CN106432274A - 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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- CN106432274A CN106432274A CN201610835411.1A CN201610835411A CN106432274A CN 106432274 A CN106432274 A CN 106432274A CN 201610835411 A CN201610835411 A CN 201610835411A CN 106432274 A CN106432274 A CN 106432274A
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- ceftriaxone sodium
- ceftriaxone
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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
- 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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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 is and in particular to a kind of medicine ceftriaxone sodium treating Postoperative infection is brilliant
Body compound.
Background technology
Ceftriaxone sodium molecular formula：C18H17N8NaO7S3Three times semihydrate, structural formula is as follows：
Ceftriaxone sodium chemistry entitled (6R, 7R) -3- [[(1,2,5,6- tetrahydrochysene -2- methyl -5,6- dioxo -1,2,4- triazines -
3- yl) 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 is no
Taste, has and draws moist, soluble in water, slightly soluble in methyl alcohol, almost insoluble in chloroform or ether.
Ceftriaxone sodium is researched and developed by Hoffmann-LaRoche company of Switzerland, and nineteen eighty-two lists in Switzerland first.Belong to
Third-generation cephalosporin class antibiotic, is widely used in the sensitive respiratory tract infection of this product, 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 it 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 China's high-end antibiotic market.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 projects.These fundamentals determine cephalo
Qusong sodium becomes the core kind leading cephalosporins market.Therefore, the refined of ceftriaxone sodium is also taken seriously therewith.
Prior art discloses multiple method for crystallising, mainly have 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 all dissolves to solid, filters, and filtrate is standby；B. stir, temperature control, the filter preparing to step a
Deca acetone in liquid, obtains mixed liquor；C. the mixed liquor that step b prepares is lowered the temperature, standing, obtain crystal solution；D. by step c system
The standby crystal solution sucking filtration obtaining, washing, it is dried, obtain ceftriaxone sodium crystal.
CN102993215B discloses a kind of preparation method of ceftriaxone sodium crystal, water-soluble to 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 add organic solvent, till the crystal being formed is not further added by；Crystal filters, 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 obtaining is best, anaphylaxiss occur
Rate is minimum, safety highest.This invention preparation method process is simple, favorable reproducibility.
Although the problems such as above-mentioned purification process to some extent solves its purity, through further investigation revealed that,
Due to the less stable of ceftriaxone sodium, it is also susceptible to degraded and polyreaction in storage process, during with depositing
Between prolongation, its impurity and high polymer content increase, the quality of impact ceftriaxone, makes 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 in itself by medicine
, 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 endogenouss impurity two class.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 produce during production process or storage.Impurity in medicine is most
There is potential source biomolecule activity, Drug safety and effectiveness can be affected with drug interaction, or even produce toxicity.Cephalo
Except anaphylactoid macromolecule impurity ceftriaxone polymerization beyond the region of objective existence can be led in Qusong sodium, also there are other impurity, such as synthesize
During residual raw material etc. although not yet there being data to show that these impurity can give people body and cause directly to injure, but it is 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 studied with regard to impurity in medicament research and development.
2010 editions impurity to ceftriaxone sodium of Chinese Pharmacopoeia and polymer have strict restriction it is desirable in ceftriaxone sodium
Maximum list is miscellaneous must not to be higher than 0.5%, and total impurities must not be higher than 2.0%, and ceftriaxone polymer must not be higher than 0.5%.Prior art obtains
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 literary composition, 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, polymer minimum is respectively 0.053%, 0.053%, 0.15%.
Disclosed in Lanzhou University of Science ＆ Technology《The optimization of ceftriaxone process for producing sodium》Production to ceftriaxone sodium in research
Technique is optimized, and final step crystallization is refined purifier units operation, adds ceftriaxone sodium crystal seed in crystallization, this
The main granularity of ceftriaxone sodium product that sample obtains 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, reduce the content that all kinds of impurity in ceftriaxone sodium include polymer, obtain high-quality product, be to ensure that
One important process of ceftriaxone sodium clinical application safety
The present inventor, with existing crude product of ceftriaxone sodium as raw material, through lot of experiments, has been obtained one kind and has been different from prior art
Novel crystal forms ceftriaxone sodium compound, and by test, surprisingly find that this crystalline compounds purity is high, polymer content
Low, good stability, and it is difficult moisture absorption, good fluidity.Using this crystal-form compound, the dry suspension good fluidity made, impurity contain
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 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 adopts the following technical scheme that：
A kind of medicine ceftriaxone sodium crystalline compounds 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 this crystalline compounds is represented with the 2 θ ± 0.2 ° angles of diffraction
It is shown,
Formula（）.
