CN110049968A - Apremilast eutectic and preparation method thereof - Google Patents
Apremilast eutectic and preparation method thereof Download PDFInfo
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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Abstract
The present invention provides a kind of Apremilast eutectics and preparation method thereof, belong to field of medicinal chemistry.The eutectic includes crystal form I: the eutectic that Apremilast and benzoic acid are formed, crystal form II: the eutectic that Apremilast and phthalic acid are formed, crystal form III: the eutectic that Apremilast and salicylic acid are formed, crystal form IV: the eutectic or crystal form V of Apremilast and 4-aminobenzoic acid formation: the eutectic that Apremilast and 4-ASA are formed.The method is dissolved in solvent by Apremilast crystal form B, and benzoic acid derivative is added, and after stirring a period of time under 10 degrees Celsius~40 degrees Celsius, the solid-state of precipitation obtains Apremilast eutectic after volatilizing solvent after filtering；This method is easy to operate, mild condition, and obtained Apremilast eutectic dissolubility is good, and dissolution rate is fast.
Description
The invention belongs to field of medicinal chemistry, specifically, the present invention relates to eutectics of Apremilast and its preparation method and application.
Apremilast; the entitled Apremilast of English; chemical name is (S) -2- [1- (3- ethoxy-4-methoxyphenyl) -2- methylsulfonylethyl] -4- acetylaminoisoindoline -1; 3- diketone; No. CAS is 608141-41-9; it is the PDE-4 inhibitor researched and developed by Celgene company; the adult patients that can be used for having activity psoriatic arthritis and the middle severe plaque psoriasis patient that can be treated with optics or systematic treatment, shown in structure such as formula (I):
Chinese patent CN102046167A discloses 7 kinds of crystal forms of A, B, C, D, E, F and G of Apremilast, and wherein Apremilast B crystal form is more stable.
Polymorph in pharmaceuticals is an important factor for influencing drug quality, the different crystal forms of same drug molecule are the properties such as appearance, solubility, fusing point, dissolution rate, biological effectiveness can there were significant differences, to directly affect the stability of drug, bioavilability and curative effect.
Existing Apremilast crystal form dissolubility is poor, and dissolution rate is lower, affects the treatment；Therefore carrying out the research of Apremilast crystal form has great meaning.
Summary of the invention
The present invention is directed to solve at least some of the technical problems in related technologies.For this purpose, the eutectic of the Apremilast has good solubility and stability an object of the present invention is to provide eutectic of Apremilast and its preparation method and application.
According to an aspect of the present invention, the invention proposes a variety of eutectics of Apremilast and benzoic acid derivative, comprising:
The eutectic that compound Apremilast and benzoic acid are formed, is named as crystal form I；
The eutectic that compound Apremilast and phthalic acid are formed, is named as crystal form II；
The eutectic that compound Apremilast and salicylic acid are formed, is named as crystal form III；
The eutectic that compound Apremilast and 4-aminobenzoic acid are formed, is named as crystal form IV；Or
The eutectic that compound Apremilast and 4-ASA are formed, is named as crystal form V；
All have preferable physicochemical property.
Crystal form I is characterized in that, by using the alpha-emitting x-ray powder diffraction instrument of Cu-K, in following 2 θ (unit: degree, error ± 0.2 degree) there is at angle diffraction maximum: 7.366,9.012,9.544,10.024 11.224,11.956,13.848 15.140,16.279,17.632 17.811,18.115,19.209 20.121.
In some embodiments of the invention, by using the alpha-emitting x-ray powder diffraction instrument of Cu-K, the crystal form I is at following 2 θ (unit: degree, error ± 0.2 degree) angle with diffraction maximum: 13.116,20.595 21.268,21.384,22.322 22.684,23.321,23.655 24.074,24.656,25.288 26.196,27.399,28.199 28.886,29.615,30.406 30.650,31.164,32.022 32.529,32.866,33.610 34.352,35.564,36.130 36.473,37 .423,38.235,38.998,39.07.
In some embodiments of the invention, the crystal form I has X-ray powder diffraction pattern (XRD spectrum) substantially as shown in.
