CN111039782A - Crystal form of 2- [4- [ (E) - (2-ketocyclohexenyl) methyl ] phenyl ] propionic acid and preparation method thereof - Google Patents
Crystal form of 2- [4- [ (E) - (2-ketocyclohexenyl) methyl ] phenyl ] propionic acid and preparation method thereof Download PDFInfo
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- CN111039782A CN111039782A CN201911362702.3A CN201911362702A CN111039782A CN 111039782 A CN111039782 A CN 111039782A CN 201911362702 A CN201911362702 A CN 201911362702A CN 111039782 A CN111039782 A CN 111039782A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
- C07C65/38—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups having unsaturation outside the aromatic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- 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
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Abstract
The invention discloses a novel crystal form of 2- [4- [ (E) - (2-ketocyclohexenyl) methyl ] phenyl ] propionic acid, and fills the blank of no crystal form report at present. And the crystal form is not easy to absorb moisture and is stable under high temperature and high humidity conditions, so that the safety of the medicine is further improved, and the subsequent preparation process is facilitated.
Description
Technical Field
The invention belongs to the field of medicine synthesis, and particularly relates to a crystal form of 2- [4- [ (E) - (2-ketocyclohexenyl) methyl ] phenyl ] propionic acid and a preparation method thereof.
Background
Pelubiprofen (Pelubiprofen), also known as Pelubiprofen, is chemically 2- [4- [ (E) - (2-ketocyclohexenyl) methyl]Phenyl radical]Propionic acid, CAS No.: 69956-77-0, is divided intoSub-formula is C16H18O3Molecular weight of 258.32, and structural formula shown in the following formula
Pelubiprofen is a non-steroidal analgesic and anti-inflammatory agent (NSAIDs) and is derived from the 2-phenylpropionic acid intermediate, and is therefore a member of the 2-arylpropionic acid family, which is also a racemic prodrug with analgesic and anti-inflammatory effects. Pelubiprofen is reported to have a higher pharmacological action and tolerability than other non-steroidal anti-inflammatory analgesic antipyretics such as loxoprofen, ketoprofen, ibuprofen, and naproxen. The results of phase III clinical trials comparing the efficacy and safety of pelubiprofen and celecoxib in patients with rheumatoid arthritis indicate that pelubiprofen is equivalent in efficacy to celecoxib in terms of pain relief and rheumatoid arthritis patient stiffness relief.
Pelubiprofen is a non-steroidal anti-inflammatory drug (NSAIDs), a prodrug of 2-aryl propionic acids, and has a relatively selective effect on cyclooxygenase-2 activity. Molecular mechanistic studies of inflammatory mediators in rat models of LPS-induced macrophages and carrageenan-induced acute inflammation indicate that pelubiprofen participates in dual inhibition of COX activity and the TAK1-IKK-NF-kB pathway, revealing the molecular basis for the anti-inflammatory properties of pelubiprofen.
The 4 metabolites of pelubiprofen included saturated ketone (M-a), unsaturated alcohol (M-B), cis-alcohol (M-C) and trans-alcohol (M-D). the main metabolites in human plasma were M-B, M-C and M-D, with half-lives (t 1/2) of 0.9, 2.6 and 1.2h, respectively, the total recovery of urine was 26% of the dose, but the change in CS-670 was less than 2% within 48 h.
The pelubiprofen compounds were first disclosed in Japanese patent registration No. 1167548 (Japanese patent application No. 1977-14298121) and Japanese patent registration No. 1637767 (Japanese patent application No. 1984-142567). Many documents are reported on the synthetic route of the pelubiprofen compound, but no relevant report is made on the crystal form of the pelubiprofen and the preparation method of the pelubiprofen. The patent US4254274 for preparing the pelubiprofen primary research compound does not mention related technologies, but white crystals are obtained in the examples, the solidification crystallization temperature is 106-108 ℃, related powder diffraction patterns are not disclosed, domestic patents and documents do not disclose related data of the pelubiprofen crystal form and a preparation method of the crystal form, and in consideration of important influences of different crystal forms on the physicochemical properties and the like of the compound, in order to obtain more effective crystal forms, the crystallization behavior of the pelubiprofen needs to be comprehensively considered, so that favorable crystal forms meeting the production requirements of preparations and the like are obtained.
