CN106565820A - Method for preparing high-purity sample of vancomycin hydrochloride impurities 3 and 8 - Google Patents
Method for preparing high-purity sample of vancomycin hydrochloride impurities 3 and 8 Download PDFInfo
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Abstract
The invention discloses a method for preparing a high-purity sample of vancomycin hydrochloride impurities 3 and 8. The method comprises the following steps: taking vancomycin hydrochloride crystalline powder, preparing the vancomycin hydrochloride crystalline powder into a solution with concentration being 40-50g/L by use of a sodium chloride aqueous solution; preserving heat for 72-73 hours at a water bath ranging from 70 DEG C to 75 DEG C; cooling the solution to 4-6 DEG C, and carrying out nanofiltration desalination; carrying out resin chromatography enrichment on nanofiltration liquor, and separately collecting desorbed solutions of an impurity 3 and an impurity 8, purity of which is greater than 80%; sequentially carrying out ultrafiltration and nanofiltration on the desorbed solutions; and desalinizing the nanofiltration liquor with a high-pressure liquid-phase chromatography preparation column to obtain high-purity samples of the impurity 3 and the impurity 8, and the purity of the samples is greater than 97%. The method disclosed by the invention is simple in process, so that preparation cost is greatly 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 3 and impurity 8.
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 3, impurity 9 (referring to Fig. 1) comparision contents in vancomycin hydrochloride finished product are low, and C18 fillers prepare post point
Need to consume substantial amounts of vancomycin hydrochloride finished product and substantial amounts of mobile phase from this impurity is prepared, preparation cost is very high.
The content of the invention
It is an object of the invention to provide a kind of preparation method of the high-purity sample of vancomycin hydrochloride related impurities 3 and impurity 8,
Quickly and more easily the impurity 3 in vancomycin hydrochloride sample, impurity 8 can be enriched to into higher purity, and component phase
To single, then highly purified impurity sample is obtained by preparative separation.
A kind of method for preparing vancomycin hydrochloride impurity 3 and the high-purity sample of impurity 8, its step includes：
1) vancomycin hydrochloride crystalline powder is taken, with sodium-chloride water solution 40-50g/L concentration is dissolved into, obtain vancomycin hydrochloride
Sodium-chloride water solution；
2) by step 1) the vancomycin hydrochloride sodium-chloride water solution heating water bath to 70～75 DEG C that obtains, it is incubated 72～73 hours；
3) by step 2) solution cool to 4～6 DEG C, carry out nanofiltration desalination；
4) to step 3) nanofiltration liquid that obtains carries out resin chromatography enrichment, and impurity 3 of the purity more than 80% and impurity are collected respectively
8 desorbed solution；
5) desorbed solution of impurity 8 of the impurity 3 and purity respectively to purity more than 80% more than 80% carries out successively ultrafiltration and nanofiltration
Concentration；
6) step 5) obtain impurity 3 and the nanofiltration liquid of impurity 8 prepares post desalination with high pressure liquid chromatography respectively, obtain purity big
Impurity 3 and the high-purity sample of impurity 8 in 97%.
Preferably, above-mentioned steps 1) in vancomycin hydrochloride crystalline powder high pressure liquid chromatography be detected as 95-98% purity.
Preferably, above-mentioned steps 1) described in sodium-chloride water solution concentration be 5%～6% (g/mL).
Preferably, above-mentioned steps 3) in the filter sizes that use of nanofiltration be 400～500Da, hydrochloric acid is through the ages in nanofiltration liquid after nanofiltration
The content of mycin is 10～50g/L.
Preferably, above-mentioned steps 4) resin that adopts for non-polar macroporous resin, such as mitsubishi chemical industry HP20SS or Shanghai Hua Zhen
Chromatogram -3, resin particle diameter 200-300 mesh；The resin chromatography condition for adopting for：
Upper 1～1.5BV/h of column flow rate, collects leakage imbibition, checked for impurities situation；
Ammonium acetate aqueous solution (3BV) prewashing of 1% (g/mL), it is unified to collect pre- washing lotion, checked for impurities situation；
The NH of 0.3% (g/mL)4HCO3The aqueous solution (pH7.9～8.0, electrical conductivity 3.52) 3BV prewashing, unified collection liquid,
Checked for impurities situation
The NH of 0.5% (g/mL)4HCO3(pH7.9～8.0, electrical conductivity 5.80) 5BV is eluted, and Fractional Collections eluent is (such as
1/10 eluent of resin column volume collection one time), detect eluent impurity situation；Merge impurity 3 of the purity more than 80% respectively
With the desorbed solution of impurity 8.
In resin chromatography, detection method is detected using high pressure liquid chromatography, and testing conditions are as follows：
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
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 impurity 3 for respectively obtaining and the final nanofiltration liquid of impurity 8, its volume is equivalent to by step 1) in take hydrochloric acid
Vancomycin crystalline powder prepares the 1/3～1/2 of liquor capacity.
