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CN104016966A - Novel 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2,6-piperidinedione crystal forms and preparation method thereof - Google Patents

Novel 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2,6-piperidinedione crystal forms and preparation method thereof Download PDF

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Publication number
CN104016966A
CN104016966A CN201410045275.7A CN201410045275A CN104016966A CN 104016966 A CN104016966 A CN 104016966A CN 201410045275 A CN201410045275 A CN 201410045275A CN 104016966 A CN104016966 A CN 104016966A
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crystal form
preparation
isoindole
dihydro
oxo
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安晓霞
吕峰
李祯
祖远远
邓义
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DAFENG CHUANGNUO PHARMACEUTICAL Co Ltd
Shanghai Chuangnuo Pharmaceutical Co Ltd
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DAFENG CHUANGNUO PHARMACEUTICAL Co Ltd
Shanghai Chuangnuo Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

The invention relates to novel 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2,6-piperidinedione crystal form and a preparation method thereof, and particularly to four novel crystal forms, namely, crystal form X, crystal form XI, crystal form XII and crystal form XIII, and the preparation method of the novel crystal forms. The four novel crystal forms are stable to store, good in flowability, small in static electricity, more applicable to medicine preparations, simple and efficient in preparation process, capable of achieving on-scale production and environmental friendly.

Description

3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2,6-dioxopiperidine new crystal and preparation method thereof
Technical field
The present invention relates to the crystal formation of organic chemistry and medical compounds, more particularly, relate to 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2, four kinds of new crystal form X, XI, XII and XIII of 6-dioxopiperidine, and the preparation method of new crystal.
Background technology
Lenalidomide, molecular formula: C 13h 13n 3o 3, molecular weight: 259.26, No. CAS: 191732-72-6, its molecular structural formula is as follows:
3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2,6-dioxopiperidine, Chinese Revlimid (Lenalidomide), commodity are called Revlimid, the medicine that is used for the treatment of lethality hematologic disease and cancer of Shi You U.S. Celgene company research and development, is to treat at present the most significant medicine of multiple myeloma curative effect, and the clothes for patients that surpasses half reaches more than 3 years with extending the survival time after this medicine.It is also effectively to treat the unique medicine of myelodysplastic syndrome (MDS) in addition, clinical effectiveness find 64% patient MDS with after Revlimid treatment without treating MDS with transfusing blood again.On December 27th, 2005, the marrow that U.S. FDA approval is same as the low danger of 5q absence type and middle danger increases abnormal syndrome (MDS) blood transfusion dependent form patient, and combines with dexamethasone to be used for the treatment of and at least accepted treatment relapsed or stubborn multiple myeloma (MM) 1 time.The EMEA of European Union ratifies Combined with Dexamethasone treatment MM indication in June, 2007, and meanwhile, these product have obtained the status of the seldom used medicine for the treatment of myelodysplastic syndrome (MDS) and the seldom used medicine for the treatment of multiple myeloma in Europe.
The forms such as Revlimid crystal form A, crystal form B, crystal C, crystal formation D, crystal formation E, crystal formation F, crystal formation G, crystal formation H are disclosed in CN1871003B; Point out that crystal form A is non-solvent compound, crystal form B is half water thing, crystal C is half acetone solvate, crystal formation D is a water thing, crystal formation E is two water things, crystal formation F is anhydride (being obtained by two water thing crystal formation E dehydrations), and crystal formation G is non-solvent compound, the crystalline material that crystal formation H is partially hydrated thing (not exclusively dewatered and obtain by crystal formation E).Wherein, preparation technology's cycle of crystal form A, crystal form B and crystal formation E is longer, is unfavorable for the raising of production capacity; Crystal C is acetone solvate, and acetone content is 10% left and right, much larger than the acceptable limit of human body (<0.5%), can cause detrimentally affect to human body, therefore can not be for medicinal; The preparation technology of crystal formation D, crystal formation F, crystal formation G and crystal formation H is unstable, repeated poor.
CN102639522A discloses a kind of new crystal form I, for containing the solvate of 1.533% solvent, Revlimid is dissolved in to 120 times of methyl alcohol, heating be concentrated into methyl alcohol 1/3 after, add approximately 200 times of water, further concentrated to remove methyl alcohol, filter, dry.The required quantity of solvent of this preparation technology is large, and energy consumption is high, and produces large amount of sewage, and process repeatability is poor.
CN102453021A discloses Revlimid crystal formation I, and Revlimid is dissolved in the organic solvents such as DMF, DMSO, DMAC under the condition of heating, drips the dissolved agent crystallizatioies such as methyl alcohol.Verified, the disclosed new crystal I of this patent is the solvate of DMF, DMSO or DMAC actually, should not be used to medicinal.
CN101817813B discloses Revlimid form IV and medicinal combination thereof, and Revlimid is under agitation dissolved in hot acetonitrile, and gradient cooling is standing to room temperature; 20 ℃ of left and right, solvent is volatilized for a long time, until crystal is slowly separated out; Solid collected by filtration, collects the solid obtaining and volatilizes under room temperature.The shortcoming of the method is that acetonitrile is about 150 times of solutes, and quantity of solvent is very large, and energy consumption and cost are all very high, and the cycle is long, and production capacity is low.
Therefore this area new crystal formation of research and development of still needing, can stably stored, pharmaceutically acceptable, and preparation technology is simply efficient, is produced on a large scale.
Summary of the invention
The new crystal form X, crystal form X I, crystal form X II and the crystal form X III that the object of this invention is to provide lenalidomide, and preparation method thereof.
A first aspect of the present invention, provides 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2, the crystal form X of 6-dioxopiperidine, its DSC collection of illustrative plates shows two endotherm(ic)peaks of existence, and the peak value of first endotherm(ic)peak is at 169 ± 4 ℃, and the peak value of second endotherm(ic)peak is at 269 ± 2 ℃.
The DSC spectrogram demonstration of the crystal form B in CN1871003B, the peak value of first endotherm(ic)peak is only 146 ℃, far below the endotherm(ic)peak of crystal form X.
In another preference, the X-ray powder diffraction collection of illustrative plates of crystal form X comprises 3 or 3 the 2 θ values that are selected from above lower group: 13.2 ± 0.2 °, 14.2 ± 0.2 °, 15.4 ± 0.2 °, 17.3 ± 0.2 °, 19.2 ± 0.2 °, 19.6 ± 0.2 °, 20.8 ± 0.2 °, 23.3 ± 0.2 °, 23.9 ± 0.2 °, 27.7 ± 0.2 °, 29.3 ± 0.2 °, 31.2 ± 0.2 °, 34.6 ± 0.2 °.
In another preference, described crystal form X has XRD spectra substantially as shown in Figure 1.
In another preference, described crystal form X has DSC spectrogram substantially as shown in Figure 5.