Disclosure of Invention
The main purpose of the present application is to provide a crystal form of 2- [4- [ (E) - (2-ketocyclohexenyl) methyl ] phenyl ] propionic acid, which is called as crystal form I because no related record about the crystal form of pelubiprofen exists in the prior art, and after research, the inventors of the present application found that the crystal form satisfies various requirements in the pharmaceutical field, and is a crystal substance with favorable properties.
In the field of pharmaceutical formulations, the pharmaceutically active substance should have a high stability, which is to be ensured even under different circumstances, including stability during the processing of the pharmaceutical composition and stability of the final storage form of the pharmaceutical composition. In addition, moisture absorption reduces the content of pharmaceutically active substances, since absorption of moisture causes an increase in weight. Therefore, care should be taken to protect moisture during storage of hygroscopic drugs, and moisture absorption may reduce the content of the active substance if it is exposed to an environment that is not protected from moisture in any way during the manufacturing process.
The application provides a crystal form I of 2- [4- [ (E) - (2-ketocyclohexenyl) methyl ] phenyl ] propionic acid, which can also be called as a crystal form I of pelubiprofen, and the structural formula of the crystal form I is as follows:
the crystal form I has characteristic peaks at 8.4 +/-0.2 degrees, 12.0 +/-0.2 degrees, 15.7 +/-0.2 degrees, 19.8 +/-0.2 degrees, 24.2 +/-0.2 degrees, 26.7 +/-0.2 degrees and 29.3 +/-0.2 degrees in an X-ray powder diffraction pattern expressed by 2 theta angles by using Cu-K α for radiation.
Furthermore, the crystal form I has characteristic peaks at 8.4 +/-0.2 degrees, 12.0 +/-0.2 degrees, 15.7 +/-0.2 degrees, 19.8 +/-0.2 degrees, 24.2 +/-0.2 degrees, 26.7 +/-0.2 degrees, 29.3 +/-0.2 degrees, 13.0 +/-0.2 degrees, 16.3 +/-0.2 degrees, 20.3 +/-0.2 degrees, 21.1 +/-0.2 degrees, 22.1 +/-0.2 degrees, 25.5 +/-0.2 degrees, 27.7 +/-0.2 degrees and 28.5 +/-0.2 degrees in an X-ray powder diffraction pattern expressed by using Cu-K α radiation and 2 theta angles.
Furthermore, the crystal form I has characteristic peaks at 8.4 + -0.2 °, 12.0 + -0.2 °, 15.7 + -0.2 °, 19.8 + -0.2 °, 24.2 + -0.2 °, 26.7 + -0.2 °, 29.3 + -0.2 °, 13.0 + -0.2 °, 16.3 + -0.2 °, 20.3 + -0.2 °, 21.1 + -0.2 °, 22.1 + -0.2 °, 25.5 + -0.2 °, 27.7 + -0.2 °, 28.5 + -0.2 °, 23.0 + -0.2 °, 23.7 + -0.2 °, 25.8 + -0.2 °, 27.1 + -0.2 °, 28.2 + -0.2 °, 33.6 + -0.2 °, 39.2 + -0.2 °, 40.2 + -0.2 ° and 40.6 + -0.2 ° in an X-ray powder diffraction pattern expressed by 2 theta angle using Cu-K α radiation.
The relative intensities of the characteristic peaks of the crystal form I in terms of 2 theta angle of X-ray powder diffraction when irradiated with Cu-K α are shown in the following table:
the pattern of X-ray powder diffraction of form I is shown in FIG. 1, and the DSC-TGA pattern obtained by differential scanning thermal analysis of form I is shown in FIG. 3, and the melting point is 122.9 ℃.
The crystal form I has a moisture content in the range of 0.01 to 0.5%, and a purity of 95% by weight or more, preferably 98% by weight or more, and most preferably 99% by weight or more.
Another objective of the present application is to provide a preparation method of the crystalline form I of pelubiprofen, which comprises mixing powdered pelubiprofen and a solvent together, then heating and stirring, then cooling and crystallizing, filtering, and vacuum drying to obtain the pelubiprofen crystals in a slightly yellowish or yellowish solid state.
