CN104147004A - Specific amoxicillin sodium and sulbactam sodium superfine powdered preparation and preparation method thereof - Google Patents
Specific amoxicillin sodium and sulbactam sodium superfine powdered preparation and preparation method thereof Download PDFInfo
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- CN104147004A CN104147004A CN201410059732.8A CN201410059732A CN104147004A CN 104147004 A CN104147004 A CN 104147004A CN 201410059732 A CN201410059732 A CN 201410059732A CN 104147004 A CN104147004 A CN 104147004A
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Abstract
The invention discloses specific amoxicillin sodium and sulbactam sodium superfine powder. The powder is prepared by the following steps of respectively purifying an amoxicillin sodium crude product and a sulbactam sodium crude product to obtain high purity amoxicillin sodium and high purity sulbactam sodium, mixing the high purity amoxicillin sodium and the high purity sulbactam sodium to obtain the amoxicillin sodium and sulbactam sodium with high purity, and performing air jet superfine powder grinding to obtain the specific amoxicillin sodium and sulbactam sodium superfine powder. The amoxicillin sodium and sulbactam sodium prepared by the method has the advantages of high stability, high purity, small particle, large specific surface area, good solubility, small toxic and side effect and the like.
Description
Technical field
The present invention relates to extraordinary superfine powder preparation of a kind of amoxicillin sodium and sulbactam sodium and preparation method thereof, belong to medical technical field.
Background technology
The compound preparation that amoxicillin sodium and sulbactam sodium is comprised of Amoxicillin Sodium and sulbactam sodium.
Amoxicillin Sodium, its chemical name is: (2S, 5R, 6R)-3,3-dimethyl-6-[(R)-(-)-2-amino-2-(4-hydroxy phenyl) ether is amino]-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-sodium formate, English Amoxicillin Sodium by name, molecular formula: C16H18N3NaO5S, molecular weight: 387.38, structural formula is as follows:
Sulbactam sodium, its chemical name is: (2S, 5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3,2,0] heptane-2-carboxylic acid sodium-4,4-dioxide, English name is Sulbactam Sodium, molecular formula: C8H10NNaO5S, molecular weight: 255.22, structural formula is as follows:
In prior art, amoxicillin sodium and sulbactam sodium, as bactericidal antibiotic, how as injection agent, can be killed multiple gram-positive cocci and gram negative bacteria clinically, particularly effective in cure to the fastbacteria of generation beta-lactamase.Amoxicillin is bactericidal properties broad ectrum antibiotic, and sulbactam sodium is irreversibility competitive type beta-lactamase inhibitor, can effectively suppress the beta-lactamase that fastbacteria produces.Many Grain-positives and gram-negative bacteria produce beta-lactamase clinically, and this enzyme can make urban district, amoxicillin antibacterial activity; Due to the existence of sulbactam sodium, can make amoxicillin exempt from the destruction of beta-lactamase, thereby make amoxicillin drug resistance and produce the antibacterial of beta-lactamase, still responsive to amoxicillin.
The shortcomings such as amoxicillin sodium and sulbactam sodium existence and stability of the prior art is poor, purity is low, granule is large, poorly soluble.
In December, 1999, " extraordinary superfine powder technology of preparing " obtains first-class National Scientific and Technological Progress Award, prize-winning unit: Institutes Of Technology Of Nanjing (Li Fengsheng), certificate number: 30-1-003-01.On January 2nd, 2014, Institutes Of Technology Of Nanjing is about " application of extraordinary superfine powder technology of preparing in pharmaceutical preparation " the Yu Chang allusion quotation of exclusively assigning pharmaceuticals, and wherein Shandong Weifang Pharmaceutical Factory Co., Ltd. is the exploiting entity of " the extraordinary superfine powder technology of preparing of amoxicillin sodium and sulbactam sodium and formulation development and industrialization ".
By antibiotic compound preparation technique Exclusive License enforcement right, authorize Shandong Weifang Pharmaceutical Factory Co., Ltd..
Summary of the invention
One of object of the present invention is to provide a kind of extraordinary superfine powder preparation of amoxicillin sodium and sulbactam sodium, and amoxicillin sodium and sulbactam sodium prepared by the present invention has the advantages such as stability is high, purity is high, granule is little, specific surface area is large, dissolubility is good, toxic and side effects.
