CN103772292B - A kind of ambrisentan DMSO cocrystallization thing and its preparation method and application - Google Patents
A kind of ambrisentan DMSO cocrystallization thing and its preparation method and application Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- 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
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Abstract
The invention provides a kind of ambrisentan DMSO cocrystallization thing, in the X-ray powder diffraction spectrum that described cocrystallization thing uses Cu-K α radiation to obtain, represent with 2 θ angles, 10.62,10.80,12.10,16.06,18.66,19.60,20.26,20.62,21.12,22.26,24.60,29.58, there is characteristic peak at 29.82 places.Additionally provide preparation this cocrystallization thing method, containing the pharmaceutical composition of described cocrystallization thing as activeconstituents, and this cocrystallization thing for the preparation for the treatment of pulmonary hypertension or high blood pressure disease in application.
Description
Technical field
The present invention relates to the new crystal of a kind of ambrisentan (Ambrisentan), be specifically related to a kind of methyl-sulphoxide (DMSO) cocrystallization thing of ambrisentan, and prepare the method for this cocrystallization thing, containing the pharmaceutical composition of described cocrystallization thing as activeconstituents, and this cocrystallization thing for the preparation for the treatment of pulmonary hypertension or high blood pressure disease in application.
Background technology
Chemistry (+)-(s)-2-[(4,6-dimethyl pyrimidine-2-base) oxygen base]-3-methoxyl group-3, the 3-henyl propionic acid by name of ambrisentan (Ambrisentan).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 reports a kind of crystal formation, and its preparation method is that ambrisentan crude product after recrystallization, filtration, washing, drying, is obtained crystal formation I in the isopropyl alcohol and water of specified proportion.
Patent WO2010091877 reports another kind of crystal formation, and its preparation method is that benzyl is taken off in the hydrogenation of ambrisentan benzyl ester catalysis, and filter catalyzer, filtrate is spin-dried for, and obtain ambrisentan crude product, in ether, recrystallization obtains crystal form II.
Report a kind of crystal formation in patent WO2011114338, its preparation method is with hydrochloric acid by the acidifying of ambrisentan salts solution, crystallization in water, after filtration, washing, drying, obtains crystal form II I.
Report a kind of crystal formation in patent WO2011004402, its preparation method says ambrisentan crude product recrystallization in second alcohol and water, filters, and use ethanol and water mixed liquid washing, drying obtains form IV.
Amorphous ambrisentan reporting a kind of novelty in patent CN201110114072.5 and preparation method thereof.
Contriver still wishes by seeking new ambrisentan crystal formation, has excellent physico-chemical property to obtain and is applicable to the crystal formation that extensive synthesis produces, simultaneously also for treating pulmonary hypertension at present or hypertensive medicine provides more material choice.
Summary of the invention
Therefore, the object of the invention is to overcome defect of the prior art, methyl-sulphoxide (DMSO) the cocrystallization thing of the ambrisentan that a kind of stability is better, solubleness is higher is provided, and prepare the method for this cocrystallization thing, containing the pharmaceutical composition of described cocrystallization thing as activeconstituents, and this cocrystallization thing for the preparation for the treatment of pulmonary hypertension or high blood pressure disease in application.
The invention provides a kind of ambrisentan DMSO cocrystallization thing, in the X-ray powder diffraction spectrum that described cocrystallization thing uses Cu-K α radiation to obtain, represent with 2 θ angles, 10.62,10.80,12.10,16.06,18.66,19.60,20.26,20.62,21.12,22.26,24.60,29.58, there is characteristic peak at 29.82 places.
According to cocrystallization thing of the present invention, wherein, in the X-ray powder diffraction spectrum that described cocrystallization thing uses Cu-K α radiation to obtain, represent with 2 θ angles, can also 11.00,24.14,25.88, there is characteristic peak at 30.10 places.
According to cocrystallization thing of the present invention, wherein, in the X-ray powder diffraction spectrum that described cocrystallization thing uses Cu-K α radiation to obtain, can in spacing d value be respectively
position have characteristic peak.
According to cocrystallization thing of the present invention, wherein, in the X-ray powder diffraction spectrum that described cocrystallization thing uses Cu-K α radiation to obtain, can also in spacing d value be respectively
position have characteristic peak.
According to cocrystallization thing of the present invention, wherein, the X-ray powder diffraction spectrum that described cocrystallization thing uses Cu-K α radiation to obtain can be as shown in Figure 1.
According to cocrystallization thing of the present invention, wherein, the infrared absorption spectrum of described cocrystallization thing is at 3428cm
-1, 2947cm
-1, 1721cm
-1, 1289cm
-1, 949cm
-1there is charateristic avsorption band at place.As preferably, the infrared absorption spectrum of described cocrystallization thing can be as shown in Figure 3.
According to cocrystallization thing of the present invention, wherein, described cocrystallization thing is at 40 ~ 250 DEG C, temperature rise rate 10 DEG C/min, uncaps, under the condition of nitrogen 40mL/min environment, record its maximum heat absorption to turn brilliant onset temperature and can be 131.99 DEG C, maximum endothermic melting peak onset temperature can be 180 DEG C.
