CN103387572A - Reference marker for everolimus impurity detection and preparation method thereof - Google Patents
Reference marker for everolimus impurity detection and preparation method thereof Download PDFInfo
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- CN103387572A CN103387572A CN2013103005746A CN201310300574A CN103387572A CN 103387572 A CN103387572 A CN 103387572A CN 2013103005746 A CN2013103005746 A CN 2013103005746A CN 201310300574 A CN201310300574 A CN 201310300574A CN 103387572 A CN103387572 A CN 103387572A
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Abstract
The invention discloses a reference marker for everolimus impurity detection and a preparation method thereof, which belong to an everolimus impurity detection technology. The reference marker is a degradation product of everolimus. Solid everolimus is dissolved in an alkaline solution; after heated reactions, an organic acid is used to neutralize excess alkali; and the neutralized mixture is concentrated into a solid mixture. The method uses a water-containing organic solvent to dissolve the solid mixture, uses a water-containing organic solvent as a desorbent to desorb a chromatography column, collects the desorbent which contains the target product in steps, and obtains the reference marker for everolimus impurity detection through concentration. The invention provides the reference marker, the structure of which is the same with or similar to those of chemical derivatives, synthesis by-products and degradation products in everolimus impurities, and the preparation method of the reference marker, so that everolimus impurity detection becomes more scientific and accurate.
Description
Technical field
The present invention relates to a kind of everolimus impurity detection technique, specially refer to a kind of everolimus impurity and detect with reference marker and preparation method thereof.
Background technology
Everolimus is the certain water miscible rapamycin derivative that has by Switzerland Novartis Co.,Ltd research and development, is mainly used to clinically to prevent the rejection after renal transplantation and heart transplant operation, can be taken orally.Its mechanism of action mainly comprises immunosuppressive action, antitumor action, antivirus action and vascular protection effect, often with other immunosuppressor such as ciclosporin, unites and uses with reduction toxicity.In addition, everolimus also is used for the treatment of advanced renal cell cancer.
As everyone knows, for the active pharmaceutical ingredient product of mankind's medication, very high to the content requirement for restriction of its impurity.Usually require the weight ratio of every kind of foreign matter content lower than 0.15%, for the weight ratio of the uncertain foreign matter content of unconfirmed toxicity, require lower than 0.1% especially.Yet, comparatively extensive for its source of the impurity in active pharmaceutical ingredient, may produce due to the degraded of product self (this is relevant with the stability of product in storage process), also may derive from preparation method's (comprising chemosynthesis).The impurity that derives from the preparation method comprises impurity and chemical derivative, synthesising by-product and the degraded product etc. that comprise in unreacted starting raw material, starting raw material.
In the medicine quality analysis technical field, chemical derivative in active pharmaceutical ingredient impurity, synthesising by-product and degraded product can adopt spectrum or other physical method to differentiate, in above-mentioned impurity and color atlas, there is incidence relation in peak position, therefore, can differentiate impurity by the relative position in color atlas according to it.Before the impurity in compound is analyzed, needs employing purity is higher and with above-mentioned impurity, have the material of identical or close structure as the reference marker, employing is equivalent to the compound to be checked of pure state as the reference standard thing, then, reference marker and reference standard thing are together detected, and the relative position of reference marker in color atlas is considered as the relative position of impurity in color atlas, and with this impurity to compound to be checked, detects and instruct.Obviously, the selection of reference marker and preparation, science and accuracy that foreign matter content in active pharmaceutical ingredient is detected have direct impact.And for the detection of everolimus foreign matter content, just need to select and prepare a kind of structure identical or close with chemical derivative, synthesising by-product and degraded product in everolimus impurity and have the material reference marker of higher degree, with science and the accuracy of raising everolimus impurity detection.
Summary of the invention
The science and the accuracy that detect for improving everolimus impurity, the present invention proposes a kind of everolimus impurity and detects with reference marker and preparation method thereof.
It is a kind of degraded product of everolimus with the reference marker that everolimus impurity of the present invention detects, and its structure is:
Everolimus impurity of the present invention detects with reference marker preparation method and adopts alkaline solution to dissolve the everolimus solid, utilizes in organic acid after reacting by heating and excessive alkali, and the mixture after neutralization is condensed into mixture solid; Adopt water-containing organic solvent dissolving mixt solid, adopt water-containing organic solvent as strippant, desorb chromatography column, Fractional Collections contain the strippant of target product, the concentrated everolimus impurity detection reference marker that obtains; Wherein,
Described alkaline solution is a kind of in sodium hydroxide, SODIUM PHOSPHATE, MONOBASIC, Sodium phosphate dibasic, potassium hydroxide, dipotassium hydrogen phosphate and potassium primary phosphate, and its strength of solution is 0.2 to 0.7mol/L;
Described reacting by heating temperature is 20 to 90 ℃;
Described organic acid is a kind of in formic acid, acetic acid, oxalic acid, phenylformic acid and succinic acid;
Described thickening temperature is 30 to 60 ℃, and adopts rotatory evaporator concentrated;
Described water-containing organic solvent is a kind of in the aqueous solution of methyl alcohol, ethanol, Virahol, acetone, acetonitrile and tetrahydrofuran (THF), and its water content is 20% to 80% weight percentage;
Described silicagel column is a kind of in C1, C4, C8 and C18 reverse phase silica gel;
Described strippant is a kind of of methyl alcohol, ethanol, Virahol, acetone, acetonitrile and tetrahydrofuran (THF) water-containing organic solvent, and water content is 30% to 70% weight fraction.
