CN105566352A - New crystal form cefmenoxine hydrochloride compound prepared by adopting particle process crystal product molecular assembling and morphology optimizing technology and preparation - Google Patents
New crystal form cefmenoxine hydrochloride compound prepared by adopting particle process crystal product molecular assembling and morphology optimizing technology and preparation Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
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- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The invention discloses a new crystal form cefmenoxine hydrochloride compound and a crystallization preparation method thereof. The new crystal form cefmenoxine hydrochloride compound is prepared by adopting the particle process crystal product molecular assembling and morphology optimizing technology. The compound has the advantages of being high in purity and good in fluidity and stability. The invention also discloses a preparation which is prepared from the cefmenoxine hydrochloride compound, namely cefmenoxine hydrochloride for injection.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of particle process crystal product molecule that adopts and assemble and the Cefmenoxime Hemihydrochloride crystal compound of form optimisation technique and preparation.
Background technology
Cefmenoxime Hemihydrochloride, its chemical name is: (6R, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyimino kharophen]-3-[[1-methyl isophthalic acid H-tetrazolium-5-base)-sulphur] methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid hydrochloride (2:1), molecular formula: C
16h
17n
9o
5s
31/2HC1, molecular weight: 529.79, structural formula is:
Cefmenoxime Hemihydrochloride is the third generation cephalosporin that Japanese Wu Tian company develops, and nineteen eighty-three, in Japanese Initial Public Offering, is a kind of Broad spectrum antibiotics, reaches germicidal action by the biosynthesizing of anti-bacteria cell walls.
About the synthetic method of Cefmenoxime Hemihydrochloride, according to bibliographical information, be mainly raw material with 7-ACA, (1) first 3 condensations, then 7 condensations; (2) first 7 condensations, then 3 condensations.Adopt Cefmenoxime Hemihydrochloride prepared by aforesaid method in the market, its purity is poor, and look level is bad, poor stability, thus have impact on its quality of the pharmaceutical preparations.
The less stable of the conventional crystal formation of Cefmenoxime Hemihydrochloride, all unstable to heat, meta-acid environment, meta-alkali environment, show that outward appearance is easy to change, content reduction, occur the problems such as degraded product.Address this problem and must research and develop novel crystallization production technology, to optimize the process parameters such as solvent, temperature, reaction times, additive, crystallization is carried out under the suitable conditions, thus ensure the quality of product.
The above problem that the present invention exists mainly for Cefmenoxime Hemihydrochloride, to solvent in crystal formation process, temperature, external force, on the basis that the factors such as additive are fully investigated, the assembling of particle process crystal product molecule and form optimisation technique is adopted to obtain a kind of purity high, look level is good, good fluidity, the Cefmenoxime Hemihydrochloride crystal compound of good stability, this synthesis step preparation process more in the past more focuses on the control of reagent in building-up process and parameter, step is simple, the raw material etc. used is low price, nontoxic or low-toxicity product, be suitable for commercial scale production.Utilize the preparation that the compound described in the present invention is made, preparation had better stability more in the past.
Summary of the invention
The first object of the present invention is to provide a kind of Cefmenoxime Hemihydrochloride crystal compound, and this compound adopts the assembling of particle process crystal product molecule to prepare with form optimisation technique, has that purity is high, look level is good, the feature of good stability.
Cefmenoxime Hemihydrochloride crystal compound X-ray powder diffraction of the present invention measures, the X-ray powder diffraction pattern represented with 2 θ diffraction angle at 6.25 ° ± 0.2 °, 13.04 ° ± 0.2 °, 14.31 ° ± 0.2 °, 17.21 ° ± 0.2 °, 18.18 ° ± 0.2 °, 19.95 ° ± 0.2 °, 22.77 ° ± 0.2 °, 23.76 ° ± 0.2 °, 25.88 ° ± 0.2 °, 29.19 ° ± 0.2 ° place's indicating characteristic diffraction peak, as shown in Figure 1.