In another preference, the thermogravimetric analysis collection of illustrative plates of described crystal form X (TGA collection of illustrative plates) is presented at 56～177 ℃ a weightless step, herein weightless 3.3-3.8%.
In another preference, the thermogravimetric analysis collection of illustrative plates of described crystal form X (TGA collection of illustrative plates) is presented at 56～177 ℃ a weightless step, herein weightlessness 3.6%.
In another preference, the TGA collection of illustrative plates of described crystal form X substantially as shown in Figure 9.
In another preference, the FTIR spectrogram of described crystal form X shows, at 3422cm -1, 3344cm -1, 2848cm -1, 1701cm -1, 1602cm -1, 1542cm -1, 1236cm -1, 1043cm -1, 988cm -1, 934cm -1, 910cm -1, 848cm -1, 795cm -1, 748cm -1, 671cm -1, 597cm -1, 552cm -1, 519cm -1, 462cm -1there is characteristic peak left and right.
In another preference, the FTIR collection of illustrative plates of described crystal form X substantially as shown in figure 13.
Second aspect present invention, provides the preparation method of the crystal form X described in first aspect, comprises the steps:
(1) lenalidomide salt is dissolved in solvent at ambient temperature, weightmeasurement ratio is about 1:10～1:30 grams per milliliter;
(2) in the solution obtaining in step (1), add sodium bicarbonate aqueous solution, adjust pH to 7.0～9.0;
(3) be warming up to 60～90 ℃, be incubated 24～48 hours;
(4) be cooled to 40～60 ℃, crystallization, thus obtain described crystal form X.
In context of the present invention, described room temperature refers to 10～30 ℃.
The 3-(4-amino-1 that step (1) is described, 3-dihydro-1-oxo-2H-isoindole-2-yl)-2,6-dioxopiperidine salt is selected from: lenalidomide mesylate, hydrochloride, tosilate.
The described solvent of step (1) is selected from: deionized water, methyl alcohol, ethanol, Methanol+Water, ethanol-water mixed solvent.
Approximately 10～30 times of the ratios of the lenalidomide salt described in step (1) and dissolution solvent, preferably 10～25 times, more preferably 15～20 times, more preferably 15～18 times.
Adjust pH to 7.0～9.5 in described step (2), preferably 7.5～9, more preferably 8.0～8.5.
Rising system temperature to 60～90 ℃ in described step (3), preferably 70～85 ℃, more preferably 80～85 ℃; Be incubated 24～48 hours, preferably 24～36 hours, more preferably 30～36 hours;
In described step (4), reduce system temperature to 40～60 ℃, preferably 45～55 ℃, more preferably 50～55 ℃.Vacuum filtration, uses deionized water filter cake 2～3 times, crystallization, thus obtain described crystal form X.
A third aspect of the present invention, 3-(4-amino-1 is provided, 3-dihydro-1-oxo-2H-isoindole-2-yl)-2, its X-ray powder diffraction collection of illustrative plates of the crystal form X I of 6-dioxopiperidine comprises 3 or 3 the 2 θ values that are selected from above lower group: 12.0 ± 0.2 °, 14.3 ± 0.2 °, 14.8 ± 0.2 °, 16.2 ± 0.2 °, 17.6 ± 0.2 °, 21.5 ± 0.2 °, 22.6 ± 0.2 °, 23.8 ± 0.2 °, 24.0 ± 0.2 °, 26.0 ± 0.2 °, 28.3 ± 0.2 °, 29.8 ± 0.2 °, 31.9 ± 0.2 °, 32.6 ± 0.2 ° and 33.5 ± 0.2 °.
In another preference, the X-ray powder diffraction collection of illustrative plates of described crystal form X I substantially as shown in Figure 2.
In another preference, the dsc of described crystal form X I is analyzed collection of illustrative plates (DSC collection of illustrative plates) and is shown that first endotherm(ic)peak is at 90 ± 5 ℃ and 107 ± 5 ℃, and second endotherm(ic)peak is at 269 ± 3 ℃.
In another preference, the dsc of described crystal form X I is analyzed collection of illustrative plates (DSC collection of illustrative plates) substantially as shown in Figure 6.
In another preference, the TGA spectrogram of described crystal form X I is presented at 62～96 ℃ a weightless step, herein weightlessness 4.5%～5.5%.
In another preference, the TGA spectrogram of described crystal form X I substantially as shown in figure 10.
In another preference, the water content of described crystal form X I is 4.5wt%～5.5wt%, records the water content of crystal formation with Karl Fischer.
In another preference, the Karl Fischer of described crystal form X I records it and contains 4.8% moisture content, therefore can judge that crystal form X I is for the hydrate containing 0.75 molecular water.
In another preference, the FTIR spectrogram of described crystal form X I shows, at 3408cm -1, 3196cm -1, 3087cm -1, 2875cm -1, 1681cm -1, 1490cm -1, 1459cm -1, 1411cm -1, 1343cm -1, 1299cm -1, 1240cm -1, 879cm -1, 744cm -1, 610cm -1, 546cm -1left and right goes out to have characteristic peak.
In another preference, the FTIR spectrogram of described crystal form X I substantially as shown in figure 14.
A fourth aspect of the present invention, provides the preparation method of the crystal form X I described in the third aspect, comprises the steps:
A) lenalidomide salt is dissolved in the mixed solvent of deionized water/organic solvent at ambient temperature;
B), in the solution obtaining in step a), add adjusting PH with base to 7.0～9.0;
C) under 0 ℃～reflux temperature, stir 0.5～4 hour, crystallization, thus obtain described crystal form X I.
In another preference, described preparation method, comprises the steps:
(1) lenalidomide salt is dissolved at ambient temperature in the mixed solvent of deionized water/organic solvent and obtains mixing solutions;
(2), in described mixing solutions, under stirring, be added dropwise to alkali and regulate pH to 7.0～9.0;
(3) drip and finish, nitrogen protection, 0 ℃ is stirred 0.5～4 hour to reflux temperature condition, and deionized water drip washing filter cake 2～3 times are used in vacuum filtration;
(4) filter cake vacuum-drying 12～36 hours under room temperature to 45 ℃ condition, crystallization, thus obtain described crystal form X I.
Described lenalidomide salt is selected from: lenalidomide mesylate, hydrochloride, tosilate.
Described organic solvent is alcoholic solvent, is selected from: methyl alcohol, ethanol, Virahol.
In the mixed solvent of described deionized water/organic solvent, the content of alcoholic solvent is about 70～95%(v/v), preferably 75～90%, more preferably 80～90%.
Described alkali is selected from: diethylamine, triethylamine, aniline, sodium bicarbonate, sodium hydroxide, sodium carbonate etc., preferably triethylamine, diethylamine.
Preferably 20～40 ℃ of temperature in step (3) or step c); Churning time 0.5～4 hour, preferably 1～5 hour, more preferably 2～4 hours.
