CN106892899A - A kind of nolatrexed dihydrochloride crystal formation III and preparation method and application - Google Patents
A kind of nolatrexed dihydrochloride crystal formation III and preparation method and application Download PDFInfo
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- CN106892899A CN106892899A CN201710061069.9A CN201710061069A CN106892899A CN 106892899 A CN106892899 A CN 106892899A CN 201710061069 A CN201710061069 A CN 201710061069A CN 106892899 A CN106892899 A CN 106892899A
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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
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a kind of nolatrexed dihydrochloride crystal formation III, the nolatrexed dihydrochloride crystal formation III is determined with powder x-ray diffraction determination method, and characteristic diffraction peak is shown 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 ° with the X-ray powder diffraction pattern that the 2 θ ± 0.2 ° angles of diffraction are represented.Crystal formation of the present invention has no report, its sharp outline, can perfect reproduction, and with regard to filtering, drying, stability, method prepare and machinability for, its valuable feature of display can be used as the purposes in antineoplastic, have broad application prospects.
Description
The application be application number 201310201585.9 (May 27 2013 applying date, it is entitled：A kind of hydrochloric acid
Nolatrexed crystal formation III and preparation method and application) divisional application.
Technical field
The present invention relates to a kind of novel crystal forms of compound, and in particular to a kind of nolatrexed dihydrochloride crystal formation III and its preparation side
Method and application.
Background technology
Nolatrexed dihydrochloride is external to be developed by Agouron Pharmaceuticals companies of the U.S. earliest.The said firm according to
Enzyme active center Three Dimensions Structure, has synthesized a series of thymidylate synthetase and has suppressed using computer simulation drug molecule technology
Agent, nolatrexed dihydrochloride is wherein to suppress one of thymidylate synthase activity highest compound.The said firm and Roche
Switzerland cooperates, and using nolatrexed dihydrochloride, it is developed as antineoplastic, trade name " Thymitaq ".The medicine from
Beginning clinical test from 1994, in August, 1996 enters III phases clinic.In January, 1999, AgouronPharmaceuticals
Company carries out product strategy adjustment, and whole research and development power of Thymitaq exclusively are transferred into Zarix companies of the U.S..But it is public
In the document report opened, the report in terms of the polymorphic of nolatrexed dihydrochloride is had not yet to see.
The content of the invention
The first object of the present invention is to provide a kind of nolatrexed dihydrochloride crystal formation III, and the crystal form is to have no report
, its sharp outline, can perfect reproduction, and with regard to filtering, drying, stability, method prepare and machinability for, its display
Valuable feature, can be used as the purposes in antineoplastic, have broad application prospects.
To achieve the above object, the present invention is adopted the following technical scheme that：
A kind of nolatrexed dihydrochloride crystal formation III, it is characterised in that the nolatrexed dihydrochloride crystal formation III is spread out with X-ray powder
Penetrate determination method measure, the X-ray powder diffraction pattern represented with the 2 θ ± 0.2 ° angles of diffraction 6.673 °, 8.838 °, 9.167 °,
12.748°、13.548°、14.443°、16.704°、17.014°、17.810°、21.807°、22.117°、22.527°、
Characteristic diffraction peak is shown at 26.672 °, 27.005 °, 27.238 °, 29.051 ° and 29.498 °.
Specifically, nolatrexed dihydrochloride crystal formation III of the present invention has x-ray diffractogram of powder as shown in Figure 1, institute
Diffraction pattern is stated to be determined using Rigaku RigakuD/MAXRC diffractometers, and according to the position of spectral line (θ of Bragg angle 2, to spend table
Show), relative abundance and interplanar distance d (withRepresent) represent, wherein crystal formation III is expressed as follows：
The fusing point of the nolatrexed dihydrochloride crystal formation III is 255-259 DEG C.From X-ray powder diffraction figure and fusing point,
The present invention has obtained a kind of brand-new nolatrexed dihydrochloride crystal.
