CN103524424A - Crystal form VI of ambrisentan as well as preparation method and application thereof - Google Patents
Crystal form VI of ambrisentan as well as preparation method and application thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
Abstract
The invention provides a crystal form VI of ambrisentan. The crystal form is represented by a 2theta angle in an X ray powder diffraction spectrum obtained by using Cu-Kalpha radiation under 40KV and 100mA, and has characteristic peaks at 8.94, 12.34, 14.14, 17.86, 18.24, 20.58 and 26.84. The invention also provides a method for preparing the crystal form, a drug composition containing the crystal form as an active ingredient, and an application of the crystal form to preparation of drugs for treating pulmonary hypertension or hypertension diseases.
Description
Technical field
The present invention relates to the new crystal VI of a kind of ambrisentan (Ambrisentan), and the method for preparing this crystal formation, contain described crystal formation as the pharmaceutical composition of activeconstituents, and this crystal formation is in the application for the preparation of in treatment pulmonary hypertension or high blood pressure disease.
Background technology
Chemistry (+)-(the s)-2-[(4 by name of ambrisentan (Ambrisentan), 6-dimethyl pyrimidine-2-yl) oxygen base]-3-methoxyl group-3,3-henyl propionic acid.Ambrisentan, as a kind of endothelin A receptor antagonist medicine, is usually used in the treatment of pulmonary hypertension at present.
Ambrisentan has multiple crystal formation.According to current patent literature, ambrisentan roughly has amorphous and four kinds of crystal habits.
Patent WO2010091877 has reported a kind of crystal formation, and its preparation method is by after recrystallization, filtration, the washing in the isopropyl alcohol and water of specified proportion of ambrisentan crude product, being dried, and obtains crystal formation I.
Patent WO2010091877 has reported another kind of crystal formation, and its preparation method is that ambrisentan benzyl ester catalytic hydrogenation is taken off to benzyl, filters catalyzer, and filtrate is spin-dried for, and obtains ambrisentan crude product, and in ether, recrystallization obtains crystal form II.
In patent WO2011114338, reported a kind of crystal formation, its preparation method be with hydrochloric acid by the acidifying of ambrisentan salts solution, crystallization in water, filter, washing, dry after, obtain crystal form II I.
In patent WO2011004402, reported a kind of crystal formation, its preparation method is to say ambrisentan crude product recrystallization in second alcohol and water, filters, and uses ethanol and water mixed liquid washing, the dry form IV that obtains.
In patent CN201110114072.5, reported amorphous ambrisentan of a kind of novelty and preparation method thereof.
Contriver still wishes by seeking new ambrisentan crystal formation to have good physico-chemical property and be applicable to the synthetic crystal formation of producing on a large scale to obtain, and is also to treat at present pulmonary hypertension or the more material choice of hypertensive drug provision simultaneously.
Summary of the invention
Therefore, the object of the invention is to overcome defect of the prior art, the ambrisentan crystal form V I that a kind of stability is better, solubleness is higher is provided, and the method for preparing this crystal formation, contain described crystal formation as the pharmaceutical composition of activeconstituents, and this crystal formation is in the application for the preparation of in treatment pulmonary hypertension or high blood pressure disease.
A crystal form V I, in the X-ray powder diffraction spectrum that described crystal formation use Cu-K α radiation, 40KV, 100mA obtain, represents with 2 θ angles, 8.94,12.34, and 14.14,17.86,18.24,20.58, there is characteristic peak at 26.84 places.
According to crystal formation of the present invention, wherein, the relative intensity of described each characteristic peak is followed successively by 100%, 36%, and 30%, 39%, 33%, 37%, 48%.
According to crystal formation of the present invention, wherein, in the X-ray powder diffraction spectrum that described use Cu-K α radiation, 40KV, 100mA obtain, with 2 θ angles, represent, can also be 13.10,15.22, there is characteristic peak at 18.90,24.28,27.52,36.66 places.
According to crystal formation of the present invention, wherein, the relative intensity of described each characteristic peak is followed successively by 24%, 22%, and 23%, 25%, 21%, 14%.
More particularly, in the resulting XRPD collection of illustrative plates of condition of contriver with Cu-K α radiation, 40KV, 100mA, take diffraction peak position (2 θ， units as °) and corresponding relative intensity thereof the percentage ratio of climax (with respect to) to represent, parameter is as follows:
Larger characteristic peak 2 θ angles (relative intensity): 8.94(100%), 12.34(36%), 14.14(30%), 17.86(39%), 18.24 (33%), 20.58(37%), 26.84(48%)
Less characteristic peak 2 θ angles (relative intensity): 13.10(24%), 15.22(22%), 18.90(23%), 24.28(25%), 27.52(21%), 36.66 (14%).
