CN102659818B - Hydrochloric acid cefotiam crystalline compound, preparation method thereof and medicine combination containing compound - Google Patents
Hydrochloric acid cefotiam crystalline compound, preparation method thereof and medicine combination containing compound Download PDFInfo
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Abstract
The invention relates to a hydrochloric acid cefotiam crystalline compound and a medicine combination containing the same. The crystalline compound is determined by a powder X-ray diffraction measurement method, and an X-ray powder diffraction pattern represented with a diffraction angle of 2theta+/-0.2 degree shows characteristic diffraction peak at the positions of 5.9 degrees, 7.9 degrees, 9.3 degrees, 13.0 degrees, 13.6 degrees, 15.7 degrees, 16.8 degrees, 20.4 degrees, 25.7 degrees, 27.0 degrees, 30.9 degrees and 32.9 degrees. The crystalline compound is high in purity, has good heat stability, and can hardly absorb moisture. Simultaneously, the invention further provides a preparation method of the crystalline compound and the medicine combination containing the crystalline compound. The method is simple in process, high in yield, strong in repeatability and suitable for industrial production. The medicine combination containing the crystalline compound is good in stability, thereby improving medication safety and effectiveness and reducing occurrence rate of adverse reactions.
Description
Technical field
The invention belongs to field of medicaments, the pharmaceutical composition that relates in particular to a kind of cefotiam hydrochloride crystalline compounds and preparation method thereof and contain this compound.
Background technology
Cefotiam hydrochloride; it is Cefotiam Dihydrochloride; chemistry (6R-is trans)-7-[[(2-amino-4-thiazolyl by name) ethanoyl] amino]-3-[[[1-[(2-(dimethylamino) ethyl]-1H-TETRAZOLE-5-yl] sulphomethyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid dihydrochloride; for applying clinically cynnematin more widely, its structural formula is:
Because cefotiam hydrochloride is positioned in the process of depositing, particularly, under the condition of high temperature (50 ℃ of >), often there is degraded and polyreaction, thereby cause active constituents of medicine content to reduce, color and luster is strengthened, and polymeric impurities content raises.In addition, expired cefotiam hydrochloride, because the shelf-time is long, also usually makes active constituents of medicine content reduce, and darkens, and polymer content raises.And in some cases, because controlling of production process is improper, in resulting cefotiam or its salt, polymer content is high especially.And polymer content is when high, easily make human body produce anaphylaxis.In order to ensure human body drug safety, national Specification, cefotiam hydrochloride, requires the content of cefotiam to be not less than 83.2%, and the content of polymkeric substance is not higher than 0.5%, and its color and luster is not higher than No. 6 looks.So, for this cefotiam that class impurity is residual or foreign matter content is high or its salt, be necessary to be further purified, obtain highly purified cefotiam hydrochloride crystal.
Application number is the purification process that 200910015122.7 Chinese patent application discloses a kind of cefotiam or its salt, by it is carried out to acid-alkali accommodation, the trip temperature of going forward side by side is controlled, can make its High-molecular weight polymer impurity containing therefrom separate out, reach the object of purifying, solved the problems such as the purity having existed since prior art is medium-term and long-term is on the low side, foreign matter content is high, product look level is high.
CN101787037A provides a kind of process for purification of cefotiam hydrochloride compound, and by acid-base reaction, absorption with macroporous adsorbent resin, has improved the purity of cefotiam hydrochloride greatly, has optimized the quality product of preparation, has ensured the safety of clinical application.
CN102241692A discloses a kind of method of preparing cefotiam hexetil hydrochloride by solvent crystallization; by cefotiam acid with 1-iodine ethyl cyclohexyl carbonic diester in reaction medium react the obtained reactant that contains cefotiam hexetil or reaction solution in add extraction agent and saturated aqueous common salt to carry out layering and extraction; in separated organic phase, add again hydrochloric crystallization to carry out crystallization with organic solvent, thereby can prepare to mass-producing cefotiam hexetil hydrochloride.
