CN103467493B - The preparation method of ampicillin anhydrous - Google Patents
The preparation method of ampicillin anhydrous Download PDFInfo
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- CN103467493B CN103467493B CN201310484718.8A CN201310484718A CN103467493B CN 103467493 B CN103467493 B CN 103467493B CN 201310484718 A CN201310484718 A CN 201310484718A CN 103467493 B CN103467493 B CN 103467493B
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Abstract
The present invention relates to the preparation method of ampicillin anhydrous, it is characterized in that comprising following step: 1. add dehydration solvent by under Ampicillin Trihydrate three water acid whipped state, be warming up to 55-65 DEG C, be incubated and be cooled to 30-40 DEG C after 30-40 minute; 2. be separated, be more again separated with after the washing of washing solvent; 3. vacuum-drying: drying temperature 45-50 DEG C, vacuum tightness is greater than-0.075MPa, time of drying 40-60 minute; Described dehydration solvent is the one in anhydrous methanol, the ethanol of moisture 0-4wt% or the Virahol of moisture 0-13wt%.Present method be used for ampicillin anhydrous have not only safe and effective, the advantage that stability is high, and because of solvent be easy to reclaim, whole technique is had, and cost is low, the technique effect of good economy performance.
Description
Technical field
The present invention relates to technical field of medicine preparation, specifically a kind of preparation method of ampicillin anhydrous.
Technical background
Ampicillin anhydrous is that the important of Ampicillin Sodium For Injection bulk drug prepares precursor, so the fine or not direct relation of ampicillin anhydrous quality drug quality and the safety of Ampicillin Sodium For Injection.Current commercial anhydrous Ampicillin Trihydrate product many employings inorganic salt drying process, it is thorough to there is dehydration in product, and moisture content is up to 1%, and heavy metal ion such as easily to exceed standard at the problem, has a strong impact on the quality and safety of medicine intermediate ampicillin anhydrous; And this kind of technique easily causes production scene to pile up dirty and messy situation, itself and new edition GMP is caused to require to contradict.
Summary of the invention
Object of the present invention is exactly the preparation method that will provide a kind of ampicillin anhydrous, to guarantee to demonstrate,prove quality product, simplifies the operation course, and makes production technique be easier to control.
The object of the present invention is achieved like this:
The preparation method of ampicillin anhydrous comprises following step:
1. add dehydration solvent by under Ampicillin Trihydrate three water acid whipped state, be warming up to 55-65 DEG C, be incubated and be cooled to 30-40 DEG C after 30-40 minute;
2. be separated, be more again separated with after the washing of washing solvent;
3. vacuum-drying: drying temperature 45-50 DEG C, vacuum tightness is greater than-0.075MPa, time of drying 40-60 minute;
Described dehydration solvent is the one in anhydrous methanol, the ethanol of moisture 0-4wt% or the Virahol of moisture 0-13wt%.
The water acid of described Ampicillin Trihydrate three is 20-35kg: 100L with the feed ratio of described dehydration solvent.
1. described the be preferably warming up to 55-60 DEG C in step.
Described washing solvent is acetone.
Present method has broken traditional dewatering type, adopt solvent to be total to heat to control to reach the intermolecular crystal water in removing Ampicillin Trihydrate by temperature, the ampicillin anhydrous dehydration that this kind of technique obtains thoroughly, the white needle-like crystals of formation rule, compared with the unformed powdered anhydrous Ampicillin Trihydrate purchased on the market, have that soluble, salify speed is fast, the advantage of stable in properties, thus improve security and the stability of the ampicillin anhydrous of medicine intermediate; In addition as the crystal having certain solid form, be more conducive to packing, solve unformed powder is difficult to packing problem because electrostatic interaction causes being easy to disperse.Present method technique is simple, strong adaptability, to external world conditional request low (as humiture etc.), and easy to operate, and production scene is regular, is beneficial to large-scale production.In addition, present method be used for ampicillin anhydrous not only have safe and effective, the advantage that stability is high, and because of solvent be easy to reclaim, whole technique is had, and cost is low, the technique effect of good economy performance.
