CN109851627A - A kind of preparation method of Cefuroxime Sodium crystal-form compound - Google Patents
A kind of preparation method of Cefuroxime Sodium crystal-form compound Download PDFInfo
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- CN109851627A CN109851627A CN201811570762.XA CN201811570762A CN109851627A CN 109851627 A CN109851627 A CN 109851627A CN 201811570762 A CN201811570762 A CN 201811570762A CN 109851627 A CN109851627 A CN 109851627A
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- cefuroxime sodium
- form compound
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Abstract
The invention belongs to pharmaceutical technology fields, and in particular to the preparation method of Cefuroxime Sodium crystal-form compound.Cefuroxime Sodium crystal form samples of the invention can be obtained by following methods: Cefuroxime Sodium is scattered in water-containing organic solvent, after stirring a few hours within the scope of 40 DEG C to 65 DEG C, is filtered, dry, can obtain Cefuroxime Sodium crystal-form compound.Cefuroxime Sodium hygroscopicity prepared by the present invention is low, and stability is good, good fluidity, solves the problems such as existing Cefuroxime Sodium color change is fast, and stability is poor.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are related to a kind of preparation method of Cefuroxime Sodium crystal-form compound.
Technical background
Cefuroxime Sodium belongs to beta-lactam antibiotic, belongs to second generation cephalosporin class product, not only blue to leather
Family name's positive cocci has stronger antibacterial activity, and also has good antibacterial activity to certain gramnegative bacteriums.Cephalo furan
Pungent sodium in vivo not by liver metabolism, therefore to liver nontoxicity, so its medication is very safe.
Cefuroxime Sodium is developed by Ge Lansu company, is listed for the first time in Britain within 1978, then in Italy, Britain, method
State and China's successively listing.Currently, Cefuroxime Sodium in antibiotic market segment, still occupies a large amount of shares.
Cefuroxime Sodium chemical structure is as follows:
Cefuroxime Sodium thermal stability is poor, and especially domestic cefuroxime sodium raw materials crystal form controls poor, many commercial product
For indefiniteness Cefuroxime Sodium or mixed crystal product.Powder diffractogram (PXRD) data show that its characteristic peak is unobvious or disperse peak
More, differential scanning calorimetry spectrogram (DSC) is at 300 DEG C or less without obvious endothermic peak.The Cefuroxime Sodium hygroscopicity of indefiniteness is strong,
Stability is bad, and long-term color of placing becomes fast.
Chinese patent 201410814452.3 reports at 20-25 DEG C, cefuroxime acid methanol acetone mixed system
After dissolution, with methanol-sodium lactate system at sodium salt after, anti-analysis Solvents Solvent effect under, in 25 DEG C or less precipitation cefuroximes
Sodium.
Chinese patent 201410316953.9 is reported in 15 DEG C of low temperature or less cefuroxime acids and sodium carbonate, sodium bicarbonate
Etc. sodium sources react to obtain 0.25 hydrate of Cefuroxime Sodium, water content 1% or so.Although its compared with Cefuroxime Sodium anhydride,
Draw moist reduction, but it draws moist still larger, color change is still very fast in long-term placement process, and water content is still in obvious change
Change.
Chinese patent 201510611808.8 reports Cefuroxime Sodium crude product in the mixed of a certain proportion of water and cyclohexanol
In bonding solvent, heating dissolves Cefuroxime Sodium, and ethyl acetate is then added and is cooled to 15 DEG C or less crystallizations.What this method used
Cyclohexanol is at high cost, is not easy to remove, and dissolvent residual is a problem.
Summary of the invention
The purpose of the present invention is to provide a kind of easy to operate, mild condition, stirring turns crystalline substance and prepares cephalo under hot conditions
The method of cefuroxime sodium crystal compound, the crystal-form compound stability prepared is good, and good fluidity, color change is slow, draws moist
It is low.This method can make the Cefuroxime Sodium of indefiniteness or other mixed crystal be changed into target crystal-form compound.
Cefuroxime Sodium crystal-form compound of the present invention is measured using Cu-K alpha ray, obtained X-ray powder diffraction
Principal character peak is in 2 θ in figure are as follows: and 3.60 °, 10.17 °, 11.38 °, 13.47 °, 14.36 °, 19.11 °, 19.75 °, 20.33 °,
21.36 °, 22.80 °, 22.71 °, 23.67 °, 24.20 °, 25.36 °, 29.06 °, 29.80 °, 30.87 °, 32.57 °；The head
The Differential Scanning Calorimetry of spore cefuroxime sodium crystal compound has endothermic peak at 172 DEG C ± 2 DEG C；The cefuroxime sodium crystal
The water content of compound is 2% or so.
