CN105037392A - Bactericidal medicine efamandole nafate compound and preparing method of bactericidal medicine efamandole nafate compound - Google Patents
Bactericidal medicine efamandole nafate compound and preparing method of bactericidal medicine efamandole nafate compound Download PDFInfo
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- CN105037392A CN105037392A CN201510495166.XA CN201510495166A CN105037392A CN 105037392 A CN105037392 A CN 105037392A CN 201510495166 A CN201510495166 A CN 201510495166A CN 105037392 A CN105037392 A CN 105037392A
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- cefamandole nafate
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- sodium
- formylcefamole
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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
- 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
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
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- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a bactericidal medicine efamandole nafate compound and a preparing method of the bactericidal medicine efamandole nafate compound, and belongs to the technical field of medicine. The efamandole nafate compound is a novel crystal compound; an X-ray powder diffraction pattern obtained through Cu-Ka ray measurement is shown as the figure 1. The efamandole nafate compound has the advantages that the purity is high; the flowability is good; moisture absorption cannot easily occur; the stability is high; the polymer content is low; the clinical application is safe and reliable.
Description
Technical field
The invention belongs to medical art, relate to a kind of germ killing drugs Cefamandole sodium compound and preparation method thereof.
Background technology
Sodium O-formylcefamole is all effective a kind of broad-spectrum antibiotics of kind disease caused Gram-negative bacteria and gram-positive microorganism, extensive at clinical middle Application comparison, but containing unstable beta-lactam nucleus in the structure of Sodium O-formylcefamole, easy generation hydrolysis and rearrangement reaction, cause structural damage and lose anti-microbial activity, some degraded product may produce anaphylaxis, and therefore the stability of this kind of microbiotic in transfusion should cause extensive attention.Meanwhile, because its basic structure is the same with microbiotic in the many semisynthetic beta-lactam gone on the market, also can forms high molecular polymer, also can cause type Ⅰ hypersensitivity reaction in Clinical practice, very harmful to patient.Meanwhile, Sodium O-formylcefamole very easily draws wet, has very adverse influence to its stability.Prior art improves its stability from aspects such as raising content, reduction impurity mostly.
Research proves, the anaphylactogen causing β-lactam antibitics type Ⅰ hypersensitivity reaction is relevant with the high molecular polymer content wherein existed.Reduce the high molecular polymer content existed in Sodium O-formylcefamole bulk drug, improve stability, make it can ensure the lower effective way being the reaction of reduction anaphylactic shock and occurring of the content of its high molecular polymer existed in long term storage.Therefore, be necessary to provide the Cefamandole nafate compounds that a kind of high molecular polymer content is low, performance is more superior.
The present invention, through large quantifier elimination, obtains a kind of crystal compound being different from prior art, and the purity of Mandokef crystalline compounds provided by the invention is high, good fluidity, not easily moisture absorption, good stability, and polymer content is low, and clinical application is safe and reliable.
Summary of the invention
Primary goal of the invention of the present invention is to propose a kind of Mandokef crystalline compounds;
Second goal of the invention of the present invention is the preparation method proposing this Mandokef crystalline compounds.
In order to realize object of the present invention, the technical scheme of employing is:
A kind of germ killing drugs Cefamandole nafate compounds, the X-ray powder diffraction pattern that described compound uses the measurement of Cu-K alpha-ray to obtain as shown in Figure 1.
The preparation method of described Sodium O-formylcefamole crystalline compounds, comprises the following steps:
(1) Sodium O-formylcefamole crude product is joined in the mixing solutions of water, acetonitrile, heat up, be stirred to and dissolve completely;
(2) under the effect of sound field, the mixing solutions of ethanol, trichloromethane, hexanaphthene is added while stirring;
(3) after the mixing solutions of ethanol, trichloromethane, hexanaphthene adds, under the effect of sound field, cooling, growing the grain 3 hours, washing, vacuum-drying, obtains Cefamandole nafate compounds.
The volume of the mixing solutions of water, acetonitrile described in wherein said step (1) is 5 times of Sodium O-formylcefamole weight, and the volume ratio of water, acetonitrile is 2:1; Intensification described in described step (1) refers to and is warming up to 25 DEG C; Described sound field frequency is 30KHz, output rating is 45W; The volume of the mixing solutions of ethanol, trichloromethane, hexanaphthene described in described step (2) is 10 times of Sodium O-formylcefamole weight, and the volume ratio of ethanol, trichloromethane, hexanaphthene is 2:1:1; Described in described step (2), stirring velocity is 85 revs/min, and adding speed is 80 ml/min; Sound field frequency described in described step (3) is 25KHz, output rating is 40W; Described in described step (3), cooling is for be cooled to-5 DEG C with 10 DEG C/h.