Accompanying drawing explanation
Fig. 1 is the Liquid Detection data of the made sample of the embodiment of the present invention 2.
Fig. 2 is the Liquid Detection data of the made sample of the embodiment of the present invention 5.
Fig. 3 is the crystalline form photo of the made sample of the embodiment of the present invention 2.
Embodiment
Embodiment 1
The preparation method of ampicillin anhydrous is as follows:
1. in enamel pot, add Ampicillin Trihydrate three water acid 300kg stir, then add 1000L recovery Virahol (moisture 13wt%) mixing;
2. above-mentioned enamel pot is heated to 50 DEG C in water-bath, and reflux stirs 40 minutes; Logical cold water is cooled to room temperature, centrifugation; By the centrifugal solid acetone washing by soaking obtained about 3 minutes, continue centrifugal compacting;
3. the dry 40-60 minute of hollow, temperature controls at 45-50 DEG C, and vacuum tightness <-0.075MPa, period is stirred 1-2 time.
Embodiment 2
Basic technology is with embodiment 1, and difference is the 2. heating in water bath to 55 DEG C in step.
Embodiment 3
Basic technology is with embodiment 1, and difference is the 2. heating in water bath to 60 DEG C in step.
Embodiment 4
Basic technology is with embodiment 1, and difference is the 2. heating in water bath to 65 DEG C in step.
Embodiment 1-4 dehydrating effect test data
| Group | Dehydration temperaturre | Dewatering time | Time of drying | Mode of washing | Moisture content |
| Embodiment 1 | 50℃ | 30 minutes | 40 minutes | Washing with acetone | 13.13％ |
| Embodiment 2 | 55℃ | 30 minutes | 40 minutes | Washing with acetone | 0.15％ |
| Embodiment 3 | 60℃ | 30 minutes | 40 minutes | Washing with acetone | 0.18％ |
| Embodiment 4 | 65℃ | 30 minutes | 40 minutes | Washing with acetone | 0.25％ |
This technique dehydration temperaturre all can complete dehydration more than 55 DEG C.As can be seen from above-mentioned test data, dehydration temperaturre can be low to 0.15% to 0.3% 55 DEG C of-65 DEG C of dehydration rates.
Embodiment 5
Basic technology is with embodiment 1, and difference is the 2. heating in water bath to 70 DEG C in step.
By liquid phase tracing detection embodiment 2 and the made sample of embodiment 5, investigating 55 DEG C and 70 DEG C of two kinds of dehydration temperaturres affects situation for ampicillin anhydrous impurity:
According to Liquid Detection data analysis: under 55 DEG C of conditions, the percentage composition of ampicillin anhydrous is greater than 99.3%, under 70 DEG C of conditions, the percentage composition of ampicillin anhydrous is about is 98.9%.Two impurity peaks wherein changed greatly are respectively the closed loop dipolymer peak of 26 minutes and the open loop trimer peak of 31.5 minutes.(major effect Ampicillin Trihydrate is anaphylactoid is exactly polymkeric substance, comprises dipolymer and trimer, and the change of other impurity is not obvious, all about 5/10000ths, can ignore) concrete data are shown in Fig. 1 and Fig. 2.
| Impurity (percentage composition) | 55℃ | 70℃ |
| 26 minutes dipolymers | 0.05 | 0.09 (about twice) |
| 31 minutes trimers | 0.06 | 0.12 (about twice) |
Embodiment 6
1. in enamel pot, add Ampicillin Trihydrate three water acid 300kg stir, then add the ethanol mixing of the moisture 4wt% of 1000L;
2. pass into hot water thermal to 55-60 DEG C in above-mentioned enamel pot coil pipe, reflux stirs 40 minutes; Logical cold water is cooled to room temperature, centrifugation; By the centrifugal solid acetone washing by soaking obtained about 3 minutes, continue centrifugal compacting;
3. the empty dry 40-60 minute of vacuum, temperature controls at 45-50 DEG C, and vacuum tightness is higher than-0.075MPa, and period is stirred 1-2 time.