In some embodiments of the invention, the differential scanning calorimetric curve of the crystal form I has endothermic peak at 170-180 degrees Celsius.
In some embodiments of the invention, the crystal form I have basically as in Figure 2 shown in differential scanning calorimetric curve (DSC map).
Crystal form II is characterized in that, by using the alpha-emitting x-ray powder diffraction instrument of Cu-K, in following 2 θ (unit: degree, error ± 0.2 degree) there is at angle diffraction maximum: 7.319,9.915,11.270,13.120 13.704,14.948,17.520,17.902 18.950,19.372,19.910 20.342.
In some embodiments of the invention, the crystal form II is by using the alpha-emitting x-ray powder diffraction instrument of Cu-K, with diffraction maximum at following 2 θ (error ± 0.2 degree) angle: 9.438,12.114,16.154 21.027,21.359,22.080 22.581,23.128,23.587 24.477,24.998,25.256 25.925,26.184,27.154 28.13,28.710,29.271 30.071,30.485,31.121 32.589,33.463,33.995 34.544,35.116,35.852 37.09,37 .68,38.649.
In some embodiments of the invention, the crystal form II has X-ray powder diffraction pattern (XRD spectrum) substantially as shown in Figure 3.
In some embodiments of the invention, the differential scanning calorimetric curve of the crystal form II has endothermic peak at 175-185 degrees Celsius.
In some embodiments of the invention, the crystal form II has differential scanning calorimetric curve (DSC map) substantially as shown in Figure 4.
Crystal form III is characterized in that, by using the alpha-emitting x-ray powder diffraction instrument of Cu-K, in following 2 θ (unit, degree, error ± 0.2 degree) there is at angle diffraction maximum: 7.486,9.687,11.329,12.033,13.244,16.436,17.804,18.254.
In some embodiments of the invention, the crystal form III is by using the alpha-emitting x-ray powder diffraction instrument of Cu-K, with diffraction maximum at following 2 θ (error ± 0.2 degree) angle: 13.998,15.307,19.390 20.295,20.775,21.458 22.509,22.848,23.208 23.514,24.106,24.836 25.479,26.378,27.564 28.339,29.043,29.818 30.654,32.198,32.620 33.022,33.85,34.477 34.698,35.778,36.36 37.482 38.444,39.267.
In some embodiments of the invention, the crystal form III has X-ray powder diffraction pattern (XRD spectrum) substantially as shown in Figure 5.
In some embodiments of the invention, the differential scanning calorimetric curve of the crystal form III has endothermic peak at 185-195 degrees Celsius.
In some embodiments of the invention, the crystal form III has differential scanning calorimetric curve (DSC map) substantially as shown in FIG. 6.
Crystal form IV is characterized in that, by using the alpha-emitting x-ray powder diffraction instrument of Cu-K, in following 2 θ (unit: degree, error ± 0.2 degree)
There is diffraction maximum: 7.2650,9.08,9.88,11.233,13.074,13.649,14.892,16.103,16.5 71,17.474 at angle.
In some embodiments of the invention, the crystal form IV is by using the alpha-emitting x-ray powder diffraction instrument of Cu-K, with diffraction maximum at following 2 θ (error ± 0.2 degree) angle: 12.094,17.875 18.061,18.887,19.264 19.429,19.851,20.278 20.968,21.334,22.016 22.513,23.063,23.342 23.624,24.185,24.440 24.933,25.257,25.867 26.151,27.121,27.862 28.085,28.368,28.667 29.193,30.006 , 30.436,31.474,31.747,32.536,33.392,33.911,35.025,35.908,37.040,37.623,38.536,39.613.
In some embodiments of the invention, the crystal form IV has X-ray powder diffraction pattern (XRD spectrum) substantially as shown in Figure 7.
In some embodiments of the invention, the differential scanning calorimetric curve of the crystal form IV has endothermic peak at 170-180 degrees Celsius.
In some embodiments of the invention, the crystal form IV has differential scanning calorimetric curve (DSC map) substantially as shown in Figure 8.
