CN105273007A - Ceftaroline fosamil glutamate and crystal thereof - Google Patents
Ceftaroline fosamil glutamate and crystal thereof Download PDFInfo
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- CN105273007A CN105273007A CN201410334985.1A CN201410334985A CN105273007A CN 105273007 A CN105273007 A CN 105273007A CN 201410334985 A CN201410334985 A CN 201410334985A CN 105273007 A CN105273007 A CN 105273007A
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- phosphine
- glutaminate
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Abstract
The invention belongs to the field of pharmaceutical chemistry, and concretely relates to a ceftaroline fosamil glutamate and a crystal thereof. Compared with ceftaroline fosamil acetate, the ceftaroline fosamil glutamate has the advantages of good stability, very good dissolvability, simple preparation, easy operation, and especial meeting of demands of medicinal preparations.
Description
Technical field
The present invention relates to medicinal chemistry art, in particular to cephalo sieve phosphine glutaminate and crystallization thereof.
Technical background
Cephalo sieve phosphine (CeftarolineFosamil; formula I); chemical name is: (6R; 7R)-7-{ (2Z)-2-(ethoxy imino)-2-[5-(phosphono)-1; 2; 4-thiadiazoles-3-base] kharophen }-3-{ [4-(1-picoline-1--4-base)-1,3-thiazoles-2-base] sulfanyl }-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.
Cephalo sieve phosphine is by Japan's military field pharmacy Development of New Generation cynnematin, in October, 2010, obtains U.S. FDA license and is used for the treatment of Community-acquired bacterial pneumonia and acute bacterial skin and skin structure infection.
CN1282335A discloses cephalo sieve phosphine and preparation method thereof, and CN1462275A discloses cephalo sieve PHOSPHONACETIC salt, propionic salt, acetonitrile compound and hydrate thereof.According to the study, cephalo sieve phosphine less stable, and the stability of cephalo sieve phosphonium salt is better than cephalo sieve phosphine, what FDA approval was gone on the market is cephalo sieve PHOSPHONACETIC salt.
General, wish that pharmaceutical preparation has excellent character in the following areas: bioavailability, stability, solvability, purity, easily preparation etc.The applicant is through a large amount of experimental studies, and discovery cephalo sieve phosphine glutaminate beyond expectation has stability more better than cephalo sieve PHOSPHONACETIC salt, and has good solvability, prepares simple to operation, meets the demand of pharmaceutical preparation especially.
Summary of the invention
The present invention relates to cephalo sieve phosphine glutaminate.Cephalo sieve phosphine glutaminate of the present invention, can be easy to crystallize out from solvent (such as acetic acid/water mixed solvent), form stable salt, and product characteristics are good, meet the demand of pharmaceutical preparation especially.
The object of the present invention is to provide a kind of stable cephalo sieve phosphonium salt, described cephalo sieve phosphonium salt is the glutaminate of cephalo sieve phosphine.
L-glutamic acid, also known as alpha-amino group pentanedioic acid, it has following structure:
Due to its chiral carbon, there are two kinds of enantiomers, Pidolidone and D-Glus in L-glutamic acid.
Pidolidone has following structure:
D-Glu has following structure:
In an embodiment of the invention, described cephalo sieve phosphine glutaminate is cephalo sieve phosphine Pidolidone salt.
In an embodiment of the invention, described cephalo sieve phosphine glutaminate is cephalo sieve phosphine D-Glu salt.
Another object of the present invention is the crystallization providing cephalo sieve phosphine glutaminate, it is characterized in that, powder x-ray diffraction collection of illustrative plates is shown in 20.15 with 2 θ angle measuring gauges, 21.59, 22.20, 25.78, 26.31, 31.18 degree has characteristic peak, preferred 19.22, 20.15, 21.59, 22.20, 23.31, 23.94, 25.78, 26.31, 30.12, 31.18, 33.91, 35.79 degree has characteristic peak, more preferably 11.76, 13.92, 16.53, 19.22, 20.15, 21.59, 22.20, 23.31, 23.94, 25.78, 26.31, 27.84, 30.12, 31.18, 33.91, 34.91, 35.79 degree has characteristic peak, most preferably 7.11, 9.75, 10.43, 11.76, 12.37, 13.92, 16.53, 19.22, 20.15, 21.59, 22.20, 23.31, 23.94, 25.78, 26.31, 27.84, 30.12, 31.18, 33.91, 34.91, 35.79 degree has characteristic peak.
