113801101A CN113801101A CN202010543540.XA CN202010543540A CN113801101A CN 113801101 A CN113801101 A CN 113801101A CN 202010543540 A CN202010543540 A CN 202010543540A CN 113801101 A CN113801101 A CN 113801101A
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- 238000002441 X-ray diffraction Methods 0.000 claims abstract description 7
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 claims description 21
- DUYJMQONPNNFPI-UHFFFAOYSA-N osimertinib Chemical compound COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 DUYJMQONPNNFPI-UHFFFAOYSA-N 0.000 claims description 21
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/347—Saturated compounds containing more than one carboxyl group containing keto groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention relates to the technical field of crystal form drug molecules, and particularly provides an AZD 9291-2-ketoglutarate, a preparation method and an application thereof, wherein the AZD 9291-2-ketoglutarate uses Cu-Kalpha radiation, and has characteristic peaks at 6.12 +/-0.2 degrees, 10.30 +/-0.2 degrees, 15.11 +/-0.2 degrees, 20.88 +/-0.2 degrees, 22.93 +/-0.2 degrees and 25.25 +/-0.2 degrees in an X-ray diffraction spectrogram expressed by 2 theta.
Description
Technical Field
The invention relates to the technical field of crystal form drug molecules, in particular to the technical field of AZD9291 crystal forms, and specifically relates to an AZD 9291-2-ketoglutarate and a preparation method and application thereof.
Background
AZD9291(Osimertinib), chemical name: n- [2- [ [2- (dimethylamino) ethyl ] (methyl) amino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl ] amino ] phenyl ] prop-2-enamide, english name: n- (2- { [2- (Dimethylamino) ethyl ] (methyl) amino } -4-methoxy-5- { [4- (1-methyl-1H)
-indol-3-yl)-2-pyrimidinyl]amino } phenyl) acrylamide. CAS number:1421373-65- 0the structural formula is shown as follows:
if the lung cancer patient has EGFR or ALK gene mutation, the targeted drug can obtain better survival benefit. However, the efficacy of these drugs is generally short-lived, and resistance occurs in months 9-11, which arises because cancer cells can evade the therapeutic activity of EGFR or ALK inhibitors by mutating and changing the growth pattern.
ADZ9291, developed by AstraZeneca (AstraZeneca), is a third generation oral, irreversible selective EGFR mutation inhibitor useful for activating and resistant mutant EGFR, i.e., 50% of acquired resistance to EGFR treatment for advanced non-small cell lung cancer patients is caused by the T790M mutation, and ADZ9291 can nullify this challenging mutation. ADZ9291 has better treatment effect on NSCLC patients with existing resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and T790M mutation.
Patent CN103702990A discloses the structure of ADZ9291 compound. Polymorphic forms of this compound and its mesylate salt are also disclosed in this patent, including form B of the ADZ9291 mesylate salt form A, ADZ9291 mesylate salt. Patent CN104961731A discloses ADZ9291 phosphate; patent CN106432231A discloses ADZ9291 pharmaceutically acceptable salts sulfate, p-toluenesulfonate, tartrate, acetate and citrate; patent CN107915725A patent discloses novel pharmaceutically acceptable salts of maleic acid, fumaric acid, gluconic acid, malonic acid, succinic acid and lactic acid.
The former company used the mesylate salt of AZD9291 for clinical studies. However, methanesulfonic acid is highly toxic and, in selective cases, unsuitable for pharmaceutical use. And the methanesulfonate has problems of high hygroscopicity and deliquescence due to high humidity. Therefore, it is necessary to develop other salts with high bioavailability, low toxicity and suitability for pharmaceutical use. Although the prior literature has disclosed numerous AZD9291 crystal forms, systematic studies on the crystal forms are still to be perfected.
Disclosure of Invention
In view of the defects of the prior art, the invention provides the AZD 9291-2-ketoglutarate and the preparation method thereof, and the crystal form prepared by the invention has good stability and high solubility and is beneficial to pharmacy.
The specific technical content of the invention is as follows:
the AZD 9291-2-ketoglutarate provided by the invention uses Cu-Kalpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 6.12 +/-0.2 degrees, 10.30 +/-0.2 degrees, 15.11 +/-0.2 degrees, 20.88 +/-0.2 degrees, 22.93 +/-0.2 degrees and 25.25 +/-0.2 degrees.
