CN104177334A - Nolatrexed dihydrochloride crystal form II and preparation method and application thereof - Google Patents
Nolatrexed dihydrochloride crystal form II and preparation method and application thereof Download PDFInfo
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- CN104177334A CN104177334A CN201310201443.2A CN201310201443A CN104177334A CN 104177334 A CN104177334 A CN 104177334A CN 201310201443 A CN201310201443 A CN 201310201443A CN 104177334 A CN104177334 A CN 104177334A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The invention discloses a nolatrexed dihydrochloride crystal form II. The nolatrexed dihydrochloride crystal form II is measured by using a powder X-ray diffraction measuring method, and an X-ray powder diffraction pattern indicated by an diffraction angle of 2 theta +/-0.2 degrees shows characteristic diffraction peaks at 6.691 degrees, 12.766 degrees, 16.720 degrees, 17.015 degrees, 17.814 degrees, 21.806 degrees, 22.114 degrees, 23.711 degrees, 24.707 degrees, 25.426 degrees, 26.674 degrees, 29.051 degrees and 29.478 degrees. The crystal form is not reported, has a clear outline, and can be perfectly reproduced; and for filtering, drying, stability, method preparation and processability, the crystal form shows valuable features, can be used as antitumor drugs in use, and has broad application prospects.
Description
Technical field
The present invention relates to a kind of new crystal of compound, be specifically related to a kind of Thymitaq crystal form II and preparation method thereof and application.
Background technology
Thymitaq is abroad developed by Agouron Pharmaceuticals company of the U.S. the earliest.The said firm, according to enzyme active center Three Dimensions Structure, adopts computer simulation drug molecule technology to synthesize a series of thymidylate synthetase inhibitors, and Thymitaq is wherein to suppress one of compound that thymidylate synthetase activity is the highest.The said firm and Roche Switzerland cooperate, and using Thymitaq, it is developed as antitumor drug, and commodity are called " Thymitaq ".The clinical trial since 1994 of this medicine, it is clinical that enter the III phase in August, 1996.In January, 1999, Agouron Pharmaceuticals company carries out product strategy adjustment, and whole research and development power of Thymitaq are exclusively transferred to Zarix company of the U.S..But in disclosed bibliographical information, have not yet to see the report about the polymorphic aspect of Thymitaq.
Summary of the invention
The first object of the present invention is to provide a kind of Thymitaq crystal form II, this crystalline form has no report, its sharp outline, can perfect reproduction, and with regard to filtering, with regard to dry, stability, method preparation and workability, it shows valuable feature, can be used as the purposes in antitumor drug, has broad application prospects.
For achieving the above object, the present invention adopts following technical scheme:
A kind of Thymitaq crystal form II, it is characterized in that, described Thymitaq crystal form II is measured by powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle locates to demonstrate characteristic diffraction peak at 6.691 °, 12.766 °, 16.720 °, 17.015 °, 17.814 °, 21.806 °, 22.114 °, 23.711 °, 24.707 °, 25.426 °, 26.674 °, 29.051 ° and 29.478 °.
Particularly, Thymitaq crystal form II of the present invention has x-ray diffractogram of powder as shown in Figure 1, described diffractogram uses Rigaku RigakuD/MAXRC diffractometer to measure, and according to position of spectral line (Bragg angle 2 θ, represent to spend), relative abundance and spacing d(with
represent) represent, wherein crystalline form III is expressed as follows:
The fusing point of described Thymitaq crystal form II is 246-250 DEG C.From X-ray powder diffraction figure and fusing point, the present invention has obtained a kind of brand-new Thymitaq crystal.
The second object of the present invention is to provide the preparation method of above-mentioned Thymitaq crystal form II, and described preparation method comprises the steps:
(1) Thymitaq crude product is dropped in methyl alcohol, stir and make into suspension; Add concentrated hydrochloric acid and be warming up to 50-70 DEG C and make to be dissolved to clearly, keep 30-60min;
(2) under stirring at low speed slow cooling to 25-40 DEG C, constant temperature growing the grain 40-80min, rear continuation slow cooling is to 15-25 DEG C, growing the grain 90-150min;
(3) filtration, the dry Thymitaq crystal form II that obtains.