Crystal form V is characterized in that, by using the alpha-emitting x-ray powder diffraction instrument of Cu-K, with diffraction maximum at following 2 θ (unit: degree, error ± 0.2 degree) angle: 7.279,9.397,11.227,13.073,13.670,16.111,16.544,17.481,17.856,18.056.
In some embodiments of the invention, the crystal form V is by using the alpha-emitting x-ray powder diffraction instrument of Cu-K, with diffraction maximum at following 2 θ (error ± 0.2 degree) angle: 9.910,12.073,14.910 18.910,19.280,19.868 20.303,20.987,21.325 22.037,22.519,23.079 23.306,23.587,24.421 24.958,25.225,25.885 26.152,27.135,28.12,28.672,29.218,30.023 30.440,31.740,32.533 33.403,33 .936,34.424,35.062,35.898,37.035.
In some embodiments of the invention, the crystal form V has X-ray powder diffraction pattern (XRD spectrum) substantially as shown in Figure 9.
In some embodiments of the invention, the differential scanning calorimetric curve of the crystal form V has endothermic peak at 180-190 degrees Celsius.
In some embodiments of the invention, the crystal form V has differential scanning calorimetric curve (DSC map) substantially as shown in Figure 10.
According to the second aspect of the invention, the invention proposes a kind of methods of eutectic for preparing mentioned-above Apremilast and benzoic acid derivative, it include: that Apremilast crystal form B is dissolved in organic solvent, benzoic acid derivative is added, for gained mixture after 10 degrees Celsius~40 degrees Celsius stirring a period of times, the solid-state of precipitation obtains the eutectic of Apremilast and benzoic acid derivative after volatilizing solvent after filtering.
In some embodiments of the invention, the organic solvent is or mixtures thereof single solvents such as acetone, ethyl acetate, acetonitrile, ethyl alcohol, methanol, isopropanol.
In some embodiments of the invention, the benzoic acid derivative is benzoic acid, phthalic acid, salicylic acid, 4-aminobenzoic acid or 4-ASA.
In some embodiments of the invention, in the method for preparing the eutectic of mentioned-above Apremilast and benzoic acid derivative, the ratio of the volume of Apremilast, the quality sum of benzoic acid derivative and solvent is 10-300 mg/ml.
In some embodiments of the invention, in the method for preparing the eutectic of mentioned-above Apremilast and benzoic acid derivative, the molar ratio of Apremilast and benzoic acid derivative is 0.5:1~1:5.
In some embodiments of the invention, in the method for preparing the eutectic of mentioned-above Apremilast and benzoic acid derivative, the mixing time is 1 hour~24 hours.
Apremilast crystal form B of the present invention is crystal form B disclosed in patent application CN 102046167.
Room temperature of the present invention is 10 degrees Celsius~40 degree Celsius range temperature.
" crystal form " of the present invention can be present in sample with 0.0001%-100%; therefore; even if as long as being greater than 0.0001% containing trace in sample; greater than 0.001%, " crystal form " of the present invention greater than 0.001% or greater than 0.01% all should be understood as falling within the scope of protection of the present invention.For the various parameters of " crystal form " of the present invention are described to become apparent from, the sample when present invention is by containing essentially pure certain " crystal form " carries out test various parameters and the crystal form is characterized and identified.Term " essentially pure ", which refers in sample, to be substantially made of a kind of main crystal form, essentially free of another or other a variety of other crystal forms or amorphous, its main crystal form purity at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%.Term " essentially free of one or more other crystal forms or amorphous " refers to that other crystal forms or unbodied the content percentage in sample total weight are less than 20% or less than 10% or less than 5%, or less than 3% or less than 1% or less than 0.5%, or less than 0.1% or less than 0.01%.
In the context of the present invention, wordings such as " about " or " about " whether or not using, all numbers being disclosed are approximation.The numerical value of each number is possible to will appear the differences such as 1%, 2% or 5%.
The differential scanning calorimetry measurement (DSC) of the crystal form has experimental error, between a machine and another machine and between a sample and another sample, the position of endothermic peak and peak value may slightly have difference, the numerical value of experimental error or difference is likely less than equal to 10 DEG C, or is less than or equal to 5 DEG C, or is less than or equal to 4 DEG C, or it is less than or equal to 3 DEG C, or be less than or equal to 2 DEG C, or be less than or equal to 1 DEG C, therefore the peak position of the DSC endothermic peak or the numerical value of peak value cannot be considered as it is absolute.