Cefmenoxime Hemihydrochloride crystal compound preparation of the present invention comprises the following steps:
(1) by methylene dichloride, ethanol, (6R, 7R)-7-amino-3-[[(1-methyl isophthalic acid-H-tetrazole-5-base) sulfo-] methyl]-8-oxo-5-thia-1-azabicyclo [4, 2, 0] oct-2-ene-2-carboxylic acid hydrochloride (7-ATCAHCl) and triethylamine hybrid reaction, add 2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetic acid sulfo-benzothiazole ester (MEAM), water extracts, merge aqueous phase, activated carbon decolorizing, collect filtrate, use salt acid for adjusting pH value, filter, washing, vacuum-drying, obtain Cefmenoxime Hemihydrochloride crude product.
(2) by soluble in water for Cefmenoxime Hemihydrochloride crude product, slowly add alkali lye, stirring reaction, regulate pH, activated carbon decolorizing, filter, collect filtrate.Entered by filtrate added drop-wise in the mixing solutions of acetone, purified water and concentrated hydrochloric acid, reaction terminates, activated carbon decolorizing, filters, adds NaHCO in filtrate
3solution and water for injection, stir growing the grain, filters, and washing is dry, obtains refining Cefmenoxime Hemihydrochloride.
Preferably, in above-mentioned preparation method, described 7-ATCAHCl and the weight ratio of MEAM are 1:1 ~ 1:3.More preferably, weight ratio is 1:2.
Preferably, in above-mentioned preparation method, the described concentration of hydrochloric acid described in step (1) is 5 ~ 8mol/L.More preferably, concentration of hydrochloric acid is 6mol/L.
Preferably, in above-mentioned preparation method, the pH that the described hydrochloric acid described in step (1) regulates is 1 ~ 3.More preferably, pH is 2.5.
Preferably, in above-mentioned preparation method, the described alkali lye described in step (2) is the sodium bicarbonate aqueous solution of 8 ~ 12%.More preferably, alkali lye is the sodium bicarbonate aqueous solution of 10%.
Preferably, in above-mentioned preparation method, the pH that the described alkali lye described in step (2) regulates is 6 ~ 8.More preferably, pH is 7.0.
Preferably, in above-mentioned preparation method, the described rearing crystal time described in step (2) is 2 ~ 4h.More preferably, rearing crystal time is 3 ~ 3.5h.
The present invention second object is to provide a kind of Cefmenoxime Hemihydrochloride pharmaceutical composition comprising Cefmenoxime Hemihydrochloride crystal compound of the present invention, and this pharmaceutical composition preparation process is simple to operate, has better stability and side effect is little compared with product in the past.
Cefmenoxime Hemihydrochloride pharmaceutical composition of the present invention counts the component comprising following weight part by weight: Cefmenoxime Hemihydrochloride (in cefmenoxime) 40 ~ 80 parts and sodium bicarbonate 20 ~ 60 parts.
Accompanying drawing explanation
Fig. 1: the X-ray powder diffraction pattern of Cefmenoxime Hemihydrochloride crystal compound, the 2 θ values that in figure, diffraction peak numbering is corresponding are see table 1.
Embodiment
Below will the present invention will be further described by embodiment; but therefore do not limit the present invention in described scope of embodiments, one skilled in the art will understand that the equivalent replacement that content of the present invention is done; or improve accordingly, still belong within protection scope of the present invention.
Embodiment 1: the preparation of Cefmenoxime Hemihydrochloride crystal compound
(1) in reaction flask, methylene dichloride 250ml is added successively, ethanol 25ml, (6R, 7R)-7-amino-3-[[(1-methyl isophthalic acid-H-tetrazole-5-base) sulfo-] methyl]-8-oxo-5-thia 1-azabicyclo [4, 2, 0] oct-2-ene-2-carboxylic acid hydrochloride (7-ATCAHCl) 25g, triethylamine 20ml, after room temperature reaction 30min, add 2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetic acid sulfo-benzothiazole ester (MEAM) 50.0g, control suitable thermotonus 8h, add water extraction 2 times, each 150ml, merge aqueous phase, decolour through gac room temperature, filter, use washing with alcohol layer of charcoal, washing lotion merges, with 6mol/L hydrochloric acid adjust pH to 1.5, growing the grain 3h, filter, water washed screening, in 40 DEG C of vacuum-dryings, obtain Cefmenoxime Hemihydrochloride crude product.
