CN109535105A - A kind of taxol novel crystal forms and preparation method thereof - Google Patents
A kind of taxol novel crystal forms and preparation method thereof Download PDFInfo
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- CN109535105A CN109535105A CN201811347234.8A CN201811347234A CN109535105A CN 109535105 A CN109535105 A CN 109535105A CN 201811347234 A CN201811347234 A CN 201811347234A CN 109535105 A CN109535105 A CN 109535105A
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 title claims abstract description 92
- 229930012538 Paclitaxel Natural products 0.000 title claims abstract description 88
- 229960001592 paclitaxel Drugs 0.000 title claims abstract description 88
- 239000013078 crystal Substances 0.000 title claims abstract description 69
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 239000012296 anti-solvent Substances 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 61
- 239000008367 deionised water Substances 0.000 claims description 45
- 229910021641 deionized water Inorganic materials 0.000 claims description 45
- 239000000725 suspension Substances 0.000 claims description 45
- 238000004108 freeze drying Methods 0.000 claims description 22
- 239000000843 powder Substances 0.000 claims description 15
- 239000002608 ionic liquid Substances 0.000 claims description 14
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 13
- 230000031709 bromination Effects 0.000 claims description 13
- 238000005893 bromination reaction Methods 0.000 claims description 13
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 244000050510 Cunninghamia lanceolata Species 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 230000008021 deposition Effects 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 230000008018 melting Effects 0.000 claims 1
- 238000002844 melting Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 16
- 238000004090 dissolution Methods 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 5
- 238000002425 crystallisation Methods 0.000 abstract description 2
- 230000008025 crystallization Effects 0.000 abstract description 2
- 238000000634 powder X-ray diffraction Methods 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000001237 Raman spectrum Methods 0.000 abstract 1
- 238000000113 differential scanning calorimetry Methods 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 12
- 229940079593 drug Drugs 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- 108010012934 Albumin-Bound Paclitaxel Proteins 0.000 description 4
- 229940028652 abraxane Drugs 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 238000001069 Raman spectroscopy Methods 0.000 description 2
- 208000030961 allergic reaction Diseases 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000004154 complement system Effects 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 229940090044 injection Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- RVEJOWGVUQQIIZ-UHFFFAOYSA-N 1-hexyl-3-methylimidazolium Chemical compound CCCCCCN1C=C[N+](C)=C1 RVEJOWGVUQQIIZ-UHFFFAOYSA-N 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 241000186216 Corynebacterium Species 0.000 description 1
- 241000252210 Cyprinidae Species 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 235000016408 Podocarpus macrophyllus Nutrition 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 241001116500 Taxus Species 0.000 description 1
- 244000162450 Taxus cuspidata Species 0.000 description 1
- 235000009065 Taxus cuspidata Nutrition 0.000 description 1
- 241001149649 Taxus wallichiana var. chinensis Species 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- -1 alcohol ester Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000002612 cardiopulmonary effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229960001805 chloramphenicol palmitate Drugs 0.000 description 1
- PXKHGMGELZGJQE-ILBGXUMGSA-N chloramphenicol palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](NC(=O)C(Cl)Cl)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 PXKHGMGELZGJQE-ILBGXUMGSA-N 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000012866 low blood pressure Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229940108949 paclitaxel injection Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 210000002706 plastid Anatomy 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Epoxy Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of taxol novel crystal forms and preparation method thereof.Taxol novel crystallization is prepared with the method that anti-solvent recrystallizes in the present invention, and is characterized comprehensively using means such as scanning electron microscope, powder x-ray diffraction, differential scanning calorimetric analysis and Raman spectrums to taxol novel crystal forms.This method has many advantages, such as that easy to operate, controllability is strong, at low cost, is easy to industrialize.And obtained taxol novel crystal forms are a kind of new crystalline states, have the dissolution rate and bioavilability of more significant raising, therefore are conducive to the improvement of the physical and chemical performance of taxol, improve patent medicine performance.
Description
Technical field
The present invention relates to anti-solvent methods to prepare taxol novel crystal forms production technology, in particular to good water solubility, is easy to discharge
The advantages that paclitaxel solid novel crystal forms.
