CN105732738B - A kind of method of purification of tobramycin - Google Patents
A kind of method of purification of tobramycin Download PDFInfo
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- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
- C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
- C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
- C07H15/234—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Abstract
The present invention provides a kind of method of purification of tobramycin, which includes the following steps：(1) it by tobramycin hydrolyzate hydrochloric acid tune pH value to 8.00, by Macroporous weak acid cation exchange resin, is washed successively with ammonium sulfate, ammonium hydroxide elution, collects ammonium hydroxide eluent；(2) the ammonium hydroxide eluent for collecting step (1) concentrates；(3) it uses ammonium hydroxide regulating step (2) concentrate pH value to 8.00, is passed through Macroporous weak acid cation exchange resin, ammonium sulfate washing impurity-removing, ammonium hydroxide elution is used to collect ammonium hydroxide eluent successively；Ammonium hydroxide eluent pH to 4.00-5.50 is adjusted with hydrochloric acid, macroporous anion exchange resin is passed through, with pure water elution；(4) the ammonium hydroxide eluent for collecting step (3) concentrates, and crystallizes, and spray drying obtains tobramycin finished product.
Description
Technical field
The invention belongs to pharmaceutical technology fields, specifically, the present invention relates to a kind of methods of purification of tobramycin.
Background technology
Tobramycin (Tobramycin) be also tobramycin, is a kind of aminoglycoside antibiotics, can be used to treat more
The kind microbial infection of bacterium infection, especially Gram-negative.Tobramycin is obtained through submerged fermentation by streptomyces tenebrarius,
The primary product of fermentation process be A Baila mycins, 6 "-O- carbamyls kanamycin Bs and 6 "-O- carbamyl tobramycin, rear 2
Person generates kanamycin B and tobramycin respectively through hydrolyzing.Since these three main component physicochemical properties that fermentation generates are close,
Especially kanamycin B (Kb) and tobramycin, the only poor hydroxyl of structure, so its chemical extraction is refined than other amino sugars
Tobramycin antibiotic is complicated, and the content for reducing kanamycin B impurity is the difficult point of chemical extraction process for refining, and in each purification work
Some coloured and not soluble in water impurity are easy tod produce in skill, cause to always exist color, kanamycin B in tobramycin finished product
The problem of impurity content and clarity.Tobramycin is developed and is listed already, but about disclosed about appropriate cloth both at home and abroad
The report of mycin purification research is very rare.
Sun Liwei reports 4 factors in adjustment column chromatography：Rod structure (ratio of height to diameter), resin saturation degree, elution flow rate
And pH value has picked the Best Point of 4 factors combination, has improved the purification efficiency of tobramycin by orthogonal test, column chromatography
Separation average yield is increased to 36.04%, reaches as high as 37.58%, refines total recovery and reaches as high as 20.21%, final to improve
The yield rate of tobramycin.But the separation yield of the column chromatography is too low, causes great waste.(Sun Liwei, orthogonal examination
Test application of the method in tobramycin refining technique, Strait Pharmaceutical Journal, 1996,8 (2)：23-24).
Hong Wenrong etc. reports 6 "-O- carbamyl tobramycin in tobramycin chemical extraction process for refining and hydrolyzes power
It learns, the used displacement chromatography agent concentration (pH) of hydrolyzate ion exchange column.For hydrolysis dynamics, the experimental results showed that,
PH value is important influence factor, and pH value is higher, and hydrolysis is faster, but light transmittance is lower, in order to balance hydrolysis rate and light transmission
Degree selectes pH 10 as best hydrolysis pH value；Displacement chromatography agent NH4When a concentration of 0.1mol/L pH 11.12 of OH, recycling
Rate up to 70.2% (flood text honor etc., the research of tobramycin chemical extraction refined nature, China Medicine University's journal, 2000,31
(4)：304-308).But inventor has found that the tobramycin impurity content prepared by this report is high, needs to carry out it
It is further to improve.
Invention content
In order to improve separation yield, the impurity content of tobramycin finished product is reduced, present inventor has performed further investigation, hairs
After existing technological parameter is adjusted improvement, the tobramycin finished product of better quality can be greatly obtained.Specifically, the present invention relates to
And a kind of method of purification of tobramycin.