(2) in reaction flask, Cefmenoxime Hemihydrochloride crude product 25.9g and water 230ml is added, stir 30min, slowly add the sodium hydrogen carbonate solution of 10%, the pH value of regulator solution is 6.5 ~ 7.0, stirring at room temperature reaction 30min, through 0.5g activated carbon decolorizing 10min, filter, frozen water washs, filtrate merges, filtrate added drop-wise is entered acetone 50ml, in the mixing solutions of purified water 100ml and concentrated hydrochloric acid 25ml, reaction terminates, add gac 0.5g decolouring 10min, filter, the sodium hydrogen carbonate solution of 10% is added in filtrate, stir growing the grain 3.5h, filter, washing with alcohol 2 times, each 50ml, 40 DEG C of vacuum-dryings, the Cefmenoxime Hemihydrochloride that must refine.
X-ray powder diffraction (XRPD) is adopted to study and characterize the new crystallized form of Cefmenoxime Hemihydrochloride.
Plant and instrument: EMPYREAN (sharp shadow) X-ray diffractometer (Dutch Panalytical company).
The X-ray powder diffraction pattern of embodiment 1 product, at 6.25 °, 13.04 °, 14.31 °, 17.21 °, 18.18 °, 19.95 °, 22.77 °, 23.76 °, 25.88 °, locates indicating characteristic diffraction peaks for 29.19 °.Specifically see Figure of description 1.
The concrete data of described XRPD diffraction are as shown in the table:
Table 1 Cefmenoxime Hemihydrochloride crystal formation
Numbering | D value | 2θ(°) | I/I 0% |
1 | 14.13 | 6.25 | 54.15 |
2 | 6.79 | 13.04 | 26.06 |
3 | 6.19 | 14.31 | 65.95 |
4 | 5.15 | 17.21 | 21.99 |
5 | 4.88 | 18.18 | 96.81 |
6 | 4.45 | 19.95 | 22.17 |
7 | 3.91 | 22.77 | 100.00 |
8 | 3.74 | 23.76 | 31.26 |
9 | 3.44 | 25.88 | 13.91 |
10 | 3.06 | 29.19 | 16.74 |
Embodiment 2: the preparation of Cefmenoxime Hemihydrochloride crystal compound
(1) in reaction flask, methylene dichloride 250ml is added successively, ethanol 25ml, (6R, 7R)-7-amino-3-[[(1-methyl isophthalic acid-H-tetrazole-5-base) sulfo-] methyl]-8-oxo-5-thia 1-azabicyclo [4, 2, 0] oct-2-ene-2-carboxylic acid hydrochloride (7-ATCAHCl) 25g, triethylamine 20ml, after room temperature reaction 30min, add 2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetic acid sulfo-benzothiazole ester (MEAM) 25.0g, control suitable thermotonus 8h, add water extraction 2 times, each 150ml, merge aqueous phase, decolour through gac room temperature, filter, use washing with alcohol layer of charcoal, washing lotion merges, with 8mol/L hydrochloric acid adjust pH to 2.0, growing the grain 3h, filter, water washed screening, in 40 DEG C of vacuum-dryings, obtain Cefmenoxime Hemihydrochloride crude product.
