CN106432278A - Crystalline compound of drug ceftriaxone sodium for treating surgical operation infections - Google Patents
Crystalline compound of drug ceftriaxone sodium for treating surgical operation infections Download PDFInfo
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- CN106432278A CN106432278A CN201610844791.5A CN201610844791A CN106432278A CN 106432278 A CN106432278 A CN 106432278A CN 201610844791 A CN201610844791 A CN 201610844791A CN 106432278 A CN106432278 A CN 106432278A
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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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- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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- 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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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention belongs to the technical field of medicines, and discloses a crystalline compound of a drug, i.e., ceftriaxone sodium for treating surgical operation infections. A structural formula of the crystalline compound of ceftriaxone sodium is represented by a formula (I), the crystalline compound is assayed by powder X-ray diffractometry, and an X-ray atlas powder diffractogram represented by a diffraction angle of 2[theta]+/-0.2 degree is shown in Figure 1. The crystalline compound is high in purity, low in polymer content, good in stability and good in fluidity and is not prone to moisture absorption. (The formula (I) shown in the description.).
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of medicine Ceftriaxone Sodium crystalline substance for treating Postoperative infection
Body compound.
Background technology
Ceftriaxone Sodium molecular formula：C18H17N8NaO7S3Three times semihydrate, structural formula is as follows：
Entitled (6R, the 7R) -3- of Ceftriaxone Sodium chemistry [[(1,2,5,6- tetrahydrochysene -2- methyl -5,6- dioxo -1,2,4- tri-
Piperazine -3- base) thio] methyl] -7- [[(2- amino -4- thiazolyl) methoxyimino acetyl group] amino] -8- oxo -5- thia -
1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid sodium salt three times semihydrate.For white or off-white color crystalline powder, odorless
Tasteless, have and draw moist, soluble in water, slightly soluble, almost insoluble in chloroform or ether in methyl alcohol.
Ceftriaxone Sodium is researched and developed by Hoffmann-LaRoche company of Switzerland, and nineteen eighty-two is listed in Switzerland first.Belong to
Third-generation cephalosporin class antibiotic, is widely used in the respiratory tract infection to this product sensitivity, urinary system infection, includes renal pelvis kidney
Inflammation, gonorrhea, septicemia, meningitiss, postoperative infection, osteoarthrosis, soft tissue, skin and wound infection, skin and wound infection, abdomen
Portion's infection, burn infection etc., and average of operation periods infection mitigation, have powerful antibacterial activity to enterobacteriaceae lactobacteriaceae.Because which has half
Decline phase length, has a broad antifungal spectrum, low toxin and paid attention to by people.
Ceftriaxone Sodium was introduced after China by Roche Group since nineteen ninety-five, opened the high-end antibiotic market of China.Nearly 5
Nian Lai, Ceftriaxone Sodium is always the medicine of former of whole body infection order of drugs in charge, and its preparation and crude drug all become
The object that gets most of the attention.The huge market demand of Ceftriaxone Sodium, clinical efficacy is projected.These fundamentals determine cephalo
Qusong sodium becomes the core kind for leading cephalosporins market.Therefore, the refined of Ceftriaxone Sodium is also taken seriously therewith.
Multiple method for crystallising are prior art discloses, is mainly had following several：
CN102875574A discloses a kind of ceftriaxone sodium crystal and preparation method thereof, and a. takes crude product of ceftriaxone sodium, adds
In purified water, temperature control stirring is all dissolved to solid, is filtered, and filtrate is standby；B. stir, temperature control, to the filter that step a is prepared
Deca acetone in liquid, obtains mixed liquor；C. the mixed liquor that step b is prepared is lowered the temperature, standing, obtain crystal solution；D. by step c system
The standby crystal solution sucking filtration for obtaining, washing, dry, obtain ceftriaxone sodium crystal.
CN102993215B discloses a kind of preparation method of ceftriaxone sodium crystal, to the water-soluble of crude product of ceftriaxone sodium
Liquid, is slowly added to organic solvent under stirring in aqueous solution（Dehydrated alcohol, acetone, ethyl acetate or isopropanol）, occur muddy
When stop stirring, standing；Continue stirring and organic solvent is added, till the crystal for being formed is not further added by；Crystal is filtered, filter cake
Washed to neutrality with dehydrated alcohol, water mixed solvent, then with absolute ethanol washing 1-3 time, less than 35 DEG C constant pressure and dries obtain final product head
Spore Qusong sodium crystal.The clarity of the ceftriaxone sodium crystal aqueous solution in all crystal for obtaining is best, anaphylaxiss occur
Rate is minimum, safety highest.Preparation method process is simple of the present invention, favorable reproducibility.
