CN112979459B - Monbunone crystal form I and preparation method thereof - Google Patents
Monbunone crystal form I and preparation method thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07C59/40—Unsaturated compounds
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- 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
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
Abstract
The invention provides a menbutone crystal form I and a preparation method thereof, and a single crystal with stable chemical property, uniform particle size distribution, high solubility, high crystallinity and high purity is obtained by using a Supercritical Fluid (SFC) technology and adjusting the concentration of a solution, the flow of the solution, the pressure, the temperature and the length and diameter of a nozzle. The invention also provides a pharmaceutical composition of the crystal form I of the montubonione, and application of the crystal form I of the montubonione and the pharmaceutical composition thereof in preparation of pharmaceutical preparations.
Description
Technical Field
The invention belongs to the technical field of chemical medicine crystal forms, and particularly relates to a novel crystal form of menbutone and a preparation method thereof.
Background
Menbutone is approved to be marketed by germany as early as 1965, is a special cholagogue for animals, can promote the secretion of bile, gastric juice and pancreatic juice to reach 2-5 times of the normal secretion amount, so that the supply of cholate, pepsin, pancreatic amylase and the like is increased, gastrointestinal dysfunction such as dyspepsia, inappetence, constipation and abdominal distension of animals is effectively treated, the digestion and absorption functions are improved, and the menbutone is widely applied to dyspepsia, anorexia, constipation, toxemia and digestive dysfunction caused by liver and pancreatic insufficiency of pigs, cows, sheep, goats, horses and dogs, and has good clinical treatment effect. The chemical name of the menbutone crystal form is as follows: 3- (4-methoxy-1-naphthalene) propionic acid of the formula:
it is known that, the bioavailability of the same drug may vary with the crystal form, and the stability, solubility, fluidity and compressibility of the same drug may also vary, and these physicochemical properties may have a certain effect on the application of the drug, thereby affecting the efficacy of the drug. Chinese patent CN104370734A discloses a menbutone crystal form, but the crystal form has poor water solubility, so that a cosolvent is required to be added to meet the market demand when a pharmaceutical preparation is prepared, and the problem that a sample is still unstable in the long-term storage process is solved. Therefore, there is a need for crystalline forms of menbutone with superior physicochemical properties, with a certain outstanding effect in the processing of pharmaceutical preparations and in the use of pharmaceutical compositions.
Disclosure of Invention
The invention aims to solve the technical problems of unstable raw material and uneven particle size distribution of the menbutone in the prior art, and the preparation method prepares a menbutone crystal form I by deeply researching the technical contents of solution concentration, solution flow, pressure, temperature, nozzle length-diameter ratio and the like by using a Supercritical Fluid (SFC) technology. Provides more choices for the demand of the menbutone on the high-quality raw materials in the development of new dosage forms.
The invention provides a crystalline form I of montmonitone, which is characterized in that the XRPD pattern has derivative peaks at 2 theta =7.14, 12.04, 12.5, 14.1, 14.4, 16.7, 18.4, 21.4, 21.6, 22.9, 23.7, 25.1, 26.8, 27.9, 29.0, 38.7 and 41.0, wherein the error range of the 2 theta value is 0.2.
The invention also provides a preparation method of the menbutone crystal form I, which adopts a supercritical fluid (SCF) technology and comprises the following specific steps:
(1) and (3) placing the raw material of the menbutone in a first feeding tank, adding acetone for dissolving, and then cooling to obtain the menbutone solution.
(2) Introducing CO into the second feeding tank2And after the gas is balanced, starting a high-pressure metering pump to pressurize, so that the whole system is filled with carbon dioxide liquid. The balance being to flood the entire system with liquid CO2If there is gaseous CO2The pressure may vary. When CO is present2From liquid to gaseous state, the process of this phase change forms supercritical CO2。
(3) And opening the preheating device to raise the temperature to the preheating temperature, and preheating the menbutone solution.
(4) And opening discharge port valves of the first feeding tank and the second feeding tank simultaneously to enable the preheated menbutone solution to be in contact with the carbon dioxide liquid at the nozzle.
(5) When liquid carbon dioxide is contacted with the solution and sprayed out through a nozzle, supercritical carbon dioxide is formed, rapid mutual mass transfer occurs, and a large amount of menbutone crystal form I is separated out. In the process of mutual mass transfer, acetone is changed from liquid state to gas state, the dissolving capacity for menbutone is reduced, and the menbutone solution is in a supersaturated state.