Fig. 1 is the XRD spectrum of crystal form I.
Fig. 2 is the DSC map of crystal form I.
Fig. 3 is the XRD spectrum of crystal form II.
Fig. 4 is the DSC map of crystal form II.
Fig. 5 is the XRD spectrum of crystal form III.
Fig. 6 is the DSC map of crystal form III.
Fig. 7 is the XRD spectrum of crystal form IV.
Fig. 8 is the DSC map of crystal form IV.
Fig. 9 is the XRD spectrum of crystal form V.
Figure 10 is the DSC map of crystal form V.
Figure 11 is the XRD spectrum of Apremilast crystal form B.
Figure 12 is the XRD spectrum of benzoic acid.
Figure 13 is the XRD spectrum of phthalic acid.
Figure 14 is salicylic XRD spectrum.
Figure 15 is the XRD spectrum of 4-aminobenzoic acid.
Figure 16 is the XRD spectrum of 4-ASA.
Figure 17 is the solubility test figure of crystal form I/II/III/IV/V and Apremilast crystal form B.
The embodiment of the present invention is described below in detail, examples of the embodiments are shown in the accompanying drawings, and in which the same or similar labels are throughly indicated same or similar element or elements with the same or similar functions.The embodiments described below with reference to the accompanying drawings are exemplary, it is intended to be used to explain the present invention, and be not considered as limiting the invention.
In order to make those skilled in the art better understand technical solution of the present invention, disclosing some non-limiting embodiments further below, the present invention is described in further detail.
Reagent used in the present invention is available on the market or described method can be prepared through the invention.
The preparation method of 1 crystal form I of embodiment
Weigh Apremilast crystal form B1.84g (4mmol), 20mL dehydrated alcohol is added, benzoic acid 0.244g (2mmol) is added after 10min is stirred at room temperature, after 12h is stirred at room temperature in reaction, suspension is filtered, the solid of collection is placed in a vacuum drying oven under the conditions of 40 DEG C dry 12h, obtains off-white color product, detection is crystal form I；Yield 92.3%.
The preparation method of 2 crystal form II of embodiment
Weigh Apremilast crystal form B1.84g (4mmol), 20mL dehydrated alcohol is added, phthalic acid 0.332g (2mmol) is added after 10min is stirred at room temperature, after 12h is stirred at room temperature in reaction, suspension is filtered, the solid of collection is placed in a vacuum drying oven under the conditions of 40 DEG C dry 12h, obtains off-white color product, detection is crystal form II；Yield 93.7%.
The preparation method of 3 crystal form III of embodiment
Weigh Apremilast crystal form B1.84g (4mmol), 20mL dehydrated alcohol is added, salicylic acid 0.276g (2mmol) is added after 10min is stirred at room temperature, after 12h is stirred at room temperature in reaction, suspension is filtered, the solid of collection is placed in a vacuum drying oven under the conditions of 40 DEG C dry 12h, obtains light yellow product, detection is crystal form III；Yield 91.1%.
The preparation method of 4 crystal form IV of embodiment
Weigh Apremilast crystal form B0.92g (2mmol), 20mL dehydrated alcohol is added, 4-aminobenzoic acid 0.137g (1mmol) is added after 10min is stirred at room temperature, after 12h is stirred at room temperature in reaction, suspension is filtered, the solid of collection is placed in a vacuum drying oven under the conditions of 40 DEG C dry 12h, obtains off-white color product, detection is crystal form IV；Yield 90.2%.
The preparation method of 5 crystal form V of embodiment
Weigh Apremilast crystal form B0.92g (2mmol), 20mL dehydrated alcohol is added, 4-ASA 0.153g (1mmol) is added after 10min is stirred at room temperature, after 12h is stirred at room temperature in reaction, suspension is filtered, the solid of collection is placed in a vacuum drying oven under the conditions of 40 DEG C dry 12h, obtains taupe product, detection is crystal form V；Yield 94.1%.
