CN105541871B - A kind of cefmetazole crystal-form compound and preparation method thereof - Google Patents
A kind of cefmetazole crystal-form compound and preparation method thereof Download PDFInfo
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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
- C07D501/57—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with a further substituent in position 7, e.g. cephamycines
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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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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
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- 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
Abstract
The invention belongs to field of medicaments, is related to a kind of cefmetazole crystal-form compound and preparation method thereof.In order to improve the security in the quality stability and clinical application of cefmetazole, the present invention provides a kind of crystal-form compound of cefmetazole and preparation method thereof, the parameter such as fusing point, IR, PXRD shows that it is different from any type novel crystal forms of the prior art, the crystal-form compound is compared compared with the cefmetazole that existing market is sold, related content of material is extremely low, stability is high, and the content of related impurities is as the extension of storage time is without obvious increase, suitably as detection and analysis or quality control Plays product.
Description
Technical field
The invention belongs to field of medicaments, and in particular to a kind of crystal-form compound of cefmetazole and preparation method thereof.
Background technology
Cefmetazole, also known as cyanogen first sulphur cephamycin, cefmotazole, Cefmetazole etc., English name：
Cefmetazole acid, its chemical name are：(6R, 7R) 7- methoxyl group -7- cyanogen methyl-thiacetamides -3- methyl-tetrazoles -
Sulfidomethyl cephalo acid, molecular formula are：C15H17N7O5S3, molecular weight：471.53, chemical structural formula is following formula (I)：
Cefmetazole is researched and developed by Japanese Sankyo Co., Ltd earliest, belongs to second generation cephalosporin.Its injection in 2 months 1980
Agent is listed in Japan, and clinical trial shows that it is to common gram-positive bacteria, Gram-negative bacteria and anaerobic bacteria, such as grape
Coccus, A groups hemolytic streptococcus, Escherichia coli, shigella dysenteriae, typhoid bacillus, proteus, Selenomonas, fragile plan bar
Bacterium etc., is respectively provided with good antibacterial activity；Cefmetazole has various beta-lactamases very strong tolerance, and stability is good, and poison is secondary
Act on small, adverse reaction is few；To the anti-microbial property of producing enzyme or not Bacillus influenzae, gonococcus, catarrh mora bacterium etc. compared with first
It is strong for cynnematin；Clinic be mainly used for treat sensitive bacteria caused by respiratory tract infection, urinary system infection contamination, septicemia, biliary tract,
Abdominal cavity infection, gynemetrics's bacterium infection and hand postoperative infection prevention etc..
Cefmetazole has good antibacterial activity, and beta-lactamase is stablized so that and its clinical practice is quite varied,
But the stability of its raw material and be that the factor of attention is needed most in clinic with the compatibility stabilities of other medicines.Zhang Chunran etc. exists
《The quality and stability study of cefmetazole sodium》One the article pointed out the cephalo of import that domestic production producer produces and external
U.S. azoles polymer content is suitable, and about 0.01% or so, but these polymer may cause more serious mistake in clinical practice
Quick reaction.And stability study shows, cefmetazole sodium to light, heat, wet unstable, in 2 years stablize by long term test；Given birth to dimension
Plain C, Aminobenzoic Acid are stablized when solution compatible use when less than 37 DEG C in 4h.As it can be seen that the aforementioned stable of cefmetazole sodium
Show that used bulk pharmaceutical chemicals are not what is be perfectly safe at present, must still pay the improvement of its bulk pharmaceutical chemicals and exert with allergy sex chromosome mosaicism
Power.
CN101695493A discloses the composition of cefmetazole and sodium citrate, with the nothing of cefmetazole and sodium citrate
Pharmaceutical composition is made in bacterium powder, which increases the water of cefmetazole to a certain extent using sodium citrate as cosolvent
Dissolubility and stability, but it does not solve the bulk pharmaceutical chemicals physico-chemical property of cefmetazole, the stability stored for a long time fundamentally
Difference, and cefmetazole impurity cefmetazole lactone in height applies environment rises rapidly, drastically influence the security of clinical application.