A kind of method of purification of tobramycin, the purification process include the following steps：
(1) by tobramycin hydrolyzate hydrochloric acid tune pH value to 8.00, by Macroporous weak acid cation exchange resin, according to
It is secondary washed with ammonium sulfate, ammonium hydroxide elution, collect ammonium hydroxide eluent；
(2) the ammonium hydroxide eluent for collecting step (1) concentrates；
(3) the concentrate pH value of ammonium hydroxide regulating step (2) is passed through Macroporous weak acid cation exchange resin to 8.00, according to
It is secondary that ammonium sulfate washing impurity-removing, ammonium hydroxide elution is used to collect ammonium hydroxide eluent；Ammonium hydroxide eluent pH to 4.00- is adjusted with hydrochloric acid
5.50, it is passed through macroporous anion exchange resin, pure water elution.
(4) the ammonium hydroxide eluent for collecting step (3) concentrates, and crystallizes, and spray drying obtains tobramycin finished product.
In the step (1), the ammonium sulfate washing is that 3.0%-5.0% ammonium sulphate gradients wash.
In the step (1), collects ammonium sulfate cleaning solution and carry out thin-layer chromatography detection, when eluent impurity composition color spot is small
When the 2% of tobramycin color spot, eluted with ammonium hydroxide.
In the step (1), the aqueous ammonia gradient that the ammonium hydroxide elution is 0.1-2.0mol/L elutes.
In the step (1), Macroporous weak acid cation exchange resin be 151 resins, D152 resins, D155 resins,
D113 resins.
Preferably, in the step (1), Macroporous weak acid cation exchange resin is 151 resins.
In the step (3), the ammonium sulfate washing is that 3.0%-5.0% ammonium sulphate gradients wash.
In the step (3), a concentration of 1.00mol/L of the ammonium hydroxide.
In the step (3), Macroporous weak acid cation exchange resin be 151 resins, D152 resins, D155 resins,
D113 resins.
Preferably, in the step (3), Macroporous weak acid cation exchange resin is 151 resins.
In the step (3), ammonium hydroxide eluent pH to 4.3 is adjusted with hydrochloric acid, is passed through macroporous anion exchange resin, it is pure
Water elution.
In the step (3), macroporous anion exchange resin is 122 resins, D301 resins, D315 resins.
Preferably, in the step (3), macroporous anion exchange resin is 122 resins.
The present inventor by the adjustment of tobramycin purifying technique make finished product color grade by it is past be difficult to reach No. 2 colors to
It can reach No. 1 color, ethyl alcohol residual drops to 800ppm or less by past 1500ppm or more；Major impurity kanamycin B is also by mistake
0.2% or more gone can be reduced to 0.1% or less；It is always miscellaneous to drop to 1.0% or less by 1.3% or so；After process above adjusts
Perplex the clarity problem of the product for many years also thoroughly solve, clarity 100% is qualified, all other single contaminants also phase
It should reduce much, product quality is fully achieved the requirement of high-end customer and gets the nod.
Specific implementation mode
151 resins, D152 resins, D155 resins, D113 resins, 122 resins, D301 resins, D315 resins are purchased from Bangbu
TianXing resin Co., Ltd.
Tobramycin hydrolyzate prepares (flood text honor etc., tobramycin chemical extraction refined nature according to the report of Hong Wenrong
Research, China Medicine University's journal, 2000,31 (4)：304-308).
Embodiment 1
Tobramycin active unit is not less than 10000u/ml in tobramycin hydrolyzate, with salt acid for adjusting pH to 8.0, root
Upper prop liquid dosage is calculated according to the adsorption capacity of D151 resin chromatography columns, after loading is complete, washing is carried out with 3.0-5.0% ammonium sulfate and removes
It is miscellaneous, it is washed by the 25% of upper column quantity, is eluted with the aqueous ammonia gradient of 0.1-2.0mol/L after having washed, ammonium hydroxide elutes initial
Flow is 1200-1400ml/ point, surveys a flow within every 4 hours, after kanamycin B and tobramycin mixed liquor start appearance
Start Fractional Collections, the flow of ammonium hydroxide elution is changed to 450-550ml/ points, a flow, overall process TLC methods are surveyed per 2h
It is controlled.
Start vacuum system, condenser system.After vacuum degree≤- 0.07MPa, is concentrated in charging, controls T≤70 DEG C,
The volume of the concentrated liquid is controlled between the 0.4-0.6 of stripping liquid volume.Unit answers >=30000 μ/ml, yield >=92% after complete.
