CN107383065A - A kind of cefotiam chloride crystalline compounds and preparation method thereof - Google Patents
A kind of cefotiam chloride crystalline compounds and preparation method thereof Download PDFInfo
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- CN107383065A CN107383065A CN201710577231.2A CN201710577231A CN107383065A CN 107383065 A CN107383065 A CN 107383065A CN 201710577231 A CN201710577231 A CN 201710577231A CN 107383065 A CN107383065 A CN 107383065A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- 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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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
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Abstract
The present invention relates to field of medicaments, relates generally to a kind of cefotiam chloride crystalline compounds and preparation method thereof.The crystal formation of the cefotiam chloride of an aspect of of the present present invention, it is characterized in that, the cefotiam chloride crystalline compounds use Cu K ɑ radionetric surveys, and principal character peak is 6.019 °, 11.542 °, 14.758 °, 16.699 °, 18.821 °, 19.100 °, 23.320 °, 23.521 °, 24.081 °, 26.101 °, 26.501 °, 30.160 °, 30.483 °, 31.700 °, 34.220 °, 34.502 °, 35.240 °, 38.020 ° place's displays in 2 θ in obtained X ray powder diffraction patterns.The cefotiam chloride crystal form samples purity of the present invention is high, and stability is good, and moisture is low, and organic solvent residual is low, even particle size distribution, good fluidity, is adapted to packing.Method production process high income, the simplicity of the present invention is easily-controllable.
Description
Technical field
The present invention relates to field of medicaments, relates generally to a kind of cefotiam chloride crystalline compounds and preparation method thereof.
Background technology
Cefotiam, also known as (6R- is trans) -7- [[(2- amino -4- thiazolyls) acetyl group] amino] -3- [[[1- [(2-
(dimethylamino) ethyl] -1H-TETRAZOLE -5- bases] sulphomethyl] -8- oxo -5- thia -1- azabicyclo [4.2.0] octyl-s 2-
Alkene -2- carboxylic acid dihydrochlorides.Its structural formula is：
Cefotiam is developed by Japanese Takede Chemical Industries Ltd earliest, and product is dihydrochloride, and added with
A certain amount of natrium carbonicum calcinatum.Its dihydrochloride is commonly used, for white or micro-yellow powder；It is slightly special smelly；Add water i.e. effervesce molten
The clear solution of solution generation weakly acidic pH, is slightly soluble in ethanol, insoluble in acetone chloroform.
This product is second generation cephalosporin class antibiotic.Effect to gram positive bacteria is close with Cefazolin, and right
Gram-negative bacteria, such as haemophilus, EHEC, klebsiella spp, proteus mirabilis effect are more excellent, to enterobacteria,
Citrobacter, indole-positive proteus etc. also have antibacterial action.Its mechanism of action be and the penicillin on bacterial cell membrane
Associated proteins (PBPs) combine, and are acylated transpeptidase, suppress the synthesis of bacterium interval and cell membrane, influence cell wall mucopeptide composition
Cross-connection, be suppressed cell division and growth, ne ar is elongated, finally dissolving and dead.
Clinically using following infection caused by this product treatment sensitive bacteria：1st, postoperative infection.2nd, infection of burn.3rd, soft group of skin
Knit infection：Subcutaneous abscess, carbuncle, furuncle etc..4th, bone and the infection of joint：Osteomyelitis, pyogenic arthritis.5th, infection in respiratory system：It is flat
Peach body inflammation (periamygdalitis, circumtonsillar abscess), bronchitis, bronchus exaggeration concurrent infection, pneumonia, pulmonary suppuration
Disease, pyothorax etc..6th, infection of biliary tract：Cholangitis, cholecystitis etc..7th, urogenital infections：Pyelonephritis, cystitis, urinary tract
Inflammation, prostatitis, endometritis, pelvic infecton, parametritis, adnexitis, bartholinitis etc..8th, ear, nose, larynx sense
Dye：Tympanitis, paranasal sinusitis, nasosinusitis.9th, other：Septicemia, encephalomyelitis, peritonitis etc..
At present, grind cefotiam chloride product due to original not report specific crystallization condition, to what is obtained
Cefotiam chloride is characterized using IR and NMR, but is not directed to product crystal formation problem.