The problems such as although above-mentioned purification process to some extent solves its purity, but through further investigation revealed that,
Due to the less stable of Ceftriaxone Sodium, which is also susceptible to degraded and polyreaction in storage process, with during storage
Between prolongation, its impurity and high polymer content increase, and affect the quality of ceftriaxone, make human body produce the risk of anaphylactic reaction
Increase, finally the safety of impact ceftriaxone and effectiveness.
Substantial amounts of research has confirmed at present, and Cephalosporins are anaphylactoid to be occurred not to be caused by medicine in itself
, but relevant with macromolecule impurity present in medicine.Research finds, the content of macromolecule impurity is lower, anaphylactoid
Incidence rate is also lower, conversely, the content of macromolecule impurity is higher, anaphylaxiss incidence rate is also higher.Height said here
Molecular impurity refers to bigger than the relative molecular mass of drug molecule itself impurity in medicine, and its source is generally divided into exogenous
Impurity and two class of endogenouss impurity.Adventitious impurities are typically derived from the fermentation technology of pharmaceutical synthesis early stage, and endogenouss impurity is
Refer to the self-polymerization product of medicine, this polymer can be produced during production process or storage.Impurity majority in medicine
With potential source biomolecule activity, Drug safety and effectiveness can be affected, or even produce toxicity with drug interaction.Cephalo
Except anaphylactoid macromolecule impurity ceftriaxone polymerization beyond the region of objective existence can be caused in Qusong sodium, also there are other impurity, such as synthesize
During the raw material etc. that remains, although not yet have data to show that these impurity can give people body and cause direct injury, but which be after all
It is " pollutant " in medicine, there is no therapeutical effect, level should be preferably minimized as far as possible, this is medicament research and development person
One important process, meets various countries to the guideline in medicament research and development with regard to impurity research.
Chinese Pharmacopoeia 2010 editions has strict restriction to the impurity of Ceftriaxone Sodium and polymer, it is desirable in Ceftriaxone Sodium
It must not be higher than 0.5% that maximum list is miscellaneous, and total impurities must not be higher than 2.0%, and ceftriaxone polymer must not be higher than 0.5%.Prior art is obtained
To Ceftriaxone Sodium product quality level substantially meeting standards of pharmacopoeia as target, or only a certain item index apparently higher than
Standards of pharmacopoeia, fails to reach the level that multiple Key Quality Indicator are above standards of pharmacopoeia.
Mei Dan et al. is delivered《Commercially available Ceftriaxone Sodium for Injection portioned product mass ratio is relatively》In one text, to commercially available 7
17 batches of Ceftriaxone Sodium for Injection products of individual manufacturer production have carried out mass ratio relatively, and selected index includes clarity, color, suction
Receipts value, moisture, pH value, particulate matter, content, catabolite or related substanceses, polymer, content uniformity, organic solvent are residual
12 aspects such as allowance and cillin bottle outer wall residual.Testing result shows, each batch products quality index respectively has excellent summary, wherein,
Maximum single miscellaneous, total impurities, the minimum of polymer are respectively 0.053%, 0.053%, 0.15%.
Disclosed in Lanzhou University of Science ＆ Technology《The optimization of ceftriaxone process for producing sodium》Production in research to Ceftriaxone Sodium
Technique is optimized, and final step crystallization is to refine purifier units operation, adds Ceftriaxone Sodium crystal seed in crystallization, this
The main granularity of Ceftriaxone Sodium product that sample is obtained is big, even particle size distribution.After process modification, assay maximum contaminant content≤
0.2%, total impurities content≤0.4%, ceftriaxone polymer≤0.1%, content 92.4%.
Therefore, reducing all kinds of impurity in Ceftriaxone Sodium includes the content of polymer, obtains high-quality product, is to ensure that
One important process of Ceftriaxone Sodium clinical application safety.
The present inventor, has been obtained a kind of different from existing with existing crude product of ceftriaxone sodium as raw material through lot of experiments
The ceftriaxone sodium compound of the novel crystal forms of technology, and by test, surprisingly find the crystalline compounds purity height, polymer
Content is low, good stability, and is difficult moisture absorption, good fluidity.The capsule dissolubility height that is made using the crystalline compounds, impurity are contained
Measure low, good stability.