CN102190667A discloses a kind of new preparation method of purifying cefotiam hydrochloride, comprising: 1) raw material cefotiam hydrochloride is soluble in water, with bisalt material, processes, and then cooling, falls the sedimentation and filtration of separating out, and obtains containing filter liquor; 2) to adding with the immiscible solvent of water in the above-mentioned aqueous solution, extract, then separate the organic phase that contains impurity, obtain the aqueous solution that contains cefotiam hydrochloride; 3) in this aqueous solution, add the poor solvent of cefotiam hydrochloride, and control temperature and carry out recrystallization, by the crystal centrifuge washing of separating out, dry, obtain the cefotiam hydrochloride of purifying.The cefotiam content of the resulting cefotiam hydrochloride highly finished product of the inventive method is not less than 86%, and macromolecule impurity content is less than 0.3%, and in its prepared injection, particulate matter content is extremely low.
Although above-mentioned purification process has solved its purity problem to a certain extent, but through further research discovery, because cefotiam hydrochloride is positioned in the process of depositing, particularly under the condition of high temperature (50 ℃ of >), often there is degraded and polyreaction, along with the prolongation of shelf-time, its superpolymer content increases, and the risk that makes human body produce anaphylaxis increases.
It is raw material that the inventor be take existing cefotiam hydrochloride crude product, through lot of experiments, made a kind of cefotiam hydrochloride compound that is different from the new crystal of prior art, and by test, found that the cefotiam hydrochloride compound of this crystal formation has good thermostability pleasantly surprisedly, its purity is higher, and substantially non-hygroscopic, and technique is simple, and yield is high, repeatability is strong, is suitable for suitability for industrialized production.And take the aseptic powder injection that the cefotiam hydrochloride compound of this new crystal prepared as raw material, there is equally good stability, thereby completed the present invention.
Summary of the invention
The first object of the present invention is to provide a kind of cefotiam hydrochloride crystalline compounds, and this crystalline compounds purity is high, and has good thermostability, and substantially non-hygroscopic.
The second object of the present invention is to provide the preparation method of described cefotiam hydrochloride crystalline compounds, and the method technique is simple, and yield is high, and repeatability is strong, is suitable for suitability for industrialized production.
The 3rd object of the present invention is to provide a kind of pharmaceutical composition, and described pharmaceutical composition contains the cefotiam hydrochloride crystalline compounds that cefotiam hydrochloride crystalline compounds provided by the present invention or preparation method of the present invention make.
For realizing the first object of the present invention, the present invention adopts following technical scheme:
A kind of cefotiam hydrochloride crystalline compounds, wherein be characterised in that, the structural formula of described cefotiam hydrochloride crystalline compounds is suc as formula shown in (I), this crystalline compounds is measured by powder x-ray diffraction assay method, the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle locates to demonstrate characteristic diffraction peak at 5.9 °, 7.9 °, 9.3 °, 13.0 °, 13.6 °, 15.7 °, 16.8 °, 20.4 °, 25.7 °, 27.0 °, 30.9 ° and 32.9 °
For realizing the second object of the present invention, the present invention adopts following technical scheme:
A preparation method for cefotiam hydrochloride crystalline compounds of the present invention, the method comprises the steps:
1) prepare crude product solution: cefotiam hydrochloride crude product is added in methyl alcohol and the formulated mixed solvent of tetrahydrofuran (THF), be stirred to dissolve, add activated carbon decolorizing, filter, obtain crude product solution, standby;
2) prepare recrystallisation solvent: by acetone and ethyl acetate 1～3: 10 ratio preparation recrystallisation solvent by volume, described recrystallisation solvent volume is 6～15 times of cefotiam hydrochloride crude product weight;
3) crystallization: under stirring, to step 1) in the crude product solution of gained, stream adds step 2) gained recrystallisation solvent, there is solid to separate out; After dropwising, continue under agitation to drip chloroform, to there being crystal to separate out; Standing 3～6h, filters, by methanol wash, dry, obtains described cefotiam hydrochloride crystalline compounds.