Preferably, above-mentioned steps 6) in prepare the separation condition of post desalination 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 | 90 | 10 | 70 |
| 28 | 90 | 10 | 70 |
| 30 | 15 | 85 | 70 |
| 34 | 15 | 85 | 70 |
| 34.8 | 93 | 7 | 100 |
| 45 | 93 | 7 | 100 |
Detection wavelength：280nm
Impurity 3, the high-purity sample of impurity 8 in vancomycin hydrochloride sample, technique can be quickly prepared by the inventive method
Simply, great amount of cost has been saved 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. 5g vancomycin hydrochloride crystalline powders (high pressure liquid chromatography detection purity is 95%) are taken, 5% aqueous sodium chloride is added
Liquid is configured to the aqueous solution of 42g/L, liquor capacity about 119mL；
2. solution water bath heat preservation step 1 prepared, temperature is 72 DEG C, and then temperature retention time 72h is cooled to 4 DEG C with cup type
Aperture carries out nanofiltration for 500Da collecting and filtering apparatus, liquor capacity 70mL after nanofiltration, 4 DEG C of preservations；
3. by the solution after nanofiltration, the HP20SS resin columns of upper 1000mL；
4. the ammonium acetate aqueous solution washing resin of 1% concentration (g/mL) of 3000mL is used after the completion of upper prop；
5. the NH of 0.3% concentration (g/ml) of 3000mL is used4HCO3The aqueous solution (pH7.9～8.0) prewashing；
6. the NH of 0.5% concentration (g/ml) of 5000mL is used4HCO3Water-soluble (pH7.9～8.0) liquid wash-out, receives per 100mL
One bottle of collection, sampling high pressure liquid chromatography detection；Merge stripping liquid 500mL of the purity of impurity 3 more than 80%；Merge impurity 8 pure
Stripping liquid 600mL of the degree more than 80%；
The condition of wherein high pressure liquid chromatography detection is as follows：
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
7. respectively impurity 3 and the desorbed solution of impurity 8 carried out into ultrafiltration and nanofiltration, the filter sizes that ultrafiltration is used are 7000Da, are received
The filter sizes that filter is used are 500Da；
8. volume is 40mL after the nanofiltration of impurity 3, and high pressure liquid chromatography detects that its content is 81.6%；Volume is after the nanofiltration of impurity 8
52mL, high pressure liquid chromatography detects that its its content is 84.1%；
9. it is prepared separation to the nanofiltration liquid of impurity 3 and impurity 8 respectively using high pressure preparative liquid chromatography, separates impurity and freeze
Detection, as a result as shown in table 3.
Table 3
| Impurity title | Chromatographic purity | Lyophilized weight |
| Impurity 3 | 98.5% | 82mg |
| Impurity 8 | 98.2% | 85.2mg |
Embodiment 2.
1. 5g vancomycin hydrochloride crystalline powders (high pressure liquid chromatography detection purity is 96%) are taken, 6% aqueous sodium chloride is added
Liquid is configured to the aqueous solution of 45g/L, liquor capacity about 111mL；
2. solution water bath heat preservation step 1 prepared, temperature is 73 DEG C, and then temperature retention time 73h is cooled to 4 DEG C with cup type
Aperture carries out nanofiltration for 500Da collecting and filtering apparatus, liquor capacity 64.6mL after nanofiltration, 4 DEG C of preservations；
3. by the solution after nanofiltration, the resin column of chromatogram -3 of upper 1000mL；
4. the ammonium acetate aqueous solution washing resin of 1% concentration of 3000mL is used after the completion of upper prop；
5. the NH of 0.3% concentration of 3000mL is used4HCO3The aqueous solution (pH7.9～8.0) prewashing；
6. the NH of 0.5% concentration of 5000mL is used4HCO3The aqueous solution (pH7.9～8.0) is eluted, and one bottle is collected per 100mL,
Sampling high pressure liquid chromatography detection (testing conditions are with embodiment 1)；Merge stripping liquid 600mL of the purity of impurity 3 more than 80%；
Merge stripping liquid 600mL of the purity of impurity 8 more than 80%.
7. respectively impurity 3 and the desorbed solution of impurity 8 carried out into ultrafiltration and nanofiltration, the filter sizes that ultrafiltration is used are 5000Da, are received
The filter sizes that filter is used are 400Da；
8. volume is 37mL after the nanofiltration of impurity 3, and high pressure liquid chromatography detects that its content is 83.6%；Volume is after the nanofiltration of impurity 8
55mL, high pressure liquid chromatography detects that its content is 84.4%；
9. it is prepared separation to the nanofiltration liquid of impurity 3 and impurity 8 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 3 | 97.5% | 90.5mg |
| Impurity 8 | 99.2% | 75.6mg |
Embodiment 3.
