CN102250095A - Carbapenem derivative or hydrate crystal and preparation method thereof - Google Patents
Carbapenem derivative or hydrate crystal and preparation method thereof Download PDFInfo
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- CN102250095A CN102250095A CN 201010178970 CN201010178970A CN102250095A CN 102250095 A CN102250095 A CN 102250095A CN 201010178970 CN201010178970 CN 201010178970 CN 201010178970 A CN201010178970 A CN 201010178970A CN 102250095 A CN102250095 A CN 102250095A
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Abstract
The invention belongs to the technical field of medicines and particularly relates to crystal of a carbapenem derivative, namely (4R,5S,6S)-3-[(3S,5S)-5-[(4- sulfonamidophen-1-ylmethyl)aminoformyl]-3-pyrrolidyl]thio-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxy-11-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, of a structural formula (I) or hydrate of carbapenem, and a preparation method thereof. When the crystal of the carbapenem derivative of structural formula (I) or hydrate of carbapenem is irradiated by Cu-Ka, a X-ray powder diffraction spectrum represented at angle of 2theta has characteristic peaks at wavelengths of 10.3+/-0.2, 14.5+/-0.2, 18.0+/-0.2, 20.8+/-0.2 and 23.3+/-0.2. The formula (I) is shown below.
Description
1, technical field
The invention belongs to medical technical field; be specifically related to (4R; 5S; 6S)-3-[(3S, 5S)-5-[(4-sulfahydantoin phenmethyl) carbamyl]-the 3-tetramethyleneimine] sulphur-6-[(R)-1-hydroxyethyl]-crystal formation of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid or its hydrate and preparation method thereof
2, background technology
Carbapenems (Carbapenems) is the novel β-Nei Xiananleikangshengsu that grows up the seventies in 20th century, because it has characteristics such as super wide spectrum, superpower effect, anti-enzyme, the status in clinical application is more and more outstanding.
The carbapenem antibiotic of listing has imipenum-cilastatin, panipenem-Betamipron, meropenem, ertapenem sodium, biapenem, S-4661 at present.But existing kind is not ideal enough, have to dehydropeptidase of kidney (DPH-I) instability, the kind that has has nervus centralis toxicity, the activity to Pseudomonas aeruginosa that has is strong inadequately, the anti-microbial activity to methicillin-resistant gold Portugal bacterium (MRSA) that has is very low; The kind of the clinical use of carbapenem antibiotic is injection, and all very short in the intravital transformation period except that ertapenem, also exist to drain fast, the severe medication often, drawbacks such as clinical application inconvenience.And along with the antibiotic excessive use in the whole world, various resistant organisms more and more, antibiotic resistance is more and more serious, therefore is badly in need of research and development and has better antibacterial activity, and have the carbapenem antibiotic of good chemical stability.
Carbapenem derivative (4R shown in the structural formula (I); 5S; 6S)-3-[(3S; 5S)-and 5-[(4-sulfoamido benzene-1-ylmethyl) amine formyl]-the 3-tetramethyleneimine] sulphur-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (being called for short following compd A in this manual) is mainly by combining with penicillin-binding protein (PBPs) on the bacterial cell membrane, suppresses the synthetic and generation germicidal action of bacteria cell wall.
Compd A shown in the structural formula (I) has a detailed description in CN200810127480.2.Crystal formation research and development are extremely important in medicament research and development, and the compound of different shape has different bioavailabilities and solution degree, and crystal formation has considerable influence to stability, processing property, bioavailability and the solubleness etc. of compound.Therefore the inventor studies the various crystal formations of compd A, has confirmed the crystal formation of compd A thus.
3, summary of the invention
It is good to the purpose of this invention is to provide storage stability, and operability is good, bioavailability and solubleness good the crystal formation and preparation method thereof of compd A.
The compd A shown in the structural formula (1) or the crystal formation of its hydrate, it has following crystalline structure: use the Cu-Ka radiation, the X-ray powder diffraction of representing with 2 θ angles has characteristic peak at 10.3 ± 0.2,14.5 ± 0.2,18.0 ± 0.2,20.8 ± 0.2,23.3 ± 0.2 places.