(2) in reaction flask, Cefmenoxime Hemihydrochloride crude product 25.1g and water 230ml is added, stir 30min, slowly add the sodium hydrogen carbonate solution of 10%, the pH value of regulator solution is 6.7 ~ 6.9, stirring at room temperature reaction 30min, through 0.5g activated carbon decolorizing 10min, filter, frozen water washs, filtrate merges, filtrate added drop-wise is entered acetone 50ml, in the mixing solutions of purified water 100ml and concentrated hydrochloric acid 25ml, reaction terminates, add gac 0.5g decolouring 10min, filter, the sodium hydrogen carbonate solution of 10% is added in filtrate, stir growing the grain 2.5h, filter, washing with alcohol 2 times, each 50ml, 40 DEG C of vacuum-dryings, the Cefmenoxime Hemihydrochloride that must refine.
The X-ray powder diffraction pattern of embodiment 2 product, at 6.25 °, 13.04 °, 14.31 °, 17.21 °, 18.18 °, 19.95 °, 22.77 °, 23.76 °, 25.88 °, locates indicating characteristic diffraction peaks for 29.19 °.
Embodiment 3: the preparation of Cefmenoxime Hemihydrochloride crystal compound
(1) in reaction flask, methylene dichloride 250ml is added successively, ethanol 25ml, (6R, 7R)-7-amino-3-[[(1-methyl isophthalic acid-H-tetrazole-5-base) sulfo-] methyl]-8-oxo-5-thia 1-azabicyclo [4, 2, 0] oct-2-ene-2-carboxylic acid hydrochloride (7-ATCAHCl) 25g, triethylamine 20ml, after room temperature reaction 30min, add 2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetic acid sulfo-benzothiazole ester (MEAM) 75.0g, control suitable thermotonus 8h, add water extraction 2 times, each 150ml, merge aqueous phase, decolour through gac room temperature, filter, use washing with alcohol layer of charcoal, washing lotion merges, with 5mol/L hydrochloric acid adjust pH to 2.0, growing the grain 3h, filter, water washed screening, in 40 DEG C of vacuum-dryings, obtain Cefmenoxime Hemihydrochloride crude product.
(2) in reaction flask, Cefmenoxime Hemihydrochloride crude product 23.7g and water 230ml is added, stir 30min, slowly add the sodium hydrogen carbonate solution of 10%, the pH value of regulator solution is 6.0 ~ 6.5, stirring at room temperature reaction 30min, through 0.5g activated carbon decolorizing 10min, filter, frozen water washs, filtrate merges, filtrate added drop-wise is entered acetone 50ml, in the mixing solutions of purified water 100ml and concentrated hydrochloric acid 25ml, reaction terminates, add gac 0.5g decolouring 10min, filter, the sodium hydrogen carbonate solution of 10% is added in filtrate, stir growing the grain 3.0h, filter, washing with alcohol 2 times, each 50ml, 40 DEG C of vacuum-dryings, the Cefmenoxime Hemihydrochloride that must refine.
The X-ray powder diffraction pattern of embodiment 3 product, at 6.25 °, 13.04 °, 14.31 °, 17.21 °, 18.18 °, 19.95 °, 22.77 °, 23.76 °, 25.88 °, locates indicating characteristic diffraction peaks for 29.19 °.
Embodiment 4: the preparation of Cefmenoxime Hemihydrochloride pharmaceutical composition
Prepare cefmenoxime hydrochloride compound according to the step of embodiment 1, adopt this raw material to prepare cefmenoxime hydrochloride in, specification 0.25g.
Prescription:
Preparation technology:
(1) batching: under ten thousand grades of cleaning conditions, takes Cefmenoxime Hemihydrochloride aseptic powder and anhydrous sodium carbonate aseptic powder puts into mixing machine, mixes 60 minutes;
(2) packing: under hundred grades of cleaning conditions, is placed in portioning machine by the sterilized powder mixed, adjustment loading amount, packing, tamponade;
(3) lid is rolled;
Comparative example 1: the preparation of cefmenoxime hydrochloride compound
Cefmenoxime hydrochloride compound is prepared according to the method described in CN102675344A.
