CN104447684A - Pomalidomide crystal form and preparation method thereof - Google Patents
Pomalidomide crystal form and preparation method thereof Download PDFInfo
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- CN104447684A CN104447684A CN201310425793.7A CN201310425793A CN104447684A CN 104447684 A CN104447684 A CN 104447684A CN 201310425793 A CN201310425793 A CN 201310425793A CN 104447684 A CN104447684 A CN 104447684A
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- degree amine
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention relates to a pomalidomide crystal form and a preparation method thereof. Specifically, the invention discloses a pomalidomide anhydrous crystal form and a preparation method thereof. The pomalidomide anhydrous crystal form of the invention has the advantages of good thermal stability, good light stability, strong antioxidant capacity and storage stability, and is suitable for application to pharmaceutical preparation.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology.Particularly, the present invention relates to pool horse degree amine anhydride crystal formation and preparation method thereof.
Background technology
Pool horse degree amination formal name used at school is called 3-amino-N-(2,6-dioxo-3-piperidyl) phthalic imidine, and its structural formula is:
Pool horse degree amine system thalidomide analogs, has anti-tumor activity, can suppress hematopoietic tumor cell hyperplasia and cell death inducing.In addition, pool horse degree amine can suppress the multiple myeloma cell line hyperplasia of resistance to Revlimid, can with dexamethasone co-induction apoptosis of tumor cells.Pool horse degree amine can also strengthen the immune response of T cell and natural killer cell mediation, suppresses monocyte to produce pro-inflammatory cytokine (as TNF-α, IL-6) simultaneously.
Pool horse degree amine is developed by Celgene drugmaker of the U.S., and be used for the treatment of multiple myeloma, U.S. FDA is ratified to go on the market in February, 2013.WO9803502 discloses pool horse degree amine compound, has no the bibliographical information about its crystal formation at present.
Summary of the invention
The object of this invention is to provide a kind of pool horse degree amine crystal formation.
In a first aspect of the present invention, provide a kind of pool horse degree amine anhydride crystal formation.
In another preference, the powder diffraction spectrum of described crystal comprises the 2 θ values that more than 3 or 3 are selected from lower group: 11.5 °, 12.0 °, 12.6 °, 13.9 °, 16.2 °, 16.6 °, 17.1 °, 18.3 °, 22.8 °, 24.7 °, 25.5 °, 27.8 °, 28.2 ° ± 0.2.
In another preference, the 2 θ values that the powder diffraction spectrum specific features of described pool horse degree amine anhydride crystal formation is as shown in table 1:
| 2θ(°±0.2) | Relative intensity (% ± 2%) |
| 11.5 | 2.5 |
| 12.0 | 65.6 |
| 12.6 | 16.6 |
| 13.9 | 86.1 |
| 16.2 | 23.9 |
| 16.6 | 48.5 |
| 17.1 | 79.1 |
| 18.3 | 41.7 |
| 22.8 | 12.5 |
| 24.7 | 18.0 |
| 25.5 | 100.0 |
| 27.8 | 27.0 |
| 28.2 | 33.4 |
In another preference, the dsc of described crystal analyzes collection of illustrative plates has thawing endotherm(ic)peak at 319.89 ± 1 DEG C, has decomposition absorption peak at 432.28 ± 1 DEG C.
In another preference, the powder diffraction spectrum of described crystal substantially as shown in Figure 1.
In another preference, the dsc of described crystal analyzes collection of illustrative plates substantially as shown in Figure 2.
In another preference, described pool horse degree amine anhydride crystal formation obtains as follows, and described method comprises step:
1) at 20-35 DEG C, horse degree amine material dissolution will be moored in organic solvent, obtain one containing the solution mooring horse degree amine;
2) solution that step 1) obtains is added to 20-100 DEG C of (preferably, 40-100 DEG C; More preferably, 60-100 DEG C; Best, 80-100 DEG C) water in, crystallize out, thus obtain pool horse degree amine anhydride crystal formation.
In another preference, described step 2) be: solution step 1) obtained is added drop-wise to 20-100 DEG C of (preferably, 40-100 DEG C; More preferably, 60-100 DEG C; Best, 80-100 DEG C) water in, insulated and stirred 20-200 minute, crystallize out, thus obtain pool horse degree amine anhydride crystal formation.
