CN104387444A - Method for preparing high-purity sample of impurity RS-2 in daptomycin - Google Patents
Method for preparing high-purity sample of impurity RS-2 in daptomycin Download PDFInfo
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- CN104387444A CN104387444A CN201410667505.3A CN201410667505A CN104387444A CN 104387444 A CN104387444 A CN 104387444A CN 201410667505 A CN201410667505 A CN 201410667505A CN 104387444 A CN104387444 A CN 104387444A
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Abstract
The invention discloses a method for preparing a high-purity sample of an impurity RS-2 in daptomycin. The method comprises the following steps of collecting a prewashing solution subjected to chromatography on FPDA resin in production of daptomycin; treating the prewashing solution by using an ultrafilter and a nanofilter; carrying out silica gel chromatography on concentrated solution; desorbing silica gel with a desorbing solution which is a mixed solution of isopropyl alcohol, a water-soluble organic solvent and an aqueous solution of salt; detecting through high-pressure liquid chromatography; selectively merging the desorbing solutions with the chromatographic purity of impurities RS-2 being more than 95%; carrying out nanofiltration on the merged desorbing solution, concentrating and desalting the concentrated desorbing solution; and finally carrying out freeze-drying on the desorbing solution in a freeze-drying machine to obtain the high-purity impurity RS-2 powder.
Description
Technical field
The invention belongs to biological fermentation pharmacy field, relate to the preparation method of the related impurities in a kind of antibiotic product, particularly relate to the preparation method of the high purity sample of daptomycin related impurities RS-2.
Background technology
Daptomycin is in streptomycete (S.reseosporus) fermented liquid, extract the Cyclic lipopeptide antibiotic obtaining a kind of brand new, it is by upsetting cytolemma to amino acid whose transhipment, thus hinder the biosynthesizing of bacteria cell wall peptidoglycan, change the character of cytoplasmic membrane, bacterial cell membrane function can be destroyed in many aspects, and kill gram-positive microorganism rapidly.Daptomycin is except acting on most of clinical related gram-positive bacterium, the more important thing is that it has strong active to the isolated strains presenting the resistance character such as X-1497 (methicillin), vancomycin and linwzolid in vitro, this characteristic has very important clinical meaning for critical infected patient.
Daptomycin related impurities RS-2 is the impurity paid close attention in daptomycin quality control, and highly purified impurity sample plays an important role to the research of RS-2 impurity.
According to " State Food and Drug Administration's import drugs registered standard " (standard No. JX20070250) description about injection daptomycin, time high-pressure liquid phase is detected daptomycin, retention time 19.9 minutes, the impurity called after RS-2 of relative daptomycin retention time 0.56.
High-pressure liquid phase testing conditions:
Chromatographic column: Phenomenex IB-sil 250 × 4.6mm
Fill filler: C8, particle diameter 5 μm
Moving phase: the solution (V) of 0.45% primary ammonium phosphate pH3.25 (phosphoric acid adjustment): acetonitrile (V)=67:33
Flow velocity: 1.5mL/min
Determined wavelength λ: 214nm
Wherein the product volume of RS-2 is for using daptomycin as standard substance, one that is calculated by the area normalization method relative numerical value facilitating us to weigh upper column quantity.
RS-2 content in daptomycin finished product is very low, and being generally no more than this impurity of 0.3%, C8 filler preparative column separation preparation needs to consume a large amount of daptomycin finished products and a large amount of moving phase, and preparation cost is very high.
Summary of the invention
The invention provides a kind of method, the highly purified RS-2 of preparation that can be quick and with low cost.
A preparation method for daptomycin impurity RS-2 high purity sample, its step comprises:
1) collect the pre-washing lotion that daptomycin produces upper FPDA resin chromatography, carry out ultrafiltration with ultrafilter, remove macromolecular pigment and albumen;
2) by step 1) filtrate after ultrafiltration concentrates with collecting and filtering apparatus;
3) by step 2) silicagel column desorb on the concentrated solution that obtains, stripping liquid used comprises the aqueous solution of Virahol, a kind of water-miscible organic solvent and a kind of salt, stripping liquid can according to every 1/10 column volume collect one bottle for subsequent use;
4) detected RS-2 foreign matter content in the stripping liquid collected by high pressure liquid chromatography, the stripping liquid of RS-2 impurity purity >=95% is merged;
5) the stripping liquid collecting and filtering apparatus of merging is carried out concentrated also desalination, until the specific conductivity≤20 μ S/cm in nanofiltration waste water;
6) nanofiltration concentrated solution is put into Freeze Drying Equipment freeze-drying, obtain the powder of highly purified RS-2 impurity.