The drying temperature that step (4) is described, preferred room temperature to 35 ℃, more preferably under room temperature condition, 12～36 hours time, preferably 12～24 hours, more preferably 18～22 hours.
In another preference, in step (3) or step c), churning time is preferably 2～4 hours, more preferably 3～4 hours.
A fifth aspect of the present invention, 3-(4-amino-1 is provided, 3-dihydro-1-oxo-2H-isoindole-2-yl)-2, the crystal form X II of 6-dioxopiperidine, its X-ray powder diffraction collection of illustrative plates comprises 3 or 3 the 2 θ values that are selected from above lower group: 13.1 ± 0.2 °, 14.1 ± 0.2 °, 15.7 ± 0.2 °, 16.4 ± 0.2 °, 17.2 ± 0.2 °, 17.4 ± 0.2 °, 19.1 ± 0.2 °, 19.5 ± 0.2 °, 20.9 ± 0.2 °, 21.3 ± 0.2 °, 26.6 ± 0.2 °, 27.4 ± 0.2 °, 28.6 ± 0.2 °, 29.2 ± 0.2 °, 32.0 ± 0.2 ° and 33.2 ± 0.2 °.
In another preference, the XRD figure of described crystal form X II is composed substantially as shown in Figure 3.
In another preference, the dsc of described crystal form X II is analyzed collection of illustrative plates (DSC collection of illustrative plates) and is shown that first endotherm(ic)peak is at 89 ± 4 ℃, and second endotherm(ic)peak is at 124 ± 4 ℃, and the 3rd endotherm(ic)peak is at 269 ± 3 ℃.
In another preference, the DSC collection of illustrative plates of described crystal form X II substantially as shown in Figure 7.
In another preference, the TGA spectrogram of described crystal form X II is presented at 75～130 ℃ obvious two weightless steps, and wherein, between 75～95 ℃, weightlessness is that between 3.4～4.2%, 110～130 ℃, weightlessness is 2.1～2.9%.In another preference, the TGA spectrogram of described crystal form X II is presented at 75～95 ℃ the weightless step that a weightlessness is 3.8%, at 110～130 ℃, has the weightless step that a weightlessness is 2.5%.
In another preference, the water content of crystal form X II is 6.0～7.0%, with Karl Fischer, records.
In another preference, Karl Fischer records described crystal form X II and contains 6.3% moisture content, therefore can judge that new crystal form X II is for the hydrate containing 1 molecular water.
In another preference, the TGA spectrogram of described crystal form X II substantially as shown in figure 11.
In another preference, the FTIR spectrogram of described crystal form X II shows, at 3559cm -1, 3502cm -1, 3425cm -1, 3224cm -1, 3085cm -1, 1954cm -1, 1491cm -1, 1419cm -1, 1351cm -1, 1048cm -1, 994cm -1, 935cm -1, 850cm -1, 796cm -1there is characteristic peak left and right.
In another preference, the FTIR spectrogram of described crystal form X II substantially as shown in figure 15.
A sixth aspect of the present invention, provides the preparation method of the crystal form X II described in the 5th aspect, comprises the steps:
A) lenalidomide salt is at room temperature dissolved in the mixed solvent of deionized water // alcoholic solvent;
B), in the solution obtaining in step a), add adjusting PH with base to 7.0～9.0;
C) under 0 ℃～reflux temperature condition, stir 5～8 hours; Crystallization, thus described crystal form X II obtained.
In another preference, described preparation method comprises the following steps:
(1) lenalidomide salt is dissolved in the mixed solvent of deionized water/organic solvent at ambient temperature;
(2), in above mixing solutions, under stirring, be added dropwise to suitable alkali regulation system and adjust pH to 7.0～9.0;
(3) drip and finish, nitrogen protection, stirs 5～8 hours under 0 ℃～reflux temperature condition, and deionized water drip washing filter cake 2～3 times are used in vacuum filtration;
(4) filter cake vacuum-drying 12～36 hours under room temperature to 45 ℃ condition.
Described lenalidomide salt is selected from: lenalidomide mesylate, hydrochloride, tosilate.
In the mixed solvent of described deionized water/organic solvent, the content of alcoholic solvent is about 65～80%(v/v), preferably 70～80%, more preferably 70～75%.
Described organic solvent is alcoholic solvent, is selected from: methyl alcohol, ethanol, Virahol.
Described alkali is selected from: diethylamine, triethylamine, aniline, sodium bicarbonate, sodium hydroxide, sodium carbonate, preferably triethylamine, diethylamine.
Step (3) or step c) in preferred room temperature～35 ℃ of temperature; Churning time 5～8 hours, preferably 5～7 hours, more preferably 5～6 hours;
The drying temperature that step (4) is described, preferred room temperature to 35 ℃, more preferably under room temperature condition, 12～36 hours time, preferably 12～24 hours, more preferably 18～22 hours.
The 7th aspect of invention, 3-(4-amino-1 is provided, 3-dihydro-1-oxo-2H-isoindole-2-yl)-2, the crystal form X III of 6-dioxopiperidine, its X-ray powder diffraction collection of illustrative plates comprises 3 or 3 the 2 θ values that are selected from above lower group: 13.3 ± 0.2 °, 13.4 ± 0.2 °, 14.2 ± 0.2 °, 16.6 ± 0.2 °, 19.6 ± 0.2 °, 20.8 ± 0.2 °, 21.4 ± 0.2 °, 29.3 ± 0.2 °.
In another preference, the X-ray powder diffraction collection of illustrative plates of described crystal form X III also comprises the 2 θ values that are selected from lower group: 11.4 ± 0.2 °, 17.3 ± 0.2 °, 21.0 ± 0.2 °, 30.6 ± 0.2 °.
In another preference, the XRD figure of described crystal form X III is composed substantially as shown in Figure 4.
In another preference, the DSC collection of illustrative plates of described crystal form X III shows that DSC spectrogram shows that first endotherm(ic)peak is at 86 ± 4 ℃, and second endotherm(ic)peak is at 123 ± 5 ℃, and the 3rd endotherm(ic)peak is at 154 ± 3 ℃, and the 4th endotherm(ic)peak is at 269 ± 3 ℃.
In another preference, the DSC collection of illustrative plates of described crystal form X III substantially as shown in Figure 8.
In another preference, the TGA spectrogram of described crystal form X III is presented at 75～130 ℃ obvious two weightless steps, and wherein, between 75～95 ℃, weightlessness is that between 6.8～7.6%, 110～160 ℃, weightlessness is 1.7～2.5%.
In another preference, the TGA spectrogram of described crystal form X III shows two weightless steps, at 75～95 ℃, has the weightless step that a weightlessness is 7.2%, at 110～160 ℃, has the weightless step that a weightlessness is 2.1%.
