CN1597684A - Sodium ceftriaxone and its preparation method - Google Patents
Sodium ceftriaxone and its preparation method Download PDFInfo
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- CN1597684A CN1597684A CN 03156952 CN03156952A CN1597684A CN 1597684 A CN1597684 A CN 1597684A CN 03156952 CN03156952 CN 03156952 CN 03156952 A CN03156952 A CN 03156952A CN 1597684 A CN1597684 A CN 1597684A
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- sodium
- ceftriaxone
- rate
- natrium
- ceftriaxone sodium
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Abstract
A ceftriaxone sodium with low relative combining rate to HSA (lower than 60%) is prepared from ceftriazone through adding sodium transferring agent, crystallizing, separating and drying.
Description
Invention field
The present invention relates to chemical pharmacy field, particularly, the present invention relates to a kind of and low, fast onset ceftriaxone sodium of the relative combination rate of human serum albumin (HSA) and preparation method thereof.
Background technology
Ceftriaxone for inj is the disodium salt of ceftriaxone, is microbiotic long-acting, wide spectrum, belongs to the third generation cephalosporin class, and gram-negative bacteria and gram positive organism are had very strong germicidal action, has in the serum characteristics such as long half time.It mainly has fungicidal activity by suppressing the synthetic of cell walls, and β-Nei Xiananmei (penicillinase and cephalosporinase) is had very high stability.Ceftriaxone for inj has following structural formula:
Ceftriaxone sodium is usually to following pathogenic bacterium performance germicidal action:
Enterobacteriaceae lactobacteriaceae there is powerful activity.MIC to escherichia coli, Klebsiella Pneumoniae, enteroaerogen, fluorine labor ground citrobacter, the positive Bacillus proteus of indoles, Pu Luweideng Pseudomonas and Serratia
90Between 0.12～0.25mg/L.Enterobacter cloacae, acinetobacter and Pseudomonas aeruginosa are poor to the susceptibility of ceftriaxone sodium.Hemophilus influenzae, Diplococcus gonorrhoeae and Neisseria meningitidis there are strong anti-microbial effect, Hemolytic streptococcus and streptococcus pneumoniae are also had good action.MIC to streptococcus aureus is 2～4mg/L.Methicillin-resistant staphylococcus and faecalis are to the ceftriaxone sodium resistance.Most bacteroides fragiliss are to ceftriaxone sodium also resistance.Ceftriaxone sodium can extensively be distributed in each tissue and the body fluid (heart, lung, liver, biliary tract, tonsilla body, middle ear, nasal mucosa, bone, cerebrospinal fluid, Pleural fluid, prostate gland and synovial membrane liquid etc.).
Ceftriaxone sodium reversibility ground and albumin bound, its combination rate increases and reduces with the concentration of ceftriaxone sodium, and for example, when the Plasma Concentration of＜100mg/L, protein binding rate is 95%, and when the Plasma Concentration of 300mg/L, protein binding rate then is 85%.However, ceftriaxone sodium is compared with other cephalosporins medicines, and protein binding rate is still higher, and apparent volume of distribution, plasma clearance, renal clearance are low.Therefore, in order effectively to control severe infection, adopt usually and improve the serum drug total concn clinically, in the hope of reducing the way of serum albumin combination rate, for example take 2 administrations every day, strengthen dosage or first dose and give way such as big lifting capacity and improve curative effect.
The inventor finds, when the preparation ceftriaxone sodium, hydrogenion concentration value by regulator solution, control adds the sodium transforming agent amount in the ceftriaxone solution, the natrium transgenic rate of control ceftriaxone, crystallization and the ceftriaxone sodium and the relative combination rate of human serum albumin (HSA)＜60% that obtain, and rapid-action, therefore finished the present invention.
Goal of the invention
The purpose of this invention is to provide and a kind ofly be lower than 60% ceftriaxone sodium with the relative combination rate of human serum albumin (HSA), and rapid-action.
Another object of the present invention provides the preparation method of above-mentioned ceftriaxone sodium.