Wherein, Thymitaq crude product is the disclosed commercially available prod of prior art described in step 1 of the present invention, and the concrete those skilled in the art that obtain and be chosen as grasp.The invention provides a kind of preparation method of described Thymitaq crude product, but be understandable that, the preparation method of Thymitaq crude product of the present invention comprises and is but not limited to following preparation method:
By in the nolatrexed mixing solutions that joins water and methyl alcohol, add a small amount of concentrated hydrochloric acid, heating makes to dissolve completely.Drip poor solvent tetrahydrofuran (THF) to crystallize out, after standing crystallization, filter and obtain Thymitaq crude product.
Wherein, nolatrexed and mass volume ratio water/methyl alcohol double solvents is 1:8-1:10, and the volume ratio of water and methyl alcohol is 1:3-1:4; The volume of concentrated hydrochloric acid is advisable with the 1/8-1/12 of volume of water.Poor solvent is herein tetrahydrofuran (THF), and its concrete addition is separated out and is as the criterion as far as possible with crystal, and concrete standing crystallization and be filtered into the conventional means that those skilled in the art can understand, the present invention is not particularly limited this.
The fusing point of aforesaid method gained Thymitaq crude product is 224-227 DEG C.
Aforesaid method gained Thymitaq crude product is under identical testing conditions; gained x-ray diffractogram of powder is shown in Fig. 2; Thymitaq crystal form II x-ray diffractogram of powder (being Fig. 1) claimed to itself and the present invention is contrasted known; the present invention has obtained a kind of brand-new crystal formation by specific recrystallization method; and this Thymitaq crystal form II and Thymitaq crude product or the disclosed Thymitaq of prior art are made to pharmacodynamics test; drug effect is suitable each other, without significant difference.
The preparation method of Thymitaq crystal form II of the present invention, in step 1, the volumetric usage of methyl alcohol is 6-9 times of Thymitaq quality; The volumetric usage of concentrated hydrochloric acid is 0.03-0.08 times of Thymitaq quality.Wherein, the volumetric usage of particular methanol be Thymitaq quality 7-8 doubly; The volumetric usage of concentrated hydrochloric acid is 0.05-0.06 times of Thymitaq quality.
In addition, the stirring velocity in step 1 there is no materially affect to technical scheme itself, conventional stirring velocity, and the present invention can adopt 50-150rmp.
Preparation method of the present invention, in described step 2 under the stirring at low speed of 50-70rpm, with the speed slow cooling of 0.5-1.5 DEG C/min to 28-35 DEG C of (now there will be the crystal grain no longer dissolving) constant temperature growing the grain 40-80min, rear continuation with the speed slow cooling of 0.4-0.8 DEG C/min to 18-20 DEG C, growing the grain 100-130min.Wherein, described filtration drying is vacuum-drying 6～7 hours under 32-36 DEG C ,-0.085～-0.095MP.
The present invention, by the Comprehensive Control of the aspects such as selection, temperature, stirring velocity and rearing crystal time to solvent, has obtained a kind of simple preparation method, can obtain fast high quality crystal of the present invention, suitable applying in actual production.
As preferred forms of the present invention, preferred described preparation method comprises the steps:
5 grams of Thymitaq crude products are dropped in 250ml four-hole boiling flask, add 37.5ml methyl alcohol, stir and make into suspension, stirring velocity is 120rmp; Add concentrated hydrochloric acid 0.25ml, be warming up to 60 DEG C, keep 45min, make to be dissolved to clearly;
By mixing speed be adjusted to 55rpm, there is crystal grain in bottle wall while cooling the temperature to 32 DEG C with the speed of 1 DEG C/min; Maintain the temperature at 32-34 DEG C in the time there is the crystal grain no longer dissolving, constant temperature growing the grain 60min, rear continuation is slow cooling to 20 DEG C with the speed of 0.6 DEG C/min, insulation growing the grain 120min;
Filter, wet-milling vacuum-drying 6.5 hours under 35 DEG C ,-0.092MP, obtains Thymitaq crystal form II.Except specified otherwise, in preparation method of the present invention, the unit of weightmeasurement ratio is g/ml.