In second aspect present invention, provide the preparation method of the crystal formation described in first aspect present invention, comprise step:
1) at 20-35 DEG C, horse degree amine material dissolution will be moored in organic solvent, obtain one containing the solution mooring horse degree amine;
2) solution that step 1 obtains is added to 20-100 DEG C of (preferably, 40-100 DEG C; More preferably, 60-100 DEG C; Best, 80-100 DEG C) water in, crystallize out, thus obtain pool horse degree amine anhydride crystal formation;
Described organic solvent is selected from lower group: DMF, N-Methyl pyrrolidone, methyl-sulphoxide, or its combination.
In another preference, described pool horse degree amine raw material and the weightmeasurement ratio of organic solvent are 1:5-20(g/ml), preferred 1:5-10(g/ml).
In another preference, described organic solvent and the volume ratio of water are 1:5-20, preferred 1:8-15.
In third aspect present invention, provide a kind of pharmaceutical composition, comprise activeconstituents: the crystal formation described in first aspect present invention; And pharmacy acceptable salt.
The advantages such as pool horse degree amine anhydride crystal formation provided by the invention, has Heat stability is good (100 DEG C normal pressure 72 hours, crystal formation is constant), stable storing, light stable (uv irradiating 72 hours, purity and crystal formation do not become), are suitable for pharmaceutical preparation.In addition, preparation method provided by the invention, can obtain the pool horse degree amine anhydride crystallization of HPLC purity more than 99.8%, and simple to operate, is applicable to industrialized production.
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and can combining mutually between specifically described each technical characteristic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, tiredly no longer one by one to state at this.
Accompanying drawing explanation
Fig. 1 is the XRD spectra of pool horse degree amine anhydride crystal formation of the present invention;
Fig. 2 is the DSC spectrogram of pool horse degree amine anhydride crystal formation of the present invention;
Fig. 3 is the XRD spectra after the thermally-stabilised experiment of pool horse degree amine anhydride crystal formation of the present invention.
Embodiment
The present inventor, through extensive and deep research, makes public for the first time a kind of pool horse degree amine anhydride crystal formation.There is the excellent excellent properties such as thermostability, light stability, be suitable for pharmaceutical preparation.In addition, preparation method provided by the invention is simple to operate, is applicable to industrialized production.On this basis, contriver completes the present invention.
The invention provides a kind of pharmaceutical composition being activeconstituents with pool horse degree amine anhydride crystal formation of the present invention.
Activeconstituents
Pool horse degree amine anhydride crystal formation of the present invention, its powder diffraction spectrum comprises the 2 θ values that more than 3 or 3 are selected from lower group: 11.5 °, 12.0 °, 12.6 °, 13.9 °, 16.2 °, 16.6 °, 17.1 °, 18.3 °, 22.8 °, 24.7 °, 25.5 °, 27.8 °, 28.2 ° ± 0.2; More preferably, the powder diffraction spectrum of described crystal substantially as shown in Figure 1.
In another preference, the dsc of described crystal analyzes collection of illustrative plates has thawing endotherm(ic)peak at 319.89 ± 1 DEG C, has decomposition absorption peak at 432.28 ± 1 DEG C; More preferably, the dsc of described crystal analyzes collection of illustrative plates substantially as shown in Figure 2.
Preparation method
The invention provides a kind of pool horse degree amine anhydride crystal formation.Those skilled in the art prepare this pool horse degree amine anhydride crystal formation by this area ordinary method.
Present invention also offers a kind of method preferably preparing this anhydride crystal formation, comprise step:
1) at 20-35 DEG C, horse degree amine material dissolution will be moored in organic solvent, obtain one containing the solution mooring horse degree amine;
Should be understood that described dissolving can be add in organic solvent by pool horse degree amine raw material, also can be add organic solvent to by pool horse degree amine raw material.
In another preference, described organic solvent is selected from lower group: DMF, N-Methyl pyrrolidone, methyl-sulphoxide, or its combination; Be preferably DMF
In another preference, described pool horse degree amine raw material and the weightmeasurement ratio of organic solvent are 1:5-20(g/ml), preferred 1:5-10(g/ml).
