CN106568620A - Preparation method of high purity samples of vancomycin hydrochloride impurities 11, 13, and 15 - Google Patents
Preparation method of high purity samples of vancomycin hydrochloride impurities 11, 13, and 15 Download PDFInfo
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Abstract
The invention discloses a preparation method of high purity samples of vancomycin hydrochloride impurities 11, 13, and 15. The preparation method comprises the following steps: preparing a vancomycin hydrochloride water solution with a concentration of 60 to 70 g/L from vancomycin hydrochloride crystallized powder, adjusting the pH to 4-6, maintaining a constant temperature of 40 to 42 DEG C for 8 to 9 hours in water bath, adjusting the pH to 6-7, carrying out macroporous resin chromatographic enrichment, collecting the coarse product liquids (with impurities from 40 to 60%) of impurities 11, 13, and 15, subjecting the coarse product liquids to ultrafiltration and nano filtration in sequence, and desalinating the nano filtrate by a high performance liquid chromatography (HPLC) column to obtain the high purity samples of vancomycin hydrochloride impurities 11, 13, and 15. The technology is simple, and the preparation cost is largely reduced.
Description
Technical field
The invention belongs to biofermentation pharmaceutical field, a kind of preparation method of the related impurities being related in antibiotic product, especially relate to
And the preparation method of the high-purity sample of vancomycin hydrochloride related impurities 11,13 and 15.
Background technology
Vancomycin hydrochloride is a kind of subsidiary product of three cyclohexanol glycosidation non-ribosomal peptides, by the Amycolatopsis orientalis of actinomyces
(being named as Nocardia orientalis in the past) is produced by fermenting.Vancomycin hydrochloride is narrow-spectrum antibiotic, only to gram positive bacteria
Effectively, such as hemolytic streptococcus, pneumococcus and enterococcus belong to sensitive, particularly sensitive to drug-resistant staphylococcus aureus this product.Its work
It is to suppress the synthesis of bacteria cell wall with mechanism, its main and bacteria cell wall is combined, and prevents some amino acid from into cell
In the glycopeptide of wall.Clinic is mainly used in the severe infections caused by penicillin resistant S. aureus L-forms, such as pneumonia, endocarditis and septicemia
Deng the infection caused to hemolytic streptococcus and septicemia etc. also have preferable curative effect.
Vancomycin hydrochloride related impurities is the emphasis of vancomycin hydrochloride quality control, and highly purified impurity sample is to its pharmacology poison
Reason research plays an important role.
The detection mode of vancomycin hydrochloride specifies that the high pressure liquid chromatography testing conditions of employing are as follows according to 2010 editions Chinese Pharmacopoeias：
Liquid chromatograph：Shimadzu LC-2010C HT
Chromatographic column：C18250 × 4.6mm brands：Thermo (the silent winged generation that of match)
Mobile phase A：Triethylamine buffer solution (take triethylamine 4mL and add water to 2000mL, with phosphorus acid for adjusting pH value to 3.2):
Acetonitrile: tetrahydrofuran=92: 7: 1
Mobile phase B：Triethylamine buffer solution: acetonitrile: tetrahydrofuran=70: 29: 1
Gradient is arranged：
Detection wavelength：λ=280 flow velocity:1.0mL/min sampling volume:20μL
According to above-mentioned detection method, high pressure liquid chromatography detection, detection collection of illustrative plates such as Fig. 1 institutes are carried out to vancomycin hydrochloride sample
Show.Respectively name is numbered to the impurity in Fig. 1, it is as shown in table 1 below：
Table 1
| Retention time (Min) | Relative retention value | Impurity is numbered |
| 3.80 | 0.43 | 1 |
| 4.653 | 0.52 | 2 |
| 5.434 | 0.61 | 3 |
| 5.969 | 0.67 | 4 |
| 6.499 | 0.73 | 5 |
| 7.07 | 0.8 | 6 |
| 8.368 | 0.94 | 7 |
| 8.874 | 1 | Vancomycin |
| 13.532 | 1.52 | 8 |
| 15.737 | 1.77 | 9 |
| 17.415 | 1.96 | 10 |
| 19.123 | 2.15 | 11 |
| 19.562 | 2.2 | 12 |
| 20.35 | 2.29 | 13 |
| 22.312 | 2.51 | 14 |
| 23.717 | 2.67 | 15 |
A quantitative calculating is carried out to impurity for convenience, with vancomycin hydrochloride as standard items, by area normalization method meter
One for obtaining facilitates us to weigh the relative numerical value of upper column quantity.
