CN113173853A - Flurbiprofen axetil crystal and preparation method thereof - Google Patents
Flurbiprofen axetil crystal and preparation method thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/62—Halogen-containing esters
- C07C69/65—Halogen-containing esters of unsaturated acids
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
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- 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 provides a flurbiprofen axetil crystal and a preparation method thereof, and particularly provides a flurbiprofen axetil crystal form I which is characterized in that characteristic peaks exist at positions of 14.2 degrees +/-0.2 degrees, 16.3 degrees +/-0.2 degrees, 16.6 degrees +/-0.2 degrees, 17.5 degrees +/-0.2 degrees, 18.1 degrees +/-0.2 degrees, 21.8 degrees +/-0.2 degrees, 22.3 degrees +/-0.2 degrees, 23.9 degrees +/-0.2 degrees, 25.6 degrees +/-0.2 degrees and 26.3 degrees +/-0.2 degrees by X-ray diffraction powder diffraction. The invention also discloses a preparation method of the flurbiprofen axetil crystal. The preparation method is simple, and has potential development and application values in the fields of industrial manufacture and pharmaceutical preparation of flurbiprofen axetil.
Description
Technical Field
The invention relates to a crystal form of flurbiprofen axetil and a preparation method thereof, in particular to a crystal form I of flurbiprofen axetil and a preparation method thereof.
Background
Flurbiprofen axetil is a prodrug of flurbiprofen and is used for post-surgery and for the analgesia of various cancers. It reduces the hyperalgesic state of surgery induced by trauma by inhibiting Cyclooxygenase (COX) in the spinal cord and periphery to decrease prostaglandin synthesis. Common dosage forms include injection and lipid microspheres. The lipid microsphere preparation has the advantages of stronger drug effect, quicker response, longer duration and difficult adverse reactions such as gastric mucosa injury and the like. Compared with other analgesic drugs, the flurbiprofen axetil has the advantages of no central inhibition effect, no influence on the recovery of a patient in an anesthetic state, and immediate use after operation.
Flurbiprofen axetil was jointly developed by japan scientific pharmaceutical company and green cross corporation, and was marketed in 1992 on the day and 2004 in china. Compared with flurbiprofen, the composition can avoid gastrointestinal dysfunction and other adverse reactions, and has the advantages of shortened onset time, enhanced drug effect, etc. The good market prospect arouses the attention of a plurality of enterprises to the variety and increases the research and development of the product.
Since flurbiprofen axetil is a low-melting-point drug, only oily liquid can be obtained in the prior art, and no report on flurbiprofen axetil crystals exists at present, the flurbiprofen axetil is purified by column chromatography or molecular distillation, such as patents CN104649906A and CN 103012144B. Although these methods can remove impurities, they are expensive and complicated in steps, and therefore, development of a new purification method is required.
In view of the above, there is an urgent need in the art to develop a novel method for purifying flurbiprofen axetil.
Disclosure of Invention
The invention aims to provide a method for obtaining high-purity flurbiprofen axetil.
It is another object of the present invention to provide a novel solid state form of flurbiprofen axetil.
The invention provides a flurbiprofen axetil crystal form I, wherein the X-ray diffraction powder diffraction of the crystal form I has characteristic peaks at 14.2 degrees +/-0.2 degrees, 16.3 degrees +/-0.2 degrees, 16.6 degrees +/-0.2 degrees, 17.5 degrees +/-0.2 degrees, 18.1 degrees +/-0.2 degrees, 21.8 degrees +/-0.2 degrees, 22.3 degrees +/-0.2 degrees, 23.9 degrees +/-0.2 degrees, 25.6 degrees +/-0.2 degrees and 26.3 degrees +/-0.2 degrees.
In another preferred embodiment, the crystalline form I of flurbiprofen axetil further has one or more characteristic peaks selected from the group consisting of: 9.9 degrees +/-0.2 degrees, 10.7 degrees +/-0.2 degrees, 11.3 degrees +/-0.2 degrees, 13.2 degrees +/-0.2 degrees, 19.0 degrees +/-0.2 degrees, 19.6 degrees +/-0.2 degrees, 20.1 degrees +/-0.2 degrees, 25.6 degrees +/-0.2 degrees, 28.3 degrees +/-0.2 degrees, 29.7 degrees +/-0.2 degrees and 30.8 degrees +/-0.2 degrees.