The crystal formation of described compd A or its hydrate, it has following crystalline structure: use the Cu-Ka radiation, the X-ray powder diffraction of representing with 2 θ angles, also 16.3 ± 0.2,17.1 ± 0.2,21.3 ± 0.2,22.0 ± 0.2, located characteristic peak.
The crystal formation of described compd A or its hydrate, there is first endothermic transition peak in its DSC at 56-64 ℃, has second endothermic transition peak at 115-122 ℃, and maximum decomposition temperature is at 168-178 ℃.
The crystal formation of described compd A hydrate, its water content are 2%-10%, preferred 5%-10%.
The present invention also provides the preparation method of the crystal formation of compd A or its hydrate.Compd A can be synthetic with former currently known methods, for example can be synthetic with disclosed method among the CN200810127480.2.The crystal formation of compd A (hereinafter to be referred as crystal formation I) can make by following method.
With compd A N, the dissolving of the aqueous solution of N '-dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) (DMSO) splashes into poor solvent in this solution then, obtains crystal, filter, and drying, promptly.
Described poor solvent, be meant the solvent less to compd A solubleness, be selected from the lower alcohol that contains 1-4 carbon atom, the lower ketones that contains 1-6 carbon atom, acetonitrile, propionitrile, methylene dichloride, trichloromethane, Nitromethane 99Min., ether, methyl tertiary butyl ether, methyl-phenoxide, ethyl acetate, ethyl formate, methylcarbonate or tetrahydrofuran (THF), preferably select Nitromethane 99Min. or methylene dichloride.The lower alcohol that the described 1-4 of a containing carbon atom is is selected from methyl alcohol, ethanol, propyl alcohol etc., particular methanol; The lower ketones of the described 1-6 of a containing carbon atom is selected from acetone, butanone etc.
To the compd A that makes by aforesaid method or the crystal formation (hereinafter to be referred as crystal formation I) of its hydrate, measure:
(1) powder x-ray diffraction
The condition that the X diffraction is measured: the Cu-Ka line,
(monochromator), record by D/MAX-RB type X-ray diffractometer.
Use the Cu-Ka radiation, the X-ray powder diffraction of representing with 2 θ angles has stronger characteristic peak at 10.3 ± 0.2,14.5 ± 0.2,18.0 ± 0.2,20.8 ± 0.2,23.3 ± 0.2 places; Also characteristic peak is arranged at 16.3 ± 0.2,17.1 ± 0.2,21.3 ± 0.2,22.0 ± 0.2 places.
When measuring crystal formation of the present invention with the X diffraction, sometimes because the instrument of measuring or the condition of mensuration, for the peak that records, error at measurment can be arranged slightly, therefore when determining crystalline texture, this error should be taken into account, so the applicant has considered limit of error (± 0.2) when determining 2 θ angles.
(2) the DSC heat absorption is measured
The DSC condition determination: the DZ3335 differential scanning calorimeter, nitrogen protection, temperature rise rate 5 degree/minute.
There is first endothermic transition peak in DSC at 56-64 ℃, has second endothermic transition peak at 115-122 ℃, and maximum decomposition temperature is at 168-178 ℃.
(3) moisture determination
Measure according to Ka Er Fischer aquametry (being called for short the K-F method), the water content of the crystal formation I of The compounds of this invention A is at 2%-10%, and preferred 5%-10% is so the crystal formation I of compd A of the present invention can be hydrate forms.
The crystal formation that the present invention also provides compd A or its hydrate treats and/or prevents application in the infectious disease medicament in preparation.
The present invention also provides the crystal formation of compd A or its hydrate and the pharmaceutical composition of one or more pharmaceutical carriers and/or thinner, is pharmaceutically acceptable arbitrary formulation, for example oral preparations and injection.When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.
