CN105646582A - Tedizolid phosphate crystal form I and preparation method thereof - Google Patents
Tedizolid phosphate crystal form I and preparation method thereof Download PDFInfo
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- CN105646582A CN105646582A CN201410670401.8A CN201410670401A CN105646582A CN 105646582 A CN105646582 A CN 105646582A CN 201410670401 A CN201410670401 A CN 201410670401A CN 105646582 A CN105646582 A CN 105646582A
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Abstract
The invention provides a tedizolid phosphate crystal form I and a preparation method thereof. Compared with the prior art, the crystal form I is better in stability and low in hygroscopicity, is not easily affected by high humidity to air-slake and is convenient for drug long-term storage and placement; the crystal form I has the advantages of simple preparation technology operation and low cost and has important value for drug optimization and development in future.
Description
Technical field
The present invention relates to chemical medicine, particularly relate to the phosphoric acid specially brilliant type of azoles amine and its preparation method.
Background technology
Phosphoric acid is azoles amine (Tedizolidphosphate) specially, is the medicine that the one of Ka Bisite drugmaker (Cubist) is used for the treatment of acute bacterial skin infections (ABSSSI), obtains FDA approval in June, 2014. Its chemical structure is as shown in formula I:
Polymorphism extensively exists in medicine. The different crystal forms of same medicine has significant difference in solubleness, fusing point, density, stability etc., thus affects the stability of medicine, homogeneity, bioavailability, efficacy and saferry to some extent. Therefore, medicament research and development carries out comprehensive and systematic screening polymorph, select the brilliant type of the most applicable exploitation, be one of very important important research content.
At present, only patent CN102439006A discloses a brilliant type of phosphoric acid specially azoles amine.
Therefore, it is necessary to develop more multistable fixed anhydrous crystal forms, for the exploitation of medicine provides more selection. It is low that the brilliant type I of phosphoric acid provided by the invention specially azoles amine has water absorbability, and good stability, is suitable for the advantage of standing storage. Further, its preparation technology is simple to operation, with low cost, and repeatability is good, and the nontoxic solvent adopted, has huge economic worth to the industrial application of this medicine.
Summary of the invention
The present invention provides the new crystal of a kind of phosphoric acid specially azoles amine, and compared with the brilliant type in patent CN102439006A, stability is better. Further, it is low that the new crystal of the present invention draws wet property, and not being subject to high humidity affects and deliquescence, facilitates the long-term storage of medicine to place.
It is an object of the present invention to provide the brilliant type of a kind of phosphoric acid specially azoles amine, the brilliant type I of called after.
On the one hand, brilliant type I provided by the invention, it is characterised in that, its X-ray powder diffraction figure is that 27.6 �� �� 0.2 ��, 23.9 �� 0.2 ��, 22.0 �� �� 0.2 �� place has characteristic peak in 2theta value.
Further, brilliant type I provided by the invention, is further characterized in that, its X-ray powder diffraction figure is that 16.4 �� �� 0.2 ��, 17.2 �� �� 0.2 ��, 21.0 �� �� 0.2 �� place has characteristic peak in 2theta value.
Further, brilliant type I provided by the invention, is further characterized in that, its X-ray powder diffraction figure is that 15.7 �� �� 0.2 ��, 24.5 �� �� 0.2 ��, 13.8 �� �� 0.2 �� place has characteristic peak in 2theta value.
Further, brilliant type I provided by the invention, is further characterized in that, its X-ray powder diffraction figure is substantially as shown in Figure 1.
On the other hand, brilliant type I provided by the invention, it is characterised in that, it is being heated to start that endotherm(ic)peak occurs near 235.3 DEG C, its differential scanning calorimetric thermogram is substantially as shown in Figure 2.
On the other hand, brilliant type I provided by the invention, it is characterised in that, when being heated to 130 DEG C, there is the weight loss gradient of about 1.3%, its thermogravimetric analysis figure is substantially as shown in Figure 3.
It is a further object to provide the preparation method of brilliant type I, it is characterised in that, its preparation method comprises the steps: the powder suspension of brilliant for phosphoric acid specially azoles amine type I in acid amides or amine solvent; Stirring more than 3 days under room temperature to 80 DEG C condition, gained solid is the phosphoric acid specially brilliant type I of azoles amine.