Another object of the present application is to provide a pharmaceutical composition prepared from the compound, which comprises the crystalline form I of pelubiprofen and a pharmaceutically acceptable carrier. The composition can be prepared into any pharmaceutically acceptable dosage form, including tablets, capsules, cataplasm and the like.
The present application uses commercially available amorphous pelubiprofen as a starting material, which is dissolved and recrystallized to obtain form I having characteristic peaks at 8.4 °, 12.0 °, 15.7 °, 19.8 °, 24.2 °, 26.7 °, and 29.3 ° in an X-ray powder diffraction pattern expressed by 2 θ ± 0.2 ° angles, wherein the characteristic peaks at both 12.0 ° and 15.7 ° are strong peaks. The prepared crystalline form I of pelubiprofen has high solubility in organic solvents such as acetone, ethyl acetate and the like, is difficult to absorb moisture and has good stability, and DSC-TGA and element analysis show that the crystalline form does not contain crystal water and is an anhydrous crystalline form.
The beneficial effect of this application lies in:
the novel crystal form of the 2- [4- [ (E) - (2-ketocyclohexenyl) methyl ] phenyl ] propionic acid prepared by the application fills the blank of no crystal form report at present. And the crystal form is not easy to absorb moisture and is stable under high temperature and high humidity conditions, so that the safety of the medicine is further improved, and the subsequent preparation process is facilitated.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of form I prepared in example 1;
FIG. 2 is an X-ray powder diffraction pattern of form I prepared in example 2;
figure 3 is a DSC-TGA profile of form I prepared in example 1;
FIG. 4 is a substance-related detection pattern of the crystalline form I prepared in example 1 after 10 days of high temperature;
FIG. 5 is a substance-related detection spectrum of the crystalline form I prepared in example 1 after 10 days of high humidity;
FIG. 6 is a substance profile of form I prepared in example 1 after being irradiated for 10 days.
Detailed Description
The present application is described in further detail below with reference to specific embodiments and the attached drawings. The following examples are intended to be illustrative of the present application only and should not be construed as limiting the present application.
Example 1 preparation of crystalline form I of pelubiprofen
The instrument model and the reagent test conditions were as follows:
reagent: acetone, purity 99.5%, manufacturer: hunan Huihu Rainbow reagent, Inc.; reagent: ethyl acetate grade: AR, manufacturer: lake south Vietnam Rainbow reagent Co Ltd
The instrument comprises the following steps: liquid chromatograph, model Acquity Arc System, manufacturer Waters; electronic analytical balance, model Ms205Du, manufacturer: the mertler.
XRD powder X-ray diffraction patterns of various polycrystalline substances were measured by a D/MAX-RB X-ray diffractometer using Cu-K α beam (2 theta degrees).
TG/DSC-Shimadzu DSC-40M (model); the heating rate is 10 ℃/min, the nitrogen atmosphere, the flow is 40 ml/min.
XRD-powder diffraction test unit is: the important laboratory of the department of nonferrous metals education of the university of China and south;
DSC-TGA test unit is: the important laboratory of the department of nonferrous metals education of the university of China and south;
the preparation method comprises the following steps:
adding 100g of pelubiprofen powder into a reaction kettle, adding 200g of acetone, heating to 40 ℃, stirring for 4h, crystallizing at 0 ℃, stirring for 12h, filtering, and vacuum drying at 30 ℃ to obtain 70g of a product.
The obtained crystalline form I of pelubiprofen was subjected to XRD-powder diffraction test, and the relative intensities of the characteristic peaks of X-ray powder diffraction expressed in terms of 2 θ angles are shown in the following table:
as shown in particular in figure 1.
DSC-TGA test is carried out on the obtained crystalline form I of the pelubiprofen, and the crystalline form I of the pelubiprofen has a single peak at 122.9 ℃ and is a melting endothermic peak; TGA: the crystal form I of the pelubiprofen is stable at the temperature of less than 230 ℃, starts to decompose at 230-250 ℃, and quickly decomposes at the temperature of more than 250 ℃. The results of the specific DSC test and TGA test are shown in figure 3. Carrying out elemental analysis on the obtained pelubiprofen crystal form I:
elemental analysis: c16H18O3
The molecular formula of pelubiprofen is C16H18O3Calculating the value: h: 6.98 percent; 74.42 percent of C; 18.60 percent of O; measurement value of pelubiprofen precipitated crystal powder: 7.02 percent of H; 74.40 percent of C; 15.58 percent of O.