Detailed Description Of The Invention
Existing ceftriaxone sodium is owing to the protein binding rate height, though can reach long lasting effect, free Plasma Concentration is low, and is fast inadequately to treatment moderate and severe infection onset.In order to improve result of treatment, according to the ceftriaxone sodium pharmacological property, the general employing reduced plasma protein binding ratio, the free Plasma Concentration method of raising, promptly rationally strengthens dosage, extends the period of treatment, and the clinical treatment expense is big.The present invention is by making a kind of and the low ceftriaxone sodium of the relative combination rate of human serum albumin (HSA), make ceftriaxone sodium and the relative combination rate of human serum albumin (HSA) be controlled at OK range about 55%, under same dose, improved free Plasma Concentration and reached rapid-action purpose, medical expense is little.
The inventor has studied hydrogen ion concentration to the influence of ceftriaxone sodium with the relative combination rate of HSA at the external capillary electrophoresis that utilizes.Adopting hydrogen ion concentration respectively is 3.16 * 10
-7, 1.0 * 10
-7, 3.98 * 10
-8, 1.99 * 10
-8The phosphate buffered saline buffer of mol/L, to contain the 0.03mg/ml ceftriaxone sodium is running buffer with above-mentioned phosphate buffered saline buffer respectively, with the phosphate buffered saline buffer that contains 0.025mmol/LHSA as sample solution, measure the relative combination rate (R) of ceftriaxone sodium and HSA, with the investigation hydrogen ion concentration to the influence of ceftriaxone sodium with the relative combination rate of HSA.Found that the damping fluid hydrogen ion concentration is by 1.99 * 10
-8Mol/L is raised to 3.16 * 10
-7Mol/L, protein binding rate rises to 76% (seeing Table 1) by 51% relatively.Illustrate that ceftriaxone sodium increases along with the rising of environment hydrogen ion concentration with the relative combination rate of HSA.
Table 1 damping fluid hydrogen ion concentration is to the influence of the relative combination rate with HSA of ceftriaxone sodium (R)
Hydrogen ion concentration
3.16×10
-7???1.0×10
-7???3.98×10
-8???1.99×10
-8
(mol/L)
R(％)?????????76????????????66???????????57????????????51
The inventor discovers, the ceftriaxone sodium of different natrium transgenic rates is because the difference on the molecular structure, and it is about 10% that the relative combination rate difference of albumen, maximum differ, and affects the pharmacological action speed of ceftriaxone sodium.By discussion, find that it reduces along with the reduction of rising of medicine natrium transgenic rate and hydrogen ion concentration with the relative combination rate of human serum albumin (HSA) to ceftriaxone sodium and protein binding mechanism.
In making ceftriaxone disodium salt process, must guarantee to have the sodium ion of 2 molecules and the ceftriaxone of 1 molecule to react.As it is on the low side to change the sodium transforming agent amount that adds in the sodium process, then the volumetric molar concentration of sodium ion and the ratio of the volumetric molar concentration of ceftriaxone are less than 2, the actual commentaries on classics of ceftriaxone sodium amount and the theoretical ratio (natrium transgenic rate) that changes the sodium amount are less than 99.5%, and then product is higher with the relative combination rate of HSA.The ratio of sodium ion and ceftriaxone and the relation of natrium transgenic rate and the relative combination rate of HSA albumen see Table 2 and accompanying drawing 1, shown that ceftriaxone sodium and the relative combination rate of HSA are subjected to the influence of sodium transforming agent amount, so the molar ratio of sodium ion and ceftriaxone answers the strictness to be controlled to be 2: 1 in the product.
The molar ratio of table 2. sodium ion and ceftriaxone and hydrogen ion concentration
And the relation of the relative combination rate of HSA albumen
Sodium ion and ceftriaxone hydrogen ion concentration
R(％)
Molar ratio (mol/L)
1??????2.27????????????????????3.16×10
-8????????53
2??????2.10????????????????????1.0×10
-7?????????54
3??????2.00????????????????????1.58×10
-7????????54
4??????1.97????????????????????3.16×10
-7????????58
5??????1.90????????????????????3.98×10
-7????????63
6??????1.85????????????????????1.0×10
-6?????????70
Technical scheme of the present invention is to change in the sodium process at ceftriaxone, adds sodium transforming agent, and control ceftriaxone natrium transgenic rate (the actual commentaries on classics of ceftriaxone sodium amount and the theoretical ratio that changes the sodium amount) makes ceftriaxone commentaries on classics sodium complete, crystallization and getting.Wherein sodium transforming agent is meant organic or inorganic soda or their mixtures such as sodium acetate, Sodium isooctanoate, sodium hydroxide, yellow soda ash, sodium bicarbonate.