In addition, the 3rd object of the present invention is the pharmaceutical composition that protection contains above-mentioned Thymitaq crystal form II, and specifically this pharmaceutical composition includes but not limited to as powder pin, tablet, capsule, lyophilized powder or transfusion etc.Composition of the present invention can further contain pharmaceutically acceptable carrier.For example, in the time being lyophilized powder, described pharmaceutically acceptable carrier can be vehicle; In the time that described composition is tablet, described pharmaceutically acceptable carrier can be disintegrating agent, vehicle etc.The Thymitaq crystal form II obtaining due to the present invention has desirable physicochemical property, therefore, those skilled in the art will envision that and be prepared into after various pharmaceutical preparations, also can further provide stability and the curative effect of described pharmaceutical preparation, and the those skilled in the art that are defined as of concrete formulation and prescription thereof grasp.
More preferably, pharmaceutical composition of the present invention is powder pin, and described powder pin props up packing by 400-500mg/, preferably props up packing by 440mg/.In addition, powder pin of the present invention can also further contain pharmaceutically acceptable various carrier, as N.F,USP MANNITOL etc.The those skilled in the art that are defined as of concrete selection and consumption grasp.
In addition, composition of the present invention can also be freeze-dried powder, this freeze-dried powder by weight, is prepared into 1000 bottles by the raw material that comprises following component: Thymitaq crystal form II 350-450g, N.F,USP MANNITOL 35-45g, water for injection add to 3500-4500ml; Wherein preferably Thymitaq crystal form II 400g, N.F,USP MANNITOL 40g, water for injection add to degerming after 4000ml, packing, freeze-drying.
Freeze-dried powder of the present invention, can adopt prior art various freeze drying process open or instruction to be prepared from.Those skilled in the art can understand, because Thymitaq crystal form II of the present invention has more preferably performance compared with the disclosed Thymitaq of prior art, be prepared into and equally also can obtain more preferably stability, solubility etc. after freeze-dried powder and, to guarantee the curative effect of preparation, ensure patient's drug safety.In order further to verify above-mentioned inference; the freeze-dried powder that contriver obtains freeze-dried powder claimed the present invention existing Thymitaq with identical prescription and preparation method is made does quality contrast; result shows that the quality of obtained freeze-drying powder injection of the present invention is improved significantly; further illustrate gained Thymitaq crystal form II of the present invention for concrete pharmaceutical composition after; the character of itself does not change; still possess desirable performance, thereby improved the overall curative effect of pharmaceutical preparation.
But in order to obtain higher-quality freeze-dried powder, the present invention also provides a kind of freeze drying process, is specially: will after the Thymitaq preparation packing preparing, put into freeze drying box, be at the uniform velocity cooled to-30 DEG C, freezing 10h from room temperature in 5h; After be warming up to-10 DEG C, insulation 10h; Continue to be warming up to 22 DEG C and be dried, insulation 15h, finishes freeze-drying, tamponade automatically, lid aluminium lid, gland.
In addition, the also further claimed above-mentioned Thymitaq crystal form II of the present invention is in the application of preparing in medicine for treating tumor thing.Thymitaq crystal form II of the present invention shows significant anti-tumor activity in pharmacodynamics test, can be widely used in the preparation of antitumor drug.
Adopt technique scheme, the present invention has following beneficial effect:
1, Thymitaq crystal form II of the present invention has the stability that is significantly better than Thymitaq crude product, and yield is good, and purity is high;
2, gained Thymitaq crystal form II of the present invention is further prepared into after related preparations, can significantly improves the stability of pharmaceutical preparation, thereby guarantee patient's drug safety;
3, preparation method of the present invention is simple, can stablize and mass production, favourable
In applying.
Brief description of the drawings
Fig. 1 is the X-ray powder diffraction figure of Thymitaq crystal form II of the present invention;
Fig. 2 is the X-ray powder diffraction figure of Thymitaq crude product.
Embodiment
Below in conjunction with drawings and Examples, the present invention is described further.
The preparation of embodiment 1 Thymitaq crude product
By in the nolatrexed 5g mixing solutions that joins 10ml water and 40ml methyl alcohol, add 1.0ml concentrated hydrochloric acid, heating makes to dissolve completely.Drip tetrahydrofuran (THF) to crystallize out, filter and obtain Thymitaq crude product according to a conventional method after standing crystallization, its x-ray diffractogram of powder is shown in Fig. 2.
