CN104892486A - Novel Apremilast crystal form and preparation method thereof - Google Patents
Novel Apremilast crystal form and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/4035—Isoindoles, e.g. phthalimide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
Abstract
The invention provides a novel Apremilast crystal form B+ shown in a formula (I). Characteristic absorption peaks of the Apremilast crystal form shown at 2theta +/- 0.2 in an X- ray powder diffraction pattern include: 11.03, 12.97, 13.31, 13.65, 14.52, 16.01, 17.74, 18.54, 22.55 and 26.75. Compared with the prior art, the Novel Apremilast crystal form B+ has the advantages of large particle size, high liquidity, high stability, high hygroscopicity and high solubility. The invention further provides a preparation method of the novel crystal form B+. The preparation method includes the steps of dissolving Apremilast in solvent, lowering system temperature after the Apremilast is dissolved completely, performing devitrification and filtration, and drying the solid in an oven to constant weight to obtain the Novel Apremilast crystal form.
Description
Technical field
The present invention relates to medicinal chemistry art, new crystal being specifically related to Apremilast and preparation method thereof.
Background technology
Polymorph in pharmaceuticals is the common phenomenon in medicament research and development, is the important factor affecting drug quality.Properties may there were significant differences in outward appearance, solubleness, fusing point, dissolution rate, biological effectiveness etc. for the different crystal forms of same drug molecule, thus directly affect the stability of medicine, bioavailability and curative effect.Therefore, in drug research and development, the polymorphic problem of medicine should be considered comprehensively, carry out crystal formation screening comprehensive system, crystal formation is furtherd investigate, thus find the crystal formation of most suitable exploitation.
Apremilast; English Apremilast by name; 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; be used for the treatment of the adult patients that there is reactivity psoriatic arthritis and can with severe plaque psoriasis patient in optics or systematic treatment treatment, structure is as shown in formula I:
Chinese patent CN102046167A discloses A, B, C, D, E, F and G 7 kinds of crystal formations of Apremilast, and wherein Apremilast B crystal form is more stable.
Summary of the invention:
The technical problem that the present invention solves is the new crystal B providing a kind of Apremilast
+and preparation method thereof, compared with prior art, Apremilast crystal form B provided by the invention
+granularity is large, good fluidity, and stability, draws moist and solubleness is all better.
The technical problem again that the present invention solves is to provide described Apremilast crystal form B
+preparation method.
Another technical problem that the present invention solves is to provide one to have Apremilast crystal form B
+pharmaceutical composition.
For solving the problems of the technologies described above, the invention provides the B of Apremilast new crystal shown in a kind of formula I
+.
At the following charateristic avsorption band of 2 θ ± 0.2 tool in its X-ray powder diffraction pattern: 11.03,12.97,13.31,13.65,14.52,16.01,17.74,18.54,22.55,26.75.
At the following charateristic avsorption band of 2 θ ± 0.2 tool in its X-ray powder diffraction pattern: 11.03,12.97,13.31,13.65,14.52,16.01,17.74,18.54,21.30,21.75,22.55,22.88,25.46,26.34,26.75.
Its X-ray powder diffraction pattern has following characteristics:
In certain embodiments, its X-ray powder diffraction pattern substantially as shown in Figure 1.
Its differential scanning calorimetry measures Apremilast new crystal B
+have endotherm(ic)peak about 144.3 DEG C ~ 152.6 DEG C greatly, its endotherm(ic)peak summit value is greatly about 147.9 DEG C.In certain embodiments, its means of differential scanning calorimetry figure substantially as shown in Figure 2.
Described Apremilast new crystal B
+when being heated to about 300 DEG C from about 40 DEG C, its thermogravimetric analysis figure comprises the mass loss lower than about 1%.In certain embodiments, its thermogravimetric analysis figure substantially as shown in Figure 3.
In certain embodiments, crystal form B
+can be characterized by size-grade distribution, in certain embodiments, crystal form B
+feature be white powder, in certain embodiments, crystal form B
+sample granularity be evenly distributed, size distribution curve is normal distribution, and D (90) value is about 120 μm.