Its complete reaction feature be through change sodium completely ceftriaxone sodium water solution hydrogenion concentration value scope be 3.16 * 10
-7～3.16 * 10
-8Mol/L, natrium transgenic rate is greater than 99.5%.The ceftriaxone sodium that the present invention makes external with the relative combination rate of human serum albumin (HSA)＜60%.
The ceftriaxone sodium of a kind of and the relative combination rate of human serum albumin (HSA)＜60% of the present invention can be used as the medicine of activeconstituents, and it is fast to be used for clinical onset of action speed.
The present invention is by adding sodium transforming agent, and the hydrogenion concentration value of control ceftriaxone sodium water solution is 3.16 * 10
-7～3.16 * 10
-8Mol/L makes the ceftriaxone natrium transgenic rate greater than 99.5%, and it is complete to change sodium, and crystallization separates, drying, must with the low ceftriaxone sodium of the relative combination rate of human serum albumin (HSA), constant product quality, the easy easy control of manufacturing process helps applying.
Description of drawings
Accompanying drawing 1 is the ceftriaxone natrium transgenic rate and the relation of the relative combination rate of HSA albumen
Embodiment
Further specify the present invention below by embodiment.It should be understood that embodiments of the invention are to be used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the improvement that the present invention carries out.Except as otherwise noted, the percentage ratio among the present invention is weight percentage, and solution is meant the aqueous solution.
Embodiment one
Under the normal temperature, in there-necked flask, drop into 5 gram ceftriaxones, add 85 milliliters water, and Na
2CO
31.1 gram, dissolving is stirred 45 minutes to reacting completely, and filters, and regulating the filtrate hydrogen ion concentration with 1mol/LNaOH is 7.94 * 10
-8Mol/L adds 400 milliliters of acetone crystallizatioies, and suction filtration with 50 milliliters of washing with acetones 2 times, is drained, drying under reduced pressure, ceftriaxone sodium 4.3 grams, measure its natrium transgenic rate 100.3%.
The sodium ions content of solution can be measured according to present technique field common method, and natrium transgenic rate is to remove the theoretical value gained with the sodium ions content of measuring.
Embodiment two
Under the normal temperature, in there-necked flask, drop into 5 gram ceftriaxones, add 85 milliliters water and Na
2CO
30.97 gram, dissolving was stirred 10 minutes, filtered, and measuring the filtrate hydrogen ion concentration is 6.3 * 10
-7Mol/L adds 400 milliliters of acetone crystallizatioies, and suction filtration with 50 milliliters of washing with acetones 2 times, is drained, drying under reduced pressure, ceftriaxone sodium 4.5 grams, measure its natrium transgenic rate 91.1%.
Embodiment one is pressed in the calculating of natrium transgenic rate.
Embodiment three different mensuration of changeing the relative combination rate of ceftriaxone sodium (R), solution hydrogen ion concentration and the stability of sodium degree with HSA.
It is an amount of to get the ceftriaxone sodium that embodiment one and two makes respectively, is solution (0.045mmol/L) 50ml that 7.4 phosphate buffered saline buffer is made into 0.03mg/ml with pH.
As running buffer, as sample solution, measure the relative combination rate (R) of ceftriaxone sodium and HSA with above-mentioned ceftriaxone sodium damping fluid with the phosphate buffered saline buffer that contains 0.025mmol/L HSA.
Press two methods of Pharmacopoeia of the People's Republic of China version in 2000, it is an amount of to get the ceftriaxone sodium that embodiment one and two makes respectively, adds water and makes the solution that contains 0.1 gram in per 1 milliliter approximately, measures the hydrogenion concentration value of its aqueous solution.
