CN103819430A - Paclitaxel purifying method of paclitaxel crude product produced by Chinese yew cell culture - Google Patents
Paclitaxel purifying method of paclitaxel crude product produced by Chinese yew cell culture Download PDFInfo
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Abstract
The invention discloses a paclitaxel purifying method of a paclitaxel crude product produced by Chinese yew cell culture and belongs to the field of compound purification. With the combination of a crystallization method and a normal phase column-chromatography method, paclitaxel is purified. Firstly, a paclitaxel crude product produced by Chinese yew cell culture is dissolved in an organic solvent with high polarity, and a reverse organic solvent is dropwisely added so as to obtain paclitaxel with purity being more than 85.0%. And then, paclitaxel is further separated and purified by column chromatography. A stationary phase is silica gel of 200 meshes-300 meshes, and a mobile phase is a binary gradient mixed solvent of dichloromethane and ethyl acetate or hexane and acetone. Combining the two methods, the defect that paclitaxel and cephalomannine cannot be separated effectively by a previous separation method is solved, and unknown impurities which are hard to separate can be removed. Thus, a paclitaxel bulk drug which accords with United States Pharmacopeia (USP) standards can be obtained. The method has advantages of good repeatability and reasonable technology, is simple to operate, and is green and safe.
Description
Technical field
The present invention relates to the purification process of taxol, be specifically related to a kind ofly cultivate from yew cell the taxol crude product of producing and remove the Cephalomannine and the unknown impuritie thing purifying that are difficult to separate and obtain the preparation method of the paclitaxel api that meets American Pharmacopeia USP standard, belong to compound purifying field.
Background technology
Taxol is a kind of new type anticancer medicine with Taxan diterpene skeleton of separation and Extraction from Chinese yew genus plants, is also unique a kind of microtubule polymerization and stable medicine of polymerization microtubule of promoting of understanding at present.It has powerful restraining effect to most of noumenal tumours, and on normal cell based this without impact, especially the determined curative effect to advanced ovarian cancer, mammary cancer, nonsmall-cell lung cancer and Kaposi's sarcoma, side effect are less.Along with further going deep into of research, the antitumous effect of taxanes medicine is more widely used, and has now become the antitumor drug of a line cancer therapy drug and wide spectrum.
Ramulus et folium taxi cuspidatae class plant as taxol main source belongs to rareness species, is listed in first-grade state protection plant in China; And taxol content in bark of Ramulus et folium taxi cuspidatae is extremely low, only accounts for 0.01%.
Although so anti-cancer medicine paclitaxel widespread use is clinically subject to the restriction of the rare shortage of raw material Ramulus et folium taxi cuspidatae class plant, can not meet the demand of market to taxol far away, medicine source deficiency has become the bottleneck of restriction taxol in clinical middle extensive application at present.
Over nearly 20 years, the contradictory problems day by day increasing in order to solve the rare shortage of taxus resource and taxol demand, people have mainly carried out the research of taxol raw material from the following aspects: the methods such as complete synthesis, the molecular design of chemistry, artificial culture, microbial fungi fermentation and yew cell cultivation.Wherein yew cell culture method does not destroy natural resources owing to having, is not subject to natural condition restriction, can in bio-reactor, carries out large scale culturing, and while the method also can produce precursor and other have the advantages such as anti-cancer active compound.Therefore, Taxol Production in Taxus Cell Cultures is the very promising method of current solution medicine source of Taxol problem.
The research that Guangdong pharmaceutcal corporation, Ltd utilizes a large amount of culture techniques of yew cell to produce taxol has been carried out for some time, has entered at present pilot scale amplification stage.So research and application that from Taxol Production in Taxus Cell Cultures crude product, purifying obtains the preparation method of the paclitaxel api that meets American Pharmacopeia USP standard seem particularly important.Guangdong pharmaceutcal corporation, Ltd adopts yew cell to cultivate the taxol of producing, and it produced multiple influence factors such as comprising biotic factor, physical factor, chemical factor, contains some unknown materials and be very difficult to remove in Purification of Taxol process.Any one influence factor all can be related to the production efficiency of taxol, also can have influence on the content of Cephalomannine and unknown impuritie thing simultaneously.And as the medicine of clinical use, require its purity very high, and the paclitaxel api of American Pharmacopeia USP standard requires its unknown impuritie to be no more than 0.1%, and European Pharmacopoeia EP standard requires to be no more than 0.05%.
