CN106674156A - New crystalline form of docetaxel and preparation method thereof - Google Patents
New crystalline form of docetaxel and preparation method thereof Download PDFInfo
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- CN106674156A CN106674156A CN201510757099.4A CN201510757099A CN106674156A CN 106674156 A CN106674156 A CN 106674156A CN 201510757099 A CN201510757099 A CN 201510757099A CN 106674156 A CN106674156 A CN 106674156A
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- docetaxel
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention discloses a crystal of docetaxel trihydrate as shown in the following formula. The crystal has characteristic peaks in the following 2<theta> angle of a powder X-ray diffraction pattern: 4.30+/-0.2 degrees, 8.74+/-0.2 degrees, 10.32+/-0.2 degrees, 11.04+/-0.2 degrees, 13.92+/-0.2 degrees and 17.7+/-0.2 degrees. Furthermore, the invention further discloses a preparation method and use of the crystal <FORMULA>.
Description
Technical field
The present invention relates to the crystallization art of compound；Specifically, the present invention relates to docetaxel trihydrate
Novel crystal forms and preparation method thereof.
Background technology
(chemistry is entitled for docetaxel：(2R, 3S) -3- t-butoxycarbonyl amino -2- hydroxyl -3- benzenpropanoic acids (4- acetyl
The α of epoxide-2-β of benzoyloxy-5, the β of 20- epoxies-1,7,10 β-α of trihydroxy-9- oxo taxanes-11- alkene-13) ester)
It is by taxanes extracting cell core thing (referred to as 10- removes acetyl bar Ka Ting or 10-DAB) Jingization main in Chinese yew
The semi-synthetic cancer therapy drug that be synthesized into, is recognized because of its excellent anti-cancer properties by increasing people
Know.Research shows that the anti-cancer properties of docetaxel are better than taxol, and toxic and side effect is lower, because
And docetaxel has obtained increasingly being widely applied.
Docetaxel is white or off-white powder, at present it has been reported that numerous crystal formations.For example,
WO2007109654 reports 9 kinds of trihydrates or anhydrous crystal formation；CN101282955 reports new nothing
Water thing crystal formation；WO2012160568 reports new trihydrate crystal formation；Report in TW200906813
Three kinds of new anhydride crystal formations etc..Current research conclusion thinks that the stability of the trihydrate of docetaxel is excellent
In without hydrate.
However, the stability of crystal form of docetaxel trihydrate of the prior art is still not enough, when longer
Between preservation after, the content of its moisture, purity, content and 7- table docetaxel isomers has change；Together
When, the method for crystallising of docetaxel trihydrate there is also various deficiencies, such as separation of solid and liquid in prior art
It is difficult；Docetaxel degraded is easily caused, 7- table docetaxel contents increase after particularly crystallizing；Dry run
Complexity, water content and Determination of Residual Organic Solvents do not meet standards of pharmacopoeia；High temperature crystallization is needed, or adds crystal seed
Induction；And, the molar yield of docetaxel trihydrate crystal is low.
Therefore, stable docetaxel trihydrate novel crystal forms and method for crystallising are badly in need of in this area.
The content of the invention
It is an object of the invention to provide a kind of stable docetaxel trihydrate novel crystal forms and to prepare this new
The method of crystal formation.
In a first aspect, the present invention provides the crystal of the docetaxel trihydrate shown in following formula, the crystal exists
There is characteristic peak at following 2 θ angles in x-ray diffractogram of powder spectrum：4.30±0.2°、8.74±0.2°、10.32±0.2°、
11.04±0.2°、13.92±0.2°、17.70±0.2°
In a particular embodiment, the crystal also has spy at following 2 θ angles that x-ray diffractogram of powder is composed
Levy peak：About 4.98 ± 0.2 °, 7.15 ± 0.2 °, 11.70 ± 0.2 °, 12.42 ± 0.2 °, 15.28 ± 0.2 °, 18.46 ± 0.2 °,
19.30±0.2°、19.76±0.2°、22.12±0.2°、27.42±0.2°、36.56±0.2°。
In a particular embodiment, the x-ray diffractogram of powder of the crystal is composed substantially as shown in.