As an embodiment of the invention, in the powder x-ray diffraction collection of illustrative plates of cephalo sieve phosphine glutaminate of the present invention crystallization, the peak position of characteristic peak and intensity are represented by following table:
| Numbering | 2 θ (degree) | Relative intensity (I/I 0) |
| 1 | 7.11 | 10 |
| 2 | 9.75 | 11 |
| 3 | 10.43 | 9 |
| 4 | 11.76 | 20 |
| 5 | 12.37 | 17 |
| 6 | 13.92 | 18 |
| 7 | 16.53 | 23 |
| 8 | 19.22 | 54 |
| 9 | 20.15 | 65 |
| 10 | 21.59 | 100 |
| 11 | 22.20 | 97 |
| 12 | 23.31 | 59 |
| 13 | 23.94 | 52 |
| 14 | 25.78 | 79 |
| 15 | 26.31 | 61 |
| 16 | 27.84 | 29 |
| 17 | 30.12 | 38 |
| 18 | 31.18 | 74 |
| 19 | 33.91 | 37 |
| 20 | 34.91 | 22 |
| 21 | 35.79 | 34 |
In an embodiment of the invention, the crystallization of described cephalo sieve phosphine glutaminate is cephalo sieve phosphine Pidolidone salt-pepper noise.
The X-ray diffraction condition determination that the present invention adopts is: CuK α line, tube voltage 40kV, tube current 50mA.For any given crystallized form, due to the preferred orientation that the factors such as such as crystal habit cause, the relative intensity of diffraction peak can change, and this is known in crystallography art.There is the place of preferred orientation impact, peak intensity changes, but the characteristic peak positions of crystal formation cannot change.In addition, for any given crystal formation, may there is slight errors in the position at peak, and this is also known in crystallography art.Such as, because the change of temperature during analytic sample, sample move or the demarcation etc. of instrument, the position at peak can be moved, and the error at measurment of 2 θ values is about sometimes ± and 0.2 degree.Therefore, when determining often kind of crystalline texture, this error should be taken into account.
Another object of the present invention is the preparation method providing cephalo sieve phosphine glutaminate, comprises the steps:
(1) cephalo sieve phosphine is joined in acetic acid/water mixing solutions, stirring and dissolving;
(2) add L-glutamic acid, stir;
(3) crystallization, optionally adds acetic acid/water mixed solution;
(4) filter, dry.
In above-mentioned steps (1) and (3), in acetic acid/water mixing solutions, the volume ratio of acetic acid and water is 1:0.1-10, is preferably 1:0.5-5, most preferably is 1:1; Wet concentration is from distilled water, D/W, mannose aqueous solution etc.
In above-mentioned steps (2), the mol ratio of cephalo sieve phosphine and L-glutamic acid is 1:1-10, is preferably 1:1-5, most preferably is 1:1.
In above-mentioned steps (3), recrystallization temperature is 0 ~ 50 DEG C, is preferably 10 ~ 30 DEG C, most preferably is 25 DEG C; Crystallization state can be standing, also can stir and carry out; Adding described mixing solutions with the volume mass ratio (mL/g) of cephalo sieve phosphine is 1-20:1, is preferably 2-10:1, most preferably is 3-5:1.
In above-mentioned steps (4), drying temperature 0 ~ 50 DEG C, is preferably 10 ~ 30 DEG C, most preferably is 25 DEG C; Drying can be carried out under decompression or normal pressure.