Example 2 preparation of crystalline form I of pelubiprofen
The experimental apparatus and conditions were the same as in example 1, and the solvent was changed to ethyl acetate.
The preparation method comprises the following steps:
adding 100g of pelubiprofen powder into a reaction kettle, adding 200g of ethyl acetate, heating to 40 ℃, stirring for 4h, crystallizing at-2 ℃, stirring for 12h, filtering, and vacuum drying at 30 ℃ to obtain 75g of a product.
XRD-powder diffraction test and DSC-TGA test are carried out on the prepared crystalline form I of the pelubiprofen, and the detection result is shown in figure 2, and the crystalline form is the same as the crystalline form obtained in example 1.
Example 3 preparation of crystalline form I of pelubiprofen
The experimental apparatus and conditions were the same as in example 1, and the solvent was replaced by dichloromethane.
The preparation method comprises the following steps:
adding 100g of pelubiprofen powder into a reaction kettle, adding 200g of dichloromethane, heating to 33 ℃, stirring for 4h, crystallizing at-3 ℃, stirring for 12h, filtering, and vacuum drying at 30 ℃ to obtain 80g of a product.
The prepared crystalline form I of the pelubiprofen to be obtained is subjected to XRD-powder diffraction test and DSC-TGA test, and is found to be the same crystalline form as the crystalline form obtained in example 1.
Example 4 preparation of crystalline form I of pelubiprofen
The experimental apparatus and conditions were the same as in example 1, and the solvent was replaced with tetrahydrofuran.
The preparation method comprises the following steps:
adding 100g of pelubiprofen powder into a reaction kettle, adding 200g of tetrahydrofuran, heating to 18 ℃, stirring for 4h, crystallizing at-5 ℃, stirring for 12h, filtering, and vacuum drying at 30 ℃ to obtain 60g of a product.
The prepared crystalline form I of the pelubiprofen to be obtained is subjected to XRD-powder diffraction test and DSC-TGA test, and is found to be the same crystalline form as the crystalline form obtained in example 1.
Example 5 preparation of crystalline form I of pelubiprofen
The experimental apparatus and conditions were the same as in example 1, and the solvent was replaced by ethanol.
The preparation method comprises the following steps:
adding 100g of pelubiprofen powder into a reaction kettle, adding 200g of ethanol, heating to 50 ℃, stirring for 4h, crystallizing at-4 ℃, stirring for 12h, filtering, and vacuum drying at 30 ℃ to obtain 68g of a product.
The prepared crystalline form I of the pelubiprofen to be obtained is subjected to XRD-powder diffraction test and DSC-TGA test, and is found to be the same crystalline form as the crystalline form obtained in example 1.
Example 6 preparation of crystalline form I of pelubiprofen
The experimental apparatus and conditions were the same as in example 1, and the solvent was replaced with toluene.
The preparation method comprises the following steps:
adding 100g of pelubiprofen powder into a reaction kettle, adding 200g of toluene, heating to 60 ℃, stirring for 4h, crystallizing at-3 ℃, stirring for 12h, filtering, and vacuum drying at 30 ℃ to obtain 85g of a product.
The prepared crystalline form I of the pelubiprofen to be obtained is subjected to XRD-powder diffraction test and DSC-TGA test, and is found to be the same crystalline form as the crystalline form obtained in example 1.
Example 7 preparation of crystalline form I of pelubiprofen
The experimental apparatus and conditions were the same as in example 1, and the solvent was replaced with methyl t-butyl ether.
The preparation method comprises the following steps:
adding 100g of pelubiprofen powder into a reaction kettle, adding 200g of methyl tert-butyl ether, heating to 55 ℃, stirring for 4h, then crystallizing at-5 ℃, stirring for 12h, filtering, and vacuum drying at 30 ℃ to obtain 82g of a product.
The prepared crystalline form I of the pelubiprofen to be obtained is subjected to XRD-powder diffraction test and DSC-TGA test, and is found to be the same crystalline form as the crystalline form obtained in example 1.