CN101548977A discloses a kind of composition of cefmetazole, and the composition is cefmetazole and arginine
Aseptic powder, the two is poured into efficient three-dimensional mixer with 1: 0.35~1: 0.70 ingredient proportion and discharged after mixing, packaging.With
The lyophilized technique of cefmetazole sodium is compared, it reduces energy consumption and production cost to a certain extent, and improves its poorly water-soluble
The defects of, but its long-time stability does not significantly improve, and impurity content significantly rises.
CN104370942A discloses a kind of cefmetazole crystal form and preparation method thereof and a kind of medicine containing cefmetazole
Compositions, its by the control of solvent ratios, lifting temperature and mixing speed, the particle of obtained cefmetazole uniformly and
Good fluidity, improves the stability of cefmetazole to a certain extent.But due to rising temperature for dissolving, and short time quenching crystallization, it is past
Toward causing to analyse cruelly, cause lattice arrangement irregular, influence the long-time stability of medicine.
The content of the invention
We to the crystallizing system of cefmetazole carry out Systematic Analysis and research in, by the optimization of crystallization processes with
And the amendment repeatedly of crystallization parameters, obtain a kind of crystal of cefmetazole.Being worth pleasantly surprised is：By to its fusing point, IR,
The aggregation of data such as PXRD are analyzed and identify its crystal structure and parameter, it is found that it is different from a kind of novel crystal forms of the prior art, its
Compared with commercially available cefmetazole, purity is very high and stability is good, and accelerated test rear impurity is without significant change, dissolution within 3 months
Also no significant difference, the degradation material to cause allergic reaction greatly reduce degree, improve peace of the cefmetazole in clinical practice
Quan Xing.
Based on this, the present invention provides a kind of crystal-form compound of cefmetazole and preparation method thereof, the crystal-form compound compared with
The cefmetazole of existing market sale is compared, related extremely low, the more excellent stability of content of material, the content of related impurities with
The extension of storage time is without obvious increase, suitably as the standard items in detection and analysis or quality control；The cefmetazole is brilliant
The preparation method preparation process of type compound is simple, can be achieved under room temperature, is easy to industrialized production.
Above-mentioned purpose of the present invention is achieved through the following technical solutions：
A kind of cefmetazole crystal-form compound, is the compound shown in following formula (I)
Above-mentioned cefmetazole crystal-form compound in X-ray powder diffraction figure with 2 θ angles represent 4.35 °, 7.69 °,
10.77°、12.52°、12.70°、13.15°、14.05°、14.61°、18.26°、18.56°、19.59°、21.02°、25.36°、
There is characteristic peak at 25.94 °, 27.05 °, 28.56 °, error is ± 0.2 °.
The X-ray powder diffraction condition of cefmetazole crystal-form compound of the present invention is：Using D/max-3A type X-ray diffractions
Instrument, in 1 rays of Cu target K α, pipe galvanic electricity pressure；40kv, electric current：2 θ, scope are measured under the conditions of 40mA, 25 DEG C/min：3°—45°.Institute
The fusing point for the cefmetazole crystal-form compound stated is between 149.8-152.8.
Fig. 1 is powder diffraction (PXRD) collection of illustrative plates of cefmetazole crystal-form compound of the present invention.Numeral 1-16 therein is to spread out
Penetrate peak.Fig. 2 is the IR collection of illustrative plates of cefmetazole crystal-form compound of the present invention, and Fig. 3 is cefmetazole crystal-form compound of the present invention
HPLC collection of illustrative plates.
The present invention also provides a kind of preparation method of above-mentioned cefmetazole crystal-form compound, the preparation side of the crystal-form compound
Dissolve cefmetazole in method using acetone-water solution as dicyandiamide solution, regulation system temperature and pH value, to body under stirring condition
2- butanone to a small amount of crystal is slowly added dropwise in system to separate out, added into system purified water and control system temperature and mixing speed into
Row crystallization, cefmetazole crystal-form compound is can obtain after the crystal solution filtering washed drying of filter cake.
