CN115197223A - Methotrexate crystal form A compound and preparation method thereof - Google Patents
Methotrexate crystal form A compound and preparation method thereof Download PDFInfo
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- CN115197223A CN115197223A CN202210578926.3A CN202210578926A CN115197223A CN 115197223 A CN115197223 A CN 115197223A CN 202210578926 A CN202210578926 A CN 202210578926A CN 115197223 A CN115197223 A CN 115197223A
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- 229960000485 methotrexate Drugs 0.000 title claims abstract description 64
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 title claims abstract description 63
- 239000013078 crystal Substances 0.000 title claims abstract description 34
- 150000001875 compounds Chemical class 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 17
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 14
- 230000008569 process Effects 0.000 claims abstract description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- ADAHADRJWVCICR-UHFFFAOYSA-N isoquinoline-6-carboxylic acid Chemical compound C1=NC=CC2=CC(C(=O)O)=CC=C21 ADAHADRJWVCICR-UHFFFAOYSA-N 0.000 claims description 4
- 239000012266 salt solution Substances 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 19
- 229940079593 drug Drugs 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000004090 dissolution Methods 0.000 abstract description 3
- 238000003860 storage Methods 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 231100000419 toxicity Toxicity 0.000 abstract description 2
- 230000001988 toxicity Effects 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025598 Malignant hydatidiform mole Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- -1 methotrexate compound Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 208000028466 reproductive system neoplasm Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 201000004595 synovitis Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
- C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
-
- 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 discloses a methotrexate crystal form A compound and a preparation method thereof, wherein an X-ray powder diffraction pattern expressed by a 2 theta +/-0.2 degree diffraction angle has characteristic peaks at 7.7 degrees, 9.3 degrees, 11.5 degrees, 12.0 degrees, 12.6 degrees, 12.9 degrees, 13.4 degrees, 14.4 degrees, 15.5 degrees, 16.1 degrees, 17.8 degrees, 19.2 degrees, 19.5 degrees, 20.7 degrees, 21.5 degrees, 22.5 degrees, 23.6 degrees, 24.2 degrees, 24.8 degrees, 25.5 degrees, 26.2 degrees, 27.0 degrees and 27.9 degrees. Through the research on the methotrexate crystal form, the crystal form stability of the methotrexate in the process of pharmaceutical preparation and medicament storage is ensured, the dissolution speed and bioavailability of the medicament can be improved, the treatment effect of the medicament is improved, and the toxicity is reduced. The preparation process is determined according to the crystal form characteristics of the methotrexate, and the batch drug equivalence of production can be effectively ensured, so that a high-quality, high-efficiency and safe preparation is prepared.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a methotrexate crystal form A compound and a preparation method thereof.
Background
Methotrexate is the first antimetabolite effective in treating tumors, and is mainly suitable for acute leukemia, breast cancer, chorioepithelioma, malignant hydatidiform mole, head and neck tumors, bone tumors, leukemia meningoencephalic spinal cord infiltration, lung cancer, reproductive system tumors, liver cancer and the like. The traditional Chinese medicine composition is also an immunosuppressant, can relieve the rheumatism process, has a particularly good curative effect on synovitis of rheumatoid arthritis, and is one of the most used medicines for patients with rheumatoid diseases.
The prior art now discloses various methotrexate-containing preparations, tablets, injections and the like.
The crystal form of the medicine has a direct relation with the quality and curative effect of the medicine, and the polymorphism affects the preparation and stability of the raw material medicine and the preparation of the medicine, the dissolution and bioavailability of the preparation, and further affects the preparation prescription and preparation process of the medicine. For most drugs, different crystal forms have certain differences in physical and chemical properties, and the differences inevitably affect the curative effects and toxic and side effects of the drugs.
At present, relatively few research reports about the crystal form of methotrexate exist, only one crystal form (CN 103980279B) is publicly reported, and the specific preparation method is that a methotrexate crude product is dissolved in dibutyl phthalate, then a mixed solution of ethanol and diethyl ether with a proportional amount is added, and the mixture is cooled and crystallized to obtain the methotrexate. The process uses a large amount of organic solvent, and uses the tube product diethyl ether, which causes large pressure for subsequent treatment.