Above-mentioned steps 2) concentrated after concentrated solution be preferably pre-wash liquid long-pending 1/180 ~ 1/200.
Above-mentioned steps 3) in use silica gel be preferably analytical pure rank chromatographic silica gel, its particle diameter is 200 ~ 300 orders; Silica gel adopts Virahol to soak dress post.Dry silica gel consumption is 2000 ~ 2010 times of weight of impurity RS-2 product volume.
Above-mentioned steps 3) in, described in stripping liquid, a kind of water-miscible organic solvent is preferably methyl alcohol or ethanol, and the aqueous solution of described a kind of salt is preferably the aqueous solution of ammonium acetate or ammonium chloride.The concentration of wherein said ammonium acetate solution was preferably for 0.4 ~ 0.43% (namely g/L contains 0.4 ~ 0.43g ammonium acetate in every 100mL solution), and was 3.4 ~ 3.6 with acetic acid regulator solution pH; The concentration of described aqueous ammonium chloride solution is preferably 0.24 ~ 0.26% (g/L), and is 3.4 ~ 3.6 with hydrochloric acid conditioning solution pH.
The aqueous solution of Virahol and described water-miscible organic solvent, salt is mixed into stripping liquid by a certain percentage, in specific embodiments more of the present invention, their blending ratio is by volume: Virahol: ethanol: ammonium acetate solution=(9 ~ 10): (11 ~ 13): (6 ~ 8); Or Virahol: methyl alcohol: aqueous ammonium chloride solution=(9 ~ 10): (8 ~ 10): (5 ~ 7).
Above-mentioned steps 5) in the method for desalination be: after all stripping liquids all take in collecting and filtering apparatus, add the aqueous acetic acid of pH=4.4 ~ 4.6 wherein, until the specific conductivity≤20 μ S/cm in nanofiltration waste water, stop adding aqueous acetic acid.After nanofiltration, concentrated solution fixing fabric structure is good at 100 ~ 200mL.
Preparation method's technique of daptomycin impurity RS-2 high purity sample provided by the invention is simple, has saved great amount of cost compared to prior art by the method that preparative column is separated.
Embodiment
Below by way of embodiment, the invention will be further described, but this is not limitation of the present invention, those skilled in the art, according to basic thought of the present invention, can make various amendment or improvement, but only otherwise depart from basic thought of the present invention, all within the scope of the present invention.
Before upper silicagel column, pre-for the resin containing RS-2 impurity washing lotion is handled as follows: collect first time FPDA resin pre-washing lotion 10000L when producing daptomycin; First use ultrafilter ultrafiltration, filtrate uses collecting and filtering apparatus nanofiltration, obtains dark brown red solution 50L.In the concentrated solution that high pressure liquid chromatography detection nanofiltration obtains, RS-2 foreign matter content is 14.623%.The material of following examples silica gel column chromatography obtains all thus.
Embodiment 1.
Take 200 ~ 300 goal analysis pure level chromatographic silica gel 4500g, soak dress post with Virahol, leave standstill 5 hours.
Get the nanofiltration concentrated solution upper prop containing 2.24g RS-2 impurity, carry out desorb after upper prop completes with stripping liquid, desorb flow 1BV/h, 1/10BV (column volume) collect one bottle.Stripping liquid is: Virahol (V): ethanol (V): 0.4% ammonium acetate solution (V)=9:11:6, detects stripping liquid in receiving flask by high pressure liquid chromatography, merges the stripping liquid of RS-2 foreign matter content >=95%.
| Desorption bottle number | RS-2 impurity chromatographic purity |
| 1# | 82.51 |
| 2# | 99.41 |
| 3# | 99.52 |
| 4# | 99.76 |
| 5# | 99.62 |
| 6# | 95.12 |
| 7# | 74.13 |
| 8# | 52.26 |
| 9# | 34.95 |
Merge stripping liquid 2# ~ 6#.Obtain concentrated solution 200mL with the concentrated also desalination of collecting and filtering apparatus, put into the RS-2 impurity powder that Freeze Drying Equipment freeze-drying obtains 1.03g.
Embodiment 2.
Take 200 ~ 300 goal analysis pure level chromatographic silica gel 4200g, soak dress post with Virahol, leave standstill 5 hours.