Embodiment 7
Basic technology is with embodiment 6, and difference is the ethanol of the moisture 4wt% in the 1. step to replace with dehydrated alcohol.
Embodiment 8
Basic technology is with embodiment 6, and difference is the ethanol of the moisture 4wt% in the 1. step to replace with anhydrous methanol.
Embodiment 9
Basic technology is with embodiment 6, and difference is the ethanol of the moisture 4wt% in the 1. step to replace with anhydrous isopropyl alcohol.
Embodiment 10
Basic technology is with embodiment 6, and difference is that the ethanol by the moisture 4wt% in the 1. step replaces with the Virahol of moisture 8wt%.
Embodiment 6-10 dehydrating effect test data
According to European Pharmacopoeia 6.0 requirement, ampicillin anhydrous water content is not higher than 2%.
Claims (2)
1. a preparation method for ampicillin anhydrous, is characterized in that comprising following step:
1. add dehydration solvent by under Ampicillin Trihydrate three water acid whipped state, be warming up to 55-65 DEG C, be incubated and be cooled to 30-40 DEG C after 30-40 minute;
2. be separated, be more again separated with after the washing of washing solvent;
3. vacuum-drying: drying temperature 55-60 DEG C, vacuum tightness is greater than-0.075MPa, time of drying 40-60 minute;
Described dehydration solvent is the one in the ethanol of moisture 4wt% or the Virahol of moisture 0-13wt%; Described washing solvent is acetone.
2. the preparation method of ampicillin anhydrous according to claim 1, is characterized in that,
The water acid of described Ampicillin Trihydrate three is 25-35kg: 100L with the feed ratio of described dehydration solvent.
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104059085B (en) * | 2014-06-19 | 2016-04-13 | 河南牧翔动物药业有限公司 | A kind of Ampicillin Trihydrate crystal and preparation method thereof |
| CN104961748B (en) * | 2015-05-22 | 2017-03-01 | 华北制药集团先泰药业有限公司 | A kind of method of residual dichloromethane level in reduction ampicillin |
| CN115448930A (en) * | 2022-09-02 | 2022-12-09 | 国药集团威奇达药业有限公司 | Process for preparing ampicillin sodium |
| CN115850298A (en) * | 2022-11-29 | 2023-03-28 | 华北制药集团先泰药业有限公司 | Ampicillin sodium raw powder and preparation method thereof |
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| WO1999020786A1 (en) * | 1997-10-17 | 1999-04-29 | Dsm N.V. | PROCESS FOR THE PREPARATION OF A β-LACTAM ANTIBIOTIC |
| CN1666990A (en) * | 2004-03-12 | 2005-09-14 | 河北张药股份有限公司 | Process for preparing ampicillin sodium |
| CN101486717A (en) * | 2008-12-05 | 2009-07-22 | 华北制药股份有限公司 | Method for preparing ampicillin sodium |
| CN101723957A (en) * | 2008-10-24 | 2010-06-09 | 华北制药股份有限公司 | Method for preparing ampicillin sodium salt |
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2013
- 2013-10-16 CN CN201310484718.8A patent/CN103467493B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999020786A1 (en) * | 1997-10-17 | 1999-04-29 | Dsm N.V. | PROCESS FOR THE PREPARATION OF A β-LACTAM ANTIBIOTIC |
| CN1666990A (en) * | 2004-03-12 | 2005-09-14 | 河北张药股份有限公司 | Process for preparing ampicillin sodium |
| CN101723957A (en) * | 2008-10-24 | 2010-06-09 | 华北制药股份有限公司 | Method for preparing ampicillin sodium salt |
| CN101486717A (en) * | 2008-12-05 | 2009-07-22 | 华北制药股份有限公司 | Method for preparing ampicillin sodium |
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| 氨苄西林钠溶析结晶的工艺研究;李润妍，等;《中国抗生素杂志》;20110930;第36卷(第9期);第676-679页 * |
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