Embodiment 2 Thymitaq crystal form II and preparations thereof
Thymitaq crude product (prepared by embodiment 1) 5g is dropped in 250ml four-hole boiling flask, add 37.5ml methyl alcohol, stir and make into suspension, stirring velocity is 120rmp; Add concentrated hydrochloric acid 0.25ml, be warming up to 60 DEG C, keep 45min, make to be dissolved to clearly;
By mixing speed be adjusted to 55rpm, there is the crystal grain no longer dissolving in bottle wall while cooling the temperature to 32 DEG C with the speed of 1 DEG C/min, constant temperature growing the grain 60min, rear continuation is slow cooling to 20 DEG C with the speed of 0.6 DEG C/min, insulation growing the grain 120min;
Filter, wet-milling vacuum-drying 6.5 hours under 35 DEG C ,-0.092MP, obtains Thymitaq crystal form II, and purity is 99.4%, and yield is 95%.
As shown in Figure 1, Thymitaq crystal form II is measured by powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle locates to demonstrate characteristic diffraction peak at 6.691 °, 12.766 °, 16.720 °, 17.015 °, 17.814 °, 21.806 °, 22.114 °, 23.711 °, 24.707 °, 25.426 °, 26.674 °, 29.051 ° and 29.478 °.
Embodiment 3 Thymitaq crystal form II and preparations thereof
Thymitaq crude product (prepared by embodiment 1) 5g is dropped in 250ml four-hole boiling flask, add 30ml methyl alcohol, stir and make into suspension, stirring velocity is 50rmp; Add concentrated hydrochloric acid 0.15ml, be warming up to 50 DEG C, keep 30min, make to be dissolved to clearly;
By mixing speed be adjusted to 50rpm, there is the crystal grain no longer dissolving in bottle wall while cooling the temperature to 25 DEG C with the speed of 0.5 DEG C/min; Constant temperature growing the grain 60min, rear continuation is slow cooling to 15 DEG C with the speed of 0.4 DEG C/min, insulation growing the grain 90min;
Filter, wet-milling vacuum-drying 6.5 hours under 34 DEG C ,-0.088MP, obtains Thymitaq crystal form II, and purity is 99.2%, and yield is 92%.
As shown in Figure 1, Thymitaq crystal form II is measured by powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle locates to demonstrate characteristic diffraction peak at 6.691 °, 12.766 °, 16.720 °, 17.015 °, 17.814 °, 21.806 °, 22.114 °, 23.711 °, 24.707 °, 25.426 °, 26.674 °, 29.051 ° and 29.478 °.
Embodiment 4 Thymitaq crystal form II and preparations thereof
Thymitaq crude product (prepared by embodiment 1) 5g is dropped in 250ml four-hole boiling flask, add 45ml methyl alcohol, stir and make into suspension, stirring velocity is 150rmp; Add concentrated hydrochloric acid 0.4ml, be warming up to 70 DEG C, keep 60min, make to be dissolved to clearly;
By mixing speed be adjusted to 70rpm, there is the crystal grain no longer dissolving in bottle wall while cooling the temperature to 40 DEG C with the speed of 1.5 DEG C/min; Constant temperature growing the grain 80min, rear continuation is slow cooling to 25 DEG C with the speed of 0.8 DEG C/min, insulation growing the grain 150min;
Filter, wet-milling vacuum-drying 7 hours under 36 DEG C ,-0.095MP, obtains Thymitaq crystal form II, and purity is 99.6%, and yield is 89%.
As shown in Figure 1, Thymitaq crystal form II is measured by powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle locates to demonstrate characteristic diffraction peak at 6.691 °, 12.766 °, 16.720 °, 17.015 °, 17.814 °, 21.806 °, 22.114 °, 23.711 °, 24.707 °, 25.426 °, 26.674 °, 29.051 ° and 29.478 °.