Another aspect of the present invention provides the crystal composition of cephalo sieve phosphine glutaminate of the present invention crystallization, wherein the crystallization of cephalo sieve phosphine glutaminate accounts for more than 50% of crystal composition weight, be better more than 80%, be more preferably more than 90%, preferably more than 95%.
The present invention provides on the other hand the pharmaceutical composition comprising cephalo sieve phosphine glutaminate, the glutaminate crystallization of cephalo sieve phosphine or cephalo sieve phosphine glutaminate crystal composition, comprises above-mentioned cephalo sieve phosphine glutaminate for the treatment of significant quantity, the glutaminate crystallization of cephalo sieve phosphine or cephalo sieve phosphine glutaminate crystal composition in this pharmaceutical composition.In addition, can also contain in this pharmaceutical composition or not contain pharmaceutically acceptable auxiliary material.
Another aspect of the invention provides cephalo sieve phosphine glutaminate, the crystallization of cephalo sieve phosphine glutaminate, cephalo sieve phosphine glutaminate crystal composition or the purposes of its pharmaceutical composition in the medicine preparing bacterial-infection resisting.
Accompanying drawing explanation
Fig. 1 is the powder x-ray diffraction collection of illustrative plates of cephalo sieve phosphine Pidolidone salt prepared by embodiment 1.
Embodiment
The present invention is described in detail by following examples, and they are only embodiments, do not limit the present invention, and every technology realized based on the present invention, all belongs to scope of the present invention.
The preparation of embodiment 1 cephalo sieve phosphine Pidolidone salt
5.00g cephalo sieve phosphine (7.3mmol) is joined in the mixed solution of 25ml distilled water and 25ml acetic acid, stirring and dissolving.Add 1.07gL-L-glutamic acid (7.3mmol), stir.Stirred at ambient temperature crystallization 18h (spending the night); Add the mixed solution of 15ml distilled water and acetic acid (1:1), stir 2h.Filtration gained precipitates, with the mixed solution washing leaching cake 3 times of 15ml distilled water and acetic acid (1:1), and with 10ml distilled water wash 5 times.With 3A molecular sieve as siccative, by this crystallization drying under reduced pressure, until reach constant weight.
Output: 3.52g (yield: 58%).
IR(KBr)cm
-1：1755，1689，1668，1640，1538，1274，1040
The preparation of embodiment 2 cephalo sieve phosphine D-Glu salt
5.0g cephalo sieve phosphine is joined in the mixed solution of 25ml distilled water and 25ml acetic acid, stirring and dissolving.Add 1.1gD-L-glutamic acid, stir.Stirred at ambient temperature crystallization 18h (spending the night); Add the mixed solution of 15ml distilled water and acetic acid (1:1), stir 2h.Filtration gained precipitates, and with the mixed solution washing leaching cake of 15ml distilled water and acetic acid (1:1), and uses 10ml distilled water wash.With 3A molecular sieve as siccative, by this crystallization drying under reduced pressure, until reach constant weight.
Output: 3.40g (yield: 56%).
The preparation of reference example 1 cephalo sieve PHOSPHONACETIC salt
Cephalo sieve PHOSPHONACETIC salt is prepared according to CN1462275A embodiment 1.100mg cephalo sieve phosphine (0.151mmol) is suspended in the mixed solution of 0.5ml distilled water for injection and 0.5ml acetic acid, is dissolved by ultrasonication, this solution is at room temperature placed and spends the night; With the crystal of spatula grinding precipitation, collecting by filtration.By this crystallization 1.2ml distilled water for injection washing, use 3A molecular sieve as siccative, through this crystallization drying under reduced pressure, until reach constant weight, obtain crystal seed.
Output 79mg (yield: 73%).
Embodiment 3 stability experiment
With reference to the Pharmacopoeia of the People's Republic of China 2010 editions two annex XIXC bulk drugs and pharmaceutical preparation stability test governing principle, cephalo sieve PHOSPHONACETIC salt, cephalo sieve phosphine Pidolidone salt are carried out stability in 60 DEG C, and 5 days and 10 days are investigated, room temperature stability is investigated, and impurity (HPLC) changing conditions is in table 1.