Below technical scheme of the present invention is made further explanation:
Sodium O-formylcefamole is Beta-lactam medicine, the easy open loop of its monoamide ring, form impurity and easily self-polymerization occur after open loop, form high molecular polymer, thus reduction medicament contg, cause drug titers to reduce, the sterilization of Sodium O-formylcefamole and fungistatic effect are reduced, and superpolymer can cause endogenous anaphylaxis.The good stability of the Cefamandole nafate compounds that the present invention prepares, not easily open loop is decomposed, its polymer content trace.
Sodium O-formylcefamole has and draws moist, can cause the change of the physico-chemical properties such as the decline of caking, mobility, deliquescence, crystal formation change, thus affect the interior qualities such as product stability, validity, security after moisture absorption.And according to the literature, many microbiotic are stablized in the dry state, but will decompose after making moist.Therefore, water absorbability has very important impact for the stability of Sodium O-formylcefamole.Therefore, if can reduce the water absorbability of Sodium O-formylcefamole, then the stability for Sodium O-formylcefamole has very important meaning.Meanwhile, bibulous medicine needs strictly to control the relative humidity between packing in formulation manufacturing processes, is no more than critical relative humidity, thus ensures quality product and stability.If not easily moisture absorption, then the production of convenient preparation, ensures stability simultaneously.
A kind of germ killing drugs Cefamandole nafate compounds of the present invention, the X-ray powder diffraction pattern that the measurement of use Cu-K alpha-ray obtains as shown in Figure 1.By to its hygroscopic research, the discovery that contriver is pleasantly surprised, its water absorbability of compound of the present invention is significantly less than existing crystalline compounds.Thus illustrate that Sodium O-formylcefamole crystalline compounds of the present invention is more stable, and more adapt to the preparation of preparation.
The purity of Sodium O-formylcefamole crystalline compounds of the present invention can reach 99.9%, and its structure is confirmed through proton nmr spectra.The preparation method of Sodium O-formylcefamole crystalline compounds of the present invention is simple, and purity is high, and yield is high, most suitable large-scale industrial production.
Sodium O-formylcefamole crystalline compounds of the present invention can be used for preparing the multiple formulation used clinically, as freeze-dried powder, aseptic powder injection, liquid drugs injection etc.And confirm through stability test, adopt Sodium O-formylcefamole crystalline compounds of the present invention, its stability, higher than prior art, is very suitable for clinical application.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction pattern that the Sodium O-formylcefamole crystalline compounds for preparing of embodiment 1 uses the measurement of Cu-K alpha-ray and obtains.
Embodiment
The specific embodiment of the present invention is only limitted to explain further and the present invention is described, does not limit Composition of contents of the present invention.
embodiment 1:the preparation of Sodium O-formylcefamole crystalline compounds
(1) joined by Sodium O-formylcefamole crude product in the mixing solutions of water that volume is 5 times of Sodium O-formylcefamole weight, acetonitrile, the volume ratio of water, acetonitrile is 2:1, is warming up to 25 DEG C, is stirred to and dissolves completely;
(2) frequency be 30KHz, under output rating is the sound field of 45W, add the mixing solutions of ethanol that volume is Sodium O-formylcefamole weight 10 times, trichloromethane, hexanaphthene while stirring, the volume ratio of ethanol, trichloromethane, hexanaphthene is 2:1:1, stirring velocity is 85 revs/min, and adding speed is 80 ml/min;
(3) after the mixing solutions of ethanol, trichloromethane, hexanaphthene adds, frequency be 25KHz, under output rating is the sound field of 40W, be cooled to-5 DEG C with 10 DEG C/h, growing the grain 3 hours, washing, vacuum-drying, obtains Cefamandole nafate compounds.
As shown in Figure 1, its purity of high-performance liquid chromatogram determination is 99.9% to the X-ray powder diffraction pattern that the measurement of use Cu-K alpha-ray obtains.
experimental example 1:accelerated test
Example 1 and commercially available Mandokef sodium raw materials, simulation listing packaging, put in sealing clean container, place 6 months under temperature 40 DEG C ± 2 DEG C, relative humidity 70% ± 5% condition, at duration of test respectively at 1,2,3,6 sampling at the end of month once, each stability high spot reviews project is tested.The results are shown in Table shown in 1.
