CN104177335A - Nolatrexed dihydrochloride crystal form III and preparation method and application thereof - Google Patents
Nolatrexed dihydrochloride crystal form III and preparation method and application thereof Download PDFInfo
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- CN104177335A CN104177335A CN201310201585.9A CN201310201585A CN104177335A CN 104177335 A CN104177335 A CN 104177335A CN 201310201585 A CN201310201585 A CN 201310201585A CN 104177335 A CN104177335 A CN 104177335A
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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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- A—HUMAN NECESSITIES
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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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- C—CHEMISTRY; METALLURGY
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- 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
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Abstract
The invention discloses a nolatrexed dihydrochloride crystal form III. The nolatrexed dihydrochloride crystal form III 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 6.673 degrees, 8.838 degrees, 9.167 degrees, 12.748 degrees, 13.548 degrees, 14.443 degrees, 16.704 degrees, 17.014 degrees, 17.810 degrees, 21.807 degrees, 22.117 degrees, 22.527 degrees, 26.672 degrees, 27.005 degrees, 27.238 degrees, 29.051 degrees and 29.498 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 crystalline form III and preparation method thereof and application.
Background technology
Thymitaq is abroad developed by U.S. Agouron Pharmaceuticals company 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 for wherein suppressing 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, AgouronPharmaceuticals company carries out product strategy adjustment, and whole research and development power of Thymitaq are exclusively transferred to U.S. Zarix company.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 crystalline form III, 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 crystalline form III, it is characterized in that, described Thymitaq crystalline form III 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 6.673 °, 8.838 °, 9.167 °, 12.748 °, 13.548 °, 14.443 °, 16.704 °, 17.014 °, 17.810 °, 21.807 °, 22.117 °, 22.527 °, 26.672 °, 27.005 °, 27.238 °, 29.051 ° and 29.498 °.
Particularly, Thymitaq crystalline form III of the present invention has x-ray diffractogram of powder as shown in Figure 1, described diffractogram is used Rigaku RigakuD/MAXRC diffractometer to measure, and according to position of spectral line (Bragg angle 2 θ, to spend expression), relative abundance and spacing d(with
represent) represent, wherein crystalline form III is expressed as follows:
The fusing point of described Thymitaq crystalline form III is 255-259 ℃.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 crystalline form III, and described preparation method comprises the steps:
(1) Thymitaq crude product is dropped in four-hole boiling flask, add the double solvents of acetonitrile and hydrochloric acid, be warming up to backflow, keep reflux state to make to form uniform egg white color contamination suspension;
(2) stop refluxing after stirring at low speed slow cooling to 50-60 ℃, constant temperature stirring at low speed 60-100 minute, rear continuation slow cooling, to 15-25 ℃, stirs 90-150 minute;
(3) filtration, the dry Thymitaq crystalline form III 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 acetonitrile, 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/acetonitrile double solvents is 1:8-1:10, and the volume ratio of water and acetonitrile 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 ℃.
Aforesaid method gained Thymitaq crude product is under identical testing conditions; gained x-ray diffractogram of powder is shown in Fig. 2; the Thymitaq crystalline form III x-ray diffractogram of powder (being Fig. 1) that itself and the present invention is claimed contrasts known; the present invention has obtained a kind of brand-new crystal formation by specific recrystallization method; and this Thymitaq crystalline form III 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 crystalline form III of the present invention, in step 1 double solvents, the volumetric usage of acetonitrile is 15-25 times of Thymitaq quality; The volumetric usage of hydrochloric acid is 0.03-0.08 times of Thymitaq quality.
Preparation method of the present invention, in described step 2, stops after refluxing the stirring at low speed with 50-70rmp; And with the speed slow cooling of 0.5-1.5 ℃/min to 50-60 ℃ to there being a large amount of crystal to separate out, the stirring at low speed 75-85min of constant temperature 20-40rmp, after with the speed slow cooling of 0.4-0.8 ℃/min to 15-25 ℃, growing the grain 100-120 minute.
Wherein, described filtration drying is vacuum-drying 6～7 hours under 32-36 ℃ ,-0.085～-0.095MP.