(6) Continuously introducing supercritical CO2Removing residual acetone solvent and obtaining the menbutone crystal form I in a settling chamber.
Preferably, the concentration of the feed liquid of the menbutone raw material and acetone in the step (1) is 10-30 mg/ml. Further preferred concentrations of the feed solution of the menbutone starting material and acetone are 10, 11, 14, 17, 21, 26, 29, 30 mg/ml.
Any one of the above is preferred, wherein the temperature is reduced to 0-5 ℃ after the dissolution of the menbutone starting material in acetone in step (1). The temperature is reduced to 0-5 ℃, so that the carbon dioxide can be ensured to be liquid carbon dioxide.
Any one of the above is preferable, in the step (2), the preheating temperature is 33 to 40 ℃. Further preferred preheating temperatures for the menbutone solution are 33, 36, 38, 40 ℃.
Any one of the above is preferably, in the step (2), the high-pressure metering pump is started to pressurize, and the pressure is increased to 9-12 Mpa. Further preferred pressures are 9, 10, 11, 12 Mpa.
Any one of the above is preferable, in the step (2), the nozzle has an inner diameter of 0.1mm and an aspect ratio of 3 to 8. The selection of the nozzle parameters influences the particle size, the further preferable length-diameter ratio is 4-6, and the selection of the nozzle parameters has no influence on the crystal form.
Preferably, in any of the above solutions, the menbutone is injected into the nozzle at a flow rate of 1 to 5 g/min. Too large flow is not beneficial to mass transfer, larger granularity, too small flow, smaller granularity and uneven distribution.
Any one of the above preferred is that the supercritical CO in the step (4)2The flow-in time of (2) was 30 min. The solvent can be fully taken away within 30min, so that the re-solvation is avoided, and the mass transfer is more sufficient.
In a preferred embodiment of the present invention, the specific preparation method is:
(1) putting a menbutone raw material into a first feeding tank, adding a certain amount of acetone for dissolving, and cooling to 0-5 ℃ by using a cooler to obtain a menbutone solution. The concentration of the acetone and the menbutone raw material is 10-30 mg/ml.
(2) Opening of CO2Steel cylinder, introducing CO into the second feeding tank2Gas, filling the whole system with CO2And after balancing, starting a high-pressure metering pump to pressurize, so that the whole system is filled with carbon dioxide liquid. And (3) pressurizing under the pressure of 9-12Mpa, opening a preheating device, setting the temperature by using a preheater, wherein the preheating temperature is 33-40 ℃, and preheating the menbutone solution. And opening discharge port valves of the first feeding tank and the second feeding tank, and injecting the preheated menbutone solution into the nozzle according to a certain flow rate to contact with the carbon dioxide liquid at the nozzle. The inner diameter of the nozzle is 0.1mm, and the length-diameter ratio is 3-8; the injection flow rate of the menbutone solution is 1-5 g/min.
(3) When liquid carbon dioxide is contacted with the solution and sprayed out through a nozzle, supercritical carbon dioxide is formed, rapid mutual mass transfer occurs, and a large amount of menbutone crystal form I is separated out. In the process of mutual mass transfer, acetone is changed from liquid state to gas state, the dissolving capacity for menbutone is reduced, and the menbutone solution becomes supersaturated state.
(4) Continuously introducing supercritical CO2 And (3) removing residual acetone solvent for 30min, obtaining the menbutone crystal form I in a settling chamber, and measuring the particle size distribution by a particle size analyzer.
The crystal form of the menbutone shown in the formula (1) has XRPD pattern which is the same as that shown in figure 1 in the specification.
The invention also provides a pharmaceutical composition which is characterized by comprising the montubulone crystal form I.
Preferably, one or more pharmaceutically acceptable carriers and/or excipients are also included.
The invention also provides the crystal form I of the montubonione and the application of the pharmaceutical composition of the crystal form I of the montubonione in the preparation of pharmaceutical preparations.
The pharmaceutical preparation can be prepared into dosage forms including but not limited to injection, soluble powder, oral liquid, sustained-release granules, other granules, freeze-dried powder, tablets, powder, injection, solid dispersion, pellets, suspension and the like. Preferably, the pharmaceutical preparation is powder or injection. The preferable carrier of the powder is starch or glucose, and preferably, the weight percentage of the menbutone crystal form I powder is 5-10%, 95-90% of starch or 95-90% of glucose powder. The preferable carrier of the injection is diethanolamine or water, and the preferable carrier is 0.5-50% of the montulone crystal form I, 99.5-50% of water or 30-60% of diethanolamine.