In another preferred embodiment, the crystalline form I of flurbiprofen axetil has characteristic peaks at 9.9 ° ± 0.2 °, 10.7 ° ± 0.2 °, 11.3 ° ± 0.2 °, 13.2 ° ± 0.2 °, 14.2 ° ± 0.2 °, 16.3 ° ± 0.2 °, 16.6 ° ± 0.2 °, 17.5 ° ± 0.2 °, 18.1 ° ± 0.2 °, 19.0 ° ± 0.2 °, 19.6 ° ± 0.2 °, 20.1 ° ± 0.2 °, 21.8 ° ± 0.2 °, 22.3 ° ± 0.2 °, 23.9 ° ± 0.2 °, 25.6 ° ± 0.2 °, 26.3 ° ± 0.2 °, 28.3 ° ± 0.2 °, 29.7 ° ± 0.2 °, 30.8 ° ± 0.2 °.
In another preferred embodiment, the X-ray powder diffraction is measured under CuK α radiation.
In another preferred embodiment, the X-ray powder diffraction is expressed by 2 theta angle.
In another preferred embodiment, the flurbiprofen axetil crystal form I has X-ray diffraction powder characteristic peaks shown in table II.
In another preferred embodiment, the flurbiprofen axetil crystal form I has a powder X-ray diffraction pattern as listed in fig. 2.
In another preferred embodiment, the melting point of form I is 36 ± 3 ℃.
In another preferred embodiment, the infrared spectrum of form I has one or more absorption peaks selected from the group consisting of: 442. 466, 488, 509, 580, 737, 841, 913, 938, and 1754 in wavelengths cm-1And (4) showing.
In another preferred embodiment, the absorption peak transmittance of the infrared spectrum of the crystal form I is expressed by percentage as follows: 58. 59, 54, 65, 54, 62, 52, 55, 34, 10.
The invention provides a preparation method of a flurbiprofen axetil crystal form I, which is characterized by comprising the following steps:
(a) adding a flurbiprofen axetil melt or crystal into a first solvent and forming a uniform dispersion mixture;
(b) adding flurbiprofen axetil crystal form I to the mixture obtained in step (a) as a seed crystal;
(c) carrying out crystallization at the temperature of-20 ℃;
(d) and filtering to obtain the flurbiprofen axetil crystal form I.
In another preferred example, the step (c) further includes: during the crystallization process, the system was thermostated and stirred.
In another preferred embodiment, the preparation method further comprises: purifying the crude product obtained by filtering.
In another preferred embodiment, said purification comprises washing with water.
In another preferred embodiment, after washing, the obtained filter cake is subjected to a lyophilization treatment to obtain purified form I.
In another preferred embodiment, in step (a), the first solvent is selected from the group consisting of: an alcohol solvent of C1-C6, a nitrile solvent of C2-C6, a ketone solvent of C2-C6, tetrahydrofuran, water, or a combination thereof.
In another preferred embodiment, the C1-C6 alcohol solvent is selected from the following group: methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, or a combination thereof.
In another preferred embodiment, the ketone solvent of C2-C6 is selected from the following group: acetone.
In another preferred embodiment, the nitrile solvent of C2-C6 is selected from the group consisting of: and (3) acetonitrile.
In another preferred embodiment, the first solvent is selected from the group consisting of: methanol, ethanol, n-propanol, sec-butanol, water, or a combination thereof.
In another preferred embodiment, the first solvent is selected from the group consisting of: methanol, ethanol, water, or a combination thereof.
In another preferred embodiment, the first solvent is selected from the group consisting of: methanol/water mixed solvent, ethanol.
In another preferred embodiment, the first solvent is selected from the group consisting of: methanol/water mixed solvent (0.8-1.2:2-4), and ethanol.
In another preferred example, in step (a), the volume (ml)/mass (g) ratio of the first solvent to the flurbiprofen axetil is (1-9):1, preferably (2-8): 1.
in another preferred embodiment, in the step (b), the mass of the added seed crystal is 0.05 wt% to 10 wt%, preferably 0.1 wt% to 5 wt% of the mass of the flurbiprofen axetil.