For solving the problems of the technologies described above, the invention provides a kind of preparation method of extraordinary superfine powder preparation of amoxicillin sodium and sulbactam sodium, the method comprises the steps:
Step 1, by (2S, 5R, 6R)-3,3-dimethyl-6-[(R)-(-)-2-amino-2-(4-hydroxy phenyl) acetylamino]-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid trihydrate, Metronidazole, Aspirin, and sodium carbonate obtains Amoxicillin Sodium crude product after fully mixing with anhydrous glucose after pulverizing and sieving;
Step 2, by (2S-cis)-3,3-dimethyl-7-oxo-4-sulfo--1-azabicyclo [3,2,0] heptane-2-carboxylic acid 4, and 4-dioxide and ethanol mix, and stir 0.5 hour to abundant crystallize, filter, washing with alcohol, obtains sulbactam sodium crude product after vacuum drying;
Step 3, the raw material of the raw material of step 1 gained Amoxicillin Sodium and step 2 gained sulbactam sodium is carried out to purification with high speed adverse current chromatogram respectively, then according to ultraviolet collection of illustrative plates, collect 96% above part, activated carbon decolorizing, filters, washing, dry, obtain highly purified Amoxicillin Sodium and highly purified sulbactam sodium, then obtain highly purified amoxicillin sodium and sulbactam sodium after highly purified Amoxicillin Sodium and highly purified sulbactam sodium are mixed according to the ratio of 2:3;
Step 4, becomes superfine powder by dry amoxicillin sodium and sulbactam sodium with comminution by gas stream, reclaims packing, the superfine powder preparation of acquisition amoxicillin sodium and sulbactam sodium.
As improvement of the present invention, raw material thing weight proportion for the preparation of Amoxicillin Sodium in this step 1 is: (2S, 5R, 6R)-3, 3-dimethyl-6-[(R)-(-)-2-amino-2-(4-hydroxy phenyl) acetylamino]-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid trihydrate 10%-18%, Metronidazole 5%-15%, Aspirin 5%-15%, sodium carbonate 5%-10%, with surplus anhydrous glucose, wherein optimum weight proportion scheme is: (2S, 5R, 6R)-3, 3-dimethyl-6-[(R)-(-)-2-amino-2-(4-hydroxy phenyl) acetylamino]-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid trihydrate 16%, Metronidazole 10%, Aspirin 15%, sodium carbonate 5% and anhydrous glucose 54%.
As improvement of the present invention, (2S-cis)-3 in this step 2,3-dimethyl-7-oxo-4-sulfo--1-azabicyclo [3,2,0] heptane-2-carboxylic acid 4, the weight proportion of 4-dioxide and ethanol is 1:10.
As improvement of the present invention, the vacuum drying temperature in this step 2 is controlled at 40 ℃.
As improvement of the present invention, the condition of the high speed adverse current chromatogram in this step 3 is with chloroform, ethanol, water and ethyl acetate configuration, to form the dicyandiamide solution of immobile phase, mobile phase, and wherein the consumption volume ratio of chloroform, ethanol, water and ethyl acetate is 4:3:1.5:1.
As improvement of the present invention, in the dicyandiamide solution of the high speed adverse current chromatogram in this step 3, upper is immobile phase mutually, lower is mobile phase mutually, in this cylinder, be full of immobile phase, mobile phase pumps in post again, after the raw material of Amoxicillin Sodium and sulbactam sodium uses respectively mobile phase as dissolution with solvents by injection valve sample introduction.
As improvement of the present invention, the dry employing boulton process in this step 3, under the condition that is 0.07MPa in 45 ℃ of temperature and vacuum dry 15 hours.
As improvement of the present invention, in this step 4, the air velocity of comminution by gas stream is 350～450m/s, and the particle diameter of superfine powder is 0.5～3 μ m.
As improvement of the present invention, in this step 4, comminution by gas stream adopts multi-stage crushing method.
Compared with prior art, the extraordinary superfine powder preparation of amoxicillin sodium and sulbactam sodium of the present invention has the advantages that stability is high, purity is high, granule is little, specific surface area is large, dissolubility is good.Along with diminishing of granularity, make it have good dispersibility, be more easily absorbed by the body, reach rapidly disease sites, thereby improved the effect of medicine, more promptly anti-bacteria; On the other hand, deliquescent raising, the enhancing of chemical reactivity can be dissolved fully rapidly when dosing, improves the utilization rate of effective ingredient, and bioavailability also improves thereupon; In addition, superfine powder treatment technology, has simplified the leaching process of medicine, has maximally utilised crude drug, improves drug quality, has reduced the wasting of resources.