Description of drawings
Fig. 1 is the powder x-ray diffraction collection of illustrative plates of compd A crystal formation I, and ordinate zou is represented diffracted intensity (CPS), and X-coordinate is represented angle of diffraction (2 θ).
Fig. 2 is the DSC collection of illustrative plates of compd A crystal formation I, and ordinate zou is represented power (mW), X-coordinate represent temperature (℃).
4. embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But the scope that should not be construed as the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
The preparation one of the crystal formation I of embodiment 1 compd A
Get the compd A of 600mg,, stir down, dropwise add the 50mL Nitromethane 99Min. with dimethyl sulfoxide (DMSO) (DMSO) dissolving of 2mL water and 3mL, stirring at room 0.5-1 hour, to filter, vacuum-drying gets white crystal 300mg.
The XRD diffraction: XRD diffraction measurement result is shown among Fig. 1;
The DSC decomposition point: maximum decomposition temperature the results are shown among Fig. 2 at 171 ℃;
Water content (K-F method): 2.44%.
The preparation two of the crystal formation I of embodiment 2 compd As
With reference to embodiment 1 operation, (DMSO) changes N into dimethyl sulfoxide (DMSO), N '-dimethyl formamide (DMF), and Nitromethane 99Min. changes methyl alcohol into, gets white crystal 320mg.
The XRD diffraction: in the XRD diffractogram, angle of diffraction (2 θ) is having characteristic peak with upper/lower positions:
10.24、14.52、16.30、17.08、17.84、20.70、21.28、21.94、23.14；
The DSC decomposition point: maximum decomposition temperature is at 172 ℃;
Water content (K-F method): 2.81%.
The preparation three of the crystal formation I of embodiment 3 compd As
With reference to embodiment 1 operation, (DMSO) changes N into dimethyl sulfoxide (DMSO), and N '-dimethyl formamide (DMF) changes Nitromethane 99Min. into methylene dichloride, gets white crystal 380mg.
The XRD diffraction: in the XRD diffractogram, angle of diffraction (2 θ) is having characteristic peak with upper/lower positions:
10.28、14.56、16.34、17.12、17.88、20.80、21.30、22.02、23.24；
The DSC decomposition point: maximum decomposition temperature is at 171 ℃;
Water content (K-F method): 5.54%.
The study on the stability of embodiment 4 crystal formation I
The investigation condition is 60 ℃ of high temperature, places sampling after 5 days, 10 days, compares with 0 day sample, measures related substance, content.Between probation, sample is packed with plastics bag overcoat foil sealing.
Trial-product:
Amorphous: self-control, the preparation method is: get 2.0 and digest compound A 7mLN, N '-dimethyl formamide (DMF) dissolving is added to above-mentioned drips of solution in the 200mL ethyl acetate then, and drying obtains pressed powder 1.52 grams, purity 91.68%.Its lot number is 110901.
Crystal formation I is made by this specification sheets embodiment 1, and lot number is 20100315-4.
The content aspect, according to 2010 editions appendix V of Chinese Pharmacopoeia D high performance liquid chromatography, adopt 0 day sample in contrast product measure with external standard method.
Operational condition
Instrument: high-efficient liquid phase chromatogram discuss (Agilent 1200 series)
Chromatographic column: Agilent C
18, filler is the octadecylsilane silica gel of 5 μ m, internal diameter 4.6mm, column length 150mm
Column temperature: 30 ℃
Moving phase: 0.02M Secondary ammonium phosphate (phosphoric acid is transferred pH=5.2): acetonitrile=100: 7
Flow velocity: 1.0mL/min
Sample size: 10 μ L
The related substance aspect according to 2010 editions appendix V of Chinese Pharmacopoeia D high performance liquid chromatography, adopts area normalization method to measure.
Operational condition
Instrument: high-efficient liquid phase chromatogram discuss (Agilent 1200 series)
Chromatographic column: Agilent C
18, filler is the octadecylsilane silica gel of 5 μ m, internal diameter 4.6mm, column length 150mm
Column temperature: 30 ℃
Moving phase: A:0.02M Secondary ammonium phosphate (phosphoric acid is transferred pH=5.2): acetonitrile=95: 5
B:0.02M Secondary ammonium phosphate (phosphoric acid is transferred pH=5.2): acetonitrile=30: 70
Gradient condition: see Table 1.
