CN106831715A - A kind of nolatrexed dihydrochloride crystal formation II and preparation method and application - Google Patents
A kind of nolatrexed dihydrochloride crystal formation II and preparation method and application Download PDFInfo
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- CN106831715A CN106831715A CN201710061146.0A CN201710061146A CN106831715A CN 106831715 A CN106831715 A CN 106831715A CN 201710061146 A CN201710061146 A CN 201710061146A CN 106831715 A CN106831715 A CN 106831715A
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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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- 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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Abstract
The invention discloses a kind of nolatrexed dihydrochloride crystal formation II, the nolatrexed dihydrochloride crystal formation II is determined with powder x-ray diffraction determination method, and characteristic diffraction peak is shown 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 ° 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 201310201443.2 (May 27 2013 applying date, it is entitled：A kind of hydrochloric acid
Nolatrexed crystal formation II 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 II 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, Agouron Pharmaceuticals
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 II, 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 II, it is characterised in that the nolatrexed dihydrochloride crystal formation II 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 6.691 °, 12.766 °, 16.720 °,
17.015 °, 17.814 °, 21.806 °, 22.114 °, 23.711 °, 24.707 °, 25.426 °, 26.674 °, 29.051 ° and
Characteristic diffraction peak is shown at 29.478 °.
Specifically, nolatrexed dihydrochloride crystal formation II 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 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 nolatrexed dihydrochloride crystal.
The second object of the present invention is the preparation method for providing above-mentioned nolatrexed dihydrochloride crystal formation II, the preparation method
Comprise the following steps：
(1) by nolatrexed dihydrochloride crude product input methyl alcohol, stirring makes into suspension；Enriching hydrochloric acid is warming up to 50-70 DEG C
Make to be dissolved to clear, holding 30-60min；
(2) under stirring at low speed slow cooling to 25-40 DEG C, constant temperature growing the grain 40-80min continues slow cooling to 15-25 afterwards
DEG C, growing the grain 90-150min；
(3) filter, be dried to obtain nolatrexed dihydrochloride crystal formation II.
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 methyl alcohol, 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/methyl alcohol double solvents is 1:8-1:10, the volume ratio of water and methyl alcohol
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 II (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 II 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 II of the present invention, in step 1, the volumetric usage of methyl alcohol is hydrochloric acid Lip river
Draw bent gram mass 6-9 times；The volumetric usage of concentrated hydrochloric acid is 0.03-0.08 times of nolatrexed dihydrochloride quality.Wherein, preferred first
The volumetric usage of alcohol is 7-8 times of nolatrexed dihydrochloride quality；The volumetric usage of concentrated hydrochloric acid is nolatrexed dihydrochloride quality
0.05-0.06 times.
Additionally, the mixing speed in step 1 has no materially affect to technical scheme in itself, conventional mixing speed,
The present invention can use 50-150rmp.
Preparation method of the present invention, in the step 2 under the stirring at low speed of 50-70rpm, with 0.5-1.5 DEG C/
The speed slow cooling of min to 28-35 DEG C of (now occur be not redissolved crystal grain) constant temperature growing the grain 40-80min, continue afterwards with
The speed slow cooling of 0.4-0.8 DEG C/min is to 18-20 DEG C, growing the grain 100-130min.Wherein, described filtration drying be
32-36 DEG C, be vacuum dried 6~7 hours under -0.085~-0.095MP.
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.
Used as preferred forms of the invention, preferably described preparation method comprises the following steps：
By in 5 grams of nolatrexed dihydrochloride crude product input 250ml four-hole boiling flasks, plus 37.5ml methyl alcohol, stirring makes into suspension,
Mixing speed is 120rmp；Enriching hydrochloric acid 0.25ml, is warming up to 60 DEG C, keeps 45min, makes to be dissolved to clearly；
There is crystal grain in bottle wall when being adjusted to speed of agitator 55rpm, cool the temperature to 32 DEG C with the speed of 1 DEG C/min；Keep
Temperature 32-34 DEG C when occur be not redissolved crystal grain when, constant temperature growing the grain 60min continues slow with the speed of 0.6 DEG C/min afterwards
Cool to 20 DEG C, insulation growing the grain 120min；
Filtering, wet-milling is vacuum dried 6.5 hours under 35 DEG C, -0.092MP, obtains nolatrexed dihydrochloride crystal formation II.Except special
Illustrate outer, in preparation method of the present invention, the unit of w/v is g/ml.