Content of the invention
It is an object of the invention to provide a kind of medicine Ceftriaxone Sodium crystalline compounds for treating Postoperative infection, should
Not only purity is high for crystalline compounds, and polymer content is low, good stability, and its hygroscopicity, mobility are substantially better than existing skill
Art.
For realizing the purpose of the present invention, the present invention is adopted the following technical scheme that：
A kind of medicine Ceftriaxone Sodium crystalline compounds for treating Postoperative infection, described Ceftriaxone Sodium crystalline compounds
Structural formula as shown in formula I, X-ray powder diffraction pattern such as Fig. 1 that the crystalline compounds are represented with the 2 θ ± 0.2 ° angles of diffraction
It is shown,
Formula（）.
Present invention also offers a kind of preparation side of the medicine Ceftriaxone Sodium crystalline compounds for treating Postoperative infection
Method, the method comprises the steps：
Crude product of ceftriaxone sodium is dissolved in 35 DEG C of water, in the mixed solvent of dimethyl sulfoxide；First added with the speed of 40ml/min
The mixed solvent of ethanol and ether, stirring while adding, control 35 DEG C of temperature, growing the grain 3 hours；Then again with the speed of 20ml/min
Isopropanol is added, growing the grain was lowered the temperature, is then kept stirring for 90 revs/min of stirring and crystallizing of speed, growing the grain 3 hours after 1 hour；Filter,
Washing, drying under reduced pressure obtains Ceftriaxone Sodium crystalline compounds.
In the present invention, described crude product of ceftriaxone sodium can be prepared by art methods, it is also possible to by which
He obtains mode.
In above-mentioned preparation method, wherein, the mixed solvent volume of the water, dimethyl sulfoxide（ml）For Ceftriaxone Sodium weight
（g）4-6 times, the volume ratio of water and dimethyl sulfoxide is 5:1.5.The ethanol is cephalo with the mixed solvent volume (ml) of ether
Qusong sodium weight（g）7-9 times, ethanol, ether volume ratio be 2:2.The volume (ml) of the isopropanol is Ceftriaxone Sodium
Weight（g）5-7 times.The cooling rate is to be cooled to -5 DEG C with 10 DEG C/h of speed.
The present invention also provides a kind of ceftriaxone natrium capsule, and described capsule contains Ceftriaxone Sodium provided by the present invention
Crystalline compounds or according to Ceftriaxone Sodium crystalline compounds obtained in above-mentioned preparation method.
Described ceftriaxone natrium capsule, in parts by weight, by the Ceftriaxone Sodium crystal chemical combination of 100-200 weight portion
Thing, the Microcrystalline Cellulose of 80-100 weight portion, the Croscarmellose Sodium of 8-12 weight portion, the micropowder silicon of 2-4 weight portion
Glue constitutes.
Preferably, described ceftriaxone natrium capsule, in parts by weight, by the Ceftriaxone Sodium of 150 weight portions, 90 weight
The Microcrystalline Cellulose, the Croscarmellose Sodium of 9 weight portions of part, the micropowder silica gel composition of 3 weight portions.
Described ceftriaxone natrium capsule, is prepared from by following preparation method：
1）Feedstock treating：With vibration screen-dividing machine, Ceftriaxone Sodium is crossed 80 mesh sieves, standby；
2）Microcrystalline Cellulose, cross-linked carboxymethyl cellulose sodium, micropowder silica gel are crossed 60 mesh sieves respectively, standby；
3）Weigh：Weighing supplementary material is carried out according to prescription；
4）Premix：Cross-linked carboxymethyl cellulose sodium of the Microcrystalline Cellulose of recipe quantity, micropowder silica gel and 1/3 recipe quantity is added to mixed
In conjunction machine, motor rotation frequency 200r/min is set, is opened mixer and mix 30 minutes；
5）Total mixed：Cross-linked carboxymethyl cellulose sodium of the Ceftriaxone Sodium of recipe quantity and 2/3 recipe quantity is added in mixer, if
Motor rotation frequency 200r/min is put, is opened mixer and mix 10 minutes；It is subsequently adding pre- mixed Microcrystalline Cellulose, micropowder silicon
Glue and cross-linked carboxymethyl cellulose sodium of 1/3 recipe quantity, arrange motor rotation frequency 150r/min, open mixer and mix 20 points
Clock；
6）Autocapsulefillingmachine fill；
7）Packaging.