A kind of preparation method of medicine ceftriaxone sodium crystalline compounds treating Postoperative infection of the present invention,
The method comprises the steps：
（1）Crude product of ceftriaxone sodium is dissolved in 35 DEG C of water and the mixed solution of carbon tetrachloride；
（2）Add the activated carbon decolorizing of 0.2 times that weight is ceftriaxone sodium weight, filter, obtain ceftriaxone sodium solution；
（3）Ceftriaxone sodium solution is heated up, to Deca propyl ether in ceftriaxone sodium solution under conditions of stirring, in 0.5h at the uniform velocity
Completion of dropping；
（4）Lower the temperature after being added dropwise to complete, continue stirring 2h under the stir speed (S.S.) of 15rmp, standing 3h separates out crystal, filters, washing,
It is vacuum dried to obtain ceftriaxone sodium crystal.
In the present invention, described crude product of ceftriaxone sodium is ceftriaxone sodium solid mixture to be further purified.Head
Spore Qusong sodium crude product can be prepared by art methods or additive method is obtained.
In above-mentioned preparation method, wherein, step（1）Described in water and carbon tetrachloride mixed solution volume（ml）For head
8-10 times of spore Qusong sodium weight（g/ml）, the volume ratio of described water and carbon tetrachloride is 4:2.5.Step（2）Described in activity
Charcoal weight is 0.2-0.4 times of ceftriaxone sodium weight.Step（3）In be warmed up to 40 DEG C, the volume of described propyl ether（ml）For head
6-8 times of spore Qusong sodium weight（g/ml）, described stir speed (S.S.) is 30rmp.Step（4）Described in cooling rate be with 15 DEG C/
The speed of hour is cooled to -10 DEG C.
The present invention also provides a kind of ceftriaxone sodium dry suspension, and described compositionss contain cephalo provided by the present invention
The ceftriaxone sodium crystal-form compound that Qusong sodium crystal compound or preparation method of the present invention are obtained.
Described ceftriaxone sodium dry suspension, in parts by weight, by the ceftriaxone sodium of 100 weight portions, 1300-1340
The cane sugar powder of weight portion, 130-150 Hypromellose, the xanthan gum composition of 130-150 weight portion.
Preferably, described ceftriaxone sodium dry suspension, in parts by weight, by the ceftriaxone sodium of 100 weight portions,
The cane sugar powder of 1320 weight portions, 140 Hypromellose, the xanthan gum composition of 140 weight portions.
Described ceftriaxone sodium dry suspension, is prepared from by following preparation method：
1）Sieve：Sucrose, ceftriaxone sodium are crossed 60 mesh sieves, 80 mesh sieves crossed by Hypromellose and xanthan gum, standby；
2）Premix：Weigh the ceftriaxone sodium of recipe quantity and cane sugar powder mixes 20 minutes；
3）Always mix：Recipe quantity Hypromellose and xanthan gum is added to be sufficiently mixed uniformly；
4）Middle product examine is tested；
5）Packaging, full inspection warehousing after passing.
Compared with prior art, the invention has the advantages that：
（1）Not only purity is high for ceftriaxone sodium crystalline compounds provided by the present invention, and polymer content is low, good stability, and
And its hygroscopicity, 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）Dry suspension good fluidity containing this ceftriaxone sodium crystal-form compound provided by the present invention, impurity content be low,
Good stability.
Brief description
Fig. 1 is the X-ray powder diffraction figure of the ceftriaxone sodium crystalline compounds of the present invention.
Fig. 2 is the heat analysis collection of illustrative plates of the 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 of case, effect have and further understand, embodiment does not limit protection scope of the present invention, protection scope of the present invention by
Claim is determining.