Due to the influence of Cefotiam Material synthesis technique, Fei Yuanyan enterprises generally use during Cefotiam is produced
Conventional vehicles crystallization refines to Cefotiam crude product, in the process there is the situation of crystal parcel organic solvent, makes
Organic solvent into final products can not remove, and dissolvent residual is exceeded, have impact on the quality of product.It is remaining organic molten in order to remove
Matchmaker, enterprise carry out nitrogen humidification to the Cefotiam highly finished product after solvent crystal or with other low boiling point solvents in process of production
Washed and starched, so not only result in production time extension, cost rise, and the dissolving of Cefotiam sample surfaces is rotten, sample
Product mobility is deteriorated, and the impurity of parcel also influences product stability.And washed and starched with other low boiling point solvents, it can draw again
Enter other noncrystalline solvent residuals, can also influence product stability and sample flow and increase production cost.Therefore, by this
There is many unsafe factors in Cefotiam preparation prepared by cefotiam chloride, it is necessary to right in production and clinical practice
The crystal formation of cefotiam chloride is studied.
The invention discloses a kind of cefotiam chloride compound crystal form and preparation method thereof.The Cefotiam hydrochloric acid
Salt crystal compound uses Cu-K ɑ radionetric surveys, in obtained X-ray powder diffraction figure principal character peak 2 θ be 6.019 °,
11.542°、14.758°、16.699°、18.821°、19.100°、23.320°、23.521°、24.081°、26.101°、
Shown at 26.501 °, 30.160 °, 30.483 °, 31.700 °, 34.220 °, 34.502 °, 35.240 °, 38.020 °.Specific system
Standby step is as follows：In whole crystal system, under the conditions of specific temperature and pressure, in supercritical fluid, solvent, mixing
Device, separate out under the collective effect of device, complete extraction, crystallization and the process dried, realize the recrystallization of cefotiam chloride.By
Organic solvent and solute in supercritical fluid extraction Diversity system, change material composition in organic solvent and supercritical fluid
In dissolution characteristics, separate out lolute crystallization, so as to realize the disposable crystallization of active principle, obtain high purity product.Therefore
The cefotiam chloride crystal form samples purity of the present invention is high, and stability is good, and moisture is low, and organic solvent residual is low, granularity
It is evenly distributed, good fluidity, is adapted to packing.Method production process high income, the simplicity of the present invention is easily-controllable.
The content of the invention
In view of the shortcomings of the prior art, it is an object of the invention to provide a kind of cefotiam chloride crystal-form compound and
Its preparation method, can solve solvent residue problem existing for common solvent crystal and avoid a series of follow-up productions thus brought
Quality problem, this method is safe and reliable, and post processing is simple easy, can effectively improve the quality of product, be Cefotiam medicine
The clinical practice of product provides safety guarantee.
To realize the purpose of the present invention, it is an aspect of the invention to provide a kind of crystal formation of cefotiam chloride.
It is another aspect of the invention to provide a kind of method for preparing Cefotiam crystal form samples of the present invention.
The crystal formation of the cefotiam chloride of an aspect of of the present present invention, it is characterised in that the cefotiam chloride is brilliant
Body compound uses Cu-K ɑ radionetric surveys, in obtained X-ray powder diffraction figure principal character peak 2 θ be 6.019 °,
11.542°、14.758°、16.699°、18.821°、19.100°、23.320°、23.521°、24.081°、26.101°、
Shown at 26.501 °, 30.160 °, 30.483 °, 31.700 °, 34.220 °, 34.502 °, 35.240 °, 38.020 °.
The technical scheme is that according to supercritical liquid extraction technique crystallization principle, exist first with supercritical fluid
The organic solvent in Cefotiam crude product solution is extracted in blender and is dissolved in the impurity of organic solvent；By adjusting pressure and temperature
Degree, Crystallization Separation is carried out to Cefotiam HCI solution in device is separated out.
It is a feature of the present invention that using organic solvent and solute in supercritical fluid extraction Diversity system, change thing
Dissolution characteristics of the matter composition in organic solvent and supercritical fluid, separate out lolute crystallization.So as to realize the one of active principle
Secondary property crystallization, and obtain high purity product.The technology integrates extraction, crystallization, dried, and has separative efficiency high, solvent-free
The advantages that residual.
According to another aspect of the present invention, cefotiam chloride crystal form samples of the invention can be obtained by following methods
：In whole crystal system, under the conditions of specific temperature and pressure, in supercritical fluid, solvent, blender, precipitation device
Collective effect under, complete extraction, crystallization and the process dried, realize the recrystallization of cefotiam chloride.