In a particular embodiment, the means of differential scanning calorimetry figure (DSC) of the crystal be displayed in 87.0 DEG C, 168.0
DEG C and 225.5 DEG C at have peak-peak.
In a particular embodiment, the means of differential scanning calorimetry figure (DSC) of the crystal is as shown in Figure 2.
In a preferred embodiment, the crystal of the docetaxel trihydrate is at 25 ± 2 DEG C, relative humidity
Place 24 months under conditions of 60 ± 10%, its moisture, purity, content and 7- table docetaxel isomers contain
Amount changes less than 10%, preferably smaller than 5%, more preferably less than 1%.
In second aspect, the present invention provides the crystal of the docetaxel trihydrate described in first aspect present invention
Preparation method, comprises the following steps：
A) docetaxel is dissolved in the mixed liquor of ketone and alcohol, so as to obtain the solution of docetaxel；With
B) in adding water to the docetaxel solution obtained to step a), so as to obtain docetaxel trihydrate
Crystal.
In a particular embodiment, the step a) includes：
A1) docetaxel and ketone are mixed, so as to obtain the ketone solution of docetaxel；With
A2) to a1) obtain docetaxel solution in add alcohol, so as to obtain docetaxel keto-alcohol mix it is molten
Liquid；And/or
The step b) includes：
B1 in) adding water to the docetaxel solution obtained to step a), so as to obtain a suspension；
B2) by step b1) suspension that obtains is filtered or centrifugation obtains solid, it is vacuum dried so as to docetaxel three
The crystal of hydrate.
In a preferred embodiment, in step a1) in, ketone and docetaxel mixture are heated into 30～55
DEG C with promote dissolve docetaxel.
In a preferred embodiment, in step a2) in, first the solution of docetaxel and ketone is cooled into 25～35
DEG C, add alcohol.
In a particular embodiment, the ketone is C3-5Ketone；It is preferred that acetone；And/or, the alcohol is C1-3's
Straight or branched alcohol；It is preferred that methyl alcohol.
In a particular embodiment, docetaxel and the mass volume ratio of ketone are 1:7-15g/ml；It is preferred that 1:10
g/ml；And/or
Alcohol is 5～20 with the volume ratio of ketone:100；Preferably, alcohol and the volume ratio of ketone are 10～15:100；With/
Or
Water is 1～4 with the volume ratio of ketone and alcohol consumption sum:1；It is highly preferred that water and ketone and the body of alcohol consumption sum
Product is than being 1.5～2.5:1；Most preferably, water and the volume ratio of ketone and alcohol consumption sum are 2:1.
In a preferred embodiment, cooling step b1) suspension that obtains；Preferably, suspension is cooled to
10～30 DEG C, more preferably to about 15 DEG C.
In a preferred embodiment, in step b1) in, at 25～35 DEG C, do under vacuum -0.096～-0.098MPa
The crystal of dry docetaxel trihydrate about 15 hours, so that its water content is between 5～7%.
In a preferred embodiment, methods described includes：
A) docetaxel is merged with acetone；
B) mixture is heated to 30～55 DEG C；
C) alcohol is added into the mixture of step b)；
D) add water to obtain suspension into the mixture of step c)；
E) step d) is filtered or centrifugation obtains solid, be vacuum dried to obtain three water docetaxel crystal.
In a preferred embodiment, the crystal of the docetaxel trihydrate that methods described is obtained exists
25 ± 2 DEG C, place 24 months under conditions of relative humidity 60 ± 10%, its moisture, purity, content and 7- tables are more
The content of Xi Tasai isomers changes less than 10%, preferably smaller than 5%, more preferably less than 1%.
In the third aspect, the present invention provides the crystal of the docetaxel trihydrate described in first aspect present invention
Prepare for treat advanced breast cancer, oophoroma, non-small cell lung cancer, incidence cancer, ED-SCLC,
Application in cancer of the stomach, cancer of pancreas, the medicine of melanoma.