The difference of the XRPD collection of illustrative plates of the crystal formation I of the XRPD collection of illustrative plates of crystal form V I of the present invention and WO2010091877 report is in Table 1:
The difference of the XRPD collection of illustrative plates of table 1 crystal form V I of the present invention and crystal formation I
From table 1:
(1) the X-ray powdery diffractometry (XRPD) (2 θ) of crystal form V I of the present invention does not have absorption peak at 14.90,26.54 places; The X-ray powdery diffractometry (XRPD) (2 θ) of WO2010091877 crystal formation I has absorption peak at 14.90,26.54 places.
(2) the X-ray powdery diffractometry (XRPD) of crystal form V I of the present invention is compared with obvious absorption peaks (2 θ): 27.56,36.60; X-ray powdery diffractometry (XRPD) absorption peak (2 θ) of WO2010091877 crystal formation I is very weak 27.56,36.60.
The difference of the XRPD collection of illustrative plates of the XRPD collection of illustrative plates of crystal form V I of the present invention and WO2011114338 report crystal form II I is in Table 2:
The difference of the XRPD collection of illustrative plates of table 2 crystal form V I of the present invention and crystal form II I
From table 2:
The X-ray powdery diffractometry (XRPD) (2 θ) of crystal form V I of the present invention does not have absorption peak at 14.90,26.54 places; The X-ray powdery diffractometry (XRPD) (2 θ) of WO2011114338 crystal formation I has absorption peak at 14.90,26.54 places.
The difference of the XRPD collection of illustrative plates of the XRPD collection of illustrative plates of crystal form V I of the present invention and WO2011004402 report form IV is in Table 3:
The difference of the XRPD collection of illustrative plates of table 3. crystal form V I of the present invention and form IV
From table 3:
The X-ray powdery diffractometry (XRPD) (2 θ) of crystal form V I of the present invention does not have absorption peak 8.24,27.24; X-ray powdery diffractometry (XRPD) absorption peak (2 θ) of WO2011004402 form IV has stronger absorption peak 8.24,27.24.
According to crystal formation of the present invention, wherein, the X-ray powder diffraction spectrum that described crystal formation is used Cu-K α radiation, 40KV, 100mA to obtain can be as shown in Figure 1.
The present invention also provides a kind of method of preparing ambrisentan crystal form V I of the present invention, and wherein, described method comprises:
1) according to the weight ratio of ambrisentan and dioxane, be 1:10～100, ambrisentan is dissolved in to dioxane, be heated to 40～100 ℃, adopt stirring or ultrasonic power to make solution clarification, obtain the dioxane solution of ambrisentan.
2) in the dioxane solution of the ambrisentan obtaining to step 1), add water, wherein the volume ratio of dioxane and water is 1～20:1, is cooled to below 30 ℃, place crystallization, filter and collect crystal, at 40～80 ℃, vacuum-drying is 3～5 hours, obtains ambrisentan crystal form V I.
The method according to this invention, wherein, in step 1), the weight ratio of described ambrisentan and dioxane can be 1:20～50.As preferably, can be heated to 50～70 ℃.
The method according to this invention, wherein, step 2) in, the volume ratio of dioxane and water can be 3～10:1.As preferably, can be cooled to 15～30 ℃.
The present invention also provides a kind of pharmaceutical composition, wherein, and the ambrisentan crystal form V I of the present invention that described pharmaceutical composition comprises significant quantity or the ambrisentan crystal form V I preparing according to method provided by the invention.
Ambrisentan crystal form V I of the present invention can make pharmaceutical composition jointly with one or more pharmaceutically acceptable vehicle.Described vehicle comprises thinner, tackiness agent, disintegrating agent, dispersion agent, glidant, lubricant etc.Wherein, can adopt lactose, starch, Microcrystalline Cellulose as thinner; Can use gelatin, methylcellulose gum, hypromellose, polyvinylpyrrolidone, starch slurry etc. as tackiness agent; Can use starch, Xylo-Mucine, carboxymethylstach sodium, low-substituted hydroxypropyl methylcellulose, polyvinylpolypyrrolidone, Microcrystalline Cellulose as disintegrating agent; Can use talcum powder, micro-part of silica gel, stearin, calcium stearate or magnesium etc. as glidant or lubricant.
According to pharmaceutical composition of the present invention, wherein, described pharmaceutical composition can be solid orally ingestible.As preferably, described solid orally ingestible can be tablet, capsule, granule.As more preferably, described tablet can be dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet.
The preparation method of described solid orally ingestible can comprise the following steps: by activeconstituents and carrier and disintegration additive composition mixture, then make aqueous solution, alcohol or the aqueous alcohol solution of this mixture and tackiness agent in suitable equipment, carry out wet method or dry granulation, dried particles, adds other disintegrating agent, lubricant and antisticking agent to make suitable preparation subsequently.