Above-mentioned solvent can use the mixing of methanol, water, DMSO, DMF or this several solvent, preferably 85% methanol/water, because its
In supercritical CO2Distribution coefficient in fluid is more than the distribution coefficient of Cefotiam；Supercritical fluid media can use CO2, alkane,
Alkene etc., preferably CO2。
Comprise the following steps that：(1) mixed solvent of the methanol/waters of 300~700g 85%, is added in fluid reservoir, adds head
Spore controls 20~50 DEG C of temperature, stirring makes its dissolving for peace hydrochloride, crude 1mol；(2), will be mixed in fluid reservoir with constant-flux pump
Close liquid pump to enter in blender, CO is pumped into pressure liquid pump2Supercritical fluid is kept to 5~30Mpa, 20~50 DEG C of stirrings
The pressure and temperature 10~30 minutes, close high-pressure pump；(3) placement 0.6~8g of crystal seed in device, is being separated out, is opening fast interface,
The liquid in blender is set to close fast interface completely into separating out in device；(4), adjust the pressure in crystallizing pond for 5~
20Mpa, 10~30 DEG C of temperature, keeping temperature pressure 30~90 minutes；(5) system decrease temperature and pressure, is treated, 50 DEG C are dried under reduced pressure to obtain head
Spore is for peace crystal of hydrochloride.
Preferred scheme is as follows：(1) mixed solvent of the methanol/waters of 500g 85%, is added in fluid reservoir, cephalo is added and replaces
Pacify hydrochloride, crude 1mol, control 30 DEG C of temperature, stirring makes its dissolving；(2), the mixed liquor in fluid reservoir is pumped into constant-flux pump
In blender, CO is pumped into pressure liquid pump2Supercritical fluid keeps the pressure and temperature 15 to divide to 20Mpa, 30 DEG C of stirrings
Clock, close high-pressure pump；(3) crystal seed 6g, is placed in device separating out, opens fast interface, make liquid in blender completely into
Separate out in device, close fast interface；(4) pressure, adjusted in crystallizing pond is 10Mpa, and 20 DEG C of temperature, keeping temperature pressure 60 is divided
Clock；(5) system decrease temperature and pressure, is treated, 50 DEG C are dried under reduced pressure to obtain cefotiam chloride crystallization.
The cefotiam chloride crystal form samples purity of the present invention is high, and stability is good, and moisture is low, organic solvent residual
It is low, even particle size distribution, good fluidity, it is adapted to packing.Method production process high income, the simplicity of the present invention is easily-controllable.
In addition, present invention also offers the Preparation equipment of cefotiam chloride crystalline compounds.
The equipment for preparing cefotiam chloride crystalline compounds, including CO2Gas cylinder, fluid reservoir, nitrogen cylinder, blender,
Separate out bottle and separator；CO2Gas cylinder and fluid reservoir are connected by pressure liquid pump and constant-flux pump with blender respectively；Blender with
Connected between precipitation bottle by the fast interface that can be opened and closed；Nitrogen cylinder is connected to precipitation bottle by heat exchanger；Separate out on bottle
It is also associated with separator and condenser；Wherein, blender is used for by being pressed to form solvent, working media and Cefotiam hydrochloric acid
The Diversity system of salt；Device is separated out to be used to pass through decompression separation solvent, working media and the Cefotiam hydrochloric acid extracted
Salt.
The present invention is for problem present in cefotiam chloride industrial crystallization, in Cefotiam conventional crystallization system third
Due to it, easily water suction, viscosity are big in ketone-aqueous solution, make its spontaneous nucleation difficult, separate out easily parcel solvent residual by force.By
Organic solvent and solute in supercritical fluid extraction Diversity system, change material composition in organic solvent and supercritical fluid
In dissolution characteristics, separate out lolute crystallization, so as to realize the disposable crystallization of active principle, obtain high purity product.Therefore
The cefotiam chloride crystal form samples purity of the present invention is high, and stability is good, and moisture is low, and organic solvent residual is low, granularity
It is evenly distributed, good fluidity, is adapted to packing.The present invention method production process crystallization time is short, high income, easy to be easily-controllable.
Brief description of the drawings
The powder x-ray diffraction figure of Fig. 1 cefotiam chlorides of the present invention.Axis of ordinates represents diffracted intensity (cps),
Axis of abscissas represents the angle of diffraction (2 θ).
The powder x-ray diffraction spectrum data of Fig. 2 cefotiam chlorides of the present invention.
The HPLC collection of illustrative plates of Fig. 3 cefotiam chlorides of the present invention.
The infared spectrum of Fig. 4 cefotiam chlorides of the present invention.
Fig. 5 is the process principle figure of preparation method of the present invention.
1、CO2Gas cylinder；2nd, pressure liquid pump；3rd, fluid reservoir；4th, constant-flux pump；5th, blender；6th, nitrogen cylinder；7th, heat exchange
Device；8th, device is separated out；9th, separator；10th, condenser.
Embodiment
The invention will be further described by way of example again below, provides the implementation detail of the present invention, but is not
It is intended to limit protection scope of the present invention.