The second object of the present invention is the preparation method for providing above-mentioned nolatrexed dihydrochloride crystal formation III, the preparation method
Comprise the following steps：
(1) by nolatrexed dihydrochloride crude product input four-hole boiling flask, the double solvents of acetonitrile and hydrochloric acid is added, is warming up to back
Stream, the state of maintaining the reflux for makes to form uniform egg white color contamination suspension；
(2) simultaneously slow cooling is to 50-60 DEG C for stirring at low speed after stopping backflow, and constant temperature stirring at low speed 60-100 minutes is follow-up
Continuous slow cooling is stirred 90-150 minutes to 15-25 DEG C；
(3) filter, be dried to obtain nolatrexed dihydrochloride crystal formation III.
Wherein, nolatrexed dihydrochloride crude product is commercially available prod disclosed in prior art described in step 1 of the present invention, specifically
Obtain and selection is grasped by those skilled in the art.The present invention provides one kind side of preparation of the nolatrexed dihydrochloride crude product
Method, but it is understood that, the preparation method of nolatrexed dihydrochloride crude product of the present invention includes but being not limited to following system
Preparation Method：
It is added to nolatrexed in the mixed solution of water and acetonitrile, adds a small amount of concentrated hydrochloric acid, heating makes to be completely dissolved.Drop
Plus poor solvent tetrahydrofuran is filtrated to get nolatrexed dihydrochloride crude product to crystal is separated out after standing crystallization.
Wherein, the nolatrexed mass volume ratio with water/acetonitrile double solvents is 1:8-1:10, the volume ratio of water and acetonitrile
It is 1:3-1:4；The volume of concentrated hydrochloric acid is advisable with the 1/8-1/12 of water volume.Poor solvent herein is tetrahydrofuran, and its is specific
Addition separated out as far as possible by crystal and be defined, and specifically stand crystallization and be filtered into those skilled in the art institute it will be appreciated that
Conventional meanses, the present invention this is not particularly limited.
The fusing point of above method gained nolatrexed dihydrochloride crude product is 224-227 DEG C.
Above method gained nolatrexed dihydrochloride crude product under identical testing conditions, be shown in by gained x-ray diffractogram of powder
Fig. 2, it is understood with the claimed x-ray diffractogram of powder of nolatrexed dihydrochloride crystal formation III (i.e. Fig. 1) contrast, this
Invention has obtained a kind of brand-new crystal formation by specific recrystallization method, and by the nolatrexed dihydrochloride crystal formation III and hydrochloric acid Lip river
Bent gram crude product or nolatrexed dihydrochloride disclosed in prior art is drawn to make pharmacodynamics test, drug effect is suitable each other, without significance difference
It is different.
The preparation method of nolatrexed dihydrochloride crystal formation III of the present invention, in step 1 double solvents, the volumetric usage of acetonitrile
It is 15-25 times of nolatrexed dihydrochloride quality；The volumetric usage of hydrochloric acid is 0.03-0.08 times of nolatrexed dihydrochloride quality.
Preparation method of the present invention, in the step 2, with the stirring at low speed of 50-70rmp after stopping flowing back；And with
The speed slow cooling of 0.5-1.5 DEG C/min to 50-60 DEG C to there is a large amount of crystal to separate out, the stirring at low speed of constant temperature 20-40rmp
75-85min, after with the speed slow cooling of 0.4-0.8 DEG C/min to 15-25 DEG C, growing the grain 100-120 minutes.
Wherein, described filtration drying is to be vacuum dried 6~7 hours under 32-36 DEG C, -0.085~-0.095MP.
Used as preferred forms of the invention, preferably described preparation method comprises the following steps：
By in 5.0 grams of nolatrexed dihydrochloride crude product input four-hole boiling flasks, plus acetonitrile 100ml, hydrochloric acid 0.05ml, it is warming up to back
Stream, maintains the reflux for state 45 minutes to form uniform egg white color contamination suspension；
Stop after backflow with the stirring at low speed of 60rmp, and with the speed slow cooling of 1 DEG C/min to 55 DEG C to there is a large amount of crystalline substances
Body is separated out；Constant temperature and with the stirring at low speed 90min of 30rmp, after slow cooling is continued to 25 DEG C with the speed of 0.6 DEG C/min, support
It is brilliant 120 minutes；
Filtering, wet-milling is vacuum dried 6.5 hours under 35 DEG C, -0.092MP, obtains nolatrexed dihydrochloride crystal formation III.