Additionally, the third object of the present invention is to protect the pharmaceutical composition containing above-mentioned nolatrexed dihydrochloride crystal formation II,
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 II 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 raw material of lower component is prepared into 1000 bottles：The 350-450g of nolatrexed dihydrochloride crystal formation II, mannitol 35-45g, water for injection are added to
3500-4500ml；The wherein preferred 400g of nolatrexed dihydrochloride crystal formation II, 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 II 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 II 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 above-mentioned nolatrexed dihydrochloride crystal formation II of further requirement protection is in tumor is prepared
Application.Nolatrexed dihydrochloride crystal formation II of the present invention shows significant antitumor activity in pharmacodynamics test, can
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 II 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 II 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 II 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 40ml methyl alcohol, 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 II of embodiment 2 and its preparation
During nolatrexed dihydrochloride crude product (prepared by embodiment 1) 5g put into 250ml four-hole boiling flasks, plus 37.5ml methyl alcohol is stirred
Mixing makes into suspension, and mixing speed is 120rmp；Enriching hydrochloric acid 0.25ml, is warming up to 60 DEG C, keeps 45min, makes to be dissolved to clearly；
Bottle wall occurs what is be not redissolved when being adjusted to speed of agitator 55rpm, cool the temperature to 32 DEG C with the speed of 1 DEG C/min
Crystal grain, constant temperature growing the grain 60min continues to be slow cooling to 20 DEG C, insulation growing the grain 120min with the speed of 0.6 DEG C/min afterwards；
Filtering, wet-milling is vacuum dried 6.5 hours under 35 DEG C, -0.092MP, obtains nolatrexed dihydrochloride crystal formation II, and purity is
99.4%, yield is 95%.
As shown in figure 1, nolatrexed dihydrochloride crystal formation II is determined with powder x-ray diffraction determination method, with 2 θ ± 0.2 ° diffraction
The X-ray powder diffraction pattern that angle represents 6.691 °, 12.766 °, 16.720 °, 17.015 °, 17.814 °, 21.806 °,
Characteristic diffraction peak is shown at 22.114 °, 23.711 °, 24.707 °, 25.426 °, 26.674 °, 29.051 ° and 29.478 °.
The nolatrexed dihydrochloride crystal formation II of embodiment 3 and its preparation
During nolatrexed dihydrochloride crude product (prepared by embodiment 1) 5g put into 250ml four-hole boiling flasks, plus 30ml methyl alcohol, stirring
Make into suspension, mixing speed is 50rmp；Enriching hydrochloric acid 0.15ml, is warming up to 50 DEG C, keeps 30min, makes to be dissolved to clearly；
Not being redissolved occurs in bottle wall when being adjusted to speed of agitator 50rpm, cool the temperature to 25 DEG C with the speed of 0.5 DEG C/min
Crystal grain；Constant temperature growing the grain 60min, continues to be slow cooling to 15 DEG C, insulation growing the grain 90min with the speed of 0.4 DEG C/min afterwards；
Filtering, wet-milling is vacuum dried 6.5 hours under 34 DEG C, -0.088MP, obtains nolatrexed dihydrochloride crystal formation II, and purity is
99.2%, yield is 92%.
As shown in figure 1, nolatrexed dihydrochloride crystal formation II is determined with powder x-ray diffraction determination method, with 2 θ ± 0.2 ° diffraction
The X-ray powder diffraction pattern that angle represents 6.691 °, 12.766 °, 16.720 °, 17.015 °, 17.814 °, 21.806 °,
Characteristic diffraction peak is shown at 22.114 °, 23.711 °, 24.707 °, 25.426 °, 26.674 °, 29.051 ° and 29.478 °.
The nolatrexed dihydrochloride crystal formation II of embodiment 4 and its preparation
During nolatrexed dihydrochloride crude product (prepared by embodiment 1) 5g put into 250ml four-hole boiling flasks, plus 45ml methyl alcohol, stirring
Make into suspension, mixing speed is 150rmp；Enriching hydrochloric acid 0.4ml, is warming up to 70 DEG C, keeps 60min, makes to be dissolved to clearly；
Not being redissolved occurs in bottle wall when being adjusted to speed of agitator 70rpm, cool the temperature to 40 DEG C with the speed of 1.5 DEG C/min
Crystal grain；Constant temperature growing the grain 80min, continues to be slow cooling to 25 DEG C, insulation growing the grain 150min with the speed of 0.8 DEG C/min afterwards；
Filtering, wet-milling is vacuum dried 7 hours under 36 DEG C, -0.095MP, obtains nolatrexed dihydrochloride crystal formation II, and purity is
99.6%, yield is 89%.
As shown in figure 1, nolatrexed dihydrochloride crystal formation II is determined with powder x-ray diffraction determination method, with 2 θ ± 0.2 ° diffraction
The X-ray powder diffraction pattern that angle represents 6.691 °, 12.766 °, 16.720 °, 17.015 °, 17.814 °, 21.806 °,
Characteristic diffraction peak is shown at 22.114 °, 23.711 °, 24.707 °, 25.426 °, 26.674 °, 29.051 ° and 29.478 °.
The nolatrexed dihydrochloride crystal formation II of embodiment 5 and its preparation
During nolatrexed dihydrochloride crude product (prepared by embodiment 1) 5g put into 250ml four-hole boiling flasks, plus 35ml methyl alcohol, stirring
Make into suspension, mixing speed is 120rmp；Enriching hydrochloric acid 0.3ml, is warming up to 55 DEG C, keeps 50min, makes to be dissolved to clearly；
Not being redissolved occurs in bottle wall when being adjusted to speed of agitator 60rpm, cool the temperature to 30 DEG C with the speed of 0.8 DEG C/min
Crystal grain；Constant temperature growing the grain 70min, continues to be slow cooling to 22 DEG C, insulation growing the grain 110min with the speed of 0.5 DEG C/min afterwards；
Filtering, wet-milling is vacuum dried 6 hours under 32 DEG C, -0.09MP, obtains nolatrexed dihydrochloride crystal formation II, and purity is
99.3%, yield is 90%.