Embodiment 1
The mixed solvent of the methanol/waters of 500g 85% is added in fluid reservoir, adds cefotiam hydrochloride crude product 562g
(1mol), controls 30 DEG C of temperature, and stirring makes its dissolving, the mixed liquor in fluid reservoir is pumped into blender with constant-flux pump, with height
Press liquid pump is pumped into CO2Supercritical fluid keeps the pressure and temperature 15 minutes to 20Mpa, 30 DEG C of stirrings, closes high pressure
Pump, crystal seed 6g is placed in device separating out, opens fast interface, the liquid in blender is closed fast completely into separating out in device
Quick access mouth, the pressure adjusted in crystallizing pond is 10Mpa, 20 DEG C of temperature, keeping temperature pressure 60 minutes, treats system decrease temperature and pressure,
50 DEG C are dried under reduced pressure to obtain cefotiam chloride crystallization 534g, yield 95%.
Embodiment 2
The mixed solvent of the methanol/waters of 300g 85% is added in fluid reservoir, adds cefotiam hydrochloride crude product 562g
(1mol), controls 30 DEG C of temperature, and stirring makes its dissolving, the mixed liquor in fluid reservoir is pumped into blender with constant-flux pump, with height
Press liquid pump is pumped into CO2Supercritical fluid keeps the pressure and temperature 15 minutes to 20Mpa, 30 DEG C of stirrings, closes high pressure
Pump, crystal seed 6g is placed in device separating out, opens fast interface, the liquid in blender is closed fast completely into separating out in device
Quick access mouth, the pressure adjusted in crystallizing pond is 10Mpa, 20 DEG C of temperature, keeping temperature pressure 60 minutes, treats system decrease temperature and pressure,
50 DEG C are dried under reduced pressure to obtain cefotiam chloride crystallization 502g, yield 94%.
Embodiment 3
The mixed solvent of the methanol/waters of 700g 85% is added in fluid reservoir, adds cefotiam hydrochloride crude product 562g
(1mol), controls 30 DEG C of temperature, and stirring makes its dissolving, the mixed liquor in fluid reservoir is pumped into blender with constant-flux pump, with height
Press liquid pump is pumped into CO2Supercritical fluid keeps the pressure and temperature 15 minutes to 20Mpa, 30 DEG C of stirrings, closes high pressure
Pump, crystal seed 6g is placed in device separating out, opens fast interface, the liquid in blender is closed fast completely into separating out in device
Quick access mouth, the pressure adjusted in crystallizing pond is 10Mpa, 20 DEG C of temperature, keeping temperature pressure 60 minutes, treats system decrease temperature and pressure,
50 DEG C are dried under reduced pressure to obtain cefotiam chloride crystallization 421g, yield 75%.
Embodiment 4
The mixed solvent of the methanol/waters of 500g 85% is added in fluid reservoir, adds cefotiam hydrochloride crude product 562g
(1mol), controls 20 DEG C of temperature, and stirring makes its dissolving, the mixed liquor in fluid reservoir is pumped into blender with constant-flux pump, with height
Press liquid pump is pumped into CO2Supercritical fluid keeps the pressure and temperature 15 minutes to 20Mpa, 20 DEG C of stirrings, closes high pressure
Pump, crystal seed 6g is placed in device separating out, opens fast interface, the liquid in blender is closed fast completely into separating out in device
Quick access mouth, the pressure adjusted in crystallizing pond is 10Mpa, 20 DEG C of temperature, keeping temperature pressure 60 minutes, treats system decrease temperature and pressure,
50 DEG C are dried under reduced pressure to obtain cefotiam chloride crystallization 511g, yield 91%.
Embodiment 5
The mixed solvent of the methanol/waters of 500g 85% is added in fluid reservoir, adds cefotiam hydrochloride crude product 562g
(1mol), controls temperature 50 C, and stirring makes its dissolving, the mixed liquor in fluid reservoir is pumped into blender with constant-flux pump, with height
Press liquid pump is pumped into CO2Supercritical fluid keeps the pressure and temperature 15 minutes to 20Mpa, 50 DEG C of stirrings, closes high pressure
Pump, crystal seed 6g is placed in device separating out, opens fast interface, the liquid in blender is closed fast completely into separating out in device
Quick access mouth, the pressure adjusted in crystallizing pond is 10Mpa, 20 DEG C of temperature, keeping temperature pressure 60 minutes, treats system decrease temperature and pressure,
50 DEG C are dried under reduced pressure to obtain cefotiam chloride crystallization 309g, yield 55%.
Embodiment 6
The mixed solvent of the methanol/waters of 500g 85% is added in fluid reservoir, adds cefotiam hydrochloride crude product 562g
(1mol), controls 30 DEG C of temperature, and stirring makes its dissolving, the mixed liquor in fluid reservoir is pumped into blender with constant-flux pump, with height
Press liquid pump is pumped into CO2Supercritical fluid keeps the pressure and temperature 15 minutes to 5Mpa, 30 DEG C of stirrings, closes high-pressure pump,
Crystal seed 6g is placed in device separating out, opens fast interface, the liquid in blender is closed fast quick access completely into separating out in device
Mouthful, the pressure adjusted in crystallizing pond is 10Mpa, 20 DEG C of temperature, keeping temperature pressure 60 minutes, treats system decrease temperature and pressure, 50 DEG C
It is dried under reduced pressure to obtain cefotiam chloride crystallization 281g, yield 50%.