Unless otherwise specified, in preparation method of the present invention, the unit of w/v is g/ml.
The Comprehensive Control that the present invention passes through the aspects such as the selection to solvent, temperature, mixing speed and rearing crystal time, obtains
A kind of preparation method simple and easy to apply, can quickly obtain high quality crystal of the present invention, and suitable popularization and application are in actual life
In product.
Additionally, the third object of the present invention is to protect the pharmaceutical composition containing above-mentioned nolatrexed dihydrochloride crystal formation III,
The specific pharmaceutical composition includes but is not limited to be powder pin, tablet, capsule, freeze-dried powder or transfusion etc..Combination of the present invention
Thing can further contain pharmaceutically acceptable carrier.For example when for freeze-dried powder, the pharmaceutically acceptable carrier can be
Excipient；When the composition is tablet, the pharmaceutically acceptable carrier can be disintegrant, excipient etc..Due to this
Nolatrexed dihydrochloride crystal formation III obtained by invention has preferable physicochemical property, therefore, those skilled in the art will envision that
After being prepared into various pharmaceutical preparations, the stability and curative effect of the pharmaceutical preparation can be also further provided for, and specific formulation
And its those skilled in the art that are defined as of prescription are grasped.
It is highly preferred that pharmaceutical composition of the present invention is powder pin, the powder pin presses the packing of 400-500mg/ branch, preferably
Dispensed by 440mg/ branch.Additionally, powder pin of the present invention can also further contain pharmaceutically acceptable various carriers, such as
Mannitol etc..The those skilled in the art that are defined as of specific selection and consumption are grasped.
Additionally, composition of the present invention can also be freeze-dried powder, the freeze-dried powder by weight, by including such as the following group
The raw material for dividing is prepared into 1000 bottles：The 350-450g of nolatrexed dihydrochloride crystal formation III, mannitol 35-45g, water for injection are added to
3500-4500ml；The wherein preferred 400g of nolatrexed dihydrochloride crystal formation III, mannitol 40g, water for injection are removed after adding to 4000ml
Bacterium, packing is freezed.
It is prepared by freeze-dried powder of the present invention, the various freeze drying process that can be disclosed or be instructed using prior art
Form.It will be appreciated by those skilled in the art that because nolatrexed dihydrochloride crystal formation III of the present invention is compared with disclosed in prior art
Nolatrexed dihydrochloride has more preferably performance, equally can also obtain more preferably stable after being prepared into freeze-dried powder
Property, solubility etc. are ensuring the curative effect of preparation, it is ensured that the drug safety of patient.In order to further verify above-mentioned inference, inventor
Claimed freeze-dried powder is made with the existing nolatrexed dihydrochloride that identical prescription and preparation method are obtained
Freeze-dried powder be quality versus, as a result show that the quality of obtained freeze-drying powder-injection of the present invention is improved significantly, furtherly
After bright present invention gained nolatrexed dihydrochloride crystal formation III is used for specific pharmaceutical composition, the property of itself does not change,
Still possesses preferable performance, so as to improve the overall curative effect of pharmaceutical preparation.
But in order to obtain higher-quality freeze-dried powder, present invention also offers a kind of freeze drying process, specially：To prepare
It is put into freeze drying box after good nolatrexed dihydrochloride preparation packing, is at the uniform velocity cooled to -30 DEG C, freezing in 5h from room temperature
10h；After be warming up to -10 DEG C, be incubated 10h；22 DEG C of dryings are continuously heating to, 15h is incubated, terminate lyophilized, automatic tamponade, lid aluminium
Lid, gland.