In fourth aspect, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes the present invention the
The crystal and optional pharmaceutically acceptable excipient of the docetaxel trihydrate described on the one hand.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and below (such as embodiment)
Can be combined with each other between each technical characteristic of middle specific descriptions, so as to constitute new or preferred technical side
Case.As space is limited, here is no longer tired out one by one and is stated.
Description of the drawings
Fig. 1 shows the X ray diffracting spectrum of the three hydration docetaxel crystal formations of the present invention；
Fig. 2 shows the DSC collection of illustrative plates of the three hydration docetaxel crystal formations of the present invention.
Fig. 3 shows the infared spectrum of the three hydration docetaxel crystal formations of the present invention.
Specific embodiment
Inventor passes through extensively and in-depth study, it was unexpectedly found that using the ternary system of ketone/alcohol/water
So that docetaxel crystallization can obtain the novel crystal forms of three hydration docetaxels.The many west of three hydrations of the present invention he
Match novel crystal forms have extremely excellent stability；And the method for crystallising of the present invention does not result in docetaxel drop
Solution, easy to operate, molar yield is high.The present invention is completed on this basis.
Term " crystal " used herein refers to the solid of molecule or atomic composite thing in particular arrangement form.
Herein, term " crystal of the present invention ", " three hydration docetaxel crystal ", " water of docetaxel three
The crystal of compound " can be to represent to obtain, possess described herein by the inventive method with used interchangeably
The crystal of the trihydrate of the docetaxel of feature.
Term X-ray polycrystalline diffraction used herein is also called X-ray powder diffraction, when X-ray can through crystal
To produce a series of diffraction, in the lab X ray diffracting spectrum can be obtained using X-ray diffractometer,
In collection of illustrative plates, different diffracted rays and the intensity of each diffracted ray are determined by the atomic group of a fixed structure
, the diffracting spectrum produced by the crystal of different structure is different, therefore can use X-ray diffractogram
Compose to determine the construction of crystal, i.e. crystal formation.
The method that the X-ray diffracting spectrum of measure crystal is adopted is known in the art.For example use
The X-ray powder diffraction instrument of RIGAKU D/max 2550VB/PC models, per minute is swept during measure with 2 °
Retouch speed and obtain collection of illustrative plates.Using copper radiation target.
The three hydration docetaxel crystal of the present invention have specific crystal habit.The X-ray of this crystal is spread out
Penetrate figure and there is specific characteristic peak.Specifically, the crystal of three hydration docetaxels of the invention is in X-ray
There is characteristic absorption peak at following 2 θ angles in powder diffraction spectrum：4.30±0.2°、8.74±0.2°、10.32±0.2°、
11.04±0.2°、13.92±0.2°、17.70±0.2°.In a preferred embodiment, three hydrations of the invention are more
The crystal of Xi Tasai also has characteristic absorption peak at following 2 θ angles in the X-ray powder diffraction pattern：About
4.98±0.2°、7.15±0.2°、11.70±0.2°、12.42±0.2°、15.28±0.2°、18.46±0.2°、19.30±0.2°、
19.76±0.2°、22.12±0.2°、27.42±0.2°、36.56±0.2°.More preferably, three hydrations west more of the invention
He matches crystal with the X ray diffracting spectrum substantially consistent with Fig. 1.
Term " differential scanning calorimetry " used herein, also known as " differential scanning calorimetry " (DSC)
It is one kind that relation between the energy difference and temperature between measured matter and reference substance is measured in heating process
Technology.Peak position, shape and peak number mesh on DSC collection of illustrative plates is relevant with the property of material, therefore can be qualitatively
For identifying material.The method commonly used in the art come detect the phase transition temperature of material, glass transition temperature,
The many kinds of parameters such as reaction heat.
DSC assay methods are well known in the art.For example can be using DSC Q20 differential scanning calorimetries point
Analyzer (NETZSCH DSC204F1), with 10 DEG C of heating rates per minute, from 25 DEG C 250 is warming up to
DEG C, obtain the DSC scanning spectras of crystal.