Embodiment 7
The mixed solvent of the methanol/waters of 500g 85% is added in fluid reservoir, adds cefotiam hydrochloride crude product 562g
(1mol), controls 30 DEG C of temperature, and stirring makes its dissolving, the mixed liquor in fluid reservoir is pumped into blender with constant-flux pump, with height
Press liquid pump is pumped into CO2Supercritical fluid keeps the pressure and temperature 15 minutes to 30Mpa, 30 DEG C of stirrings, closes high pressure
Pump, crystal seed 6g is placed in device separating out, opens fast interface, the liquid in blender is closed fast completely into separating out in device
Quick access mouth, the pressure adjusted in crystallizing pond is 10Mpa, 20 DEG C of temperature, keeping temperature pressure 60 minutes, treats system decrease temperature and pressure,
50 DEG C are dried under reduced pressure to obtain cefotiam chloride crystallization 545g, yield 97%.
Embodiment 8
The mixed solvent of the methanol/waters of 500g 85% is added in fluid reservoir, adds cefotiam hydrochloride crude product 562g
(1mol), controls 30 DEG C of temperature, and stirring makes its dissolving, the mixed liquor in fluid reservoir is pumped into blender with constant-flux pump, with height
Press liquid pump is pumped into CO2Supercritical fluid keeps the pressure and temperature 10 minutes to 20Mpa, 30 DEG C of stirrings, closes high pressure
Pump, crystal seed 6g is placed in device separating out, opens fast interface, the liquid in blender is closed fast completely into separating out in device
Quick access mouth, the pressure adjusted in crystallizing pond is 10Mpa, 20 DEG C of temperature, keeping temperature pressure 60 minutes, treats system decrease temperature and pressure,
50 DEG C are dried under reduced pressure to obtain cefotiam chloride crystallization 506g, yield 90%.
Embodiment 9
The mixed solvent of the methanol/waters of 500g 85% is added in fluid reservoir, adds cefotiam hydrochloride crude product 562g
(1mol), controls 30 DEG C of temperature, and stirring makes its dissolving, the mixed liquor in fluid reservoir is pumped into blender with constant-flux pump, with height
Press liquid pump is pumped into CO2Supercritical fluid keeps the pressure and temperature 30 minutes to 20Mpa, 30 DEG C of stirrings, closes high pressure
Pump, crystal seed 6g is placed in device separating out, opens fast interface, the liquid in blender is closed fast completely into separating out in device
Quick access mouth, the pressure adjusted in crystallizing pond is 10Mpa, 20 DEG C of temperature, keeping temperature pressure 60 minutes, treats system decrease temperature and pressure,
50 DEG C are dried under reduced pressure to obtain cefotiam chloride crystallization 534g, yield 95%.
Embodiment 10
The mixed solvent of the methanol/waters of 500g 85% is added in fluid reservoir, adds cefotiam hydrochloride crude product 562g
(1mol), controls 30 DEG C of temperature, and stirring makes its dissolving, the mixed liquor in fluid reservoir is pumped into blender with constant-flux pump, with height
Press liquid pump is pumped into CO2Supercritical fluid keeps the pressure and temperature 15 minutes to 20Mpa, 30 DEG C of stirrings, closes high pressure
Pump, crystal seed 0.6g is placed in device separating out, opens fast interface, the liquid in blender is closed completely into separating out in device
Fast interface, it is 10Mpa to adjust the pressure in crystallizing pond, 20 DEG C of temperature, keeping temperature pressure 60 minutes, treats system cooling drop
Pressure, 50 DEG C are dried under reduced pressure to obtain cefotiam chloride crystallization 422g, yield 75%.