It should be noted that, for the X-ray powder diffraction peak of the above crystal formation, between a machine and another machine and between a sample and another sample, 2 θ of X-ray powder diffraction may slightly change, its numerical value may differ about 1 unit, or differ about 0.8 unit, or differ about 0.5 unit, or differ about 0.3 unit, or differ about 0.2 unit, or differ about 0.1 unit, therefore given numerical value can not be considered as absolute.
For the value of the DSC of the above crystal formation, between a machine and another machine and between a sample and another sample, fusing point may slightly change, its numerical value may differ and approximately be less than or equal to 5 DEG C, or difference is approximately less than or equal to 4 DEG C, or difference is approximately less than or equal to 3 DEG C, or difference is approximately less than or equal to 2 DEG C, and therefore given numerical value can not be considered as absolute.
For second technical problem of the present invention, the invention provides above-mentioned Apremilast new crystal B
+preparation method, preparation method is: by Apremilast dissolve in a solvent, until completely dissolved, reduce system temperature, crystallization, filter, solid is dried to constant weight in an oven, obtains the new crystal of Apremilast.
The preparation method of Apremilast new crystal of the present invention comprises with suitable dissolution with solvents Apremilast, reduces temperature of reaction system with certain rate of temperature fall, is stirring or crystallize out under static condition with certain rotating speed.The Apremilast new crystal that described preparation method obtains is substantially pure crystal form B
+, crystal form B
+be stable, non-moisture absorption is a kind of crystal formation being conducive to pharmaceutical preparation exploitation.
Preparation method of the present invention the Apremilast of any existence form can be comprised formerly grind the Apremilast crystal form A described in patent, B, C, D, E, F, G change Apremilast crystal form B into
+.
In certain embodiments, be dissolved in by Apremilast in suitable solvent, this solvent can be single solvent, also can be the mixed solvent of two kinds of solvents or the mixed solvent of at least two kinds of solvents.Preferably, described solvent is ethanol, acetonitrile, methyl alcohol, Virahol, propyl carbinol, acetone single solvent, or ethanol, methyl alcohol, Virahol, acetone, acetonitrile, propyl carbinol, the mixed solvent of in water two kinds or more, the consumption of solvent is 1 ~ 20 times amount (ml/g) of Apremilast crude product, preferably 10 times amount (ml/g).
Preferably, the volume ratio of each component of described mixed solvent is ethanol/water=1:9 ~ 9:1, preferred 1:1; Or methanol/water=1:9 ~ 9:1, preferred 1:1; Acetonitrile/water=1:9 ~ 9:1, preferred 1:2; Acetone/water=1:9 ~ 9:1, preferred 1:2.
Preferably, the temperature of dissolving Apremilast is 25 DEG C ~ 100 DEG C, preferably 85 DEG C.
Preferably, after crude product dissolves completely, rate of temperature fall when reducing system temperature is reduction per hour 5 DEG C ~ 90 DEG C, preferred reduction 8-12 DEG C per hour, preferably 10 DEG C further.
Concrete preparation method is: take Apremilast crude product, join the ethanol of 10 times amount (ml/g): in the mixed solvent of water=1:1, stir, be heated to backflow, whole dissolving, reflux 10 minutes, then reduce reacting liquid temperature to about 30 DEG C with the cooling rate of about 10 DEG C per hour, stir 3 hours with the stirring velocity of 30 revs/min at this temperature, filter, the solid obtained is dried overnight at about 60 DEG C, and X-ray powder diffraction result as shown in Figure 1, is Apremilast crystal form B
+.
For the 3rd technical problem of the present invention, the invention provides a kind of pharmaceutical composition, described composition comprises Apremilast new crystal B as claimed in claim 1
+and pharmaceutically acceptable vehicle or carrier.
Relational language defines:
Term " crystal formation " refer to because of in molecule or intermolecular bonding mode different, cause molecule different in lattice vacancy arrangement, form different crystalline structure.
