CN103604894A - Method for separating and determining bortezomib chiral isomers through high-performance liquid chromatography - Google Patents
Method for separating and determining bortezomib chiral isomers through high-performance liquid chromatography Download PDFInfo
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Abstract
The invention provides a bortezomib isomer separating and determining method. The bortezomib isomer separating and determining method is characterized in that a chiral chromatographic column is adopted, the surface of the stationary phase silica gel of the chiral chromatographic column is coated with amylose-tris(3, 5-xylyl carbamate), a mobile phase is a combination of a mobile phase A and a mobile phase B, the mobile phase A is a normal hexane solution containing 0.1% of trifluoroacetic acid, the mobile B is an absolute methanol/isopropanol solution, the ratio of absolute methanol to isopropanol is 1: 1, the flow velocity is 0.1-0.7ml/min, and the column temperature is 25-40 DEG C. By adopting the method, bortezomib and three chiral isomers thereof can be effectively separated, the degree of separation reaches 1.7-4.2, peak shapes are good, and the number of theoretical plates is high. The bortezomib isomer separating and determining method can be used for the control on the production quality of bortezomib raw drugs.
Description
Technical field
The present invention relates to Pharmaceutical Analysis field, be specifically related to the method for separating and assaying of anticarcinogen bortezomib isomeride.
Background technology
Bortezomib is a kind of artificial synthetic dipeptides borate, belongs to reversible proteasome inhibitor, can optionally be combined with the threonine in proteasome activity site, and the chymotrypsin/tryptic activity of proteasome enzyme inhibition 26S subunit.Meanwhile, he can also improve the antitumor action of other antineoplastic, presents collaborative or sensitization with many drug combinations, rather than simple summation action.By brand-new mechanism, reach the effect of anti-myeloma.Clinical research both at home and abroad show bortezomib list medicine and with the Combination chemotherapy of conventional chemotherapy ingredients to initial therapy, and the MM patient of recurrence refractory all has good efficacy.It is regarded as treating the breakthrough therapy of recurrent and obstinate type Huppert's disease, studies show that this medicine can slow down, reverses or stop once accepting two or more therapies but failed conditions of patients continues to worsen.The bortezomib of usining has been recommended one of important selection as multiple myeloma patients treatment by the comprehensive cancer coorporative network of American National as main Combination chemotherapy.
This compound is developed to injection (injection bortezomib), and in twenties country's listings such as Australia, Belgium, Denmark, Austria, Finland, the ,Yuan Yan producer of going on the market at home for 2005 is U.S. Millennium Pharmaceuticals at present.Bortezomib is chemical to be called [(1R)-3-methyl isophthalic acid-[[(2S)-1-oxygen-3-phenyl-2-[(pyrazine formyl) amino] propyl group] amino] butyl]-boric acid, its structural formula is:
For the security consideration to medicine, must the strict impurity content of controlling bortezomib bulk drug.From above-mentioned bortezomib structural formula, it contains two chiral centers, has except bortezomib three chiral isomer BIO1, BIO2, BIO3, and structural formula is as follows:
When carrying out bortezomib quality control, need the strict content of controlling isomeride, because character between isomeride approaches, adopt prior art the HPLC analytical method of bortezomib to be difficult to the content of separation determination isomeride.The separation case of disclosed liquid-phase chromatography method to bortezomib and 9 related impuritieses thereof in document " Development and Validation of a Stability Indicating LC Method for the Assay and Related Substances Determination of a Proteasome Inhibitor Bortezomib ", the BIO1 that wherein comprises above-mentioned bortezomib, two chiral isomers of BIO2, and BIO3 is not within the scope of document investigation, the method adopts RP18 chromatographic column, mobile phase A: acetonitrile/water (0.1% formic acid), Mobile phase B: methanol/water (0.1% formic acid), detect wavelength 270nm, flow velocity 1.0ml/min, 35 ℃ of column temperatures, sample size 20ul, separating resulting for the chiral isomer of bortezomib is only can be by BIO1, the overlap peak of BIO2 separates with bortezomib, BIO3 peak and bortezomib overlap of peaks, therefore the method fails to realize the separation of bortezomib and an excess-three chiral isomer thereof.