The present invention's " pool horse degree amine raw material " used can be the pool horse degree amine of pool horse degree amine amorphous substance or any known form.
2) solution that step 1 obtains is added to 20-100 DEG C of (preferably, 40-100 DEG C; More preferably, 60-100 DEG C; Best, 80-100 DEG C) water in, crystallize out, thus obtain pool horse degree amine anhydride crystal formation;
In another preference, described organic solvent and the volume ratio of water are 1:5-20, preferred 1:8-15.
In another preference, described step 2) be: solution step 1) obtained adds (as dripped) to 20-100 DEG C of (preferably, 40-100 DEG C; More preferably, 60-100 DEG C; Best, 80-100 DEG C) water in, insulated and stirred 20-200 minute, crystallize out, thus obtain pool horse degree amine anhydride crystal formation.
Preferably, the pool horse degree amine anhydride crystal formation obtained can be made further drying treatment, as carried out drying under reduced pressure for some time (as 10-30 hour) under certain temperature (as 40-60 DEG C).
Pharmaceutical composition
Pharmaceutical composition of the present invention for activeconstituents, also can contain pharmacy acceptable salt with pool horse degree amine anhydride crystal formation of the present invention.
" pharmaceutically acceptable carrier " refers to: one or more biocompatible solid or liquid filler or gelatinous mass, and they are suitable for people and use, and must have enough purity and enough low toxicity." consistency " to referred to herein as in composition each component energy and compound of the present invention and they between mutually admix, and the drug effect of not obvious reduction compound.Pharmaceutically acceptable carrier part example has cellulose and its derivates (as Xylo-Mucine, ethyl cellulose sodium, cellulose ethanoate etc.), 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 the compounds of this invention or pharmaceutical composition is not particularly limited.The compounds of this invention can be individually dosed, or with other pharmaceutically acceptable compound Combined Preparation.
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or according to the condition that manufacturer advises.Unless otherwise indicated, otherwise per-cent and number calculate by weight.
In embodiment, pool horse degree amine raw material used prepares with reference to WO9803502." room temperature " of the present invention is 25-28 DEG C.
X-ray powder diffractometer device: Dedye ~ Scherrer INEL CPS ~ 120X-ray powder diffractometer; Source of radiation:
strength ratio α
1/ α
2be 0.5; Producer (Generator) kv:40kv; Producer (Generator) mA:30mA; Initial 2 θ: 2.000 °, sweep limit: 2.0000 ~ 50.000 °.
Dsc (DSC) instrument: the Q2000 type of TA company of the U.S., within the scope of 20 ~ 450 DEG C, heating rate 10 DEG C/min, nitrogen flow rate 50ml/min.
Embodiment 1
In pool horse degree amine raw material (10.0g), add DMF (80ml), stirred at ambient temperature is to clarification.The solution obtained slowly is added drop-wise in the hot water (800ml) of 90 DEG C.Drip and finish, insulated and stirred 1 hour.Filter, 50 DEG C of drying under reduced pressure 16 hours, obtain 9.2g light yellow crystal, HPLC purity is 99.86%.As shown in Figure 1, Differential Scanning Calorimetry analysis (DSC) figure as shown in Figure 2 for its powder x-ray diffraction (XRD) spectrogram.
Embodiment 2
In pool horse degree amine raw material (2.0g), add DMSO (20ml), stirred at ambient temperature is to clarification.The solution obtained slowly is added drop-wise in the hot water (250ml) of 80 DEG C.Drip and finish, insulated and stirred 1 hour.Filter, 60 DEG C of drying under reduced pressure 15 hours, obtain 1.8g light yellow crystal, HPLC purity is 99.80%.Its XRD spectra, DSC spectrogram are basic consistent with embodiment 1.
Embodiment 3
In pool horse degree amine raw material (2.0g), add N-Methyl pyrrolidone (15ml), stirring at room temperature is to clarification.The solution obtained slowly is added drop-wise in the hot water (120ml) of 100 DEG C.Drip and finish, insulated and stirred 30 minutes.Filter, 50 DEG C of drying under reduced pressure 16 hours, obtain 1.8g light yellow crystal, HPLC purity is 99.81%.Its powder XRD spectra, DSC spectrogram are basic consistent with embodiment 1.