In a particular embodiment, the three hydration docetaxel crystal of the present invention are measured 168.0 using DSC
DEG C and 225.5 DEG C have peak-peak.In a preferred embodiment, three hydration docetaxels of the invention are brilliant
Body has the DSC collection of illustrative plates basically identical with Fig. 2, more preferably has peak-peak at 87.0 DEG C.
Infared spectrum method (IR) may also be employed to determine crystal structure, its assay method is known in the art
's.PE Spectrum One B can be for example adopted, with KBr:Sample=200:1 compressing tablet, and in 400～4000cm-1
Range scans.The three hydration docetaxel crystal of the present invention have characteristic peak in following wave number：3451cm-1、3380
cm-1、2980cm-1、1736cm-1、1712cm-1、1268cm-1、1246cm-1、709cm-1.It is preferred that
With the infared spectrum basically identical with Fig. 3.
The crystal formation of the present invention is three water, i.e. the water containing 3 molecules in each molecule docetaxel in crystal.
The water content moisture titration of the crystal formation determines its result for 5～7%.
The three hydration docetaxel crystal of the present invention possess excellent stability.In a particular embodiment,
The docetaxel trihydrate crystal of the present invention places 24 at 25 ± 2 DEG C under conditions of relative humidity 60 ± 10%
Individual month, the content of its moisture, purity, content and 7- table docetaxel isomers changed less than 10%, preferably
Less than 5%, more preferably less than 1%.
Those skilled in the art know, docetaxel can be used to treating advanced breast cancer, oophoroma, non-little thin
Born of the same parents' lung cancer, incidence cancer, ED-SCLC, cancer of the stomach, cancer of pancreas, melanoma etc..Therefore, the present invention
The crystal of the docetaxel trihydrate of offer also can be used to treat advanced breast cancer, oophoroma, non-small cell
Lung cancer, incidence cancer, ED-SCLC, cancer of the stomach, cancer of pancreas, melanoma, i.e. for preparing treatment
The medicine of above-mentioned disease.
Based on the crystal of the docetaxel trihydrate of the present invention, the present invention also provides a kind of pharmaceutical composition,
The crystal of docetaxel trihydrate of the described pharmaceutical composition comprising the present invention and optional pharmaceutically acceptable
Excipient.
The three hydration docetaxel crystal of the present invention are using ketone, the specific ternary system of alcohol and water, by this
Three hydration docetaxel crystal preparation methods of invention are obtained.The method comprising the steps of：
A) docetaxel is dissolved in the mixed liquor of ketone and alcohol, so as to obtain the solution of docetaxel；With
B) in adding water to the docetaxel solution obtained to step a), so as to obtain docetaxel trihydrate
Crystal.
In a particular embodiment, the step of methods described a) includes：
A1) docetaxel and ketone are mixed, so as to obtain the ketone solution of docetaxel；With a2) to a1) obtain
Docetaxel solution in add alcohol, so as to obtain the keto-alcohol mixed solution of docetaxel；And/or
The step of methods described, b) included：
B1 in) adding water to the docetaxel solution obtained to step a), so as to obtain a suspension；With
B2) by step b1) suspension that obtains is filtered or centrifugation obtains solid, it is vacuum dried so as to docetaxel three
The crystal of hydrate.
In a preferred embodiment, in step a1) in, ketone and docetaxel mixture are heated into 30～55
DEG C with promote dissolve docetaxel.In another preferred embodiment, in step a2) in, first will many west he
Match is cooled to 25～35 DEG C with the solution of ketone, adds alcohol.
The inventive method can utilize rudimentary ketone or alcohol.In a particular embodiment, the inventive method is utilized
C3-5Ketone；It is preferred that acetone；Using C1-3Straight or branched alcohol；It is preferred that methyl alcohol.