The preparation of embodiment 1 ceftriaxone sodium crystalline compounds
（1）Crude product of ceftriaxone sodium is dissolved into the water of 8 times that 35 DEG C of volumes are ceftriaxone sodium weight and the mixed of carbon tetrachloride
Close in solution, the volume ratio of described water and carbon tetrachloride is 4:2.5；
（2）Add the activated carbon decolorizing of 0.2 times that weight is ceftriaxone sodium weight, filter, obtain ceftriaxone sodium solution；
（3）Ceftriaxone sodium solution is warmed up to 40 DEG C, to Deca propyl ether in ceftriaxone sodium solution, propyl ether under conditions of stirring
Volume be 6 times of ceftriaxone sodium weight, at the uniform velocity completion of dropping in 0.5h, described stir speed (S.S.) is 30rmp；
（4）It is cooled to -10 DEG C with 15 DEG C/h of speed after being added dropwise to complete, continue stirring 2h under the stir speed (S.S.) of 15rmp,
Standing 3h separates out crystal, filters, and washing is vacuum dried to obtain ceftriaxone sodium crystal.
Measured as shown in figure 1, the X-ray powder being represented with the 2 θ ± 0.2 ° angles of diffraction is spread out with powder X-ray diffraction algoscopy
Penetrate collection of illustrative plates and show characteristic diffraction peak at 2.8 °, 4.9 °, 7.1 °, 7.7 °, 13.9 °, 17.2 °, 26.8 °, 33.5 °, 34.6 °.
Measuring moisture using Ka Shi aquametry is 9.52wt%, substantially identical with theoretical value.
Measured using thermogravimetric analysiss, result is as shown in Fig. 2 crystal water content is 9.53wt%, substantially identical with theoretical value.
The preparation of embodiment 2 ceftriaxone sodium crystalline compounds
（1）Crude product of ceftriaxone sodium is dissolved into the water of 9 times that 35 DEG C of volumes are ceftriaxone sodium weight and the mixed of carbon tetrachloride
Close in solution, the volume ratio of described water and carbon tetrachloride is 4:2.5；
（2）Add the activated carbon decolorizing of 0.3 times that weight is ceftriaxone sodium weight, filter, obtain ceftriaxone sodium solution；
（3）Ceftriaxone sodium solution is warmed up to 40 DEG C, to Deca propyl ether in ceftriaxone sodium solution, propyl ether under conditions of stirring
Volume be 7 times of ceftriaxone sodium weight, at the uniform velocity completion of dropping in 0.5h, described stir speed (S.S.) is 30rmp；
（4）It is cooled to -10 DEG C with 15 DEG C/h of speed after being added dropwise to complete, continue stirring 2h under the stir speed (S.S.) of 15rmp,
Standing 3h separates out crystal, filters, and washing is vacuum dried to obtain ceftriaxone sodium crystal.
Measured 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 embodiment 3 ceftriaxone sodium crystalline compounds
（1）Crude product of ceftriaxone sodium is dissolved into the water of 10 times that 35 DEG C of volumes are ceftriaxone sodium weight and the mixed of carbon tetrachloride
Close in solution, the volume ratio of described water and carbon tetrachloride is 4:2.5；
（2）Add the activated carbon decolorizing of 0.4 times that weight is ceftriaxone sodium weight, filter, obtain ceftriaxone sodium solution；
（3）Ceftriaxone sodium solution is warmed up to 40 DEG C, to Deca propyl ether in ceftriaxone sodium solution, propyl ether under conditions of stirring
Volume be 8 times of ceftriaxone sodium weight, at the uniform velocity completion of dropping in 0.5h, described stir speed (S.S.) is 30rmp；
（4）It is cooled to -10 DEG C with 15 DEG C/h of speed after being added dropwise to complete, continue stirring 2h under the stir speed (S.S.) of 15rmp,
Standing 3h separates out crystal, filters, and washing is vacuum dried to obtain ceftriaxone sodium crystal.