Further, described acid amides is preferably N, dinethylformamide (DMF); Described amine solvent is preferably triethylamine (TEA).
Further, described whipping temp preferably 50��80 DEG C; Described churning time preferably 3 days.
It is a further object to provide a kind of phosphoric acid specially brilliant type I of azoles amine and medicinal compositions of pharmaceutical excipient comprising effective therapeutic dose. Generally the phosphoric acid for the treatment of significant quantity specially brilliant type I and one or more pharmaceutical excipients of azoles amine is mixed or contacted make medicinal compositions or preparation, this medicinal compositions or preparation be know in pharmacy field in the way of be prepared.
Further, in medicinal compositions of the present invention, the brilliant type I of phosphoric acid specially azoles amine can be used for the purposes prepared in treatment acute bacterial skin infections (ABSSSI) pharmaceutical preparation.
The useful effect of the present invention is:
Compared with prior art, brilliant type provided by the invention has better stability. Can avoid better medicament storage and performance history occurring turn brilliant, thus avoid the change of bioavailability and drug effect.
It is low that brilliant type provided by the invention draws wet property, and not being subject to high humidity affects and deliquescence, facilitates the long-term storage of medicine to place.
Brilliant type preparation technology provided by the invention is simple, with low cost, and optimization and exploitation to this medicine following have important value.
Accompanying drawing explanation
Fig. 1 is the XRPD figure of the phosphoric acid specially brilliant type I of azoles amine
Fig. 2 is the DSC figure of the phosphoric acid specially brilliant type I of azoles amine
Fig. 3 is the TGA figure of the phosphoric acid specially brilliant type I of azoles amine
Fig. 4 is the DVS figure of the phosphoric acid specially brilliant type I of azoles amine
Fig. 5 is the transforming relationship XRPD comparison diagram (upper figure be the XRPD figure of brilliant type in patent CN102439006A, and figure below is that the XRPD that in patent CN102439006A, crystalline substance type is converted into crystalline substance type I in DMF schemes) of the phosphoric acid specially brilliant type of azoles amine
Embodiment
Hereinafter will set forth the present invention further by specific embodiment, but be not limited to protection scope of the present invention. Preparation method and use instrument can be made improvements by those skilled in the art in right, and these improvement also should be considered as protection scope of the present invention. Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
In following embodiment, the described test method condition that conveniently condition or manufacturer advise usually is implemented; The initiator of described phosphoric acid specially azoles amine is obtained by commercially available method.
Being explained as follows of abbreviation used in the present invention:
XRPD:X ray powder diffraction
DSC: differential scanning calorimetric analysis
TGA: thermogravimetric analysis
DVS: dynamic water is adsorbed
X-ray powder diffraction figure of the present invention gathers on PanalyticalEmpyreanX ray powder diffractometer. The method parameter of X-ray powder diffraction of the present invention is as follows:
X ray reflection parameter: Cu, K ��
K��11.540598; K �� 21.544426
K �� 2/K �� 1 intensity: 0.50
Voltage: 45 KVs (kV)
Electric current: 40 milliampere(mA)s (mA)
Divergent slit: automatically
Scan pattern: continuously
Sweep limit: from 3.0 to 40.0 degree
Sampling step length: 0.013 degree
Differential scanning calorimetric analysis of the present invention (DSC) figure gathers on TAQ2000.The method parameter of differential scanning calorimetric analysis of the present invention (DSC) is as follows:
Scanning speed: 10 DEG C/min
Shielding gas: nitrogen
Thermogravimetric analysis of the present invention (TGA) figure gathers on TAQ500. The method parameter of thermogravimetric analysis of the present invention (TGA) is as follows:
Scanning speed: 10 DEG C/min
Shielding gas: nitrogen
Dynamic water of the present invention absorption (DVS) figure gathers on the Intrinsic dynamic water absorption instrument produced by SMS company (SurfaceMeasurementSystemsLtd.). The method parameter of described dynamic water absorption instrument is as follows:
Temperature: 25 DEG C
Carrier gas, flow velocity: N2,200 ml/min
Unit time quality change: 0.002%/minute
RH range: 0%RH-95%RH
Embodiment 1
The preparation method of the phosphoric acid specially brilliant type I of azoles amine:
By the powder suspension of 98.3mg phosphoric acid specially azoles amine in 1.5 milliliters of DMF solvent, then stir 3 days under 50 DEG C of conditions, collect solid and namely obtain brilliant type I. The X-ray powder diffraction data of the brilliant type I that the present embodiment obtains are as shown in table 1. Its XRPD schemes such as Fig. 1, and its DSC schemes such as Fig. 2, and its TGA schemes such as Fig. 3.
