CN106957312B - Raltitrexed hydrate crystal forms and preparation method thereof - Google Patents
Raltitrexed hydrate crystal forms and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to pharmaceutical synthesis fields, and in particular to crystal form of Raltitrexed and preparation method thereof.Raltitrexed crystal form of the invention is hydrate, and the molar ratio of Raltitrexed and water is 1:0.5~3.The present invention uses the in the mixed solvent that Raltitrexed is dissolved in water and organic solvent, then the method that anti-solvent water is added dropwise thereto prepares Raltitrexed novel crystal forms, and the organic solvent is tetrahydrofuran, Isosorbide-5-Nitrae-dioxane.Crystal form of the invention is able to maintain good storage stability, easy to industrialized production, moist without drawing, and avoids absorbing water, and provides conveniently for transport, production, pharmaceutical preparation, has certain prospect in medicine.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to novel crystal forms, preparation method and the purposes of Raltitrexed.
Background technique
Raltitrexed is the development that cooperated by the cancer research administration of the Royal Marsden hospital of Britain and Zeneca
Drug.It is a kind of thymus gland synthetase inhibitors, belongs to the derivative of folic acid, for treating advanced stage carcinoma of the colon and rectum patient.
It is listed in Britain's Initial Public Offering, trade name Tomudex, the same year in the country such as France within 1996.It is as advanced colorectal cancer
First-line treatment drug has many advantages, such as small toxic side effect, convenient drug administration, cheap, big in the demand of China.
Raltitrexed physicochemical properties are unstable, to light, wet, hot more sensitive.
Synthetic method, refining methd etc. are concentrated on to the report of Raltitrexed at present, to the research report of Raltitrexed crystal form
Road is less.
It is disclosed in United States Patent (USP) US4992550B and Raltitrexed monohydrate is obtained by the refining methd of alkali-soluble acid analysis,
Fusing point is 180-184 DEG C (hereinafter referred to as crystal form I), and this method can generate a large amount of sodium chloride, sodium chloride is caused to remain, post-process
Cheng Zhongxu could be removed by repeatedly mashing.Chinese patent CN103570702A, which is disclosed, rotates crystallization preparation by anhydrous methanol
Raltitrexed crystalline solid, fusing point are 171-183 DEG C.Chinese patent CN102424679B, which is disclosed, is dissolved in methanol for crude product, then
Purified water is added thereto and obtains the refining methd of faint yellow solid.Chinese patent CN102127063A is disclosed using methanol-
The method of anhydrous ether recrystallization.
The inventors discovered that using the obtained Raltitrexed of method that current document is recorded or by the thunder of commercially available purchase
Draw moist strong, easy to absorb moisture for Qu Sai, lead to that its character changes and purity reduces, to transport, storage and pharmaceutical preparation
It makes troubles.
Summary of the invention
Poor the technical problem to be solved by the present invention is to overcome the easy moisture absorption of the Raltitrexed of prior art preparation, stability
Defect, provide a kind of stable Raltitrexed crystal form with and its preparation method and application.
The present invention provides the Raltitrexed hydrates having following structure, hereinafter referred to as crystal form II:
Wherein, n=0.5~3, preferably n=0.5~1.
Crystal form II of the invention is radiated by Cu-Ka, the X-ray powder diffraction indicated with 2 θ angles 2 θ values for 6.0 ±
0.2°、7.1±0.2°、8.1±0.2°、13.5±0.2°、14.3±0.2°、16.3±0.2°、18.4±0.2°、19.2±
There is characteristic peak at 0.2 °, 20.6 ± 0.2 °, 26.5 ± 0.2 °；Preferably, X-ray powder diffraction 2 θ values be 6.0 ± 0.2 °,
7.1±0.2°、8.1±0.2°、13.5±0.2°、14.3±0.2°、15.2±0.2°、16.3±0.2°、17.7±0.2°、
18.4±0.2°、19.2±0.2°、20.6±0.2°、21.8±0.2°、24.2±0.2°、26.5±0.2°、28.0±0.2°、
There is characteristic peak at 31.0 ± 0.2 °；It is highly preferred that it is with X-ray powder diffraction pattern as shown in Figure 1.
Through thermogravimetric analysis (TGA) it is found that weight loss, weight occurs within the scope of 50~150 DEG C in crystal form II of the invention
The mass fraction of loss is 1.7%~4.4%；In a preferred embodiment of the invention, the TGA map of the crystal form II is such as
Shown in Fig. 2；In another preferred embodiment of the invention, the TGA map of the crystal form II is as shown in Figure 5.