The present invention also provides ambrisentan crystal form V I of the present invention, or the ambrisentan crystal form V I preparing according to method of the present invention is in the purposes for the preparation of in treatment pulmonary hypertension or high blood pressure disease.
Ambrisentan crystal form V I of the present invention is effectively in quite wide measures range, and the dosage of taking clinical every day, within the scope of 2～50mg/ people, can divide once or administration for several times.The actual dosage of taking should be decided according to relevant situation by doctor, and these situations comprise the person's of being treated physical state, patient's route of administration, age, body weight, to severity of the individual reaction of medicine and symptom etc.Thereby as preferred, the ambrisentan crystal form V I that described every tablet of tablet and/or every seed lac wafer contain 2～50mg.
Ambrisentan crystal form V I of the present invention has but is not limited to following beneficial effect:
1. compare with other crystal formations, the solubility property of ambrisentan crystal form V I of the present invention is better, and this obtains higher bioavailability by being conducive to crystal formation of the present invention, has good medicinal characteristic.
2. compare with other crystal formations, ambrisentan crystal form V I of the present invention also has better light durability and high-temperature stability, the impurity producing under its prolonged preservation still less, for example crystal form V I of the present invention in illumination the impurity after 10 days to increase number be only nearly 1/3 of crystal formation I under similarity condition, it is only 1/2 of crystal formation I under similarity condition that impurity at high temperature after 10 days increases number, and at high humidity the impurity after 10 days to increase number be only 1/4 of crystal formation I under similarity condition, visible its has good storage performance, contributes to promote medicine quality, ensures drug safety.
3. the preparation manipulation of ambrisentan crystal form V I of the present invention is simple, and process costs is cheap, is conducive to production quality control, is applicable to scale operation and technology popularization.
Accompanying drawing explanation
Below, describe by reference to the accompanying drawings embodiment of the present invention in detail, wherein:
Fig. 1 shows the X-ray powder diffraction spectrum (PXRD) of the ambrisentan crystal form V I of embodiment 5.
Fig. 2 shows the result data that the X-ray powder diffraction spectrum of the ambrisentan crystal form V I of embodiment 5 is carried out to peak value retrieval.
Fig. 3 shows the full stripping curve mensuration figure of the preparation that contains ambrisentan crystal form V I that embodiment 9～13 makes.
Embodiment
Below by specific embodiment, further illustrate the present invention, still, should be understood to, these embodiment are only used for the use specifically describing more in detail, and should not be construed as for limiting in any form the present invention.
General description is carried out to the material and the test method that use in the present invention's test in this part.Although be well known in the art for realizing many materials and the working method that the object of the invention used, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that in context, if not specified, material therefor of the present invention and working method are well known in the art.
With the following Examples, the present invention is as follows to the condition determination of crystal formation:
X-ray powder diffraction (PXRD):
Instrument: Rigaku D/Max-2500 type 18KW
Company: centralab of Nankai University
Diffractometer: polycrystal powder diffractometer
Target: Cu-K α radiation, λ=1.5405
, 2 θ=3～50 °
Pipe is pressed: 40KV
Pipe stream: 100mA
Sweep velocity: 8 ℃/min
Crystalline graphite monochromator
DS/SS=1°
RS:0.3mm
The present embodiment is for illustrating the preparation of ambrisentan crystal form V I of the present invention.
Get 50ml beaker, add respectively 200mg ambrisentan and 20ml dioxane, be heated to 50 ℃, the ultrasonic solution that makes becomes clarification, adds 20ml water, is naturally cooled to 30 ℃, sufficient standing crystallization.Filter, collect crystal and put into vacuum drying oven, under 50 ℃ of vacuum conditions, be dried 3 hours, obtain ambrisentan crystal form V I.
Described crystal formation is carried out to PXRD analysis, take diffraction peak position (2 θ， units as °) and corresponding relative intensity thereof the percentage ratio of climax (with respect to) to represent, parameter is as follows:
Larger characteristic peak 2 θ angles (relative intensity): 8.94(100%), 12.34(36%), 14.14(30%), 17.86(39%), 18.24 (33%), 20.58(37%), 26.84(48%)
Less characteristic peak 2 θ angles (relative intensity): 13.10(24%), 15.22(22%), 18.90(23%), 24.28(25%), 27.52(21%), 36.66 (14%).
The present embodiment is for illustrating the preparation of ambrisentan crystal form V I of the present invention.
