CN116514697A - Piracetam polymorphic form and preparation method thereof - Google Patents
Piracetam polymorphic form and preparation method thereof Download PDFInfo
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- CN116514697A CN116514697A CN202310498621.6A CN202310498621A CN116514697A CN 116514697 A CN116514697 A CN 116514697A CN 202310498621 A CN202310498621 A CN 202310498621A CN 116514697 A CN116514697 A CN 116514697A
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- piracetam
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- 229960004526 piracetam Drugs 0.000 title claims abstract description 77
- GMZVRMREEHBGGF-UHFFFAOYSA-N Piracetam Chemical compound NC(=O)CN1CCCC1=O GMZVRMREEHBGGF-UHFFFAOYSA-N 0.000 title claims abstract description 76
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000013078 crystal Substances 0.000 claims abstract description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 238000001816 cooling Methods 0.000 claims description 19
- 238000002425 crystallisation Methods 0.000 claims description 17
- 230000008025 crystallization Effects 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 17
- 238000010438 heat treatment Methods 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims 3
- 239000007787 solid Substances 0.000 claims 1
- 239000000047 product Substances 0.000 description 18
- 239000012535 impurity Substances 0.000 description 10
- 238000000634 powder X-ray diffraction Methods 0.000 description 10
- 239000000126 substance Substances 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000010268 HPLC based assay Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000011010 flushing procedure Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000000113 differential scanning calorimetry Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000002411 thermogravimetry Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000005260 alpha ray Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical class NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 201000009570 retrograde amnesia Diseases 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000000646 scanning calorimetry Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a piracetam polymorphism and a preparation method thereof. Thus, piracetam having a polymorphic form is obtained. At present, related patent reports on the study of the piracetam polymorphic form are not available, the invention widens the crystal form of the piracetam, and simultaneously improves the quality study of the piracetam finished product.
Description
Technical Field
The application belongs to the field of pharmaceutical chemicals, and particularly relates to a piracetam polymorphism and a preparation method thereof.
Background
Piracetam is a brain metabolism improving medicine, belongs to a ring-shaped derivative of gamma-aminobutyric acid, has the effects of promoting the synthesis of acetylcholine, positively enhancing the conduction of nerve excitation and promoting brain metabolism, can resist brain function injury caused by physical factors and chemical factors, has the effect of improving retrograde amnesia caused by hypoxia, and can enhance memory and improve learning ability.
Piracetam (Piracetam) chemical name: 2-oxo-1-pyrrolidinylacetamide having the structural formula:
as is well known to those skilled in the art, a chemical may or may not exist in a crystalline form; if different crystal forms exist in chemical substances, the different crystal forms can be obviously different in aspects of appearance, solubility, melting point, dissolution rate, bioavailability and the like, so that the stability, bioavailability and curative effect of the chemical substances serving as medicines are affected. At present, the crystal forms of piracetam are reported to be two of a crystal form I and a crystal form II.
The inventor finds that the piracetam exists in a polymorphic form in the process of experimental study on the piracetam, and determines the preparation method for obtaining the piracetam polymorphic form through the experimental study.
It is an object of the present application to provide a piracetam polymorph; the piracetam polymorphic form has good stability.
The piracetam polymorphic form provided by the application uses Cu-kalpha radiation, and at least has main characteristic absorption peaks at the following positions in an X-ray powder diffraction pattern expressed in terms of 2Theta angles: 15.89 + -0.2 deg., 21.67 + -0.2 deg., 23.48 + -0.2 deg., 31.92 + -0.2 deg., 33.22 + -0.2 deg..
One example of the present application provides a crystalline form of piracetam having an X-ray powder diffraction pattern, expressed as a 2Theta angle, using Cu-ka radiation, as shown in figure 1.
Any one of the piracetam polymorphs provided in the present application has a DSC chart showing an absorption peak at 151.8-161 ℃.