The specific embodiment
Below in conjunction with the specific embodiment, the present invention is further described in detail, the embodiment providing is only in order to illustrate the present invention, rather than in order to limit the scope of the invention.Any pro forma accommodation that the present invention is made and/or change all will fall into protection scope of the present invention.
Embodiment 1
By 160 grams of (2S, 5R, 6R)-3, 3-dimethyl-6-[(R)-(-)-2-amino-2-(4-hydroxy phenyl) acetylamino]-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid trihydrate, 100 grams of Metronidazoles, after 150 grams of Aspirins and 50 grams of sodium carbonate pulverize and sieve, after fully mixing with 54 milliliters of anhydrous glucose, obtain Amoxicillin Sodium crude product, again by 100 grams of (2S-cis)-3, 3-dimethyl-7-oxo-4-sulfo--1-azabicyclo [3, 2, 0] heptane-2-carboxylic acid 4, 4-dioxide and 1000 milliliters of ethanol mix, stir after 0.5 hour to abundant crystallize, filter, washing with alcohol, after dry under 40 ℃ of temperature conditions, obtain sulbactam sodium crude product.
After being dried Amoxicillin Sodium and sulbactam sodium crude product carry out purification with high speed adverse current chromatogram, this chromatograph forms the dicyandiamide solution of immobile phase, mobile phase with chloroform, ethanol, water and ethyl acetate configuration, wherein the consumption volume ratio of chloroform, ethanol, water and ethyl acetate is 4:3:1.5:1.In the dicyandiamide solution of this chromatograph, upper is immobile phase mutually, lower is mobile phase mutually, after the raw material of Amoxicillin Sodium and sulbactam sodium uses respectively mobile phase as dissolution with solvents by injection valve sample introduction, then according to ultraviolet collection of illustrative plates, collect 96% above part, activated carbon decolorizing, filter, washing, then adopt boulton process, under the condition that is 0.07MPa in 45 ℃ of temperature and vacuum dry 15 hours, after afterwards Amoxicillin Sodium and sulbactam sodium being mixed according to the ratio of 2:3, obtain highly purified amoxicillin sodium and sulbactam sodium.
Through HPLC, analyze, the purity of amoxicillin sodium and sulbactam sodium is 99.6%, and effective theoretical plate number is 2046.
The air-flow that the speed of take is 350m/s is ground into particle diameter as the superfine powder of 1～3 μ m by dried amoxicillin sodium and sulbactam sodium, reclaims packing, the extraordinary superfine powder preparation finished product of acquisition amoxicillin sodium and sulbactam sodium.
Embodiment 2
By 160 grams of (2S, 5R, 6R)-3, 3-dimethyl-6-[(R)-(-)-2-amino-2-(4-hydroxy phenyl) acetylamino]-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid trihydrate, 100 grams of Metronidazoles, after 150 grams of Aspirins and 50 grams of sodium carbonate pulverize and sieve, after fully mixing with 54 milliliters of anhydrous glucose, obtain Amoxicillin Sodium crude product, again by 100 grams of (2S-cis)-3, 3-dimethyl-7-oxo-4-sulfo--1-azabicyclo [3, 2, 0] heptane-2-carboxylic acid 4, 4-dioxide and 1000 milliliters of ethanol mix, extremely abundant crystallize after stirring 0.5h, filter, washing with alcohol, after dry under 40 ℃ of temperature conditions, obtain sulbactam sodium crude product.
After being dried Amoxicillin Sodium and sulbactam sodium crude product carry out purification with high speed adverse current chromatogram, this chromatograph forms the dicyandiamide solution of immobile phase, mobile phase with chloroform, ethanol, water and ethyl acetate configuration, wherein the consumption volume ratio of chloroform, ethanol, water and ethyl acetate is 4:3:1.5:1.In the dicyandiamide solution of this chromatograph, upper is immobile phase mutually, lower is mobile phase mutually, after the raw material of Amoxicillin Sodium and sulbactam sodium uses respectively mobile phase as dissolution with solvents by injection valve sample introduction, then according to ultraviolet collection of illustrative plates, collect 96% above part, activated carbon decolorizing, filter, washing, then adopt boulton process, under the condition that is 0.07MPa in 45 ℃ of temperature and vacuum dry 15 hours, then obtain highly purified amoxicillin sodium and sulbactam sodium after highly purified Amoxicillin Sodium and highly purified sulbactam sodium are mixed according to the ratio of 2:3.