Preferably, the AZD 9291-2-ketoglutarate has an X-ray diffraction spectrum expressed in 2 theta using Cu-K alpha radiation with characteristic peaks at 6.12 +/-0.2 degrees, 9.81 +/-0.2 degrees, 10.30 +/-0.2 degrees, 11.30 +/-0.2 degrees, 14.12 +/-0.2 degrees, 15.11 +/-0.2 degrees, 19.66 +/-0.2 degrees, 20.31 +/-0.2 degrees, 20.88 +/-0.2 degrees, 22.93 +/-0.2 degrees, 25.25 +/-0.2 degrees, 25.32 +/-0.2 degrees.
Preferably, the AZD 9291-2-ketoglutarate salt has an X-ray diffraction pattern as shown in figure 1, using Cu-ka radiation.
Preferably, the AZD 9291-2-ketoglutarate has an endothermic peak detected by Differential Scanning Calorimetry (DSC), the starting point of which is 141.14 ℃ and the peak is 155.52 ℃. The AZD 9291-2-oxoglutarate salt presents a DSC/TGA pattern as shown in figure 4.
The invention provides a method for preparing the AZD 9291-2-ketoglutarate, which comprises the following steps:
adding AZD9291 and 2-ketoglutaric acid into an organic solvent, performing ultrasonic treatment until all the components are dissolved, filtering, placing the filtrate in an evaporator, standing at room temperature for natural volatilization, and filtering to obtain a light yellow blocky crystal; drying to obtain the product.
The mol ratio of the AZD9291 to the 2-ketoglutaric acid is 1: 1 to 2.
The mass-volume ratio of the AZD9291 to the organic solvent is 15-50: 1, wherein the mass is in mg and the volume is in ml.
The organic solvent is one or a combination of several of methanol, ethanol, acetone, acetonitrile or tetrahydrofuran.
The ultrasonic power of the ultrasonic instrument is 150-300W.
The room temperature is 10-30 ℃.
And standing for natural volatilization for 2-7 days.
The drying temperature is 40-70 ℃.
The drying time is 2-7 h.
Confirmation of Crystal Structure of AZD 9291-2-oxoglutarate
The X-ray crystal data of the invention is collected on a Japan science XtaLAB Synergy model instrument, the temperature is measured at 293(2) K, CuKa radiation is used, and data is collected in an omega scanning mode and Lp correction is carried out. Analyzing the structure by a direct method, finding out all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and refining the structure by a least square method.
The X-ray powder diffraction test instrument and the test conditions of the invention are as follows: PANALYTIC EMPyrean X-ray powder diffractometer; light source Cu target, flat sample stage, incident light path: BBHD, diffraction path: PIXCEL, voltage 45KV, current 40mA, divergence slit 1/4 degrees, anti-divergence slit 1 degree, cable-stayed slit 0.04rad degree, counting time of each step 0.5s, and scanning range 3-50 degrees.
The TGA/DSC thermal analysis tester and the test conditions in the invention are as follows: TGA/DSC thermogram METTLERTODO TGA/DSC3 +; dynamic temperature section: 30-300 ℃; heating rate: 10 ℃/min; segment gas N2(ii) a Gas flow rate: 50 mL/min; crucible: an aluminum crucible of 40. mu.l.
The crystallographic data obtained by testing and analyzing the AZD 9291-2-oxoglutarate prepared by the invention are (see Table 1): the crystallographic parameters are as follows: triclinic system, space group is P-1; the unit cell parameters are: a is 95.8135(10) °, β is 103.3820(13) °, γ is 101.0568(12) °, unit cell volumeThe ORTEP chart of AZD 9291-2-ketoglutarate salt of the present invention shows that one molecule of AZD9291 binds to one molecule of 2-ketoglutarate acid, as shown in FIG. 2.
TABLE 1 Main crystallographic data for AZD 9291-2-ketoglutarate
According to the crystallography data, the characteristic peaks in the X-ray powder diffraction pattern (Cu-K alpha) corresponding to the AZD 9291-2-ketoglutarate are shown in the attached figure 1 and the table 2 in detail.