Disclosure of Invention
In order to solve the problems, the invention aims to provide a methotrexate crystal form A compound and a preparation method thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
an X-ray powder diffraction pattern of the methotrexate crystal form A compound expressed by a 2 theta +/-0.2 degree diffraction angle has characteristic peaks at 7.7 degrees, 9.3 degrees, 11.5 degrees, 12.0 degrees, 12.6 degrees, 12.9 degrees, 13.4 degrees, 14.4 degrees, 15.5 degrees, 16.1 degrees, 17.8 degrees, 19.2 degrees, 19.5 degrees, 20.7 degrees, 21.5 degrees, 22.5 degrees, 23.6 degrees, 24.2 degrees, 24.8 degrees, 25.5 degrees, 26.2 degrees, 27.0 degrees and 27.9 degrees.
Although methotrexate is a known substance, the inventor finds that the stability of methotrexate is poor in the practical application process, and the content of active ingredients is obviously reduced in the long-term storage process, so that the medication safety of patients is seriously threatened.
The inventor finds that a brand-new methotrexate compound crystal form can be induced by selecting different solvent systems and controlling a recrystallization method in the process of recrystallizing and purifying the methotrexate, and the X-ray powder diffraction pattern of the compound is compared with the currently disclosed methotrexate powder diffraction pattern, so that the invention obtains the brand-new methotrexate crystal form.
The invention also provides a preparation method of the methotrexate crystal form A compound, which is green and environment-friendly, mild in reaction condition and safe in operation.
Through the research on the crystal form of the methotrexate, the crystal form stability of the methotrexate in the process of pharmaceutical preparation and drug storage is ensured, the dissolution rate and bioavailability of the drug can be improved, the treatment effect of the drug is improved, and the toxicity is reduced. The preparation process is determined according to the characteristics of the methotrexate crystal form, and the batch drug equivalence of production can be effectively ensured, so that a high-quality, high-efficiency and safe preparation is prepared.
As a preferable scheme of the invention, the methotrexate crystal form A compound is shown as a formula (I):
the invention provides a preparation method of the methotrexate crystal form A compound, which comprises the following steps:
1) Dissolving the disodium salt of methotrexate in water to obtain a disodium salt solution of methotrexate;
2) Adding activated carbon into the methotrexate disodium salt solution obtained in the step 1), heating for decoloring and filtering;
3) And (3) dropwise adding dilute acid into the filtrate obtained in the step 2) to adjust the pH, cooling, stirring, crystallizing, filtering again, and drying in vacuum to obtain a target compound, wherein an X-ray powder diffraction pattern shows that the methotrexate crystal form A compound is obtained.
The disodium salt of methotrexate used in the present invention is a commercially available product, and the specific means of acquisition is within the skill of those in the art.
The preparation method disclosed by the invention is simple to operate, low in requirements on equipment and labor, strong in reproducibility, high in purity and yield, and suitable for popularization and production.
As a preferable scheme of the invention, the mass of the water for dissolving the disodium salt of methotrexate is 10-15 times of that of the disodium salt of methotrexate.
In a preferable embodiment of the present invention, in the step 2), the temperature for decoloring the activated carbon is 35 to 40 ℃.
In a preferable embodiment of the present invention, in the step 3), the temperature of the filtrate for adjusting the pH is 35 to 40 ℃.
In a preferable embodiment of the present invention, in step 3), the dilute acid is any one of dilute sulfuric acid, dilute hydrochloric acid, and dilute nitric acid with a mass fraction of 5-10%.
In a preferred embodiment of the present invention, in step 3), the pH is 4.0 ± 0.5.
In a preferable embodiment of the present invention, in the step 3), the temperature for cooling crystallization is 20 to 30 ℃.
In a preferable embodiment of the present invention, in the step 3), the vacuum drying temperature is 45 to 50 ℃.
Compared with the prior art, the invention has the following beneficial effects:
1) The invention provides an X-ray powder diffraction pattern of methotrexate crystal form A, which fills up the blank of research;
2) The preparation method disclosed by the invention is simple to operate, green and environment-friendly, mild in reaction conditions, low in requirements on equipment and labor, strong in reproducibility, high in purity and yield, and suitable for popularization and production;
3) The crystal form of the product prepared by the invention is single and stable.
Drawings
Figure 1 shows an X-ray powder diffraction pattern of methotrexate form a obtained via example 1.
Figure 2 shows an X-ray powder diffraction pattern of methotrexate form a obtained via example 2.