As preferred forms of the present invention, preferred described preparation method comprises the steps:
5.0 grams of Thymitaq crude products are dropped in four-hole boiling flasks, add acetonitrile 100ml, hydrochloric acid 0.05ml, be warming up to backflow, keep reflux state 45 minutes to form uniform egg white color contamination suspension;
Stop after refluxing the stirring at low speed with 60rmp, and with the speed slow cooling to 55 of 1 ℃/min ℃ to there being a large amount of crystal to separate out; Constant temperature with the stirring at low speed 90min of 30rmp, after with the speed of 0.6 ℃/min, continue slow cooling to 25 ℃, growing the grain 120 minutes;
Filter, wet-milling vacuum-drying 6.5 hours under 35 ℃ ,-0.092MP, obtains Thymitaq crystalline form III.
Except specified otherwise, in preparation method of the present invention, the unit of weightmeasurement ratio is g/ml.
The present invention, by the Comprehensive Control to aspects such as the selection of solvent, temperature, stirring velocity and rearing crystal times, has obtained a kind of simple preparation method, can obtain fast high quality crystal of the present invention, suitable applying in actual production.
In addition, the 3rd object of the present invention is the pharmaceutical composition that protection contains above-mentioned Thymitaq crystalline form III, 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, when for lyophilized powder, described pharmaceutically acceptable carrier can be vehicle; When described composition is tablet, described pharmaceutically acceptable carrier can be disintegrating agent, vehicle etc.Because the resulting Thymitaq crystalline form III of 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 by 440mg/, props up packing.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 lyophilized powder, and this lyophilized powder by weight, is prepared into 1000 bottles by the raw material that comprises following component: Thymitaq crystalline form III 350-450g, N.F,USP MANNITOL 35-45g, water for injection add to 3500-4500ml; Wherein preferably Thymitaq crystalline form III 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 crystalline form III 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, guarantee patient's drug safety.In order further to verify above-mentioned inference; the freeze-dried powder that contriver obtains the claimed freeze-dried powder of the present invention existing Thymitaq with identical prescription and preparation method is made is done quality contrast; result shows that the quality of obtained freeze-drying powder injection of the present invention is improved significantly; further illustrate gained Thymitaq crystalline form III of the present invention for concrete pharmaceutical composition after; the character of itself does not change; still possess desirable performance, thereby improved the whole 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 ℃, freezing 10h from room temperature in 5h; After be warming up to-10 ℃, insulation 10h; Continue to be warming up to 22 ℃ and be dried, insulation 15h, finishes freeze-drying, tamponade automatically, lid aluminium lid, gland.
In addition the also further application of claimed above-mentioned Thymitaq crystalline form III in preparation treatment antitumor drug of the present invention.Thymitaq crystalline form III 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 crystalline form III 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 crystalline form III 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, is conducive to apply.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction figure of Thymitaq crystalline form III 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 mixing solutions that joins 10ml water and 33ml acetonitrile of 5g, 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 crystalline form III and preparations thereof
5.0 grams of Thymitaq crude products (embodiment 1 preparation) are dropped in four-hole boiling flasks, add acetonitrile 100ml, hydrochloric acid 0.4ml, be warming up to backflow, keep reflux state 45 minutes to form uniform egg white color contamination suspension;
Stop after refluxing the stirring at low speed with 60rmp, and with the speed slow cooling to 55 of 1 ℃/min ℃ to there being a large amount of crystal to separate out; Constant temperature is with the stirring at low speed of 30rmp 90 minutes, after with the speed of 0.6 ℃/min, continue slow cooling to 25 ℃, growing the grain 120 minutes;
Filter, wet-milling vacuum-drying 6.5 hours under 35 ℃ ,-0.092MP, obtains Thymitaq crystalline form III 4.81g.Purity is 99.5%, and yield is 93.2%.
As shown in Figure 1, Thymitaq crystalline form III 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 6.673 °, 8.838 °, 9.167 °, 12.748 °, 13.548 °, 14.443 °, 16.704 °, 17.014 °, 17.810 °, 21.807 °, 22.117 °, 22.527 °, 26.672 °, 27.005 °, 27.238 °, 29.051 ° and 29.498 °.