Get 50ml beaker, add respectively 500mg ambrisentan and 25ml dioxane, be heated to 40 ℃, the ultrasonic solution that makes becomes clarification, adds 10ml water, is naturally cooled to 15 ℃, sufficient standing crystallization.Filter, collect crystal and put into vacuum drying oven, under 60 ℃ of vacuum conditions, be dried 3 hours, obtain ambrisentan crystal form V I.
Described crystal formation is carried out to PXRD analysis, take diffraction peak position (2 θ， units as °) and corresponding relative intensity thereof the percentage ratio of climax (with respect to) to represent, parameter is as follows:
Larger characteristic peak 2 θ angles (relative intensity): 8.94(100%), 12.34(36%), 14.14(30%), 17.86(39%), 18.24 (33%), 20.58(37%), 26.84(48%)
Less characteristic peak 2 θ angles (relative intensity): 13.10(24%), 15.22(22%), 18.90(23%), 24.28(25%), 27.52(21%), 36.66 (14%).
The present embodiment is for illustrating the preparation of ambrisentan crystal form V I of the present invention.
Get 50ml beaker, add respectively 1g ambrisentan and 10ml dioxane, be heated to 100 ℃, stir and make solution become clarification, add 3ml water, be naturally cooled to 15 ℃, sufficient standing crystallization.Filter, collect crystal and put into vacuum drying oven, under 60 ℃ of vacuum conditions, be dried 3 hours, obtain ambrisentan crystal form V I.
Described crystal formation is carried out to PXRD analysis, take diffraction peak position (2 θ， units as °) and corresponding relative intensity thereof the percentage ratio of climax (with respect to) to represent, parameter is as follows:
Larger characteristic peak 2 θ angles (relative intensity): 8.94(100%), 12.34(36%), 14.14(30%), 17.86(39%), 18.24 (33%), 20.58(37%), 26.84(48%)
Less characteristic peak 2 θ angles (relative intensity): 13.10(24%), 15.22(22%), 18.90(23%), 24.28(25%), 27.52(21%), 36.66 (14%).
The present embodiment is for illustrating the preparation of ambrisentan crystal form V I of the present invention.
Get 250ml beaker, add respectively 5g ambrisentan and 100ml dioxane, be heated to 70 ℃, the ultrasonic solution that makes becomes clarification, adds 10ml water, is naturally cooled to 20 ℃, sufficient standing crystallization.Filter, collect crystal and put into vacuum drying oven, under 40 ℃ of vacuum conditions, be dried 5 hours, obtain ambrisentan crystal form V I.
Described crystal formation is carried out to PXRD analysis, take diffraction peak position (2 θ， units as °) and corresponding relative intensity thereof the percentage ratio of climax (with respect to) to represent, parameter is as follows:
Larger characteristic peak 2 θ angles (relative intensity): 8.94(100%), 12.34(36%), 14.14(30%), 17.86(39%), 18.24 (33%), 20.58(37%), 26.84(48%)
Less characteristic peak 2 θ angles (relative intensity): 13.10(24%), 15.22(22%), 18.90(23%), 24.28(25%), 27.52(21%), 36.66 (14%).
The present embodiment is for illustrating the preparation of ambrisentan crystal form V I of the present invention.
Get 500ml flask, add respectively 10g ambrisentan and 300ml dioxane, be heated to 50 ℃, the ultrasonic solution that makes becomes clarification, adds 15ml water, is naturally cooled to 20 ℃, sufficient standing crystallization.Filter, collect crystal and put into vacuum drying oven, under 40 ℃ of vacuum conditions, be dried 4 hours, obtain ambrisentan crystal form V I.
Described crystal formation is carried out to PXRD analysis, take diffraction peak position (2 θ， units as °) and corresponding relative intensity thereof the percentage ratio of climax (with respect to) to represent, parameter is as follows:
Larger characteristic peak 2 θ angles (relative intensity): 8.94(100%), 12.34(36%), 14.14(30%), 17.86(39%), 18.24 (33%), 20.58(37%), 26.84(48%)
Less characteristic peak 2 θ angles (relative intensity): 13.10(24%), 15.22(22%), 18.90(23%), 24.28(25%), 27.52(21%), 36.66 (14%).
Specifically ask for an interview Fig. 1 and Fig. 2.
The present embodiment is for illustrating the preparation of ambrisentan crystal form V I of the present invention.
Get 1L flask, add respectively 25g ambrisentan and 600ml dioxane, be heated to 100 ℃, stir and make solution become clarification, add 200ml water, be naturally cooled to 15 ℃, sufficient standing crystallization.Filter, collect crystal and put into vacuum drying oven, under 80 ℃ of vacuum conditions, be dried 5 hours, obtain ambrisentan crystal form V I.