The X-ray powder diffraction data of the brilliant type I of table 1
| 2theta | D interval | Relative intensity % |
| 10.94 | 8.09 | 2.95 |
| 11.99 | 7.38 | 2.81 |
| 13.78 | 6.43 | 11.52 |
| 14.88 | 5.96 | 7.49 |
| 15.66 | 5.66 | 14.97 |
| 16.37 | 5.42 | 26.05 |
| 17.19 | 5.16 | 25.87 |
| 17.76 | 5.00 | 6.35 |
| 19.22 | 4.62 | 2.96 |
| 20.00 | 4.44 | 2.70 |
| 20.64 | 4.30 | 6.66 |
| 21.01 | 4.23 | 22.84 |
| 22.03 | 4.04 | 27.02 |
| 22.96 | 3.87 | 10.15 |
| 23.86 | 3.73 | 55.24 |
| 24.48 | 3.64 | 13.70 |
| 26.31 | 3.39 | 5.09 |
| 27.57 | 3.24 | 100.00 |
| 28.93 | 3.09 | 2.89 |
| 30.29 | 2.95 | 3.94 |
| 31.74 | 2.82 | 2.27 |
| 33.99 | 2.64 | 1.50 |
| 38.60 | 2.33 | 1.67 |
Embodiment 2
The preparation method of the phosphoric acid specially brilliant type I of azoles amine:
By the powder suspension of 99.0mg phosphoric acid specially azoles amine in 1.5 milliliters of TEA solvents, then stir 5 days under 50 DEG C of conditions, collect solid and namely obtain brilliant type I. The X-ray powder diffraction data of the brilliant type I that the present embodiment obtains are as shown in table 2.
The X-ray powder diffraction data of the brilliant type I of table 2
| 2theta | D interval | Relative intensity % |
| 10.42 | 8.49 | 5.25 |
| 10.69 | 8.27 | 1.60 |
| 10.96 | 8.08 | 7.79 |
| 12.01 | 7.37 | 12.82 |
| 13.79 | 6.42 | 19.06 |
| 14.38 | 6.16 | 6.67 |
| 14.88 | 5.95 | 27.05 |
| 15.45 | 5.73 | 15.78 |
| 15.68 | 5.65 | 22.75 |
| 16.37 | 5.41 | 100.00 |
| 17.20 | 5.16 | 44.83 |
| 17.77 | 4.99 | 8.21 |
| 19.23 | 4.61 | 10.68 |
| 20.01 | 4.44 | 6.95 |
| 20.65 | 4.30 | 12.03 |
| 21.02 | 4.23 | 29.42 |
| 21.39 | 4.15 | 4.70 |
| 22.01 | 4.04 | 57.10 |
| 22.97 | 3.87 | 25.19 |
| 23.85 | 3.73 | 58.96 |
| 24.49 | 3.63 | 19.19 |
| 25.37 | 3.51 | 2.55 |
| 25.69 | 3.47 | 4.32 |
| 26.31 | 3.39 | 8.33 |
| 27.57 | 3.24 | 87.28 |
| 28.87 | 3.09 | 4.13 |
| 30.28 | 2.95 | 4.15 |
| 31.73 | 2.82 | 1.62 |
| 32.14 | 2.79 | 1.65 |
| 33.12 | 2.70 | 2.90 |
| 34.04 | 2.63 | 2.85 |
| 38.61 | 2.33 | 1.59 |
Embodiment 3
The brilliant type I of the present invention draws the experiment of wet property:
Get the brilliant type I of the present invention to be about 10mg and adopt dynamic water absorption (DVS) instrument to test it to draw wet property. Experimental result is as shown in table 3. The DVS drawing the experiment of wet property schemes as shown in Figure 4.