Additionally, the present invention also further requirement protects above-mentioned nolatrexed dihydrochloride crystal formation III preparing treatment antineoplastic
In application.Nolatrexed dihydrochloride crystal formation III of the present invention shows significant antitumor activity, energy in pharmacodynamics test
Enough it is widely used in the preparation of antineoplastic.
Using above-mentioned technical proposal, the present invention has the advantages that：
1st, nolatrexed dihydrochloride crystal formation III of the present invention has the stability for being significantly better than nolatrexed dihydrochloride crude product, and yield
Good, purity is high；
2nd, after present invention gained nolatrexed dihydrochloride crystal formation III being further prepared into related preparations, medicine can be significantly improved
The stability of thing preparation, so that it is guaranteed that the drug safety of patient；
3rd, preparation method of the present invention is simple and easy to apply, can stablize and mass production, is conducive to popularization and application.
Brief description of the drawings
Fig. 1 is the X-ray powder diffraction figure of nolatrexed dihydrochloride crystal formation III of the present invention；
Fig. 2 is the X-ray powder diffraction figure of nolatrexed dihydrochloride crude product.
Specific embodiment
The present invention is described further with reference to the accompanying drawings and examples.
The preparation of the nolatrexed dihydrochloride crude product of embodiment 1
It is added to 5g is nolatrexed in the mixed solution of 10ml water and 33ml acetonitriles, adds 1.0ml concentrated hydrochloric acids, heating makes
It is completely dissolved.Tetrahydrofuran is added dropwise to crystal is separated out, nolatrexed dihydrochloride crude product is filtrated to get after standing crystallization according to a conventional method,
Its x-ray diffractogram of powder is shown in Fig. 2.
The nolatrexed dihydrochloride crystal formation III of embodiment 2 and its preparation
By in 5.0 grams of nolatrexed dihydrochloride crude product (prepared by embodiment 1) input four-hole boiling flasks, plus acetonitrile 100ml, hydrochloric acid
0.4ml, is warming up to backflow, maintains the reflux for state 45 minutes to form uniform egg white color contamination suspension；
Stop after backflow with the stirring at low speed of 60rmp, and with the speed slow cooling of 1 DEG C/min to 55 DEG C to there is a large amount of crystalline substances
Body is separated out；Constant temperature with the stirring at low speed 90 minutes of 30rmp, after slow cooling to 25 DEG C, growing the grain is continued with the speed of 0.6 DEG C/min
120 minutes；
Filtering, wet-milling is vacuum dried 6.5 hours under 35 DEG C, -0.092MP, obtains the 4.81g of nolatrexed dihydrochloride crystal formation III.
Purity is 99.5%, and yield is 93.2%.
As shown in figure 1, nolatrexed dihydrochloride crystal formation III is determined with powder x-ray diffraction determination method, with 2 θ ± 0.2 ° diffraction
The X-ray powder diffraction pattern that angle represents 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°、
Characteristic diffraction peak is shown at 29.051 ° and 29.498 °.
The nolatrexed dihydrochloride crystal formation III of embodiment 3 and its preparation
By in 5.0 grams of nolatrexed dihydrochloride crude product (embodiment 1 is prepared or commercially available) input four-hole boiling flasks, plus acetonitrile 75ml,
Hydrochloric acid 0.15ml, is warming up to backflow, maintains the reflux for state 60 minutes to form uniform egg white color contamination suspension；
Stop after backflow with the stirring at low speed of 50rmp, and with the speed slow cooling of 0.5 DEG C/min to 50 DEG C it is a large amount of to having
Crystal is separated out；Constant temperature and with the stirring at low speed 60 minutes of 20rmp, after slow cooling is continued to 15 DEG C with the speed of 0.4 DEG C/min,
Growing the grain 90 minutes；
Filtering, wet-milling is vacuum dried 6.5 hours under 34 DEG C, -0.088MP, obtains the 4.81g of nolatrexed dihydrochloride crystal formation III.
Purity is 99.4%, and yield is 92%.