Table 1 Acceleration study result
experimental example 2:wettability test
1 instrument
PL203 electronic balance, LRH-250-S fixed temperature and humidity incubator, HH-400SD testing chamber for medicine stability;
2 methods
Get the glass desicator (for ensureing that salts solution is saturated, excessive salt should be had bottom moisture eliminator to exist) that bottom fills salt supersaturated solution, the built-in weighing bottle of moisture eliminator, places 48h to constant humidity in thermostat container.Sample thief is about 2g, puts in weighing bottle, accurately weighed, bottle cap is opened, puts into moisture eliminator top, put in 25 DEG C of fixed temperature and humidity incubators or 20 DEG C of stability test casees by differing temps requirement and preserve, parallel running 3 parts, weighs respectively at different time, calculates the rate of moisture absorption of different time.
Calculation formula: rate of moisture absorption=(medicinal powder weight after moisture absorption-moisture absorption prodrug grain weight amount)/moisture absorption prodrug grain weight amount × 100%.Result is as table 2:
Table 2 hygroscopicity test results
According to above-mentioned experiment, the water absorbability of Sodium O-formylcefamole crystalline compounds prepared by the present invention is low, good stability.
experimental example 3:mobility is tested
The mobility of this experimental example to the Sodium O-formylcefamole crystalline compounds of the embodiment of the present invention 1 detects, adopt fixed funnel method, funnel is placed in the suitable height on graph paper, Sodium O-formylcefamole crystalline compounds is freely flowed down from flare opening, until the cone top formed contacts with flare opening, measure hypotenuse and the horizontal angle (slope of repose θ) of Sodium O-formylcefamole crystalline compounds accumulation horizon.Experimental result is as shown in table 3.
Table 3: mobility experimental result
From the interpretation of table 3, the mobility of the Sodium O-formylcefamole crystalline compounds that the embodiment of the present invention 1 prepares is fine.
Claims (9)
1. a germ killing drugs Cefamandole nafate compounds, is characterized in that: the X-ray powder diffraction pattern that described compound uses the measurement of Cu-K alpha-ray to obtain as shown in Figure 1.
2. prepare a method for germ killing drugs Cefamandole nafate compounds according to claim 1, it is characterized in that comprising the following steps:
(1) Sodium O-formylcefamole crude product is joined in the mixing solutions of water, acetonitrile, heat up, be stirred to and dissolve completely;
(2) under the effect of sound field, the mixing solutions of ethanol, trichloromethane, hexanaphthene is added while stirring;
(3) after the mixing solutions of ethanol, trichloromethane, hexanaphthene adds, under the effect of sound field, cooling, growing the grain 3 hours, washing, vacuum-drying, obtains Cefamandole nafate compounds.
3. the preparation method of germ killing drugs Cefamandole nafate compounds according to claim 2, is characterized in that: the volume of the mixing solutions of water, acetonitrile described in step (1) is 5 times of Sodium O-formylcefamole weight, and the volume ratio of water, acetonitrile is 2:1.
4. the preparation method of germ killing drugs Cefamandole nafate compounds according to claim 2, is characterized in that: intensification described in step (1) refers to and is warming up to 25 DEG C.
5. the preparation method of germ killing drugs Cefamandole nafate compounds according to claim 2, is characterized in that: sound field frequency described in step (2) is 30KHz, output rating is 45W.
6. the preparation method of germ killing drugs Cefamandole nafate compounds according to claim 2, it is characterized in that: the volume of the mixing solutions of ethanol, trichloromethane, hexanaphthene described in step (2) is 10 times of Sodium O-formylcefamole weight, the volume ratio of ethanol, trichloromethane, hexanaphthene is 2:1:1.
7. the preparation method of germ killing drugs Cefamandole nafate compounds according to claim 2, is characterized in that: described in step (2), stirring velocity is 85 revs/min, and adding speed is 80 ml/min.
8. the preparation method of germ killing drugs Cefamandole nafate compounds according to claim 2, is characterized in that: sound field frequency described in step (3) is 25KHz, output rating is 40W.