In the method for the invention, docetaxel and the mass volume ratio of ketone are 1:7-15g/ml；It is preferred that 1:10
g/ml；And/or
Alcohol is 5～20 with the volume ratio of ketone:100；Preferably, alcohol and the volume ratio of ketone are 10～15:100；With/
Or
Water is 1～4 with the volume ratio of ketone and alcohol consumption sum:1；It is highly preferred that water and ketone and the body of alcohol consumption sum
Product is than being 1.5～2.5:1；Most preferably, water and the volume ratio of ketone and alcohol consumption sum are 2:1.
To obtain the docetaxel crystal of higher yields, can cooling suspension increasing precipitation.Preferred real
In applying mode, cooling step b1) suspension that obtains；Preferably, suspension is cooled into 10～30 DEG C, more preferably
To about 15 DEG C.
In the present invention, can be by simple filtration suspension recovery crystalline docetaxel, it is highly preferred that reclaiming
Crystalline docetaxel pure water 2～3 times.The docetaxel crystal that various methods can be adopted to be dried to obtain.
For example, in a particular embodiment, at 25～35 DEG C, under vacuum -0.096～-0.098MPa docetaxel is dried
The crystal of trihydrate about 15 hours, so that its water content is between 5～7%.
In a preferred embodiment, the preparation method of docetaxel crystal of the invention includes：
A) docetaxel is merged with acetone；
B) mixture is heated to 30～55 DEG C；
C) alcohol is added into the mixture of step b)；
D) add water to obtain suspension into the mixture of step c)；
E) step d) is filtered or centrifugation obtains solid, be vacuum dried to obtain three water docetaxel crystal.
In a preference, methods described obtain docetaxel trihydrate crystal at 25 ± 2 DEG C, relatively
Place 24 months under conditions of humidity 60 ± 10%, its moisture, purity, content and 7- table docetaxel isomers
Content change less than 10%, preferably smaller than 5%, more preferably less than 1%.
Advantages of the present invention：
1. the novel crystal forms of the three hydration docetaxels of the present invention have extremely excellent stability；
2. the method for the present invention is easy to carry out separation of solid and liquid；
3. the method for the present invention does not result in docetaxel degraded, and the content of 7- tables docetaxel is not before and after crystallization
Raise；
4. the dry run of the docetaxel crystal that the inventive method is obtained is simple, water content 6.0～6.9% it
Between, and Determination of Residual Organic Solvents meets standards of pharmacopoeia；
5. the method for the present invention is easy to operate, without the need for high temperature crystallization, is induced without addition crystal seed,
Water is instilled under room temperature and separates out solid naturally；With
6. the molar yield of the three hydration docetaxel crystal that the method for the present invention is obtained is up to cause more than 95%.
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are only used for
The bright present invention rather than restriction the scope of the present invention.The experiment side of unreceipted actual conditions in the following example
Method, generally according to normal condition or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise institute
Some percentage, ratio, ratio or number are by weight.
The unit in percent weight in volume in the present invention be it is well-known to those skilled in the art, e.g.
Refer to the weight of the solute in 100 milliliters of solution.
Unless otherwise defined, all specialties used in text are ripe with one skilled in the art institute with scientific words
The meaning known is identical.Additionally, any similar to described content or impartial method and material all can be applicable to
In the inventive method.Preferable implementation described in text only presents a demonstration with material and is used.
Embodiment 1
Weigh 5g docetaxels (purity 99.5%, 7- tables docetaxel 0.07%), add 50ml acetone, 50 DEG C
Solid dissolving is heated under water-bath limpid, then makes solution be cooled to 25 DEG C, add 5ml methyl alcohol, stirred,
Pure water is added dropwise, during to solution muddiness, stops being added dropwise, stir about grows crystal in 20 minutes, then proceedes to drop
Plus pure water, the total dripping quantity of pure water is 110ml.Pure water completion of dropping, is cooled to 15 DEG C, filters, and uses pure water
Washing filter cake 3 times.Solid is dug out, at 25 DEG C, is dried 15 hours under vacuum -0.097～-0.098MPa, obtained
5.15g white solids.Determine its water content is for 99.62%, 7- table docetaxels for 6.6%, HPLC purity
0.07%, molar yield is 96.6%.