The nolatrexed dihydrochloride crystal formation III of embodiment 4 and its preparation
By in 5.0 grams of nolatrexed dihydrochloride crude product (prepared by embodiment 1) input four-hole boiling flasks, plus acetonitrile 125ml, hydrochloric acid
0.4ml, is warming up to backflow, maintains the reflux for state 50 minutes to form uniform egg white color contamination suspension；
Stop after backflow with the stirring at low speed of 70rmp, and with the speed slow cooling of 1.5 DEG C/min to 60 DEG C it is a large amount of to having
Crystal is separated out；Constant temperature and with the stirring at low speed 100 minutes of 40rmp, after slow cooling to 25 is continued with the speed of 0.8 DEG C/min
DEG C, growing the grain 150 minutes；
Filtering, wet-milling is vacuum dried 7 hours under 36 DEG C, -0.095MP, obtains the 4.81g of nolatrexed dihydrochloride crystal formation III.It is pure
It is 99.3% to spend, and yield is 89%.
The nolatrexed dihydrochloride crystal formation III of embodiment 5 and its preparation
By in 5.0 grams of nolatrexed dihydrochloride crude product (prepared by embodiment 1) input four-hole boiling flasks, plus acetonitrile 120ml, hydrochloric acid
0.2ml, is warming up to backflow, maintains the reflux for state 55 minutes to form uniform egg white color contamination suspension；
Stop after backflow with the stirring at low speed of 65rmp, and with the speed slow cooling of 0.8 DEG C/min to 55 DEG C it is a large amount of to having
Crystal is separated out；Constant temperature and with the stirring at low speed 85 minutes of 35rmp, after slow cooling is continued to 22 DEG C with the speed of 0.7 DEG C/min,
Growing the grain 120 minutes；
Filtering, wet-milling is vacuum dried 6 hours under 32 DEG C, -0.09MP, obtains the 4.81g of nolatrexed dihydrochloride crystal formation III.Purity
It is 99.4%, yield is 88%.
Freeze-dried powder of the embodiment 6 containing nolatrexed dihydrochloride crystal formation III
The preparation-obtained nolatrexed dihydrochloride crystal formation III of 400g embodiments 2,40g mannitol are taken, is injected water to
4000ml, dissolving is abundant, degerming, is freezed after packing, and freeze drying process is specially：The nolatrexed dihydrochloride preparation packing that will be prepared
After be put into freeze drying box, be at the uniform velocity cooled to -30 DEG C in 5h from room temperature, be incubated 10h；After be warming up to -10, be incubated 10h；
22 DEG C of re-dries are continuously heating to, 15h is incubated, terminate lyophilized, automatic tamponade, lid aluminium lid, gland.
Freeze-dried powder of the embodiment 7 containing nolatrexed dihydrochloride crystal formation III
The preparation-obtained nolatrexed dihydrochloride crystal formation III of 400g embodiments 3,35g mannitol are taken, is injected water to
4000ml, dissolving is abundant, degerming, is freezed after packing, and freeze drying process is specially：The nolatrexed dihydrochloride preparation packing that will be prepared
After be put into freeze drying box, be at the uniform velocity cooled to -30 DEG C in 5h from room temperature, freeze 10h；After be warming up to -10 DEG C, insulation
10h；22 DEG C of dryings are continuously heating to, 15h is incubated, terminate lyophilized, automatic tamponade, lid aluminium lid, gland.
Freeze-dried powder of the embodiment 8 containing nolatrexed dihydrochloride crystal formation III
The preparation-obtained nolatrexed dihydrochloride crystal formation III of 450g embodiments 4,45g mannitol are taken, is injected water to
4000ml, dissolving is abundant, degerming, is freezed after packing, and freeze drying process is specially：The nolatrexed dihydrochloride preparation packing that will be prepared
After be put into freeze drying box, be at the uniform velocity cooled to -30 DEG C in 5h from room temperature, freeze 10h；After be warming up to -10 DEG C, insulation
10h；22 DEG C of re-dries are continuously heating to, 15h is incubated, terminate lyophilized, automatic tamponade, lid aluminium lid, gland.Obtain final product.Embodiment 8 contains
There is the powder pin of nolatrexed dihydrochloride crystal formation III
The preparation-obtained nolatrexed dihydrochloride crystal formation III of 350g embodiments 2 is taken, is dispensed by 440mg/ branch, obtained final product.