Wherein impurity 11,13 and 15 (referring to Fig. 1) comparision contents in vancomycin hydrochloride finished product are low, and C18 fillers prepare post
Separation prepares this impurity to be needed to consume substantial amounts of vancomycin hydrochloride finished product and substantial amounts of mobile phase, and preparation cost is very high.
The content of the invention
It is an object of the invention to provide the high-purity sample of a kind of vancomycin hydrochloride related impurities 11, impurity 13 and impurity 15
Preparation method, quickly and more easily can be enriched to the impurity 11,13 and 15 in vancomycin hydrochloride sample higher pure
Degree, and component is relatively single, then highly purified impurity sample is obtained by preparative separation.
A kind of preparation method of vancomycin hydrochloride impurity 11,13 and 15 high-purity samples, its step includes：
1) vancomycin hydrochloride crystalline powder is taken, the vancomycin hydrochloride aqueous solution that concentration is 60～70g/L is configured to；
2) by step 1) the vancomycin hydrochloride aqueous solution that obtains adjusts pH 4～6, and at 40～42 DEG C of water-bath 8～9 hours are incubated；
3) to step 2) alkali is slowly added in the vancomycin hydrochloride aqueous solution after insulation, adjust back pH to 6～7；
4) to step 3) readjustment pH after the vancomycin hydrochloride aqueous solution carry out macroreticular resin chromatographic enrichment, purity is collected respectively
For the crude product liquid of 40～60% impurity 11, impurity 13 and impurity 15；
5) respectively ultrafiltration and nanofiltration are carried out successively to the crude product liquid of impurity 11, impurity 13 and impurity 15；
6) step 5) obtain the nanofiltration liquid of impurity 11, impurity 13 and impurity 15 and prepare post separation with high pressure liquid chromatography respectively,
Obtain the high-purity sample of impurity 11, impurity 13 and impurity 15.
Preferably, above-mentioned steps 1) in vancomycin hydrochloride crystalline powder high pressure liquid chromatography be detected as 95～97% purity.
Preferably, above-mentioned steps 2) in adjust pH4～6 with the oxalic acid solution of concentration 1%～2% (g/mL).
Preferably, above-mentioned steps 3) adjust back pH with the sodium bicarbonate solution or sodium hydroxide solution of 1%-2% (g/mL).
Preferably, above-mentioned steps 4) resin that adopts for weak-acid ion exchange resin, the FPDA13 of preferred mitsubishi chemical industry or
The HZPD-30 resins of Shanghai Hua Zhen；Resin chromatography condition is：
Upper 1～1.5BV/h of column flow rate, collects leakage imbibition, checked for impurities situation；
0.03mol/L NH4The Cl aqueous solution (3BV) prewashing, it is unified to collect pre- washing lotion, checked for impurities situation；
0.3mol/L NH4The Cl aqueous solution elutes (5BV), Fractional Collections eluent (every bottle of 1/10BV), detects eluent impurity
Situation；
From the beginning of prewashing, 0.5～0.8BV/h of flow control.
Preferably, above-mentioned steps 5) in the filter sizes that use of ultrafiltration be 5000～7000Da；The filter sizes that nanofiltration is used are
400～500Da；The nanofiltration liquid volume of each impurity is equivalent to by step 1) take vancomycin hydrochloride crystalline powder and prepare solution body
Long-pending 1/5-1/4.
Preferably, above-mentioned steps 6) in prepare the separation condition of post and be：
Prepare filler：C18HCE
Mobile phase A：Acetonitrile
Mobile phase B：0.1% (V/V) TFA aqueous solution
Gradient is arranged：
Table 2
| Time (min) | Mobile phase B | Mobile phase A | Flow velocity (mL/min) |
| 0 | 92 | 8 | 70 |
| 31 | 83 | 17 | 70 |
| 33 | 8 | 92 | 70 |
| 35 | 10 | 90 | 70 |
| 37.1 | 93 | 7 | 100 |
| 45 | 93 | 7 | 100 |
Detection wavelength：280nm.
Impurity 11 in vancomycin hydrochloride sample, impurity 13 and the high-purity of impurity 15 can be quickly prepared by the inventive method
Sample, process is simple has saved great amount of cost compared to the method that this several impurity are prepared in prior art.
Description of the drawings
Fig. 1 is the high pressure liquid chromatography detection collection of illustrative plates of vancomycin hydrochloride sample.