Get the nanofiltration concentrated solution upper prop containing 2.1g RS-2 impurity, after upper prop completes, carry out desorb with stripping liquid, desorb flow 1BV/h, 1/10BV volume collection one bottle.Stripping liquid is: Virahol (V): ethanol (V): 0.43% ammonium acetate solution (V)=10:13:8, detects stripping liquid in receiving flask by high pressure liquid chromatography, merges the stripping liquid of RS-2 foreign matter content >=95%.
| Desorption bottle number | RS-2 impurity chromatographic purity |
| 1# | 83.67 |
| 2# | 99.52 |
| 3# | 99.66 |
| 4# | 99.72 |
| 5# | 99.57 |
| 6# | 94.51 |
| 7# | 79.26 |
| 8# | 49.72 |
| 9# | 32.81 |
Merge stripping liquid 2# ~ 6#.Obtain concentrated solution 100mL with the concentrated also desalination of collecting and filtering apparatus, put into the RS-2 impurity powder that Freeze Drying Equipment freeze-drying obtains 0.93g.
Embodiment 3.
Take 200 ~ 300 goal analysis pure level chromatographic silica gel 3700g, soak dress post with Virahol, leave standstill 5 hours.
Get the nanofiltration concentrated solution upper prop containing 1.85g RS-2 impurity, after upper prop completes, carry out desorb with stripping liquid, desorb flow 1BV/h, 1/10BV volume collection one bottle.Stripping liquid is: Virahol (V): methyl alcohol (V): 0.24% aqueous ammonium chloride solution (V)=9:8:5, detects the stripping liquid in receiving flask by high pressure liquid chromatography, merges the stripping liquid of RS-2 foreign matter content >=95%.
| Desorption bottle number | RS-2 impurity chromatographic purity |
| 1# | 81.34 |
| 2# | 99.23 |
| 3# | 99.81 |
| 4# | 99.69 |
| 5# | 99.31 |
| 6# | 95.11 |
| 7# | 76.38 |
| 8# | 53.14 |
| 9# | 43.61 |
Merge stripping liquid 2# ~ 6#.Obtain concentrated solution 180mL with the concentrated also desalination of collecting and filtering apparatus, put into the RS-2 impurity powder that Freeze Drying Equipment freeze-drying obtains 0.82g.
Embodiment 4.
Take 200 ~ 300 goal analysis pure level chromatographic silica gel 5260g, soak dress post with Virahol, leave standstill 5 hours.
Get the nanofiltration concentrated solution upper prop containing 2.56g RS-2 impurity, after upper prop completes, carry out desorb with stripping liquid, desorb flow 1BV/h, 1/10BV volume collection one bottle.Stripping liquid is: Virahol (V): methyl alcohol (V): 0.26% aqueous ammonium chloride solution (V)=10:10:7, detects receiving flask with high-pressure liquid phase, merges the stripping liquid of RS-2 foreign matter content >=95%.
| Desorption bottle number | RS-2 impurity chromatographic purity |
| 1# | 82.76 |
| 2# | 98.97 |
| 3# | 99.52 |
| 4# | 99.64 |
| 5# | 99.23 |
| 6# | 96.31 |
| 7# | 85.33 |
| 8# | 61.57 |
| 9# | 36.43 |
Merge stripping liquid 2# ~ 6#.Obtain concentrated solution 165mL with the concentrated also desalination of collecting and filtering apparatus, put into the RS-2 impurity powder that Freeze Drying Equipment freeze-drying obtains 1.15g.
Claims (8)
1. a preparation method for daptomycin impurity RS-2 high purity sample, comprises the following steps:
1) collect the pre-washing lotion that daptomycin produces upper FPDA resin chromatography, carry out ultrafiltration with ultrafilter;
2) by step 1) filtrate after ultrafiltration concentrates with collecting and filtering apparatus;
3) by step 2) silicagel column desorb on the concentrated solution that obtains, stripping liquid used comprises the aqueous solution of Virahol, a kind of water-miscible organic solvent and a kind of salt;
4) detected RS-2 foreign matter content in the stripping liquid collected by high pressure liquid chromatography, the stripping liquid of RS-2 impurity purity >=95% is merged;
5) the stripping liquid collecting and filtering apparatus of merging is carried out concentrated also desalination, until the specific conductivity≤20 μ S/cm in nanofiltration waste water;
6) nanofiltration concentrated solution is put into Freeze Drying Equipment freeze-drying, obtain the powder of highly purified RS-2 impurity.