Compared with prior art, the invention has the advantages that：
（1）Not only purity is high for Ceftriaxone Sodium crystalline compounds of the present invention, and polymer content is low, good stability, and its moisture absorption
Property, mobility etc. are substantially better than prior art；
（2）The preparation method process is simple of Ceftriaxone Sodium provided by the present invention, high income, repeatability is strong, is suitable for industry
Metaplasia is produced；
（3）Capsule dissolubility containing the Ceftriaxone Sodium crystalline compounds provided by the present invention is high, impurity content is low, stable
Property is good.
Description of the drawings
Fig. 1 is the X-ray powder diffraction figure of Ceftriaxone Sodium crystalline compounds of the present invention；
Fig. 2 is the heat analysis collection of illustrative plates of Ceftriaxone Sodium crystalline compounds of the present invention.
Specific embodiment
With embodiment, technical scheme is described in detail below, it will help the technical side to the present invention
The advantage, effect of case has and further understands, and embodiment does not limit protection scope of the present invention, protection scope of the present invention by
Claim is determining.
The preparation of 1 Ceftriaxone Sodium crystalline compounds of embodiment
By Ceftriaxone Sodium be dissolved in 35 DEG C of volumes be 4 times of water of Ceftriaxone Sodium weight, in the mixed solvent of dimethyl sulfoxide,
Water is 5 with the volume ratio of dimethyl sulfoxide:1.5；First volume is added as 7 times of Ceftriaxone Sodium weight with the speed of 40ml/min
The mixed solvent of ethanol and ether, ethanol, the volume ratio of ether are 2:2, stirring while adding, control 35 DEG C of temperature, growing the grain 3 is little
When；Then again volume is added as 5 times of Ceftriaxone Sodium weight of isopropanol with the speed of 20ml/min, growing the grain is after 1 hour, with
10 DEG C/h of speed is cooled to -5 DEG C, is then kept stirring for 90 revs/min of stirring and crystallizing of speed, growing the grain 3 hours；Filter, wash
Wash, drying under reduced pressure obtains Ceftriaxone Sodium crystalline compounds.
Determined with powder X-ray diffraction algoscopy, the X-ray powder diffraction collection for being represented with the 2 θ ± 0.2 ° angles of diffraction is such as
Shown in Fig. 1, at 7.0 °, 9.2 °, 12.8 °, 15.6 °, 21.9 °, 25.0 °, show characteristic diffraction peak.
It is 9.52wt% moisture to be determined using Ka Shi aquametry, is coincide with theoretical value substantially.
Determined using thermogravimetric analysiss, as a result as shown in Fig. 2 crystal water content is 9.53wt%, to be coincide with theoretical value substantially.
The preparation of 2 Ceftriaxone Sodium crystalline compounds of embodiment
By Ceftriaxone Sodium be dissolved in 35 DEG C of volumes be 5 times of water of Ceftriaxone Sodium weight, in the mixed solvent of dimethyl sulfoxide,
Water is 5 with the volume ratio of dimethyl sulfoxide:1.5；First volume is added as 8 times of Ceftriaxone Sodium weight with the speed of 40ml/min
The mixed solvent of ethanol and ether, ethanol, the volume ratio of ether are 2:2, stirring while adding, control 35 DEG C of temperature, growing the grain 3 is little
When；Then again volume is added as 6 times of Ceftriaxone Sodium weight of isopropanol with the speed of 20ml/min, growing the grain is after 1 hour, with
10 DEG C/h of speed is cooled to -5 DEG C, is then kept stirring for 90 revs/min of stirring and crystallizing of speed, growing the grain 3 hours；Filter, wash
Wash, drying under reduced pressure obtains Ceftriaxone Sodium crystalline compounds.
Determined with powder X-ray diffraction algoscopy, same with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction represent
Embodiment 1.