Technical background
Taxol (Paclitaxel) is Americanized scholar Wani in 1971 etc. from brachyplast Chinese yew (Taxus
Breuifilia it) is isolated in bark.Taxol inhibits cell division by the micro-pipe in conjunction with growth, is a kind of spectral class
Cell toxicant anticancer drug.It is clinical since U.S. FDA in 1992 ratifies taxol as treatment Advanced Ovarian cancer drug for the first time
It was found that taxol is to oophoroma, breast cancer, lymph cancer, prostate cancer, malignant mela noma and head and neck neoplasm, gastrointestinal cancer,
The treatment of cellule type and lung cancer in non-cellule type has significant curative effect.However the water solubility of taxol is extremely low, has it very low
Bioavilability, to cause administration difficult.Taxol is significantly limited in the application of oncotherapy.Its structural formula is such as
Shown in the following figure.
The main injection liquid that taxol is clinically applied at present is that taxol is dissolved in Emulsifier EL-60
Made of the in the mixed solvent of (Cremophore EL) and dehydrated alcohol (1:1).However Emulsifier EL-60 easily causes stomach and intestine
A variety of toxic reactions such as road reaction, allergic reaction, low blood pressure, renal toxicity, cardiac toxic and bone marrow suppression, significantly limit purple
The clinical application of China fir alcohol.Taxol albumin suspension injections in 2005 are ratified to list by U.S. FDA, trade name
Abraxane.And Abraxane shows more non-Abraxane treatment group more in the III phase clinical trial of breast cancer treatment
High esthesioneurosis variability.And Abraxane overall price it is more traditional paclitaxel injection it is more expensive.Japanese yew alcohol ester
Plastid (L-PTX) injection was listed in 2003 by SFDA approval at home, but that there are encapsulation rates is low for Paclitaxel liposome, unstable
The problems such as determining.And the study found that due to a large amount of cholesterol in the biggish particle radii of liposome and its lipid bilayer
Intracorporal complement system can be activated, the pseudo-allergic reaction CARPA mediated so as to cause complement system.This reaction is clinically
It shows as the damage of cardio-pulmonary function more, therefore limits the application of Paclitaxel liposome clinically.The purple of clinical use at present
The equal Shortcomings of the different dosage form of China fir alcohol, therefore research and develop a kind of safety low-poison, taxol novel form significant in efficacy, which has been carved, not to be allowed
It is slow.
Crystal form drug refers to active pharmaceutical ingredient (Active Pharmaceutical Ingredient, API) with specific
Solid drugs existing for crystal form state.A kind of drug can there are many crystal forms to exist, the different crystal forms of same drug, in vivo
Dissolution and absorb may be different, also will affect the dissolution and release of its preparation, and then influence clinical efficacy and safety.Drug
Polymorphism is found in 1832, but the 1960s is dense by the blood medicine of discovery two kinds of crystal forms of chloramphenicol palmitate such as Aguiar
Spend the highest attention that the phenomenon that difference is huge, this crystal form changes pharmaceutical properties obtains domestic and international study of pharmacy personnel.
In the 1970s, China copy drug greatest differences are shown on clinical effectiveness, to the research of this phenomenon be the discovery that due to
The different crystal forms of medicine material.When solid drugs crystal form difference, the property such as fusing point, stability, solubility, vivo biodistribution availability
There may be differences for matter.Thus the polymorphic research of drug starts to receive extensive attention in China.Also, it is related at present purple
Research in terms of China fir alcohol drug crystal forms is also rare.
The method that the present invention uses anti-solvent recrystallization is gone with 1 hexyl of bromination, 3 methylimidazole ([HMIm] Br) for solvent
Ionized water is anti-solvent, is prepared taxol novel crystal forms, preparation method have easy to operate, high-efficient, controllability is strong, at
The advantages that this is low, easy to industrialized production, and taxol novel crystal forms compared with taxol raw medicine have the dissolution rate significantly improved and
Bioavilability, crystallinity is low, at regular crystal habit, therefore is conducive to the process of drug and changing for physical and chemical performance
It is kind, improve patent medicine performance.