Has the advantages that:
1) the invention can control the granularity of the crystal by using the SCF crystallization method, obtain single crystal with uniform granularity distribution and high purity, and the obtained menbutone crystal form I has uniform granularity distribution and D90 of 1-3 mu m.
2) The crystal form I of the montubonione obtained by the invention has good stability and high crystallinity, and the transportation and storage stability in extreme weather is not influenced.
3) The obtained crystal form I of the montmonillonone has better solubility, the solubility in water is 2.1mg/mL, and the solubility of the reported crystal form (patent CN 104370734A) in water is 0.08mg/mL, so the crystal form has better advantages for preparing a water-soluble preparation.
Drawings
Fig. 1 is an XRPD pattern of crystalline menbutone form i of formula (1) as provided in preferred embodiment 1 of the present invention;
fig. 2 is an infrared spectrum of crystalline form i of menbutone of formula (1) provided in preferred embodiment 1 of the present invention.
Detailed Description
The invention will now be further described by way of the following examples, which are not intended to limit the scope of the invention in any way. It will be understood by those skilled in the art that equivalent substitutions for the technical features of the present invention, or corresponding modifications, can be made within the scope of the present invention.
Example 1
In a first feeding tank, 20g of menbutone is taken and dissolved in 2L of acetone, the concentration of feed liquid is 10mg/ml, and a cooler is cooled to 0-5 ℃. Opening of CO2Steel cylinder, introducing CO into the second feeding tank2And (5) after the gas is balanced, starting a high-pressure metering pump to pressurize to 10Mpa, so that the whole system is filled with carbon dioxide liquid. And (4) opening a preheating device, setting the preheater at 35 ℃, and preheating the menbutone solution. And opening discharge port valves of the first feeding tank and the second feeding tank simultaneously to enable the preheated menbutone solution to be injected into the nozzle according to a certain flow rate and to be contacted with carbon dioxide liquid at the nozzle, wherein the inner diameter of the nozzle is 0.1mm, and the length-diameter ratio of the nozzle is 3. When liquid carbon dioxide is contacted with the solution and sprayed out through a nozzle, supercritical carbon dioxide is formed, rapid mutual mass transfer occurs, and a large amount of menbutone crystal form I is separated out. In the process of mutual mass transfer, acetone is changed from liquid state to gas state, the dissolving capacity for menbutone is reduced, and the menbutone solution becomes supersaturated state. After the whole process is finished, continuously introducing supercritical CO2And (3) taking away residual acetone solvent for 30min, and obtaining the menbutone crystal form I in a settling chamber. Measured by a particle size analyzerThe fixed particle size distribution D90 was 2.8 um. As can be seen from fig. 1, the XRPD pattern has specific characteristic absorption peaks at 2 θ =7.14, 12.04, 12.5, 14.1, 14.4, 16.7, 18.4, 21.4, 21.6, 22.9, 23.7, 25.1, 26.8, 27.9, 29.0, 38.7 and 41.0, and is the form i, and the crystallinity is 94%. As shown in fig. 2, is an infrared spectrum of the menbutone crystal form i of formula (1).
Example 2
In a first feeding tank, 50g of menbutone is taken and dissolved in 2.5L of acetone, the concentration of feed liquid is 25mg/ml, and a cooler is cooled to 0-5 ℃. Opening of CO2Steel cylinder, introducing CO into the second feeding tank2And (5) after the gas is balanced, starting a high-pressure metering pump to pressurize to 9Mpa, so that the whole system is filled with carbon dioxide liquid. The preheating device is started, the preheater is set to be 33 ℃, and the menbutone solution is preheated. And opening discharge port valves of the first feeding tank and the second feeding tank simultaneously to enable the preheated menbutone solution to be injected into the nozzle according to a certain flow rate and to be contacted with carbon dioxide liquid at the nozzle, wherein the inner diameter of the nozzle is 0.1mm, and the length-diameter ratio of the nozzle is 5. When liquid carbon dioxide is contacted with the solution and sprayed out through a nozzle, supercritical carbon dioxide is formed, rapid mutual mass transfer occurs, and a large amount of menbutone crystal form I is separated out. In the process of mutual mass transfer, acetone is changed from liquid state to gas state, the dissolving capacity for menbutone is reduced, and the menbutone solution becomes supersaturated state. After the whole process is finished, continuously introducing supercritical CO2And (3) taking away residual acetone solvent for 30min, and obtaining the menbutone crystal form I in a settling chamber. The particle size distribution D90 was 2.1 μm as determined by a particle sizer. The results show form i with a crystallinity of 94%.