Measured through differential scanning calorimetric analysis (DSC), crystal form II of the invention its DSC map respectively 100~110 DEG C,
There is endothermic peak within the scope of 170~185 DEG C；In a preferred embodiment of the invention, the DSC map of the crystal form II is as schemed
Shown in 3；In another preferred embodiment of the invention, the DSC map of the crystal form II is as shown in Figure 6.
In addition, the present invention also provides the monocrystalline of Raltitrexed trihydrate, X-ray single crystal diffraction statistics indicate that, be
Monoclinic system, axial lengthCrystal face angle α=90.00 °, β=
90.00 °, γ=90.00 °, X single crystal diffraction map is as shown in Figure 7.One of water is other 2 water in conjunction with water as seen from the figure
For channel water.
On the other hand, the present invention provides the preparation method of crystal form II, the method includes the steps of: (a) by thunder for song
Crude product is filled in dissolve by heating in the mixed solvent of water and organic solvent；(b) it is cooled to 0~10 DEG C, stands crystallization；(c) it separates, it is dry
To obtain the final product.Wherein the organic solvent is selected from tetrahydrofuran, Isosorbide-5-Nitrae-dioxane.
In step (a), the mass ratio of water and organic solvent is 1:0.25~4.
In step (b), optionally, anti-solvent water is added into system, the amount of anti-solvent water is the quality specific gravity for adding to water
It is 80~90%.
In step (c), drying mode is preferably dried in vacuo, and preferably drying temperature is 30~60 DEG C.Drying temperature and time
The hydrate of different molar contents can be obtained in difference, as shown in the table:
(1) screening of recrystallization solvent
Experiment shows that Raltitrexed is insoluble in water, is also insoluble in the organic solvents such as tetrahydrofuran, but inventor is surprised
Ground discovery, in Raltitrexed tetrahydrofuran suspension or Isosorbide-5-Nitrae-dioxane suspension, after a certain proportion of water is added,
The enhancing of Raltitrexed dissolubility.Available Raltitrexed crystal is recrystallized in the mixed system of water and organic solvent.Following table
It is specific screening process, the water and organic solvent that mass ratio is 1:1 carries out crude product Raltitrexed as recrystallization solvent
Recrystallization, as a result as follows:
| Solvent | Crude product dissolubility | Recrystallize result |
| Water/THF | Dissolution | Crystal form II |
| Water/Isosorbide-5-Nitrae-dioxane | Dissolution | Crystal form II |
| Water/isopropanol | It is partly dissolved | It is unformed |
| Water/N-Methyl pyrrolidone | It is partly dissolved | It is unformed |
Upper table shows the available crystal form II in water/THF, water/Isosorbide-5-Nitrae-dioxane, and water/isopropanol or water/
It is unformed obtained in N-Methyl pyrrolidone mixed system.
(2) research of mixed solvent ratio
Inventor also found the production obtained by the water of different proportion and the in the mixed solvent recrystallization of above-mentioned two kinds of organic solvents
The crystal form of product is different, and crystal form II of the invention only can be just obtained in the in the mixed solvent of special ratios.With water and tetrahydrofuran
For, shown in table specific as follows:
Above-mentioned test result shows when water and tetrahydrofuran mass ratio are 1:0.25~4, available crystal form II.Hair
Bright people has also investigated water and Isosorbide-5-Nitrae-dioxane ratio, equally, the available crystal form II in the proportional region.
Beneficial effects of the present invention: inventors unexpectedly discovered that being formed with the poor solvent of two kinds of Raltitrexeds mixed
Bonding solvent (water/organic solvent) is the novel crystal forms that Raltitrexed can be prepared in recrystallization solvent, by X-ray powder diffraction
Map, DSC map and TGA map characterization, the novel crystal forms are different from current crystal form reported in the literature.And the novel crystal forms have
Amazing advantage, current crystal form reported in the literature or commercially available crystal form draw it is moist extremely strong, even if placing at room temperature
It is easy the moisture absorption, and crystal form II of the invention successfully overcomes this defect, crystal form II of the invention is moist without drawing, to storage, fortune
Defeated and preparation brings great convenience.Meanwhile crystal form II of the invention is compared with crystal form prepared by existing literature, in dissolubility
Also has unexpected advantage in terms of photostability.In terms of dissolubility, crystal form II is in disodium hydrogen phosphate/hydroxide
It can faster be dissolved in the buffer solution of sodium compared with crystal form I, advantage is had more on preparation；In terms of photostability, crystalline substance of the invention
Type II also increases significantly compared with crystal form I.