Further, everolimus impurity of the present invention detects with reference marker preparation method, comprises the following steps:
S1, adopt alkaline solution to dissolve the everolimus solid, described alkaline solution is a kind of in sodium hydroxide, SODIUM PHOSPHATE, MONOBASIC, Sodium phosphate dibasic, potassium hydroxide, dipotassium hydrogen phosphate and potassium primary phosphate, and its strength of solution is 0.2 to 0.7mol/L;
S2, reacting by heating, its reacting by heating temperature are 20 to 90 ℃;
S3, adopt in organic acid and above-mentioned everolimus solution, its organic acid is a kind of in formic acid, acetic acid, oxalic acid, phenylformic acid and succinic acid;
S4, enriched mixture, adopt rotatory evaporator to concentrate at 30 to 60 ℃, makes mixture solid;
S5, the mixture solid that adopts water-containing organic solvent dissolving step S4 to make, its water-containing organic solvent are a kind of in the aqueous solution of methyl alcohol, ethanol, Virahol, acetone, acetonitrile and tetrahydrofuran (THF), and its water content is 20% to 80% weight percentage;
S6, desorb chromatography column, the silicagel column of employing are a kind of in C1, C4, C8 and C18 reverse phase silica gel, and strippant is a kind of of methyl alcohol, ethanol, Virahol, acetone, acetonitrile and tetrahydrofuran (THF) water-containing organic solvent, and water content is 30% to 70% weight fraction;
S7, collection contain the strippant of target product;
S8, the concentrated strippant that contains target product obtain everolimus impurity detection reference marker.
A kind of structure reference marker identical or close with chemical derivative, synthesising by-product and degraded product in everolimus impurity and preparation method thereof has been provided with providing of reference marker and preparation method thereof for everolimus impurity of the present invention, effectively improved science and the accuracy of the detection of everolimus impurity.
Description of drawings
Accompanying drawing 1 is that everolimus impurity of the present invention detects the schematic flow sheet with reference marker preparation method.
Below in conjunction with the drawings and specific embodiments, everolimus impurity of the present invention is detected and is further described with reference marker and preparation method thereof.
Embodiment
Accompanying drawing 1 is that everolimus impurity of the present invention detects the schematic flow sheet with reference marker preparation method, and as seen from the figure, it is a kind of degraded product of everolimus with the reference marker that everolimus impurity of the present invention detects, and its structure is:
Everolimus impurity of the present invention detects with reference marker preparation method and adopts alkaline solution to dissolve the everolimus solid, utilizes in organic acid after reacting by heating and excessive alkali, and the mixture after neutralization is condensed into mixture solid; Adopt water-containing organic solvent dissolving mixt solid, adopt water-containing organic solvent as strippant, desorb chromatography column, Fractional Collections contain the strippant of target product, the concentrated everolimus impurity detection reference marker that obtains; Wherein,
Described alkaline solution is a kind of in sodium hydroxide, SODIUM PHOSPHATE, MONOBASIC, Sodium phosphate dibasic, potassium hydroxide, dipotassium hydrogen phosphate and potassium primary phosphate, and its strength of solution is 0.2 to 0.7mol/L;
Described reacting by heating temperature is 20 to 90 ℃;
Described organic acid is a kind of in formic acid, acetic acid, oxalic acid, phenylformic acid and succinic acid;
Described thickening temperature is 30 to 60 ℃, and adopts rotatory evaporator concentrated;
Described water-containing organic solvent is a kind of in the aqueous solution of methyl alcohol, ethanol, Virahol, acetone, acetonitrile and tetrahydrofuran (THF), and its water content is 20% to 80% weight percentage;
Described silicagel column is a kind of in C1, C4, C8 and C18 reverse phase silica gel;
Described strippant is a kind of of methyl alcohol, ethanol, Virahol, acetone, acetonitrile and tetrahydrofuran (THF) water-containing organic solvent, and water content is 30% to 70% weight fraction.