Example 3
In a first feeding tank, taking 20g of menbutone, dissolving the menbutone in 1L of acetone, wherein the concentration of feed liquid is 20mg/ml, and cooling a cooler to 0-5 ℃. Opening of CO2Steel cylinder, introducing CO into the second feeding tank2And (5) after the gas is balanced, starting a high-pressure metering pump to pressurize to 12Mpa, so that the whole system is filled with carbon dioxide liquid. The preheating device is started, the preheater is set to be 33 ℃, and the menbutone solution is preheated. Simultaneously opening discharge port valves of the first feeding tank and the second feeding tank to ensure that the preheated menbutone solution flows according to a certain flowThe amount was injected into the nozzle and contacted with carbon dioxide liquid at the nozzle, the nozzle inner diameter was 0.1mm and the aspect ratio was 8. When liquid carbon dioxide is contacted with the solution and sprayed out through a nozzle, supercritical carbon dioxide is formed, rapid mutual mass transfer occurs, and a large amount of menbutone crystal form I is separated out. In the process of mutual mass transfer, acetone is changed from liquid state to gas state, the dissolving capacity for menbutone is reduced, and the menbutone solution becomes supersaturated state. After the whole process is finished, continuously introducing supercritical CO2And (3) taking away residual acetone solvent for 30min, and obtaining the menbutone crystal form I in a settling chamber. The particle size distribution D90 was 1.8um as determined by a particle sizer. The results show form i with a crystallinity of 92%.
Comparative example 1
In a first feeding tank, 15g of menbutone is taken and dissolved in 1L of ethanol, the concentration of feed liquid is 15mg/ml, and a cooler is cooled to 0-5 ℃. Opening of CO2Steel cylinder, introducing CO into the second feeding tank2And (5) after the gas is balanced, starting a high-pressure metering pump to pressurize to 12Mpa, so that the whole system is filled with carbon dioxide liquid. And (4) opening a preheating device, setting the preheater at 35 ℃, and preheating the menbutone solution. And opening discharge port valves of the first feeding tank and the second feeding tank simultaneously to enable the preheated menbutone solution to be injected into the nozzle according to a certain flow rate and to be contacted with carbon dioxide liquid at the nozzle, wherein the inner diameter of the nozzle is 0.1mm, and the length-diameter ratio of the nozzle is 6. When liquid carbon dioxide is contacted with the solution and sprayed out through the nozzle, supercritical carbon dioxide is formed, rapid mutual mass transfer occurs, and a large amount of menbutone crystal forms are separated out. In the process of mutual mass transfer, the ethanol will change from liquid to gaseous state, the dissolving capacity for menbutone is reduced, and the menbutone solution becomes supersaturated. After the whole process is finished, continuously introducing supercritical CO2Taking away residual ethanol solvent after 30min, and determining the obtained menbutone crystal form by a particle size analyzer to obtain a particle size distribution D90 of 1.9 um. The result showed 62% crystallinity as form II (CN 104370734A).
Comparative example 2
In a first feeding tank, taking 12g of menbutone, dissolving the menbutone in 1L of methanol, wherein the concentration of feed liquid is 12mg/ml, and cooling a cooler to 0-5 ℃. Opening of CO2Steel cylinder into the second feeding tankIntroducing CO2And (5) after the gas is balanced, starting a high-pressure metering pump to pressurize to 10Mpa, so that the whole system is filled with carbon dioxide liquid. The preheating device is turned on, the preheater is set to be 37 ℃, and the menbutone solution is preheated. And opening discharge port valves of the first feeding tank and the second feeding tank simultaneously to enable the preheated menbutone solution to be injected into the nozzle according to a certain flow rate and to be contacted with carbon dioxide liquid at the nozzle, wherein the inner diameter of the nozzle is 0.1mm, and the length-diameter ratio of the nozzle is 4. When liquid carbon dioxide is contacted with the solution and sprayed out through the nozzle, supercritical carbon dioxide is formed, rapid mutual mass transfer occurs, and a large amount of menbutone crystal forms are separated out. In the process of mutual mass transfer, the methanol is changed from liquid to gas, the dissolving capacity for the menbutone is reduced, and the menbutone solution becomes supersaturated. After the whole process is finished, continuously introducing supercritical CO2 Taking away residual methanol solvent after 30min, and determining the obtained menbutone crystal form to have the particle size distribution D90 of 2.7um by a particle size analyzer. The results show form i with a crystallinity of 68%.