Described crystal formation is carried out to PXRD analysis, take diffraction peak position (2 θ， units as °) and corresponding relative intensity thereof the percentage ratio of climax (with respect to) to represent, parameter is as follows:
Larger characteristic peak 2 θ angles (relative intensity): 8.94(100%), 12.34(36%), 14.14(30%), 17.86(39%), 18.24 (33%), 20.58(37%), 26.84(48%)
Less characteristic peak 2 θ angles (relative intensity): 13.10(24%), 15.22(22%), 18.90(23%), 24.28(25%), 27.52(21%), 36.66 (14%).
The present embodiment is for illustrating the preparation of ambrisentan crystal form V I of the present invention.
Get 3L flask, add respectively 50g ambrisentan and 1.5L dioxane, be heated to 100 ℃, stir and make solution become clarification, add 500ml water, be naturally cooled to 20 ℃, sufficient standing crystallization.Filter, collect crystal and put into vacuum drying oven, under 70 ℃ of vacuum conditions, be dried 5 hours, obtain ambrisentan crystal form V I.
Described crystal formation is carried out to PXRD analysis, take diffraction peak position (2 θ， units as °) and corresponding relative intensity thereof the percentage ratio of climax (with respect to) to represent, parameter is as follows:
Larger characteristic peak 2 θ angles (relative intensity): 8.94(100%), 12.34(36%), 14.14(30%), 17.86(39%), 18.24 (33%), 20.58(37%), 26.84(48%)
Less characteristic peak 2 θ angles (relative intensity): 13.10(24%), 15.22(22%), 18.90(23%), 24.28(25%), 27.52(21%), 36.66 (14%).
The present embodiment is for illustrating the preparation of ambrisentan crystal form V I of the present invention.
Get 5L flask, add respectively 100g ambrisentan and 3L dioxane, be heated to 100 ℃, stir and make solution become clarification, add 1L water, be naturally cooled to 15 ℃, sufficient standing crystallization.Filter, collect crystal and put into vacuum drying oven, under 80 ℃ of vacuum conditions, be dried 5 hours, obtain ambrisentan crystal form V I.
Described crystal formation is carried out to PXRD analysis, take diffraction peak position (2 θ， units as °) and corresponding relative intensity thereof the percentage ratio of climax (with respect to) to represent, parameter is as follows:
Larger characteristic peak 2 θ angles (relative intensity): 8.94(100%), 12.34(36%), 14.14(30%), 17.86(39%), 18.24 (33%), 20.58(37%), 26.84(48%)
Less characteristic peak 2 θ angles (relative intensity): 13.10(24%), 15.22(22%), 18.90(23%), 24.28(25%), 27.52(21%), 36.66 (14%).
The present embodiment is for illustrating the preparation of the tablet that contains ambrisentan crystal form V I of the present invention.
Technique:
Crystal formation and auxiliary material are crossed respectively to 100 mesh sieves standby.The crystal formation of first getting recipe quantity mixes with polyvinylpolypyrrolidone, the Microcrystalline Cellulose, the lactose that add successively again recipe quantity, fully mix, then add the 2% hypromellose aqueous solution to prepare in right amount softwood, 20 mesh sieves are granulated, 55 ℃ of dry about 1h, the whole grain of 18 mesh sieves, finally add Magnesium Stearate to mix, compressing tablet after mensuration active constituent content.
The present embodiment is for illustrating the preparation of the tablet that contains ambrisentan crystal form V I of the present invention.
Technique:
Crystal formation and auxiliary material are crossed respectively to 100 mesh sieves standby.The crystal formation of first getting recipe quantity mixes with croscarmellose sodium, the Microcrystalline Cellulose, the lactose that add successively again recipe quantity, fully mix, then add the 10% PVP K30 aqueous solution to prepare in right amount softwood, 20 mesh sieves are granulated, 55 ℃ of dry about 1h, the whole grain of 18 mesh sieves, finally add Magnesium Stearate and talcum powder to mix, compressing tablet after mensuration active constituent content.
The present embodiment is for illustrating the preparation of the tablet that contains ambrisentan crystal form V I of the present invention.
Technique:
Crystal formation and auxiliary material are crossed respectively to 100 mesh sieves standby.The crystal formation of first getting recipe quantity mixes with sodium carboxymethylstarch, the Microcrystalline Cellulose, the lactose that add successively again recipe quantity, fully mix, then add 10% starch slurry to prepare in right amount softwood, 20 mesh sieves are granulated, 55 ℃ of dry about 1h, the whole grain of 18 mesh sieves, finally add Magnesium Stearate and talcum powder to mix, compressing tablet after mensuration active constituent content.
The present embodiment is for illustrating the preparation of the tablet that contains ambrisentan crystal form V I of the present invention.