In the present invention, cefotiam hydrochloride crude product can adopt the method for prior art to prepare, and also can buy commercially available cefotiam hydrochloride bulk drug.
In preparation method of the present invention, wherein, step 1) described in, the weightmeasurement ratio of cefotiam hydrochloride crude product and described mixed solvent is 1: 5～10.
In described mixed solvent, the volume ratio of methyl alcohol and tetrahydrofuran (THF) is 3～7: 1.
The consumption of gac step 1) is 0.1% of cefotiam hydrochloride crude product weight.
Step 3) in, stream adds step 2) stirring velocity during gained recrystallisation solvent is 880～1000r/min; Stirring velocity while dripping chloroform is 400～600r/min.
The speed that described stream adds is 10～15ml/min; The speed of described dropping is 3～7ml/min.
Alleged in the present invention " weight " unit be gram or kilogram, corresponding " volume " unit be milliliter or rises with it, when the weight unit of cefotiam hydrochloride crude product use is gram, in operating process, the volume unit of solvent is milliliter; When the weight unit of using when cefotiam hydrochloride crude product be kilogram, in operating process the volume unit of solvent for liter.
In the present invention, described methyl alcohol can be anhydrous methanol.
For realizing the 3rd object of the present invention, the present invention adopts following technical scheme:
, described pharmaceutical composition contains the cefotiam hydrochloride crystalline compounds that cefotiam hydrochloride crystalline compounds of the present invention or preparation method of the present invention make.
Pharmaceutical composition of the present invention also contains anhydrous sodium carbonate.
In described pharmaceutical composition, the mass ratio of cefotiam hydrochloride and anhydrous sodium carbonate is 80～90: 10～20, preferably 80～85: 15～20, and more preferably 83: 17.
Described pharmaceutical composition is that cefotiam hydrochloride crystalline compounds mixes by after aseptic subpackaged and makes sterilized powder by described mass ratio with anhydrous sodium carbonate.
Sterilized powder of the present invention can carry out packing by the specification of 0.25g/ bottle, 0.5g/ bottle, 1.0g/ bottle, 2.0g/ bottle etc.The specification is here in cefotiam, and 1g cefotiam is equivalent to 1.141g cefotiam hydrochloride.
Compared with prior art, tool of the present invention has the following advantages:
(1) cefotiam hydrochloride crystalline compounds purity provided by the present invention is high, and has good thermostability, and substantially non-hygroscopic;
(2) preparation method's technique of cefotiam hydrochloride provided by the present invention is simple, and yield is high, and repeatability is strong, is suitable for suitability for industrialized production;
(3) the pharmaceutical composition stability that contains this cefotiam hydrochloride crystalline compounds provided by the present invention is fine, thereby has improved drug safety and validity, has reduced the incidence of untoward reaction.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction figure of cefotiam hydrochloride crystalline compounds of the present invention.
Embodiment
Be below the specific embodiment of the present invention, described embodiment is in order to further describe the present invention, rather than restriction the present invention.
The preparation of [embodiment 1] cefotiam hydrochloride crystal
1) prepare crude product solution: it is in the formulated mixed solvent of the ratio of 5: 1 by methyl alcohol and tetrahydrofuran (THF) by volume that cefotiam hydrochloride crude product 200g is added to 1500ml, be stirred to dissolve, 0.1% the activated carbon decolorizing that adds cefotiam hydrochloride crude product weight, filter, obtain crude product solution, standby;
2) prepare recrystallisation solvent: by acetone and the ethyl acetate ratio of 2: 10 by volume preparation recrystallisation solvent, described recrystallisation solvent volume is 12 times of cefotiam hydrochloride crude product weight;
3) crystallization: under stirring, to step 1) in the crude product solution of gained, stream adds step 2) gained recrystallisation solvent, there is solid to separate out; After dropwising, continue under agitation to drip chloroform, to there being crystal to separate out; Standing 5h, filters, by methanol wash, dry, obtains described cefotiam hydrochloride compound.Yield 92%, the content that HPLC method is measured cefotiam is 87.8%, the content that size exclusive chromatography is measured high molecular polymer is 0.01%, m.p.=195～197 ℃.