Commonly using single or mixed solvent as dicyandiamide solution, knot of the dicyandiamide solution for crystal form in crystal form medicine preparation
Structure and preparation are quite important.The volatility of dicyandiamide solution is stronger, can make it that the molecules align time in crystallizing system is not abundant enough, easily
Drug molecule crystal form is caused to present incomplete, even unformed powder, therefore select suitable crystallizing system very crucial.Shen
The dicyandiamide solution asked someone by many experiments exploration crystallizing system, and determine the dosage of each dicyandiamide solution in system.Preferably,
The rate of charge (W/V) of the step 1) cefmetazole and acetone is 1：3~8；The use of the step 1) cefmetazole and purified water
It is 1 to measure (W/W)：0.1~0.5；The dosage (W/V) of the step 2) cefmetazole and 2- butanone is 1：2.5~6；Step 3) institute
The dosage (W/V) for stating cefmetazole and purified water is 1：2~4；
The chemical purity of medicine also directly affects the growth of crystal form, when the chemical purity of compound is higher, then easier length
Into single crystal form medicine；Conversely, the interference because of relatively large number of impurity component, it is not easy to grow up to the medicine of pure crystal form.Preferably,
The purity of the cefmetazole is not less than 95%；In addition the change of crystallizing system pH value, it is more also to directly result in drug molecule generation
Crystal form.Preferably, the crystallizing system pH value described in step 1) is between 1.6~2.5；
In specific crystallizing system, temperature is to influence the key parameter of drug molecule solubility and crystal growth, temperature
Change the growth rate and granular size of the crystal form molecule of direct relation drug molecule.For specific supersaturated crystallizing system,
In the case where having there is nucleus to grow up to, temperature is raised, accelerates interaction of the solvent molecule to drug molecule, promotes intermolecular
Movement and rearrangement, realize medicine rearranging in growth course and accumulate.Preferably, the cefmetazole described in step 1)
Solution temperature control at 4-10 DEG C；Step 3) the crystalline system temperature control is at 20-25 DEG C；
The change of crystallization time, can also cause the polymorphism of medicine, in a certain temperature conditions, some drugs point
Son can be final to realize part or be fully converted to new more stable crystal form automatically to other more stable transformation of crystal.It is excellent
Selection of land, the mixing time described in step 3) are 40-60min；Crystallization time after step 3) the dropwise addition purified water is 2h；
In recrystallization process, churned mechanically speed and agitating mode provide enough energy for drug molecule, with true
Protect the energy barrier that certain one or more transformation of crystal must be crossed over.Mass transfer and biography in the length velocity relation of stirring to crystallization process
Thermal velocity, so as to cause the change of crystal form and crystallization rate, such as：In supersaturated system, cool down crystallization, and simultaneous is violent
Stirring, easily obtains the tiny solid of particle；And after cooling down, allow solution left standstill to crystallize, frequently result in the larger material of particle.It is preferred that
Ground, the mixing speed described in step 2) are 110-150r/min；Mixing speed described in step 3) is 50-80r/min.
Applicant explores the preparation process of the crystal-form compound according to the factor that above-mentioned influence crystallizes, it is preferable that
The preparation method of the crystal-form compound specifically comprises the following steps：
1) acetone of 60-160 parts by volume and the purified water of 2-5 parts by volume are added into three-necked flask, puts into 20 thereto
The cefmetazole of mass parts, stirring are completely dissolved it, this process control system temperature is 4-10 DEG C and regulation system pH is
1.6-2.5；
2) it is 120r/min to control mixing speed, and the 2- butanone of 50-120 parts by volume is slowly added dropwise into above-mentioned system, drop
There is a small amount of crystal to separate out during adding in system；
3) purified water of 40-60 parts by volume is added into system, control system temperature is 20-25 DEG C and reduces mixing speed
Crystallized to 80r/min, wherein mixing time is 40-60min, crystallization time 2h；
4) system being filtered, filter cake is washed twice with the ethyl acetate of 20 parts by volume, is drained, at 35 DEG C, the bar of 0.05Mpa
2~4h is dried in vacuo under part, that is, obtains lily cefmetazole crystal-form compound.
The rate of addition of 2- butanone is 8 parts by volume/min in the step 2).