Summary of the invention
The deficiencies of in order to overcome the water solubility of existing taxol lower with bioavilability, the present invention provides a kind of Japanese yews
Novel crystal forms of alcohol and preparation method thereof, water-soluble, dissolution rate and bioavilability all increase.
Taxol novel crystal forms crystal provided by the invention, X-ray powder diffraction pattern 2 θ=5.068 ° of the angle of diffraction ±
0.1,5.923 ° ± 0.1,9.562 ° ± 0.1,10.794 ° ± 0.1,13.491 ° ± 0.1,13.667 ° ± 0.1,15.225 ° ±
There is characteristic peak at 0.1,16.312 ° ± 0.1 and 20.146 ° ± 0.1, as shown in Fig. 1
Taxol novel crystal forms crystal provided by the invention, with scanning electron microscopic observation, pattern is in corynebacterium crystal, shape
Looks and original powder have bigger difference, as shown in Fig. 2.
Taxol novel crystal forms crystal provided by the invention is measured with differential scanning calorimeter (DSC), at 147.88 ± 1 DEG C
There is a fusing endothermic peak, as shown in Fig. 3.40-300 DEG C of test condition range, heat up 10 DEG C/min, protects nitrogen 80mL/
min。
Taxol novel crystal forms crystal of the present invention, molecular weight 854.4, as shown in Fig. 4.
Taxol novel crystal forms crystal of the present invention, Raman map is without significantly stretching and vibrating, such as 5 institute of attached drawing
Show.
Taxol novel crystal forms crystal of the present invention, saturation solubility are about increased to 6.05 μ from 1.16 original μ g/mL
G/mL about improves nearly 6 times.
Taxol novel crystal forms crystal of the present invention, with faster dissolution rate, as shown in Fig. 6.
Taxol novel crystal forms crystal of the present invention, oral administration biaavailability about increase 10.88 than taxol raw medicine
Times, as shown in Fig. 7.
Taxol novel crystal forms crystal of the present invention the preparation method is as follows:
It takes appropriate purity to be more than or equal to 98% taxol, is dissolved in ionic liquid and forms solution for later use, concentration 10-
70mg/mL measures a certain amount of anti-solvent by solvent and the certain proportion of anti-solvent, by taxol under certain preparation temperature
Solution is slowly added in anti-solvent and is stirred continuously, deposition a period of time, and centrifugation gained precipitating is washed with deionized, i.e.,
Vortex 1-2min after appropriate amount of deionized water is added to be dispersed in deionized water to suspension, then 10000r/min is centrifuged
5min is washed repeatedly 8-10 times.Suspension is moved into freeze-drying bottle, moves into freeze dryer, freezes afterwards for 24 hours in -40 DEG C of refrigerator pre-freezes
It can be obtained taxol crystal form powder after dry 72h.Obtain taxol novel crystallization product.
The solvent is 1 hexyl of ionic liquid bromination, 3 methylimidazole, and the anti-solvent is deionized water.
The preparation temperature is 25-95 DEG C.
The advantages of preparation method of taxol novel crystal forms provided by the invention, is that preparation method is easy to operate, crystallizes
Journey is easily controllable, and taxol novel crystal forms have the dissolution rate significantly improved and bioavilability compared with taxol original powder, and
Its crystallinity is low, at regular crystal habit.
Detailed description of the invention
Fig. 1 is the x-ray diffraction pattern of taxol novel crystal forms；
Fig. 2 is the scanning electron microscope (SEM) photograph of taxol novel crystal forms；
Fig. 3 is the differential scanning calorimetric thermogram of taxol novel crystal forms；
Fig. 4 is the mass spectrogram of taxol novel crystal forms；
Fig. 5 is the Raman spectrogram of taxol novel crystal forms；
Fig. 6 is the dissolution figure of taxol novel crystal forms；
Fig. 7 is the bioavilability figure of taxol novel crystal forms.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to the accompanying drawings and embodiments, right
The present invention is further elaborated.Described herein specific examples are only used to explain the present invention, is not used to limit
The present invention.