As shown in figure 1, nolatrexed dihydrochloride crystal formation II is determined with powder x-ray diffraction determination method, with 2 θ ± 0.2 ° diffraction
The X-ray powder diffraction pattern that angle represents 6.691 °, 12.766 °, 16.720 °, 17.015 °, 17.814 °, 21.806 °,
Characteristic diffraction peak is shown at 22.114 °, 23.711 °, 24.707 °, 25.426 °, 26.674 °, 29.051 ° and 29.478 °.
Freeze-dried powder of the embodiment 6 containing nolatrexed dihydrochloride crystal formation II
The preparation-obtained nolatrexed dihydrochloride crystal formation II 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 II
The preparation-obtained nolatrexed dihydrochloride crystal formation II 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 II
The preparation-obtained nolatrexed dihydrochloride crystal formation II 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.
Powder pin of the embodiment 9 containing nolatrexed dihydrochloride crystal formation II
The preparation-obtained nolatrexed dihydrochloride crystal formation II of 350g embodiments 2 is taken, is dispensed by 400mg/ branch, obtained final product.
Powder pin of the embodiment 10 containing nolatrexed dihydrochloride crystal formation II
The preparation-obtained nolatrexed dihydrochloride crystal formation II 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 II
The preparation-obtained nolatrexed dihydrochloride crystal formation II 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 II 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 II of the embodiment of the present invention 2；
Experimental group 2 is the gained nolatrexed dihydrochloride crystal formation II 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
Above-mentioned result of the test shows：Stabilization of the gained nolatrexed dihydrochloride crystal formation II of the invention compared with nolatrexed dihydrochloride crude product
Property has clear improvement.Additionally, powder pin of the present invention is used the direct packaging of nolatrexed dihydrochloride crystal formation II is obtained, it is anticipated that
, the stability of the powder pin is necessarily better than the powder pin obtained as raw material using nolatrexed dihydrochloride crude product.
Test example 2
This test example have detected the stability of the freeze-dried powder prepared by nolatrexed dihydrochloride crystal formation II 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 II, it is characterised in that the nolatrexed dihydrochloride crystal formation II 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 6.691 °, 12.766 °, 16.720 °,
17.015 °, 17.814 °, 21.806 °, 22.114 °, 23.711 °, 24.707 °, 25.426 °, 26.674 °, 29.051 ° and
Characteristic diffraction peak is shown at 29.478 °.
2. nolatrexed dihydrochloride crystal formation II according to claim 1, it is characterised in that：The nolatrexed dihydrochloride crystal formation II
Fusing point be 246-250 DEG C.
3. the preparation method of nolatrexed dihydrochloride crystal formation II described in claim 1 or 2, it is characterised in that：Comprise the following steps：
(1) by nolatrexed dihydrochloride crude product input methyl alcohol, stirring makes into suspension；Enriching hydrochloric acid be warming up to 50-70 DEG C make it is molten
Xie Zhiqing, keeps 30-60min；
(2) under stirring at low speed slow cooling to 25-40 DEG C, constant temperature growing the grain 40-80min continues slow cooling to 15-25 DEG C afterwards,
Growing the grain 90-150min；
(3) filter, be dried to obtain nolatrexed dihydrochloride crystal formation II.
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 methyl alcohol, 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 step 1, the volumetric usage of methyl alcohol is
6-9 times of nolatrexed dihydrochloride quality；The volumetric usage of hydrochloric acid is 0.03-0.08 times of nolatrexed dihydrochloride quality.
6. preparation method according to claim 3, it is characterised in that：In the step 2, in the stirring at low speed of 50-70rpm
Under, 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, continue afterwards with 0.4-0.8 DEG C/
The speed slow cooling of min is to 18-20 DEG C, growing the grain 100-130min.
7. preparation method according to claim 3, it is characterised in that：Described preparation method comprises the following steps：
By in 5 grams of nolatrexed dihydrochloride crude product input 250ml four-hole boiling flasks, plus 37.5ml methyl alcohol, stirring makes into suspension, stirs
Speed is 120rmp；Enriching hydrochloric acid 0.25ml, is warming up to 60 DEG C, keeps 45min, makes to be dissolved to clearly；Speed of agitator is adjusted to
55rpm, there is the crystal grain not being redissolved in bottle wall when cooling the temperature to 32 DEG C with the speed of 1 DEG C/min, constant temperature growing the grain 60min, after
Continue to be slow cooling to 20 DEG C, insulation growing the grain 120min with the speed of 0.6 DEG C/min；
Filtering, wet-milling is vacuum dried 6.5 hours under 35 DEG C, -0.092MP, obtains nolatrexed dihydrochloride crystal formation II.
8. the pharmaceutical composition of nolatrexed dihydrochloride crystal formation II described in any one of claim 1 or 2 is contained.
9. pharmaceutical composition 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 II 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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