Embodiment 11
The mixed solvent of the methanol/waters of 500g 85% is added in fluid reservoir, adds cefotiam hydrochloride crude product 562g
(1mol), controls 30 DEG C of temperature, and stirring makes its dissolving, the mixed liquor in fluid reservoir is pumped into blender with constant-flux pump, with height
Press liquid pump is pumped into CO2Supercritical fluid keeps the pressure and temperature 15 minutes to 20Mpa, 30 DEG C of stirrings, closes high pressure
Pump, crystal seed 6g is placed in device separating out, opens fast interface, the liquid in blender is closed fast completely into separating out in device
Quick access mouth, the pressure adjusted in crystallizing pond is 5Mpa, 20 DEG C of temperature, keeping temperature pressure 60 minutes, treats system decrease temperature and pressure, 50
DEG C it is dried under reduced pressure to obtain cefotiam chloride crystallization 253g, yield 45%.
Embodiment 12
The mixed solvent of the methanol/waters of 500g 85% is added in fluid reservoir, adds cefotiam hydrochloride crude product 562g
(1mol), controls 30 DEG C of temperature, and stirring makes its dissolving, the mixed liquor in fluid reservoir is pumped into blender with constant-flux pump, with height
Press liquid pump is pumped into CO2Supercritical fluid keeps the pressure and temperature 15 minutes to 20Mpa, 30 DEG C of stirrings, closes high pressure
Pump, crystal seed 6g is placed in device separating out, opens fast interface, the liquid in blender is closed fast completely into separating out in device
Quick access mouth, the pressure adjusted in crystallizing pond is 20Mpa, 20 DEG C of temperature, keeping temperature pressure 60 minutes, treats system decrease temperature and pressure,
50 DEG C are dried under reduced pressure to obtain cefotiam chloride crystallization 478g, yield 85%.
Embodiment 13
The mixed solvent of the methanol/waters of 500g 85% is added in fluid reservoir, adds cefotiam hydrochloride crude product 562g
(1mol), controls 30 DEG C of temperature, and stirring makes its dissolving, the mixed liquor in fluid reservoir is pumped into blender with constant-flux pump, with height
Press liquid pump is pumped into CO2Supercritical fluid keeps the pressure and temperature 15 minutes to 20Mpa, 30 DEG C of stirrings, closes high pressure
Pump, crystal seed 6g is placed in device separating out, opens fast interface, the liquid in blender is closed fast completely into separating out in device
Quick access mouth, the pressure adjusted in crystallizing pond is 10Mpa, 10 DEG C of temperature, keeping temperature pressure 60 minutes, treats system decrease temperature and pressure,
50 DEG C are dried under reduced pressure to obtain cefotiam chloride crystallization 540g, yield 96%.
Embodiment 14
The mixed solvent of the methanol/waters of 500g 85% is added in fluid reservoir, adds cefotiam hydrochloride crude product 562g
(1mol), controls 30 DEG C of temperature, and stirring makes its dissolving, the mixed liquor in fluid reservoir is pumped into blender with constant-flux pump, with height
Press liquid pump is pumped into CO2Supercritical fluid keeps the pressure and temperature 15 minutes to 20Mpa, 30 DEG C of stirrings, closes high pressure
Pump, crystal seed 6g is placed in device separating out, opens fast interface, the liquid in blender is closed fast completely into separating out in device
Quick access mouth, the pressure adjusted in crystallizing pond is 10Mpa, 30 DEG C of temperature, keeping temperature pressure 60 minutes, treats system decrease temperature and pressure,
50 DEG C are dried under reduced pressure to obtain cefotiam chloride crystallization 500g, yield 89%.
Embodiment 15
The mixed solvent of the methanol/waters of 500g 85% is added in fluid reservoir, adds cefotiam hydrochloride crude product 562g
(1mol), controls 30 DEG C of temperature, and stirring makes its dissolving, the mixed liquor in fluid reservoir is pumped into blender with constant-flux pump, with height
Press liquid pump is pumped into CO2Supercritical fluid keeps the pressure and temperature 15 minutes to 20Mpa, 30 DEG C of stirrings, closes high pressure
Pump, crystal seed 6g is placed in device separating out, opens fast interface, the liquid in blender is closed fast completely into separating out in device
Quick access mouth, the pressure adjusted in crystallizing pond is 10Mpa, 20 DEG C of temperature, keeping temperature pressure 30 minutes, treats system decrease temperature and pressure,
50 DEG C are dried under reduced pressure to obtain cefotiam chloride crystallization 523g, yield 93%.
Embodiment 16
The mixed solvent of the methanol/waters of 500g 85% is added in fluid reservoir, adds cefotiam hydrochloride crude product 562g
(1mol), controls 30 DEG C of temperature, and stirring makes its dissolving, the mixed liquor in fluid reservoir is pumped into blender with constant-flux pump, with height
Press liquid pump is pumped into CO2Supercritical fluid keeps the pressure and temperature 15 minutes to 20Mpa, 30 DEG C of stirrings, closes high pressure
Pump, crystal seed 6g is placed in device separating out, opens fast interface, the liquid in blender is closed fast completely into separating out in device
Quick access mouth, the pressure adjusted in crystallizing pond is 10Mpa, 20 DEG C of temperature, keeping temperature pressure 90 minutes, treats system decrease temperature and pressure,