Figure 3 shows an X-ray powder diffraction pattern of methotrexate form a dried at 80 ℃ for 24 h.
Figure 4 shows an X-ray powder diffraction pattern of methotrexate form a after 90 days of standing at room temperature.
Detailed Description
The present invention will be further described with reference to specific embodiments, and advantages and features of the present invention will become apparent as the description proceeds. 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 manufacturers, and are all conventional products available by actual purchase.
The examples are exemplary only and do not limit the scope of the invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and substitutions are intended to be within the scope of the invention.
Details of the X-ray powder diffraction instrument: d8 ADVANCE, cu,40kV,40mA, a scanning range of 3-40 degrees, a scanning step length of 0.02 degree and a retention time of 0.1s in each step.
Example 1
The present example provides a method of preparing a methotrexate form a compound comprising:
adding 110g of methotrexate disodium salt and 1100mL of water into a 2L reaction bottle, setting the external temperature to be 35 ℃, stirring until the mixture is dissolved, adding 5.5g of activated carbon, continuing to stir for 1h under heat preservation, filtering, washing a filter cake with 110mL of water, combining the filter liquor, slowly dropwise adding 5% dilute sulfuric acid into the filter liquor, adjusting the pH to 4.03, stirring for 1h under heat preservation after the adjustment is finished, cooling to 20 ℃, filtering, washing the filter cake with 220mL of water, and drying for 12h under vacuum at 45 ℃ to obtain 48.5g of crystal form A methotrexate. The X-ray powder diffraction pattern is shown in fig. 2, and is characterized by having characteristic peaks at 2 θ values of 7.8 °, 9.4 °, 11.6 °, 12.1 °, 12.7 °, 13.0 °, 13.4 °, 14.5 °, 15.6 °,16.2 °, 17.9 °, 19.3 °, 19.7 °, 20.7 °, 21.5 °, 22.5 °, 23.6 °, 24.3 °, 24.8 °, 25.5 °, 26.2 °, 27.1 °, and 28.0 °.
Example 2
The embodiment provides a preparation method of a methotrexate crystal form A compound, which comprises the following steps:
125g of methotrexate disodium salt and 1250mL of water are added into a 2L reaction bottle, the external temperature is set to 40 ℃, the mixture is stirred until the mixture is dissolved clearly, 6.25g of activated carbon is added, the mixture is stirred for 1 hour under the condition of heat preservation, the mixture is filtered, a filter cake is washed by 125mL of water, the filtrate is combined, 5 percent dilute hydrochloric acid is slowly dripped into the filtrate, the pH value is adjusted to 3.95, the mixture is stirred for 1 hour under the condition of heat preservation after the adjustment is finished, the temperature is reduced to 25 ℃, the filter cake is filtered, the filter cake is washed by 250mL of water, and the mixture is dried for 12 hours under the vacuum condition at 50 ℃ to obtain 55g of crystal form A methotrexate. The X-ray powder diffraction pattern is shown in figure 2, and is characterized in that the characteristic peaks are found at 2 theta values of 7.7 degrees, 9.3 degrees, 11.5 degrees, 12.0 degrees, 12.6 degrees, 12.9 degrees, 13.4 degrees, 14.4 degrees, 15.5 degrees, 16.1 degrees, 17.8 degrees, 19.2 degrees, 19.5 degrees, 20.7 degrees, 21.5 degrees, 22.5 degrees, 23.6 degrees, 24.2 degrees, 24.8 degrees, 25.5 degrees, 26.2 degrees, 27.0 degrees and 27.9 degrees.
Experimental part
Experiment I, high-temperature stability experiment of crystal form A
Methotrexate obtained from example 1 of the present invention was dried 24 at 80 ℃ and its characteristic 2 θ value ratio is shown in table 1:
TABLE 1 methotrexate drying 24 characteristic 2 theta values at 80 deg.C vs
The results show that the methotrexate crystal form A is stable and has no obvious change after being dried for 24 hours at 80 ℃.
Experiment II, long-term stability experiment of crystal form A
Methotrexate obtained in example 1 of the present invention was allowed to stand at room temperature for 90 days, and the characteristic 2 θ values were shown in table 2 as follows:
TABLE 2 characteristic 2 θ value comparison of methotrexate on 90 days at room temperature
The result shows that the methotrexate crystal form A is stable and has no obvious change after being placed at room temperature for 90 days.