The preparation method of 6 crystal form III of embodiment
Weigh Apremilast crystal form B1.84g (4mmol), 20mL anhydrous methanol is added, salicylic acid 0.276g (2mmol) is added after 10min is stirred at room temperature, after 12h is stirred at room temperature in reaction, suspension is filtered, the solid of collection is placed in a vacuum drying oven under the conditions of 40 DEG C dry 12h, obtains light yellow product, detection is crystal form III；Yield 93.4%.
The preparation method of 7 crystal form III of embodiment
Weigh Apremilast crystal form B 1.84g (4mmol), 20mL isopropanol is added, salicylic acid 0.276g (2mmol) is added after 10min is stirred at room temperature, after 12h is stirred at room temperature in reaction, suspension is filtered, the solid of collection is placed in a vacuum drying oven under the conditions of 40 DEG C dry 12h, obtains light yellow product, detection is crystal form III；Yield 91.9%.
The preparation method of 8 crystal form III of embodiment
Weigh Apremilast crystal form B 1.84g (4mmol), 20mL ethyl acetate is added, salicylic acid 0.276g (2mmol) is added after 10min is stirred at room temperature, after 12h is stirred at room temperature in reaction, suspension is filtered, the solid of collection is placed in a vacuum drying oven under the conditions of 40 DEG C dry 12h, obtains light yellow product, detection is crystal form III；Yield 90.8%.
The preparation method of 9 crystal form III of embodiment
Weigh Apremilast crystal form B 1.84g (4mmol), 20mL acetonitrile is added, salicylic acid 0.276g (2mmol) is added after 10min is stirred at room temperature, after 12h is stirred at room temperature in reaction, suspension is filtered, the solid of collection is placed in a vacuum drying oven under the conditions of 40 DEG C dry 12h, obtains light yellow product, detection is crystal form III；Yield 91.6%.
The preparation method of 10 crystal form III of embodiment
Weigh Apremilast crystal form B 1.84g (4mmol), 20mL acetone is added, salicylic acid 0.276g (2mmol) is added after 10min is stirred at room temperature, after 12h is stirred at room temperature in reaction, suspension is filtered, the solid of collection is placed in a vacuum drying oven under the conditions of 40 DEG C dry 12h, obtains light yellow product, detection is crystal form III；Yield 92.4%.
Solubility test
The dissolution rate of the embodiment 1-5 crystal form being prepared and Apremilast crystal form B is detected respectively, obtains Figure 17.
Conclusion: as can be seen from Figure 17, the dissolution rate for the crystal form that embodiment 1-5 is prepared is all than Apremilast crystal form B high；Wherein Apremilast/phthalic acid eutectic (crystal form II) dissolution rate highest can be rapidly achieved 3.3 times of Apremilast crystal form B dissolution rate, and concentration can be kept for a long time constant.
Single crystal data test
Single crystal data test is carried out to the crystal form that embodiment 1-3 is prepared respectively, obtains following data:
1 monocrystalline crystal data table of table
Test equipment and method
(1) powder x-ray diffraction (XRD) is studied
X-ray powder diffraction (XRD) pattern is collected on the Dutch PANalytical Empyrean x-ray diffractometer of Transflective sample stage for being equipped with automation zero Background Samples frame of 3*15.Radiation source used be (Cu, k α, K α 1 (): 1.540598；Kα2(): 1.544426；1 intensity of K α 2/K α: 0.50), wherein voltage is set in 45KV, and electric current is set in the divergence of 40mA.X- ray, i.e., the effective dimensions that X-ray constrains on sample, θ-θ continuous scanning mode is used for 10mm., obtains 3 °~40 ° of effective 2 θ range.It takes appropriate amount of sample under environmental condition (about 18 DEG C~32 DEG C) at zero Background Samples frame circular groove, is gently pressed with clean glass slide, obtain a smooth plane, and zero Background Samples frame is fixed.Sample is generated into traditional XRD diagram case with 0.0168 ° of scanning step within the scope of 3~40 ° of 2 θ.Software for data collection is Data Collector, and data are analyzed and shown with Data Viewer and HighScore Plus.