2. preparation method according to claim 1, is characterized in that, step 2) collecting and filtering apparatus concentrate after concentrated solution be pre-wash liquid long-pending 1/180 ~ 1/200.
3. preparation method according to claim 1, is characterized in that, step 3) silica gel that uses is analytical pure rank chromatographic silica gel, its particle diameter is 200 ~ 300 orders; Silica gel adopts Virahol to soak dress post.
4. preparation method according to claim 1, is characterized in that, step 3) dry silica gel consumption is 2000 ~ 2010 times of impurity RS-2 product volume by weight.
5. preparation method according to claim 1, is characterized in that, step 3) described in a kind of water-miscible organic solvent be methyl alcohol or ethanol; The aqueous solution of described a kind of salt is the aqueous solution of ammonium acetate or ammonium chloride.
6. preparation method according to claim 5, is characterized in that, the concentration of described ammonium acetate solution is 0.40 ~ 0.43%, pH3.4 ~ 3.6; The concentration of described aqueous ammonium chloride solution is 0.24 ~ 0.26%, pH3.4 ~ 3.6.
7. preparation method according to claim 6, it is characterized in that, step 3) stripping liquid used is Virahol by volume: ethanol: ammonium acetate solution=(9 ~ 10): (11 ~ 13): the mixing solutions of (6 ~ 8); Or Virahol by volume: methyl alcohol: aqueous ammonium chloride solution=(9 ~ 10): (8 ~ 10): the mixing solutions of (5 ~ 7).
8. preparation method according to claim 1, it is characterized in that, step 5) in the method for desalination be: after all stripping liquids all take in collecting and filtering apparatus, add the aqueous acetic acid of pH=4.4 ~ 4.6, until the specific conductivity≤20 μ S/cm in nanofiltration waste water, stop adding aqueous acetic acid.
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Cited By (8)
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| CN106565820A (en) * | 2015-10-12 | 2017-04-19 | 北大方正集团有限公司 | Method for preparing high-purity sample of vancomycin hydrochloride impurities 3 and 8 |
| CN106565818A (en) * | 2015-10-12 | 2017-04-19 | 北大方正集团有限公司 | Method for preparing high-purity samples of impurities of vancomycin hydrochloride |
| CN106565819A (en) * | 2015-10-12 | 2017-04-19 | 北大方正集团有限公司 | Method for preparation of high purity samples of 3 impurities in vancomycin hydrochloride |
| CN106568620A (en) * | 2015-10-12 | 2017-04-19 | 北大方正集团有限公司 | Preparation method of high purity samples of vancomycin hydrochloride impurities 11, 13, and 15 |
| CN106866790A (en) * | 2015-12-11 | 2017-06-20 | 北大方正集团有限公司 | The preparation method of Daptomycin RS-5/6, RS-7 and RS-7a/7b impurity |
| CN106866789A (en) * | 2015-12-11 | 2017-06-20 | 北大方正集团有限公司 | A kind of method for isolating and purifying Daptomycin RS-8 impurity |
| CN106866791A (en) * | 2015-12-11 | 2017-06-20 | 北大方正集团有限公司 | A kind of preparation method of high-purity daptomycin lactone hydrolysate |
| CN113929743A (en) * | 2020-06-29 | 2022-01-14 | 鲁南制药集团股份有限公司 | Method for preparing daptomycin impurity RS-1 and impurity RS-3 |
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| CN106565818A (en) * | 2015-10-12 | 2017-04-19 | 北大方正集团有限公司 | Method for preparing high-purity samples of impurities of vancomycin hydrochloride |
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| CN106866790A (en) * | 2015-12-11 | 2017-06-20 | 北大方正集团有限公司 | The preparation method of Daptomycin RS-5/6, RS-7 and RS-7a/7b impurity |
| CN106866789A (en) * | 2015-12-11 | 2017-06-20 | 北大方正集团有限公司 | A kind of method for isolating and purifying Daptomycin RS-8 impurity |
| CN106866791A (en) * | 2015-12-11 | 2017-06-20 | 北大方正集团有限公司 | A kind of preparation method of high-purity daptomycin lactone hydrolysate |
| CN113929743A (en) * | 2020-06-29 | 2022-01-14 | 鲁南制药集团股份有限公司 | Method for preparing daptomycin impurity RS-1 and impurity RS-3 |
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