Powder pin of the embodiment 9 containing nolatrexed dihydrochloride crystal formation III
The preparation-obtained nolatrexed dihydrochloride crystal formation III of 350g embodiments 2 is taken, is dispensed by 420mg/ branch, obtained final product.
Powder pin of the embodiment 10 containing nolatrexed dihydrochloride crystal formation III
The preparation-obtained nolatrexed dihydrochloride crystal formation III of 350g embodiments 3 is taken, is dispensed by 440mg/ branch, obtained final product.
Powder pin of the embodiment 11 containing nolatrexed dihydrochloride crystal formation III
The preparation-obtained nolatrexed dihydrochloride crystal formation III of 350g embodiments 4 is taken, is dispensed by 500mg/ branch, obtained final product.
The stability test of test example 1
The present invention furthermore provides following test example, is illustrated with to technical scheme.
This test example have detected the stability of nolatrexed dihydrochloride crystal formation III provided by the present invention, and (result of the test is with each
Test group nolatrexed dihydrochloride weight is calculated).
Subjects：
Experimental group 1 is the gained nolatrexed dihydrochloride crystal formation III of the embodiment of the present invention 2；
Experimental group 2 is the gained nolatrexed dihydrochloride crystal formation III of the embodiment of the present invention 3；
Control group 1 is nolatrexed dihydrochloride crude product (gained of the embodiment of the present invention 1)；
Test method：
Accelerated test：Sample is packed with bottle, the closed container (drier) that relative humidity is 75% ± 5% is put into
In, drier is put into incubator, placed 6 months in 40 DEG C ± 2 DEG C, respectively at 0,1,2,3, June respectively takes a packaging and carries out
Investigate.
Long term test：Sample is packed with bottle, 25 DEG C ± 2 DEG C of temperature, the condition of relative humidity 60% ± 10% is stored in
Under, regular sampling and testing.
This result of the test is shown in Tables 1 and 2：
The accelerated test result of table 1
The long-term test results of table 2
Test example 2
This test example have detected the stability of the freeze-dried powder prepared by nolatrexed dihydrochloride crystal formation III provided by the present invention
(result of the test is calculated with each test group nolatrexed dihydrochloride weight).
Subjects：
Experimental group 1 is the gained nolatrexed dihydrochloride freeze-dried powder of the embodiment of the present invention 6；
Experimental group 2 is the gained nolatrexed dihydrochloride freeze-dried powder of the embodiment of the present invention 7；
Control group 1 is as raw material, by the identical prescription of embodiment 6 and preparation with nolatrexed dihydrochloride crude product (embodiment 1)
The freeze-dried powder that method is obtained；
Test method：
Accelerated test：By freeze-dried powder sample, by intending commercially available back, in 40 DEG C ± 2 DEG C of temperature, relative humidity 75% ± 5%
Under conditions of place 6 months, respectively at 0, sampling in 1,2,3,6 month is tested.
Long term test：By test sample 3 batches, by commercially available back, 25 DEG C ± 2 DEG C of temperature is stored in, relative humidity 60% ±
Under conditions of 10%, regular sampling and testing.
Result of the test is shown in Table 3 and table 4.
The accelerated test result of table 3
The long-term test results of table 4
Embodiment in above-described embodiment can be further combined or replace, and embodiment is only to of the invention
Preferred embodiment is described, and not the spirit and scope of the present invention are defined, and is not departing from design philosophy of the present invention
Under the premise of, the various changes and modifications that professional and technical personnel in the art make to technical scheme belong to this hair
Bright protection domain.