Everolimus impurity of the present invention detects with reference marker preparation method, comprises the following steps:
S1, adopt alkaline solution to dissolve the everolimus solid, described alkaline solution is a kind of in sodium hydroxide, SODIUM PHOSPHATE, MONOBASIC, Sodium phosphate dibasic, potassium hydroxide, dipotassium hydrogen phosphate and potassium primary phosphate, and its strength of solution is 0.2 to 0.7mol/L;
S2, reacting by heating, its reacting by heating temperature are 20 to 90 ℃;
S3, adopt in organic acid and above-mentioned everolimus solution, its organic acid is a kind of in formic acid, acetic acid, oxalic acid, phenylformic acid and succinic acid;
S4, enriched mixture, adopt rotatory evaporator to concentrate at 30 to 60 ℃, makes mixture solid;
S5, the mixture solid that adopts water-containing organic solvent dissolving step S4 to make, its water-containing organic solvent are a kind of in the aqueous solution of methyl alcohol, ethanol, Virahol, acetone, acetonitrile and tetrahydrofuran (THF), and its water content is 20% to 80% weight percentage;
S6, desorb chromatography column, the silicagel column of employing are a kind of in C1, C4, C8 and C18 reverse phase silica gel, and strippant is a kind of of methyl alcohol, ethanol, Virahol, acetone, acetonitrile and tetrahydrofuran (THF) water-containing organic solvent, and water content is 30% to 70% weight fraction;
S7, collection contain the strippant of target product;
S8, the concentrated strippant that contains target product obtain everolimus impurity detection reference marker.
Embodiment 1
The 10.00g everolimus is utilized the sodium dihydrogen phosphate dissolving of 50ml concentration for 0.5mol/L, be heated to 35 ℃, after heating 30min, utilize acetic acid to adjust pH value to neutral, utilize rotatory evaporator to concentrate at 40 ℃, obtain the 10.23g mixture solid.
Embodiment 2
The 12.00g everolimus is utilized the disodium phosphate soln dissolving of 60ml concentration for 0.6mol/L, be heated to 40 ℃, after heating 45min, utilize acetic acid to adjust pH value to neutral, utilize rotatory evaporator to concentrate at 45 ℃, obtain the 12.13g mixture solid.
Embodiment 3
The 10.00g everolimus is utilized the disodium phosphate soln dissolving of 50ml concentration for 0.5mol/L, be heated to 40 ℃, after heating 40min, utilize formic acid to adjust pH value to neutral, utilize rotatory evaporator to concentrate at 45 ℃, obtain the 10.17g mixture solid.
Embodiment 4
(it is 35.77% with reference marker content that its everolimus impurity detects to the mixture solid that obtains after 5g is concentrated, adopt the high performance liquid chromatography area normalization method to detect), utilizing 100ml concentration is the acetone solution of 60% weight ratio, the anti-phase C4 silica gel column chromatography of upper 1000ml, utilizing concentration is that the acetone of 73% weight ratio is made strippant, the desorb chromatography column, Fractional Collections, the liquid phase monitoring, merging the concentrated everolimus impurity that obtains detects with reference marker 1.6g, it is 95.33% with reference marker content that its everolimus impurity detects, everolimus content is 2.31%, other foreign matter contents are 2.36%.
Embodiment 5
(it is 44.28% with reference marker content that its everolimus impurity detects to the mixture solid that obtains after 3g is concentrated, adopt the high performance liquid chromatography area normalization method to detect), utilizing 100ml concentration is the Virahol dissolving of 65% weight ratio, the anti-phase C8 silica gel column chromatography of upper 1000ml, utilizing concentration is that the Virahol of 76% weight ratio is made strippant, the desorb chromatography column, Fractional Collections, the liquid phase monitoring, merging the concentrated dried everolimus impurity that obtains detects with reference marker 0.83g, it is 96.18% with reference marker content that its everolimus impurity detects, everolimus content is 2.17%, other foreign matter contents are 1.65%.
Embodiment 6
(it is 48.97% with reference marker content that its everolimus impurity detects to the mixture solid that obtains after 5g is concentrated, adopt the high performance liquid chromatography area normalization method to detect), utilizing 100ml concentration is the acetonitrile dissolving of 45% weight ratio, the anti-phase C8 silica gel column chromatography of upper 1000ml, utilizing concentration is that the acetonitrile of 58% weight ratio is made strippant, the desorb chromatography column, Fractional Collections, the liquid phase monitoring, merging the concentrated dried everolimus impurity that obtains detects with reference marker 1.34g, it is 97.02% with reference marker content that its everolimus impurity detects, everolimus content is 1.31%, other foreign matter contents are 1.67%.