Measured 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 embodiment 4 ceftriaxone sodium crystalline compounds
（1）Crude product of ceftriaxone sodium is dissolved into the water of 8 times that 35 DEG C of volumes are ceftriaxone sodium weight and the mixed of carbon tetrachloride
Close in solution, the volume ratio of described water and carbon tetrachloride is 4:2.5；
（2）Add the activated carbon decolorizing of 0.3 times that weight is ceftriaxone sodium weight, filter, obtain ceftriaxone sodium solution；
（3）Ceftriaxone sodium solution is warmed up to 40 DEG C, to Deca propyl ether in ceftriaxone sodium solution, propyl ether under conditions of stirring
Volume be 8 times of ceftriaxone sodium weight, at the uniform velocity completion of dropping in 0.5h, described stir speed (S.S.) is 30rmp；
（4）It is cooled to -10 DEG C with 15 DEG C/h of speed after being added dropwise to complete, continue stirring 2h under the stir speed (S.S.) of 15rmp,
Standing 3h separates out crystal, filters, and washing is vacuum dried to obtain ceftriaxone sodium crystal.
Measured 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 embodiment 5 ceftriaxone sodium crystalline compounds
（1）Crude product of ceftriaxone sodium is dissolved into the water of 10 times that 35 DEG C of volumes are ceftriaxone sodium weight and the mixed of carbon tetrachloride
Close in solution, the volume ratio of described water and carbon tetrachloride is 4:2.5；
（2）Add the activated carbon decolorizing of 0.2 times that weight is ceftriaxone sodium weight, filter, obtain ceftriaxone sodium solution；
（3）Ceftriaxone sodium solution is warmed up to 40 DEG C, to Deca propyl ether in ceftriaxone sodium solution, propyl ether under conditions of stirring
Volume be 6 times of ceftriaxone sodium weight, at the uniform velocity completion of dropping in 0.5h, described stir speed (S.S.) is 30rmp；
（4）It is cooled to -10 DEG C with 15 DEG C/h of speed after being added dropwise to complete, continue stirring 2h under the stir speed (S.S.) of 15rmp,
Standing 3h separates out crystal, filters, and washing is vacuum dried to obtain ceftriaxone sodium crystal.
Measured 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 sodium dry suspension
In parts by weight, prescription consists of：100 parts of ceftriaxone sodium, 1320 parts of sucrose, 140 parts of Hypromellose, xanthan
140 parts of glue.
Ceftriaxone sodium is the ceftriaxone sodium crystal-form compound prepared by the embodiment of the present invention 1.
Preparation method：
1）Sieve：Sucrose, ceftriaxone sodium are crossed 60 mesh sieves, 80 mesh sieves crossed by Hypromellose and xanthan gum, standby；
2）Premix：Weigh the ceftriaxone sodium of recipe quantity and cane sugar powder mixes 20 minutes；
3）Always mix：Recipe quantity Hypromellose and xanthan gum is added to be sufficiently mixed uniformly；
4）Middle product examine is tested；
5）Packaging, full inspection warehousing after passing.
【Example of formulations 2】Ceftriaxone sodium dry suspension
In parts by weight, prescription consists of：100 parts of ceftriaxone sodium, 1300 parts of sucrose, 150 parts of Hypromellose, xanthan gum
130 parts.
Preparation method：With example of formulations 1, except that ceftriaxone sodium used is the head prepared by embodiment 2
Spore Qusong sodium crystal compound.
【Example of formulations 3】Ceftriaxone sodium dry suspension
In parts by weight, prescription consists of：100 parts of ceftriaxone sodium, 1340 parts of sucrose, 130 parts of Hypromellose, xanthan gum
150 parts.
Preparation method：With example of formulations 1, except that ceftriaxone sodium used is the head prepared by embodiment 3
Spore Qusong sodium crystal compound.
【Example of formulations 4】Ceftriaxone sodium dry suspension
In parts by weight, prescription consists of：100 parts of ceftriaxone sodium, 1300 parts of sucrose, 130 parts of Hypromellose, xanthan gum
130 parts.
Preparation method：With example of formulations 1, except that ceftriaxone sodium used is the head prepared by embodiment 4
Spore Qusong sodium crystal compound.
【Example of formulations 5】Ceftriaxone sodium dry suspension
In parts by weight, prescription consists of：100 parts of ceftriaxone sodium, 1340 parts of sucrose, 150 parts of Hypromellose, xanthan gum
150 parts.
Preparation method：With example of formulations 1, except that ceftriaxone sodium used is the head prepared by embodiment 5
Spore Qusong sodium crystal compound.