Detailed description of the invention
Fig. 1 is the X-ray powder diffraction pattern of 1 crystal form II of embodiment
Fig. 2 is the thermogravimetric analysis map of 1 crystal form II of embodiment
Fig. 3 is the DSC map of 1 crystal form II of embodiment
Fig. 4 is the X-ray powder diffraction pattern of 4 crystal form II of embodiment
Fig. 5 is the thermogravimetric analysis map of 4 crystal form II of embodiment
Fig. 6 is the DSC map of 4 crystal form II of embodiment
Fig. 7 is the mono-crystalline structures figure of 5 trihydrate of embodiment
Fig. 8 is the X-ray powder diffraction pattern of 1 crystal form I of comparative example
Fig. 9 is the thermogravimetric analysis map of 1 crystal form I of comparative example
Figure 10 is the DSC map of 1 crystal form I of comparative example
Specific embodiment
Technical solution of the present invention is further illustrated combined with specific embodiments below, but does not limit the present invention.
Raltitrexed crude product can be used with N- [5- (N- methylamino) -2- Thenoyl]-Pidolidone diethylester and 2-
Methyl -6- bromomethyl -3- hydrogen-quinazoline-4-one is raw material, is prepared through condensation, hydrolysis, acid out.
1. powder diffractometer is produced by Arl Inc., Switzerland, manufacturer, instrument model: X'TRA, Tube voltage 40KV, tube current 30mA, 8 °/min of scanning speed.
2. differential scanning calorimeter and thermogravimetric analyzer are produced by PerKinElmer company, the U.S., instrument model: Pyris
1DSC, using nitrogen atmosphere, 10 DEG C/min of heating rate.
3. karl Fischer moisture tester model: Mettler Toledo V30Volumetric KF Titrator
Embodiment 1: the preparation (n=1) of crystal form II
10g Raltitrexed crude product is dissolved in water (280g) and THF (150g) mixed solvent, is dissolved by heating, filtering, at room temperature
Water 620g is slowly added dropwise, is cooled to 5 DEG C, stands overnight, precipitate crystal, separates, 30 DEG C of vacuum drying 3h obtain light yellow crystal
9.2g, HPLC purity 99.8%.
XRPD map is as shown in Figure 1；
Thermogravimetric analysis map, with 4.12% weightlessness, is analyzed as shown in Fig. 2, when being heated to 155 DEG C by Thermogravimetric Data
It gets a point and contains a hydrone in sub- Raltitrexed；
DSC map is as shown in figure 3, have endothermic peak at 109 DEG C, 178 DEG C, and in 109 DEG C of sons that dry out, 178 DEG C are molten
Change peak.
It is 4.00% that karl Fischer Moisture Meter, which measures moisture content,.
Embodiment 2: the preparation (n=1) of crystal form II
10g Raltitrexed crude product is dissolved in water (250g) and tetrahydrofuran (250g) mixed solvent, stirring and dissolving filters,
The crystal seed of 0.05g crystal form II is added at room temperature, water 1000g is added dropwise, is cooled to 10 DEG C, stands overnight, precipitate crystal, separates, 40
DEG C vacuum drying 3h, obtains light yellow crystal 8.9g, HPLC purity is 99.8%.
XRPD map, thermogravimetric analysis map, DSC map are consistent with 1 gained crystal form of embodiment.
Embodiment 3: the preparation (n=1) of crystal form II
10g Raltitrexed crude product is dissolved in water (100g) and Isosorbide-5-Nitrae-dioxane (300g) mixed solvent, is dissolved by heating, mistake
Water 1100g is added at room temperature, precipitates crystal for filter, separates, and 40 DEG C of vacuum drying 3h obtain light yellow crystal 8.8g, HPLC purity
It is 99.7%.
XRPD map, thermogravimetric analysis map, DSC map are consistent with 1 gained crystal form of embodiment.
Embodiment 4: the preparation (n=0.5) of crystal form II
10g Raltitrexed crude product is dissolved in water (100g) and tetrahydrofuran (400g) mixed solvent, stirring and dissolving filters,
Water 1500g is added at room temperature, precipitates crystal, separates, dry 8h, obtains light yellow crystal 9.1g, HPLC purity is at 60 DEG C
99.8%.
Sample is taken to carry out X-ray powder diffraction, TG, dsc analysis.
X-ray powder diffraction pattern is as shown in figure 4, consistent with Fig. 1.
Thermogravimetric analysis is as shown in figure 5, when being heated to 150 DEG C, with 1.98% weightlessness, by Thermogravimetric Data analyze one
Contain 0.5 hydrone in molecule Raltitrexed；
DSC map is as shown in fig. 6, have endothermic peak at 110 DEG C, 178 DEG C, and in 110 DEG C of sons that dry out, 178 DEG C are molten
Change peak.