50 DEG C are dried under reduced pressure to obtain cefotiam chloride crystallization 534g, yield 95%.
Embodiment 17
The mixed solvent of 500g 85%DMF/ water is added in fluid reservoir, adds cefotiam hydrochloride crude product 562g
(1mol), controls 30 DEG C of temperature, and stirring makes its dissolving, the mixed liquor in fluid reservoir is pumped into blender with constant-flux pump, with height
Press liquid pump is pumped into CO2Supercritical fluid keeps the pressure and temperature 15 minutes to 20Mpa, 30 DEG C of stirrings, closes high pressure
Pump, crystal seed 6g is placed in device separating out, opens fast interface, the liquid in blender is closed fast completely into separating out in device
Quick access mouth, the pressure adjusted in crystallizing pond is 10Mpa, 20 DEG C of temperature, keeping temperature pressure 60 minutes, treats system decrease temperature and pressure,
50 DEG C are dried under reduced pressure to obtain cefotiam chloride crystallization 84.3g, yield 15%.
Embodiment 18
The mixed solvent of the methanol/waters of 500g 85% is added in fluid reservoir, adds cefotiam hydrochloride crude product 562g
(1mol), controls 30 DEG C of temperature, and stirring makes its dissolving, the mixed liquor in fluid reservoir is pumped into blender with constant-flux pump, with height
Press liquid pump is pumped into ethene supercritical fluid to 20Mpa, 30 DEG C of stirrings, and keeps the pressure and temperature 15 minutes, closes high pressure
Pump, crystal seed 6g is placed in device separating out, opens fast interface, the liquid in blender is closed fast completely into separating out in device
Quick access mouth, the pressure adjusted in crystallizing pond is 10Mpa, 20 DEG C of temperature, keeping temperature pressure 60 minutes, treats system decrease temperature and pressure,
50 DEG C are dried under reduced pressure to obtain cefotiam chloride crystallization 107g, yield 19%.
Embodiment 19
We also to according to embodiment 1-16 products obtained therefroms and commercially available prod carry out solution color, purity, pH value, water content,
Dissolvent residual, angle of repose and water-soluble measure, measurement result are shown in Table 1.
The solution colors of 1 different cefotiam chlorides of table, purity, pH value, water content, dissolvent residual, angle of repose and water-soluble
Property measure
As a result
From the result of table 1, cefotiam chloride crystal form samples purity of the present invention is high, and stability is good, moisture
Content is low, and organic solvent residual is low, good fluidity, is adapted to packing.
Embodiment 20
Detect the dissolution velocity of above group for the cefotiam chloride of embodiment 1, and with the Cefotiam salt listed
Hydrochlorate does control experiment.
The dissolution velocity comparative experiments result of table 2
| Numbering | Dissolution velocity |
| Embodiment 1 | 14s |
| List cefotiam chloride | 30s |
From the result of table 2, cefotiam chloride dissolution velocity of the present invention significantly improves.
Embodiment 21
By the operation standard of long-term experiment and Acceleration study, detection above group is the cefotiam chloride of embodiment 1
Stability, and with listing cefotiam chloride do control experiment.Wherein cefotiam chloride and related impurities content
Detected using high performance liquid chromatography (HPLC).Specific testing conditions are as follows：
Pillar：CAPCELL PAK ACR-C18 liquid-phase chromatographic columns, internal diameter 4.6mm, length 25cm, 5 μm of particle diameter.Post
Temperature：35℃.Detection wavelength：254nm.Flow velocity：1ml/min.Mobile phase：Phosphate buffer (uses 0.05mol/L phosphoric acid hydrogen
Disodium and 0.05mol/L potassium dihydrogen phosphate are prepared, and pH is adjusted into 7.6-7.8 (volume ratios about 4：1) eluent A) is used as,
Acetonitrile is as eluent B.
Long-term stable experiment condition：Sample is placed in climatic chamber, 25 DEG C ± 2 of keeping temperature；Humidity 60% ±
5, regular inspection by sampling, the experimental results are shown inthe following table：
The long-term experiment result of the embodiment cefotiam chloride of table 3
Table 4 lists the long-term experiment result of cefotiam chloride
Accelerated stability test condition：Sample is placed in climatic chamber, 40 DEG C ± 2 of keeping temperature；Humidity 75% ±
5, regular inspection by sampling, the experimental results are shown inthe following table：
The Acceleration study result of the embodiment cefotiam chloride of table 5
The Acceleration study result of 6 commercially available cefotiam chloride of table
The long-term experiment and acceleration of the cefotiam chloride of the present invention and listing cefotiam chloride are real more than
Test result to show, cefotiam chloride crystal-form compound provided by the invention has higher than the cefotiam chloride of listing
Purity and more preferable stability, and cefotiam chloride quality safety of the invention is stable during storing, Ke Yichang
Phase stores.