Can find out from above-described embodiment, it is a kind of degraded product of everolimus with the reference marker that everolimus impurity of the present invention detects, its structure is identical or close with chemical derivative, synthesising by-product and degraded product in everolimus impurity, can effectively improve science and accuracy that everolimus impurity detects.
Obviously, a kind of structure reference marker identical or close with chemical derivative, synthesising by-product and degraded product in everolimus impurity and preparation method thereof has been provided with providing of reference marker and preparation method thereof for everolimus impurity of the present invention, effectively improved science and the accuracy of the detection of everolimus impurity.
Claims (3)
1. an everolimus impurity detects and uses the reference marker, it is characterized in that, this reference marker is a kind of degraded product of everolimus, and its structure is:
。
2. the described everolimus impurity of claim 1 detects with reference marker preparation method, it is characterized in that, adopt alkaline solution to dissolve the everolimus solid, utilize in organic acid after reacting by heating and excessive alkali, the mixture after neutralization is condensed into mixture solid; Adopt water-containing organic solvent dissolving mixt solid, adopt water-containing organic solvent as strippant, desorb chromatography column, Fractional Collections contain the strippant of target product, the concentrated everolimus impurity detection reference marker that obtains; Wherein,
Described alkaline solution is a kind of in sodium hydroxide, SODIUM PHOSPHATE, MONOBASIC, Sodium phosphate dibasic, potassium hydroxide, dipotassium hydrogen phosphate and potassium primary phosphate, and its strength of solution is 0.2 to 0.7mol/L;
Described reacting by heating temperature is 20 to 90 ℃;
Described organic acid is a kind of in formic acid, acetic acid, oxalic acid, phenylformic acid and succinic acid;
Described thickening temperature is 30 to 60 ℃, and adopts rotatory evaporator concentrated;
Described water-containing organic solvent is a kind of in the aqueous solution of methyl alcohol, ethanol, Virahol, acetone, acetonitrile and tetrahydrofuran (THF), and its water content is 20% to 80% weight percentage;
Described silicagel column is a kind of in C1, C4, C8 and C18 reverse phase silica gel;
Described strippant is a kind of of methyl alcohol, ethanol, Virahol, acetone, acetonitrile and tetrahydrofuran (THF) water-containing organic solvent, and water content is 30% to 70% weight fraction.
3. everolimus impurity detects with reference marker preparation method according to claim 2, it is characterized in that, this preparation method comprises the following steps:
S1, adopt alkaline solution to dissolve the everolimus solid, described alkaline solution is a kind of in sodium hydroxide, SODIUM PHOSPHATE, MONOBASIC, Sodium phosphate dibasic, potassium hydroxide, dipotassium hydrogen phosphate and potassium primary phosphate, and its strength of solution is 0.2 to 0.7mol/L;
S2, reacting by heating, its reacting by heating temperature are 20 to 90 ℃;
S3, adopt in organic acid and above-mentioned everolimus solution, its organic acid is a kind of in formic acid, acetic acid, oxalic acid, phenylformic acid and succinic acid;
S4, enriched mixture, adopt rotatory evaporator to concentrate at 30 to 60 ℃, makes mixture solid;
S5, the mixture solid that adopts water-containing organic solvent dissolving step S4 to make, its water-containing organic solvent are a kind of in the aqueous solution of methyl alcohol, ethanol, Virahol, acetone, acetonitrile and tetrahydrofuran (THF), and its water content is 20% to 80% weight percentage;
S6, desorb chromatography column, the silicagel column of employing are a kind of in C1, C4, C8 and C18 reverse phase silica gel, and strippant is a kind of of methyl alcohol, ethanol, Virahol, acetone, acetonitrile and tetrahydrofuran (THF) water-containing organic solvent, and water content is 30% to 70% weight fraction;
S7, collection contain the strippant of target product;
S8, the concentrated strippant that contains target product obtain everolimus impurity detection reference marker.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115716839A (en) * | 2022-11-15 | 2023-02-28 | 无锡福祈制药有限公司 | Synthesis method of everolimus impurity |
| WO2023213731A1 (en) * | 2022-05-02 | 2023-11-09 | Roche Diagnostics Gmbh | Hemolysis and derivatization reagents and methods for determining lactone analytes |
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Patent Citations (5)
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| US20090325197A1 (en) * | 2006-12-29 | 2009-12-31 | Abbott Laboratories | Assay for immunosuppressant drugs |
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| CN102215682A (en) * | 2008-03-11 | 2011-10-12 | 万能医药公司 | Macrocyclic lactone compounds and methods for their use |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023213731A1 (en) * | 2022-05-02 | 2023-11-09 | Roche Diagnostics Gmbh | Hemolysis and derivatization reagents and methods for determining lactone analytes |
| CN115716839A (en) * | 2022-11-15 | 2023-02-28 | 无锡福祈制药有限公司 | Synthesis method of everolimus impurity |
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