In another preference, the water content recording with Karl Fischer, the moisture of crystal form X III is 8.9～10.2%.
In another preference, Karl Fischer records described crystal form X III and contains 9.5% moisture content, therefore can judge that new crystal form X III is for the hydrate containing 1.5 molecular waters.
In another preference, the TGA spectrogram of described crystal form X III substantially as shown in figure 12.
In another preference, the FTIR spectrogram of described new crystal form X III shows, at 3428cm -1, 3241cm -1, 3065cm -1, 1742cm -1, 1634cm -1, 1447cm -1, 1359cm -1, 987cm -1there is characteristic peak left and right.
In another preference, the FTIR spectrogram of described crystal form X III substantially as shown in figure 16.
A eighth aspect of the present invention, provides the preparation method of the crystal form X III described in the 7th aspect, comprises the steps:
A) lenalidomide salt is dissolved in the mixed solvent of deionized water/alcoholic solvent at ambient temperature;
B), in the solution obtaining in step a), add adjusting PH with base to 7.0～9.0;
C) under 0 ℃～reflux temperature, stir 9～24 hours;
D) dry crystallization, thus described crystal form X III obtained.
In another preference, described preparation method comprises the steps:
(1) lenalidomide salt is dissolved in the mixed solvent of deionized water/organic solvent at ambient temperature;
(2), in the solution obtaining in step (1), under stirring, be added dropwise to suitable alkali regulation system and adjust pH to 7.0～9;
(3) drip and finish, nitrogen protection, stirs 9～24 hours under 0 ℃～reflux temperature condition, and deionized water drip washing filter cake 2～3 times are used in vacuum filtration;
(4) filter cake vacuum-drying 12～36 hours under room temperature to 45 ℃ condition.
Described 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2,6-dioxopiperidine salt is selected from: lenalidomide mesylate, hydrochloride, tosilate etc.;
In the mixed solvent of described deionized water/organic solvent, the content of alcoholic solvent is about 50～75%(v/v), preferred 60～65%(v/v).
Described organic solvent is alcoholic solvent, is selected from: methyl alcohol, ethanol, Virahol.
Described alkali is selected from: diethylamine, triethylamine, aniline, sodium bicarbonate, sodium hydroxide, sodium carbonate etc., preferably triethylamine, diethylamine;
Step (3) or step c) in preferred room temperature～40 ℃ of temperature; Churning time 9～24 hours, preferably 9～14 hours, more preferably 9～11 hours, even 9～10 hours.
The drying temperature that step (4) is described, preferred room temperature to 35 ℃, more preferably under room temperature condition, 12～36 hours time, preferably 12～24 hours, more preferably 18～22 hours.
A ninth aspect of the present invention, provides a kind of pharmaceutical composition, comprises pharmaceutically acceptable carrier and is selected from one or more the crystal combination in lower group:
(a) crystal form X described in first aspect;
(b) the crystal form X I described in the third aspect;
(c) the crystal form X II described in the 5th aspect;
(d) the crystal form X III described in the 7th aspect.
A tenth aspect of the present invention, a kind of 3-(4-amino-1 is provided, 3-dihydro-1-oxo-2H-isoindole-2-yl)-2,6-dioxopiperidine composition or mixture, comprise at least 95% crystal form X, at least 95% crystal form X I, 95% crystal form X II or at least 95% crystal form X III.
A eleventh aspect of the present invention, provides crystal form X described in (a) first aspect; (b) the crystal form X I described in the third aspect; (c) the crystal form X II described in the 5th aspect; Or (d) purposes of the crystal form X III described in the 7th aspect, for the preparation of the medicine that prevents and/or treats lethality hematologic disease or tumour.
3-(4-provided by the invention amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2, four kinds of new crystal form X of 6-dioxopiperidine, crystal form X I, crystal form X II and crystal form X III, stable storing (all not turning brilliant in the accelerated tests such as high temperature, high humidity, illumination, grinding, compressing tablet), and good fluidity, static are little, are more suitable for pharmaceutical preparation.
Compared with prior art; the preparation technology of lenalidomide new crystal form X of the present invention, crystal form X I, crystal form X II and crystal form X III is simply efficient; can accomplish scale production, and environmentally friendly.
In should be understood that within the scope of the present invention, above-mentioned each technical characterictic of the present invention and can combining mutually between specifically described each technical characterictic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, at this, tire out and state no longer one by one.
Accompanying drawing explanation
Fig. 1 is the XRD spectra of lenalidomide new crystal form X of the present invention;
Fig. 2 is the XRD spectra of lenalidomide new crystal form X I of the present invention;
Fig. 3 is the XRD spectra of lenalidomide new crystal form X II of the present invention;
Fig. 4 is the XRD spectra of lenalidomide new crystal form X III of the present invention;
Fig. 5 is the DSC spectrogram of lenalidomide new crystal form X of the present invention;
Fig. 6 is the DSC spectrogram of lenalidomide new crystal form X I of the present invention;
Fig. 7 is the DSC spectrogram of lenalidomide new crystal form X II of the present invention;
Fig. 8 is the DSC spectrogram of lenalidomide new crystal form X III of the present invention;
Fig. 9 is the TGA spectrogram of lenalidomide new crystal form X of the present invention;
Figure 10 is the TGA spectrogram of lenalidomide new crystal form X I of the present invention;
Figure 11 is the TGA spectrogram of lenalidomide new crystal form X II of the present invention;
Figure 12 is the TGA spectrogram of lenalidomide new crystal form X III of the present invention;
Figure 13 is the FTIR spectrogram of lenalidomide new crystal form X of the present invention;
Figure 14 is the FTIR spectrogram of lenalidomide new crystal form X I of the present invention;
Figure 15 is the FTIR spectrogram of lenalidomide new crystal form X II of the present invention;
Figure 16 is the FTIR spectrogram of lenalidomide new crystal form X III of the present invention;
Figure 17 is the DSC spectrogram of known crystal form B.
Embodiment
Present inventor is through extensively and in depth research; develop first 3-(4-amino-1; 3-dihydro-1-oxo-2H-isoindole-2-yl)-2; four kinds of new crystal of 6-dioxopiperidine, stable storing, good fluidity, static are little, are more suitable for pharmaceutical preparation; and preparation technology is simply efficient; reproducible, and can accomplish scale production, and environmentally friendly.On this basis, completed the present invention.
Crystal form X, crystal form X I, crystal form X II and crystal form X III
The invention provides four kinds of new crystal of lenalidomide, is crystal form X, crystal form X I, crystal form X II and crystal form X III.
The X-ray powder diffraction collection of illustrative plates of crystal form X comprises 3 or 3 the 2 θ values that are selected from above lower group: 13.2 ± 0.2 °, 14.2 ± 0.2 °, 15.4 ± 0.2 °, 17.3 ± 0.2 °, 19.2 ± 0.2 °, 19.6 ± 0.2 °, 20.8 ± 0.2 °, 23.3 ± 0.2 °, 23.9 ± 0.2 °, 27.7 ± 0.2 °, 29.3 ± 0.2 °, 31.2 ± 0.2 °, 34.6 ± 0.2 °.