TABLE 2AZD 9291-2-oxoglutarate major XRD peaks
AZD 9291-2-ketoglutarate prepared by the invention has an endothermic peak detected by differential scanning thermal analysis (DSC), the starting point of which is 141.14 ℃, and the peak value of which appears at 155.52 ℃. The AZD 9291-2-oxoglutarate salt presents a DSC/TGA pattern as shown in figure 4.
All AZD 9291-2-ketoglutarate samples prepared by the invention have the same crystallographic parameters, X-ray powder diffraction pattern and TGA/DSC thermogram.
The invention also provides a pharmaceutical composition which comprises the AZD 9291-2-oxoglutarate prepared as described above and contains other active ingredients and/or pharmaceutically acceptable auxiliary components that can be used in combination.
Preferably, the pharmaceutical composition can be prepared into spray, tablets, capsules, powder injections, liquid injections and the like by using standard or conventional technology.
The invention also provides application of the AZD 9291-2-ketoglutarate in preparing a medicament for treating lung cancer, in particular application in preparing a medicament for treating non-small cell lung cancer.
Compared with the prior art, the AZD 9291-2-ketoglutarate prepared by the invention has obviously improved solubility and good stability and is suitable for preparing medicaments.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of AZD 9291-2-ketoglutarate salt;
FIG. 2 is an ORTEP diagram of AZD 9291-2-ketoglutarate salt;
FIG. 3 is a schematic representation of the stacking cell of AZD 9291-2-ketoglutarate;
FIG. 4 is a TGA/DSC thermogram of AZD 9291-2-ketoglutarate salt.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
Example 1
Adding 2.5g of AZD9291 and 1.2g of 2-ketoglutaric acid into 100mL of acetone, performing ultrasonic treatment by using a sonicator 200W until all the components are dissolved, filtering, placing the filtrate in an evaporator with a small-hole membrane seal, standing at 10 ℃ for natural volatilization for 5 days, filtering to obtain a light yellow block crystal, and drying in an oven at 50 ℃ for 2 hours to obtain AZD 9291-2-ketoglutarate with the yield of 95.61% and the purity of 99.98%.
Example 2
Adding 2.5g of AZD9291 and 1.32g of 2-ketoglutaric acid into 75mL of methanol, performing ultrasonic treatment by an ultrasonic instrument of 250W until the mixture is completely dissolved, filtering, placing the filtrate in an evaporator with a small-hole membrane seal, standing at 15 ℃ for natural volatilization for 4 days, filtering to obtain light yellow blocky crystals, drying in an oven at 60 ℃ for 5 hours to obtain AZD 9291-2-ketoglutarate, wherein the yield is 93.39%, and the purity is 99.97%.
Example 3
Adding 2.5g of AZD9291 and 0.85g of 2-ketoglutaric acid into a mixed solvent of 50mL of acetone and 75mL of methanol, performing ultrasonic treatment by using an ultrasonic instrument of 150W until the mixture is completely dissolved, filtering, placing the filtrate in an evaporator with a small-hole membrane seal, standing at 20 ℃ for natural volatilization for 6 days, filtering to obtain a light yellow blocky crystal, and drying in an oven at 42 ℃ for 4.5h to obtain AZD 9291-2-ketoglutarate with the yield of 90.54% and the purity of 99.96%.
Example 4
Adding 5.0g of AZD9291 and 3.0g of 2-ketoglutaric acid into 100mL of acetonitrile, performing ultrasonic treatment by a sonicator 300W until all the components are dissolved, filtering, placing the filtrate in an evaporator with a small-hole membrane seal, standing at 23 ℃ for natural volatilization for 7 days, filtering to obtain a light yellow block crystal, and drying in an oven at 70 ℃ for 7 hours to obtain AZD 9291-2-ketoglutarate with the yield of 88.07% and the purity of 99.96%.
Example 5
Adding 2.5g of AZD9291 and 0.73g of 2-ketoglutaric acid into 167mL of tetrahydrofuran, performing ultrasonic treatment by using an ultrasonic instrument 150W until the mixture is completely dissolved, filtering, placing the filtrate in an evaporator with a small-hole membrane seal, standing at 30 ℃ for natural volatilization for 2 days, filtering to obtain light yellow blocky crystals, drying in an oven at 40 ℃ for 2 hours to obtain AZD 9291-2-ketoglutarate, wherein the yield is 83.97%, and the purity is 99.95%.