Embodiment 2
The concentrate that Example 1 obtains, is divided into 2 batches, carries out experiment A respectively and tests the experiment of B, experimental procedure and reality
It is as follows to test result：
Test A：
Ammonium hydroxide adjusts the concentrate pH value of embodiment 1 to 8.00, D151 resin chromatography columns is passed through, with 3% ammonium sulfate
Washing impurity-removing is washed by the 25% of upper column quantity, and flow control is detected in 0.40 ± 0.1BV with thin-layered chromatography, and washing is miscellaneous
Component color spot answers≤TB color spots 2% when, stop washing, ammonium hydroxide eluent is collected in ammonium hydroxide elution.
Test B：
Ammonium hydroxide adjusts the concentrate pH value of embodiment 1 to 8.00, D151 resin chromatography columns is passed through, with 3%-5% ammonium sulfate
Solution washing impurity-removing is washed by the 25% of upper column quantity, and flow control is detected in 0.40 ± 0.1BV with thin-layered chromatography, is washed
Wash miscellaneous component color spot answer≤TB color spots 2% when, stop washing, ammonium hydroxide elution, collect ammonium hydroxide eluent.
Experimental result such as table 1.
Table 1
| Impurity content | The concentrate of embodiment 1 | Test A | Test B |
| F1+F2 impurity | 4.98% | 2.37% | 1.04% |
| X impurity | 3.08% | 2.28% | 1.99% |
| Kanamycin B | 1.18% | 0.96% | 0.62% |
| Unknown maximum contaminant | 0.69% | 0.58% | 0.34% |
| It is total miscellaneous | 14.57% | 10.08% | 7.36% |
Conclusion：Experiment B is compared with experiment A, and the ammonium sulfate of washing impurity-removing is changed to the washing of 3%-5% ammonium sulphate gradients,
But test the various related impurities of B in experimental result and be all greatly lowered after upper prop parsing, impurity-eliminating effect is more excellent；And
By detection, the time for testing the ammonium sulphate gradient washing of B is more shorter than the wash time for testing A, and production efficiency is improved.
The definition of F1 and F2 impurity：F impurity is mainly made of F1 and F2.If refinery liquor detects immediately after derivative, F is miscellaneous
Matter nearby has more small impurity peaks, and after derivative liquid is placed 16 hours, small impurity peaks can be reduced or be disappeared.F impurity is
The by-product generated in extractive process belongs to small molecular sugar aminated compounds, F1 is respectively designated as due to the difference of space structure
And F2.It in refining technique, is washed by certain density ammonium sulfate, major part F impurity can be removed；In crystallization process
Also part that can be removed F impurity.
The definition of X impurity：X is miscellaneous, and the entitled Ni Bo of chemistry draws amine (Nebramine), is the catabolite in extractive process.
The definition of unknown maximum contaminant：In drug standard, except the known chemical constitution of clear specified limit and
Outside the ingredient of safety, the maximum structure of content and the non-principal component of safety.
Total miscellaneous definition：To being present in the summation of all known impurities and unknown impuritie in drug.
Embodiment 3
6 parts of embodiments 2 are taken to test the ammonium hydroxide eluent concentration that B is obtained, every part of embodiment 2 tests the ammonium hydroxide elution that B is obtained
Liquid concentration 500ml is passed through D122 resin chromatography columns with salt acid for adjusting pH value respectively to 4.0,4.3,4.5,5.0,5.5,6.0
In, it is 1: 8 that the experiment condition of D122 resin chromatography columns, which is glass column diameter height ratio, and resin loads 500ml, and pure water elution flow rate is
100ml/h collects eluent.Concentration, spray drying obtain tobramycin.It the results are shown in Table 2.
Table 2
Conclusion：It is 5.578g, pH value point that 500ml embodiments 2, which test tobramycin one-component in the ammonium hydroxide eluent that B is obtained,
When not to 4.0,4.3,4.5,5.0,5.5,6.0, the tobramycin one-component of acquisition be respectively 5.382g, 5.531g, 5.425g,
5.313g, 4.921g, 4.529g, yield are respectively 96.5%, 99.2%, 97.3%, 95.2%, 88.2%, 81.2%.Therefore
When pH value is 4.0-5.0, yield is higher than 95%, when wherein pH value is 4.3, yield highest.