Using above-mentioned condition, XRD detection is carried out to the crystal form of embodiment 1-5 preparation respectively, as a result sees Fig. 1, Fig. 3, Fig. 5, Fig. 7, Fig. 9 respectively.
(2) differential scanning calorimetry (DSC) is analyzed
Dsc measurement is in TA InstrumentsTMIt is carried out in model Q2000 with sealed disk assembly.Sample (about 1~3mg) is weighed in aluminium dish,
With Tzero gland, precision is recorded 1 percent milligrams, and sample is transferred in instrument and is measured.Instrument is purged with nitrogen with 50mL/min.Data are collected with the rate of heat addition of 10 DEG C/min between 300 DEG C in room temperature.It is drawn downwards with endothermic peak, data are analyzed and shown with TA UniversalAnalysis.
(3) Single Crystal X-ray spreads out method
Grmini A Ultra single crystal diffractometer (Agilent company, the U.S.) is furnished with graphite monochromator, with Cu Ka ray (λ=1.5418), the true fixed sum data reduction of structure cell and absorption correction are determined using CrysAlis PRO software processing space group according to the delustring rule of system, and by refine result verification.Crystal structure uses SHELXS-97 program, is added with the coordinate of the hydrogen atom connected on complete matrix least square method correcting principle, with nitrogen and oxygen atom by Residual electron density figure.
Stability test
Test specimen
Crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form B
Instrument and equipment
Test method
Manner of packing: using transparent polyethylene bag (PE bags) for packaging material, band sealing, and (40 ± 2 DEG C, 4 batches × 4 wrap totally 32 packets under the conditions of RH75 ± 5%；30 ± 2 DEG C, ± 5% condition 4 batches × 6 of RH65 packet).
Above-mentioned packaged sample is put into accelerated test case (40 ± 2 DEG C, RH75 ± 5%) (30 ± 2 DEG C, RH65 ± 5%) progress accelerated test examinations.
Sampling time point 1,2,3, June.
The result shows that I/II/III/IV/V/B of crystal form all has good stability, XRD does not change, and in the error range that DSC allows at 2 DEG C, stability of crystal form is good.
In the description of this specification, the description of reference term " one embodiment ", " some embodiments ", " example ", " specific example " or " some examples " etc. means that particular features, structures, materials, or characteristics described in conjunction with this embodiment or example are included at least one embodiment or example of the invention.In the present specification, the schematic representation of the above terms does not necessarily have to refer to the same embodiment or example.Moreover, particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more of the embodiments or examples.In addition, without conflicting with each other, the feature of different embodiments or examples described in this specification and different embodiments or examples can be combined by those skilled in the art.
Although the embodiments of the present invention has been shown and described above, it can be understood that, above-described embodiment is exemplary, and is not considered as limiting the invention, and those skilled in the art can make changes, modifications, alterations, and variations to the above described embodiments within the scope of the invention.
Claims (21)
- A kind of eutectic of Apremilast and benzoic acid derivative formation characterized by comprising crystal form I: the eutectic that Apremilast and benzoic acid are formed；Crystal form II: the eutectic that Apremilast and phthalic acid are formed；Crystal form III: the eutectic that Apremilast and salicylic acid are formed；Crystal form IV: the eutectic of Apremilast and 4-aminobenzoic acid formation；Or crystal form V: the eutectic that Apremilast and 4-ASA are formed.
- The eutectic that Apremilast and benzoic acid derivative as described in claim 1 are formed, which is characterized in that radiated using Cu-K α, the X-ray powder diffraction spectrum indicated with 2 θ (error ± 0.2 degree), wherein, the X-ray powder diffraction spectrum of crystal form I contains following characteristic peak: 7.366,9.012,9.544,10.024,11.224,11.956 13.848,15.140,16.279 17.632,17.811,18.115 19.209,20.121.
- The eutectic that as claimed in claim 2 Apremilast and benzoic acid derivative are formed, which is characterized in that wherein, the X-ray powder diffraction spectrum of crystal form I contains following characteristic peak: 13.116,20.595 21.268,21.384,22.322 22.684,23.321,23.655 24.074,24.656,25.288 26.196,27.399,28.199 28.886,29.615.