Through HPLC, analyze, the purity of amoxicillin sodium and sulbactam sodium is 99.6%, and effective theoretical plate number is 2046.
The air-flow that the speed of take is 400m/s is pulverized dried amoxicillin sodium and sulbactam sodium, and gained particle diameter is the superfine powder of 0.8～2 μ m, reclaims packing, the extraordinary superfine powder preparation finished product of acquisition amoxicillin sodium and sulbactam sodium.
Embodiment 3(contrast)
By the method step of embodiment 1, make the amoxicillin sodium and sulbactam sodium of purification, the air-flow that the speed of take is 500m/s is pulverized dried amoxicillin sodium and sulbactam sodium, gained particle diameter is the superfine powder of 0.8～3 μ m, reclaim, packing, the extraordinary superfine powder preparation of acquisition amoxicillin sodium and sulbactam sodium.
When the particle diameter of the superfine powder of amoxicillin sodium and sulbactam sodium is 0.5～3 μ m, can be that amoxicillin sodium and sulbactam sodium has good dissolubility; When particle diameter is less than 0.5 μ m, dissolubility no longer increases along with diminishing of particle diameter, thereby it is very cost-effective that the particle diameter of the superfine powder of amoxicillin sodium and sulbactam sodium adopts 0.5～3 μ m.
Adopt high velocity air method to spray grinding mode and prepare superfine powder, production process is simple and easy to control, and when air velocity is greater than 450m/s, particle diameter no longer diminishes along with the increase of speed, quoted passage, it is rationally effectively that comminution by gas stream adopts the speed of 350～450m/s.
Compared with prior art, the extraordinary superfine powder preparation of amoxicillin sodium and sulbactam sodium of the present invention has the advantages that stability is high, purity is high, granule is little, specific surface area is large, dissolubility is good.Along with diminishing of granularity, make it have good dispersibility, be more easily absorbed by the body, reach rapidly disease sites, thereby improved the effect of medicine, more promptly anti-bacteria; On the other hand, deliquescent raising, the enhancing of chemical reactivity can be dissolved fully rapidly when dosing, improves the utilization rate of effective ingredient, and bioavailability also improves thereupon; In addition, superfine powder treatment technology, has simplified the leaching process of medicine, has maximally utilised crude drug, improves drug quality, has reduced the wasting of resources.
Claims (10)
1. the extraordinary superfine powder preparation of an amoxicillin sodium and sulbactam sodium, it is characterized in that: the extraordinary superfine powder of described amoxicillin sodium and sulbactam sodium is respectively Amoxicillin Sodium crude product and sulbactam sodium crude product to be obtained to highly purified Amoxicillin Sodium and sulbactam sodium after purification, after again both being mixed, obtain highly purified amoxicillin sodium and sulbactam sodium, through air flow super, obtain the extraordinary superfine powder of amoxicillin sodium and sulbactam sodium.
2. a preparation method for the extraordinary superfine powder preparation of amoxicillin sodium and sulbactam sodium, is characterized in that: the method comprises the steps:
Step 1, by (2S, 5R, 6R)-3,3-dimethyl-6-[(R)-(-)-2-amino-2-(4-hydroxy phenyl) acetylamino]-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid trihydrate, Metronidazole, Aspirin, and sodium carbonate obtains Amoxicillin Sodium crude product after fully mixing with anhydrous glucose after pulverizing and sieving;
Step 2, by (2S-cis)-3,3-dimethyl-7-oxo-4-sulfo--1-azabicyclo [3,2,0] heptane-2-carboxylic acid 4, and 4-dioxide and ethanol mix, and stir 0.5 hour to abundant crystallize, filter, washing with alcohol, obtains sulbactam sodium crude product after vacuum drying;
Step 3, the crude product of the crude product of step 1 gained Amoxicillin Sodium and step 2 gained sulbactam sodium is carried out to purification with high speed adverse current chromatogram respectively, then according to ultraviolet collection of illustrative plates, collect 96% above part, activated carbon decolorizing, filters, washing, dry, obtain highly purified Amoxicillin Sodium and highly purified sulbactam sodium, then obtain highly purified amoxicillin sodium and sulbactam sodium after highly purified Amoxicillin Sodium and highly purified sulbactam sodium are mixed according to the ratio of 2:3;
Step 4, becomes superfine powder by the amoxicillin sodium and sulbactam sodium of step 3 gained with comminution by gas stream, reclaims packing, the superfine powder preparation of acquisition amoxicillin sodium and sulbactam sodium.