Embodiment 5 Thymitaq crystal form II and preparations thereof
Thymitaq crude product (prepared by embodiment 1) 5g is dropped in 250ml four-hole boiling flask, add 35ml methyl alcohol, stir and make into suspension, stirring velocity is 120rmp; Add concentrated hydrochloric acid 0.3ml, be warming up to 55 DEG C, keep 50min, make to be dissolved to clearly;
By mixing speed be adjusted to 60rpm, there is the crystal grain no longer dissolving in bottle wall while cooling the temperature to 30 DEG C with the speed of 0.8 DEG C/min; Constant temperature growing the grain 70min, rear continuation is slow cooling to 22 DEG C with the speed of 0.5 DEG C/min, insulation growing the grain 110min;
Filter, wet-milling vacuum-drying 6 hours under 32 DEG C ,-0.09MP, obtains Thymitaq crystal form II, and purity is 99.3%, and yield is 90%.
As shown in Figure 1, Thymitaq crystal form II is measured by powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle locates to demonstrate characteristic diffraction peak at 6.691 °, 12.766 °, 16.720 °, 17.015 °, 17.814 °, 21.806 °, 22.114 °, 23.711 °, 24.707 °, 25.426 °, 26.674 °, 29.051 ° and 29.478 °.
The lyophilized powder that embodiment 6 contains Thymitaq crystal form II
Get the preparation-obtained Thymitaq crystal form II of 400g embodiment 2,40g N.F,USP MANNITOL, inject water to 4000ml, dissolve fully, degerming, freeze-drying after packing, freeze drying process is specially: will after the Thymitaq preparation packing preparing, put into freeze drying box, be at the uniform velocity cooled to-30 DEG C from room temperature in 5h, insulation 10h; After be warming up to-10, insulation 10h; Continue to be warming up to 22 DEG C and be dried, insulation 15h, finishes freeze-drying, tamponade automatically, lid aluminium lid, gland.
The lyophilized powder that embodiment 7 contains Thymitaq crystal form II
Get the preparation-obtained Thymitaq crystal form II of 400g embodiment 3,35g N.F,USP MANNITOL, inject water to 4000ml, dissolve fully, degerming, freeze-drying after packing, freeze drying process is specially: will after the Thymitaq preparation packing preparing, put into freeze drying box, be at the uniform velocity cooled to-30 DEG C, freezing 10h from room temperature in 5h; After be warming up to-10 DEG C, insulation 10h; Continue to be warming up to 22 DEG C and be dried, insulation 15h, finishes freeze-drying, tamponade automatically, lid aluminium lid, gland.
The lyophilized powder that embodiment 8 contains Thymitaq crystal form II
Get the preparation-obtained Thymitaq crystal form II of 450g embodiment 4,45g N.F,USP MANNITOL, inject water to 4000ml, dissolve fully, degerming, freeze-drying after packing, freeze drying process is specially: will after the Thymitaq preparation packing preparing, put into freeze drying box, be at the uniform velocity cooled to-30 DEG C, freezing 10h from room temperature in 5h; After be warming up to-10 DEG C, insulation 10h; Continue to be warming up to 22 DEG C and be dried, insulation 15h, finishes freeze-drying, tamponade automatically, lid aluminium lid, gland.Obtain.The powder pin that embodiment 9 contains Thymitaq crystal form II
Get the preparation-obtained Thymitaq crystal form II of 350g embodiment 2, prop up packing by 400mg/, to obtain final product.
The powder pin that embodiment 10 contains Thymitaq crystal form II
Get the preparation-obtained Thymitaq crystal form II of 350g embodiment 3, prop up packing by 440mg/, to obtain final product.
The powder pin that embodiment 11 contains Thymitaq crystal form II
Get the preparation-obtained Thymitaq crystal form II of 350g embodiment 4, prop up packing by 500mg/, to obtain final product.
Test example 1 stability test
The present invention also further provides following test example, so that technical scheme of the present invention is described.
This test example has detected the stability (test-results is all calculated with each test group Thymitaq weight) of Thymitaq crystal form II provided by the present invention.
Subjects:
Experimental group 1 is the embodiment of the present invention 2 gained Thymitaq crystal form IIs;
Experimental group 2 is the embodiment of the present invention 3 gained Thymitaq crystal form IIs;
Control group 1 is Thymitaq crude product (embodiment of the present invention 1 gained);
Test method:
Accelerated test: sample is packed with bottle, put into relative humidity and be 75% ± 5% encloses container (moisture eliminator), moisture eliminator is put into incubator, place 6 months in 40 DEG C ± 2 DEG C, respectively at 0,1,2,3, respectively get a packaging June and investigate.