In another preferred example, the mass of the seed crystal added is 0.3 to 5 wt% of the mass of the flurbiprofen axetil.
In another preferred example, the mass of the seed crystal added is 0.5 to 2 wt% of the mass of the flurbiprofen axetil.
In another preferred example, the seed crystal added is a product of grinding flurbiprofen axetil after low-temperature solidification.
In another preferred example, the seed crystal added is flurbiprofen axetil crystal I.
In another preferred embodiment, in the step (c), the crystallization temperature is-10 to 20 ℃.
In another preferred embodiment, in the step (c), the crystallization temperature is-5 to 20 ℃.
In another preferred embodiment, in the step (c), the crystallization temperature is-5 to 12 ℃.
In another preferred embodiment, in the step (c), the crystallization time is 2-8 h.
In another preferred embodiment, in the step (c), the crystallization time is 3-8 h.
In a third aspect of the present invention, there is provided a pharmaceutical composition, which comprises (a) an active ingredient, wherein the active ingredient is flurbiprofen axetil crystal form I according to the first aspect of the present invention; and (b) a pharmaceutically acceptable carrier.
In another preferred embodiment, the pharmaceutical composition or formulation is in a dosage form selected from the group consisting of: powder, capsule, granule, tablet, pill or injection.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
Figure 1 is a DSC curve of flurbiprofen axetil form I;
figure 2 is an XRD spectrum of flurbiprofen axetil form I;
figure 3 is an IR spectrum of crystalline form I of flurbiprofen axetil;
fig. 4 is an IR spectrum of liquid flurbiprofen axetil;
FIG. 5 is a TGA curve of liquid flurbiprofen axetil;
figure 6 is a TGA curve of crystalline form I of flurbiprofen axetil;
FIG. 7 is a NMR hydrogen spectrum of flurbiprofen axetil;
FIG. 8 is a NMR hydrogen spectrum of crystalline form I of flurbiprofen axetil;
FIG. 9 shows the change of the impurity content of solid-liquid flurbiprofen axetil at 25 ℃/illumination;
FIG. 10 shows the change of impurity content of solid-liquid flurbiprofen axetil at 25 deg.C/RH 90%;
FIG. 11 shows the change of the impurity content of solid-liquid flurbiprofen axetil under the condition of 25 ℃/shading;
FIG. 12 is an XRD pattern of flurbiprofen axetil form I after 30 days at 25 deg.C and 25 deg.C/RH 90%;
FIG. 13 is a DSC of crystalline form I of flurbiprofen axetil placed at 25 ℃ for 30 days;
figure 14 is a DSC profile of flurbiprofen axetil form I at 25 ℃/RH 90% for 30 days.
Detailed Description
The present inventors have conducted extensive and intensive studies for a long time to provide a solid state form of flurbiprofen axetil, which is named as form I. The preparation method of the crystal form I is simple, and high-purity crystals can be obtained in a conventional operation mode. Based on the above findings, the inventors have completed the present invention.
Flurbiprofen axetil and crystal forms thereof
The chemical name of flurbiprofen axetil is: (±) 1-acetoxy ethyl 2- (2-fluoro-4-biphenylyl) propionate having the formula:
the molecular formula is as follows: c19H19FO4
Molecular weight: 330.36
CAS：91503-79-6
In the prior art, the prepared flurbiprofen axetil is generally an oily liquid, however, the inventor finds that the flurbiprofen axetil can be directly precipitated from the solution in the form of crystals under the condition that a seed crystal exists and the temperature is proper. According to the infrared spectrum, the nuclear magnetic resonance hydrogen spectrum, the thermal weight loss curve (TGA), the DSC curve and the XRD diffraction pattern of the solid product, and the comparison with the TGA, the nuclear magnetic resonance hydrogen spectrum and the infrared spectrum of the oily flurbiprofen axetil, the solid product is confirmed to be a new crystal form, and is named as the flurbiprofen axetil crystal form I.