For guaranteeing the quality of bortezomib bulk drug and using clinical security, need to find a kind of reliable chiral isomer of analytical approach separation determination bortezomib effectively.
Summary of the invention
The technical matters that the present invention solves has been to provide a kind of method of separating and assaying of high performance liquid chromatography to bortezomib chiral isomer that adopt, can effective separated bortezomib and 3 chiral isomers thereof, realize the quality control of chiral impurity in bortezomib bulk drug.
The method of a kind of high efficiency liquid chromatography for separating and determining bortezomib isomeride provided by the invention, it is characterized in that, the chromatographic condition that the method adopts is: fixedly phase Silica Surface applies chromatographic column adopting is amylose one three (3,5 one xylyl carbamates) chiral chromatographic column, mobile phase adopts mobile phase A to contain the combination of hexane solution and the absolute methanol/aqueous isopropanol that Mobile phase B is 1:1 of 0.1% trifluoroacetic acid, flow velocity is 0.1-0.7ml/min, and column temperature is 25-40 ℃.
Chiral chromatographic column (Chiral HPLC Columns) is by having optically active monomer, is fixed on and on silica gel or other polymkeric substance, makes chiral stationary phase (Chiral Stationary Phases).For the separation of chiral isomer, the isomeride of different chemical character need adopt dissimilar chiral column, and it is very important how according to the molecular structure of compound, selecting applicable chiral chromatographic column.On market, selectable chiral chromatographic column is more and more, according to the fixing chemical constitution of phase, chiral chromatographic column is divided into following several: brush type, glycan, cyclodextrin type, macrocyclic antibiotic type, protein type, ligand exchange type, crown ether type etc.Inventor once attempted selecting a plurality of chiral chromatographic columns of the cyclodextrin type that separating chiral compound is more conventional to carry out the separation determination of bortezomib and chiral isomer thereof, in any case but adjustment mobile phase and other chromatographic condition all cannot be separated by each peak, the signal of chromatographic peak is weak and peak shape is poor.Inventor investigates polysaccharide derivates type chromatographic column, comprises a plurality of chromatographic columns of fixing phase Silica Surface coated fiber element derivant and straight chain starch derivative.To fixing mutually for Silica Surface coating be the chromatographic column investigation of cellulose derivative time, the chromatographic condition of first selecting is: instrument----Shimazu high performance liquid chromatograph; Reagent----bortezomib reference substance and isomeride reference substance BIO1, BIO2, BIO3; Chromatographic column----Chiralcel OD-RH5 μ m250mm * 4.6mm; Detecting device and detection wavelength----UV270nm; Mobile phase----A: normal hexane B: isopropyl alcohol; Flow velocity----0.5ml/min; Sample size----10 μ l; Column temperature----room temperature; Determination method----extracting sample solution 10 μ l, sample introduction, records chromatogram.Under above-mentioned existing chromatographic condition, by changing a plurality of mobile phase ratios, investigate separating effect, the results are shown in following table:
Mobile phase ratio | Degree of separation | Remarks |
A:B=60:40 | 1.3、1.2、0.8 | Degree of separation is bad, and number of theoretical plate is lower |
A:B=70:30 | 1.4、1.7 | Obtain three chromatographic peaks, and peak shape is poor, number of theoretical plate is low |
A:B=80:20 | 1.3、1.4 | Obtain three chromatographic peaks, and number of theoretical plate is lower |
A:B=90:10 | 1.1、1.6、2.6 | Number of theoretical plate is lower, and hangover is serious |
According to the above results, inventor attempts adding in mobile phase the absolute methanol that polarity is larger, and trifluoroacetic acid improves degree of separation and obtains good chromatographic peak profile with expectation, adjustment mobile phase A is normal hexane (0.1% trifluoroacetic acid), line of flow B is absolute methanol: isopropyl alcohol (1:1), ratio is 90:10, investigates separation case by adjusting flow velocity simultaneously, the results are shown in following table:
Flow velocity ml/min | Degree of separation | Remarks |
1.0 | 2.2 | Obtain 2 pairs of non-mapping chromatographic peaks, and number of theoretical plate is lower |
0.7 | 2.7 | Obtain 2 pairs of non-mapping chromatographic peaks, and number of theoretical plate is lower |
0.7 | 1.6、0.9、1.4 | Isomer separation, number of theoretical plate is lower, and there is hangover at peak |
0.3 | 1.3、1.5、1.1 | Isomer separation, degree of separation does not reach requirement |
As seen from the above table, when flow velocity is 0.3ml/min, isomeride can be separated with major component, but degree of separation does not reach baseline separation, and chromatographic peak profile is poor, and number of theoretical plate is lower.Under this chromatographic condition, change other cellulose derivative chromatographic column and investigate.