Embodiment 3 Thymitaq crystalline form III and preparations thereof
5.0 grams of Thymitaq crude products (embodiment 1 preparation or commercially available) are dropped in four-hole boiling flasks, add acetonitrile 75ml, hydrochloric acid 0.15ml, be warming up to backflow, keep reflux state 60 minutes to form uniform egg white color contamination suspension;
Stop after refluxing the stirring at low speed with 50rmp, and with the speed slow cooling to 50 of 0.5 ℃/min ℃ to there being a large amount of crystal to separate out; Constant temperature with the stirring at low speed of 20rmp 60 minutes, after with the speed of 0.4 ℃/min, continue slow cooling to 15 ℃, growing the grain 90 minutes;
Filter, wet-milling vacuum-drying 6.5 hours under 34 ℃ ,-0.088MP, obtains Thymitaq crystalline form III 4.81g.Purity is 99.4%, and yield is 92%.
Embodiment 4 Thymitaq crystalline form III and preparations thereof
5.0 grams of Thymitaq crude products (embodiment 1 preparation) are dropped in four-hole boiling flasks, add acetonitrile 125ml, hydrochloric acid 0.4ml, be warming up to backflow, keep reflux state 50 minutes to form uniform egg white color contamination suspension;
Stop after refluxing the stirring at low speed with 70rmp, and with the speed slow cooling to 60 of 1.5 ℃/min ℃ to there being a large amount of crystal to separate out; Constant temperature with the stirring at low speed of 40rmp 100 minutes, after with the speed of 0.8 ℃/min, continue slow cooling to 25 ℃, growing the grain 150 minutes;
Filter, wet-milling vacuum-drying 7 hours under 36 ℃ ,-0.095MP, obtains Thymitaq crystalline form III 4.81g.Purity is 99.3%, and yield is 89%.
Embodiment 5 Thymitaq crystalline form III and preparations thereof
5.0 grams of Thymitaq crude products (embodiment 1 preparation) are dropped in four-hole boiling flasks, add acetonitrile 120ml, hydrochloric acid 0.2ml, be warming up to backflow, keep reflux state 55 minutes to form uniform egg white color contamination suspension;
Stop after refluxing the stirring at low speed with 65rmp, and with the speed slow cooling to 55 of 0.8 ℃/min ℃ to there being a large amount of crystal to separate out; Constant temperature with the stirring at low speed of 35rmp 85 minutes, after with the speed of 0.7 ℃/min, continue slow cooling to 22 ℃, growing the grain 120 minutes;
Filter, wet-milling vacuum-drying 6 hours under 32 ℃ ,-0.09MP, obtains Thymitaq crystalline form III 4.81g.Purity is 99.4%, and yield is 88%.
The lyophilized powder that embodiment 6 contains Thymitaq crystalline form III
Get the preparation-obtained Thymitaq crystalline form III 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 ℃ from room temperature in 5h, insulation 10h; After be warming up to-10, insulation 10h; Continue to be warming up to 22 ℃ and be dried, insulation 15h, finishes freeze-drying, tamponade automatically, lid aluminium lid, gland.
The lyophilized powder that embodiment 7 contains Thymitaq crystalline form III
Get the preparation-obtained Thymitaq crystalline form III 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 ℃, freezing 10h from room temperature in 5h; After be warming up to-10 ℃, insulation 10h; Continue to be warming up to 22 ℃ and be dried, insulation 15h, finishes freeze-drying, tamponade automatically, lid aluminium lid, gland.
The lyophilized powder that embodiment 8 contains Thymitaq crystalline form III
Get the preparation-obtained Thymitaq crystalline form III 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 ℃, freezing 10h from room temperature in 5h; After be warming up to-10 ℃, insulation 10h; Continue to be warming up to 22 ℃ and be dried, insulation 15h, finishes freeze-drying, tamponade automatically, lid aluminium lid, gland.Obtain.
The powder pin that embodiment 8 contains Thymitaq crystalline form III
Get the preparation-obtained Thymitaq crystalline form III of 350g embodiment 2, by 440mg/, prop up packing, obtain.
The powder pin that embodiment 9 contains Thymitaq crystalline form III
Get the preparation-obtained Thymitaq crystalline form III of 350g embodiment 2, by 420mg/, prop up packing, obtain.
The powder pin that embodiment 10 contains Thymitaq crystalline form III
Get the preparation-obtained Thymitaq crystalline form III of 350g embodiment 3, by 440mg/, prop up packing, obtain.