- The eutectic that Apremilast and benzoic acid derivative as claimed in claim 2 are formed, which is characterized in that wherein, the DSC endothermic peak of crystal form I is at 171~175 DEG C.
- The eutectic that Apremilast and benzoic acid derivative as described in claim 1 are formed, which is characterized in that radiated using Cu-K α, the X-ray powder diffraction spectrum indicated with 2 θ (error ± 0.2 degree), wherein the X-ray powder diffraction spectrum of crystal form II contains following characteristic peak: 7.319,9.915,11.270,13.120,13.704 14.948,17.520,17.902 18.950,19.372,19.910 20.342.
- The eutectic that as claimed in claim 5 Apremilast and benzoic acid derivative are formed, which is characterized in that wherein, the X-ray powder diffraction spectrum of crystal form II contains following characteristic peak: 9.438,12.114,16.154,21.027,21.359,22.080,22.581,23.128,23.587,24.477 24.998,25.256,25.925 26.184,27.154,28.13,28.710,29.271.
- The eutectic that Apremilast and benzoic acid derivative as claimed in claim 5 are formed, which is characterized in that wherein, the DSC endothermic peak of crystal form II is at 180~184 DEG C.
- The eutectic that Apremilast and benzoic acid derivative as described in claim 1 are formed, which is characterized in that radiated using Cu-K α, the X-ray powder diffraction spectrum indicated with 2 θ (error ± 0.2 degree), wherein, the X-ray powder diffraction spectrum of crystal form III contains following characteristic peak: 7.486,9.687,11.329,12.033 13.244,16.436,17.804 18.254.
- The eutectic that as claimed in claim 8 Apremilast and benzoic acid derivative are formed, which is characterized in that wherein, the X-ray powder diffraction spectrum of crystal form III contains following characteristic peak: 13.998,15.307,19.390,20.295,20.775,21.458,22.509,22.848,23.208,23.514 24.106,24.836,25.479 26.378,27.564,28.339 29.043,29.818.
- The eutectic that Apremilast and benzoic acid derivative as claimed in claim 8 are formed, which is characterized in that wherein, the DSC endothermic peak of crystal form III is at 186~190 DEG C.
- The eutectic that Apremilast and benzoic acid derivative as described in claim 1 are formed, which is characterized in that radiated using Cu-K α, the X-ray powder diffraction spectrum indicated with 2 θ (error ± 0.2 degree), wherein the X-ray powder diffraction spectrum of crystal form IV contains following characteristic peak: 7.2650,9.08,9.88,11.233,13.074,13.649 14.892,16.103,16.571 17.474.
- The eutectic that Apremilast and benzoic acid derivative as claimed in claim 11 are formed, which is characterized in that wherein, the X of crystal form IV is penetrated Line Powder Diffraction pattern contains following characteristic peak: 12.094,17.875,18.061,18.887,19.264,19.429,19.851,20.278,20.968,21.334,22.016,22.513,23.063,23.342,23.624,24.185,24.440,24.933,25.257,25.867,26.151,27.121,27.862,28.085,28.368,28.667,29.193.
- The eutectic that Apremilast and benzoic acid derivative as claimed in claim 11 are formed, which is characterized in that wherein, the DSC endothermic peak of crystal form IV is at 171~175 DEG C.
- The eutectic that Apremilast and benzoic acid derivative as described in claim 1 are formed, which is characterized in that radiated using Cu-K α, the X-ray powder diffraction spectrum indicated with 2 θ (error ± 0.2 degree), wherein the X-ray powder diffraction spectrum of crystal form V contains following characteristic peak: 7.279,9.397,11.227,13.073,13.670,16.111 16.544,17.481,17.856 18.056.
- The eutectic that as claimed in claim 14 Apremilast and benzoic acid derivative are formed, which is characterized in that wherein, the X-ray powder diffraction spectrum of crystal form V contains following characteristic peak: 9.910,12.073,14.910,18.910,19.280,19.868,20.303,20.987,21.325,22.037,22.519,23.079,23.306,23.587,24.421,24.958,25.225,25.885,26.152,27.135,28.12,28.672,29.218.