From the above-mentioned result of repeatedly investigating, the chromatographic column that the cellulose derivative of take is fixing phase can be by bortezomib and chiral isomer thereof separately, but separating effect is undesirable, does not reach baseline separation, chromatographic peak hangover.So it is fixing mutually for the chromatographic column of silica gel coating straight chain starch derivative continues investigation that inventor is replaced by chromatographic column, the impact of column temperature investigated simultaneously.
Instrument: Shimazu high performance liquid chromatograph, normal hexane, isopropyl alcohol, absolute methanol.
Reagent: bortezomib reference substance and isomeride reference substance BIO1, BIO2, BIO3
Detecting device and detection wavelength: UV-270nm
Mobile phase: A: normal hexane (0.1% trifluoroacetic acid); B:(absolute methanol: isopropyl alcohol=1:1)
Mobile phase ratio A:B=90:10
Flow velocity: 0.3ml/min,
Sample size: 5 μ l
Column temperature: see the following form
Determination method: extracting sample solution 5 μ l, sample introduction, records chromatogram.
Result is as following table:
Above-mentioned two kinds of chromatographic columns are Silica Surface coating amylose one or three (3 for fixing mutually, 5 one xylyl carbamates) chiral chromatographic column, be the chiral column that Japanese Daicel company produces, other company also applies for chiral column of the same type, as U.S.'s match point Chiralomix SA chiral column that science and technology is produced, the CHIRALCN AD-H chiral column of creation product etc. is ground in Guangzhou.From upper table result, such chiral chromatographic column can reach desirable separating effect, and find unexpectedly when investigating column temperature on the affecting of degree of separation, in the positive elution system of not thinking for those skilled in the art, reduce column temperature and be conducive to improve degree of separation, but column temperature is higher, degree of separation is better, and particularly during 40 ℃ of column temperatures, degree of separation is best.
Based on above-mentioned screening process, further optimized chromatographic condition, the preferred 90:10 of volume ratio of described mobile phase A and Mobile phase B; The preferred 0.2-0.5ml/min of described flow velocity, most preferably 0.3ml/min; The preferred 30-40 ℃ of described column temperature, most preferably 40 ℃; Detecting device is UV-detector, wavelength selective 2 70nm, and sample size is 5 μ l or 10 μ l, preferably 5 μ l.
Before injecting high phase liquid chromatograph, during the preparation of bortezomib sample solution, adopt absolute methanol to dissolve, and with mobile phase solution dilution, be configured to contain in every 1ml the solution of 0.5mg sample.
The invention provides a kind of method of separating and assaying of bortezomib isomeride, can effective separated bortezomib and three chiral isomers thereof under the method chromatographic condition, degree of separation reaches 1.7-4.2, peak shape is good, theoretical cam curve is high, can be used in the quality control in bortezomib production of raw medicine process.