Table 1 determination of related substances chromatogram gradient condition
| T(min) | 0 | 5 | 15 | 18 | 25 | 30 | 35 | 40 | 42 | 47 |
| B％ | 0 | 3 | 4 | 15 | 30 | 65 | 100 | 100 | 0 | 0 |
Flow velocity: 1.0ml/min
Sample size: 10 μ l
Gained test-results: see Table 2.
Table 2 study on the stability
Remarks: because the compd A facile hydrolysis, the beta-lactam ring is opened after the hydrolysis, is major impurity, is called for short ring-opening product, and with the content of a ring-opening product factor as study on the stability; Open loop % is meant the content of ring-opening product; Increase % and be meant that high temperature places related substance and the amount of comparing increase in 0 day after 5 days, 10 days for 60 ℃.
As can be seen from Table 2, the crystal formation I of compd A and amorphous after placing 5 days, 10 days through 60 ℃ of high temperature the ring-opening product in the related substance and total substances content all become greatly total content decline.But after 60 ℃ of high temperature were placed 5 days, 10 days, the amount that the more amorphous ring-opening product of the amount that crystal formation I ring-opening product increases increases was little, and the amount that the more amorphous total impurities content of the amount that crystal formation I total impurities content increases increases is little; The amount that the more amorphous content of the amount that crystal formation I content reduces reduces is little; So the crystal formation I and amorphous phase ratio of compd A, what its foreign matter content increased lacks, and what content reduced lacks, and the character of each side is all good than unbodied, and character is more stable.
Claims (9)
1. carbapenem derivative (the 4R shown in the structural formula (I); 5S; 6S)-3-[(3S; 5S)-and 5-[(4-sulfoamido benzene-1-ylmethyl) amine formyl]-the 3-tetramethyleneimine] sulphur-6-[(R)-1-hydroxyethyl]-crystal formation of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid or its hydrate; it is characterized in that; use the Cu-Ka radiation, the X-ray powder diffraction of representing with 2 θ angles has characteristic peak at 10.3 ± 0.2,14.5 ± 0.2,18.0 ± 0.2,20.8 ± 0.2,23.3 ± 0.2 places.
Formula (I)
2. the crystal formation of carbapenem derivative as claimed in claim 1 or its hydrate, it is characterized in that, use the Cu-Ka radiation, the X-ray powder diffraction of representing with 2 θ angles, except that right requires 1 characteristic peak of being explained, also characteristic peak is arranged at 16.3 ± 0.2,17.1 ± 0.2,21.3 ± 0.2,22.0 ± 0.2 places.
3. as the crystal formation of each described carbapenem derivative of claim 1-2 or its hydrate, it is characterized in that, there is first endothermic transition peak in its DSC at 56-64 ℃, has second endothermic transition peak at 115-122 ℃, and maximum decomposition temperature is at 168-178 ℃.
4. as the crystal formation of each described carbapenem derivative hydrate of claim 1-2, it is characterized in that its water content is 2%-10%.
5. the crystal formation of carbapenem derivative hydrate as claimed in claim 4 is characterized in that, its water content is 5%-10%.
6. as the preparation method of the crystal formation of each described carbapenem derivative of claim 1-2 or its hydrate; it is characterized in that; with carbapenem derivative (4R; 5S; 6S)-3-[(3S; 5S)-and 5-[(4-sulfoamido benzene-1-ylmethyl) amine formyl]-the 3-tetramethyleneimine] sulphur-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid N; N '-dimethyl formamide (DMF); the aqueous solution dissolving of dimethyl sulfoxide (DMSO) (DMSO); poor solvent is splashed in this solution then; obtain crystal; filter, drying, promptly.