Example 6
Adding 2.5g of AZD9291 and 1.8g of 2-ketoglutaric acid into a mixed solvent of 125mL of acetone and 75mL of acetonitrile, performing ultrasonic treatment by an ultrasonic instrument of 250W until the mixture is completely dissolved, filtering, placing the filtrate in an evaporator with a small-hole membrane seal, standing at 20 ℃ for natural volatilization, filtering to obtain a light yellow blocky crystal, drying in an oven at 55 ℃ for 3 hours to obtain AZD 9291-2-ketoglutarate, wherein the yield is 66.64%, and the purity is 99.95%.
Verification test
(1) Stability test
The stability test was performed on the AZD 9291-2-oxoglutarate prepared in examples 1-6 of the present invention. The specific stability test method is carried out according to the guidance method of stability investigation in the fourth part of the Chinese pharmacopoeia 2015 edition, the purity is detected by an HPLC method, and the specific test results are shown in Table 3.
TABLE 3 stability test results of AZD 9291-2-ketoglutarate crystal form under illumination, high temperature and high humidity conditions
As can be seen from Table 3, the purity of the AZD 9291-2-oxoglutarate prepared in the embodiments 1-6 of the present invention does not change significantly under the conditions of illumination, high temperature and high humidity, and it can be seen that the AZD 9291-2-oxoglutarate prepared in the present invention has good stability.
(2) Solubility test
A comparative study of the solubility of AZD 9291-2-ketoglutarate prepared according to the invention from example 1 and AZD9291 mesylate in the prior art form A, AZD9291 fumarate was carried out. The method comprises the following steps: respectively measuring 10ml of medium (water, 0.1mol/LHCl solution and phosphate buffer solution with pH of 6.8) into a penicillin bottle, adding excessive samples to be detected, sealing the penicillin bottle, placing the penicillin bottle in a constant-temperature water bath at 25 ℃, stirring for 1 hour, filtering through a 0.45-micron filter membrane, and taking filtrate; the absorbance was measured at a wavelength of 210nm, and the solubility was calculated by measuring the absorbance of a standard control.
TABLE 4 solubility of AZD 9291-2-oxoglutarate in different media (mg/ml)
From the test data, compared with AZD9291 mesylate crystal form A, AZD9291 fumarate in the prior art, the AZD 9291-2-ketoglutarate prepared in the embodiment 1 of the invention has obviously improved solubility in water and phosphoric acid media, which shows that the AZD 9291-2-ketoglutarate prepared in the invention has good solubility, and can be prepared into a pharmaceutical preparation to be beneficial to absorption by human bodies.
Through tests, the AZD 9291-2-ketoglutarate prepared in the embodiments 2-6 has similar solubility to the AZD 9291-2-ketoglutarate prepared in the embodiment 1, and compared with AZD9291 mesylate crystal form A, AZD9291 fumarate in the prior art, the solubility of the AZD 9291-2-ketoglutarate in water and a phosphoric acid medium is remarkably improved.
Claims (9)
1. AZD 9291-2-ketoglutarate, which is characterized in that: the AZD 9291-2-ketoglutarate uses Cu-K alpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 6.12 +/-0.2 degrees, 10.30 +/-0.2 degrees, 15.11 +/-0.2 degrees, 20.88 +/-0.2 degrees, 22.93 +/-0.2 degrees, and 25.25 +/-0.2 degrees.
2. AZD 9291-2-ketoglutarate salt according to claim 1, characterized in that: the AZD 9291-2-ketoglutarate uses Cu-Kalpha radiation, and has characteristic peaks at 6.12 +/-0.2 degrees, 9.81 +/-0.2 degrees, 10.30 +/-0.2 degrees, 11.30 +/-0.2 degrees, 14.12 +/-0.2 degrees, 15.11 +/-0.2 degrees, 19.66 +/-0.2 degrees, 20.31 +/-0.2 degrees, 20.88 +/-0.2 degrees, 22.93 +/-0.2 degrees, 25.25 +/-0.2 degrees and 25.32 +/-0.2 degrees in an X-ray diffraction spectrum expressed by 2 theta.