Below in conjunction with embodiment and the Figure of description of embodiment and be further described.
Figure of description
In accompanying drawing 1 embodiment mono-, locate solution 1 (BIO1) chromatogram
In accompanying drawing 2 embodiment mono-, locate solution 2 (BIO2) chromatogram
In accompanying drawing 3 embodiment mono-, locate solution 3 (BIO3) chromatogram
Accompanying drawing 4 embodiment mono-system flexibility solution chromatograms (bortezomib, BIO1, BIO2, BIO3)
Accompanying drawing 6 bortezomib bulk drug sample chromatogram figure
Embodiment
Embodiment mono-
Instrument: SHIMAZU LC-20AT high performance liquid chromatograph, SPD-10AVP UV-detector, CTO-10ASVP column oven;
Chromatographic column: Chiralomix SA chromatographic column (5 μ m, 250mm * 4.6mm);
Mobile phase: normal hexane (0.1% trifluoroacetic acid): (absolute methanol: isopropyl alcohol=1:1)=90:10;
Column temperature: 40 ℃;
Flow velocity: 0.3ml/min;
Detect wavelength: 270nm;
The preparation of location solution 1: it is appropriate that precision takes bortezomib isomeride BIO1, adds absolute methanol and dissolves and make 10 μ g/ml; The preparation of location solution 2: it is appropriate that precision takes bortezomib isomeride BIO2, adds absolute methanol and dissolves and make 10 μ g/ml; The preparation of location solution 3: it is appropriate that precision takes bortezomib isomeride BIO3, adds absolute methanol and dissolves and make 10 μ g/ml; The preparation of system suitability solution: get bortezomib reference substance and isomeride BIO1, BIO2, BIO2 reference substance, add mobile phase after adding that absolute methanol is appropriate and dissolving and dilute and make 10 μ g/ml;
Measure: respectively get location solution 1, location solution 2, location solution 3 and each 5 μ l of system suitability solution and inject high performance liquid chromatograph, record chromatogram, accompanying drawing 1-4 is shown in by collection of illustrative plates.System suitability solution goes out peak by the order of BIO3, bortezomib, BIO1, BIO2, and each peak-to-peak degree of separation and number of theoretical plate are as following table:
Project | BIO3 | Bortezomib | BIO1 | BIO2 |
Degree of separation | --- | 1.7 | 4.2 | 1.8 |
Number of theoretical plate | 13263 | 7723 | 9554 | 6097 |
Tailing factor | 1.2 | 1.2 | 1.2 | 1.1 |
The mensuration of isomeride in embodiment bis-bortezomib bulk drugs
Chromatographic condition and system suitability adopt chiral chromatographic column (Chiralpak AD-H, 4.6 * 250mm); Take normal hexane (0.1% trifluoroacetic acid): (isopropyl alcohol: absolute methanol=1:1))=90:10 is mobile phase; Flow velocity is 0.3ml/min; 40 ℃ of column temperatures; Detect wavelength 270nm; Get bortezomib reference substance and isomeride reference substance, after adding that absolute methanol is appropriate and dissolving, adding mobile phase dilute and makes the mixed solution that every 1ml contains 10 μ g, as system suitability solution, precision measures this solution 5 μ l injection liquid chromatographies, record chromatogram (accompanying drawing 5), order by BIO3, bortezomib, BIO1, BIO2 goes out peak, system suitability result:
Project | BIO3 | Bortezomib | BIO1 | BIO2 |
Degree of separation | --- | 1.5 | 3.5 | 1.9 |
Number of theoretical plate | 12710 | 5420 | 8222 | 5352 |
Tailing factor | 1.2 | 1.2 | 1.2 | 1.1 |
Determination method is got the about 50mg of bortezomib bulk drug, accurately weighed, put and in 10ml measuring bottle, add absolute methanol and dissolve and be settled to scale, shake up, precision measures this solution and adds mobile phase and dilute and make in every 1ml the solution containing 0.5mg, shake up, as need testing solution, precision measures need testing solution 5 μ l injection liquid chromatographies, record chromatogram (accompanying drawing 6), by areas of peak normalization method, calculate, containing BIO1, should cross 0.20%, containing BIO2, should cross 0.20%, containing BIO3, should cross 0.20%.