Embodiment 4
Test C：
Step I, the concentrate pH value that ammonium hydroxide adjusts embodiment 1 is passed through D151 resin chromatography columns, uses 3%-5% to 8.00
Ammonium sulfate washing impurity-removing is washed by the 25% of upper column quantity, and flow control is in 0.40 ± 0.1BV, with thin-layered chromatography
Detection, wash miscellaneous component color spot answer≤TB color spots 2% when, stop washing, ammonium hydroxide elution, collect ammonium hydroxide eluent.
Step II, the ammonium hydroxide eluent concentration that step a is obtained is taken, with salt acid for adjusting pH value to 4.3, is passed through D122 resin layers
It analyses in column, it is 1: 8 that the experiment condition of D122 resin chromatography columns, which is glass column diameter height ratio, and resin loads 500ml, pure water elution stream
Speed is 100ml/h, collects eluent.Concentration crystallizes, and spray drying obtains tobramycin.
Test D：
Step III：The concentrate of Example 1 is passed through with salt acid for adjusting pH value to 4.3 in D122 resin chromatography columns,
It is 1: 8 that the experiment condition of D122 resin chromatography columns, which is glass column diameter height ratio, and resin loads 500ml, and pure water elution flow rate is
100ml/h collects eluent.
Step IV：Ammonium hydroxide regulating step III eluents, concentration, pH value to 8.00 are passed through D151 resin chromatography columns, use
3%-5% ammonium sulfate washing impurity-removings are washed by the 25% of upper column quantity, and flow control is in 0.40 ± 0.1BV, with thin layer
Chromatography detect, wash miscellaneous component color spot answer≤TB color spots 2% when, stop washing, ammonium hydroxide elution, collect ammonium hydroxide eluent.
Concentration crystallizes, and spray drying obtains tobramycin.
Experimental result is shown in Table 3.
Table 3
| Test C finished products | Test D finished products | |
| Color grade | No. 2 colors | No. 1 color |
| Ethyl alcohol remains | 1500ppm | 342ppm |
| Kanamycin B content | 0.2% | 0.05% |
| Total miscellaneous content | 1.3% | 0.5% |
| Clarity when redissolution | It is unqualified | It is qualified |
The grade scale of tobramycin finished product color grade is：Precision weighs sample 0.6g and sets in 10ml colorimetric cylinders, and 5ml is added and steams
Distilled water makes dissolving, shakes up, and sample solution and standard color solution are observed and remembered under clarity detecting apparatus lamp from up to down immediately
The color of sample solution is recorded, product solution colour should be not more than No. 3 yellow or yellow green.
The clarity detecting step of tobramycin finished product is：Precision weighs sample 0.6g and sets in 10ml colorimetric cylinders, and 5ml is added
Distilled water makes dissolving, shakes up, immediately by sample solution and turbidity standard (No. 0.5) under clarity detecting apparatus lamp, from level
Direction observes and records the clarity of sample solution.
Experiment conclusion：The finished product that experiment D is obtained is from color grade, ethyl alcohol residual, kanamycin B content and impurity content and again
When molten from the aspect of clarity, it is superior to the finished product that experiment C is obtained, therefore tests purification side of the method for purification of D due to testing C
Method.
Embodiment 5
(1) tobramycin active unit is not less than 10000u/ml in tobramycin hydrolyzate, with salt acid for adjusting pH to 8.0,
Upper prop liquid dosage is calculated according to the adsorption capacity of D151 resin chromatography columns, after loading is complete, is washed with 3.0-5.0% ammonium sulfate
Removal of impurities, is washed by the 25% of upper column quantity, and the aqueous ammonia gradient elution of 0.1-2.0mol/L, ammonium hydroxide elute initial after having washed
Flow is 1200-1400ml/ points, surveys a flow within every 4 hours, starts to be segmented after Kb and tobramycin mixed liquor start to occur
It collects, the flow of ammonium hydroxide elution is changed to 450-550ml/ points, and a flow is surveyed per 2h, and overall process is controlled with TLC methods.
(2) start vacuum system, condenser system.After vacuum degree≤- 0.07MPa, is concentrated in charging, control T≤70
DEG C, between the control volume of the concentrated liquid is the 0.4-0.6 of stripping liquid volume.Unit answers >=30000 μ/ml, yield >=92% after complete.