Cefuroxime Sodium crystal-form compound of the present invention is the preparation method is as follows: Cefuroxime Sodium is scattered in 10 times 98%
In ethyl alcohol, stirring turns 2 hours brilliant at 50 DEG C, filters while hot, dry to get Cefuroxime Sodium crystal-form compound.
The preparation method of Cefuroxime Sodium crystal-form compound described in above-mentioned steps, Cefuroxime Sodium is insoluble and disperses
In 2-50 times of water-containing organic solvent, within the scope of 45 DEG C~65 DEG C, stirring turns crystalline substance 0.5-6h, obtains Cefuroxime Sodium crystal form chemical combination
Object；The organic solvent be mainly methanol, ethyl alcohol, isopropanol, isobutanol, normal propyl alcohol, n-butanol, acetone, in tetrahydrofuran
The mixture of one or more of arbitrary proportions；The water content is 1.8%~4%；The mixing time is 0.5~5h；
Described turn of brilliant temperature is 40 DEG C~65 DEG C.Turn brilliant temperature and be lower than 40 DEG C, turn brilliant effect is poor, with indefiniteness or unstable mixing crystal form
Based on.
Present invention has an advantage that providing a kind of easy to operate, mild condition, high temperature turns brilliant cefuroxime sodium crystal
The method of compound, using the Cefuroxime Sodium crystal-form compound of this method preparation in mobility, stability aspect and existing state
Producing Cefuroxime Sodium and comparing has greater advantage, and the Cefuroxime Sodium crystal-form compound low in hygroscopicity, crystallinity is high, raw to preparation
It is low to produce workshop requirement, facilitates production.
Detailed description of the invention
Attached drawing 1: Cefuroxime Sodium crystal-form compound PXRD figure
Attached drawing 2: the resulting Cefuroxime Sodium PXRD figure of document registration method
Attached drawing 3: Cefuroxime Sodium crystal-form compound differential scanning calorimetry (DSC) map；
Attached drawing 4: the resulting Cefuroxime Sodium DSC figure of document registration method
Specific embodiment
Below with reference to embodiment to the detailed description of the invention.Following embodiment will be helpful to those skilled in the art and further manage
The solution present invention, but the invention is not limited in any way.It should be pointed out that for the spectrogram technique personnel of this field,
Under the premise of not departing from present inventive concept, several adjustment and improvement can also be made, these belong to protection category of the invention.
Cefuroxime Sodium crystal-form compound powder diffraction spectrum of the invention is detailed in attached drawing 1；Cefuroxime Sodium of the invention
Crystal-form compound DSC map is detailed in attached drawing 3；Cefuroxime Sodium crystal-form compound draws wet situation, and see Table 1 for details；Cefuroxime sodium crystal
Compound keeps sample, and see Table 2 for details for steadiness.
The preparation of 1 Cefuroxime Sodium crystal-form compound of embodiment
10g Cefuroxime Sodium is scattered in 98% ethyl alcohol of 50ml, is heated to 45 DEG C, is stirred 2h, is filtered while hot, and 40 DEG C true
The dry 4h of sky, yield 99.3%, water content 2.09%.
The preparation of 2 Cefuroxime Sodium crystal-form compound of embodiment
100g Cefuroxime Sodium is scattered in 98% methanol of 1000ml, is heated to 50 DEG C, is stirred 1.5h, is filtered while hot, 40
DEG C vacuum drying 4h, yield 96.3%, water content 2.07%.
The preparation of 3 Cefuroxime Sodium crystal-form compound of embodiment
100g Cefuroxime Sodium is scattered in 98% acetone of 800ml, is heated to 40 DEG C, is stirred 2h, is filtered while hot, 40 DEG C
It is dried in vacuo 4h, yield 99.1%, water content 2.07%.
The preparation of 4 Cefuroxime Sodium crystal-form compound of embodiment
100g Cefuroxime Sodium is scattered in 98.5% isopropanol of 1200ml, is heated to 65 DEG C, is stirred 4h, is filtered while hot,
40 DEG C of vacuum drying 4h, yield 99.5%, water content 2.05%.
The preparation of 5 Cefuroxime Sodium crystal-form compound of embodiment
50g Cefuroxime Sodium is scattered in 96% tetrahydrofuran of 1000ml, is heated to 50 DEG C, is stirred 6h, is filtered while hot,
40 DEG C of vacuum drying 4h, yield 98.4%, water content 1.99%.
The preparation of 6 Cefuroxime Sodium crystal-form compound of embodiment
10g Cefuroxime Sodium is scattered in 98% ethyl alcohol of 100ml, is heated to 65 DEG C, is stirred 3h, is filtered while hot, and 40 DEG C true
The dry 4h of sky, yield 98.8%, water content 1.98%.