Technique:
Crystal formation and auxiliary material are crossed respectively to 100 mesh sieves standby.The crystal formation of first getting recipe quantity mixes with low-substituted hydroxypropyl methylcellulose, the Microcrystalline Cellulose, lactose, the pregelatinized Starch that add successively again recipe quantity, fully mix, then add 2% methylated cellulose aqueous solution to prepare in right amount softwood, 20 mesh sieves are granulated, 55 ℃ of dry about 1h, the whole grain of 18 mesh sieves, finally add Magnesium Stearate and silicon-dioxide to mix, compressing tablet after mensuration active constituent content.
The present embodiment is for illustrating the preparation of the tablet that contains ambrisentan crystal form V I of the present invention.
Technique:
Crystal formation and auxiliary material are crossed respectively to 100 mesh sieves standby.The crystal formation of first getting recipe quantity mixes with croscarmellose sodium, then adds successively Microcrystalline Cellulose, the lactose of recipe quantity, fully mixes, and then adds Magnesium Stearate to mix, compressing tablet after mensuration active constituent content.
comparative example 1
This comparative example is for illustrating the preparation of the tablet that contains background technology crystal formation I.
Technique:
According to the record in the embodiment 7 of patent WO2010091877, prepare its ambrisentan crystal formation I, its key step comprises: by 30.4g(1.32mol) Lithamide be dissolved in the DMF of 200ml, in water-bath, be heated to 20 ℃.In 20 minutes, dropwise add 120g(0.44mol) (2S)-2-hydroxy-3-methoxy-3,3-henyl propionic acid is dissolved in the solution of 750ml DMF.Then, in 20 minutes, dropwise add 90.3g(0.48mol) 4,6-dimethyl-2-(methylsulfonyl)-pyrimidine is dissolved in 500mlN, and the solution of dinethylformamide stirs gained mixture 17 hours.In mixture, add the water of 3000ml and the citric acid of 800ml 2M.The dichloromethane extraction reaction mixture of use 2000ml three times, the organic phase of then using dried over sodium sulfate gained to merge, removal of solvent under reduced pressure.Use 800ml Virahol and 2000ml water to carry out recrystallization to gained yellow oily residue, filter and obtain crystal (103.2g), washing, is dried, and obtains the crystal of needle-like.Be its ambrisentan crystal formation I.
Crystal formation I and auxiliary material are crossed respectively to 100 mesh sieves standby.The crystal formation of first getting recipe quantity mixes with polyvinylpolypyrrolidone, the Microcrystalline Cellulose, the lactose that add successively again recipe quantity, fully mix, then add the 2% hypromellose aqueous solution to prepare in right amount softwood, 20 mesh sieves are granulated, 55 ℃ of dry about 1h, the whole grain of 18 mesh sieves, finally add Magnesium Stearate to mix, compressing tablet after mensuration active constituent content.
test example 1
This test example is for measuring the solubleness of ambrisentan crystal form V I of the present invention.
Precision takes the about 10mg of ambrisentan crystal form V I of preparation in embodiment 5 and the about 10mg of ambrisentan crystal formation I as a comparison, be placed in respectively 100ml measuring bottle, add the about 60ml of deionized water, jolting approximately 20 minutes, add deionized water and be diluted to scale, shake up, getting supernatant liquor is 263nm at 200～400nm place mensuration maximum wavelength, at this wavelength, measures obtained the maximum absorption (ABS).The results are shown in following table 4.
The solubility test data of table 4 different crystal forms
| Sample | Claim sample (mg) | Concentration (mg/ml) | ABS absorption value |
| Crystal form V I of the present invention | 10.4 | 0.104 | 0.759 |
| Ambrisentan crystal formation I (contrast) | 10.4 | 0.104 | 0.722 |
Data from upper table 4, ambrisentan crystal form V I of the present invention is higher with respect to the solubleness of ambrisentan crystal formation I as a comparison, illustrates that crystal formation of the present invention has better solvability, and this is conducive to improve the bioavailability of effective constituent.
test example 2
This test example is for measuring the stability of ambrisentan crystal form V I of the present invention.
Ambrisentan crystal form V I of the present invention and ambrisentan crystal formation I are as a comparison carried out to influence factor test, under the super-humid conditions of illumination 4500 ± 500Lx, 60 ℃ of high temperature or relative humidity 92.5%, place 10 days respectively, with 0 day comparison outward appearance, impurity number and total impurities.
Chromatographic condition and the instrument below for HPLC, measured:
HPLC chromatographic condition:
Chromatographic column: C18,250mm * 4.6mm, 5um
Moving phase: methyl alcohol: water: acetic acid=85: 15: 0.25
Wavelength: 263nm
Flow velocity: 0.5ml/min
Sample size: 20uL
Column temperature: 30 ℃
Instrument:
Thermo AS 1000 automatic samplers
Series III liquid phase pump
Lab Alliance Chinese chromatographic working station
1. light durability test
The ambrisentan crystal form V I of preparation in embodiment 5 and ambrisentan crystal formation I as a comparison are evenly shared respectively to opening wide in culture dish, thickness≤5mm, adjustable range, making intensity of illumination is 4500 ± 500Lx, respectively at 5 days and sampling detection in 10 days, and contrast with the result of 0 day.The results are shown in Table 5.