Comparative example 3
In a first feeding tank, 28g of menbutone is taken and dissolved in 1L of dichloromethane, the concentration of feed liquid is 28mg/ml, and a cooler is cooled to 0-5 ℃. Opening of CO2Steel cylinder, introducing CO into the second feeding tank2And (5) after the gas is balanced, starting a high-pressure metering pump to pressurize to 11Mpa, so that the whole system is filled with carbon dioxide liquid. The preheating device is turned on, the preheater is set to be 37 ℃, and the menbutone solution is preheated. And opening discharge port valves of the first feeding tank and the second feeding tank simultaneously to enable the preheated menbutone solution to be injected into the nozzle according to a certain flow rate and to be contacted with carbon dioxide liquid at the nozzle, wherein the inner diameter of the nozzle is 0.1mm, and the length-diameter ratio of the nozzle is 5. When liquid carbon dioxide is contacted with the solution and sprayed out through the nozzle, supercritical carbon dioxide is formed, rapid mutual mass transfer occurs, and a large amount of menbutone crystal forms are separated out. In the process of mutual mass transfer, the dichloromethane is changed from liquid to gaseous state, the dissolving capacity for menbutone is reduced, and the menbutone solution becomes supersaturated. After the whole process is finished, continuously introducing supercritical CO2Taking away residual dichloromethane solvent after 30min, and determining the obtained menbutone crystal form by a particle size analyzer to obtain a particle size distribution D90 of 2.3 mu m. The results are shownShown as form II (CN 104370734A), the crystallinity was 73%.
Example 4
The stability of the obtained menbutone crystal form I is researched, and an illumination, high temperature and high humidity influence factor experiment and an acceleration experiment are respectively carried out, wherein the experimental result and data statistics are as follows:
TABLE 1 stability test under light, high temperature, high humidity conditions
TABLE 2 accelerated stability test
According to the above experimental data, it can be seen that the menbutone crystal form i has a smaller content variation during the stability study period compared with the CN104370734A crystal form ii and amorphous menbutone, which indicates that the menbutone crystal form i obtained by the present invention has better stability.
Example 5 drug dissolution effect test
By means of a comparative study of the solubility of crystalline menbutone form i in water, the results are given in the following table:
TABLE 3 solubility test
From the table above it can be seen that the solubility of crystalline form i of montmonillonone in water at 0-20 ℃ is significantly greater than that of the amorphous form of montmonillonone and the crystalline form ii of the comparative example.
Experimental example 6 formulation influencing factors test sample 1: the menbutone powder prepared in form i of formulation example 1 according to the invention was used. Test sample 2: the menbutone powder prepared in comparative example form ii was used. Test sample 3: menbutone powder prepared by using amorphous menbutone raw material.
Test sample 4: the menbutone injection prepared from the formulation of the invention, example 1, form i, was used. Test sample 5: the menbutone injection prepared in comparative example form ii was used. Test sample 6: menbutone injection prepared by using amorphous menbutone raw material.
The compositions of the powders in the test products 1-3 were menbutone powder accounting for 10% of the mass of the powder and starch accounting for 90%.
The compositions of the injections in the test articles 4 to 6 were: the 100mL injection consists of the following components: 10g of menbutone, 5.5g of diethanolamine, 0.2g of chlorocresol, 0.2g of sodium metabisulfite or sodium sulfite, 0.2g of edetic acid and the balance of water for injection.
The test samples 1, 2 and 3 were subjected to the influence factor test of 4500 ± 500Lux, 60 ℃ high temperature and 92.5% high humidity RH (10 days) and the test of the dissolution rate of the test samples 4, 5 and 6 in water, respectively, and the test results and data statistics are as follows:
TABLE 4 stability influencing factor test results for menbutone powder
TABLE 5 dissolution Rate test of Monbunone injection
From the above results, it was found that the stability and the water solubility of the injection containing the crystalline form i of menbutone of the present invention are superior to those of the comparative crystalline form ii and amorphous menbutone.