It is 2.00% that karl Fischer Moisture Meter, which measures moisture content,.
Embodiment 5: the preparation of trihydrate monocrystalline
200mg Raltitrexed is dissolved in water: the in the mixed solvent of tetrahydrofuran (mass ratio=1:1) passes through 0.45 μm
Filter paper filters out undissolved solid, and obtained saturation filtrate is sealed with the film for pricking hole, slowly evaporates into solid precipitation,
Filtering, vacuum drying collect solid up to trihydrate crystal form.X-ray single crystal diffraction is carried out to single crystal, as a result such as Fig. 7
It is shown.
Comparative example 1: the method preparation of reference literature US4992550B
By N- [5- [N- (3,4- dihydro -2- methyl -4- oxo -6- quinazolyl)-methyl]-N- methyl] -2- thiophene first
Acyl group-Pidolidone diethylester (1g), NaOH (1.2g) are added in water (10mL) and ethyl alcohol (10mL), stir at room temperature.Reaction
It is concentrated under reduced pressure after the completion, adjusts pH to 3 with 2N hydrochloric acid solution, white solid is precipitated, filter, washing is dry that Raltitrexed is brilliant
Type I.
XRPD characterizes map as shown in figure 8, it is significantly different with the XRPD map of crystal form obtained by Examples 1 to 4；
Thermogravimetric analysis map, with 4.17% weightlessness, is analyzed as shown in figure 9, when being heated to 50 DEG C by Thermogravimetric Data
It gets a point and contains a hydrone in sub- Raltitrexed；
Differential Scanning Calorimetry is as shown in Figure 10, has endothermic peak at 80 DEG C, 179 DEG C, in 80 DEG C of sons that dry out,
179 DEG C are melting hump.
Comparative example 2: the method preparation of reference literature CN103570702A
It takes the wet crude product 13.8g of undried Raltitrexed to be added in 600ml methanol, is stirred at room temperature 0.5 hour, room temperature
Lower filtering is concentrated crystallization at 28-35 DEG C of filtrate, sets in 4 DEG C of refrigerators and refrigerate 3 hours, filters, a small amount of purifying water washing of product,
Room temperature in vacuo is 10 hours dry, obtains faint yellow solid 2.7g.
Comparative example 3: the method preparation of reference literature CN102424679B
It takes Raltitrexed crude product 10g to be placed in a reaction flask, 500mL methanol is added and is heated to reflux to clarification, filtering, filtrate are cold
But to 5-10 DEG C, it is slowly added into about 4200mL purified water stirring and crystallizing, is filtered, solid purifying water washing, 40 DEG C of vacuum drying
24 hours, faint yellow solid 3.5g is obtained, is analyzed through X-ray powder diffraction, is unformed.
Comparative example 4: the method preparation of reference literature CN102127063A
Take 0.2gN- [5- [N- (3,4- dihydro -2- methyl -4- oxo -6- quinazolyl)-methyl]-N- methyl] -2- thiophene
Pheno formoxyl-Pidolidone diethylester is dissolved in 10mL ethyl alcohol and 10mL acetone, and 3N sodium hydrate aqueous solution 14mL, room temperature is added
It is stirred to react 3h.Ethyl alcohol and acetone is evaporated off, with 2N salt acid for adjusting pH to 4, faint yellow solid is filtered to obtain, with methanol-
Anhydrous ether recrystallization, obtains faint yellow solid, analyzes through X-ray powder diffraction, is unformed.
6 draws moist test of embodiment
According to the method for 2015 editions drug draws moist test guidelines of Chinese Pharmacopoeia to embodiment 1, embodiment 4, comparison
The sample of example 1~4 carries out draws moist test.As a result as follows:
It is wet that the above results show that crystal form II of the invention hardly draws, and the obtained sample of comparative example 1~4 have compared with
Strong drawing is moist.
7 dissolubility comparative test of embodiment
The Raltitrexed clinically ratified at present is freeze-dried powder, is needed bulk pharmaceutical chemicals Raltitrexed in production process first
It is added in disodium hydrogen phosphate/sodium hydroxide buffer solution and dissolves, be lyophilized.Therefore bulk pharmaceutical chemicals are molten in buffer solution
Solution property is particularly significant for preparation process.
The sample progress dissolubility comparative test of Example 1, embodiment 4, comparative example 1, comparative example 2.