The result is as shown in the table:
Table 3: different relative combination rate of ceftriaxone sodium (R) and the solution hydrogen ions that change the sodium degree with HSA
The measurement result of concentration
| Embodiment | One | Two |
| Change sodium state (%) | ??100.3 | ??91.1 |
| ??R(％) | ??56 | ??63 |
| The solution hydrogen ion concentration | ??1.26×10 -7mol/L | ??5.01×10 -7mol/L |
This shows that the relative combination rate of ceftriaxone sodium and HSA is relevant with the commentaries on classics sodium state of ceftriaxone, it is incomplete that ceftriaxone changes sodium, and solution hydrogen ion concentration height raises with the relative combination rate of albumen of HSA.The reserved sample observing result shows that the ceftriaxone sodium stability difference of different commentaries on classics sodium degree is little.
Table 4: the different ceftriaxone sodium reserved sample observing results that change the sodium degree
| Sequence number | Keep sample the time (moon) | Outward appearance | The solution color and luster | Clarity | Content | Natrium transgenic rate (%) |
| Embodiment one | ????0 | White crystalline powder | No. 4,＜yellow-green colour | ＜0.5 | ????92.7 | 100.3 |
| ????6 | White crystalline powder | No. 4,＜yellow-green colour | ＜0.5 | ????92.4 | ||
| ????12 | White crystalline powder | No. 4,＜yellow-green colour | ＜0.5 | ????92.15 | ||
| ????18 | White crystalline powder | No. 5,＜yellow-green colour | ＜0.5 | ????91.9 | ||
| ????24 | White crystalline powder | No. 5,＜yellow-green colour | ＜0.5 | ????91.8 | ||
| Embodiment two | ????0 | White crystalline powder | No. 4,＜yellow-green colour | ＜0.5 | ????92.2 | 91.1 |
| ????6 | White crystalline powder | No. 4,＜yellow-green colour | ＜0.5 | ????92.0 | ||
| ????12 | White crystalline powder | No. 4,＜yellow-green colour | ＜0.5 | ????91.8 | ||
| ????18 | White crystalline powder | No. 5,＜yellow-green colour | ＜0.5 | ????91.2 | ||
| ????24 | White crystalline powder | No. 5,＜yellow-green colour | ＜0.5 | ????91.3 |
Embodiment four
Under the normal temperature, in reaction flask, add 50 milliliters CH
2Cl
2, dropping into 5 gram 7-ACT, active thioester 4.7 grams stirred 120 minutes, added 4.6 gram NaHCO
3With 15 ml waters, divide water-yielding stratum, be 1.0 * 10 with 1mol/L NaOH regulator solution hydrogen ion concentration
-7Mol/L, it is complete to crystallization to add 380 liters of ethanol, suction filtration with 60 milliliters of washings of acetone 2 times, is drained, drying under reduced pressure, ceftriaxone sodium 6.3 grams, natrium transgenic rate 99.8%.
Embodiment one is pressed in the calculating of natrium transgenic rate.
Embodiment five
Under the normal temperature, in there-necked flask, drop into 5 gram ceftriaxones, add 85 milliliters water, Sodium isooctanoate 1.0 gram and NaHCO
31.0 gram, dissolving is stirred 50 minutes to reacting completely, and filters, and recording the solution hydrogen ion concentration is 6.3 * 10
-8Mol/L adds 400 milliliters of acetone crystallizatioies, and suction filtration with 50 milliliters of washing with acetones 2 times, is drained, drying under reduced pressure, ceftriaxone sodium 4.1 grams, measure its natrium transgenic rate 101.1%.
Embodiment one is pressed in the calculating of natrium transgenic rate.
Claims (6)
1, a kind of ceftriaxone sodium is characterized in that relative combination rate with human serum albumin is lower than 60%, and wherein the molar ratio of sodium ion and ceftriaxone acid is 2: 1, and its aqueous solution hydrogenion concentration value scope is 3.16 * 10
-7～3.16 * 10
-8Mol/L.
2,, it is characterized in that it reduces along with the rising of medicine natrium transgenic rate and along with the reduction of its aqueous solution hydrogen ion concentration with the relative combination rate of human serum albumin according to the ceftriaxone sodium of claim 1.