Any of the piracetam polymorphs provided herein, whose TGA profile shows onset of decomposition at about 160 ℃.
Any one of the piracetam polymorphs provided by the application has a melting point of 151-154 ℃ as measured by infrared heterodyne scanning calorimetry.
A second object of the present application is to provide a process for the preparation of any one of the piracetam polymorphs of the present application; the preparation method of the piracetam polymorphic form has the advantages of simple process route and low cost, and is suitable for industrial production.
The application provides a preparation method of any piracetam polymorphic form, which comprises the following steps: and heating, refluxing and dissolving the crude piracetam product by using methanol or/and ethyl acetate, cooling to 0-40 ℃ and crystallizing to obtain the piracetam mixed crystal product.
The cooling speed is 2-10 ℃/h;
the crystallization time is 4-20h.
The inventor finds that the mixed crystal piracetam can be obtained by adopting methanol or/and ethyl acetate solvent and combining specific crystallization temperature, cooling rate and crystallization time and the mutual coordination of the parameter steps, the medicine requirements of different piracetam crystal forms under different conditions can be met, and the whole preparation process adopts methanol or/and ethyl acetate, so that the medicine safety of the piracetam is not influenced. In addition, the method is simple to operate, good in reproducibility and easy to industrialize.
Optionally, when the cooling speed is 3-5 ℃/h, the crystallization temperature is 0-20 ℃, and the crystallization time is 15-20h, so as to obtain the piracetam polymorphic form.
Preferably, the crystallization temperature is 0-10 ℃.
Preferably, the crystallization time is 16h.
Optionally, when the cooling speed is 10-15 ℃/h, the crystallization temperature is 20-30 ℃, and the crystallization time is 4-10h, the piracetam polymorphism is obtained.
The inventor has found through intensive research that by further controlling different cooling rates and different crystallization temperatures and combining crystallization time, the polymorphism can be stably obtained, and the repeatability is good, so that the method is easy for industrial production. In addition, by further controlling the crystallization time, the crystallization time is prevented from being too short or too long, resulting in incomplete crystallization or failure to obtain the target crystal form.
When the cooling speed is 5-10 ℃/h, but does not comprise 5 ℃/h and 10 ℃/h, the crystallization temperature and time can be adjusted in a combined way, and a single piracetam polymorphism is obtained through mutual matching of the parameters.
Optionally, the mass-volume ratio of the crude piracetam to the methanol or/and the ethyl acetate is 1g: (4-16) mL.
Preferably, the mass volume ratio of the crude piracetam to the methanol or/and ethyl acetate is 1g:12mL.
Optionally, when the purity of the piracetam in the crude piracetam is not lower than 90%, related substances of the obtained piracetam polymorphic form and the like can meet the related requirements of the piracetam bulk drug; when the purity of the piracetam in the crude piracetam is lower than 90%, related substances and the like of the obtained piracetam cannot meet the related requirements of the piracetam bulk drug.
Optionally, the preparation method of the piracetam polymorphic form further comprises the steps of filtering, washing and drying after crystallization; a step of
The mass-volume ratio of the crude piracetam to the washed solvent is 1g: (1-3) mL, wherein the solvent is ethyl acetate.
Optionally, the drying is vacuum drying;
the drying temperature is 40-60 ℃.
Optionally, the drying time is 6-12h.
Optionally, the preparation method of the piracetam polymorphic form further comprises the steps of adding active carbon after heating, refluxing and dissolving, stirring and hot filtering before the cooling.
Drawings
Figure 1 XRPD pattern of piracetam polymorphic form.
Figure 2-piracetam polymorphic TG diagram.
Figure 3-piracetam polymorphic DSC profile.
Detailed Description
The present invention will be further described in detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
In order to better illustrate the present invention, the following examples are provided for further illustration. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
In this application:
XRPD: x ray powder diffraction, x-ray powder diffraction (also known as XRD);
TGA: thermogravimetric Analysis, thermogravimetric analysis;
DSC: differential scanning calorimetry, differential scanning calorimetry.