Embodiment 1
The paclitaxel solid that 100mg purity is 98% is added in 1 hexyl of 10mL ionic liquid bromination, 3 methylimidazole, is stirred
It mixes and makes it completely dissolved for use, measure deionized water 50mL, paclitaxel solution is slowly added in deionized water at 25 DEG C, by
Gradually form milky suspension.To reaction terminating, suspension 15000r/min is centrifuged 10min.Centrifuged deposit spend from
Sub- water washing, i.e., vortex 1-2min is dispersed in deionized water to suspension plus after appropriate amount of deionized water, then 10000r/
Min is centrifuged 5min, washes repeatedly 8-10 times.Suspension is moved into freeze-drying bottle, moves into freeze-drying afterwards for 24 hours in -40 DEG C of refrigerator pre-freezes
In machine, taxol crystal form powder can be obtained after 72h is lyophilized.
Embodiment 2
The paclitaxel solid that 300mg purity is 98% is added in 1 hexyl of 10mL ionic liquid bromination, 3 methylimidazole, is stirred
It mixes and makes it completely dissolved for use, measure deionized water 50mL, paclitaxel solution is slowly added in deionized water at 25 DEG C, by
Gradually form milky suspension.To reaction terminating, suspension 15000r/min is centrifuged 10min.Centrifuged deposit spend from
Sub- water washing, i.e., vortex 1-2min is dispersed in deionized water to suspension plus after appropriate amount of deionized water, then 10000r/
Min is centrifuged 5min, washes repeatedly 8-10 times.Suspension is moved into freeze-drying bottle, moves into freeze-drying afterwards for 24 hours in -40 DEG C of refrigerator pre-freezes
In machine, taxol crystal form powder can be obtained after 72h is lyophilized.
Embodiment 3
The paclitaxel solid that 500mg purity is 98% is added in 1 hexyl of 10mL ionic liquid bromination, 3 methylimidazole, is stirred
It mixes and makes it completely dissolved for use, measure deionized water 50mL, paclitaxel solution is slowly added in deionized water at 25 DEG C, by
Gradually form milky suspension.To reaction terminating, suspension 15000r/min is centrifuged 10min.Centrifuged deposit spend from
Sub- water washing, i.e., vortex 1-2min is dispersed in deionized water to suspension plus after appropriate amount of deionized water, then 10000r/
Min is centrifuged 5min, washes repeatedly 8-10 times.Suspension is moved into freeze-drying bottle, moves into freeze-drying afterwards for 24 hours in -40 DEG C of refrigerator pre-freezes
In machine, taxol crystal form powder can be obtained after 72h is lyophilized.
Embodiment 4
The paclitaxel solid that 700mg purity is 98% is added in 1 hexyl of 10mL ionic liquid bromination, 3 methylimidazole, is stirred
It mixes and makes it completely dissolved for use, measure deionized water 50mL, paclitaxel solution is slowly added in deionized water at 25 DEG C, by
Gradually form milky suspension.To reaction terminating, suspension 15000r/min is centrifuged 10min.Centrifuged deposit spend from
Sub- water washing, i.e., vortex 1-2min is dispersed in deionized water to suspension plus after appropriate amount of deionized water, then 10000r/
Min is centrifuged 5min, washes repeatedly 8-10 times.Suspension is moved into freeze-drying bottle, moves into freeze-drying afterwards for 24 hours in -40 DEG C of refrigerator pre-freezes
In machine, taxol crystal form powder can be obtained after 72h is lyophilized.
Embodiment 5
The paclitaxel solid that 500mg purity is 98% is added in 1 hexyl of 10mL ionic liquid bromination, 3 methylimidazole, is stirred
It mixes and makes it completely dissolved for use, measure deionized water 50mL, paclitaxel solution is slowly added in deionized water at 50 DEG C, by
Gradually form milky suspension.To reaction terminating, suspension 15000r/min is centrifuged 10min.Centrifuged deposit spend from
Sub- water washing, i.e., vortex 1-2min is dispersed in deionized water to suspension plus after appropriate amount of deionized water, then 10000r/
Min is centrifuged 5min, washes repeatedly 8-10 times.Suspension is moved into freeze-drying bottle, moves into freeze-drying afterwards for 24 hours in -40 DEG C of refrigerator pre-freezes
In machine, taxol crystal form powder can be obtained after 72h is lyophilized.