The Apremilast new crystal B that the present invention obtains
+substantially pure, term " substantially pure " refers to that a kind of crystal formation is substantially devoid of one or more other crystal formations, its crystal form purity at least 60%, or at least 70%, or 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%, except this main crystal formation, other a small amount of crystal formations can also be mixed, the weight percent of other crystal formations is less than 20%, or be less than 10%, or be less than 5%, or be less than 3%, or be less than 1%, or be less than 0.5%, or be less than 0.1%, or be less than 0.01%.
When term " relative intensity " refers to that the intensity at the last the first peak in all diffraction peaks of X-ray powder diffraction pattern is 100%, the ratio of the intensity at the intensity at other peaks and the last the first peak.
Term " Apremilast " refers to (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-diketone, its
1h-NMR spectrum is substantially as follows: δ (CDCl
3): 1.47 (t, 3H); 2.26 (s, 3H); 2.87 (s, 3H); 3.71 ~ 3.75 (dd, 1H); 3.85 (s, 3H); 4.09 ~ 4.13 (q, 2H); 4.54 ~ 4.58 (dd, 1H); 5.86 ~ 5.89 (dd, 1H); 6.83 (d, 1H); 7.1 (d, 2H); 7.48 (d, 1H); 7.65 (t, 1H); 9.46 (s, 1H), its fusing point is essentially 144.5 DEG C ~ 147.5 DEG C.
In the context of the present invention, 2 θ values in X-ray powder diffraction pattern are all to spend (°) for unit.
Apremilast of the present invention can be prepared according to the method reported in published patent or document, such as nonrestrictive can according to disclosed in U.S. Patent number US 7893101 method preparation.
Accompanying drawing explanation
Fig. 1 is Apremilast crystal form B
+x-ray powder diffraction pattern;
Fig. 2 is Apremilast crystal form B
+means of differential scanning calorimetry (DSC) figure;
Fig. 3 is Apremilast crystal form B
+thermogravimetric analysis (TG) figure;
Fig. 4 is Apremilast crystal form B
+infrared absorption spectrum (IR) figure;
Fig. 5 is the X-ray powder diffraction pattern of Apremilast crystal form A;
Fig. 6 is the X-ray powder diffraction pattern of Apremilast crystal form B;
Fig. 7 is the X-ray powder diffraction pattern of Apremilast crystal C;
Fig. 8 is the X-ray powder diffraction pattern of Apremilast crystal formation D;
Fig. 9 is the X-ray powder diffraction pattern of Apremilast crystal formation E;
Figure 10 is the X-ray powder diffraction pattern of Apremilast crystal formation F;
Figure 11 is the X-ray powder diffraction pattern of Apremilast crystal formation G;
Figure 12 is Apremilast crystal form B
+x-ray powder diffraction pattern;
Figure 13 is Apremilast crystal form B
+x-ray powder diffraction pattern;
Figure 14 is Apremilast crystal form B+high temperature 30 days X-ray powder diffraction patterns;
Figure 15 is Apremilast crystal form B+high humidity 30 days X-ray powder diffraction patterns;
Figure 16 is Apremilast crystal form B+illumination 30 days X-ray powder diffraction patterns;
Figure 17 is Apremilast crystal form B+acceleration 6 months X-ray powder diffraction pattern;
Figure 18 is Apremilast crystal form B+long-term 6 months X-ray powder diffraction patterns;
Figure 19 is Apremilast crystal form B
+strong pressure experimental X-ray powder diffractogram;
Figure 20 is Apremilast crystal form B
+dissolution rate graphic representation in water;
Figure 21 is Apremilast crystal form B
+dissolution rate graphic representation in methyl alcohol.
Embodiment
In order to make those skilled in the art better understand technical scheme of the present invention, below disclose further some non-limiting embodiments the present invention is described in further detail.
Reagent used in the present invention all can be buied from the market or can be obtained by method described in the invention preparation.