The cefotiam hydrochloride crystalline compounds obtaining is measured by powder x-ray diffraction assay method, the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle locates to demonstrate characteristic diffraction peak at 5.9 °, 7.9 °, 9.3 °, 13.0 °, 13.6 °, 15.7 °, 16.8 °, 20.4 °, 25.7 °, 27.0 °, 30.9 ° and 32.9 °, as shown in Figure 1.
Be below embodiments of the invention 2-9, step is with embodiment 1, and concrete technology parameter is in Table 1:
Table 1, embodiment 2-9
The resulting cefotiam hydrochloride crystalline compounds of embodiment 2-9 crystalline compounds is measured by powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle is with embodiment 1.
[FORMULATION EXAMPLE 1] cefotiam hydrochloride aseptic powder injection
Specification:
Preparation method:
1, interior packaging material is processed
The technique cleaning routinely of antibiotic glass bottle, plug, aluminium lid, oven dry, sterilizing, standby;
2, concrete steps
(1) take anhydrous sodium carbonate and the prepared cefotiam hydrochloride crystal of embodiment 1 of recipe quantity, in sterile chamber, mix;
(2) product check in the middle of;
(3) by specification, undertaken aseptic subpackaged;
(4) vacuumize, tamponade, roll lid;
(5) packing, full inspection, warehouse-in.
[FORMULATION EXAMPLE 2] cefotiam hydrochloride aseptic powder injection
Specification:
Preparation method: with FORMULATION EXAMPLE 1, difference is that cefotiam hydrochloride used is the prepared cefotiam hydrochloride crystal of embodiment 2.
[FORMULATION EXAMPLE 3] cefotiam hydrochloride aseptic powder injection
Specification:
Preparation method: with FORMULATION EXAMPLE 1, difference is that cefotiam hydrochloride used is the prepared cefotiam hydrochloride crystal of embodiment 3.
[FORMULATION EXAMPLE 4] cefotiam hydrochloride aseptic powder injection
Specification:
Preparation method: with FORMULATION EXAMPLE 1, difference is that cefotiam hydrochloride used is the prepared cefotiam hydrochloride crystal of embodiment 4.
[FORMULATION EXAMPLE 5] cefotiam hydrochloride aseptic powder injection
Specification:
Preparation method: with FORMULATION EXAMPLE 1, difference is that cefotiam hydrochloride used is the prepared cefotiam hydrochloride crystal of embodiment 5.
[FORMULATION EXAMPLE 6] cefotiam hydrochloride aseptic powder injection
Specification:
Preparation method: with FORMULATION EXAMPLE 1, difference is that cefotiam hydrochloride used is the prepared cefotiam hydrochloride crystal of embodiment 6.
[FORMULATION EXAMPLE 7] cefotiam hydrochloride aseptic powder injection
Specification:
Preparation method: with FORMULATION EXAMPLE 1, difference is that cefotiam hydrochloride used is the prepared cefotiam hydrochloride crystal of embodiment 7.
Comparative example 1
Cefotiam hydrochloride is positioned in the process of depositing, and particularly, under the condition of high temperature (50 ℃ of >), degraded and polyreaction often occurs, thereby causes active constituents of medicine content to reduce, and color and luster is strengthened, and polymeric impurities content raises.This comparative example is for investigating the prepared cefotiam hydrochloride crystalline compounds of the present invention and the thermal stability difference of cefotiam hydrochloride of the prior art.
In this comparative example, each sample is numbered:
Trial target 1: the cefotiam hydrochloride crystalline compounds that the embodiment of the present invention 1 is prepared;
Trial target 2: the cefotiam hydrochloride crystalline compounds that the embodiment of the present invention 6 is prepared;
The method of reference substance 1:CN102190667A embodiment 1 is carried out the cefotiam hydrochloride after purifying to cefotiam hydrochloride;
The method of reference substance 2:CN101544662A embodiment 1 is carried out the cefotiam hydrochloride crystal after purifying to cefotiam hydrochloride.