3. the preparation method of the extraordinary superfine powder preparation of a kind of amoxicillin sodium and sulbactam sodium according to claim 2, it is characterized in that: the raw material thing weight proportion for the preparation of Amoxicillin Sodium in described step 1 is: (2S, 5R, 6R)-3, 3-dimethyl-6-[(R)-(-)-2-amino-2-(4-hydroxy phenyl) acetylamino]-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid trihydrate 10%-18%, Metronidazole 5%-15%, Aspirin 5%-15%, sodium carbonate 5%-10%, with surplus anhydrous glucose, wherein optimum weight proportion scheme is: (2S, 5R, 6R)-3, 3-dimethyl-6-[(R)-(-)-2-amino-2-(4-hydroxy phenyl) acetylamino]-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid trihydrate 16%, Metronidazole 10%, Aspirin 15%, sodium carbonate 5% and anhydrous glucose 54%.
4. the preparation method of the extraordinary superfine powder preparation of a kind of amoxicillin sodium and sulbactam sodium according to claim 2, it is characterized in that: (2S-cis)-3 in described step 2,3-dimethyl-7-oxo-4-sulfo--1-azabicyclo [3,2,0] heptane-2-carboxylic acid 4, and the weight proportion of 4-dioxide and ethanol is 1:10.
5. the preparation method of the extraordinary superfine powder preparation of a kind of amoxicillin sodium and sulbactam sodium according to claim 2, is characterized in that: the vacuum drying temperature in described step 2 is controlled at 40 ℃.
6. the preparation method of the extraordinary superfine powder preparation of a kind of amoxicillin sodium and sulbactam sodium according to claim 2, it is characterized in that: the condition of the high speed adverse current chromatogram in described step 3 is for forming the dicyandiamide solution of immobile phase, mobile phase with chloroform, ethanol, water and ethyl acetate configuration, wherein the consumption volume ratio of chloroform, ethanol, water and ethyl acetate is 4:3:1.5:1.
7. the preparation method of the extraordinary superfine powder preparation of a kind of amoxicillin sodium and sulbactam sodium according to claim 6, it is characterized in that: in the dicyandiamide solution of described high speed adverse current chromatogram, upper is immobile phase mutually, lower is mobile phase mutually, in this cylinder, be full of immobile phase, mobile phase pumps in post again, after the raw material of Amoxicillin Sodium and sulbactam sodium uses respectively mobile phase as dissolution with solvents by injection valve sample introduction.
8. the preparation method of the extraordinary superfine powder preparation of a kind of amoxicillin sodium and sulbactam sodium according to claim 2, it is characterized in that: the dry employing boulton process in described step 3, under the condition that is 0.07MPa in 45 ℃ of temperature and vacuum dry 15 hours.
9. the preparation method of the extraordinary superfine powder preparation of a kind of amoxicillin sodium and sulbactam sodium according to claim 2, is characterized in that: in described step 4, the air velocity of comminution by gas stream is 350～450m/s, and the particle diameter of superfine powder is 0.5～3 μ m.
10. the preparation method of the extraordinary superfine powder preparation of a kind of amoxicillin sodium and sulbactam sodium according to claim 2, is characterized in that: the comminution by gas stream in described step 4 adopts multi-stage crushing method.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106946908A (en) * | 2017-04-25 | 2017-07-14 | 四川制药制剂有限公司 | A kind of production technology of amoxicillin sodium for injection sulbactam |
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| CN101721366A (en) * | 2010-01-13 | 2010-06-09 | 洛阳惠中兽药有限公司 | Components and preparation method of beta-lactam injection |
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2014
- 2014-02-21 CN CN201410059732.8A patent/CN104147004A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101322701A (en) * | 2008-08-01 | 2008-12-17 | 海南百那医药发展有限公司 | Amoxicillin sodium and sulbactam sodium for injection and preparation of freeze-dried injection thereof |
| CN101721366A (en) * | 2010-01-13 | 2010-06-09 | 洛阳惠中兽药有限公司 | Components and preparation method of beta-lactam injection |
Non-Patent Citations (1)
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106946908A (en) * | 2017-04-25 | 2017-07-14 | 四川制药制剂有限公司 | A kind of production technology of amoxicillin sodium for injection sulbactam |
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