Instrument parameter
Make separate stipulations except in distribution free, all analyses are carried out all at ambient temperature.
X-ray powder diffraction (XRPD)
X ' celerator the detector being furnished with the 2 θ scopes with 120 ° is used to carry out X-ray powder diffraction (XRPD) analysis.Cu-K α radiation is used to start to collect real time data with 0.01672 θ resolving power at about 3 ° of 2 θ.Tube voltage and amperage are set as 45kV and 40mA respectively.Antiscatter slits is set as 6.6mm, and divergent slit is 1 degree.The pattern of display 3 ~ 45 ° of 2 θ.Get appropriate Apremilast crystal form B
+be placed in zero Background Samples frame circular groove place, gently press with clean slide glass, obtain a smooth plane, and zero Background Samples frame is fixed, to obtain final product, sample to be placed on automatic sampling apparatus, successively sample introduction, sample analysis 99 seconds.Silicon is used to carry out instrument calibration with reference to standard specimen.
Dsc (DSC)
TA Instruments differential scanning calorimeter 2000 is used to carry out dsc (DSC).Sample put into aluminium DSC dish and accurately record weight.This dish lid covers, and then crimping or maintenance do not crimp.Sample pool is balanced at 40 DEG C the outlet temperature being also heated to 350 DEG C under nitrogen purge with the speed of 10 DEG C/min.Use indium metal as calibration sample.
Embodiment 1: Apremilast crystal form B
+preparation
With reference to US Patent No. 7893101 (Chinese CN102046167A of the same clan, [0240] section) method, by 250g (S)-2-(3-oxyethyl group-4-methoxyl group)-1-(methylsulfonyl)-ethyl-2-amine-N-ethanoyl-L-Leu salt, 121g 3-kharophen Tetra hydro Phthalic anhydride, 2500ml glacial acetic acid joins in reaction flask, be heated to backflow spend the night, cooling, remove solvent under reduced pressure, residue is dissolved in ethyl acetate, through water, saturated sodium bicarbonate solution, salt water washing, add anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain Apremilast crude product.
Crystal form A, B, C, D, E, F and G 7 kinds of crystal formations are obtained respectively according to the method for CN102046167A.Method is as follows respectively:
Crystal form A preparation method: take Apremilast crude product 5.0g, join in 30ml acetone soln, be heated to backflow, all dissolve, reflux 10 minutes, then reaction flask is placed in-20 DEG C, stir 3 hours with the stirring velocity of 30 revs/min at this temperature, filter, obtain solid dried overnight at 60 DEG C, X-ray powder diffraction result shows the crystal form A that its crystal formation is reported for patent CN102046167A, and its X-ray powder diffraction substantially as shown in Figure 5.
Crystal form B preparation method: take Apremilast crude product 5.0g, join in 15ml acetone soln, be heated to backflow, all dissolve, add 30ml dehydrated alcohol wherein again, reflux 10 minutes, slowly stir under room temperature condition and spend the night, adularescent solid is separated out, filter, obtain solid dried overnight at 60 DEG C, X-ray powder diffraction result shows the crystal form B that its crystal formation is reported for patent CN102046167A, and its X-ray powder diffraction substantially as shown in Figure 6.
Crystal C preparation method: take Apremilast crude product 5.0g, join in 20ml acetone soln, be heated to 40 DEG C, all dissolve, then add 60ml toluene wherein, stir 3 hours at 40 DEG C of temperature, there is solid to separate out, filter, obtain solid dried overnight at 60 DEG C, X-ray powder diffraction result shows the crystal C that its crystal formation is reported for patent CN102046167A, and its X-ray powder diffraction substantially as shown in Figure 7.
Crystal formation D preparation method: take Apremilast crude product 5.0g, join in 30ml dichloromethane solution, solution crosses 4.5 μm of filter membranes, filtrate reduce pressure at 35 DEG C of temperature (vacuum tightness is-0.09MPa) steam desolventize, there is solid to separate out, filter, obtain solid dried overnight at 60 DEG C, X-ray powder diffraction result shows the crystal formation D that its crystal formation is reported for patent CN102046167A, and its X-ray powder diffraction substantially as shown in Figure 8.