The DSC collection of illustrative plates of crystal form X shows two endotherm(ic)peaks of existence, and the peak value of first endotherm(ic)peak is at 169 ± 4 ℃, and the peak value of second endotherm(ic)peak is at 269 ± 2 ℃.
Described crystal form X has XRD spectra substantially as shown in Figure 1.
Described crystal form X has DSC spectrogram substantially as shown in Figure 5.
The TGA collection of illustrative plates of described crystal form X substantially as shown in Figure 9.
The FTIR collection of illustrative plates of described crystal form X substantially as shown in figure 13.
The X-ray powder diffraction collection of illustrative plates of crystal form X I comprises 3 or 3 the 2 θ values that are selected from above lower group: 12.0 ± 0.2 °, 14.3 ± 0.2 °, 14.8 ± 0.2 °, 16.2 ± 0.2 °, 17.6 ± 0.2 °, 21.5 ± 0.2 °, 22.6 ± 0.2 °, 23.8 ± 0.2 °, 24.0 ± 0.2 °, 26.0 ± 0.2 °, 28.3 ± 0.2 °, 29.8 ± 0.2 °, 31.9 ± 0.2 °, 32.6 ± 0.2 ° and 33.5 ± 0.2 °.The dsc of described crystal form X I is analyzed collection of illustrative plates (DSC collection of illustrative plates) and is shown that first endotherm(ic)peak is at 90 ± 5 ℃ and 107 ± 5 ℃, and second endotherm(ic)peak is at 269 ± 3 ℃.
The X-ray powder diffraction collection of illustrative plates of described crystal form X I substantially as shown in Figure 2.
The dsc of described crystal form X I is analyzed collection of illustrative plates (DSC collection of illustrative plates) substantially as shown in Figure 6.
The TGA spectrogram of described crystal form X I substantially as shown in figure 10.
The FTIR spectrogram of described crystal form X I substantially as shown in figure 14.
The X-ray powder diffraction collection of illustrative plates of crystal form X II comprises 3 or 3 the 2 θ values that are selected from above lower group: 13.1 ± 0.2 °, 14.1 ± 0.2 °, 15.7 ± 0.2 °, 16.4 ± 0.2 °, 17.2 ± 0.2 °, 17.4 ± 0.2 °, 19.1 ± 0.2 °, 19.5 ± 0.2 °, 20.9 ± 0.2 °, 21.3 ± 0.2 °, 26.6 ± 0.2 °, 27.4 ± 0.2 °, 28.6 ± 0.2 °, 29.2 ± 0.2 °, 32.0 ± 0.2 ° and 33.2 ± 0.2 °.
The XRD figure spectrum of described crystal form X II substantially as shown in Figure 3.
The DSC collection of illustrative plates of described crystal form X II substantially as shown in Figure 7.
The TGA spectrogram of described crystal form X II substantially as shown in figure 11.
The FTIR spectrogram of described crystal form X II substantially as shown in figure 15.
The X-ray powder diffraction collection of illustrative plates of crystal form X III comprises 3 or 3 the 2 θ values that are selected from above lower group: 13.3 ± 0.2 °, 13.4 ± 0.2 °, 14.2 ± 0.2 °, 16.6 ± 0.2 °, 19.6 ± 0.2 °, 20.8 ± 0.2 °, 21.4 ± 0.2 °, 29.3 ± 0.2 °.
The XRD figure spectrum of described crystal form X III substantially as shown in Figure 4.
The DSC collection of illustrative plates of described crystal form X III substantially as shown in Figure 8.
The TGA spectrogram of described crystal form X III substantially as shown in figure 12.
The FTIR spectrogram of described crystal form X III substantially as shown in figure 16.
Pharmaceutical composition
The present invention also provides a kind of pharmaceutical composition, and it comprises the activeconstituents in safe and effective weight range, and pharmaceutically acceptable carrier.
" activeconstituents " of the present invention refers to crystal form X, crystal form X I, crystal form X II and/or the crystal form X III of lenalidomide of the present invention.
" activeconstituents " of the present invention and pharmaceutical composition are for the preparation of the medicine that prevents and/or treats lethality hematologic disease or tumour.In another preference, for the preparation of the medicine that prevents and/or treats multiple myeloma.In another preference, for the preparation of the medicine that prevents and/or treats myelodysplastic syndrome.
" safe and effective amount " refers to: the amount of activeconstituents is enough to obviously improve the state of an illness, and is unlikely to produce severe side effect.Conventionally, pharmaceutical composition contains 1-2000mg activeconstituents/agent, more preferably, contains 10-200mg activeconstituents/agent.Preferably, described " potion " is a tablet.
" pharmaceutically acceptable carrier " refers to: one or more consistency solids or liquid filler or gelatinous mass, they are suitable for people uses, and must have enough purity and enough low toxicity." consistency " referred to herein as each component energy and activeconstituents of the present invention and blending mutually between them in composition, and the drug effect of not obvious reduction activeconstituents.Pharmaceutically acceptable carrier part example have Mierocrystalline cellulose and derivative (as Xylo-Mucine, ethyl cellulose sodium, cellulose ethanoate etc.) thereof, gelatin, talcum, solid lubricant (as stearic acid, Magnesium Stearate), calcium sulfate, vegetables oil (as soya-bean oil, sesame oil, peanut oil, olive wet goods), polyvalent alcohol (as propylene glycol, glycerine, N.F,USP MANNITOL, sorbyl alcohol etc.), emulsifying agent ( ), wetting agent (as sodium lauryl sulphate), tinting material, seasonings, stablizer, antioxidant, sanitas, apirogen water etc.
The method of application of activeconstituents of the present invention or pharmaceutical composition is not particularly limited, and representational method of application comprises (but being not limited to): in oral, knurl, rectum, parenteral (intravenously, intramuscular or subcutaneous) etc.
Solid dosage for oral administration comprises capsule, tablet, pill, powder and granule.
In these solid dosages, activeconstituents mixes with at least one conventional inert excipient (or carrier), as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade, or mixes with following compositions: (a) filler or expanding material, for example, starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid; (b) tackiness agent, for example, Walocel MT 20.000PV, alginate, gelatin, Polyvinylpyrolidone (PVP), sucrose and gum arabic; (c) wetting Agent for Printing Inks, for example, glycerine; (d) disintegrating agent, for example, agar, calcium carbonate, yam starch or tapioca (flour), alginic acid, some composition silicate and sodium carbonate; (e) retarding solvent, for example paraffin; (f) absorb accelerator, for example, quaternary ammonium compound; (g) wetting agent, for example hexadecanol and glyceryl monostearate; (h) sorbent material, for example, kaolin; (i) lubricant, for example, talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture.In capsule, tablet and pill, formulation also can comprise buffer reagent.