The preparation of 3 Ceftriaxone Sodium crystalline compounds of embodiment
By Ceftriaxone Sodium be dissolved in 35 DEG C of volumes be 6 times of water of Ceftriaxone Sodium weight, in the mixed solvent of dimethyl sulfoxide,
Water is 5 with the volume ratio of dimethyl sulfoxide:1.5；First volume is added as 9 times of Ceftriaxone Sodium weight with the speed of 40ml/min
The mixed solvent of ethanol and ether, ethanol, the volume ratio of ether are 2:2, stirring while adding, control 35 DEG C of temperature, growing the grain 3 is little
When；Then again volume is added as 7 times of Ceftriaxone Sodium weight of isopropanol with the speed of 20ml/min, growing the grain is after 1 hour, with
10 DEG C/h of speed is cooled to -5 DEG C, is then kept stirring for 90 revs/min of stirring and crystallizing of speed, growing the grain 3 hours；Filter, wash
Wash, drying under reduced pressure obtains Ceftriaxone Sodium crystalline compounds.
Determined with powder X-ray diffraction algoscopy, same with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction represent
Embodiment 1.
The preparation of 4 Ceftriaxone Sodium crystalline compounds of embodiment
By Ceftriaxone Sodium be dissolved in 35 DEG C of volumes be 4 times of water of Ceftriaxone Sodium weight, in the mixed solvent of dimethyl sulfoxide,
Water is 5 with the volume ratio of dimethyl sulfoxide:1.5；First volume is added as 8 times of Ceftriaxone Sodium weight with the speed of 40ml/min
The mixed solvent of ethanol and ether, ethanol, the volume ratio of ether are 2:2, stirring while adding, control 35 DEG C of temperature, growing the grain 3 is little
When；Then again volume is added as 5 times of Ceftriaxone Sodium weight of isopropanol with the speed of 20ml/min, growing the grain is after 1 hour, with
10 DEG C/h of speed is cooled to -5 DEG C, is then kept stirring for 90 revs/min of stirring and crystallizing of speed, growing the grain 3 hours；Filter, wash
Wash, drying under reduced pressure obtains Ceftriaxone Sodium crystalline compounds.
Determined with powder X-ray diffraction algoscopy, same with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction represent
Embodiment 1.
The preparation of 5 Ceftriaxone Sodium crystalline compounds of embodiment
By Ceftriaxone Sodium be dissolved in 35 DEG C of volumes be 6 times of water of Ceftriaxone Sodium weight, in the mixed solvent of dimethyl sulfoxide,
Water is 5 with the volume ratio of dimethyl sulfoxide:1.5；First volume is added as 7 times of Ceftriaxone Sodium weight with the speed of 40ml/min
The mixed solvent of ethanol and ether, ethanol, the volume ratio of ether are 2:2, stirring while adding, control 35 DEG C of temperature, growing the grain 3 is little
When；Then again volume is added as 7 times of Ceftriaxone Sodium weight of isopropanol with the speed of 20ml/min, growing the grain is after 1 hour, with
10 DEG C/h of speed is cooled to -5 DEG C, is then kept stirring for 90 revs/min of stirring and crystallizing of speed, growing the grain 3 hours；Filter, wash
Wash, drying under reduced pressure obtains Ceftriaxone Sodium crystalline compounds.
Determined with powder X-ray diffraction algoscopy, same with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction represent
Embodiment 1.
【Example of formulations 1】Ceftriaxone natrium capsule
In parts by weight, prescription composition is as follows：100 parts of Ceftriaxone Sodium, 80 parts of Microcrystalline Cellulose, Croscarmellose Sodium
8 parts, 2 parts of micropowder silica gel.
Ceftriaxone Sodium is Ceftriaxone Sodium crystalline compounds obtained in the embodiment of the present invention 1.
Preparation method：
1）Feedstock treating：With vibration screen-dividing machine, Ceftriaxone Sodium is crossed 80 mesh sieves, standby；
2）Microcrystalline Cellulose, cross-linked carboxymethyl cellulose sodium, micropowder silica gel are crossed 60 mesh sieves respectively, standby；
3）Weigh：Weighing supplementary material is carried out according to prescription；
4）Premix：Cross-linked carboxymethyl cellulose sodium of the Microcrystalline Cellulose of recipe quantity, micropowder silica gel and 1/3 recipe quantity is added to mixed
In conjunction machine, motor rotation frequency 200r/min is set, is opened mixer and mix 30 minutes；
5）Total mixed：Cross-linked carboxymethyl cellulose sodium of the Ceftriaxone Sodium of recipe quantity and 2/3 recipe quantity is added in mixer, if
Motor rotation frequency 200r/min is put, is opened mixer and mix 10 minutes；It is subsequently adding pre- mixed Microcrystalline Cellulose, micropowder silicon
Glue and cross-linked carboxymethyl cellulose sodium of 1/3 recipe quantity, arrange motor rotation frequency 150r/min, open mixer and mix 20 points
Clock；
6）Autocapsulefillingmachine fill；
7）Packaging.