3,, it is characterized in that its natrium transgenic rate is greater than 99.5% according to the ceftriaxone sodium of claim 1.
4, according to the preparation method of the ceftriaxone sodium of one of claim 1-3, it is characterized in that adding sodium transforming agent in ceftriaxone solution, the hydrogenion concentration value of control ceftriaxone sodium water solution is 3.16 * 10
-7～3.16 * 10
-8Mol/L, it is complete to make ceftriaxone change sodium, crystallization and getting.
5, ceftriaxone sodium preparation method according to claim 4, wherein sodium transforming agent is meant sodium acetate, Sodium isooctanoate, sodium hydroxide, yellow soda ash, sodium bicarbonate or their mixture.
6, the preparation method of ceftriaxone sodium according to claim 5 is characterized in that the ceftriaxone natrium transgenic rate is greater than 99.5%.
Priority Applications (1)
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|---|---|---|---|
| CNB031569528A CN1314692C (en) | 2003-09-16 | 2003-09-16 | Sodium ceftriaxone and its preparation method |
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|---|---|---|---|
| CNB031569528A CN1314692C (en) | 2003-09-16 | 2003-09-16 | Sodium ceftriaxone and its preparation method |
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|---|---|
| CN1597684A true CN1597684A (en) | 2005-03-23 |
| CN1314692C CN1314692C (en) | 2007-05-09 |
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|---|---|---|---|
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101244137B (en) * | 2008-02-28 | 2011-05-04 | 郑明刚 | Medicament for treating pulmonitis, and high fever, lower fever, and preparation method |
| CN102993215A (en) * | 2012-05-16 | 2013-03-27 | 悦康药业集团有限公司 | Preparation method of ceftriaxone sodium crystal and evaluation method of ceftriaxone sodium aqueous solution turbidity |
| CN104341435A (en) * | 2013-07-30 | 2015-02-11 | 北大方正集团有限公司 | Ceftriaxone sodium purifying method |
| CN104876948A (en) * | 2015-05-28 | 2015-09-02 | 华北制药河北华民药业有限责任公司 | Preparation method of ceftriaxone sodium |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875574A (en) * | 2012-08-31 | 2013-01-16 | 石药集团中诺药业（石家庄）有限公司 | Crystal form of ceftriaxone sodium and preparation method for crystal form |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1234385B (en) * | 1989-05-23 | 1992-05-18 | Sbd Synthetic And Biolog Devel | IMPROVED PROCEDURE FOR THE PRODUCTION OF AN ANTIBIOTIC SUBSTANCE BELONGING TO THE CEPHALOSPORINE GROUP |
| AU690482B2 (en) * | 1996-03-18 | 1998-04-23 | Ranbaxy Laboratories Limited | Process for producing cephalosporin antibiotics |
-
2003
- 2003-09-16 CN CNB031569528A patent/CN1314692C/en not_active Expired - Lifetime
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101244137B (en) * | 2008-02-28 | 2011-05-04 | 郑明刚 | Medicament for treating pulmonitis, and high fever, lower fever, and preparation method |
| CN102993215A (en) * | 2012-05-16 | 2013-03-27 | 悦康药业集团有限公司 | Preparation method of ceftriaxone sodium crystal and evaluation method of ceftriaxone sodium aqueous solution turbidity |
| CN102993215B (en) * | 2012-05-16 | 2013-11-20 | 悦康药业集团有限公司 | Preparation method of ceftriaxone sodium crystal and evaluation method of ceftriaxone sodium aqueous solution turbidity |
| CN104341435A (en) * | 2013-07-30 | 2015-02-11 | 北大方正集团有限公司 | Ceftriaxone sodium purifying method |
| CN104341435B (en) * | 2013-07-30 | 2016-06-22 | 北大方正集团有限公司 | The process for purification of ceftriaxone sodium |
| CN104876948A (en) * | 2015-05-28 | 2015-09-02 | 华北制药河北华民药业有限责任公司 | Preparation method of ceftriaxone sodium |
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|---|---|
| CN1314692C (en) | 2007-05-09 |
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