On the other hand, taxol resource preciousness, price are high, and the purity of separation and yield become the key factor of preparation paclitaxel api cost.Based on above-mentioned factor, from utilizing yew cell to cultivate the taxol crude product of producing that purifying obtains the preparation method of the paclitaxel api that meets American Pharmacopeia USP standard and novel purifying process has become the focal issue in taxol research.Carry out purifying and yew cell is cultivated to the taxol crude product of producing, effectively separate some unknown materials that are difficult to removal, the preparation method who finally obtains the paclitaxel api that meets American Pharmacopeia USP standard has no relevant report at present.
At present conventional purification of paclitaxel and the method for taxol similar compound mainly contain column chromatography, powders using crystallization method, tlc, miccellar electrokinetic chromatography method, membrane separation process, resin absorption partition method, chemical reaction method etc.But what can really be applicable to scale operation from now on only has two kinds of column chromatography and powders using crystallization methods, additive method is all confined to laboratory study.
About the patent application of taxol purifying has multinomial: as Chinese patent CN 1611496A " a kind of method of utilizing high pressure liquid chromatography to prepare high-purity taxol "; Chinese patent CN 03135916.7 " from the method for the thick purifying products taxol of taxol "; Chinese patent CN200610117672.6 " a kind of preparation method of high purity taxol compound "; Chinese patent CN 201310251956.4 " a kind of method from taxol medicinal extract purification of paclitaxel "; Chinese patent CN 200480009790.4 " from improving one's methods of natural matter separation and purification of paclitaxel "; Chinese patent CN200610047378.2 " a kind of method of efficiently purifying taxol " etc.The weak point of existing taxol purification process is mainly: the method for current various purification of paclitaxel still can not effectively fully separate and remove Cephalomannine and unknown impuritie thing from taxol crude product; All there is certain defect in the column chromatography and the powders using crystallization method that comprise normal phase column method and reversed-phase column method.Normal phase column chromatography method often needs to introduce oxidizing reaction, by changing the chemical structure of Cephalomannine, to increase the resolution of Cephalomannine and taxol, and will repeatedly cross post, the removal of unknown impuritie thing also be can not meet to requirement simultaneously.Importantly, loaded down with trivial details operation steps has reduced the yield of taxol, has increased production cost, though can obtain purer taxol, has changed Cephalomannine structure, can only be abandoned as waste material, has not only wasted resource but also contaminate environment.Although reversed phase column chromatography method need not change the chemical structure of separate object, the method need to be used special and expensive reversed-phase column silica gel in actual applications, has greatly increased the production cost of isolation of taxol, has limited its widespread use.Powders using crystallization method makes taxol yield low, loss is large, also increased undoubtedly the production cost of isolation of taxol, and the separation removal that this method can not be fully effective and closely similar bearing taxanes-Cephalomannine and a certain amount of some unknown materials that are difficult to removal of taxol structure.
Summary of the invention
The object of the invention is to cultivate the taxol crude product of producing as raw material take yew cell, a kind of separation purification method is provided, obtain meeting the paclitaxel api of American Pharmacopeia USP standard, meet and improve taxol yield, reduce costs and the actual demand of applicable suitability for industrialized production.
For realizing the object of the invention, technical scheme is as follows: the method isolation of taxol that adopts powders using crystallization method and normal phase column chromatography method to combine; First, yew cell is cultivated to the taxol dissolving crude product of producing in the larger organic solvent of polarity, make Japanese yew and organic solvent mass volume ratio at 0.04-0.10 g/mL, then dropwise add reverse organic solvent, obtain the taxol of purifying; And then adopt the further isolation of taxol of normal phase column chromatography method: stationary phase is 200 order～300 order silica gel, and moving phase is the binary gradient mixed solvent of methylene dichloride and ethyl acetate or normal hexane and acetone.The organic solvent that described polarity is larger selects butanols, propyl alcohol, acetone, ethyl acetate, ethyl acetate or methylene dichloride; Described reverse organic solvent is pentane, iso-pentane, normal hexane, hexanaphthene, octane-iso or sherwood oil.
Drip reverse organic solvent, reverse organic solvent when initial: the volume ratio of organic solvent=(10-30): (90-70), the reverse organic solvent of terminal hour: organic solvent volume ratio=(80-60): (20-40).
While adopting normal phase column chromatography method isolation of taxol, moving phase adopts methylene dichloride: ethyl acetate volume ratio is respectively the binary gradient elution system of 3:1,2:1 and 1:1; Or employing normal hexane: the score of acetone volume Wei 4:1,3:1 and the binary gradient elution system of 2:1.