Test of long duration: sample is packed with bottle, be stored in 25 DEG C ± 2 DEG C of temperature, under relative humidity 60% ± 10% condition, regularly sampling and testing.
This test-results is in table 1 and table 2:
Table 1 accelerated test result
Table 2 long-term test results
Above-mentioned test-results shows: gained Thymitaq crystal form II of the present invention has clear improvement compared with the stability of Thymitaq crude product.In addition, powder pin of the present invention adopts Thymitaq crystal form II direct packaging is obtained, and predictably, the stability of described powder pin must be better than the powder pin obtaining as raw material using Thymitaq crude product.
Test example 2
This test example has detected the stability (test-results is all calculated with each test group Thymitaq weight) of the prepared lyophilized powder of Thymitaq crystal form II provided by the present invention.
Subjects:
Experimental group 1 is the embodiment of the present invention 6 gained Thymitaq lyophilized powders;
Experimental group 2 is the embodiment of the present invention 7 gained Thymitaq lyophilized powders;
Control group 1 is taking Thymitaq crude product (embodiment 1) as raw material, the lyophilized powder obtaining by the identical prescription of embodiment 6 and preparation method;
Test method:
Accelerated test: by lyophilized powder sample, by intending commercially available back, 40 DEG C ± 2 DEG C of temperature, place 6 months under the condition of relative humidity 75% ± 5%, respectively at 0,1, sampling in 2,3,6 months is tested.
Test of long duration: by 3 batches of trial-products, by commercially available back, be stored in 25 DEG C ± 2 DEG C of temperature, under the condition of relative humidity 60% ± 10%, regularly sampling and testing.
Test-results is in table 3 and table 4.
Table 3 accelerated test result
Table 4 long-term test results
Embodiment in above-described embodiment can further combine or replace; and embodiment is described the preferred embodiments of the present invention; not the spirit and scope of the present invention are limited; do not departing under the prerequisite of design philosophy of the present invention; the various changes and modifications that in this area, professional and technical personnel makes technical scheme of the present invention, all belong to protection scope of the present invention.
Claims (10)
1. a Thymitaq crystal form II, it is characterized in that, described Thymitaq crystal form II is measured by powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle locates to demonstrate characteristic diffraction peak at 6.691 °, 12.766 °, 16.720 °, 17.015 °, 17.814 °, 21.806 °, 22.114 °, 23.711 °, 24.707 °, 25.426 °, 26.674 °, 29.051 ° and 29.478 °.
2. Thymitaq crystal form II according to claim 1, is characterized in that: the fusing point of described Thymitaq crystal form II is 246-250 DEG C.
3. the preparation method of Thymitaq crystal form II described in claim 1 or 2, is characterized in that: comprise the steps:
(1) Thymitaq crude product is dropped in methyl alcohol, stir and make into suspension; Add concentrated hydrochloric acid and be warming up to 50-70 DEG C and make to be dissolved to clearly, keep 30-60min;
(2) under stirring at low speed slow cooling to 25-40 DEG C, constant temperature growing the grain 40-80min, rear continuation slow cooling is to 15-25 DEG C, growing the grain 90-150min;
(3) filtration, the dry Thymitaq crystal form II that obtains.
4. preparation method according to claim 3, is characterized in that: in described step 1, Thymitaq crude product is adopted with the following method and is prepared from:
By in the nolatrexed mixing solutions that joins water and methyl alcohol, add a small amount of concentrated hydrochloric acid, heating makes to dissolve completely, drips poor solvent tetrahydrofuran (THF) to crystallize out, after standing crystallization, filters and obtains Thymitaq crude product.
5. according to the preparation method described in claim 3 or 4, it is characterized in that: in described step 1, the volumetric usage of methyl alcohol is 6-9 times of Thymitaq quality; The volumetric usage of hydrochloric acid is 0.03-0.08 times of Thymitaq quality.
6. according to the preparation method described in claim 3-5 any one, it is characterized in that: in described step 2, under the stirring at low speed of 50-70rpm, with the speed slow cooling of 0.5-1.5 DEG C/min to 28-35 DEG C, constant temperature growing the grain 40-80min, rear continuation with the speed slow cooling of 0.4-0.8 DEG C/min to 18-20 DEG C, growing the grain 100-130min.