Embodiment 6
The paclitaxel solid that 500mg purity is 98% is added in 1 hexyl of 10mL ionic liquid bromination, 3 methylimidazole, is stirred
It mixes and makes it completely dissolved for use, measure deionized water 30mL, paclitaxel solution is slowly added in deionized water at 75 DEG C, by
Gradually form milky suspension.To reaction terminating, suspension 15000r/min is centrifuged 10min.Centrifuged deposit spend from
Sub- water washing, i.e., vortex 1-2min is dispersed in deionized water to suspension plus after appropriate amount of deionized water, then 10000r/
Min is centrifuged 5min, washes repeatedly 8-10 times.Suspension is moved into freeze-drying bottle, moves into freeze-drying afterwards for 24 hours in -40 DEG C of refrigerator pre-freezes
In machine, taxol crystal form powder can be obtained after 72h is lyophilized.
Embodiment 7
The paclitaxel solid that 500mg purity is 98% is added in 1 hexyl of 10mL ionic liquid bromination, 3 methylimidazole, is stirred
It mixes and makes it completely dissolved for use, measure deionized water 50mL, paclitaxel solution is slowly added in deionized water at 95 DEG C, by
Gradually form milky suspension.To reaction terminating, suspension 15000r/min is centrifuged 10min.Centrifuged deposit spend from
Sub- water washing, i.e., vortex 1-2min is dispersed in deionized water to suspension plus after appropriate amount of deionized water, then 10000r/
Min is centrifuged 5min, washes repeatedly 8-10 times.Suspension is moved into freeze-drying bottle, moves into freeze-drying afterwards for 24 hours in -40 DEG C of refrigerator pre-freezes
In machine, taxol crystal form powder can be obtained after 72h is lyophilized.
Embodiment 8
The paclitaxel solid that 500mg purity is 98% is added in 1 hexyl of 10mL ionic liquid bromination, 3 methylimidazole, is stirred
It mixes and makes it completely dissolved for use, measure deionized water 30mL, paclitaxel solution is slowly added in deionized water at 25 DEG C, by
Gradually form milky suspension.To reaction terminating, suspension 15000r/min is centrifuged 10min.Centrifuged deposit spend from
Sub- water washing, i.e., vortex 1-2min is dispersed in deionized water to suspension plus after appropriate amount of deionized water, then 10000r/
Min is centrifuged 5min, washes repeatedly 8-10 times.Suspension is moved into freeze-drying bottle, moves into freeze-drying afterwards for 24 hours in -40 DEG C of refrigerator pre-freezes
In machine, taxol crystal form powder can be obtained after 72h is lyophilized.
Embodiment 9
The paclitaxel solid that 500mg purity is 98% is added in 1 hexyl of 10mL ionic liquid bromination, 3 methylimidazole, is stirred
It mixes and makes it completely dissolved for use, measure deionized water 70mL, paclitaxel solution is slowly added in deionized water at 95 DEG C, by
Gradually form milky suspension.To reaction terminating, suspension 15000r/min is centrifuged 10min.Centrifuged deposit spend from
Sub- water washing, i.e., vortex 1-2min is dispersed in deionized water to suspension plus after appropriate amount of deionized water, then 10000r/
Min is centrifuged 5min, washes repeatedly 8-10 times.Suspension is moved into freeze-drying bottle, moves into freeze-drying afterwards for 24 hours in -40 DEG C of refrigerator pre-freezes
In machine, taxol crystal form powder can be obtained after 72h is lyophilized.