According to adjusting Rf value, the mixed solvent recycling use of mobile phase dichloromethane and ethyl acetate or normal hexane and acetone.
Innovative point of the present invention is: the method that adopts powders using crystallization method to combine with normal phase column chromatography method separates in Taxol Production in Taxus Cell Cultures crude product and is difficult to separate Cephalomannine and the unknown material removed, finally obtains meeting the paclitaxel api of American Pharmacopeia USP standard.The present invention is reproducible, technique is reasonable, cost is low, simple to operate, green safety, both can meet the requirement that improves taxol yield, reduces production costs, can meet again the actual demand that is applicable to suitability for industrialized production, and Cephalomannine is not oxidized, can recycle, have a good application prospect.
Accompanying drawing explanation
Fig. 1 is the HPLC collection of illustrative plates of taxol after the embodiment of the present invention 1 purifying;
Fig. 2 is the HPLC collection of illustrative plates of taxol after the embodiment of the present invention 2 purifying;
Fig. 3 is the HPLC collection of illustrative plates of taxol after the embodiment of the present invention 3 purifying;
Fig. 4 is the HPLC collection of illustrative plates of Nat'l Pharmaceutical & Biological Products Control Institute's content 99.6% taxol reference substance.
Embodiment
For the present invention is illustrated better, as follows for embodiment:
Embodiment 1
In the single port flask of 150 mL, (Guangdong pharmaceutcal corporation, Ltd produces and provides to add yew cell to cultivate the taxol crude product of production, wherein content of taxol 63.0 %, Cephalomannine and unknown material are respectively 1.74 % and 3.56 %) 1.20 g, then add organic solvent-analytical pure propyl alcohol 18.9 mL that polarity is larger, make taxol quality g/ propyl alcohol volume mL=0.04 g/mL, fully stir until complete dissolution sample, then in this system, slowly drip reverse organic solvent-analytical pure pentane 2.10 mL, make pentane: propyl alcohol=10:90(volume ratio), fully stir 10 min, and then dropwise add pentane 2.63 mL, and make pentane: propyl alcohol=20:80(volume ratio), fully stir 10 min, 10.0 % ascending rate improve the volume content of pentane gradually, slowly drip, until floss appears in the solution in single port flask, more than fully stirring 1.5 h, then still 10.0 % ascending rate improve the volume content of pentane gradually, fully stir 10 min, until pentane: propyl alcohol=60:40(volume ratio after slowly dripping).Finally, adopt G4 sand core funnel to filter, vacuum 40-℃ obtains purity after dry is 85.1 % taxol sample 0.74 g, and yield is 83.3 %.
Then the taxol sample take 0.74 g purity as 85.1 % carries out normal phase column chromatography as raw material: raw material dissolves in order to wet method loading with a small amount of methylene dichloride; Stationary phase is 200 order～300 order silica gel, and silica gel is 100:1 with raw materials quality ratio; Moving phase adopts methylene dichloride: ethyl acetate=3:1,2:1,1:1(volume ratio) binary gradient elution system; Adopt methylene dichloride wet method dress post, then loading, finally rushes post wash-out by the moving phase preparing.Methylene dichloride: ethyl acetate=3:1(volume ratio) after 2.1 column volumes of moving phase punching, start to have Cephalomannine to flow out, after 0.5 column volume, for single taxol flows out, then be changed to methylene dichloride: ethyl acetate=2:1(volume ratio) moving phase, after 4.9 column volumes, taxol can be separated completely, finally uses methylene dichloride: ethyl acetate=1:1(volume ratio) 1.6 column volumes of moving phase wash-out to be to remove unknown impuritie thing.After a wash-out, the taxol of purity 98.9 % accounts for 80.7 %, further crystallization and purification; Other taxol effluent liquid merging obtain purity 96.2 % taxols and account for 19.3 %, with separating compared with pure sample product merging upper prop after the crystallization of taxol crude product.The sample of last further crystallization and purification is at P
2o
5under existence condition, vacuum 40-℃ of dry 48 h, obtain the paclitaxel api that meets American Pharmacopeia USP standard after testing.(separating-purifying process is carried out monitoring analysis with HPLC.）
Sample analysis the results are shown in Table 1, and as shown in Figure 1, other technologies index also all meets American Pharmacopeia USP standard to its HPLC collection of illustrative plates after testing.