Preparation process:
In reaction flask, add methylene dichloride 260ml, ethanol 50ml and Virahol 35ml, cool to-8 DEG C, add 7-ACT40g hydrochloride and MEAM 40g successively, drip triethylamine 20ml, 20min drips complete.Drip complete timing insulation-4 DEG C and carry out condensation reaction 5h.Use high performance liquid chromatography endpoint detection.Reaction is finished, and add salt-free water 20ml, layering, organic phase extracts once by 90ml salt-free water more again, merges aqueous phase, uses methylene dichloride strip aqueous.Aqueous phase acid for adjusting pH value to 6 ~ 7, add gac 0.5g decolouring 20min, filter, filter cake 70ml water washing.In another reaction flask, add the concentrated hydrochloric acid 90ml of acetone 20ml and 35%, filtrate is dripped in this mixed solution, temperature control 35 DEG C, separate out white solid.In 25 DEG C of growing the grain 2h, suction filtration, wash with acetone 120ml with after 100ml water washing, suction filtration is dry, obtains product 50g.
Comparative example 2:
Get comparative example 1 and prepare cefmenoxime hydrochloride compound, adopt this raw material to prepare cefmenoxime hydrochloride in, specification 0.25g.
Prescription:
Preparation technology:
(1) batching: under ten thousand grades of cleaning conditions, takes Cefmenoxime Hemihydrochloride aseptic powder and anhydrous sodium carbonate aseptic powder puts into mixing machine, mixes 60 minutes;
(2) packing: under hundred grades of cleaning conditions, is placed in portioning machine by the sterilized powder mixed, adjustment loading amount, packing, tamponade;
(3) lid is rolled;
Test example 1:
The present inventor has carried out purity detecting to cefmenoxime hydrochloride compound prepared by the embodiment of the present invention 1 and comparative example 1.
Table 2 purity detecting result
Result: the cefmenoxime compound that Cefmenoxime Hemihydrochloride crystal compound purity prepared by the present invention is prepared apparently higher than prior art.
Test example 2:
The present inventor has carried out accelerated stability to cefmenoxime hydrochloride in prepared by the embodiment of the present invention 4 and comparative example 2 and has investigated test.Investigation condition is temperature 40 DEG C ± 2 DEG C, relative humidity 75% ± 5%.Place 6 months, respectively at sampling at 0,1,2,3,6 the end of month.Inspection target is proterties, clarity, solution colour, potential of hydrogen, content and related substance.In table 3.
Result: embodiment and comparative example product place 6 months at the conditions of the experiments described above, and pH value, content and related substance all do not occur considerable change, steady quality.Compare, comparatively comparative example is good for the color of embodiment, and content comparatively comparative example is high.
Cefmenoxime Hemihydrochloride crystal compound of the present invention and preparation thereof are investigated through indices inspection and accelerated test and are shown good stability, reliable in quality.
Claims (10)
1. a Cefmenoxime Hemihydrochloride crystal compound, it is characterized in that, the X-ray powder diffraction pattern represented with 2 θ diffraction angle at 6.25 ° ± 0.2 °, 13.04 ° ± 0.2 °, 14.31 ° ± 0.2 °, 17.21 ° ± 0.2 °, 18.18 ° ± 0.2 °, 19.95 ° ± 0.2 °, 22.77 ° ± 0.2 °, 23.76 ° ± 0.2 °, 25.88 ° ± 0.2 °, 29.19 ° ± 0.2 ° place's indicating characteristic diffraction peak.