Claims (10)
1. a kind of nolatrexed dihydrochloride crystal formation III, it is characterised in that the nolatrexed dihydrochloride crystal formation III uses powder x-ray diffraction
Determination method is determined, the X-ray powder diffraction pattern represented with the 2 θ ± 0.2 ° angles of diffraction 6.673 °, 8.838 °, 9.167 °,
12.748°、13.548°、14.443°、16.704°、17.014°、17.810°、21.807°、22.117°、22.527°、
Characteristic diffraction peak is shown at 26.672 °, 27.005 °, 27.238 °, 29.051 ° and 29.498 °.
2. nolatrexed dihydrochloride crystal formation III according to claim 1, it is characterised in that：The nolatrexed dihydrochloride crystal formation III
Fusing point be 255-259 DEG C.
3. the preparation method of nolatrexed dihydrochloride crystal formation III described in claim 1 or 2, it is characterised in that：Comprise the following steps：
(1) by nolatrexed dihydrochloride crude product input four-hole boiling flask, the double solvents of acetonitrile and hydrochloric acid is added, is warming up to backflow,
The state of maintaining the reflux for makes to form uniform egg white color contamination suspension；
(2), to 50-60 DEG C, constant temperature stirring at low speed 60-100 minute continues to delay afterwards for stirring at low speed and slow cooling after stopping backflow
Slowly it is cooled to 15-25 DEG C, growing the grain 90-150 minutes；
(3) filter, be dried to obtain nolatrexed dihydrochloride crystal formation III.
4. preparation method according to claim 3, it is characterised in that：Nolatrexed dihydrochloride crude product is used in the step 1
Following method is prepared from：
It is added to nolatrexed in the mixed solution of water and acetonitrile, adds a small amount of concentrated hydrochloric acid, heating makes to be completely dissolved, and is added dropwise not
Good solvent tetrahydrofuran is filtrated to get nolatrexed dihydrochloride crude product to crystal is separated out after standing crystallization.
5. the preparation method according to claim 3 or 4, it is characterised in that：In the double solvents of the step 1, acetonitrile
Volumetric usage is 15-25 times of nolatrexed dihydrochloride quality；The volumetric usage of hydrochloric acid is the 0.03- of nolatrexed dihydrochloride quality
0.08 times.
6. preparation method according to claim 3, it is characterised in that：In the step 2, with 50-70rmp after stopping flowing back
Stirring at low speed；And with the speed slow cooling of 0.5-1.5 DEG C/min to 50-60 DEG C, constant temperature is with the stirring at low speed of 20-40rmp
75-85min, after with the speed slow cooling of 0.4-0.8 DEG C/min to 15-25 DEG C, growing the grain 100-120 minutes.
7. preparation method according to claim 3, it is characterised in that：Described preparation method comprises the following steps：
By in 5.0 grams of nolatrexed dihydrochloride crude product input four-hole boiling flasks, plus acetonitrile 100ml, hydrochloric acid 0.05ml, backflow is warming up to,
State is maintained the reflux for 45 minutes to form uniform egg white color contamination suspension；
Stop after backflow with the stirring at low speed of 60rmp, and with the speed slow cooling of 1 DEG C/min to 55 DEG C to there is a large amount of crystal to analyse
Go out；Constant temperature and with the stirring at low speed 90min of 30rmp, after slow cooling to 25 DEG C, growing the grain 120 is continued with the speed of 0.6 DEG C/min
Minute；
Filtering, wet-milling is vacuum dried 6.5 hours under 35 DEG C, -0.092MP, obtains nolatrexed dihydrochloride crystal formation III.
8. the pharmaceutical composition of nolatrexed dihydrochloride crystal formation III described in any one of claim 1 or 2 is contained.
9. the pharmaceutical composition stated according to claim 8, it is characterised in that：Described pharmaceutical composition is powder pin or freeze-dried powder
Pin.
10. application of the nolatrexed dihydrochloride crystal formation III described in claim 1 or 2 in treatment antineoplastic is prepared.
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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 |
-
2013
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| 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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