9. the preparation method of germ killing drugs Cefamandole nafate compounds according to claim 2, is characterized in that: described in step (3), cooling is for be cooled to-5 DEG C with 10 DEG C/h.
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Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4006138A (en) * | 1975-04-11 | 1977-02-01 | Eli Lilly And Company | Crystalline form of sodium O-formylcefamandole |
| CN101108856A (en) * | 2007-07-27 | 2008-01-23 | 苏州中联化学制药有限公司 | Method for synthesizing antibiotic cefamandole nafate |
| CN101219117A (en) * | 2007-08-14 | 2008-07-16 | 山东罗欣药业股份有限公司 | Cefamandole nafate powder injection, production method of powder injection and raw machine thereof |
| CN101880290A (en) * | 2010-06-28 | 2010-11-10 | 海南新中正制药有限公司 | Preparation method of cefamandole nafate |
| CN102093392A (en) * | 2011-01-28 | 2011-06-15 | 海南灵康制药有限公司 | New method for preparing Cefamandole Nafate |
| CN102276629A (en) * | 2011-08-22 | 2011-12-14 | 苏州二叶制药有限公司 | Synthetic route for cefamandole nanfate |
| CN102372728A (en) * | 2011-11-28 | 2012-03-14 | 齐鲁安替制药有限公司 | Synthesizing method for cephalosporin compound |
| CN102702232A (en) * | 2012-04-17 | 2012-10-03 | 山东鲁抗医药股份有限公司 | Method for preparation of fine cefamandole nafate |
| CN102816172A (en) * | 2012-08-17 | 2012-12-12 | 苏州中联化学制药有限公司 | Preparation process of cefamandole nafate |
| CN103073562A (en) * | 2013-01-11 | 2013-05-01 | 海口市制药厂有限公司 | Method for refining cefamandole nafate, cefamandole nafate and application thereof |
| CN103145736A (en) * | 2013-03-29 | 2013-06-12 | 四川省惠达药业有限公司 | Medicine composite containing cefamandole nafate compound |
-
2015
- 2015-08-13 CN CN201510495166.XA patent/CN105037392A/en active Pending
Patent Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4006138A (en) * | 1975-04-11 | 1977-02-01 | Eli Lilly And Company | Crystalline form of sodium O-formylcefamandole |
| CN101108856A (en) * | 2007-07-27 | 2008-01-23 | 苏州中联化学制药有限公司 | Method for synthesizing antibiotic cefamandole nafate |
| CN101219117A (en) * | 2007-08-14 | 2008-07-16 | 山东罗欣药业股份有限公司 | Cefamandole nafate powder injection, production method of powder injection and raw machine thereof |
| CN101880290A (en) * | 2010-06-28 | 2010-11-10 | 海南新中正制药有限公司 | Preparation method of cefamandole nafate |
| CN102093392A (en) * | 2011-01-28 | 2011-06-15 | 海南灵康制药有限公司 | New method for preparing Cefamandole Nafate |
| CN102276629A (en) * | 2011-08-22 | 2011-12-14 | 苏州二叶制药有限公司 | Synthetic route for cefamandole nanfate |
| CN102372728A (en) * | 2011-11-28 | 2012-03-14 | 齐鲁安替制药有限公司 | Synthesizing method for cephalosporin compound |
| CN102702232A (en) * | 2012-04-17 | 2012-10-03 | 山东鲁抗医药股份有限公司 | Method for preparation of fine cefamandole nafate |
| CN102816172A (en) * | 2012-08-17 | 2012-12-12 | 苏州中联化学制药有限公司 | Preparation process of cefamandole nafate |
| CN103073562A (en) * | 2013-01-11 | 2013-05-01 | 海口市制药厂有限公司 | Method for refining cefamandole nafate, cefamandole nafate and application thereof |
| CN103145736A (en) * | 2013-03-29 | 2013-06-12 | 四川省惠达药业有限公司 | Medicine composite containing cefamandole nafate compound |
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Effective date of registration: 20170608 Address after: 050050 No. 188 worker peasant Road, Hebei, Shijiazhuang Applicant after: Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd., Shiyao Group Address before: 108, room 2, building 266109, Qingdao blue bio Pharmaceutical Industrial Park, 368 Hedong Road, Hedong District, Qingdao, Shandong Applicant before: QINGDAO LANSHENGYANG MEDICAL BIOLOGICAL TECHNOLOGY CO., LTD. |
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Application publication date: 20151111 |