7. preparation method as claimed in claim 6; it is characterized in that; described poor solvent; be meant carbapenem derivative (4R; 5S; 6S)-3-[(3S; 5S)-and 5-[(4-sulfoamido benzene-1-ylmethyl) amine formyl]-the 3-tetramethyleneimine] sulphur-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-less solvent of 2-carboxylic acid solubleness, be selected from the lower alcohol that contains 1-4 carbon atom; the lower ketones that contains 1-6 carbon atom; acetonitrile; propionitrile; methylene dichloride; trichloromethane; Nitromethane 99Min.; ether; methyl tertiary butyl ether; methyl-phenoxide; ethyl acetate; ethyl formate; methylcarbonate or tetrahydrofuran (THF).
8. as each described carbapenem derivative (4R of claim 1-2; 5S; 6S)-3-[(3S, 5S)-5-[(4-sulfoamido benzene-1-ylmethyl) amine formyl]-the 3-tetramethyleneimine] sulphur-6-[(R)-1-hydroxyethyl]-crystal formation of 4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid or its hydrate treats and/or prevents application in the infectious disease medicament in preparation.
9. comprise each described (4R of claim 1-2; 5S; 6S)-3-[(3S; 5S)-and 5-[(4-sulfoamido benzene-1-ylmethyl) amine formyl]-the 3-tetramethyleneimine] sulphur-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid or the crystal formation of its hydrate and the pharmaceutical composition of one or more pharmaceutical carriers and/or thinner, be pharmaceutically acceptable arbitrary formulation.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010178970 CN102250095A (en) | 2010-05-21 | 2010-05-21 | Carbapenem derivative or hydrate crystal and preparation method thereof |
| US13/699,550 US20130079322A1 (en) | 2010-05-21 | 2011-05-20 | Crystalline of carbapenem derivative or its hydrate, preparation methods and uses thereof |
| PCT/CN2011/000874 WO2011143935A1 (en) | 2010-05-21 | 2011-05-20 | Crystalline of carbapenem derivative or its hydrate, preparation methods and uses thereof |
| CN2011800253620A CN102918041A (en) | 2010-05-21 | 2011-05-20 | Crystalline of carbapenem derivative or its hydrate, preparation methods and uses thereof |
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| CN 201010178970 CN102250095A (en) | 2010-05-21 | 2010-05-21 | Carbapenem derivative or hydrate crystal and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103025733A (en) * | 2010-06-03 | 2013-04-03 | 山东轩竹医药科技有限公司 | Crystalline form of carbapenem derivative or its hydrates and preparation methods and uses thereof |
| CN112174965A (en) * | 2019-07-03 | 2021-01-05 | 轩竹生物科技有限公司 | Deuterium modified carbapenem derivative |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101372489A (en) * | 2007-06-28 | 2009-02-25 | 山东轩竹医药科技有限公司 | Carbapenem derivative containing sulfhydryl pyrrolidine formamide benzyl |
-
2010
- 2010-05-21 CN CN 201010178970 patent/CN102250095A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101372489A (en) * | 2007-06-28 | 2009-02-25 | 山东轩竹医药科技有限公司 | Carbapenem derivative containing sulfhydryl pyrrolidine formamide benzyl |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103025733A (en) * | 2010-06-03 | 2013-04-03 | 山东轩竹医药科技有限公司 | Crystalline form of carbapenem derivative or its hydrates and preparation methods and uses thereof |
| US8822445B2 (en) | 2010-06-03 | 2014-09-02 | Xuanzhu Pharma Co., Ltd. | Crystalline form of carbapenem derivative or its hydrates and preparation methods and uses thereof |
| CN103025733B (en) * | 2010-06-03 | 2015-11-25 | 山东轩竹医药科技有限公司 | Crystal formation of Carbpenem derivants or its hydrate and preparation method thereof and purposes |
| CN112174965A (en) * | 2019-07-03 | 2021-01-05 | 轩竹生物科技有限公司 | Deuterium modified carbapenem derivative |
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Application publication date: 20111123 |