It is further preferred that the preparation method of the cefmetazole crystal-form compound specifically comprises the following steps：
1) acetone of 80 parts by volume and the purified water of 5 parts by volume are added under ice-water bath cooling condition into three-necked flask, to
The cefmetazole of 20 mass parts is wherein put into, stirring is completely dissolved it, and control system temperature is 4-10 DEG C and adjusts body at this time
It is that pH is 1.6-2.0；
2) it is 120r/min to control mixing speed, and the 2- butanone of 70 parts by volume is slowly added dropwise into above-mentioned system, was added dropwise
There is a small amount of crystal to separate out in journey in system；
3) purified water of 50 parts by volume is added into system, control system temperature is 20-25 DEG C and reduces mixing speed extremely
80r/min is crystallized, and wherein mixing time is 40-60min, crystallization time 2h；
4) system being filtered, filter cake is washed twice with the ethyl acetate of 20 parts by volume, is drained, at 35 DEG C, the bar of 0.05Mpa
2~4h is dried in vacuo under part, that is, obtains lily cefmetazole crystal-form compound.
The rate of addition of 2- butanone is 8 parts by volume/min in the step 2).
A kind of pharmaceutical preparation of cefmetazole is also claimed in the present invention, and the pharmaceutical preparation of the cefmetazole is including upper
State the cefmetazole crystal-form compound.It can be used for cefmetazole existing preparation all clinical indications treatment it
In, the stability higher of cefmetazole in the pharmaceutical preparation, and the content in relation to material is low, it is than existing cefmetazole preparation
Security higher, storage time is longer.The pharmaceutical preparation of above-mentioned cefmetazole, which includes but not limited to ejection preparation, includes injection
Liquid, aseptic powder needle for injection agent, concentrated solution for injection etc.；Oral formulations for example tablet, granule, capsule, oral liquid, pill,
Supensoid agent etc.；External preparation such as suppository, drops etc.；The preparation optimizing injection, more preferably injection sterile powder
A kind of application of above-mentioned cefmetazole crystal-form compound is also claimed in the present invention, i.e. the cefmetazole is used as
Detection and analysis or quality control procedure standard items.Fig. 3 is the HPLC collection of illustrative plates of cefmetazole crystal-form compound of the present invention, by collection of illustrative plates
As can be seen that the crystal-form compound purity of the preparation-obtained cefmetazole of the present invention is more than 99.6%.Experimental data shows,
The present invention is for existing cefmetazole standard items, quality stability higher, and related material raises not in Acceleration study
Substantially, and physical property is more excellent, therefore it is very suitable for as detection and analysis or quality control procedure standard items.
Cefmetazole crystal-form compound of the present invention and preparation method thereof compared with prior art, has following technology
Advantage：
1) cefmetazole crystal-form compound of the present invention is for existing cefmetazole standard items, and quality stability is more
Height, related material rise unobvious in Acceleration study, and physical property is more excellent, therefore it is as detection and analysis or quality control
Standard items are very suitable for during system.
2) cefmetazole crystal-form compound of the present invention can be used for all clinical indications of the existing preparation of cefmetazole
Among treatment, the stability higher of cefmetazole in the pharmaceutical preparation, and the content in relation to material is low, it is more beautiful than existing cephalo
The security higher of azoles preparation, storage time are longer.
3) cefmetazole crystal form described in the cefmetazole bulk pharmaceutical chemicals that use preparation process of the present invention is prepared
Compounds content is high, more than 99%, is adapted to make relevant pharmaceutical preparation, and preparation method of the present invention, prepares work
Skill is simple, and the dicyandiamide solution selected in crystallization process is reasonable, of low cost, is very suitable for the industrial metaplasia of the crystal-form compound
Production.
Brief description of the drawings
Fig. 1 is powder diffraction (PXRD) collection of illustrative plates of cefmetazole crystal-form compound of the present invention.Numeral 1-16 therein is to spread out
Penetrate peak.
Fig. 2 is the IR collection of illustrative plates of cefmetazole crystal-form compound of the present invention.
Fig. 3 is the HPLC collection of illustrative plates of cefmetazole crystal-form compound of the present invention.