Crystal formation E preparation method: take Apremilast crude product 5.0g, join in 50ml acetonitrile solution, solution crosses 4.5 μm of filter membranes, filtrate reduce pressure at 40 DEG C of temperature (vacuum tightness is-0.09MPa) steam desolventize, there is solid to separate out, filter, obtain solid dried overnight at 60 DEG C, X-ray powder diffraction result shows the crystal formation E that its crystal formation is reported for patent CN102046167A, and its X-ray powder diffraction substantially as shown in Figure 9.
Crystal formation F preparation method: take Apremilast crude product 5.0g, join in 15ml acetone soln, reflux, all dissolves, add 15ml water more wherein, reflux 15 minutes, leave standstill crystallization under room temperature condition, have solid to separate out, filter, obtain solid dried overnight at 60 DEG C, X-ray powder diffraction result shows the crystal formation F that its crystal formation is reported for patent CN102046167A, and its X-ray powder diffraction substantially as shown in Figure 10.
Crystal formation G preparation method: take Apremilast crude product 5.0g, join 15ml ethyl acetate, reflux, all dissolve, add 15ml sherwood oil more wherein, reflux 15 minutes, under room temperature condition, slow stirring and crystallizing, has solid to separate out, filter, obtain solid dried overnight at 60 DEG C, X-ray powder diffraction result shows the crystal formation G that its crystal formation is reported for patent CN102046167A, and its X-ray powder diffraction substantially as shown in figure 11.
Take Apremilast crude product or crystal form A, B, C, D, E, F and G 5.0g, join 50ml ethanol: in the mixed solvent of water=1:1 (volume ratio), stir, be heated to backflow, whole dissolving, reflux 10 minutes, then reacting liquid temperature is reduced to about 30 DEG C with the cooling rate of about 10 DEG C per hour, 3 hours are stirred at this temperature with the stirring velocity of 30 revs/min, filter, the solid obtained is dried overnight at about 60 DEG C, X-ray powder diffraction result as shown in Figure 1, Apremilast crystal form B
+peak position, peak intensity are as shown in table 1, are Apremilast crystal form B
+.As shown in Figure 2, its differential scanning calorimetry measures Apremilast new crystal B to differential scanning heat (DSC) figure
+have endotherm(ic)peak about 144.3 DEG C ~ 152.6 DEG C greatly, its endotherm(ic)peak summit value is greatly about 147.9 DEG C.Thermogravimetric analysis (TG) figure as shown in Figure 3, described Apremilast new crystal B
+the mass loss that thermal weight loss is less than about 1%, is especially less than the mass loss of 1%.Apremilast B
+infrared absorpting light spectra (IR) as shown in Figure 4.
Table 1 Apremilast crystal form B
+peak position, spacing, peak intensity list
Embodiment 2 Apremilast crystal form B
+preparation
Take Apremilast crude product 5.0g, join 50ml ethanol: in the mixed solvent of water=2:1, stir, be warming up to backflow, whole dissolving, reflux 10 minutes, reduce reacting liquid temperature to about 30 DEG C with the rate of temperature fall of 10 DEG C per hour, stir 3 hours with the stirring velocity of 30 revs/min at this temperature, filter, the solid obtained is dried overnight at about 60 DEG C, and X-ray powder diffraction result as shown in figure 12, is Apremilast crystal form B
+.
Embodiment 3 Apremilast crystal form B
+preparation
Take Apremilast crude product 5.0g, join 50ml methyl alcohol: in the mixed solvent of water=1:1, stir, be warming up to backflow, whole dissolving, reflux 10 minutes, reduce reacting liquid temperature to about 30 DEG C with the rate of temperature fall of 10 DEG C per hour, stir 3 hours with the stirring velocity of 30 revs/min at this temperature, filter, the solid obtained is dried overnight at about 60 DEG C, and X-ray powder diffraction result as shown in figure 13, is Apremilast crystal form B
+.