1. 5g vancomycin hydrochloride crystalline powders (high pressure liquid chromatography detection purity is 95.6%) are taken, 6% aqueous sodium chloride is added
Liquid is configured to the aqueous solution of 50g/L, liquor capacity about 100mL；
2. solution water bath heat preservation step 1 prepared, temperature is 72.5 DEG C, and then temperature retention time 72.5h is cooled to 4 DEG C with cup
Formula aperture carries out nanofiltration for 500Da collecting and filtering apparatus, liquor capacity 60.8mL after nanofiltration, 4 DEG C of preservations；
3. by the solution after nanofiltration, the resin column of chromatogram -3 of upper 1000mL；
4. the ammonium acetate aqueous solution washing resin of 1% concentration of 3000mL is used after the completion of upper prop；
5. the NH of 0.3% concentration of 3000mL is used4HCO3The aqueous solution (pH7.9～8.0) prewashing；
6. the NH of 0.5% concentration of 5000mL is used4HCO3The aqueous solution (pH7.9～8.0) is eluted, and one bottle is collected per 100mL,
Sampling high pressure liquid chromatography detection (testing conditions are with embodiment 1)；Merge stripping liquid 500mL of the purity of impurity 3 more than 80%；
Merge stripping liquid 500mL of the purity of impurity 8 more than 80%.
7. respectively impurity 3 and the desorbed solution of impurity 8 carried out into ultrafiltration and nanofiltration, the filter sizes that ultrafiltration is used are 7000Da, are received
The filter sizes that filter is used are 400Da；
8. volume is 42mL after the nanofiltration of impurity 3, and high pressure liquid chromatography detects that its content is 82.1%；Volume is after the nanofiltration of impurity 8
45mL, high pressure liquid chromatography detects that its its content is 83.6%；
9. it is prepared separation to the nanofiltration liquid of impurity 3 and impurity 8 respectively using high pressure preparative liquid chromatography, separates impurity and freeze
Detection, as a result as shown in table 5.
Table 5
| Impurity title | Chromatographic purity | Lyophilized weight |
| Impurity 3 | 98.1% | 81.5mg |
| Impurity 8 | 98.9% | 86.1mg |
Claims (10)
1. a kind of method for preparing vancomycin hydrochloride impurity 3 and the high-purity sample of impurity 8, comprises the following steps：
1) vancomycin hydrochloride crystalline powder is taken, with sodium-chloride water solution 40-50g/L concentration is dissolved into, obtain vancomycin hydrochloride
Sodium-chloride water solution；
2) by step 1) the vancomycin hydrochloride sodium-chloride water solution heating water bath to 70～75 DEG C that obtains, it is incubated 72～73 hours；
3) by step 2) solution cool to 4～6 DEG C, carry out nanofiltration desalination；
4) to step 3) nanofiltration liquid that obtains carries out resin chromatography enrichment, and impurity 3 of the purity more than 80% and impurity are collected respectively
8 desorbed solution；
5) respectively to step 4) collect impurity 3 and impurity 8 desorbed solution carry out successively ultrafiltration and nanofiltration concentration；
6) step 5) obtain impurity 3 and the nanofiltration liquid of impurity 8 prepares post desalination with high pressure liquid chromatography respectively, obtain purity big
Impurity 3 and the high-purity sample of impurity 8 in 97%.
2. the method for claim 1, it is characterised in that step 1) in vancomycin hydrochloride crystalline powder high pressure liquid chromatography
It is detected as 95-98% purity.
3. the method for claim 1, it is characterised in that step 1) described in the concentration of sodium-chloride water solution be 5%～6%.
4. the method for claim 1, it is characterised in that step 3) in the filter sizes that use of nanofiltration be 400～500Da,
The content of vancomycin hydrochloride is 10～50g/L in nanofiltration liquid after nanofiltration.
5. the method for claim 1, it is characterised in that step 4) resin that adopts is for non-polar macroporous resin.
6. method as claimed in claim 5, it is characterised in that the non-polar macroporous resin be mitsubishi chemical industry HP20SS or on
Hai Huazhen chromatogram -3, the mesh of resin particle diameter 200～300.
7. method as claimed in claim 5, it is characterised in that step 4) actual conditions of resin chromatography is：Upper column flow rate 1～1.5
BV/h；The 1% of 3BV ammonium acetate aqueous solution prewashing is used after the completion of upper prop；The 0.3% of 3BV NH is used again4HCO3
Aqueous solution prewashing；Finally use the 0.5% of 5BV NH4HCO3Wash-out, Fractional Collections eluent is simultaneously detected.
8. the method for claim 1, it is characterised in that step 5) in the filter sizes that use of ultrafiltration be 5000～7000Da；
The filter sizes that nanofiltration is used are 400～500Da.
9. the method for claim 1, it is characterised in that step 5) impurity 3 that respectively obtains and impurity 8 final nanofiltration
Liquid, its volume is equivalent to by step 1) in take the 1/3～1/2 of the liquor capacity that vancomycin hydrochloride crystalline powder is prepared.
10. the method for claim 1, it is characterised in that step 6) separation condition that uses of mesohigh liquid chromatography preparation post
For：Filler is prepared for C18HCE；Mobile phase A is acetonitrile；Mobile phase B is water-soluble for the trifluoroacetic acid of 0.1% (V/V)
Liquid；Gradient is set to shown in table 2：
Table 2
Detection wavelength is 280nm.
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| 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 |
| CN113429462A (en) * | 2021-08-17 | 2021-09-24 | 丽珠集团福州福兴医药有限公司 | Purification method of high-purity vancomycin |
| 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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