Embodiment
Following embodiments merely to further describe the present invention, but those skilled in the art should be able to know, its not with
Any mode limits the present invention, and the scope of patent protection of the present invention is subject to claims.
Embodiment 1：The preparation method of cefmetazole crystal-form compound of the present invention
20g cefmetazole crude products are put into three-necked flask at 6 DEG C, the acetone and 5mL water stirring and dissolvings of 80mL is added, adds
Enter 2 mass parts of import activated carbon to stir 30 minutes, filtering, with the pH to 1.5-2.5 of 30% phosphorus acid-conditioning solution, controls solution
Temperature is 25 DEG C, under 150 turns per minute of mixing speed, 70mL2- butanone is slowly added dropwise with the speed of 8mL/min, to crystal
Separate out, then again under 80 turns per minute of stirring, control the degree of supersaturation of solution, continuously add 50mL purified waters, make crystallization
Completely, filter, washed twice, drained with 20mL ethyl acetate, is dried under reduced pressure, obtain cefmetazole acid crystal-form compound 16.6g,
Yield is 83.0%, (purity 99.6%, melts 149.8 DEG C)
2 are shown in Table for the case study on implementation 2~10 of the present invention, detailed crystallization processes parameter below, embodiment 2-10 removes following ginsengs
Number is different outer, remaining technological process is the same as embodiment 1.
Table 2：2~10 technological parameter of case study on implementation and product quality of the present invention collects
Powder diffraction (PXRD) collection of illustrative plates of the cefmetazole crystal-form compound of the present invention of embodiment 11
The cefmetazole crystal-form compound that embodiment 1 is prepared is measured into its crystal parameter by X-ray powder diffraction,
The X-ray powder diffraction condition of its cefmetazole crystal-form compound of the present invention is：Using D/max-3A type X-ray diffractometers,
1 rays of Cu target K α, pipe galvanic electricity pressure；40kv, electric current：2 θ, scope are measured under the conditions of 40mA, 25 DEG C/min：3°-45°.
1 embodiment of the present invention of table 1 cefmetazole powder diffraction (PXRD) collection of illustrative plates peak intensity
Fig. 1 is powder diffraction (PXRD) collection of illustrative plates of cefmetazole crystal-form compound of the present invention.Numeral 1-16 therein is to spread out
Peak is penetrated, table 2 is 2 θ of cefmetazole crystal-form compound of the present invention and peak intensity.It is beautiful that comprehensive income embodiment of the present invention 1-10 obtains cephalo
Azoles crystal-form compound in X ray diffracting spectrum, in the present invention cefmetazole crystal-form compound in X ray diffracting spectrum with 2 θ angles tables
Show 4.35 °, 7.69 °, 10.77 °, 12.52 °, 12.70 °, 13.15 °, 14.05 °, 14.61 °, 18.26 °, 18.56 °,
There is characteristic peak at 19.59 °, 21.02 °, 25.36 °, 25.94 °, 27.05 °, 28.56 °, error is ± 0.2 °.
The cefmetazole crystal-form compound of the present invention of embodiment 12 and the quality versus of commercially available cefmetazole standard items
The cefmetazole as obtained by the embodiment of the present invention 1,2,3 is corresponding respectively to be criticized 1, criticizes 2 and criticize 3, its quality critical index
Testing result is shown in Table 3.
The cefmetazole crystal-form compound of the present invention of table 3 and the quality versus of commercially available cefmetazole standard items
From the data analysis of table 1 as it can be seen that cefmetazole Partial key index obtained by the present invention and presently commercially available mark
Quasi- product (being purchased from middle inspection institute, batch number 130580-201301) are more excellent compared to quality, its dissolution velocity faster, related thing
Matter content substantially reduces, its fusing point is slightly above standard items between 149.8-152.8.Its excellent quality can make it that it can be with
It is used for the quality control or detection and analysis of cefmetazole bulk pharmaceutical chemicals or preparation as cefmetazole standard items.