3. AZD 9291-2-ketoglutarate salt according to claim 1, characterized in that: the AZD 9291-2-ketoglutarate salt has an X-ray diffraction pattern shown in figure 1 by using Cu-Ka radiation.
4. A process for the preparation of AZD 9291-2-ketoglutarate salt according to claims 1 to 3, characterised in that it comprises the following steps:
adding AZD9291 and 2-ketoglutaric acid into an organic solvent, performing ultrasonic treatment until all the components are dissolved, filtering, placing the filtrate in an evaporator, standing at room temperature for natural volatilization, and filtering to obtain a light yellow blocky crystal; drying to obtain the product.
5. The method of claim 4, wherein: the mol ratio of the AZD9291 to the 2-ketoglutaric acid is 1: 1 to 2.
6. The method of claim 4, wherein: the mass-volume ratio of the AZD9291 to the organic solvent is 15-50: 1, wherein the mass is in mg and the volume is in ml.
7. The method of claim 4, wherein: the organic solvent is one or a combination of several of methanol, ethanol, acetone, acetonitrile or tetrahydrofuran.
8. A pharmaceutical composition comprising AZD 9291-2-oxoglutarate salt according to any one of claims 1 to 4, and further active ingredients and/or pharmaceutically acceptable auxiliary components which may be used in combination.
9. Use of an AZD9291-2 ketoglutarate salt according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of lung cancer.
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103702990A (en) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
CN104961731A (en) * | 2015-02-05 | 2015-10-07 | 苏州晶云药物科技有限公司 | Phosphate of epidermal growth factor receptor inhibitor, and crystal form and preparation method thereof |
CN106432231A (en) * | 2016-09-09 | 2017-02-22 | 无锡佰翱得生物科学有限公司 | AZD 9291 pharmaceutical salt and crystal form and preparation method thereof |
CN106674202A (en) * | 2015-11-05 | 2017-05-17 | 惠州信立泰药业有限公司 | Dimethyl sulfonate of compound A, crystal form of dimethyl sulfonate, and medicinal composition containing dimethyl sulfonate |
CN107176954A (en) * | 2017-06-02 | 2017-09-19 | 无锡双良生物科技有限公司 | Pharmaceutical salts and its crystal formation, the preparation method and application of a kind of EGFR inhibitor |
CN107915725A (en) * | 2017-10-20 | 2018-04-17 | 复旦大学 | Pharmaceutical salts of AZD9291 and preparation method thereof |
CN110483486A (en) * | 2019-09-17 | 2019-11-22 | 鲁南制药集团股份有限公司 | A kind of western Tenylidone of Austria coughs up hydrochlorate crystal form and preparation method thereof |
-
2020
- 2020-06-15 CN CN202010543540.XA patent/CN113801101A/en active Pending
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103702990A (en) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
CN104961731A (en) * | 2015-02-05 | 2015-10-07 | 苏州晶云药物科技有限公司 | Phosphate of epidermal growth factor receptor inhibitor, and crystal form and preparation method thereof |
CN106674202A (en) * | 2015-11-05 | 2017-05-17 | 惠州信立泰药业有限公司 | Dimethyl sulfonate of compound A, crystal form of dimethyl sulfonate, and medicinal composition containing dimethyl sulfonate |
CN106432231A (en) * | 2016-09-09 | 2017-02-22 | 无锡佰翱得生物科学有限公司 | AZD 9291 pharmaceutical salt and crystal form and preparation method thereof |
CN107176954A (en) * | 2017-06-02 | 2017-09-19 | 无锡双良生物科技有限公司 | Pharmaceutical salts and its crystal formation, the preparation method and application of a kind of EGFR inhibitor |
CN107915725A (en) * | 2017-10-20 | 2018-04-17 | 复旦大学 | Pharmaceutical salts of AZD9291 and preparation method thereof |
CN110483486A (en) * | 2019-09-17 | 2019-11-22 | 鲁南制药集团股份有限公司 | A kind of western Tenylidone of Austria coughs up hydrochlorate crystal form and preparation method thereof |
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