- The eutectic that Apremilast and benzoic acid derivative as claimed in claim 14 are formed, which is characterized in that wherein, the DSC endothermic peak of crystal form V is at 185~189 DEG C.
- A method of preparing the eutectic that the claims the 1-16 any Apremilast and benzoic acid derivative are formed, it include: that Apremilast crystal form B is dissolved in organic solvent, then benzoic acid derivative is added, after gained mixture is placed in 10 DEG C~40 DEG C stirring a period of times, solid is precipitated, obtains the eutectic of Apremilast and benzoic acid derivative after suction filtration.
- According to the method for claim 17, it is characterised in that the solvent be acetone, ethyl acetate, acetonitrile, ethyl alcohol, methanol, isopropanol, or combinations thereof.
- According to the method for claim 17, it is characterised in that the ratio of the volume of the quality sum and solvent of the Apremilast, benzoic acid derivative is 10-300mg/ml.
- According to the method for claim 17, it is characterised in that the molar ratio of the Apremilast and benzoic acid derivative is 0.5:1~1:5.
- According to the method for claim 17, it is characterised in that the mixing time is 1 hour~24 hours.
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| PCT/CN2017/108853 WO2018086473A1 (en) | 2016-11-09 | 2017-11-01 | Apremilast eutectic and preparation method thereof |
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1652772A (en) * | 2002-03-20 | 2005-08-10 | 细胞基因公司 | (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione: methods of using and compositions thereof |
| CN102046167A (en) * | 2008-03-27 | 2011-05-04 | 细胞基因公司 | Solid forms comprising (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, compositions thereof, and uses thereof |
| US20110189275A1 (en) * | 2010-02-03 | 2011-08-04 | Schultheiss Nathan C | Pterostilbene cocrystals |
| CN102781443A (en) * | 2009-11-19 | 2012-11-14 | 细胞基因公司 | Apremilast For The Treatment Of Sarcoidosis |
| CN104892486A (en) * | 2015-06-25 | 2015-09-09 | 济南纽华医药科技有限公司 | Novel Apremilast crystal form and preparation method thereof |
| WO2016135755A1 (en) * | 2015-02-27 | 2016-09-01 | Mylan Laboratories Limited | Amorphous apremilast, premixes thereof, and novel crystalline forms of apremilast |
| WO2017033116A1 (en) * | 2015-08-26 | 2017-03-02 | Glenmark Pharmaceuticals Limited | Process for preparation of apremilast |
-
2017
- 2017-11-01 WO PCT/CN2017/108853 patent/WO2018086473A1/en active Application Filing
- 2017-11-01 CN CN201780068131.5A patent/CN110049968A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1652772A (en) * | 2002-03-20 | 2005-08-10 | 细胞基因公司 | (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione: methods of using and compositions thereof |
| CN102046167A (en) * | 2008-03-27 | 2011-05-04 | 细胞基因公司 | Solid forms comprising (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, compositions thereof, and uses thereof |
| CN102781443A (en) * | 2009-11-19 | 2012-11-14 | 细胞基因公司 | Apremilast For The Treatment Of Sarcoidosis |
| US20110189275A1 (en) * | 2010-02-03 | 2011-08-04 | Schultheiss Nathan C | Pterostilbene cocrystals |
| WO2016135755A1 (en) * | 2015-02-27 | 2016-09-01 | Mylan Laboratories Limited | Amorphous apremilast, premixes thereof, and novel crystalline forms of apremilast |
| CN104892486A (en) * | 2015-06-25 | 2015-09-09 | 济南纽华医药科技有限公司 | Novel Apremilast crystal form and preparation method thereof |
| WO2017033116A1 (en) * | 2015-08-26 | 2017-03-02 | Glenmark Pharmaceuticals Limited | Process for preparation of apremilast |
Non-Patent Citations (1)
| Title |
|---|
| 方亮主编: "《药剂学》", 31 March 2016, 中国医药科技出版社 * |
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