2. a kind of Cefmenoxime Hemihydrochloride crystal compound as claimed in claim 1, it is characterized in that, preparation method's concrete steps are:
(1) by methylene dichloride, ethanol, (6R, 7R)-7-amino-3-[[(1-methyl isophthalic acid-H-tetrazole-5-base) sulfo-] methyl]-8-oxo-5-thia-1-azabicyclo [4, 2, 0] oct-2-ene-2-carboxylic acid hydrochloride (7-ATCAHCl) and triethylamine hybrid reaction, add 2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetic acid sulfo-benzothiazole ester (MEAM), water extracts, merge aqueous phase, activated carbon decolorizing, collect filtrate, use salt acid for adjusting pH value, filter, washing, vacuum-drying, obtain Cefmenoxime Hemihydrochloride crude product,
(2) by soluble in water for Cefmenoxime Hemihydrochloride crude product, slowly add alkali lye, stirring reaction, regulate pH, activated carbon decolorizing, filter, collect filtrate; Entered by filtrate added drop-wise in the mixing solutions of acetone, purified water and concentrated hydrochloric acid, reaction terminates, activated carbon decolorizing, filters, adds NaHCO in filtrate
3solution and water for injection, stir growing the grain, filters, and washing is dry, obtains the Cefmenoxime Hemihydrochloride refined.
3. a kind of method preparing Cefmenoxime Hemihydrochloride crystal compound as claimed in claim 2, is characterized in that the weight ratio of described 7-ATCAHCl and MEAM is 1:1 ~ 1:3.
4. a kind of method preparing Cefmenoxime Hemihydrochloride crystal compound as claimed in claim 2, is characterized in that the concentration of hydrochloric acid described in step (1) is 5 ~ 8mol/L.
5. a kind of method preparing Cefmenoxime Hemihydrochloride crystal compound as claimed in claim 2, is characterized in that the pH that the hydrochloric acid described in step (1) regulates is 1 ~ 3.
6. a kind of method preparing Cefmenoxime Hemihydrochloride crystal compound as claimed in claim 2, is characterized in that the alkali lye described in step (2) is the sodium bicarbonate aqueous solution of 8 ~ 12%.
7. a kind of method preparing Cefmenoxime Hemihydrochloride crystal compound as claimed in claim 2, is characterized in that the pH that the alkali lye described in step (2) regulates is 6 ~ 8.
8. a kind of method preparing Cefmenoxime Hemihydrochloride crystal compound as claimed in claim 2, is characterized in that the rearing crystal time described in step (2) is 2 ~ 4h.
9. a Cefmenoxime Hemihydrochloride pharmaceutical composition, is characterized in that its Cefmenoxime Hemihydrochloride crystal compound containing Cefmenoxime Hemihydrochloride crystal compound according to claim 1 or the preparation method described in claim 2 ~ 8 any one and obtain.
10. pharmaceutical composition as claimed in claim 9, is characterized in that counting the component comprising following weight part by weight: Cefmenoxime Hemihydrochloride (in cefmenoxime) 40 ~ 80 parts and sodium bicarbonate 20 ~ 60 parts.
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WO2017140074A1 (en) * | 2016-02-18 | 2017-08-24 | 海南灵康制药有限公司 | Cefmenoxime hydrochloride new crystalline form and formulation |
CN109134504A (en) * | 2017-06-16 | 2019-01-04 | 陈立平 | 1/2 water cefmenoxime hydrochloride compound of one kind and its drug combination preparation |
CN112661776A (en) * | 2020-12-29 | 2021-04-16 | 苏州盛达药业有限公司 | Preparation method of cefmenoxime hydrochloride |
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CN114540454B (en) * | 2022-03-09 | 2023-10-17 | 浙江东邦药业有限公司 | Method for synthesizing cefcapene pivoxil hydrochloride by enzyme method and synthesis intermediate thereof |
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CN105566352A (en) * | 2016-02-18 | 2016-05-11 | 海南灵康制药有限公司 | New crystal form cefmenoxine hydrochloride compound prepared by adopting particle process crystal product molecular assembling and morphology optimizing technology and preparation |
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WO2017140074A1 (en) * | 2016-02-18 | 2017-08-24 | 海南灵康制药有限公司 | Cefmenoxime hydrochloride new crystalline form and formulation |
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CN112661776A (en) * | 2020-12-29 | 2021-04-16 | 苏州盛达药业有限公司 | Preparation method of cefmenoxime hydrochloride |
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