After the explanation of this method has been read, those skilled in the art can make various changes or modification to the present invention,
These equivalent form of values equally fall within the application appended claims and limit scope.
Claims (8)
- A kind of 1. cefotiam chloride crystalline compounds, it is characterised in that：The cefotiam chloride crystalline compounds make With Cu-K ɑ radionetric surveys, in obtained X-ray powder diffraction figure principal character peak 2 θ be 6.019 °, 11.542 °, 14.758°、16.699°、18.821°、19.100°、23.320°、23.521°、24.081°、26.101°、26.501°、 Shown at 30.160 °, 30.483 °, 31.700 °, 34.220 °, 34.502 °, 35.240 °, 38.020 °.
- 2. cefotiam chloride crystalline compounds according to claim 1, it is characterised in that：Its X-ray powder diffraction Collection of illustrative plates is as shown in Figure 1.
- 3. the preparation method of the cefotiam chloride crystalline compounds described in claim 1, it is characterised in that：Entirely crystallizing In system, under the conditions of specific temperature and pressure, supercritical fluid, solvent, blender, separate out device collective effect under, Extraction, crystallization and the process dried are completed, realizes the recrystallization of cefotiam chloride.
- 4. according to the method for claim 3, it is characterised in that：The solvent is methanol, water, DMSO, DMF or this is several molten Any mixing of agent；The supercritical fluid media is CO2, alkane or alkene.
- 5. according to the method for claim 4, it is characterised in that：The solvent is 85% methanol/water；Supercritical fluid media For CO2。
- 6. according to the method for claim 3, it is characterised in that：Comprise the following steps that：(1) mixed solvent of the methanol/waters of 300~700g 85%, is added in fluid reservoir, adds cefotiam hydrochloride crude product 1mol, controls 20~50 DEG C of temperature, and stirring makes its dissolving；(2), the mixed liquor in fluid reservoir is pumped into blender with constant-flux pump, CO is pumped into pressure liquid pump2Supercritical fluid is extremely 5~30Mpa, 20~50 DEG C of stirrings, and keep the pressure and temperature 10~30 minutes, close high-pressure pump；(3) placement 0.6~8g of crystal seed in device, is being separated out, is opening fast interface, is making the liquid in blender completely into precipitation device It is interior, close fast interface；(4) pressure, adjusted in crystallizing pond is 5~20Mpa, 10~30 DEG C of temperature, keeping temperature pressure 30~90 minutes；(5) system decrease temperature and pressure, is treated, 50 DEG C are dried under reduced pressure to obtain cefotiam chloride crystallization.
- 7. according to the method for claim 3, it is characterised in that：Concretely comprise the following steps：(1) mixed solvent of the methanol/waters of 500g 85%, is added in fluid reservoir, adds cefotiam hydrochloride crude product 1mol, 30 DEG C of temperature is controlled, stirring makes its dissolving；(2), the mixed liquor in fluid reservoir is pumped into blender with constant-flux pump, CO is pumped into pressure liquid pump2Supercritical fluid is extremely 20Mpa, 30 DEG C of stirrings, and keep the pressure and temperature 15 minutes, close high-pressure pump；(3) placement crystal seed 6g in device, is being separated out, is opening fast interface, the liquid in blender is closed completely into separating out in device Close fast interface；(4) pressure, adjusted in crystallizing pond is 10Mpa, 20 DEG C of temperature, keeping temperature pressure 60 minutes；(5) system decrease temperature and pressure, is treated, 50 DEG C are dried under reduced pressure to obtain cefotiam chloride crystallization.
- 8. prepare the equipment of the cefotiam chloride crystalline compounds described in claim 1, it is characterised in that：Including CO2Gas Bottle, fluid reservoir, nitrogen cylinder, blender, precipitation bottle and separator；CO2Gas cylinder and fluid reservoir pass through pressure liquid pump peace respectively Stream pump is connected with blender；Connected between blender and precipitation bottle by the fast interface that can be opened and closed；Nitrogen cylinder is handed over by heat Parallel operation is connected to precipitation bottle；Separate out and be also associated with separator and condenser on bottle；Wherein, blender is used for molten by being pressed to form The Diversity system of agent, working media and cefotiam chloride；Device is separated out to be used for by decompression separation solvent, working media And the cefotiam chloride extracted.
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