HPLC testing conditions is as follows:
Chromatographic column: ThermoBDSC18 (5 μm, 4.6mm × 250mm)
Mobile phase A: 0.05%H
3pO
4the aqueous solution
Mobile phase B: acetonitrile
Linear gradient elution, program is as follows:
Determined wavelength: 242nm detects
Flow velocity: 1.0ml/min
Column temperature: 25 DEG C
Sample size: 10 μ l
Solvent: water (pH6.5)-acetonitrile (4:1)
The preparation of need testing solution: get trial-product, precision takes in right amount, and solubilizing agent dissolves and dilutes the solution making 1mg/mL, as need testing solution.
Table 1 cephalo sieve phosphine Pidolidone salt-stable is tested
Result shows, and cephalo sieve phosphine Pidolidone salt has stability more better than cephalo sieve PHOSPHONACETIC salt.
Claims (10)
1. the glutaminate of cephalo sieve phosphine shown in formula (I)
2. cephalo sieve phosphine glutaminate according to claim 1, it is characterized in that, L-glutamic acid is Pidolidone.
3. cephalo sieve phosphine glutaminate according to claim 1, it is characterized in that, L-glutamic acid is D-Glu.
4. the crystallization of the cephalo sieve phosphine glutaminate described in any one of claim 1-3, it is characterized in that, powder x-ray diffraction collection of illustrative plates is shown in 20.15,21.59,22.20,25.78,26.31,31.18 degree with 2 θ angle measuring gauges characteristic peak.
5. crystallization according to claim 4, it is characterized in that, powder x-ray diffraction collection of illustrative plates is shown in 19.22,20.15,21.59,22.20,23.31,23.94,25.78,26.31,30.12,31.18,33.91,35.79 degree with 2 θ angle measuring gauges characteristic peak.
6. crystallization according to claim 5, it is characterized in that, powder x-ray diffraction collection of illustrative plates is shown in 7.11,9.75,10.43,11.76,12.37,13.92,16.53,19.22,20.15,21.59,22.20,23.31,23.94,25.78,26.31,27.84,30.12,31.18,33.91,34.91,35.79 degree with 2 θ angle measuring gauges characteristic peak.
7. the preparation method of cephalo sieve phosphine glutaminate, comprises the steps:
(1) cephalo sieve phosphine is joined in acetic acid/water mixing solutions, stirring and dissolving;
(2) add L-glutamic acid, stir;
(3) crystallization, optionally adds acetic acid/water mixed solution;
(4) filter, dry.
8. crystal composition, the cephalo sieve phosphine glutaminate crystallization wherein described in any one of claim 4-6 accounts for more than 50% of crystal composition weight, is better more than 80%, is more preferably more than 90%, and preferably more than 95%.
9. pharmaceutical composition, it comprises crystal composition described in cephalo sieve phosphine glutaminate crystallization described in the treatment cephalo sieve phosphine glutaminate described in any one of claim 1-3 of significant quantity, any one of claim 4-6 or claim 8.
10. the cephalo sieve phosphine glutaminate described in any one of claim 1-3, the cephalo sieve phosphine glutaminate crystallization described in any one of claim 4-6, crystal composition according to claim 8 or the purposes of pharmaceutical composition according to claim 9 in the medicine preparing bacterial-infection resisting.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410334985.1A CN105273007A (en) | 2014-07-14 | 2014-07-14 | Ceftaroline fosamil glutamate and crystal thereof |
| PCT/CN2015/083860 WO2016008393A1 (en) | 2014-07-14 | 2015-07-13 | Ceftaroline fosamil amino acid salt and crystal thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410334985.1A CN105273007A (en) | 2014-07-14 | 2014-07-14 | Ceftaroline fosamil glutamate and crystal thereof |
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| CN105273007A true CN105273007A (en) | 2016-01-27 |
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| CN201410334985.1A Pending CN105273007A (en) | 2014-07-14 | 2014-07-14 | Ceftaroline fosamil glutamate and crystal thereof |
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