Specific embodiment
By the following examples the invention will be further described, but this is not limitation of the present invention, those skilled in the art
Basic thought of the invention, various modifications may be made or improve, but without departing from the present invention basic thought,
Within the scope of the present invention.
Embodiment 1.
1. 10g vancomycin hydrochloride crystalline powders (high pressure liquid chromatography detection purity is 95.1%) are taken, adds 5% purified water to match somebody with somebody
The aqueous solution of 52g/L is made, liquor capacity is 192.4mL；
2. solution is adjusted into pH to 4.15 with 2% oxalic acid solution, kept for 8 hours at 40～42 DEG C of water-bath；
3. add 2% sodium bicarbonate solution to adjust pH to 6.37 in the solution after insulation；
4. the solution after readjustment pH is carried out into FPDA13 resin chromatographies, FPDA13 resin columns loading amount is 1500mL, flow velocity
2250mL/h。
5. with the 0.03mol/L NH of 4500mL after the completion of upper prop4Cl aqueous solution prewashing resins, flow velocity 1200mL/h；
6. with the 0.3mol/L NH of 5500mL4The Cl aqueous solution is eluted, flow velocity 900mL/h, and 150mL collects one bottle, takes
Sample high pressure liquid chromatography detection (detection method with the vancomycin hydrochloride specified according to 2010 editions Chinese Pharmacopoeias detection mode, under
Together), the desorbed solution of vancomycin impurities 11, impurity 13 and impurity 15 of the purity more than 40% is collected and combined respectively；
7. respectively the impurity 11 collected, impurity 13 and the desorbed solution of impurity 15 carried out into ultrafiltration with the milipore filter of 7000D respectively,
Carry out nanofiltration with the NF membrane of 500D again, nanofiltration concentrate carries out high pressure liquid chromatography detection, the content of vancomycin impurities 11
For 42.6%, volume 38mL, the content of impurity 13 is 53.6%, volume 48mL, and the content of impurity 15 is 46.3%, body
Product 43mL；
8. it is prepared separation to the nanofiltration liquid of impurity 11,13 and 15 respectively using high pressure preparative liquid chromatography, separates impurity and freeze
Dry detection, as a result as shown in table 3.
Table 3
| Impurity title | Chromatographic purity | Lyophilized weight |
| Impurity 11 | 97.2% | 52mg |
| Impurity 13 | 97.7% | 43mg |
| Impurity 15 | 98.3% | 60.2mg |
Embodiment 2.
1. 10g vancomycin hydrochloride crystalline powders (high pressure liquid chromatography detection purity is 96.3%) are taken, adds 5% purified water to match somebody with somebody
The aqueous solution of 56g/L is made, liquor capacity is 178.6mL；
2. solution is adjusted into pH to 4.69 with 1% oxalic acid solution, kept for 9 hours at 40～42 DEG C of water-bath；；
3. add 1.5% sodium bicarbonate solution to adjust pH to 6.93 in the solution after insulation；
4. the solution after readjustment pH is carried out into FPDA13 resin chromatographies, FPDA13 resin columns loading amount is 1500mL, flow velocity
2250mL/h。
5. with the 0.03mol/L NH of 4500mL after the completion of upper prop4Cl aqueous solution prewashing resins, flow velocity 1100mL/h
6. with the 0.3mol/L NH of 5500mL4The Cl aqueous solution is eluted, flow velocity 1000mL/h, and 150mL collects one bottle, takes
The detection of sample high pressure liquid chromatography, collects and combines respectively vancomycin impurities 11 of the purity more than 40%, impurity 13 and impurity 15
Desorbed solution；
7. respectively the impurity 11 collected, impurity 13 and the desorbed solution of impurity 15 carried out into ultrafiltration with the milipore filter of 5000D respectively,
Carry out nanofiltration with the NF membrane of 400D again, nanofiltration concentrate carries out high pressure liquid chromatography detection, the content of vancomycin impurities 11
For 43.2%, volume 40mL, the content of impurity 13 is 51.9%, volume 41mL, and the content of impurity 15 is 57.2%, body
Product 43mL；
8. it is prepared separation to the nanofiltration liquid of impurity 11,13 and 15 respectively using high pressure preparative liquid chromatography, separates impurity and freeze
Dry detection, as a result as shown in table 4.
Table 4
| Impurity title | Chromatographic purity | Lyophilized weight |
| Impurity 11 | 97.6% | 54.2mg |
| Impurity 13 | 97.5% | 46mg |
| Impurity 15 | 98.4% | 62.3mg |
Embodiment 3.