7. according to the preparation method described in claim 3-6 any one, it is characterized in that: described preparation method comprises the steps:
5 grams of Thymitaq crude products are dropped in 250ml four-hole boiling flask, add 37.5ml methyl alcohol, stir and make into suspension, stirring velocity is 120rmp; Add concentrated hydrochloric acid 0.25ml, be warming up to 60 DEG C, keep 45min, make to be dissolved to clearly; By mixing speed be adjusted to 55rpm, there is the crystal grain no longer dissolving in bottle wall while cooling the temperature to 32 DEG C with the speed of 1 DEG C/min, constant temperature growing the grain 60min, rear continuation is slow cooling to 20 DEG C with the speed of 0.6 DEG C/min, insulation growing the grain 120min;
Filter, wet-milling vacuum-drying 6.5 hours under 35 DEG C ,-0.092MP, obtains Thymitaq crystal form II.
8. contain the pharmaceutical composition of Thymitaq crystal form II described in claim 1 or 2 any one.
9. pharmaceutical composition according to claim 8, is characterized in that: described pharmaceutical composition is powder pin or freeze-dried powder.
10. the application of Thymitaq crystal form II in preparation treatment antitumor drug described in claim 1 or 2.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710061146.0A CN106831715A (en) | 2013-05-27 | 2013-05-27 | A kind of nolatrexed dihydrochloride crystal formation II and preparation method and application |
| CN201310201443.2A CN104177334A (en) | 2013-05-27 | 2013-05-27 | Nolatrexed dihydrochloride crystal form II and preparation method and application thereof |
Applications Claiming Priority (1)
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| CN201310201443.2A CN104177334A (en) | 2013-05-27 | 2013-05-27 | Nolatrexed dihydrochloride crystal form II and preparation method and application thereof |
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| CN201710061146.0A Division CN106831715A (en) | 2013-05-27 | 2013-05-27 | A kind of nolatrexed dihydrochloride crystal formation II and preparation method and application |
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| CN201310201443.2A Pending CN104177334A (en) | 2013-05-27 | 2013-05-27 | Nolatrexed dihydrochloride crystal form II and preparation method and application thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1765895A (en) * | 2005-07-18 | 2006-05-03 | 康辰医药发展有限公司 | Nolatrexed hydrochloride synthesis process |
| CN101353343A (en) * | 2007-07-27 | 2009-01-28 | 上海医药工业研究院 | Preparation of high-purity nolatrexed dihydrochloride dihydrate |
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- 2013-05-27 CN CN201310201443.2A patent/CN104177334A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1765895A (en) * | 2005-07-18 | 2006-05-03 | 康辰医药发展有限公司 | Nolatrexed hydrochloride synthesis process |
| CN101353343A (en) * | 2007-07-27 | 2009-01-28 | 上海医药工业研究院 | Preparation of high-purity nolatrexed dihydrochloride dihydrate |
Non-Patent Citations (2)
| Title |
|---|
| ALEKHA K.DASH ET AL.: ""Solid-State Characterization of AG337 (Thymitaq)，a Novel Antitumor Drug"", 《JOURNAL OF PHARMACEUTICAL SCIENCES》 * |
| SUNEEL RASTOGI ET AL.: ""Solid-State Phase Transitions of AG337，an Antitumor Agent"", 《PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY》 * |
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| CN106831715A (en) | 2017-06-13 |
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Address after: 101500 Miyun Economic Development Zone, Beijing, No. 11 South Road Applicant after: Konruns Pharmaceutical Co., Ltd. Address before: 100085, A, building 7, building 9, Wah Wah building, 707 3rd Street, Beijing, Haidian District Applicant before: Konruns Pharmaceutical Co., Ltd. |
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Address after: 101500 Miyun Economic Development Zone, Beijing, No. 11 South Road Applicant after: BEIJING KONRUNS PHARMACEUTICAL CO., LTD. Address before: 101500 Miyun Economic Development Zone, Beijing, No. 11 South Road Applicant before: Konruns Pharmaceutical Co., Ltd. |
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