Embodiment 4 Apremilast crystal form B
+preparation
To take in embodiment 1 preparation Apremilast crude product or or crystal form A, B, C, D, E, F and G, sample is joined in corresponding solvent, be heated to backflow, temperature of reaction is reduced again with certain rate of temperature fall per hour, crystallization, filter, the solid obtained is dried overnight at about 60 DEG C, X-ray powder diffraction detects the Apremilast crystal formation obtained, and specific experiment result is as shown in table 2.
Table 2 Apremilast crystal form B
+different condition preparation research
| Sequence number | Starting form | Solvent system | Cooling rate | XRPD analyzes |
| 1 | Crude product | Ethanol: water=1:1 | 10℃/h | Crystal form B + |
| 2 | Crystal form A | Ethanol: water=1:1 | 10℃/h | Crystal form B + |
| 3 | Crystal form B | Ethanol: water=1:1 | 10℃/h | Crystal form B + |
| 4 | Crystal C | Ethanol: water=1:1 | 15℃/h | Crystal form B + |
| 5 | Crystal formation D | Ethanol: water=1:1 | 10℃/h | Crystal form B + |
| 6 | Crystal formation E | Ethanol: water=1:1 | 10℃/h | Crystal form B + |
| 7 | Crystal formation F | Ethanol: water=1:1 | 10℃/h | Crystal form B + |
| 8 | Crystal formation G | Ethanol: water=1:1 | 10℃/h | Crystal form B + |
| 9 | Crude product | Ethanol: water=1:1 | 15℃/h | Crystal form B + |
| 10 | Crude product | Ethanol: water=2:1 | 10℃/h | Crystal form B + |
| 11 | Crude product | Methyl alcohol: water=1:1 | 10℃/h | Crystal form B + |
| 12 | Crude product | Acetonitrile: water=1:2 | 10℃/h | Crystal form B + |
| 13 | Crude product | Acetone: water=1:2 | 10℃/h | Crystal form B + |
| 14 | Crude product | Ethanol | 10℃/h | Crystal form B + |
| 15 | Crude product | Acetonitrile | 10℃/h | Crystal form B + |
| 16 | Crude product | Methyl alcohol | 10℃/h | Crystal form B + |
| 17 | Crude product | Virahol | 10℃/h | Crystal form B + |
| 18 | Crude product | Propyl carbinol | 10℃/h | Crystal form B + |
| 19 | Crude product | Acetone | 10℃/h | Crystal form B + |
Embodiment 5 size-grade distribution
By Apremilast crystal form B in embodiment 1
+grind crystal form B that patent US7893101 reports and carry out size-grade distribution with former and compare.
Adopt Malvern laser particle size analyzer, measure requirement according to " Chinese Pharmacopoeia " version in 2010 two annex Ⅸ E the 3rd methods to measure, take water as dispersion medium, 2% Triton is dispersion agent, ultrasound intensity is 12, ultrasonic time is 4min, surface sweeping scope is 0.02 ~ 2000 μm and measures, record result as shown in table 3.
Table 3 granularity distribution result
| Sample | D(10)/μm | D(50)/μm | D(90)/μm |
| Crystal form B | 2.85 | 6.99 | 18.18 |
| Crystal form B + | 4.36 | 14.97 | 57.39 |
From above experimental result, Apremilast crystal form B
+the granularity of size ratio crystal form B large, good fluidity, is more conducive to the technical studies such as preparation.
Embodiment 6 stability experiment
(1) influence factor test (exposed placement)
Placement condition: illumination: 5500lx; High temperature: 60 DEG C; High humidity: 92.5%
By the Apremilast crystal form B prepared in embodiment
+under being positioned over above-mentioned condition respectively, respectively at crystal formation and the related substance of the 5th, 10,30 day sampling and measuring sample, the results are shown in Table 4.