1. 10g vancomycin hydrochloride crystalline powders (high pressure liquid chromatography detection purity is 95.3%) are taken, adds 5% purified water to match somebody with somebody
The aqueous solution of 60g/L is made, liquor capacity is 166.7mL；
2. solution is adjusted into pH to 5.86 with 1.5% oxalic acid solution, kept for 8.5 hours at 40～42 DEG C of water-bath；
3. add 1.5% sodium bicarbonate solution to adjust pH to 6.21 in the solution after insulation；
4. the solution after readjustment pH is carried out into FPDA13 resin chromatographies, FPDA13 resin columns loading amount is 1500mL, flow velocity
1500mL/h。
5. with the 0.03mol/L NH of 4500mL after the completion of upper prop4Cl aqueous solution prewashing resins, flow velocity 1100mL/h
6. with the 0.3mol/L NH of 5500mL4The Cl aqueous solution is eluted, flow velocity 900mL/h, and 150mL collects one bottle, takes
The detection of sample high pressure liquid chromatography, collects and combines respectively vancomycin impurities 11 of the purity more than 40%, impurity 13 and impurity 15
Desorbed solution；
7. respectively the impurity 11 collected, impurity 13 and the desorbed solution of impurity 15 carried out into ultrafiltration with the milipore filter of 5000D respectively,
Carry out nanofiltration with the NF membrane of 400D again, nanofiltration concentrate carries out high pressure liquid chromatography detection, the content of vancomycin impurities 11
For 40.2%, volume 33mL, the content of impurity 13 is 43.6%, volume 38mL, and the content of impurity 15 is 52.9%, body
Product 40mL；
8. it is prepared separation to the nanofiltration liquid of impurity 11,13 and 15 respectively using high pressure preparative liquid chromatography, separates impurity and freeze
Dry detection, as a result as shown in table 5.
Table 5
| Impurity title | Chromatographic purity | Lyophilized weight |
| Impurity 11 | 97.2% | 39.6mg |
| Impurity 13 | 97.1% | 47.2mg |
| Impurity 15 | 97.9% | 62.8mg |
Embodiment 4.
1. 10g vancomycin hydrochloride crystalline powders (high pressure liquid chromatography detection purity is 96.1%) are taken, adds 5% purified water to match somebody with somebody
The aqueous solution of 55g/L is made, liquor capacity is 181.8mL；
2. solution is adjusted into pH to 5.39 with 1.5% oxalic acid solution, kept for 9 hours at 40～42 DEG C of water-bath；
3. add 2% sodium bicarbonate solution to adjust pH to 6.32 in the solution after insulation；
4. the solution after readjustment pH is carried out into FPDA13 resin chromatographies, FPDA13 resin columns loading amount is 1500mL, flow velocity
1500mL/h。
5. with the 0.03mol/L NH of 4500mL after the completion of upper prop4Cl aqueous solution prewashing resins, flow velocity 900mL/h；
6. with the 0.3mol/L NH of 5500mL4The Cl aqueous solution is eluted, flow velocity 1000mL/h, and 150mL collects one bottle,
Sampling high pressure liquid chromatography detection, collects and combines respectively vancomycin impurities 11 of the purity more than 40%, impurity 13 and impurity 15
Desorbed solution；
7. respectively the impurity 11 collected, impurity 13 and the desorbed solution of impurity 15 carried out into ultrafiltration with the milipore filter of 5000D respectively,
Carry out nanofiltration with the NF membrane of 400D again, nanofiltration concentrate carries out high pressure liquid chromatography detection, the content of vancomycin impurities 11
For 47.2%, volume 42mL, the content of impurity 13 is 53.1%, volume 38mL, and the content of impurity 15 is 55.8%, body
Product 36mL；
8. it is prepared separation to the nanofiltration liquid of impurity 11,13 and 15 respectively using high pressure preparative liquid chromatography, separates impurity and freeze
Dry detection, as a result as shown in table 6.
Table 6
| Impurity title | Chromatographic purity | Lyophilized weight |
| Impurity 11 | 98.1% | 50.7mg |
| Impurity 13 | 97.4% | 52.1mg |
| Impurity 15 | 98.6% | 59.7mg |
Claims (10)
1. the preparation method of a kind of vancomycin hydrochloride impurity 11,13 and 15 high-purity samples, comprises the following steps：
1) vancomycin hydrochloride crystalline powder is taken, the vancomycin hydrochloride aqueous solution that concentration is 60～70g/L is configured to；
2) by step 1) the vancomycin hydrochloride aqueous solution that obtains adjusts pH 4～6, and at 40～42 DEG C of water-bath 8～9 hours are incubated.