The flurbiprofen axetil crystal form I of the present invention is completely different from existing flurbiprofen axetil in physical properties and states as confirmed by the examination of the two properties according to conventional methods and techniques. Specifically, the flurbiprofen axetil crystals of the present invention are all solid white powders, and the DSC chart shows a distinct melting point, while the existing flurbiprofen axetil is a colorless transparent oily liquid.
By comparing the hydrogen spectra of the flurbiprofen axetil crystal form I and the liquid flurbiprofen axetil, and the TGA curve, it was confirmed that the crystal was not a solvate, and only the flurbiprofen axetil molecule was included in the unit cell.
The difference between the new flurbiprofen axetil crystal form I and the liquid flurbiprofen axetil is also obvious by the infrared spectrum, and the difference is mainly concentrated in the fingerprint area, thus showing that the flurbiprofen axetil crystal form I is a new crystal form.
Preparation method of flurbiprofen axetil crystal form I
The present invention also provides a method for preparing flurbiprofen axetil crystalline form I as described herein, in particular, the method comprises:
1. and (3) mixing the flurbiprofen axetil melt or the crystal with any crystal form with a solvent.
In this step, the solvent is preferably methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, acetone, acetonitrile, tetrahydrofuran, water or a mixture thereof, and more preferably methanol, isopropanol and acetone. The volume of the added organic solvent is 2-8 times of the mass of the flurbiprofen axetil.
2. Seed crystals of flurbiprofen axetil were added to the above solution.
Wherein the mass of the seed crystal added is preferably 0.1-5% of that of flurbiprofen axetil, and more preferably 0.5-2%. The seed crystal can be a milled product of the flurbiprofen axetil after low-temperature solidification, and can also be a flurbiprofen axetil crystal, but the seed crystal is preferably the flurbiprofen axetil crystal form I.
3. Stirring at-20 deg.c for crystallization, suction filtering, water washing and freeze drying to obtain flurbiprofen axetil crystal.
Wherein the content of the first and second substances,
in the step, the crystallization temperature is not too high or too low, the crystallization temperature is too high, and the solubility of flurbiprofen axetil in the solvent is also high, so that the supersaturation degree of the flurbiprofen axetil is reduced, and the crystallization is too slow or even impossible. When the crystallization temperature is too low, a solution system becomes very viscous, so that molecular motion becomes slow, the probability of mutual collision is reduced, further the nucleation of the flurbiprofen axetil is hindered, and the crystallization is too slow or even cannot be performed. The crystallization temperature is preferably-20 to 20 ℃, and more preferably-5 to 12 ℃.
The crystallization time can be selected from any suitable time range, for example, in a preferred embodiment, the crystallization time is 2-8 h.
Pharmaceutical composition containing flurbiprofen axetil crystal form I
The flurbiprofen axetil crystal form I of the present invention is completely different from existing flurbiprofen axetil in physical properties and states as confirmed by the examination of the two properties according to conventional methods and techniques. The flurbiprofen axetil crystal and the flurbiprofen axetil oily liquid have very obvious differences in properties, and therefore, the flurbiprofen axetil crystal can be prepared into different preparations from those in the prior art, such as solid preparations (tablets, pills, powders, etc.).
In another aspect of the present invention, there is provided a pharmaceutical composition comprising a crystalline flurbiprofen axetil, preferably having a powder X-ray diffraction pattern as set forth in table II or fig. 2, as an active ingredient.
In the pharmaceutical composition, the crystalline flurbiprofen axetil of the present invention is formulated in an oral pharmaceutical composition in admixture with at least one pharmaceutical excipient. When preparing a solid composition in the form of a tablet, the major active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, etc., and prepared by a conventional process in the art to obtain a solid pharmaceutical composition. In particular, since the crystalline form I of flurbiprofen axetil of the present invention is a solid phase, it is suitable for preparing a solid composition.
Furthermore, the solid composition may be coated or otherwise suitably treated so that the tablet has a prolonged or retarded action and so that the tablet releases a predetermined amount of the active ingredient in a continuous manner.
Also, a capsule can be obtained by mixing the active ingredient with a diluent and filling the resulting mixture into a soft capsule or a hard capsule.