Example 8 preparation of crystalline form I of pelubiprofen
The experimental apparatus and conditions were the same as in example 1, and the solvent was changed to acetonitrile.
The preparation method comprises the following steps:
adding 100g of pelubiprofen powder into a reaction kettle, adding 200g of acetonitrile, heating to 40 ℃, stirring for 4h, crystallizing at-5 ℃, stirring for 12h, filtering, and vacuum drying at 30 ℃ to obtain 78g of a product.
The prepared crystalline form I of the pelubiprofen to be obtained is subjected to XRD-powder diffraction test and DSC-TGA test, and is found to be the same crystalline form as the crystalline form obtained in example 1.
Example 9 determination of the Properties of crystalline form I of pelubiprofen
1. Chemical stability experiment of pelubiprofen crystal I
Test samples: crystal I
A. High temperature test
High temperature conditions: placing the mixture at 60 ℃ in an open air.
The results are as follows:
B. high humidity test
High humidity conditions: RH 75%, open mouth.
The results are as follows:
from the comparison of the change rates of the above indexes, it can be seen that the crystal is relatively stable under high temperature or high humidity conditions, and the specific detection spectra are shown in fig. 4 to 5.
C. Light test
The illumination condition is as follows: total illumination intensity is 1.2X 106Lux, 25 ℃, near ultraviolet energy is not less than 200 w.hr/m, RH is 60%, and the product is left open.
Under the condition of illumination, impurities are increased, the pelubiprofen crystal I is not easy to stabilize under ultraviolet light and is likely to generate configuration conversion, and the exposure to strong light should be avoided, and a specific detection map is shown in fig. 6.
D. Evaluation of solubility of pelubiprofen
Through tests, the pelubiprofen crystal I obtained in example 1 is easily soluble in ethanol, N-dimethylformamide, acetonitrile and acetone, slightly soluble in absolute ethanol and diethyl ether, almost insoluble in water and soluble in 0.1mol/L sodium hydroxide (4.3 g prepared into 1000 ml) solution.
The foregoing is a more detailed description of the present application in connection with specific embodiments thereof, and it is not intended that the present application be limited to the specific embodiments thereof. For those skilled in the art to which the present application pertains, several simple deductions or substitutions may be made without departing from the concept of the present application, and all should be considered as belonging to the protection scope of the present application.
Claims (9)
- A crystal form of 2- [4- [ (E) - (2-ketocyclohexenyl) methyl ] phenyl ] propionic acid, which is crystal form I, characterized in that it has characteristic peaks at 8.4 + -0.2 °, 12.0 + -0.2 °, 15.7 + -0.2 °, 19.8 + -0.2 °, 24.2 + -0.2 °, 26.7 + -0.2 °, 29.3 + -0.2 ° in an X-ray powder diffraction pattern expressed in terms of 2 θ angle using Cu-K α radiation.
- 2. The crystalline form of claim 1, having characteristic peaks, expressed in terms of 2 Θ angle, at 13.0 ± 0.2 °, 16.3 ± 0.2 °, 20.3 ± 0.2 °, 21.1 ± 0.2 °, 22.1 ± 0.2 °, 25.5 ± 0.2 °, 27.7 ± 0.2 °, 28.5 ± 0.2 ° in an X-ray powder diffraction pattern.
- 3. The crystalline form of claim 1 or 2, having characteristic peaks, expressed in terms of 2 Θ angles, at 23.0 ± 0.2 °, 23.7 ± 0.2 °, 25.8 ± 0.2 °, 27.1 ± 0.2 °, 28.2 ± 0.2 °, 33.6 ± 0.2 °, 39.2 ± 0.2 °, 40.2 ± 0.2 °, 40.6 ± 0.2 ° in an X-ray powder diffraction pattern.
- 4. The crystalline form of claim 1, wherein the relative intensity of the peak at diffraction angles 2 Θ of 12.0 ± 0.2 ° is greater than 99.5%.
- 5. The crystalline form of claim 1, wherein the melting point in DSC is 122.9 ℃.