By each sample be exposed to respectively that relative humidity is 75%, temperature is under the environment of 60 ℃, (high performance liquid chromatography and size exclusive chromatography are according to second of pharmacopeia in 2005 to adopt the content of cefotiam after high performance liquid chromatography test different time and the content that size exclusive chromatography is measured high molecular polymer, the relevant condition of appendix VD and appendix VH is measured), the results are shown in Table 2.
Table 2, thermostability comparative result
As can be seen from the above table, adopt the thermostability of the cefotiam hydrochloride crystalline compounds that method of the present invention makes to be significantly better than adopting the method for prior art to carry out the cefotiam hydrochloride crystal obtaining after purifying.
The cefotiam hydrochloride crystalline compounds of other FORMULATION EXAMPLE of the present invention has also been carried out to above-mentioned test, and the result of its acquisition is similar.
Comparative example 2
High wet test
This comparative example is processed the water absorbability difference of the cefotiam hydrochloride crystal obtaining for investigating the prepared cefotiam hydrochloride compound of the present invention and the purification process that adopts prior art.
The compound of sample 1-4 numbering representative is with comparative example 1.
Each sample opening is put in clean culture dish, the thin layer that spread out into≤5mm is thick, each two parts, put into respectively constant humidity encloses container, under 25 ℃ of conditions respectively at relative humidity 75% and 92.5%, place 10 days, in the 5th day and sampling in the 10th day, by the moisture content of each sample of weight loss on drying experiment measuring, test-results and comparison in 0 day, test-results is in Table 3.
Table 3, high humidity test-results
As can be seen from the above table, cefotiam hydrochloride crystalline compounds prepared by the present invention is substantially non-hygroscopic under high humidity, and its stability under high humidity environment is obviously better than adopting the purification process of prior art to process the cefotiam hydrochloride crystal obtaining.
The cefotiam hydrochloride crystalline compounds of other embodiment of the present invention has also been carried out to above-mentioned test, and the result of its acquisition is similar.
Comparative example 3
Stability test
By FORMULATION EXAMPLE 2 samples of preparation of the present invention and (Shanghai Xinxianfeng Pharmaceutical Co., Ltd.'s production of the cefotiam hydrochloride powder injection of listing, specification 1.0g/ bottle) under 60 ℃ of high temperature, illumination 4500Lx condition, place and within 10 days, carry out influence factor test investigation, the results are shown in Table 4; Under 40 ℃ of high temperature, relative humidity 75% ± 5% condition, place 6 months, carry out accelerated test investigation, the results are shown in Table 5; Under 25 ℃ of high temperature, relative humidity 60% ± 10% condition, place 18 months, carry out test of long duration investigation, detect the variation of every quality index, the results are shown in Table 6.
Table 4, influence factor result
Table 5, accelerated test result
Table 6, long-term test results
By found that above, accelerated test March, June, the cefotiam hydrochloride aseptic powder injection clarity that test of long duration was gone on the market when December, 18 months is against regulation, and pH value declines larger, and content reduces obviously, and related substance raises; And sample appearance proterties prepared by the present invention does not have considerable change, redissolve well, clarity, pH value, content and related substance significantly do not change yet.Illustrate that sample stable quality after long time storage prepared by the present invention is better.
The cefotiam hydrochloride aseptic powder injection of other FORMULATION EXAMPLE of the present invention has also been carried out to above-mentioned test, and the result of its acquisition is similar.
Claims (8)
1. a cefotiam hydrochloride crystalline compounds, it is characterized in that, the structural formula of described cefotiam hydrochloride crystalline compounds is as shown in formula I, and this crystalline compounds is measured by powder x-ray diffraction assay method, the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle is as Fig. 1
Formula I.