The brilliant type I of table 3 draws the experiment of wet property
About drawing wet property feature description and draw defining (Chinese Pharmacopoeia version annex XIXJ medicine in 2010 draws wet property test direction principle, experiment condition: 25 DEG C �� 1 DEG C, 80% relative humidity) of wet property weightening finish:
Deliquescence: absorb enough water and divide formation liquid
Have and draw wet property: draw wet weightening finish and be not less than 15%
Have and draw wet property: draw wet weightening finish and be less than 15% but be not less than 2%
Slightly draw wet property: draw wet weightening finish and be less than 2% but be not less than 0.2%
Without or almost without drawing wet property: draw wet weightening finish and be less than 0.2%
Result shows, the brilliant type I of the present invention increases weight 0.3% after balancing under 80% humidity, according to the defining standard drawing the weightening finish of wet property, belongs to and slightly draws wet property, draw wet property low.
Embodiment 4
The stability comparative study of the disclosed brilliant type of brilliant type I and patent CN102439006A:
Get disclosed in about 100mg patent CN102439006A patent brilliant type suspension in the DMF of 1.5 milliliters to stir, it is positioned over 50 degree with the speed magnetic agitation 3 days of 500 rpms, centrifugal, get solid test XRPD. Result is as shown in table 4:
Transforming relationship between the disclosed brilliant type of the brilliant type I and patent CN102439006A of table 4
Result shows, in DMF solvent, under 50 DEG C of conditions, the disclosed brilliant type of patent CN102439006A can transfer the brilliant type I of the present invention to.
Claims (9)
1. the brilliant type I of a phosphoric acid specially azoles amine, it is characterised in that, its X-ray powder diffraction figure is that 27.6 �� �� 0.2 ��, 23.9 �� 0.2 ��, 22.0 �� �� 0.2 �� place has characteristic peak in 2theta value.
2. brilliant type I according to claim 1, is further characterized in that, its X-ray powder diffraction figure is that 16.4 �� �� 0.2 ��, 17.2 �� �� 0.2 ��, 21.0 �� �� 0.2 �� place has characteristic peak in 2theta value.
3. brilliant type I according to claim 2, is further characterized in that, its X-ray powder diffraction figure is that 15.7 �� �� 0.2 ��, 24.5 �� �� 0.2 ��, 13.8 �� �� 0.2 �� place has characteristic peak in 2theta value.
4. brilliant type I according to claim 1, it is characterised in that, its X-ray powder diffraction figure is substantially consistent with Fig. 1.
5. the preparation method of a phosphoric acid specially brilliant type I of azoles amine, it is characterised in that, comprise the steps: the powder suspension of phosphoric acid specially azoles amine in acid amides or amine solvent; Stirring under room temperature to 80 DEG C condition, collecting solid is the phosphoric acid specially brilliant type I of azoles amine.
6. preparation method according to claim 5, described acid amides is N, dinethylformamide; Described amine solvent is triethylamine.
7. preparation method according to claim 5, described whipping temp is 50 DEG C��80 DEG C.
8. a medicinal compositions, described medicinal compositions includes the brilliant type I of the claim 1 of effective amount and pharmaceutically acceptable vehicle.
9. medicinal compositions according to claim 8, it is characterised in that, described brilliant type I is for the preparation of the purposes in treatment acute bacterial skin infections (ABSSSI) pharmaceutical preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410670401.8A CN105646582A (en) | 2014-11-20 | 2014-11-20 | Tedizolid phosphate crystal form I and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410670401.8A CN105646582A (en) | 2014-11-20 | 2014-11-20 | Tedizolid phosphate crystal form I and preparation method thereof |
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| CN105646582A true CN105646582A (en) | 2016-06-08 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107353304A (en) * | 2017-07-12 | 2017-11-17 | 浙江普洛得邦制药有限公司 | Phosphoric acid safe ground azoles amine trishydroxymethylaminomethane salt and its crystal formation A, preparation method and application |
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2014
- 2014-11-20 CN CN201410670401.8A patent/CN105646582A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107353304A (en) * | 2017-07-12 | 2017-11-17 | 浙江普洛得邦制药有限公司 | Phosphoric acid safe ground azoles amine trishydroxymethylaminomethane salt and its crystal formation A, preparation method and application |
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