While the invention has been described with respect to a preferred embodiment, it will be understood by those skilled in the art that the foregoing and other changes, omissions and deviations in the form and detail thereof may be made without departing from the scope of this invention. Those skilled in the art can make various changes, modifications and alterations without departing from the spirit and scope of the present invention, and all equivalent changes, modifications and alterations to the present invention are equivalent embodiments of the present invention; meanwhile, any changes, modifications and variations of the above-described embodiments, which are equivalent to those of the technical spirit of the present invention, are within the scope of the technical solution of the present invention.
Claims (10)
1. The methotrexate crystal form A compound is characterized in that an X-ray powder diffraction pattern of the methotrexate crystal form A compound expressed by a 2 theta +/-0.2 degree diffraction angle has characteristic peaks at 7.7 degrees, 9.3 degrees, 11.5 degrees, 12.0 degrees, 12.6 degrees, 12.9 degrees, 13.4 degrees, 14.4 degrees, 15.5 degrees, 16.1 degrees, 17.8 degrees, 19.2 degrees, 19.5 degrees, 20.7 degrees, 21.5 degrees, 22.5 degrees, 23.6 degrees, 24.2 degrees, 24.8 degrees, 25.5 degrees, 26.2 degrees, 27.0 degrees and 27.9 degrees.
2. A methotrexate form a compound according to claim 1, wherein the methotrexate form a compound is represented by formula (I):
3. a process for the preparation of methotrexate form a compound as claimed in claim 1 or 2, comprising the following steps:
1) Dissolving the disodium salt of methotrexate in water to obtain a disodium salt solution of methotrexate;
2) Adding activated carbon into the methotrexate disodium salt solution obtained in the step 1), heating for decoloring and filtering;
3) And (3) dropwise adding dilute acid into the filtrate obtained in the step 2) to adjust the pH value, cooling, stirring, crystallizing, filtering again, and drying in vacuum to obtain a target compound, wherein an X-ray powder diffraction pattern shows that the methotrexate crystal form A compound is obtained.
4. The method for preparing a methotrexate crystalline form A compound according to claim 3, wherein the mass of the water for dissolving the disodium salt of methotrexate is 10-15 times that of the disodium salt of methotrexate.
5. The method for preparing methotrexate form A compound according to claim 3, wherein the temperature for decoloring the activated carbon in the step 2) is 35-40 ℃.
6. The method for preparing a methotrexate form A compound according to claim 3, wherein in the step 3), the temperature for adjusting the pH of the filtrate is 35-40 ℃.
7. The method for preparing the methotrexate crystalline form A compound according to claim 3, wherein in the step 3), the diluted acid is any one of diluted sulfuric acid, diluted hydrochloric acid and diluted nitric acid with the mass fraction of 5-10%.
8. The process for the preparation of methotrexate form a compound according to claim 3, wherein in step 3) the pH is 4.0 ± 0.5.
9. The method for preparing a methotrexate form A compound as claimed in claim 3, wherein the temperature for cooling crystallization in step 3) is 20-30 ℃.
10. The process for the preparation of methotrexate form a compound according to claim 3, wherein in step 3), the vacuum drying temperature is 45-50 ℃.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202210578926.3A CN115197223A (en) | 2022-05-25 | 2022-05-25 | Methotrexate crystal form A compound and preparation method thereof |
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| CN202210578926.3A CN115197223A (en) | 2022-05-25 | 2022-05-25 | Methotrexate crystal form A compound and preparation method thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103980279A (en) * | 2014-04-16 | 2014-08-13 | 悦康药业集团有限公司 | Methotrexate compound and methotrexate for injection |
| CN114516874A (en) * | 2022-03-11 | 2022-05-20 | 国药一心制药有限公司 | Methotrexate new crystal form and preparation method thereof |
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- 2022-05-25 CN CN202210578926.3A patent/CN115197223A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103980279A (en) * | 2014-04-16 | 2014-08-13 | 悦康药业集团有限公司 | Methotrexate compound and methotrexate for injection |
| CN114516874A (en) * | 2022-03-11 | 2022-05-20 | 国药一心制药有限公司 | Methotrexate new crystal form and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| RENU CHADHA 等: "Characterization of solvatomorphs of methotrexate using thermoanalytical and other techniques", ACTA PHARM, vol. 59, no. 3, pages 245 - 257 * |
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