Furthermore, the crystalline modification I according to the invention can likewise be prepared as water-dispersible powders or granules which can contain the active ingredient in admixture with dispersing or wetting agents or suspending agents, such as polyvinylpyrrolidone, and with sweetening or flavoring agents.
If it is desired to formulate the active ingredient for rectal administration, suppositories are used which are prepared by binders which are meltable at the rectal temperature, such as cocoa butter or polyethylene glycols.
For parenteral administration, aqueous suspensions, saline solutions, or other sterile injectable solutions are employed.
The active ingredient may also be formulated with one or more carriers, additives and in the form of microcapsules.
Compared with the prior art, the invention has the main advantages that:
(1) the invention provides a flurbiprofen axetil crystal form I, which is simple in preparation method and can obtain high-purity crystals in a conventional operation mode.
(2) The invention provides a preparation method of a crystal form I, thereby optimizing a purification method of flurbiprofen axetil, solving the defects of high purification cost and complex operation of the flurbiprofen axetil, and providing potential development and application values for the fields of industrial manufacture and pharmaceutical preparations of the flurbiprofen axetil.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
In the examples, a flurbiprofen axetil oily liquid used as a control was obtained by purifying commercially available liquid flurbiprofen axetil by the method described in CN 103012144B.
Example 1:
the reactor was charged with 30g of flurbiprofen axetil melt and 60mL of methanol and mixed with stirring, whereupon the solution cleared. 0.3g of flurbiprofen axetil form I was added as seed. Stirring at 10 deg.C for 4 hr, and crystallizing. And (4) carrying out suction filtration by using a Buchner funnel, washing the filter cake for three times by using water, and freeze-drying the washed filter cake. 24g of flurbiprofen axetil crystal form I are obtained, the yield is 80%, and the melting point is 35 +/-3 ℃.
The obtained product is solid white powder, and the DSC pattern of the product is shown in figure 1, and the result shows that the solid powder has a remarkable melting point in the DSC pattern, while the existing flurbiprofen axetil is colorless transparent oily liquid, which indicates that the prepared solid white powder is in a crystal form.
The obtained flurbiprofen axetil crystal form I was subjected to a powder X-ray diffraction test, and the results thereof are shown in fig. 2, and the map data are shown in table II. The X-ray diffraction pattern of the powder was determined using a D8 ADVANCE (Bruker AXS, Germany) diffractometer.
Table II XRD spectra of crystalline form I of flurbiprofen axetil
The obtained white powder and the existing liquid flurbiprofen axetil were subjected to NMR measurement, and the results are shown in fig. 7 and fig. 8, and there was no difference in hydrogen spectra compared with the crystalline form I of flurbiprofen axetil and the liquid flurbiprofen axetil, which confirmed that the crystal was flurbiprofen axetil.
TGA tests were performed on flurbiprofen axetil crystalline form I and liquid flurbiprofen axetil, and the results are shown in fig. 5 and 6. The results show that there is only one stage of weight loss during the TGA test of both, which can prove that the crystal is not a solvate and the unit cell contains only flurbiprofen axetil molecules.
The infrared spectrum test of the obtained flurbiprofen axetil crystal form I and the liquid flurbiprofen axetil is carried out, and the results are shown in fig. 3 and 4, which clearly show that the difference of the infrared spectrum of the two flurbiprofen axetil crystal forms is very obvious, and the difference is mainly concentrated in a fingerprint area. Comparing FIG. 3 with FIG. 4, according to wavelength (cm)-1) And intensity, the results of the comparison of the characteristic lines are shown in table I below, where the multiple absorption peaks and the transmission rates are significantly different, indicating that the two are in different microscopic morphologies.
Table I infrared spectral discrimination of flurbiprofen axetil crystal form I and oily liquid
As can be seen from Table I, the characteristic absorption of crystalline form I of flurbiprofen axetil is 442cm-1,466cm-1,488cm-1,509cm-1,580cm-1,737cm-1,841cm-1,913cm-1,938cm-1,1754cm-1While flurbiprofen axetil in the liquid state does not have these absorptions.