Claims (9)
1. Crystalline form i of montobulone having an XRPD pattern with derivative peaks at 2 Θ =7.14, 12.04, 12.5, 14.1, 14.4, 16.7, 18.4, 21.4, 21.6, 22.9, 23.7, 25.1, 26.8, 27.9, 29.0, 38.7, 41.0 with an error in the 2 Θ value in the range of 0.2.
2. A process for the preparation of crystalline menbutone form i according to claim 1, using supercritical fluid technology, comprising the following specific steps:
(1) putting a menbutone raw material into a first feeding tank, adding acetone for dissolving, and then cooling to obtain a menbutone solution;
(2) introducing CO into the second feeding tank2After the gas is balanced, a high-pressure metering pump is started to pressurize, so that the whole system is filled with carbon dioxide liquid, and the balance is to fill the whole system with liquid CO2If there is gaseous CO2The pressure will change when CO2From liquid to gaseous state, the process of this phase change forms supercritical CO2；
(3) Opening a preheating device to raise the temperature to a preheating temperature, and preheating the menbutone solution;
(4) simultaneously opening discharge port valves of the first feeding tank and the second feeding tank to enable the preheated menbutone solution to be in contact with the carbon dioxide liquid at a nozzle;
(5) when liquid carbon dioxide is contacted with the solution and sprayed out through a nozzle, supercritical carbon dioxide is formed, rapid mutual mass transfer occurs, and a large amount of menbutone crystal form I is separated out; in the mutual mass transfer process, the acetone is changed from liquid state to gas state, the dissolving capacity for the menbutone is reduced, and the menbutone solution is in a supersaturated state;
(6) continuously introducing supercritical CO2Removing residual acetone solvent and obtaining the menbutone crystal form I in a settling chamber.
3. The preparation method according to claim 2, wherein the concentration of the menbutone raw material and acetone in step (1) is 10-30 mg/ml; after the menbutone raw material in the step (1) is dissolved in acetone, the temperature is reduced to 0-5 ℃.
4. The method according to claim 2, wherein the preheating temperature in the step (3) is 33 to 40 ℃.
5. The preparation method according to claim 2, wherein the high pressure metering pump is started to pressurize in the step (2), and the pressure is increased to 9-12 MPa.
6. The method according to claim 2, wherein the nozzle in step (4) has an inner diameter of 0.1mm and an aspect ratio of 3 to 8, and the menbutone solution is injected into the nozzle at a flow rate of 1 to 5 g/min.
7. The method of claim 2, wherein supercritical CO is used in step (4)2The flow-in time of (2) was 30 min.
8. A pharmaceutical composition comprising crystalline menbutone form I according to any one of claims 1 to 7.
9. The pharmaceutical composition of claim 8, further comprising one or more pharmaceutically acceptable carriers and/or excipients.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104370734A (en) * | 2014-11-19 | 2015-02-25 | 西南大学 | Improved synthesis method of menbutone |
| CN112047831A (en) * | 2020-10-14 | 2020-12-08 | 天津市中升挑战生物科技有限公司 | Monbunone crystallization process, single crystal and culture method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104370734A (en) * | 2014-11-19 | 2015-02-25 | 西南大学 | Improved synthesis method of menbutone |
| CN112047831A (en) * | 2020-10-14 | 2020-12-08 | 天津市中升挑战生物科技有限公司 | Monbunone crystallization process, single crystal and culture method thereof |
Non-Patent Citations (1)
| Title |
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| "新型结晶技术研究进展";赵途等;《无机盐工业》;20170430;第49卷(第4期);第14页右栏第1-2段 * |
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Effective date of registration: 20220214 Address after: 300300 No. 6 Liujing Road, Dongli Development Zone, Dongli District, Tianjin Patentee after: RINGPU (TIANJIN) BIO-PHARMACY Co.,Ltd. Address before: No.1, Dongjiu Road, Tianjin Binhai New Area pilot free trade zone (Airport Economic Zone), 300450 Patentee before: TIANJIN RINGPU BIO-TECHNOLOGY Co.,Ltd. Patentee before: Ruipu (Tianjin) biopharmaceutical Co., Ltd |