The stability test of the cefmetazole crystal-form compound of the present invention of embodiment 14 and Acceleration study
According to《Chinese Pharmacopoeia》Annex：Bulk pharmaceutical chemicals stability test guideline, inquires into the inherent stability of medicine, understands
Influence the factor and possible degradation pathway and catabolite of its stability, condition of storage and side with reference to cefmetazole bulk pharmaceutical chemicals
Method, it is contemplated that cefmetazole color change and the increased stability factor of related material may be influenced.
Control group is that the cephalo obtained according to the preparation method described in embodiment 1 in patent application 201310350113.X is beautiful
Azoles crystal-form compound.Its preparation method is：Cefmetazole 10g is added in reaction bulb, it is 65% to add 100mL volume fractions
Acetone-ethanol solution, is progressively warming up to 30 DEG C, adds after stirring and dissolving after 0.5g activated carbons stir 20-30 minutes and filters while hot,
After adding 20mL ethanol, stirred with 100r/min and to be cooled to room temperature with 1 DEG C/min, room temperature 30min is kept, with 80r/min
Stir and be cooled to -15 DEG C with 2 DEG C/min, stir about one hour, filtration drying obtains cefmetazole production after solid separates out completely
Product, filtration drying obtain cefmetazole crystal form.
(1) high temperature is tested
Cefmetazole obtained by precise experiment case study 4, spreads out into≤three parts of 10mm thickness layers, is placed in sizeable
In cillin bottle, stability test is carried out at 60 ± 2 DEG C, the change of crucial investigation project is detected respectively at 5 days, 10 days, sampling in 15 days
Change situation.
Table 3：Cefmetazole crystal-form compound of the present invention is with control group in 60 ± 2 DEG C of study on the stability result of the tests
The maximum single miscellaneous and total miscellaneous content of cefmetazole crystal-form compound of the present invention is can be seen that 60 from 3 test data of table
± 2 DEG C, without significant change, therefore no longer carry out 40 DEG C of experiments, and cefmetazole crystal-form compound of the present invention is during experiment
Maximum single miscellaneous content and total miscellaneous content are below control group, and control group cefmetazole crystal-form compound was in study on the stability 15 days
Maximum single miscellaneous content and total miscellaneous content drastically raise.
(2) high humidity is tested
Cefmetazole obtained by precise embodiment 4, spreads out into≤three parts of 10mm thickness layers, in sizeable XiLin
In bottle, then it is placed on equipped with KNO3In the close drying device of saturated solution (relative humidity is about 90 ± 5%, 25 DEG C), high humility
Under the conditions of carry out factors affecting stability experiment, respectively at 5 days, 10 days, the change feelings of 15 days crucial investigation projects of sampling detection
Condition.
Table 4：The stability of cefmetazole crystal-form compound of the present invention and control group at 90 ± 5%, 25 DEG C of relative humidity
Experimental result
Experimental result is shown, in the environment of 90 ± 5%, 25 DEG C of relative humidity, the present invention is in clarity, moisture, maximum
Control group is superior in terms of single miscellaneous and total miscellaneous content, control group stores 15d rear impurity contents in the environment substantially to be increased.To this
Other batch cefmetazoles of inventive embodiments use above-mentioned identical experimental method, gained stability result no significant difference.
(3) Acceleration study
Using preserving identical packaging for a long time with cefmetazole, in 40 ± 2 DEG C of temperature, relative humidity for 75% ±
5% condition is tested, and is sampled, is investigated by quality standard and detection method, institute respectively at January, 2 months, March and 6 months
It is as shown in table 5 to obtain result of the test：
Table 5：The Acceleration study result of cefmetazole crystal-form compound of the present invention and control group
Experimental result shows, in 40 ± 2 DEG C of temperature, under the conditions of relative humidity is 75% ± 5%, the present invention clarity,
Control group is superior in terms of moisture, maximum single miscellaneous and total miscellaneous content, it is obvious that control group stores 15d rear impurity contents in the environment
Increase.
To sum up, cefmetazole crystal-form compound of the present invention stable quality in the environment of high temperature, high humidity and accelerated test,
Suitable long-term storage, the single miscellaneous and total miscellaneous content of its maximum in above-mentioned environment are significantly lower than control group, this shows, the present invention
Cefmetazole crystal-form compound quality higher, and long-time stability are more preferable.