Example 2:
the reactor was charged with 30g of flurbiprofen axetil melt, 60mL of methanol and 180mL of purified water, and mixed by stirring, whereupon the solution was in the form of an emulsion. 1.5g of flurbiprofen axetil form I was added as seed. Stirring at constant temperature of 20 ℃ for 8h, and crystallizing. And (4) carrying out suction filtration by using a Buchner funnel, washing the filter cake for three times by using water, and freeze-drying the washed filter cake. 28g of flurbiprofen axetil crystal form I are obtained, the yield is 93.3%, and the melting point is 35 +/-3 ℃.
Examples 3 to 11:
examples 3 to 11 were carried out using the same process as in example 1, with only the process parameters being changed, as outlined in Table III below:
TABLE III
Example 12: stability test of flurbiprofen axetil crystal form I
The determination method comprises the following steps: taking the crystalline form I of the flurbiprofen axetil prepared in example 1 and a proper amount of commercially available liquid flurbiprofen axetil. After being divided into small parts, the small parts are respectively placed in a watch glass, and samples are taken on the 0 th day, the 5 th day, the 10 th day and the 30 th day under the three conditions of 25 ℃/RH 90%, 25 ℃/illumination and 25 ℃/shading. Samples were examined for appearance changes and impurity level changes were detected by HPLC. In addition, the flurbiprofen axetil crystal form I is observed for crystal form by XRD and melting point by DSC.
And (3) measuring results:
appearance: the flurbiprofen axetil crystal form I has no change in appearance under the conditions of 25 ℃/RH 90% and 25 ℃/shading, and is white powder. The color of the black pigment is unchanged for 10 days at the temperature of 25 ℃/illumination, and slightly yellowed for 30 days.
The liquid flurbiprofen axetil has no change in appearance under the conditions of 25 ℃/RH 90% and 25 ℃/shading, and is colorless liquid. Slightly yellow for 5 days and yellow for 30 days at 25 deg.C/light.
Impurity level: the changes in impurity levels for the two flurbiprofen axetil under the three conditions are summarized in fig. 9, 10 and 11. Fig. 9 shows the change of the impurity content of the solid-liquid flurbiprofen axetil under the condition of 25 ℃/illumination, and the result shows that the total impurity content of the crystal form I of the present invention is significantly reduced after being placed for 30 days, compared with the flurbiprofen axetil oil-like liquid, which suggests that the crystal form I of the present invention has better illumination stability.
Fig. 10 shows the change of the impurity content of the solid-liquid flurbiprofen axetil under the condition of 25 ℃/RH 90%, fig. 11 shows the change of the impurity content of the solid-liquid flurbiprofen axetil under the condition of 25 ℃/shading, and the result shows that the total impurity content of the crystal form I of the present invention does not change significantly relative to the flurbiprofen axetil oil-like liquid after being placed for 30 days under the condition of high humidity or shading, so the moisture absorption stability and the stability under the conventional storage condition are equivalent to the flurbiprofen axetil oil-like liquid. The detailed values of the above results are shown in table IV and table V, wherein table IV lists the HPLC detection results of the stability of the flurbiprofen axetil crystal form I of the present invention, and table V lists the HPLC detection results of the stability of the commercially available liquid flurbiprofen axetil.
TABLE IV
TABLE V
And (3) crystal form stability: the XRD result shows that no obvious change of the pattern is observed in the sample under the conventional conditions of 25 ℃ and 25 ℃/RH 90% for 30 days, and the specific result is shown in figure 12; DSC results show that no significant melting point change is observed in the sample under the conventional conditions of 25 deg.C and 25 deg.C/RH 90% for 30 days, and the specific results are shown in FIGS. 13 and 14.
The results show that the flurbiprofen axetil crystal form I is stable even under high humidity conditions. The two flurbiprofen axetil are stable at 25 ℃/RH 90% and 25 ℃/shading, and the impurity water level is increased under the condition of 25 ℃/illumination. However, the solid flurbiprofen axetil is stable to short-term light and remarkably improved in stability under long-term light, as compared with the liquid flurbiprofen axetil.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A flurbiprofen axetil crystal form I is characterized in that characteristic peaks exist at 14.2 degrees +/-0.2 degrees, 16.3 degrees +/-0.2 degrees, 16.6 degrees +/-0.2 degrees, 17.5 degrees +/-0.2 degrees, 18.1 degrees +/-0.2 degrees, 21.8 degrees +/-0.2 degrees, 22.3 degrees +/-0.2 degrees, 23.9 degrees +/-0.2 degrees, 25.6 degrees +/-0.2 degrees and 26.3 degrees +/-0.2 degrees in X-ray diffraction powder diffraction.