Respectively Example 1, embodiment 4, comparative example 1, comparative example 2 sample 100mg be placed at 25 DEG C 100mL buffering
In solution, with identical magnetic stirring speed, observation dissolution speed situation is such as considered as completely without visual visible particles of solute
Dissolution.Buffer preparation: weighing 2g disodium hydrogen phosphate and be dissolved in 800mL distilled water, is adjusted with 0.1M sodium hydrate aqueous solution
The pH value of solution adds water to be settled to 1L to 7.6.
The result is as follows:
8 stability test of embodiment
By embodiment 1, embodiment 4, the sample opening of comparative example 1~4 be placed on 25 DEG C, humidity be 40% in the environment of, put
It sets 30 days, was sampled in the 15th day and the 30th day, investigate appearance and the variation of related substance, as a result see the table below:
The above results show at room temperature place one month, crystal form II of the invention no matter appearance, water content also
It is unchanged in terms of being related substance, there is good storage stability, and the sample of comparative example 1~4 is appearance color first
It changes, is followed by easy the moisture absorption, while HPLC detection chemical purity finds that the content in relation to substance also increases.With existing text
The Raltitrexed sterling offered is compared, and crystal form II of the invention has significant advantage.
9 exposure experiments to light of embodiment
Presently commercially available Raltitrexed and the Raltitrexed prepared according to existing literature, which exist, asks light sensitive
Topic, the present inventor have investigated stability problem of the crystal form II under illumination condition.
Embodiment 1, embodiment 4, the sample opening of comparative example 1~4 are placed in the lighting box equipped with fluorescent lamp, Yu Zhaodu
It to be placed 10 days under conditions of 4500lx ± 500lx, was sampled in the 5th day and the 10th day, investigates appearance and the variation of related substance.
To the description of appearance color in upper table, faint yellow, yellow, pale brown, yellowish-brown indicate that color is successively deepened.
Exposure experiments to light shows the crystal form II of the preparation of embodiment 1,4 compared with the crystal form I of comparative example 1, and stability is increased
Add, is conducive to the storage of bulk pharmaceutical chemicals.
Claims (7)
1. Raltitrexed hydrate, it is characterised in that have a structure that
Wherein, n=0.5~1 is radiated using Cu-Ka, and X-ray powder diffraction pattern is as shown in Figure 1.
2. hydrate according to claim 1, which is characterized in that n=1 and its with thermogravimetric analysis as shown in Figure 2
Map and DSC map as shown in Figure 3.
3. hydrate according to claim 1, which is characterized in that n=0.5 and its with thermogravimetric as shown in Figure 5 point
Analyse map and DSC map as shown in FIG. 6.
4. a kind of method for preparing any one of claim 1-3 hydrate, which is characterized in that comprise the steps of: that (a) will
Raltitrexed is dissolved in the mixed solvent of water and organic solvent；(b) it is cooled to 0~10 DEG C, stands crystallization；(c) it separates, drying is
；Wherein the organic solvent is selected from tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, and the mass ratio of water and organic solvent is in step (a)
1:0.25~4.
5. according to the method described in claim 4, it is characterized in that, also being comprised the steps of: before cooling in step (b)
Anti-solvent water is added into system.
6. according to the method described in claim 5, it is characterized in that, the amount of anti-solvent water is to add to the quality of water in step (b)
Specific gravity is 80~90%.
7. according to the method described in claim 4, it is characterized in that, dry for vacuum drying, drying temperature 40 in step (c)
~60 DEG C.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4992550A (en) * | 1986-03-27 | 1991-02-12 | Imperial Chemical Industries Plc | Anti-tumour agents |
| CN102127063A (en) * | 2011-01-06 | 2011-07-20 | 深圳市普迈达科技有限公司 | New synthesis technology of anti-cancer drug Raltitrexed |
| CN104447724A (en) * | 2014-12-31 | 2015-03-25 | 四川峨嵋山药业股份有限公司 | Refining method of raltitrexed |
| CN105111197A (en) * | 2015-08-26 | 2015-12-02 | 上海鼎雅药物化学科技有限公司 | Synthesis methods of raltitrexed |
-
2016
- 2016-12-29 CN CN201611245842.9A patent/CN106957312B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4992550A (en) * | 1986-03-27 | 1991-02-12 | Imperial Chemical Industries Plc | Anti-tumour agents |
| CN102127063A (en) * | 2011-01-06 | 2011-07-20 | 深圳市普迈达科技有限公司 | New synthesis technology of anti-cancer drug Raltitrexed |
| CN104447724A (en) * | 2014-12-31 | 2015-03-25 | 四川峨嵋山药业股份有限公司 | Refining method of raltitrexed |
| CN105111197A (en) * | 2015-08-26 | 2015-12-02 | 上海鼎雅药物化学科技有限公司 | Synthesis methods of raltitrexed |
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