Embodiment 2
In the single port flask of 100 mL, (Guangdong pharmaceutcal corporation, Ltd produces and provides to add yew cell to cultivate the taxol crude product of production, wherein content of taxol 65.0 %, Cephalomannine and unknown material content are respectively 1.80 % and 3.51 %) 1.20 g, then add organic solvent-analytical pure ethyl acetate 11.1 mL that polarity is larger, make taxol quality g/ ethyl acetate volume mL=0.07 g/mL, fully stir until complete dissolution sample, then in this system, slowly drip reverse organic solvent-analytical pure normal hexane 2.78 mL, make normal hexane: ethyl acetate=20:80(volume ratio), fully stir 10 min, and then dropwise add normal hexane 1.98 mL, and make normal hexane: ethyl acetate=30:70(volume ratio), fully stir 10 min, 10.0 % ascending rate improve the volume content of normal hexane gradually, slowly drip, until floss appears in the solution in single port flask, more than fully stirring 1.5 h, then still improve gradually the volume content of normal hexane with 10.0 % ascending rate, after slowly dripping, fully stir 10 min, until normal hexane: ethyl acetate=70:30(volume ratio).Finally, adopt G4 sand core funnel to filter, then after vacuum 40-℃ of dry 12 h, to obtain purity be 85.6 % taxol sample 0.76 g, yield is 83.4 %.
Taxol sample take 0.76 g purity as 85.6 % carries out normal phase column chromatography as raw material: a small amount of acetone solution of raw material is in order to wet method loading; Stationary phase is 200 order～300 order silica gel, and silica gel is 100:1 with raw materials quality ratio; Moving phase adopts normal hexane: acetone=4:1,3:1,2:1(volume ratio) binary gradient elution system; Adopt normal hexane wet method dress post, then loading, finally rushes post wash-out by the moving phase preparing.Normal hexane: acetone=4:1(volume ratio) after 4.30 column volumes of moving phase punching, start to have Cephalomannine to flow out, after 1.4 column volumes, for single taxol flows out, then be changed to normal hexane: acetone=3:1(volume ratio) moving phase, after 6.2 column volumes, taxol can be separated completely, finally uses normal hexane: acetone=2:1(volume ratio) moving phase washes 2.3 column volumes to remove unknown impuritie thing.After a wash-out, the taxol of purity 99.2 % accounts for 81.5 %, further crystallization and purification; Other taxol effluent liquid merging obtain purity 96.4 % taxols and account for 18.5 %, with separating compared with pure sample product merging upper prop after the crystallization of taxol crude product.The sample of last further crystallization and purification is vacuum 40-℃ of dry 48 h under P2O5 existence condition, can obtain after testing the paclitaxel api that meets American Pharmacopeia USP standard.(separating-purifying process is carried out monitoring analysis with HPLC.）
Sample analysis the results are shown in Table 1, and as shown in Figure 2, other technologies index also all meets American Pharmacopeia USP standard to sample HPLC collection of illustrative plates after testing.
In the single port flask of 100 mL, (Guangdong pharmaceutcal corporation, Ltd produces and provides to add yew cell to cultivate the taxol crude product of production, wherein content of taxol 68.0 %, Cephalomannine and unknown material content are respectively 1.86 % and 3.95 %) 1.20 g, then add organic solvent-analytical pure methylene dichloride 8.16 mL that polarity is larger, make taxol quality g/ methylene chloride volume mL=0.10 g/mL, fully stir until complete dissolution sample, then in this system, slowly drip reverse organic solvent-analytical pure octane-iso 3.50 mL, make octane-iso: methylene dichloride=30:70(volume ratio), fully stir 10 min, and then dropwise add octane-iso 1.94 mL, and make octane-iso: methylene dichloride=40:60(volume ratio), fully stir 10 min, 10.0 % ascending rate improve the volume content of octane-iso gradually, slowly drip, until floss appears in the solution in single port flask, more than fully stirring 1.5 h, then still 10.0 % ascending rate improve the volume content of octane-iso gradually, fully stir 10 min, until octane-iso: methylene dichloride=80:20(volume ratio after slowly dripping).Finally, adopt G4 sand core funnel to filter, then after vacuum 40-℃ of dry 12 h, to obtain purity be 87.5 % taxol sample 0.78 g, yield is 84.3 %.