2. a preparation method for cefotiam hydrochloride crystalline compounds claimed in claim 1, is characterized in that, the method comprises the steps:
1) prepare crude product solution: cefotiam hydrochloride crude product is added by methyl alcohol and tetrahydrofuran (THF) with in the formulated mixed solvent of volume ratio 3～7:1, be stirred to dissolve, add activated carbon decolorizing, filter, obtain crude product solution, standby; Wherein, the weightmeasurement ratio of described cefotiam hydrochloride crude product and described mixed solvent is 1:5～10;
2) prepare recrystallisation solvent: by acetone and the ethyl acetate ratio preparation recrystallisation solvent of 1～3:10 by volume, described recrystallisation solvent volume is 6～15 times of cefotiam hydrochloride crude product weight;
3) crystallization: stirring velocity is under 880～1000r/min, adds step 2 to the data rate stream with 10～15ml/min in the crude product solution of step 1) gained) gained recrystallisation solvent, there is solid to separate out; After dropwising, continuing low whipping speed is that under 400～600r/min, the speed with 3～7ml/min drips chloroform, to there being crystal to separate out; Standing 3～6h, filters, by methanol wash, dry, obtains described cefotiam hydrochloride crystalline compounds.
3. a pharmaceutical composition, is characterized in that, described pharmaceutical composition contains cefotiam hydrochloride crystalline compounds claimed in claim 1.
4. pharmaceutical composition according to claim 3, is characterized in that, described pharmaceutical composition also contains anhydrous sodium carbonate.
5. pharmaceutical composition according to claim 4, is characterized in that, in described pharmaceutical composition, the mass ratio of cefotiam hydrochloride and anhydrous sodium carbonate is 80～90:10～20.
6. pharmaceutical composition according to claim 5, is characterized in that, in described pharmaceutical composition, the mass ratio of cefotiam hydrochloride and anhydrous sodium carbonate is 80～85:15～20.
7. pharmaceutical composition according to claim 6, is characterized in that, in described pharmaceutical composition, the mass ratio of cefotiam hydrochloride and anhydrous sodium carbonate is 83:17.
8. according to the pharmaceutical composition described in claim 5 or 6 or 7, it is characterized in that, described pharmaceutical composition is that cefotiam hydrochloride crystalline compounds mixes by after aseptic subpackaged and makes sterilized powder by described mass ratio with anhydrous sodium carbonate.
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| CN103232476B (en) * | 2013-04-25 | 2015-09-23 | 四川海思科制药有限公司 | A kind of antimicrobial compounds |
| CN105085548A (en) * | 2015-09-10 | 2015-11-25 | 青岛蓝盛洋医药生物科技有限责任公司 | Pharmaceutical cefotiam composition for treating infectious diseases |
| CN105125558A (en) * | 2015-09-18 | 2015-12-09 | 青岛华之草医药科技有限公司 | Antibacterial cefotiam hydrochloride drug composition |
| CN106420617A (en) * | 2016-09-21 | 2017-02-22 | 临沂草之美医药科技有限公司 | Medicine ceftibuten powder injection for treating surgical infection |
| CN106831822A (en) * | 2017-01-03 | 2017-06-13 | 浙江永宁药业股份有限公司 | A kind of cefotiam hydrochloride crystalline compounds and preparation method thereof |
| CN107383065A (en) * | 2017-07-14 | 2017-11-24 | 浙江永宁药业股份有限公司 | A kind of cefotiam chloride crystalline compounds and preparation method thereof |
| CN107383063B (en) * | 2017-07-14 | 2020-07-31 | 浙江永宁药业股份有限公司 | Novel crystal form of cefotiam hydrochloride and preparation method |
| CN109134506A (en) * | 2017-07-19 | 2019-01-04 | 宁应 | One water cefotiam hydrochloride compound of one kind and its pharmaceutical composition |
| CN109160924A (en) * | 2017-07-26 | 2019-01-08 | 海南美大制药有限公司 | Two water cefotiam hydrochloride compounds of one kind and its drug combination preparation |
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