2. The crystalline flurbiprofen axetil form I according to claim 1, wherein the melting point of form I is 36 ± 3 ℃.
3. The crystalline flurbiprofen axetil form I according to claim 1, wherein the infrared spectrum of the crystalline form I has one or more absorption peaks selected from the group consisting of: 442. 466, 488, 509, 580, 737, 841, 913, 938, and 1754 in wavelengths cm-1And (4) showing.
4. A preparation method of a flurbiprofen axetil crystal form I is characterized by comprising the following steps:
(a) adding a flurbiprofen axetil melt or crystal into a first solvent and forming a uniform dispersion mixture;
(b) adding flurbiprofen axetil crystal form I to the mixture obtained in step (a) as a seed crystal;
(c) carrying out crystallization at the temperature of-20 ℃;
(d) and filtering to obtain the flurbiprofen axetil crystal form I.
5. The method of claim 4, wherein in step (a), the first solvent is selected from the group consisting of: an alcohol solvent of C1-C6, a nitrile solvent of C2-C6, a ketone solvent of C2-C6, tetrahydrofuran, water, or a combination thereof.
6. The method according to claim 4, wherein in step (a), the volume (ml)/mass (g) ratio of the first solvent to the flurbiprofen axetil is (1-9):1, preferably (2-8): 1.
7. the method according to claim 4, wherein in the step (b), the mass of the seed crystal added is 0.05 to 10 wt%, preferably 0.1 to 5 wt% of the mass of flurbiprofen axetil.
8. The method according to claim 4, wherein the crystallization temperature in the step (c) is-5 to 12 ℃.
9. The method according to claim 4, wherein in the step (c), the crystallization time is 2 to 8 hours.
10. A pharmaceutical composition comprising (a) an active ingredient which is flurbiprofen axetil crystalline form I according to claim 1; and (b) a pharmaceutically acceptable carrier.
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| CN202210501830.7A CN115353456A (en) | 2021-05-08 | 2022-05-09 | Flurbiprofen axetil crystal and preparation method thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05246892A (en) * | 1992-03-04 | 1993-09-24 | Pola Chem Ind Inc | Antiphlogistic and analgesic external preparation |
| US20110160273A1 (en) * | 2008-05-21 | 2011-06-30 | Helmut Heinrich Buschmann | Co-crystals of duloxetine and cox-inhibitors for the treatment of pain |
| CN104894179A (en) * | 2015-06-02 | 2015-09-09 | 江南大学 | Green production process of (erythorbic) ascorbic acid ester derivatives |
| CN105777544A (en) * | 2016-04-13 | 2016-07-20 | 成都倍特药业有限公司 | Method for preparing S-(+)-flurbiprofen axetil high in optical purity |
-
2021
- 2021-05-08 CN CN202110502353.1A patent/CN113173853A/en active Pending
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2022
- 2022-05-09 CN CN202210501830.7A patent/CN115353456A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05246892A (en) * | 1992-03-04 | 1993-09-24 | Pola Chem Ind Inc | Antiphlogistic and analgesic external preparation |
| US20110160273A1 (en) * | 2008-05-21 | 2011-06-30 | Helmut Heinrich Buschmann | Co-crystals of duloxetine and cox-inhibitors for the treatment of pain |
| CN104894179A (en) * | 2015-06-02 | 2015-09-09 | 江南大学 | Green production process of (erythorbic) ascorbic acid ester derivatives |
| CN105777544A (en) * | 2016-04-13 | 2016-07-20 | 成都倍特药业有限公司 | Method for preparing S-(+)-flurbiprofen axetil high in optical purity |
Non-Patent Citations (1)
| Title |
|---|
| 俞伟等: "氟比洛芬酯的合成进展", 《广东化工》 * |
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| CN115353456A (en) | 2022-11-18 |
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