- 6. A method of preparing a composition of 2- [4- [ (E) - (2-ketocyclohexenyl) methyl ] phenyl ] propanoic acid wherein a portion of 2- [4- [ (E) - (2-ketocyclohexenyl) methyl ] phenyl ] propanoic acid is present as form I, characterized by having characteristic peaks at 8.4 ± 0.2 °, 12.0 ± 0.2 °, 15.7 ± 0.2 °, 19.8 ± 0.2 °, 24.2 ± 0.2 °, 26.7 ± 0.2 °, 29.3 ± 0.2 ° in an X-ray powder diffraction pattern expressed in terms of 2 Θ using radiation of Cu-K α, the method comprising crystallizing 2- [4- [ (E) - (2-ketocyclohexenyl) methyl ] phenyl ] propanoic acid from a solvent system selected from the group consisting of (I) acetone, (ii) tetrahydrofuran, (iii) ethyl acetate, (iv) dichloromethane, (v) methyl tert-butyl ether, (vi) ethanol, (vii) toluene, (viii) acetonitrile.
- 7. A method of preparing a composition of 2- [4- [ (E) - (2-ketocyclohexenyl) methyl ] phenyl ] propanoic acid wherein a portion of 2- [4- [ (E) - (2-ketocyclohexenyl) methyl ] phenyl ] propanoic acid is present as form I, characterized by having characteristic peaks at 13.0 ± 0.2 °, 16.3 ± 0.2 °, 20.3 ± 0.2 °, 21.1 ± 0.2 °, 22.1 ± 0.2 °, 25.5 ± 0.2 °, 27.7 ± 0.2 °, 28.5 ± 0.2 ° in an X-ray powder diffraction pattern expressed in terms of 2 Θ using radiation of Cu-K α, comprising crystallizing 2- [4- [ (E) - (2-ketocyclohexenyl) methyl ] phenyl ] propanoic acid from a solvent system selected from the group consisting of (I) acetone, (ii) tetrahydrofuran, (iii) ethyl acetate, (iv) dichloromethane, (v) methyl tert-butyl ether, (vi) ethanol, (vii) acetonitrile.
- 8. A method of preparing a composition of 2- [4- [ (E) - (2-ketocyclohexenyl) methyl ] phenyl ] propanoic acid wherein a portion of 2- [4- [ (E) - (2-ketocyclohexenyl) methyl ] phenyl ] propanoic acid is present as form I, characterized by having characteristic peaks at 23.0 ± 0.2 °, 23.7 ± 0.2 °, 25.8 ± 0.2 °, 27.1 ± 0.2 °, 28.2 ± 0.2 °, 33.6 ± 0.2 °, 39.2 ± 0.2 °, 40.2 ± 0.2 °, 40.6 ± 0.2 ° in an X-ray powder diffraction pattern expressed in terms of 2 Θ using Cu-K α radiation, the method comprising crystallizing 2- [4- [ (E) - (2-ketocyclohexenyl) methyl ] phenyl ] propanoic acid from a solvent system selected from the group consisting of (I) acetone, (ii) tetrahydrofuran, (iii) ethyl acetate, (iv) dichloromethane, (v) methyl (vi) ethanol, (vii) toluene tert-butyl ether.
- 9. Use of a method according to any one of claims 6 to 8 in the preparation of a pharmaceutical crystalline form.
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| PCT/CN2020/138563 WO2021129651A1 (en) | 2019-12-26 | 2020-12-23 | 2-[4-[(e)-(2-ketocyclohexenyl)methyl]phenyl]propionic acid crystal form and preparation method therefor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4673761A (en) * | 1984-07-10 | 1987-06-16 | Sankyo Company, Limited | Process for preparing anti-inflammatory cycloalkylidenemethylphenylacetic acid derivatives |
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| CN111039782A (en) * | 2019-12-26 | 2020-04-21 | 湖南九典制药股份有限公司 | Crystal form of 2- [4- [ (E) - (2-ketocyclohexenyl) methyl ] phenyl ] propionic acid and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4673761A (en) * | 1984-07-10 | 1987-06-16 | Sankyo Company, Limited | Process for preparing anti-inflammatory cycloalkylidenemethylphenylacetic acid derivatives |
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| 吕扬 等: "《晶型药物》", 31 October 2009, 人民卫生出版社 * |
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