Described solid dosage also can adopt dressing and the preparation of shell material, as casing and other material well known in the art.They can comprise opacifying agent, and, in the mode that in this composition, the release of activeconstituents can postpone certain part in digestive tube, discharge.The example of adoptable embedding component is polymeric material and Wax.
Liquid dosage form for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.Except activeconstituents, liquid dosage form can comprise the conventional inert diluent adopting in this area, as water or other solvent, solubilizing agent and emulsifying agent, example is known, the mixture of ethanol, Virahol, ethyl-carbonate, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethyl formamide and oil, particularly Oleum Gossypii semen, peanut oil, maize germ, sweet oil, Viscotrol C and sesame oil or these materials etc.Except these inert diluents, composition also can comprise auxiliary agent, as wetting agent, emulsifying agent and suspension agent, sweeting agent, correctives and spices.
Except activeconstituents, suspension can comprise suspension agent, for example, and the mixture of ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, Microcrystalline Cellulose, aluminum methylate and agar or these materials etc.
Composition for parenteral injection can comprise physiologically acceptable aseptic moisture or anhydrous solution, dispersion liquid, suspension or emulsion, and for being again dissolved into aseptic Injectable solution or the sterilized powder of dispersion liquid.Suitable moisture and nonaqueous carrier, thinner, solvent or vehicle comprises water, ethanol, polyvalent alcohol and suitable mixture thereof.
The compounds of this invention can be individually dosed, or with other treatment medicine (as chemotherapeutic) Combined Preparation.
While making pharmaceutical composition, the compounds of this invention of safe and effective amount to be applicable to need the Mammals (as people) for the treatment of, the effective dosage of dosage for pharmaceutically thinking while wherein using, for the people of 60kg body weight, day dosage is generally 1～2000mg, preferably 20～500mg.Certainly, concrete dosage also should be considered the factors such as route of administration, patient health situation, and these are all within skilled practitioners skill.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.The experimental technique of unreceipted actual conditions in the following example, conventionally according to normal condition or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise per-cent and umber calculate by weight.
Universal method
XRD figure spectrum measuring method
On Bruker AXS/D8Advance X-ray powder diffraction instrument, carry out, transmitting target is Cu target, and power supply is set to 40kV, 40mA, and transmitting slit is that 1mm, reception slit are 0.1mm, scanning speed is that 0.5 °/min, step-length are 0.02 °, and 2 θ sweep limits are 3～40 °.
DSC collection of illustrative plates measuring method
In airtight aluminium crucible, pass into 50ml/min nitrogen gas stream, at temperature between 25～300 ℃, heating rate is 10 ℃/min, DSC Q2000(U.S. TA company) measure differential scanning calorimetric analysis (DSC) figure in equipment.
TGA collection of illustrative plates measuring method
In encloses container, pass into the nitrogen gas stream of 100ml/min, at temperature between 20～450 ℃, heating rate is 10 ℃/min, thermogravimetric analysis (TGA) figure in SDT Q600 (U.S. TA company) equipment.
FTIR collection of illustrative plates measuring method
On the PE instrument of PerkinElmer Spectrum65 type Fourier transformation infrared spectrometer (FTIR), carry out Infrared spectroscopy, sweep limit is set as 4000cm -1-450cm -1, scanning times 4 times, resolving power is 4cm -1, adopt KBr compressing tablet.
Bulk density measuring method
First take the product of certainweight, pour in the graduated tap density graduated cylinder of 100ml tool, be then fixed on FZS4-4B type tap density determinator and vibrate, until solid volume, without considerable change, reads volume, calculate tap density.
HPLC measuring method
Get the about 10mg of this product, add thinner (methyl alcohol/0.01molL -1potassium primary phosphate, uses H 3pO 4tune pH is 3.5=50/50) dissolve and be diluted to 20ml, shake up, as need testing solution.According to high performance liquid chromatography experiment, select XTerra RP18 chromatographic column (4.6*250mm, 5 μ m), Mobile phase B is acetonitrile, and moving phase C is methyl alcohol, and moving phase D is 0.01molL -1potassium primary phosphate, uses H 3pO 4adjusting pH is 3.50, and according to the form below carries out gradient elution, rear working time 15min, flow velocity is 1.0ml/min, column temperature is 30 ℃, sample chamber temperature is 10 ℃, wavelength is 210nm.
Time (min) Solution B (%) Solution C (%) Solution D (%)
0 4 6 90
15 4 6 90
35 20 30 50
50 20 30 50
Embodiment 1
The preparation of lenalidomide new crystal form X
By 43g3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2,6-dioxopiperidine mesylate raw material and 690ml deionized water, add in a 1L there-necked flask, stirs fully and mix, until solute dissolves completely under room temperature; Solution decompression is filtered, and gained clear liquor is transferred in another 2L there-necked flask.Regulate mechanical stirrer, the sodium bicarbonate aqueous solution 400ml that dropping concentration is 0.525mol/L, starts reaction crystallization process; Drip to finish, under nitrogen protection, ℃ insulation of rising system temperature to 80～82, after 30 hours, reduces system temperature to 53～56 ℃, by magma suction filtration, and the deionized water wash of 55 ℃ of left and right of certain volume 3 times for filter cake; By at room temperature vacuum-drying of filter cake 24 hours, obtain 30.0g off-white color crystal, mass yield is 69.8%, and molar yield is 95.6%, and bulk density is 0.41g/ml, and good fluidity, static are little.
Its x-ray diffractogram of powder as shown in Figure 1, carry out the resulting differential scanning calorimetric analysis of dsc analysis (DSC) figure as shown in Figure 5, carry out TGA and analyze resulting thermogravimetric analysis (TGA) figure as shown in Figure 9, the Infrared spectroscopy figure of gained as shown in figure 13.
Figure 17 is the DSC spectrogram of the known crystal form B in CN1871003B, and this figure shows that the peak value of first endotherm(ic)peak is only 146 ℃, the endotherm(ic)peak of the crystal form X of preparing far below embodiment 1.The relatively known crystal form B of new crystal form X, have particle integrity, good fluidity, static little, be more conducive to the advantages such as preparation process.
Embodiment 2
The preparation of lenalidomide new crystal form X
By 30g3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2,6-dioxopiperidine mesylate raw material and 750ml deionized water, add in a 1L there-necked flask, stirs fully and mix, until solute dissolves completely under room temperature; Solution decompression is filtered, and gained clear liquor is transferred in another 2L there-necked flask.Regulate mechanical stirrer, the sodium bicarbonate aqueous solution 300ml that dropping concentration is 0.525mol/L, starts reaction crystallization process; Drip to finish, under nitrogen protection, ℃ insulation of rising system temperature to 80～83, after 28 hours, reduces system temperature to 55～58 ℃, by magma suction filtration, and the deionized water wash of 55 ℃ of left and right of certain volume 2 times for filter cake; By at room temperature vacuum-drying of filter cake 12 hours, obtain 20.5g off-white color crystal, mass yield is 68.4%, and molar yield is 93.8%, and bulk density is 0.36g/ml, and good fluidity, static are little.