Table 5 light durability testing data
Note: 22～26 ℃ of temperature variation, relative humidity variations 45～56%.
Known by the data in table 5, with respect to the 0th day, in illumination, the impurity number after 10 days only increased by 3 to ambrisentan crystal form V I of the present invention, and total impurities amount only increases by 0.07%, and the impurity number of crystal formation I has increased by 8, and total impurities amount has increased 0.19%.Visible, it is only the nearly 1/3 of crystal formation I that the impurity of crystal form V I of the present invention increases number, and its rate of deterioration is nearly 1/3 of crystal formation I.This illustrate ambrisentan crystal form V I of the present invention to the stability of illumination significantly better than crystal formation I.
2. thimble test
The ambrisentan crystal form V I of preparation in embodiment 5 and ambrisentan crystal formation I are as a comparison positioned over respectively in sealed junction crystal glass bottle, are placed in 60 ℃ of thermostatic drying chambers, respectively at 5 days and sampling detection in 10 days, and contrast with the result of 0 day.The results are shown in Table 6.
Table 6 thimble test data
Known by the data in table 6, with respect to the 0th day, the impurity number that ambrisentan crystal form V I of the present invention placed after 10 days under hot conditions only increased by 3, and the impurity number of crystal formation I has increased by 7.Visible, it is only the nearly 1/2 of crystal formation I that the impurity of crystal form V I of the present invention increases number, and its rate of deterioration is nearly 1/2 of crystal formation I.This illustrate ambrisentan crystal form V I of the present invention to the stability of hot conditions significantly better than crystal formation I.
3. high humidity stability test
The ambrisentan crystal form V I of preparation in embodiment 5 and ambrisentan crystal formation I as a comparison are evenly shared respectively to opening wide in culture dish, thickness≤5mm, be placed in the incubator of 25 ℃ of constant temperature, relative humidity 92.5% constant humidity, respectively at 5 days and sampling detection in 10 days, and contrast with the result of 0 day.The results are shown in Table 7.
Table 7 high humidity stability test data
Known by the data in table 7, with respect to the 0th day, the impurity number that ambrisentan crystal form V I of the present invention placed after 10 days under hot conditions only increased by 1, and the impurity number of crystal formation I has increased by 5.Visible, it is only the nearly 1/4 of crystal formation I that the impurity of crystal form V I of the present invention increases number, and its rate of deterioration is nearly 1/4 of crystal formation I.This illustrate ambrisentan crystal form V I of the present invention to the stability of super-humid conditions significantly better than crystal formation I.
test example 3
This test example is for measuring the dissolution rate curve of the pharmaceutical composition that the present invention contains crystal form V I.
According to dissolution method (two appendix XC of Chinese Pharmacopoeia version in 2010, the dissolution method three therapeutic methods of traditional Chinese medicine), get respectively each 5mg of tablet in tablet prepared in embodiment 9～13 and comparative example as a comparison 1, the pH6.8 phosphoric acid buffer 200ml of take is solvent, 50 revs/min of rotating speeds, operation in accordance with the law, respectively at 5, 10, 20, 30, 45, 60 minutes sampling and measuring, with the filter membrane of 0.8 μ m, filter, get subsequent filtrate 3ml as need testing solution, according to ultraviolet spectrometry light light-intensity method, at 264nm place, measure absorption value, data are in Table 8, data results is treated to full stripping curve and sees Fig. 3.
Dissolution determination condition:
Instrument: ZRS-8 medicament dissolution instrument, rotating speed: 50 revs/min
Measuring method: adopt ultraviolet spectrophotometry, detect wavelength 264nm
The full stripping curve measurement result of the tablet of table 8 embodiment 9～13 and comparative example 1
| Time (dividing) | 5 | 10 | 20 | 30 | 45 | 60 |
| |
54.20% | 72.30% | 80.20% | 88.30% | 92.70% | 96.40 |
| Embodiment | ||||||
| 10 | 48.20% | 78.20% | 83.40% | 92.10% | 96.70% | 99.30 |
| Embodiment | ||||||
| 11 | 44.50% | 56.20% | 74.90% | 82.80% | 90.30% | 95.20 |
| Embodiment | ||||||
| 12 | 41.20% | 55.70% | 70.40% | 78.20% | 87.20% | 93.70 |
| Embodiment | ||||||
| 13 | 60.40% | 80.60% | 88.40% | 93.50% | 97.20% | 99.50% |
| Comparative example 1 | 38.10% | 47.60% | 65.40% | 77.40% | 81.30% | 90.60% |
From table 8 data and Fig. 3, the full stripping curve of the medicinal composition tablets that the present invention is prepared is obviously better than the tablet (being the tablet of crystal formation I) of comparative example 1, and therefore the prepared tablet of ambrisentan crystal form V I of the present invention has better solubility property.