Taxol sample take 0.78 g purity as 87.5 % carries out normal phase column chromatography as raw material: raw material dissolves in order to wet method loading with a small amount of methylene dichloride; Stationary phase is 200 order～300 order silica gel, and silica gel is 100:1 with raw materials quality ratio; Moving phase adopts methylene dichloride: ethyl acetate=3:1,2:1,1:1(volume ratio) binary gradient elution system; Adopt methylene dichloride wet method dress post, then loading, finally rushes post wash-out by the moving phase preparing.Methylene dichloride: ethyl acetate=3:1(volume ratio) after 2.2 column volumes of moving phase punching, start to have Cephalomannine to flow out, after 0.6 column volume, for single taxol flows out, then be changed to methylene dichloride: ethyl acetate=2:1(volume ratio) moving phase, after 5.2 column volumes, taxol can be separated completely, finally uses methylene dichloride: ethyl acetate=1:1(volume ratio) 1.7 column volumes of moving phase wash-out to be to remove unknown impuritie thing.After a wash-out, the taxol of purity 99.5 % accounts for 81.9 %, further crystallization and purification; Other taxol effluent liquid merging obtain purity 96.8 % taxols and account for 18.1 %, with separating compared with pure sample product merging upper prop after the crystallization of taxol crude product.The sample of further crystallization and purification is at P
2o
5under condition, vacuum 40-℃ of dry 48 h, can obtain the paclitaxel api that meets American Pharmacopeia USP standard after testing.(separating-purifying process is carried out monitoring analysis with HPLC.）
Sample analysis the results are shown in Table 1, and as shown in Figure 3, other technologies index also all meets American Pharmacopeia USP standard to sample HPLC collection of illustrative plates after testing.
Fig. 4 is that the HPLC of Nat'l Pharmaceutical & Biological Products Control Institute's content 99.6% taxol reference substance amplifies collection of illustrative plates, wherein unknown material 0.082%, Cephalomannine 0.12%, taxol 99.80%.
3 embodiment sample analysis results of table 1
Claims (4)
1. a method of cultivating purification of paclitaxel the taxol crude product of producing from yew cell, it is characterized in that, the method isolation of taxol that adopts powders using crystallization method and normal phase column chromatography method to combine, first, to cultivate the taxol dissolving crude product of producing from yew cell the larger organic solvent of polarity, make taxol crude product and organic solvent mass volume ratio at 0.04-0.10 g/mL, then dropwise add reverse organic solvent, obtain the taxol of purifying; And then adopt the further isolation of taxol of normal phase column chromatography method: stationary phase is 200 order～300 order silica gel, and moving phase is the binary gradient mixed solvent of methylene dichloride and ethyl acetate or normal hexane and acetone;
The organic solvent that described polarity is larger selects butanols, propyl alcohol, acetone, ethyl acetate, ethyl acetate or methylene dichloride; Described reverse organic solvent is pentane, iso-pentane, normal hexane, hexanaphthene, octane-iso or sherwood oil.
2. method of cultivating purification of paclitaxel the taxol crude product of producing from yew cell as claimed in claim 1, it is characterized in that, reverse organic solvent when initial: the volume ratio of organic solvent=(10-30): (90-70), the reverse organic solvent of terminal hour: organic solvent volume ratio=(60-80): (40-20).
3. method of cultivating purification of paclitaxel the taxol crude product of producing from yew cell as claimed in claim 1, it is characterized in that, while adopting normal phase column chromatography method isolation of taxol, moving phase adopts methylene dichloride: ethyl acetate volume ratio is respectively the binary gradient elution system of 3:1,2:1 and 1:1 or adopts normal hexane: the score of acetone volume Wei 4:1,3:1 and the binary gradient elution system of 2:1.
4. as the method for from yew cell cultivating the taxol crude product produced purification of paclitaxel of claim 1-3 as described in one of them, it is characterized in that, according to adjusting Rf value, the mixed solvent recycling use of mobile phase dichloromethane and ethyl acetate or normal hexane and acetone.
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| CN113717131A (en) * | 2021-08-27 | 2021-11-30 | 常熟纳微生物科技有限公司 | Separation and purification method of paclitaxel |
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| CN101020671A (en) * | 2006-08-03 | 2007-08-22 | 沈阳天峰生物工程技术有限公司 | Process of separating and purifying taxol efficiently |
| CN101314597A (en) * | 2008-07-04 | 2008-12-03 | 华中科技大学 | Method for separating paclitaxel from yew cell suspending culture solution |
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| CN101020671A (en) * | 2006-08-03 | 2007-08-22 | 沈阳天峰生物工程技术有限公司 | Process of separating and purifying taxol efficiently |
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| CN113717131A (en) * | 2021-08-27 | 2021-11-30 | 常熟纳微生物科技有限公司 | Separation and purification method of paclitaxel |
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