3) to step 2) alkali is slowly added in the vancomycin hydrochloride aqueous solution after insulation, adjust back pH to 6～7；
4) to step 3) readjustment pH after the vancomycin hydrochloride aqueous solution carry out macroreticular resin chromatographic enrichment, purity is collected respectively
For the crude product liquid of 40～60% impurity 11, impurity 13 and impurity 15；
5) respectively ultrafiltration and nanofiltration are carried out successively to the crude product liquid of impurity 11, impurity 13 and impurity 15；
6) step 5) obtain the nanofiltration liquid of impurity 11, impurity 13 and impurity 15 and prepare post separation with high pressure liquid chromatography respectively,
Obtain the high-purity sample of impurity 11, impurity 13 and impurity 15.
2. preparation method as claimed in claim 1, it is characterised in that step 1) in vancomycin hydrochloride crystalline powder high pressure liquid phase
Chromatogram is detected as 95～97% purity.
3. preparation method as claimed in claim 1, it is characterised in that step 2) in adjusted with the oxalic acid solution of concentration 1%～2%
PH4～6.
4. preparation method as claimed in claim 1, it is characterised in that step 3) sodium bicarbonate solution with 1%～2% or hydrogen-oxygen
Change sodium solution readjustment pH.
5. preparation method as claimed in claim 1, it is characterised in that step 4) resin that adopts is for weak-acid ion exchange resin.
6. preparation method as claimed in claim 5, it is characterised in that the weak-acid ion exchange resin is mitsubishi chemical industry
The HZPD-30 resins of FPDA13 or Shanghai Hua Zhen.
7. preparation method as claimed in claim 5, it is characterised in that step 4) resin chromatography condition is：Upper 1～1.5BV/h of column flow rate；
The 0.03mol/L NH of 3BV4Cl prewashing；The 0.3mol/L NH of 5BV4Cl wash-outs, Fractional Collections eluent and detection are washed
De- liquid impurity situation；From the beginning of prewashing, 0.5～0.8BV/h of flow control.
8. preparation method as claimed in claim 1, it is characterised in that step 5) in the filter sizes that use of ultrafiltration be 5000～7000
Da；The filter sizes that nanofiltration is used are 400～500Da.
9. preparation method as claimed in claim 1, it is characterised in that step 5) nanofiltration liquid volume is equivalent to by step 1) taken
The 1/5～1/4 of the liquor capacity that vancomycin hydrochloride crystalline powder is formulated as.
10. preparation method as claimed in claim 1, it is characterised in that step 6) separation that uses of mesohigh liquid chromatography preparation post
Condition is：Filler is prepared for C18HCE；Mobile phase A is acetonitrile；Mobile phase B is the trifluoroacetic acid of 0.1% (V/V)
The aqueous solution；Gradient is set to shown in table 2：
Table 2
Detection wavelength is 280nm.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110156876A (en) * | 2019-05-25 | 2019-08-23 | 聊城大学 | A kind of high-purity A40926B0 preparation method of suitable industrialized production |
| CN110903346A (en) * | 2019-11-08 | 2020-03-24 | 丽珠集团新北江制药股份有限公司 | Method for preparing vancomycin hydrochloride impurity impC |
| CN114112612A (en) * | 2021-10-28 | 2022-03-01 | 丽珠集团福州福兴医药有限公司 | Separation and purification method of teicoplanin I5 impurity and application thereof |
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| CN114112612A (en) * | 2021-10-28 | 2022-03-01 | 丽珠集团福州福兴医药有限公司 | Separation and purification method of teicoplanin I5 impurity and application thereof |
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Effective date of registration: 20221012 Address after: 3007, Hengqin international financial center building, No. 58, Huajin street, Hengqin new area, Zhuhai, Guangdong 519031 Patentee after: New founder holdings development Co.,Ltd. Patentee after: CHONGQING DAXIN PHARMACEUTICAL Co.,Ltd. Patentee after: Peking University Medical Management Co.,Ltd. Address before: 100871, fangzheng building, 298 Fu Cheng Road, Beijing, Haidian District Patentee before: PEKING UNIVERSITY FOUNDER GROUP Co.,Ltd. Patentee before: CHONGQING DAXIN PHARMACEUTICAL Co.,Ltd. Patentee before: PKU HEALTHCARE INDUSTRY Group |