Its XRD figure, DSC figure, TGA figure and embodiment 1 are basically identical.
Embodiment 3
The preparation of lenalidomide new crystal form X I
By 37g3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2, deionized water/methanol mixed solvent that 6-dioxopiperidine mesylate raw material and 400ml volume ratio are 20:80, adds in a 1L there-necked flask, under room temperature, stir fully and mix, until solute dissolves completely; Solution decompression is filtered, and gained clear liquor is transferred in another 1L there-necked flask.Fully stir, in solution, slowly add triethylamine, start reaction crystallization process; In dropping process, there are a large amount of off-white color solids to separate out; After system pH is adjusted to 8.3, nitrogen protection, stirs under room temperature 4 hours, magma is filtered to filter cake deionized water wash 3 times; By at room temperature vacuum-drying of filter cake 20 hours, obtain 23.9g off-white color crystal, mass yield is 64.6%, and molar yield is 88.5%, and its bulk density is 0.37g/ml, and good fluidity, static are little.
Get the prepared 3-(4-of the present embodiment amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2, the crystallisate sample of 6-dioxopiperidine new crystal form X I, X-ray powder diffraction (XRD) spectrogram of measuring as shown in Figure 2, differential scanning calorimetric analysis (DSC) figure as shown in Figure 6, as shown in figure 10, Infrared spectroscopy figure as shown in figure 14 for thermogravimetric analysis (TGA) figure.
Embodiment 4
The preparation of lenalidomide new crystal form X I
By 43g3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2, ethanol/deionized water mixed solvent that 6-dioxopiperidine tosilate and 600ml volume ratio are 85:15, adds in a 1L there-necked flask, under room temperature, stir fully and mix, until solute dissolves completely; Solution decompression is filtered, and gained clear liquor is transferred in another 1L there-necked flask, fully stirs, and in solution, slowly adds triethylamine, starts reaction crystallization process; In dropping process, there are a large amount of off-white color solids to separate out; After system pH is adjusted to 8.1, nitrogen protection, stirs under room temperature 3.5 hours, magma is filtered to filter cake deionized water wash 3 times; By at room temperature vacuum-drying of filter cake 19 hours, obtain 23.6g off-white color crystal, mass yield is 54.9%, molar yield is 91.0%.Its XRD figure, DSC figure, TGA figure and embodiment 3 are basically identical.
Embodiment 5
The preparation of lenalidomide new crystal form X II
By 52g3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2, Virahol/deionized water mixed solvent that 6-dioxopiperidine hydrochloride raw material and 800ml volume ratio are 75:25, add in a 1L there-necked flask, under room temperature, stir fully and mix, until solute dissolves completely, in solution, slowly add triethylamine, start reaction crystallization process; In dropping process, there are a large amount of off-white color solids to separate out; After system pH is adjusted to 7.7, nitrogen protection, stirs 5.5 hours at 35 ℃, and magma is filtered, and Virahol filter cake for/deionized water mixed solvent washs 2～3 times; By filter cake vacuum-drying 17 hours at 35 ℃, obtain 41.7g off-white color crystal, mass yield is 80.2%, and molar yield is 91.4%, and bulk density is 0.35g/ml, and good fluidity, static are little.
Get the prepared 3-(4-of the present embodiment amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2, the crystallisate sample of 6-dioxopiperidine new crystal form X II, carry out X-ray powder diffraction (XRD) spectrogram of XRD analysis mensuration as shown in Figure 3, differential scanning calorimetric analysis (DSC) figure as shown in Figure 8, as shown in figure 13, Infrared spectroscopy figure as shown in figure 17 for thermogravimetric analysis (TGA) figure.
Embodiment 6
The preparation of lenalidomide new crystal form X II
By 15g3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2, ethanol/deionized water mixed solvent that 6-dioxopiperidine mesylate raw material and 180ml volume ratio are 73:27, adds in a 500mL there-necked flask, under room temperature, stir fully and mix, until solute dissolves completely; In solution, slowly add triethylamine, start reaction crystallization process; In dropping process, there are a large amount of off-white color solids to separate out; After system pH is adjusted to 7.8, nitrogen protection, stirs under room temperature 5 hours, magma is filtered to ethanol for filter cake/deionized water mixed solvent washing 2 times; By filter cake vacuum-drying 19 hours at 35 ℃, obtain 9.7g off-white color crystal, mass yield is 64.7%, molar yield is 88.6%.
Its XRD figure, DSC figure, TGA figure and embodiment 5 are basically identical.
Embodiment 7
The preparation of lenalidomide new crystal form X III
By 56g3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2, methyl alcohol/deionized water mixed solvent that 6-dioxopiperidine mesylate raw material and 600ml volume ratio are 65:35, adds in a 1L there-necked flask, under room temperature, stir fully and mix, until solute dissolves completely; In solution, slowly add diethylamine, start reaction crystallization process; In dropping process, there are a large amount of off-white color solids to separate out; After system pH is adjusted to 8.2, nitrogen protection, stirs under room temperature 9 hours, magma is filtered to methyl alcohol for filter cake/deionized water mixed solvent washing 3 times; By at room temperature vacuum-drying of filter cake 33 hours, obtain 38.5g off-white color crystal, mass yield is 68.8%, and molar yield is 94.0%, and bulk density is 0.35g/ml, and good fluidity, static are little.
Get the prepared 3-(4-of the present embodiment amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2, the crystallisate sample of 6-dioxopiperidine new crystal form X III, carry out X-ray powder diffraction (XRD) spectrogram of XRD analysis mensuration as shown in Figure 4, differential scanning calorimetric analysis (DSC) figure as shown in Figure 8, as shown in figure 12, Infrared spectroscopy figure as shown in figure 16 for thermogravimetric analysis (TGA) figure.
Embodiment 8
The preparation of lenalidomide new crystal form X III
By 10g3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2, methyl alcohol/deionized water mixed solvent that 6-dioxopiperidine mesylate raw material and 100ml volume ratio are 65:35, adds in a 250mL there-necked flask, under room temperature, stir fully and mix, until solute dissolves completely; In solution, slowly add triethylamine, start reaction crystallization process; In dropping process, there are a large amount of off-white color solids to separate out; After system pH is adjusted to 8.8, nitrogen protection, stirs under room temperature 9.5 hours, magma is filtered to filter cake deionized water wash 2 times; By at room temperature vacuum-drying of filter cake 30 hours, obtain 6.2g off-white color crystal, mass yield is 69.5%, molar yield is 85.0%.