XRPD patterns were collected on a Bruker D8 advanced X-ray powder diffraction analyzer, X-ray powder hydrochloric acid test conditions: cu K alpha ray, 40KV and 40mA
TGA-DSC plots were collected on a Netzach DSC 3500/Perkinelmer TGA4000 thermal analyzer, thermogravimetric analysis and differential scanning calorimetry test conditions: measuring the temperature range to 25-280 ℃; the temperature rising rate is 10K/min; and nitrogen atmosphere, 60mL/min.
The HPLC purity detection method of the different piracetam finished products and crude piracetam products prepared in each example is as follows:
HPLC purity detection method
The chromatographic conditions used octadecylsilane chemically bonded silica as packing material (Kromasil 100-5C 18 column, 4.6 mm. Times.250 mm,5 μm or equivalent potency chromatographic column); gradient elution was performed using 0.1% dipotassium hydrogen phosphate solution (pH adjusted to 6.0±0.05 with phosphoric acid) as mobile phase a and acetonitrile as mobile phase B, as follows; the flow rate was 1.0mL per minute, the detection wavelength was 205nm, and the sample volume was 20. Mu.L.
The sample solution is taken out, dissolved by adding a solvent and diluted to prepare a solution containing about 0.5mg per liter of mL.
Example 1
Adding 30mL of methanol and 90mL of ethyl acetate into 10 g of piracetam crude product, stirring and heating until reflux and dissolution are complete, stopping heating, continuously stirring and cooling to 0-5 ℃ at a cooling rate of 3-5 ℃/h, stirring, preserving heat and crystallizing for 16h, filtering, flushing with 15mL of ethyl acetate, drying at 60 ℃ under reduced pressure for 10h to obtain 5.8g of refined product, and obtaining the yield: 58%, purity (HPLC assay): 99.92%, and the single impurity is less than 0.1%. The resulting refined product was subjected to XRPD, the resulting XRPD pattern is shown in figure 1, and typical TGA and DSC patterns are shown in figures 2 and 3. The resulting refined product is the piracetam polymorph of the present application.
Example 2
Adding 40mL of methanol into 10 g of piracetam crude product, stirring and heating until reflux and dissolution are complete, stopping heating, continuing stirring and cooling to 5-10 ℃ at a cooling rate of 3-5 ℃/h, stirring, preserving heat and crystallizing for 16h, filtering, flushing with 12mL of ethyl acetate, and drying at 60 ℃ under reduced pressure for 10h to obtain 6.1g of refined product, wherein the yield: 61%, purity (HPLC assay): 99.89%, and the single impurity is less than 0.1%. The resulting refined product is the piracetam polymorph of the present application.
Example 3
Adding 20mL of methanol and 70mL of ethyl acetate into 10 g of piracetam crude product, stirring and heating until reflux and dissolution are complete, stopping heating, continuously stirring and cooling to 0-5 ℃ at a cooling rate of 3-5 ℃/h, stirring, preserving heat and crystallizing for 16h, filtering, flushing with 20mL of ethyl acetate, drying at 60 ℃ under reduced pressure for 10h to obtain 6.1g of refined product, and obtaining the yield: 61%, purity (HPLC assay): 99.93%, and the single impurity is less than 0.1%. The resulting refined product is the piracetam polymorph of the present application.
Example 4
Adding 25mL of methanol and 100mL of ethyl acetate into 10 g of piracetam crude product, stirring and heating until reflux and dissolution are complete, stopping heating, continuously stirring and cooling to 0-5 ℃ at a cooling rate of 3-5 ℃/h, stirring, preserving heat and crystallizing for 12h, filtering, flushing with 20mL of ethyl acetate, drying at 60 ℃ under reduced pressure for 10h to obtain 6.5g of refined product, and obtaining the yield: 65%, purity (HPLC assay): 99.91 percent, and single impurities are less than 0.1 percent. The resulting refined product is the piracetam polymorph of the present application.