The preparation of 7 Cefuroxime Sodium crystal-form compound of embodiment
100g Cefuroxime Sodium is scattered in 96% isobutanol of 1200ml, is heated to 55 DEG C, is stirred 4h, is filtered while hot, 40
DEG C vacuum drying 4h, yield 98.0%, water content 2.00%.
The preparation of 8 Cefuroxime Sodium crystal-form compound of embodiment
10g Cefuroxime Sodium is scattered in 98% ethyl alcohol of 50ml, is heated to 45 DEG C, is stirred 2h, is filtered while hot, and 40 DEG C true
The dry 4h of sky, yield 99.1%, water content 2.00%.
The preparation of 9 Cefuroxime Sodium crystal-form compound of embodiment
10g Cefuroxime Sodium is scattered in the mixed solution of 98% ethyl alcohol of 50ml and methanol, is heated to 50 DEG C, stirs 5h,
It filters while hot, 40 DEG C of vacuum drying 4h, yield 97.2%, water content 1.99%.
The preparation of 10 Cefuroxime Sodium crystal-form compound of embodiment
50g Cefuroxime Sodium is scattered in the mixed solution of 98% acetone of 1000ml and methanol, is heated to 50 DEG C, stirring
4h is filtered while hot, 40 DEG C of vacuum drying 4h, yield 97.7%, water content 2.03%.
The preparation of 11 Cefuroxime Sodium crystal-form compound of embodiment
50g Cefuroxime Sodium is scattered in the mixed solution of 98.5% normal propyl alcohol of 1000ml and methanol, is heated to 50 DEG C,
3h is stirred, is filtered while hot, 40 DEG C of vacuum drying 4h, yield 98.7%, water content 2.05%.
The preparation of 12 Cefuroxime Sodium crystal-form compound of embodiment
50g Cefuroxime Sodium is scattered in the mixed solution of 96% n-butanol of 5000ml and acetone, is heated to 55 DEG C, is stirred
4h is mixed, is filtered while hot, 40 DEG C of vacuum drying 4h, yield 99.3%, water content 2.08%.
Table 1, Cefuroxime Sodium crystal-form compound draw wet situation summary sheet under the conditions of 25 DEG C, RH 75%
Table 2, Cefuroxime Sodium crystal-form compound keep sample steadiness summary sheet
| Keep sample condition | Cefuroxime Sodium crystal-form compound | Domestic commercially available Cefuroxime Sodium |
| 50℃5d | < Y2 | Y4 |
| 50℃10d | < Y3 | < Y5 |
| 60℃5d | < Y4 | Y6 |
| 60℃10d | < Y4 | Y7 |
| 40℃1M | < Y2 | Y3 |
| 40℃2M | Y2 | < Y4 |
| 40℃3M | Y3 | Y4 |
Cefuroxime Sodium crystal-form compound of the present invention is measured using Cu-K alpha ray, in obtained X-ray powder diffraction figure
Principal character peak is in 2 θ are as follows: and 3.60 °, 10.17 °, 11.38 °, 13.47 °, 14.36 °, 19.11 °, 19.75 °, 20.33 °,
21.36 °, 22.80 °, 22.71 °, 23.67 °, 24.20 °, 25.36 °, 29.06 °, 29.80 °, 30.87 °, 32.57 °；The head
The Differential Scanning Calorimetry of spore cefuroxime sodium crystal compound has endothermic peak at 172 DEG C ± 2 DEG C；The cefuroxime sodium crystal
The water content of compound is 2% or so.
Claims (7)
1. the preparation method of Cefuroxime Sodium crystal-form compound, it is characterised in that: Cefuroxime Sodium is dispersed in aqueous C1-C4It is low
Grade alcohol, aqueous acetone, water-containing tetrahydrofuran one or more of arbitrary proportions mixing organic solvent in, in 40 DEG C of -65 DEG C of models
In enclosing, stirring turns a 0.5~6h of crystalline substance, filters while hot, dry Cefuroxime Sodium crystalline compounds.
2. according to claim 1, it is characterised in that in the step, organic solvent C1-C4Lower alcohol is methanol, ethyl alcohol, isopropyl
Alcohol, isobutanol, normal propyl alcohol, n-butanol, water are 1.8%~4%.
3. according to claim 2, it is characterised in that in the step, organic solvent is ethyl alcohol.
4. according to claim 1, it is characterised in that in the step, the temperature is 40 DEG C -65 DEG C.
5. according to claim 4, it is characterised in that in the step, the temperature is 50 DEG C -55 DEG C.
6. according to claim 1, it is characterized in that the water content of organic solvent is 1.8%~4%.
7. according to claim 1, it is characterised in that in the step, mixing time is 1.5~4 hours.
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