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 4；
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
It is in the environment of 75%, temperature is 40 DEG C that each sample is respectively exposed to relative humidity, according to Chinese Pharmacopoeia 2010 editions the
Two annex measure the content of high molecular polymer about substance detecting method and molecular exclusion chromatography, the results are shown in Table 1a, table
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 the one-tenth of 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 that pharmaceutical technology is flourishing, drug safety standard is not by
Disconnected lifting, the purity also more and more higher of prepared medicine, it is effectively reduced impurity content, 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 needs to store and transport just can cure the sickness to save the patient from production to the process of circulation, therefore, medicine in storage and transportation
Quality is particularly important, and stability is the key determining drug quality quality, in medicine storage and transportation, stability
Bad, impurity change directly affects greatly people's drug safety.
The relevant material of the ceftriaxone sodium crystalline compounds as can be seen from the above table, being obtained using the method for the present invention,
Polymer equal size is all very low, and heat stability is significantly better than the cephalo song being obtained after purification using the method for prior art
Loose sodium, improves the stability of drug safety and storage effectively, 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 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：Take sample particle, from
Flow in fixing little funnel in the surface plate of circle, until obtaining highest cone, measure cone height H and radius R,
Calculate α angle of repose by tan α=H/R, the results are shown in Table 2, angle of repose is bigger, mobility is poorer.
Table 2 fluidity test result
As known from Table 2, the ceftriaxone sodium compound flow compared with ceftriaxone sodium of the prior art, prepared by the present invention
Property significantly improve, be conducive to improving the accuracy of subpackage, and be easily mixed uniform when mix with other compositions.
Experimental example 3：Wettability test
Each sample opening is put in clean culture dish, spreads out into≤thick the thin layer of 5mm, each two parts, be 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.
Table 3 hygroscopicity test results
As can be seen from the above table, the ceftriaxone sodium crystalline compounds of present invention preparation are substantially non-hygroscopic under high humidity conditions,
Its stability under high humidity environment is substantially better than the ceftriaxone sodium obtaining using the purification process process of prior art.
Above-mentioned experimental example 1-3 is also carried out to the ceftriaxone sodium crystal-form compound of other embodiments of the present invention, its acquisition
Result similar.
Experimental example 4：Prescription screening is tested（Using dry suspension preparation method of the present invention preparation）
Table 4 prescription screening experimental result
As can be seen from the above table, the ceftriaxone sodium dry suspension that the present invention is obtained（Prescription six）Not only good fluidity, Er Qieju
Compound, always miscellaneous content significantly reduce.
Experimental example 5：Preparation influence factor tests
Formulation test product 1：Ceftriaxone sodium dry suspension prepared by invention formulation embodiment 1.
Formulation test product 2：Ceftriaxone sodium dry suspension prepared by invention formulation embodiment 3.
Hot test takes trial target, and opening is put in sealing clean container, places 10 days, by stability at a temperature of 60 DEG C of degree
High spot reviews project is detected.
High wet test takes trial target, and opening is put in constant-humidity clean container（Relative humidity 90% ± 5%）Place 10 days, by steady
Qualitative high spot reviews project is detected.
Highlight test takes trial target, and opening is put in lighting box, places 10 days, by stability emphasis under the conditions of 4500LX
Investigation project is detected.
Table 5 preparation influence factor's result of the test
Found by result above, the compositionss dry suspension containing this ceftriaxone sodium crystal-form compound prepared by the present invention
Good fluidity, impurity content are low, good stability.
Above-mentioned test is also carried out to the ceftriaxone sodium dry suspension of present invention other example of formulations, its knot obtaining
Really similar.
Claims (1)
1. a kind of medicine ceftriaxone sodium crystalline compounds treating Postoperative infection it is characterised in that：Described cephalo is bent
The structural formula of loose sodium crystal compound as shown in formula I, the x-ray powder that this crystalline compounds is represented with the 2 θ ± 0.2 ° angles of diffraction
Diffracting spectrum as shown in figure 1,
Formula I.
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| CN108047253A (en) * | 2018-01-04 | 2018-05-18 | 北京红太阳药业有限公司 | A kind of Ceftriaxone Sodium crystal-form compound |
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