(3) the concentrate pH value that ammonium hydroxide regulating step (2) obtains is passed through D151 resin chromatography columns, uses 3%-5% to 8.00
Ammonium sulfate washing impurity-removing is washed by the 25% of upper column quantity, and flow control is in 0.40 ± 0.1BV, with thin-layered chromatography
Detection, wash miscellaneous component color spot answer≤TB color spots 2% when, stop washing, ammonium hydroxide elution, collect ammonium hydroxide eluent.
Ammonium hydroxide eluent concentrates, and with salt acid for adjusting pH value to 4.3, is passed through in D122 resin chromatography columns, D122 resin chromatographies
The experiment condition of column is that glass column diameter height ratio is 1: 8, and resin loads 500ml, and pure water elution flow rate is 100ml/h, and collection is washed
De- liquid.
(4) it concentrates, crystallizes, spray drying obtains tobramycin.
It is carried out continuously 3 batches of experiments, the tobramycin finished product result such as table 4 of gained.
Table 4
Conclusion：Continuous three batches of experiments, color grade are No. 1 color, and ethyl alcohol residual is low, and impurity content is qualified, as a result reproducibility
It is good.
Claims (8)
1. a kind of method of purification of tobramycin, the method for purification include the following steps：
(1) tobramycin hydrolyzate hydrochloric acid tune pH value to 8.00 is used successively by Macroporous weak acid cation exchange resin
Ammonium sulfate washing, ammonium hydroxide elution, collect ammonium hydroxide eluent；
(2) the ammonium hydroxide eluent for collecting step (1) concentrates；
(3) it uses ammonium hydroxide regulating step (2) concentrate pH value to 8.00, is passed through Macroporous weak acid cation exchange resin, uses successively
Ammonium sulfate washing impurity-removing, ammonium hydroxide elution, collects ammonium hydroxide eluent；Ammonium hydroxide eluent pH to 4.00-5.50 is adjusted with hydrochloric acid,
It is passed through macroporous anion exchange resin, with pure water elution, collects pure water elution；
(4) the pure water elution for collecting step (3) concentrates, and crystallizes, and spray drying obtains tobramycin finished product,
Wherein, in the step (1) and step (3), the ammonium sulfate washing is that 3.0%-5.0% ammonium sulphate gradients are washed
It washs.
2. the method for purification of tobramycin as described in claim 1, which is characterized in that in the step (1), collect ammonium sulfate
Cleaning solution carries out thin-layer chromatography detection, when eluent impurity composition color spot is less than the 2% of tobramycin color spot, is carried out with ammonium hydroxide
Elution；
In the step (1), the aqueous ammonia gradient that the ammonium hydroxide elution is 0.1-2.0mol/L elutes.
3. the method for purification of tobramycin as described in claim 1, which is characterized in that in the step (1) and (3), macropore
Weak-acid cation-exchange resin is D151 resins, D152 resins, D155 resins, D113 resins.
4. the method for purification of tobramycin as claimed in claim 3, which is characterized in that in the step (1) and (3), macropore
Weak-acid cation-exchange resin is D151 resins.
5. the method for purification of tobramycin as described in claim 1, which is characterized in that in the step (3), the ammonium hydroxide
A concentration of 1.00mol/L.
6. the method for purification of tobramycin as described in claim 1, which is characterized in that in the step (3), adjusted with hydrochloric acid
Ammonium hydroxide eluent pH to 4.3 is passed through macroporous anion exchange resin, pure water elution.
7. the method for purification of tobramycin as described in claim 1, which is characterized in that in the step (3), large pore anion
Exchanger resin is D122 resins, D301 resins, D315 resins.
8. the method for purification of tobramycin as claimed in claim 7, which is characterized in that in the step (3), large pore anion
Exchanger resin is D122 resins.
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| CN107674101B (en) * | 2016-08-02 | 2019-08-30 | 北大方正集团有限公司 | A kind of purification process of tobramycin |
| CN107686497B (en) * | 2016-08-05 | 2019-08-30 | 北大方正集团有限公司 | A method of purifying tobramycin |
| CN109705174B (en) * | 2019-02-19 | 2020-09-04 | 北大方正集团有限公司 | Method for extracting tobramycin |
| CN111693622B (en) * | 2020-06-16 | 2022-09-27 | 上海市食品药品检验研究院 | Tobramycin raw material and related preparation impurity mass spectrum analysis method |
| CN112625072B (en) * | 2020-12-25 | 2022-03-22 | 山东安信制药有限公司 | Method for preparing amikacin sulfate by purifying acidic cationic resin |
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