Embodiment 2
Weigh 5g docetaxels (purity 96.4%, 7- tables docetaxel 0.5%), add 50ml acetone, 45 DEG C
Solid dissolving is heated under water-bath limpid, then makes solution be cooled to 25 DEG C, add 7.5ml methyl alcohol, stirred,
Pure water is added dropwise, during to solution muddiness, stops being added dropwise, stir about grows crystal in 20 minutes, then proceedes to drop
Plus pure water, the total dripping quantity of pure water is 115ml.Pure water completion of dropping, is cooled to 18 DEG C, filters, and uses pure water
Washing filter cake 2 times.Solid is dug out, at 30 DEG C, is dried 15 hours under vacuum -0.096～-0.097MPa, obtained
5.08g white solids.Determine its water content is for 98.1%, 7- table docetaxels for 6.2%, HPLC purity
0.46%, molar yield is 95.3%.
Comparative example 1.
Inventor is tied using methanol/water binary system according to CN101415697 to docetaxel
Crystalline substance, it is described in detail below：
5g docetaxels (purity 99.5%, 7- tables docetaxel 0.07%) are weighed, 55ml methyl alcohol is added,
Solid dissolving is heated under 50 DEG C of water-baths limpid, then makes solution be cooled to 25 DEG C, stirring is added dropwise pure water,
During to solution muddiness, stop being added dropwise, stir about grows crystal in 20 minutes, then proceed to that pure water is added dropwise, it is pure
The total dripping quantity of water is 110ml.Pure water completion of dropping, is cooled to 15 DEG C, filters, with pure water filter cake 3
It is secondary.Solid is dug out, at 25 DEG C, is dried 15 hours under vacuum -0.097～-0.098MPa, obtain 5.1g whites solid
Body.
Jing is determined, and the water content of the solid is that 6.3%, HPLC purity is 98.60%, 7- table docetaxels
For 1.08%, molar yield is 95.7%.7- table docetaxel contents are higher, and it is that crystallization process is unstable leads
Cause docetaxel degraded and produce.
The all documents referred in the present invention are all incorporated as in this application reference, just as each document
It is individually recited as with reference to such.In addition, it is to be understood that after the above-mentioned instruction content for having read the present invention,
Those skilled in the art can make various changes or modifications to the present invention, and these equivalent form of values equally fall within this Shen
Please appended claims limited range.
Claims (11)
1. the crystal of the docetaxel trihydrate shown in a kind of following formula, it is characterised in that the crystal is in powder
There is characteristic peak at following 2 θ angles in X ray diffracting spectrum：4.30±0.2°、8.74±0.2°、10.32±0.2°、
11.04±0.2°、13.92±0.2°、17.70±0.2°
2. the crystal of docetaxel trihydrate as claimed in claim 1 described, it is characterised in that：The crystal
Also there is characteristic peak at following 2 θ angles of x-ray diffractogram of powder spectrum：About 4.98 ± 0.2 °, 7.15 ± 0.2 °,
11.70±0.2°、12.42±0.2°、15.28±0.2°、18.46±0.2°、19.30±0.2°、19.76±0.2°、22.12±0.2°、
27.42±0.2°、36.56±0.2°。
3. the crystal of the docetaxel trihydrate as described in right 1 is required, it is characterised in that the crystal
X-ray diffractogram of powder is composed substantially as shown in.
4. the crystal of the docetaxel trihydrate as any one of claim 1-3, it is characterised in that
The means of differential scanning calorimetry figure (DSC) of the crystal is displayed at 87.0 DEG C, 168.0 DEG C and 225.5 DEG C peak-peak.
5. the crystal of docetaxel trihydrate as claimed in claim 4, it is characterised in that the crystal
Means of differential scanning calorimetry figure (DSC) is as shown in Figure 2.
6. the preparation method of the crystal of the docetaxel trihydrate as any one of claim 1-5, wraps
Include following steps：
A) docetaxel is dissolved in the mixed liquor of ketone and alcohol, so as to obtain the solution of docetaxel；With
B) in adding water to the docetaxel solution obtained to step a), so as to obtain docetaxel trihydrate
Crystal.