Claims (6)
1. a kind of cefmetazole crystal-form compound, in X-ray powder diffraction figure with 2 θ angles represent 4.35 °, 7.69 °,
10.77°、12.52°、12.70°、13.15°、14.05°、14.61°、18.26°、18.56°、19.59°、21.02°、25.36°、
There is characteristic peak at 25.94 °, 27.05 °, 28.56 °, error is ± 0.2 °；The wherein described X-ray powder diffraction condition is：Adopt
With D/max-3A type X-ray diffractometers, in 1 rays of Cu target K α, pipe galvanic electricity pressure；40kv, electric current：Under the conditions of 40mA, 25 DEG C/min
Measure 2 θ, scope：3°-45°；The fusing point of the cefmetazole crystal-form compound is between 149.8 DEG C -152.8 DEG C.
A kind of 2. preparation method of cefmetazole crystal-form compound described in claim 1, it is characterised in that the preparation side of the crystal
Dissolve cefmetazole in method using acetone-water solution as dicyandiamide solution, regulation system temperature and pH value, to body under stirring condition
2- butanone to a small amount of crystal is slowly added dropwise in system to separate out, added into system purified water and control system temperature and mixing speed into
Row crystallization, cefmetazole crystal-form compound is can obtain after the crystal solution filtering washed drying of filter cake；It specifically includes following step
Suddenly：
1) acetone of 60-160 parts by volume and the purified water of 2-5 parts by volume are added under ice-water bath cooling condition into three-necked flask,
The cefmetazole of 20 mass parts is put into thereto, and stirring is completely dissolved cefmetazole, and control system temperature is 4-10 DEG C at this time
And regulation system pH is 1.6-2.5；
2) it is 120r/min to control mixing speed, and the 2- butanone of 50-120 parts by volume is slowly added dropwise into above-mentioned system, was added dropwise
There is a small amount of crystal to separate out in journey in system；
3) purified water of 40-60 parts by volume is added into system, control system temperature is 20-25 DEG C and reduces mixing speed extremely
80r/min is crystallized, and wherein mixing time is 40-60min, crystallization time 2h；
4) system is filtered, filter cake is washed twice with the ethyl acetate of 20 parts by volume, is drained, at 35 DEG C, under conditions of 0.05Mpa
2~4h is dried in vacuo, that is, obtains lily cefmetazole crystal-form compound.
3. the preparation method of cefmetazole crystal-form compound as claimed in claim 2, it is characterised in that it specifically includes as follows
Step：
1) acetone of 80 parts by volume and the purified water of 5 parts by volume are added under ice-water bath cooling condition into three-necked flask, thereto
The cefmetazole of 20 mass parts is put into, stirring is completely dissolved cefmetazole, and control system temperature for 4-10 DEG C and is adjusted at this time
System pH is 1.6-2.0；
2) it is 120r/min to control mixing speed, the 2- butanone of 70 parts by volume is slowly added dropwise into above-mentioned system, during dropwise addition
There is a small amount of crystal to separate out in system；
3) purified water of 50 parts by volume is added into system, control system temperature is 20-25 DEG C and reduces mixing speed to 80r/
Min is crystallized, and wherein mixing time is 40-60min, crystallization time 2h；
4) system is filtered, filter cake is washed twice with the ethyl acetate of 20 parts by volume, is drained, at 35 DEG C, under conditions of 0.05Mpa
2~4h is dried in vacuo, that is, obtains lily cefmetazole crystal-form compound.
4. the preparation method of cefmetazole crystal-form compound as described in Claims 2 or 3 is any, it is characterised in that the step
2) rate of addition of 2- butanone is 8 parts by volume/min in.
5. a kind of pharmaceutical preparation of cefmetazole, it is characterised in that the pharmaceutical preparation includes the head described in claim 1
Spore U.S. azoles crystal-form compound.
6. pharmaceutical preparation as claimed in claim 5, it is characterised in that the pharmaceutical preparation is the injection for including cefmetazole
Preparation, oral formulations or external preparation.
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