【Example of formulations 2】Ceftriaxone natrium capsule
In parts by weight, prescription composition is as follows：100 parts of Ceftriaxone Sodium, 90 parts of Microcrystalline Cellulose, Croscarmellose Sodium
12 parts, 2 parts of micropowder silica gel.
Preparation method：With example of formulations 1, except that Ceftriaxone Sodium used is the head prepared by embodiment 2
Spore Qusong sodium crystal.
【Example of formulations 3】Ceftriaxone natrium capsule
In parts by weight, prescription composition is as follows：150 parts of Ceftriaxone Sodium, 90 parts of Microcrystalline Cellulose, Croscarmellose Sodium
9 parts, 3 parts of micropowder silica gel.
Preparation method：With example of formulations 1, except that Ceftriaxone Sodium used is the head prepared by embodiment 3
Spore Qusong sodium crystal.
【Example of formulations 4】Ceftriaxone natrium capsule
In parts by weight, prescription composition is as follows：200 parts of Ceftriaxone Sodium, 80 parts of Microcrystalline Cellulose, Croscarmellose Sodium
12 parts, 2 parts of micropowder silica gel.
Preparation method：With example of formulations 1, except that Ceftriaxone Sodium used is the head prepared by embodiment 4
Spore Qusong sodium crystal.
【Example of formulations 5】Ceftriaxone natrium capsule
In parts by weight, prescription composition is as follows：200 parts of Ceftriaxone Sodium, 100 parts of Microcrystalline Cellulose, cross-linked carboxymethyl cellulose
12 parts of sodium, 4 parts of micropowder silica gel.
Preparation method：With example of formulations 1, except that Ceftriaxone Sodium used is the head prepared by embodiment 5
Spore Qusong sodium crystal.
Trial target 1：Ceftriaxone Sodium crystalline compounds prepared by the embodiment of the present invention 1；
Trial target 2：Ceftriaxone Sodium crystalline compounds prepared by the embodiment of the present invention 3；
Reference substance 1：Method according to CN102432629B embodiment 1 is obtained Ceftriaxone Sodium；
Reference substance 2：Deliver according to Wang Donghai et al.《The improvement of Recrystal Method of Ceftriaxone Sodium》The preparation of 1.2 Ceftriaxone Sodium
Method is obtained Ceftriaxone Sodium；
Reference substance 3：Method according to CN102617605B embodiment 1 is obtained Ceftriaxone Sodium；
Reference substance 4：Method according to CN102993215B embodiment 1 is obtained Ceftriaxone Sodium；
Reference substance 5：Method according to CN104031067B embodiment 1 is obtained Ceftriaxone Sodium；
Reference substance 6：Method according to CN104341435B embodiment 1 is obtained Ceftriaxone Sodium；
Reference substance 7：Method according to CN104370941A embodiment 1 is obtained ceftriaxone sodium crystal；
Reference substance 8：Method according to CN104873466A embodiment 1 is obtained Ceftriaxone Sodium；
Reference substance 9：Method according to CN104876948A embodiment 1 is obtained Ceftriaxone Sodium；
Reference substance 10：Method according to CN104887621A embodiment 1 is obtained Ceftriaxone Sodium；
Reference substance 11：Method according to CN105061472A embodiment 1 is obtained Ceftriaxone Sodium；
Reference substance 12：Method according to CN102875574A embodiment 1 is obtained Ceftriaxone Sodium.
Experimental example 1：Heat stabilization test
Each sample is respectively exposed to relative humidity for 75%, in the environment of temperature is 40 DEG C, according to Chinese Pharmacopoeia 2010 editions the
Two annex determine the content of high molecular polymer about substance detecting method and molecular exclusion chromatography, the results are shown in Table 1a, 1b：
Table 1a heat stabilization test result
Table 1b heat stabilization test result
The height of drug quality is directly connected to the health of millions upon millions of working people's bodies, is also related to becoming for China's economic construction
Effect, the consolidation of national defence and nationality flourishing；It has been far from the thing of medical industry enterprise scope itself, but the whole people
Race, the major issue in the world.Those skilled in the art all clearly know, in the present age of pharmaceutical technology prosperity, drug safety standard is not by
Disconnected lifting, the purity of prepared medicine also more and more higher, impurity content is effectively reduced, even several percentage points of zero point,
The generation of untoward reaction can also be effectively reduced, therefore impurity content is most important to drug quality and people's drug safety.