7. method as claimed in claim 6, it is characterised in that
The step a) includes：
A1) docetaxel and ketone are mixed, so as to obtain the ketone solution of docetaxel；With
A2) to a1) obtain docetaxel solution in add alcohol, so as to obtain docetaxel keto-alcohol mix it is molten
Liquid；And/or
The step b) includes：
B1 in) adding water to the docetaxel solution obtained to step a), so as to obtain a suspension；
B2) by step b1) suspension that obtains is filtered or centrifugation obtains solid, it is vacuum dried so as to docetaxel three
The crystal of hydrate.
8. method as claimed in claims 6 or 7, it is characterised in that the ketone is C3-5Ketone；It is preferred that acetone；
And/or, the alcohol is C1-3Straight or branched alcohol；It is preferred that methyl alcohol.
9. method as claimed in claims 6 or 7, it is characterised in that docetaxel is with the mass volume ratio of ketone
1:7-15g/ml；It is preferred that 1:10g/ml；And/or
Alcohol is 5～20 with the volume ratio of ketone:100；Preferably, alcohol and the volume ratio of ketone are 10～15:100；With/
Or
Water is 1～4 with the volume ratio of ketone and alcohol consumption sum:1；It is highly preferred that water and ketone and the body of alcohol consumption sum
Product is than being 1.5～2.5:1；Most preferably, water and the volume ratio of ketone and alcohol consumption sum are 2:1.
10. the crystal of the docetaxel trihydrate any one of claim 1-5 is being prepared for treating
Advanced breast cancer, oophoroma, non-small cell lung cancer, incidence cancer, ED-SCLC, cancer of the stomach, cancer of pancreas,
Application in the medicine of melanoma.
11. a kind of pharmaceutical compositions, it is characterised in that described pharmaceutical composition is appointed comprising in claim 1-5
The crystal of the docetaxel trihydrate described in and optional pharmaceutically acceptable excipient.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111718316A (en) * | 2020-07-02 | 2020-09-29 | 无锡紫杉药业有限公司 | Production process of docetaxel trihydrate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040116720A1 (en) * | 2002-12-16 | 2004-06-17 | Sharma Arun Prakash | Process for preparation of paclitaxel trihydrate and docetaxel trihydrate |
| CN1548426A (en) * | 2003-05-08 | 2004-11-24 | �Ϻ�����ŵ��ѧ��ҩ����˾ | Prepn of polyene taxol trihydrate |
| JP2010138084A (en) * | 2008-12-10 | 2010-06-24 | Mercian Corp | Manufacturing method of crystalline docetaxel trihydrate |
| US20100197944A1 (en) * | 2007-07-04 | 2010-08-05 | Dr. Reddy's Laboratories Limited | Docetaxel process and polymorphs |
| WO2012115402A2 (en) * | 2011-02-22 | 2012-08-30 | Dong-A Pharm.Co.,Ltd. | Crystalline form of docetaxel and process for preparation thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040116720A1 (en) * | 2002-12-16 | 2004-06-17 | Sharma Arun Prakash | Process for preparation of paclitaxel trihydrate and docetaxel trihydrate |
| CN1548426A (en) * | 2003-05-08 | 2004-11-24 | �Ϻ�����ŵ��ѧ��ҩ����˾ | Prepn of polyene taxol trihydrate |
| US20100197944A1 (en) * | 2007-07-04 | 2010-08-05 | Dr. Reddy's Laboratories Limited | Docetaxel process and polymorphs |
| JP2010138084A (en) * | 2008-12-10 | 2010-06-24 | Mercian Corp | Manufacturing method of crystalline docetaxel trihydrate |
| WO2012115402A2 (en) * | 2011-02-22 | 2012-08-30 | Dong-A Pharm.Co.,Ltd. | Crystalline form of docetaxel and process for preparation thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111718316A (en) * | 2020-07-02 | 2020-09-29 | 无锡紫杉药业有限公司 | Production process of docetaxel trihydrate |
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