(2) accelerated test
Instrument: fixed temperature and humidity incubator
Condition: temperature 40 DEG C ± 2 DEG C, relative humidity RH75% ± 5%
By the Apremilast crystal form B prepared in embodiment
+put into fixed temperature and humidity incubator, respectively at the 1st, the crystal formation of 2,3,6 months sampling and measuring samples and related substance, the results are shown in Table 4.
(3) test of long duration
Instrument: fixed temperature and humidity incubator
Condition: temperature 25 DEG C ± 2 DEG C, relative humidity RH60% ± 5%
By the Apremilast crystal form B prepared in embodiment
+product put into fixed temperature and humidity incubator, respectively at the 0th, the crystal formation of 3,6,9,12,18,24,36 months sampling and measuring samples and related substance, the results are shown in Table 4.
(4) strong pressure experiment
Instrument: pressing machine
Condition: 140kgf/cm
2hyperpressure, 1 minute
By the Apremilast crystal form B prepared in embodiment
+put into pressing machine, give its 140kgf/cm
2hyperpressure, continue 1 minute, the crystal formation of working sample and related substance, the results are shown in Table 4.
Table 4 influence factor experimental result
Embodiment 7 draws moist experiment
Require regulation according to annex Ⅺ Ⅹ J continuous item in " Chinese Pharmacopoeia " version in 2010, contrived experiment, records the Apremilast crystal form B in embodiment 1
+the moist result that records of drawing be about 0.12%, result display Apremilast crystal form B
+moist without drawing, the specific experiment data weighed in experimentation are as shown in table 5.
Concrete experimentation is as follows:
(1) getting dry glass weighing bottle is placed in 25 DEG C ± 1 DEG C suitable thermostatic drier in experiment the day before yesterday, accurately weighed weight (m
1);
(2) get trial-product 1.0g, be laid in above-mentioned weighing bottle, trial-product is mixed spends about 1mm, accurately weighed weight (m
2);
(3) weighing bottle is uncovered, and with bottle cap with being placed in above-mentioned fixed temperature and humidity condition lower 24 hours;
(4) weighing bottle lid is built, accurately weighed weight (m
3).
Table 5 draws moist experimental data
| Empty bottle (m 1) | Sample | Bottle+sample (m 2) | Bottle after 24 hours+sample (m 3) | Moisture absorption is increased weight |
| 12.30495g | 1.00421g | 13.30916g | 13.31037g | 0.12％ |
Embodiment 8 solubility experiment
Require to carry out contrived experiment mensuration according to solubility test in " Chinese Pharmacopoeia " version in 2010 two notes on the use.
By the Apremilast crystal form B in embodiment 1
+be developed into powder, add a certain amount of solvent in 25 DEG C ± 2 DEG C, in powerful jolting 30 second every 5 minutes, dissolve situation according to HPLC external standard method.Apremilast crystal form B
+solubleness is as shown in table 6.Apremilast crystal form B
+in water, dissolution rate as shown in figure 20; Apremilast crystal form B
+in methyl alcohol, dissolution rate as shown in figure 21.
Table 6 solubility test result
| Solvent species | Solubleness |
| Water | 9.6μg/ml |
| Virahol | 0.34mg/ml |
| Methyl alcohol | 1.03mg/ml |
| Acetonitrile | 166.67mg/ml |
Although illustrate and describe embodiments of the invention, those having ordinary skill in the art will appreciate that: can carry out multiple change, amendment, replacement and modification to these embodiments when not departing from principle of the present invention and aim, scope of the present invention is by claim and equivalents thereof.
Claims (10)
1. Apremilast new crystal B shown in a formula I
+,
At the following charateristic avsorption band of 2 θ ± 0.2 tool in its X-ray powder diffraction pattern: 11.03,12.97,13.31,13.65,14.52,16.01,17.74,18.54,22.55,26.75.
2. Apremilast new crystal B according to claim 1
+it is characterized in that, at the following charateristic avsorption band of 2 θ ± 0.2 tool in its X-ray powder diffraction pattern: 11.03,12.97,13.31,13.65,14.52,16.01,17.74,18.54,21.30,21.75,22.55,22.88,25.46,26.34,26.75.