The measurement result of isomeride in bortezomib bulk drug sample:
Lot number | BIO3 | BIO1 | BIO2 |
2013001 | Do not detect | 0.027% | 0.022% |
Result shows: this method can be good at chiral isomer in bortezomib raw material to carry out content control.
Claims (10)
1. a method that adopts high efficiency liquid chromatography for separating and determining bortezomib and chiral isomer thereof, it is characterized in that, the chromatographic condition that the method adopts is: fixedly phase Silica Surface applies chromatographic column adopting is amylose one three (3,5 one xylyl carbamates) chiral chromatographic column, mobile phase adopts mobile phase A to contain the combination of hexane solution and the absolute methanol/aqueous isopropanol that Mobile phase B is 1:1 of 0.1% trifluoroacetic acid, flow velocity is 0.1-0.7ml/min, and column temperature is 25-40 ℃.
2. according to the method described in claim l, it is characterized in that, the volume ratio of described mobile phase A and Mobile phase B is 90:10.
3. method according to claim 1, is characterized in that, described flow velocity is 0.2-0.5ml/min.
4. method according to claim 1, is characterized in that, described flow velocity is 0.3ml/min.
5. method according to claim 1, is characterized in that, described column temperature is 30-40 ℃.
6. method according to claim 1, is characterized in that, described column temperature is 40 ℃.
7. method according to claim 1, is characterized in that, detecting device is UV-detector, wavelength selective 2 70nm.
8. method according to claim 1, is characterized in that, sample size is 5 μ l or 10 μ l.
9. method according to claim 1, is characterized in that, sample size is 5 μ l.
10. method according to claim 1, is characterized in that, sample dissolves with absolute methanol before injecting high phase liquid chromatograph, and with mobile phase solution dilution, is configured to contain in every 1ml the solution of 0.5mg sample.
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Cited By (4)
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CN106556664A (en) * | 2015-09-24 | 2017-04-05 | 北京康辰药业股份有限公司 | A kind of method of separating and assaying of bortezomib and its optical isomer |
CN106706796A (en) * | 2017-01-13 | 2017-05-24 | 南京海辰药业股份有限公司 | Method for detecting optical isomer of key intermediate 1R-trifluoroacetate of bortezomib by HPLC (high performance liquid chromatography) |
CN106770877A (en) * | 2017-03-29 | 2017-05-31 | 昆明贵研药业有限公司 | A kind of detection method of bortezomib chiral isomer |
CN114689761A (en) * | 2022-05-31 | 2022-07-01 | 天津市汉康医药生物技术有限公司 | Method for detecting parecoxib sodium positional isomer through liquid chromatography |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106556664A (en) * | 2015-09-24 | 2017-04-05 | 北京康辰药业股份有限公司 | A kind of method of separating and assaying of bortezomib and its optical isomer |
CN106706796A (en) * | 2017-01-13 | 2017-05-24 | 南京海辰药业股份有限公司 | Method for detecting optical isomer of key intermediate 1R-trifluoroacetate of bortezomib by HPLC (high performance liquid chromatography) |
CN106770877A (en) * | 2017-03-29 | 2017-05-31 | 昆明贵研药业有限公司 | A kind of detection method of bortezomib chiral isomer |
CN114689761A (en) * | 2022-05-31 | 2022-07-01 | 天津市汉康医药生物技术有限公司 | Method for detecting parecoxib sodium positional isomer through liquid chromatography |
CN114689761B (en) * | 2022-05-31 | 2023-03-03 | 天津市汉康医药生物技术有限公司 | Method for detecting parecoxib sodium positional isomer through liquid chromatography |
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