The powder pin that embodiment 11 contains Thymitaq crystalline form III
Get the preparation-obtained Thymitaq crystalline form III of 350g embodiment 4, by 500mg/, prop up packing, obtain.
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 crystalline form III provided by the present invention.
Subjects:
Experimental group 1 is the embodiment of the present invention 2 gained Thymitaq crystalline form IIIs;
Experimental group 2 is the embodiment of the present invention 3 gained Thymitaq crystalline form IIIs;
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 ℃ ± 2 ℃, respectively at 0,1,2,3, respectively get a packing June and investigate.
Test of long duration: sample is packed with bottle, be stored in 25 ℃ ± 2 ℃ of temperature, under relative humidity 60% ± 10% condition, regular sampling and testing.
This test-results is in Table 1 and table 2:
Table 1 accelerated test result
Table 2 long-term test results
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 crystalline form III 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 that to take Thymitaq crude product (embodiment 1) be 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 ℃ ± 2 ℃ 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 ℃ ± 2 ℃ of temperature, under the condition of relative humidity 60% ± 10%, regular 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 crystalline form III, it is characterized in that, described Thymitaq crystalline form III 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 6.673 °, 8.838 °, 9.167 °, 12.748 °, 13.548 °, 14.443 °, 16.704 °, 17.014 °, 17.810 °, 21.807 °, 22.117 °, 22.527 °, 26.672 °, 27.005 °, 27.238 °, 29.051 ° and 29.498 °.
2. Thymitaq crystalline form III according to claim 1, is characterized in that: the fusing point of described Thymitaq crystalline form III is 255-259 ℃.
3. the preparation method of Thymitaq crystalline form III described in claim 1 or 2, is characterized in that: comprise the steps:
(1) Thymitaq crude product is dropped in four-hole boiling flask, add the double solvents of acetonitrile and hydrochloric acid, be warming up to backflow, keep reflux state to make to form uniform egg white color contamination suspension;
(2) stop refluxing after stirring at low speed slow cooling to 50-60 ℃, constant temperature stirring at low speed 60-100 minute, rear continuation slow cooling is to 15-25 ℃, growing the grain 90-150 minute;
(3) filtration, the dry Thymitaq crystalline form III 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 acetonitrile, 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 the double solvents of described step 1, the volumetric usage of acetonitrile is 15-25 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, stop after refluxing the stirring at low speed with 50-70rmp; And with the speed slow cooling of 0.5-1.5 ℃/min to 50-60 ℃, constant temperature is with the stirring at low speed 75-85min of 20-40rmp, after with the speed slow cooling of 0.4-0.8 ℃/min to 15-25 ℃, growing the grain 100-120 minute.
7. according to the preparation method described in claim 3-6 any one, it is characterized in that: described preparation method comprises the steps:
5.0 grams of Thymitaq crude products are dropped in four-hole boiling flasks, add acetonitrile 100ml, hydrochloric acid 0.05ml, be warming up to backflow, keep reflux state 45 minutes to form uniform egg white color contamination suspension;
Stop after refluxing the stirring at low speed with 60rmp, and with the speed slow cooling to 55 of 1 ℃/min ℃ to there being a large amount of crystal to separate out; Constant temperature with the stirring at low speed 90min of 30rmp, after with the speed of 0.6 ℃/min, continue slow cooling to 25 ℃, growing the grain 120 minutes;
Filter, wet-milling vacuum-drying 6.5 hours under 35 ℃ ,-0.092MP, obtains Thymitaq crystalline form III.
8. the pharmaceutical composition that contains Thymitaq crystalline form III described in claim 1 or 2 any one.
9. the pharmaceutical composition of stating according to Claim 8, is characterized in that: described pharmaceutical composition is powder pin or freeze-dried powder.
10. the application of Thymitaq crystalline form III in preparation treatment antitumor drug described in claim 1 or 2.
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| CN201710061069.9A CN106892899A (en) | 2013-05-27 | 2013-05-27 | A kind of nolatrexed dihydrochloride crystal formation III and preparation method and application |
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| 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 |
-
2013
- 2013-05-27 CN CN201310201585.9A patent/CN104177335A/en active Pending
- 2013-05-27 CN CN201710061069.9A patent/CN106892899A/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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| CN106892899A (en) | 2017-06-27 |
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