Embodiment 4-6
Method is with embodiment 1, and difference is the hot water adopting 90 DEG C in the hot water alternative embodiment 1 of following temperature.
| Embodiment 4 | Embodiment 5 | Embodiment 6 | |
| Water temperature | 70℃ | 50℃ | 30℃ |
Result shows: the crystal that embodiment 4-6 obtains, and all >=99%, powder XRD spectra, DSC spectrogram are basic consistent with embodiment 1 for HPLC purity.
Embodiment 7: stability experiment
Pool horse degree amine anhydride obtained by Example 1-6 any embodiment, by its 100 DEG C, normal pressure, relative humidity is place 2 days for 60% time.Get the sample after above-mentioned process, carry out XRD analysis, spectrogram as shown in Figure 3.Fig. 3 by analysis, discovery high temperature 100 DEG C, the crystal formation of high humidity after 60%, 2 days do not change, and the pool horse degree amine anhydride crystal formation obtained by explanation has good thermostability.
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.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 (9)
1. a pool horse degree amine anhydride crystal formation.
2. crystal formation as claimed in claim 1, it is characterized in that, the powder diffraction spectrum of described crystal comprises the 2 θ values that more than 3 or 3 are selected from lower group: 11.5 °, 12.0 °, 12.6 °, 13.9 °, 16.2 °, 16.6 °, 17.1 °, 18.3 °, 22.8 °, 24.7 °, 25.5 °, 27.8 °, 28.2 ° ± 0.2.
3. crystal formation as claimed in claim 1, is characterized in that, the dsc of described crystal analyzes collection of illustrative plates has thawing endotherm(ic)peak at 319.89 ± 1 DEG C, has decomposition absorption peak at 432.28 ± 1 DEG C.
4. crystal formation as claimed in claim 1, it is characterized in that, the powder diffraction spectrum of described crystal substantially as shown in Figure 1.
5. crystal formation as claimed in claim 1, is characterized in that, the dsc of described crystal analyzes collection of illustrative plates substantially as shown in Figure 2.
6. the preparation method of the crystal formation as described in any one of claim 1-5, is characterized in that, comprises step:
1) at 20-35 DEG C, horse degree amine material dissolution will be moored in organic solvent, obtain one containing the solution mooring horse degree amine;
2) solution that step 1 obtains is added in the water of 20-100 DEG C, crystallize out, thus obtains pool horse degree amine anhydride crystal formation;
Described organic solvent is selected from lower group: DMF, N-Methyl pyrrolidone, methyl-sulphoxide or its combination.
7. preparation method as claimed in claim 6, it is characterized in that, described pool horse degree amine raw material and the weightmeasurement ratio of organic solvent are 1:5-20(g/ml).
8. preparation method as claimed in claim 6, it is characterized in that, described organic solvent and the volume ratio of water are 1:5-20.
9. a pharmaceutical composition, is characterized in that, comprises:
Activeconstituents: the crystal formation as described in any one of claim 1-5; And
Pharmacy acceptable salt.
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| CN201310425793.7A CN104447684A (en) | 2013-09-17 | 2013-09-17 | Pomalidomide crystal form and preparation method thereof |
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| CN201310425793.7A CN104447684A (en) | 2013-09-17 | 2013-09-17 | Pomalidomide crystal form and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113387901A (en) * | 2020-01-17 | 2021-09-14 | 吉林大学 | Limited-area high-density anhydrous alkali metal polymeric nitrogen Cm-NaN5High pressure preparation method of |
-
2013
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113387901A (en) * | 2020-01-17 | 2021-09-14 | 吉林大学 | Limited-area high-density anhydrous alkali metal polymeric nitrogen Cm-NaN5High pressure preparation method of |
| CN113387901B (en) * | 2020-01-17 | 2023-05-05 | 吉林大学 | Limited high-density anhydrous alkali metal polymeric nitrogen Cm-NaN 5 High pressure process of (2) |
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