Embodiment 10
The paclitaxel solid that 500mg purity is 98% is added in 1 hexyl of 10mL ionic liquid bromination, 3 methylimidazole, is stirred
It mixes and makes it completely dissolved for use, measure deionized water 90mL, paclitaxel solution is slowly added in deionized water at 95 DEG C, by
Gradually form milky suspension.To reaction terminating, suspension 15000r/min is centrifuged 10min.Centrifuged deposit spend from
Sub- water washing, i.e., vortex 1-2min is dispersed in deionized water to suspension plus after appropriate amount of deionized water, then 10000r/
Min is centrifuged 5min, washes repeatedly 8-10 times.Suspension is moved into freeze-drying bottle, moves into freeze-drying afterwards for 24 hours in -40 DEG C of refrigerator pre-freezes
In machine, taxol crystal form powder can be obtained after 72h is lyophilized.
Claims (6)
1. a kind of taxol novel crystal forms of the present invention and preparation method thereof, it is characterised in that X-ray powder pattern is in diffraction
± 0.1,5.923 ° ± 0.1,9.562 ° ± 0.1,10.794 ° ± 0.1,13.491 ° ± 0.1,13.667 ° of 2 θ=5.068 ° of angle ±
There is characteristic peak at 0.1,15.225 ° ± 0.1,16.312 ° ± 0.1 and 20.146 ° ± 0.1.
2. a kind of taxol novel crystal forms as described in claim 1 and preparation method thereof, which is characterized in that the difference of the novel crystal forms
Show that scanning thermometric analysis has feature melting peak at 147.88 ± 1 DEG C.
3. a kind of taxol novel crystal forms as described in claim 1 and preparation method thereof, which is characterized in that the drawing of the novel crystal forms
Graceful map is without significantly stretching and vibrating.
4. taxol novel crystal forms as described in claim 1 the preparation method is as follows: take appropriate purity be more than or equal to 98% purple
China fir alcohol, is dissolved in ionic liquid and forms solution for later use, concentration 10-70mg/mL, by the certain proportion amount of solvent and anti-solvent
A certain amount of anti-solvent is taken, paclitaxel solution is slowly added in anti-solvent and is stirred continuously under room temperature, deposition a period of time, from
Gained precipitating is washed with deionized the heart, i.e., vortex 1-2min is dispersed in suspension plus after appropriate amount of deionized water
In ionized water, then 10000r/min is centrifuged 5min, washes repeatedly 8-10 times.Suspension is moved into freeze-drying bottle, in -40 DEG C of ice
Case pre-freeze moves into freeze dryer afterwards for 24 hours, can be obtained taxol crystal form powder after 72h is lyophilized.
5. a kind of taxol novel crystal forms according to claim 1 and preparation method thereof, which is characterized in that the ionic liquid
Body is 1 hexyl of bromination, 3 methylimidazole, and the anti-solvent is deionized water.
6. a kind of taxol novel crystal forms according to claim 1 and preparation method thereof, which is characterized in that the preparation temperature
Degree is 25-95 DEG C.
Priority Applications (1)
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| CN103768046A (en) * | 2014-02-21 | 2014-05-07 | 中国人民解放军军事医学科学院毒物药物研究所 | Injection paclitaxel nanocrystal and preparation method thereof |
| CN106243066A (en) * | 2016-08-05 | 2016-12-21 | 上海贝美医药科技有限公司 | The crystallization purifications of paclitaxel |
| CN106749114A (en) * | 2017-02-24 | 2017-05-31 | 中国农业科学院麻类研究所 | A kind of method that taxol is extracted from Chinese yew |
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| CN103768046A (en) * | 2014-02-21 | 2014-05-07 | 中国人民解放军军事医学科学院毒物药物研究所 | Injection paclitaxel nanocrystal and preparation method thereof |
| CN106243066A (en) * | 2016-08-05 | 2016-12-21 | 上海贝美医药科技有限公司 | The crystallization purifications of paclitaxel |
| CN106749114A (en) * | 2017-02-24 | 2017-05-31 | 中国农业科学院麻类研究所 | A kind of method that taxol is extracted from Chinese yew |
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| FOSS, MARGIT等: "Taxol crystals can masquerade as stabilized microtubules", PLOS ONE, vol. 3, no. 1, pages 1476 * |
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