Although the present invention has carried out description to a certain degree, significantly, do not departing under the condition of the spirit and scope of the present invention, can carry out the suitable variation of each condition.Be appreciated that and the invention is not restricted to described embodiment, and be attributed to the scope of claim, it comprises the replacement that is equal to of described each factor.
Claims (11)
1. an ambrisentan crystal form V I, is characterized in that, in the X-ray powder diffraction spectrum that described crystal formation use Cu-K α radiation, 40KV, 100mA obtain, with 2 θ angles, represents, 8.94,12.34,14.14,17.86, there is characteristic peak at 18.24,20.58,26.84 places.
2. crystal formation according to claim 1, is characterized in that, the relative intensity of described each characteristic peak is followed successively by 100%, 36%, 30%, 39%, 33%, 37%, 48%.
3. crystal formation according to claim 1, is characterized in that, in the X-ray powder diffraction spectrum that described use Cu-K α radiation, 40KV, 100mA obtain, with 2 θ angles, represents, also 13.10,15.22, there is characteristic peak at 18.90,24.28,27.52,36.66 places.
4. crystal formation according to claim 3, is characterized in that, the relative intensity of described each characteristic peak is followed successively by 24%, 22%, 23%, 25%, 21%, 14%.
5. according to the crystal formation described in any one in claim 1 to 4, it is characterized in that, the X-ray powder diffraction spectrum that described crystal formation use Cu-K α radiation, 40KV, 100mA obtain as shown in Figure 1.
6. a method of preparing the ambrisentan crystal form V I described in any one in claim 1 to 5, is characterized in that, described method comprises:
1) according to the weight ratio of ambrisentan and dioxane, be 1:10～100, ambrisentan is dissolved in to dioxane, be heated to 40～100 ℃, adopt stirring or ultrasonic power to make solution clarification, obtain the dioxane solution of ambrisentan;
2) in the dioxane solution of the ambrisentan obtaining to step 1), add water, wherein the volume ratio of dioxane and water is 1～20:1, is cooled to below 30 ℃, place crystallization, filter and collect crystal, at 40～80 ℃, vacuum-drying is 3～5 hours, obtains ambrisentan crystal form V I.
7. method according to claim 6, is characterized in that, in step 1), the weight ratio of described ambrisentan and dioxane is 1:20～50; Preferably, be heated to 50～70 ℃.
8. according to the method described in claim 6 or 7, it is characterized in that step 2) in, the volume ratio of dioxane and water is 3～10:1; Preferably, be cooled to 15～30 ℃.
9. a pharmaceutical composition, is characterized in that, the ambrisentan crystal form V I in the claim 1 to 5 that described pharmaceutical composition comprises significant quantity described in any one or the ambrisentan crystal form V I preparing according to the method described in any one in claim 6 to 8.
10. pharmaceutical composition according to claim 9, is characterized in that, described pharmaceutical composition is solid orally ingestible; Preferably, described solid orally ingestible is tablet, capsule, granule; More preferably, described tablet is dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet.
Ambrisentan crystal form V I in 11. claims 1 to 5 described in any one, or the ambrisentan crystal form V I preparing according to the method described in any one in claim 6 to 8 is in the purposes for the preparation of in treatment pulmonary hypertension or high blood pressure disease.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109320463A (en) * | 2018-10-07 | 2019-02-12 | 威海贯标信息科技有限公司 | A kind of purification process of small grain size ambrisentan |
| CN109320464A (en) * | 2018-10-07 | 2019-02-12 | 威海贯标信息科技有限公司 | A kind of purification process of small grain size ambrisentan |
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| WO2010091877A2 (en) * | 2009-02-13 | 2010-08-19 | Ratiopharm Gmbh | Process for producing ambrisentan |
| WO2011114338A1 (en) * | 2010-03-15 | 2011-09-22 | Natco Pharma Limited | A process for the preparation of highly pure ambrisentan |
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| CN109320463A (en) * | 2018-10-07 | 2019-02-12 | 威海贯标信息科技有限公司 | A kind of purification process of small grain size ambrisentan |
| CN109320464A (en) * | 2018-10-07 | 2019-02-12 | 威海贯标信息科技有限公司 | A kind of purification process of small grain size ambrisentan |
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