Its XRD figure, DSC figure, TGA figure and embodiment 7 are basically identical.
Embodiment 9
Stability test
Get the prepared 3-(4-of above-described embodiment amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2,6-dioxopiperidine new crystal form X, crystal form X I, crystal form X II and crystal form X III, at 60 ℃, 105 ℃ normal pressures, place 10d respectively, relative humidity is that 25 ℃ of 80%, 92.5% normal temperature are placed 10d, illumination 10d, compressing tablet, the powerful 30min that grinds in mortar.Get the sample after above-mentioned seven kinds of different conditions are processed, carrying out XRD, DSC and HPLC analyzes, find that above condition placement is after 10 days, the crystal formation of product does not all change, chemical purity is almost constant, illustrate that prepared lenalidomide new crystal form X, crystal form X I, crystal form X II and crystal form X III have good physical stability and chemical stability.
All documents of mentioning in the present invention are all quoted as a reference in this application, just as each piece of document, are quoted as a reference separately.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.

Claims (10)

1. (4-amino-1 for a 3-, 3-dihydro-1-oxo-2H-isoindole-2-yl)-2, the crystal form X of 6-dioxopiperidine, is characterized in that, the DSC spectrogram of described crystal form X shows that the peak value of first endotherm(ic)peak is at 169 ± 4 ℃, and the peak value of second endotherm(ic)peak is at 269 ± 4 ℃.
2. crystal form X according to claim 1, is characterized in that, the charateristic avsorption band of the infrared absorption spectra of described crystal form X is at 3422cm -1, 3344cm -1, 2848cm -1, 1701cm -1, 1602cm -1, 1542cm -1, 1236cm -1, 1043cm -1, 988cm -1, 934cm -1, 910cm -1, 848cm -1, 795cm -1, 748cm -1, 671cm -1, 597cm -1, 552cm -1, 519cm -1, 462cm -1.
3. the preparation method of crystal form X according to claim 1 and 2, is characterized in that, comprises the following steps:
A) at room temperature, lenalidomide salt is dissolved in solvent, weightmeasurement ratio is about 1:10～1:30 grams per milliliter;
B) in the solution obtaining in step a), add sodium bicarbonate aqueous solution, adjust pH to 7.0～9;
C) be warming up to 60～90 ℃, be incubated 24～48 hours;
D) be cooled to 40～60 ℃, crystallization, thus obtain described crystal form X.
4. 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2, the crystal form X I of 6-dioxopiperidine, its X-ray powder diffraction collection of illustrative plates comprises 3 or 3 the 2 θ values that are selected from above lower group: 12.0 ° ± 0.2 °, 14.3 ° ± 0.2 °, 14.8 ° ± 0.2 °, 16.2 ° ± 0.2 °, 17.6 ° ± 0.2 °, 21.5 ± 0.2 °, 22.6 ° ± 0.2 °, 23.8 ° ± 0.2 °, 24.0 ° ± 0.2 °, 26.0 ° ± 0.2 °, 28.3 ° ± 0.2 °, 29.8 ± 0.2 °, 31.9 ° ± 0.2 °, 32.6 ° ± 0.2 ° and 33.5 ° ± 0.2 °.
5. the preparation method of crystal form X I as claimed in claim 4, comprises the steps:
A) lenalidomide salt is dissolved in the mixed solvent of deionized water/organic solvent at ambient temperature;
B), in the solution obtaining in step a), add adjusting PH with base to 7.0～9;
C) under 0 ℃～reflux temperature, stir 0.5～4 hour, crystallization, thus obtain described crystal form X I.
6. 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2, the crystal form X II of 6-dioxopiperidine, its X-ray powder diffraction collection of illustrative plates comprises 3 or 3 the 2 θ values that are selected from above lower group: 13.1 ± 0.2 °, 14.1 ± 0.2 °, 15.7 ± 0.2 °, 16.4 ± 0.2 °, 17.2 ± 0.2 °, 17.4 ± 0.2 °, 19.1 ± 0.2 °, 19.5 ± 0.2 °, 20.9 ± 0.2 °, 21.3 ± 0.2 °, 26.6 ± 0.2 °, 27.4 ± 0.2 °, 28.6 ± 0.2 °, 29.2 ± 0.2 °, 32.0 ± 0.2 ° and 33.2 ± 0.2 °.
7. the preparation method of crystal form X II as claimed in claim 6, comprises the steps:
A) lenalidomide salt is at room temperature dissolved in the mixed solvent of deionized water/alcoholic solvent;
B), in the solution obtaining in step a), add adjusting PH with base to 7.0～9;
C) under 0 ℃～reflux temperature condition, stir 5～8 hours; Crystallization, thus described crystal form X II obtained.
8. 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2, the crystal form X III of 6-dioxopiperidine, its X-ray powder diffraction collection of illustrative plates comprises 3 or 3 the 2 θ values that are selected from above lower group: 13.3 ± 0.2 °, 13.4 ± 0.2 °, 14.2 ± 0.2 °, 16.6 ± 0.2 °, 19.6 ± 0.2 °, 20.8 ± 0.2 °, 21.4 ± 0.2 °, 29.3 ± 0.2 °.
9. the preparation method of crystal form X III as claimed in claim 8, comprises the steps:
A) lenalidomide salt is dissolved in the mixed solvent of deionized water/alcoholic solvent at ambient temperature;
B), in the solution obtaining in step a), add adjusting PH with base to 7.0～9;
C) under 0 ℃～reflux temperature, stir 9～24 hours;
D) dry crystallization, thus described crystal form X III obtained.
10. a pharmaceutical composition, is characterized in that, described pharmaceutical composition comprises pharmaceutically acceptable carrier and is selected from one or more the crystal combination in lower group:
(a) crystal form X described in claim 1 or 2;
(b) crystal form X I claimed in claim 4;
(c) crystal form X II claimed in claim 6;
(d) crystal form X III claimed in claim 8.
CN201410045275.7A 2014-01-30 2014-01-30 Novel 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2,6-piperidinedione crystal forms and preparation method thereof Pending CN104016966A (en)

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CN107400115A (en) * 2017-08-04 2017-11-28 正大天晴药业集团股份有限公司 A kind of new crystallization of lenalidomide and its pharmaceutical composition
CN108191826A (en) * 2018-01-08 2018-06-22 浙江省医学科学院 A kind of lenalidomide crystal and preparation method thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107400115A (en) * 2017-08-04 2017-11-28 正大天晴药业集团股份有限公司 A kind of new crystallization of lenalidomide and its pharmaceutical composition
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CN108191826A (en) * 2018-01-08 2018-06-22 浙江省医学科学院 A kind of lenalidomide crystal and preparation method thereof

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Application publication date: 20140903