Medicine is needed to the process of circulation to store and transport just cure the sickness to save the patient from production, therefore, medicine in storage and transportation
Quality is particularly important, and stability is the key for determining drug quality quality, in medicine storage and transportation, stability
Bad, impurity change directly affects greatly people's drug safety.
As can be seen from the above table, the relevant material of Ceftriaxone Sodium crystalline compounds of the present invention, polymer equal size be all very
Low, and heat stability is significantly better than the Ceftriaxone Sodium for being obtained using the method for prior art after purification, is effectively lifted
The stability of drug safety and storage, reduces the generation of untoward reaction.
Above-mentioned test is also carried out to the Ceftriaxone Sodium crystalline compounds of other embodiments of the present invention, its result for obtaining
Similar.
Experimental example 2：Fluidity test
This experimental example evaluates the mobility of sample by the angle of repose of determination sample, and concrete grammar is as follows：Sample particle is taken, from
Flow in fixing little funnel in the surface plate of circle, until highest cone is obtained, cone height H and radius R measured,
α angle of repose is calculated by tan α=H/R, 2 are the results are shown in Table, angle of repose is bigger, and mobility is poorer.
2 fluidity test result of table
As known from Table 2, compared with Ceftriaxone Sodium of the prior art, Ceftriaxone Sodium compound flow of the present invention is significantly carried
Height, is conducive to improving the accuracy of subpackage, and is easily mixed when being mixed with other compositions uniform.
Above-mentioned test is also carried out to the Ceftriaxone Sodium crystalline compounds of other embodiments of the present invention, its result for obtaining
Similar.
Experimental example 3：Wettability test
Each sample opening is put in clean culture dish ,≤thick the thin layer of 5mm is spread out into, each two parts, is respectively put into constant humidity hermetic container
In, place 10 days under conditions of relative humidity 75% and 92.5% at 25 DEG C, sampled in the 5th day and the 10th day, pass through
The moisture of loss on drying experiment measurement each sample, result of the test was compared with 0 day, and experimental result is shown in Table 3.
3 hygroscopicity test results of table
As can be seen from the above table, Ceftriaxone Sodium crystalline compounds of the present invention are substantially non-hygroscopic under high humidity conditions, and which is in height
Stability under wet environment is substantially better than and is processed the Ceftriaxone Sodium for obtaining using the purification process of prior art.
Above-mentioned test is also carried out to the Ceftriaxone Sodium crystalline compounds of other embodiments of the present invention, its result for obtaining
Similar.
Experimental example 4：Prescription screening is tested（Prepared using capsule preparation method thereof of the present invention）
Table 4a prescription screening experimental result
Table 4b prescription screening experimental result
As can be seen from the above table, ceftriaxone natrium capsule obtained in the present invention（Prescription 11）Not only mobility, dissolution are good, and
And polymer, always miscellaneous content are significantly reduced.
Experimental example 5：Preparation influence factor tests
Formulation test product 1：Ceftriaxone natrium capsule prepared by invention formulation embodiment 1.
Formulation test product 2：Ceftriaxone natrium capsule prepared by invention formulation embodiment 3.
By formulation test product simulation listing packaging, in 60 DEG C of high temperature, illumination 4500Lx, high humidity（RH90%±5%）Under the conditions of
Place 10 days, detected by stability high spot reviews project, compare with 0 day sample, the results are shown in Table 5.
5 preparation influence factor's result of the test of table
Found by result above, the capsule dissolubility containing the Ceftriaxone Sodium crystalline compounds prepared by the present invention is high, miscellaneous
Matter content is low, good stability.
Above-mentioned test is also carried out to the ceftriaxone natrium capsule of other example of formulations of the present invention, its result phase for obtaining
Seemingly.
Claims (1)
1. a kind of medicine Ceftriaxone Sodium crystalline compounds for treating Postoperative infection, it is characterised in that：Described cephalo song
The structural formula of loose sodium crystal compound as shown in formula I, the x-ray powder that the crystalline compounds are represented with the 2 θ ± 0.2 ° angles of diffraction
Diffracting spectrum as shown in figure 1,
Formula（）.
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