Example 5
Adding 20mL of methanol and 120mL of ethyl acetate into 10 g of piracetam crude product, stirring and heating until reflux and dissolution are complete, stopping heating, continuously stirring and cooling to 0-5 ℃ at a cooling rate of 10-15 ℃/h, stirring, preserving heat and crystallizing for 12h, filtering, flushing with 20mL of ethyl acetate, drying at 60 ℃ under reduced pressure for 10h to obtain 5.7g of refined product, and obtaining the yield: 57%, purity (HPLC assay): 99.87%, and the single impurities are less than 0.1%. The resulting refined product is the piracetam polymorph of the present application.
Example 6 stability experiment
A series of stability test investigations were carried out on the piracetam polymorphs prepared in examples 1 to 5, mainly influencing factor tests, and the experimental results are shown in Table 1:
TABLE 1 influence factor test results
The test results of the influence factors in table 1 show that the indexes of the Piracetam crystal form stability key investigation project have no obvious change compared with the initial time (0 month), the purity is more than 99.5%, the single impurity is less than 0.1%, and the Piracetam crystal form stability is stable.
In the above embodiments:
"colorless" means: clarifying the solution;
"turbidity standard solution No. 1" means: no. 1 turbidity standard solution in the Chinese pharmacopoeia 2020 edition four general rules 0902.
"Total impurities" means: total amount of impurities contained in the piracetam polymorphic form, and mass percent;
"loss on drying" means: the amount of the piracetam polymorphism, the mass percentage, is reduced after drying;
"content" means: the content of the active ingredient of the piracetam in the piracetam polymorphic form (taking a standard product as a comparison) is calculated according to the mass percentage;
"RH" means: relative humidity;
the dry weight loss measurement method comprises the following steps: the product is taken and dried at 105 ℃ to constant weight, and the weight loss (four general rules 0831 of Chinese pharmacopoeia 2020 edition) is measured.
The method for measuring the content of single impurities and total impurities comprises the following steps: the measurement is carried out according to high performance liquid chromatography (four general rules 0512 of Chinese pharmacopoeia 2020 edition).
Claims (5)
1. A method for preparing a piracetam polymorphic form, which is characterized in that: the preparation method comprises the following steps:
and adding the crude piracetam product into an organic solvent, dissolving and clarifying under the heating condition, cooling, stirring for crystallization, filtering and drying to obtain the piracetam mixed crystal product.
2. A process for the preparation of a polymorph of piracetam according to claim 1, characterized in that: the organic solvent is one or more of methanol and ethyl acetate.
3. A process for the preparation of a polymorph of piracetam according to claim 1, characterized in that: under the condition of heating and refluxing, the crude piracetam product is dissolved and clarified.
4. A process for the preparation of a polymorph of piracetam according to claim 1, characterized in that: the mass volume ratio of the crude piracetam to the organic solvent is 1:4.0-16.0.
5. A process for the preparation of a polymorph of piracetam according to claim 1, characterized in that: and (3) keeping the temperature at 0-40 ℃ to separate out the solid from the solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310498621.6A CN116514697A (en) | 2023-05-06 | 2023-05-06 | Piracetam polymorphic form and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310498621.6A CN116514697A (en) | 2023-05-06 | 2023-05-06 | Piracetam polymorphic form and preparation method thereof |
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| Publication Number | Publication Date |
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| CN116514697A true CN116514697A (en) | 2023-08-01 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN202310498621.6A Pending CN116514697A (en) | 2023-05-06 | 2023-05-06 | Piracetam polymorphic form and preparation method thereof |
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| Country | Link |
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| CN (1) | CN116514697A (en) |
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2023
- 2023-05-06 CN CN202310498621.6A patent/CN116514697A/en active Pending
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