3. Apremilast new crystal B according to claim 2
+, it is characterized in that, its X-ray powder diffraction pattern has following characteristics:
4. the Apremilast new crystal B according to any one of claim 1-3
+, it is characterized in that, its differential scanning calorimetry measures Apremilast new crystal B
+have endotherm(ic)peak about 144.3 DEG C ~ 152.6 DEG C greatly, its endotherm(ic)peak summit value is greatly about 147.9 DEG C.
5. the Apremilast new crystal B according to any one of claim 1-3
+, it is characterized in that, described Apremilast new crystal B
+the mass loss that thermal weight loss is less than about 1%.
6. the Apremilast new crystal B described in any one of claim 1-5
+preparation method, it is characterized in that, preparation method is: by Apremilast dissolve in a solvent, until completely dissolved, reduce system temperature, crystallization, filter, solid is dried to constant weight in an oven, obtains the new crystal of Apremilast.
7. preparation method according to claim 7, it is characterized in that, described solvent is ethanol, acetonitrile, methyl alcohol, Virahol, propyl carbinol, acetone single solvent, or ethanol, methyl alcohol, Virahol, acetone, acetonitrile, propyl carbinol, the mixed solvent of in water two kinds or more, the consumption of solvent is 1 ~ 20 times amount (ml/g) of Apremilast crude product, preferably 10 times amount (ml/g).
8. preparation method according to claim 7, is characterized in that, the volume ratio of each component of described mixed solvent is ethanol/water=1:9 ~ 9:1, preferred 1:1; Or methanol/water=1:9 ~ 9:1, preferred 1:1; Acetonitrile/water=1:9 ~ 9:1, preferred 1:2; Acetone/water=1:9 ~ 9:1, preferred 1:2.
9. preparation method according to claim 7, is characterized in that, after crude product dissolves completely, rate of temperature fall when reducing system temperature is reduction per hour 5 DEG C ~ 90 DEG C, preferred reduction per hour 10 DEG C.
10. a pharmaceutical composition, is characterized in that, described composition comprises Apremilast new crystal B as claimed in claim 1
+and pharmaceutically acceptable vehicle or carrier.
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| PCT/CN2016/085029 WO2016206534A1 (en) | 2015-06-25 | 2016-06-07 | New crystal form of apremilast and preparation method therefor |
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| WO2016206534A1 (en) * | 2015-06-25 | 2016-12-29 | 济南纽华医药科技有限公司 | New crystal form of apremilast and preparation method therefor |
| CN107151227A (en) * | 2016-03-04 | 2017-09-12 | 广东东阳光药业有限公司 | The unbodied preparation method of Apremilast |
| CN107305198A (en) * | 2016-04-19 | 2017-10-31 | 重庆华邦胜凯制药有限公司 | A kind of high performance liquid chromatography separation is with determining Apremilast and the method about material |
| CN110049968A (en) * | 2016-11-09 | 2019-07-23 | 广东东阳光药业有限公司 | Apremilast eutectic and preparation method thereof |
| WO2021000934A1 (en) * | 2019-07-04 | 2021-01-07 | 南京明德新药研发有限公司 | Crystal form of benzimidazole-2-one compound, solvate thereof, crystal form of solvate thereof, and preparation method therefor |
| EP4183389A1 (en) * | 2021-11-18 | 2023-05-24 | KRKA, d.d., Novo mesto | Pharmaceutical composition comprising apremilast |
| WO2023118043A1 (en) * | 2021-12-22 | 2023-06-29 | Biohorm, S.L. | Pharmaceutical compositions of apremilast |
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| WO2019073431A1 (en) * | 2017-10-12 | 2019-04-18 | Piramal Enterprises Limited | An improved process for the preparation of apremilast and its intermediate |
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| WO2016206534A1 (en) | 2016-12-29 |
| CN104892486B (en) | 2017-12-08 |
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