Present invention also offers a kind of method preparing ambrisentan DMSO cocrystallization thing of the present invention, wherein, described method comprises:
1) be 1:5 ~ 50 according to the weight ratio of ambrisentan and methyl-sulphoxide, ambrisentan be dissolved in methyl-sulphoxide, be heated to 40 ~ 100 DEG C, adopt and to stir or ultrasonic power makes solution clarify, obtain the dimethyl sulfoxide solution of ambrisentan.
2) add water in the dimethyl sulfoxide solution of the ambrisentan obtained to step 1), wherein the volume ratio of methyl-sulphoxide and water is 1 ~ 20:1, is cooled to less than 30 DEG C, place crystallization, collecting by filtration crystal, vacuum-drying 3 ~ 5 hours at 40 ~ 80 DEG C, obtains ambrisentan DMSO cocrystallization thing.
According to method of the present invention, wherein, in step 1), the weight ratio of described ambrisentan and methyl-sulphoxide is 1:10 ~ 30.As preferably, be heated to 50 ~ 70 DEG C.
According to method of the present invention, wherein, step 2) in, the volume ratio of methyl-sulphoxide and water is 3 ~ 10:1.As preferably, be cooled to 15 ~ 30 DEG C.As more preferably, vacuum drying vacuum tightness is 300 ~ 3000Pa.
Present invention also offers a kind of pharmaceutical composition, wherein, the ambrisentan DMSO cocrystallization thing of the present invention that described pharmaceutical composition includes effective amount or the ambrisentan DMSO cocrystallization thing prepared according to method of the present invention.
Ambrisentan DMSO cocrystallization thing 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, lactose, starch, Microcrystalline Cellulose can be adopted as thinner; Gelatin, methylcellulose gum, hypromellose, polyvinylpyrrolidone, starch slurry etc. can be used as tackiness agent; Starch, Xylo-Mucine, carboxymethylstach sodium, low-substituted hydroxypropyl methylcellulose, polyvinylpolypyrrolidone, Microcrystalline Cellulose can be used as disintegrating agent; Talcum powder, micro-part of silica gel, stearin, calcium stearate or magnesium etc. can be used 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 comprises the following steps: by activeconstituents and carrier and disintegration additive composition mixture, then the aqueous solution of this mixture and tackiness agent, alcoholic or moisture alcoholic solution is made to carry out wet method or dry granulation in suitable equipment, dried particles, adds other disintegrating agent, lubricant and antisticking agent subsequently and makes suitable preparation.
Present invention also offers ambrisentan DMSO cocrystallization thing of the present invention, or the ambrisentan DMSO cocrystallization thing prepared according to method of the present invention for the preparation for the treatment of pulmonary hypertension or high blood pressure disease in purposes.
Ambrisentan DMSO cocrystallization thing of the present invention is effective in quite wide measures range, and the dosage taken clinical every day, within the scope of 2 ~ 50mg/ people, can divide once or administration for several times.The actual dosage taken should be decided according to relevant situation by doctor, and these situations comprise the physical state of patient, the route of administration of patient, the age, body weight, to the individual reaction of medicine and the severity of symptom etc.
Ambrisentan DMSO cocrystallization thing of the present invention has but is not limited to following beneficial effect:
1. compared with other crystal formations, the solubility property of ambrisentan DMSO cocrystallization thing of the present invention is better, be almost such as 2 times of the solubleness of ambrisentan crystal formation I, this obtains higher bioavailability by being conducive to cocrystallization thing of the present invention, has good medicinal characteristic.
2. compared with other crystal formations, ambrisentan DMSO cocrystallization thing of the present invention also has better light durability and high-temperature stability, and it is less that it preserves the lower impurity produced for a long time, thus has good storage performance, contribute to promoting medicine quality, ensure drug safety.
3. the preparation manipulation of ambrisentan DMSO cocrystallization thing 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 embodiment of the present invention in detail by reference to the accompanying drawings, wherein:
Fig. 1 shows the X-ray powder diffraction spectrum (PXRD) of the ambrisentan DMSO cocrystallization thing of embodiment 6.
Fig. 2 shows the result data X-ray powder diffraction spectrum of the ambrisentan DMSO cocrystallization thing of embodiment 6 being carried out to peak value retrieval.
Fig. 3 shows the infrared absorption spectrum (IR) of the ambrisentan DMSO cocrystallization thing of embodiment 6.
Fig. 4 shows the means of differential scanning calorimetry mensuration figure (DSC figure) of the ambrisentan DMSO cocrystallization thing of embodiment 6.
Embodiment
Further illustrate the present invention below by specific embodiment, but should be understood to, these embodiments are only used for the use specifically described more in detail, and should not be construed as limiting the present invention in any form.
General description is carried out to the material used in the present invention's test and test method in this part.Although for realizing many materials that the object of the invention uses and working method is well known in the art, the present invention still describes in detail as far as possible at this.It will be apparent to those skilled in the art that within a context, if not specified, material therefor of the present invention and working method are well known in the art.
With the following Examples, the condition determination of the present invention to crystal formation is as follows:
1.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,
2θ=3~50°
Pipe pressure: 40KV
Guan Liu: 100mA
Sweep velocity: 8 DEG C/min
Crystalline graphite monochromator
DS/SS=1°
RS:0.3mm
2. infrared absorption spectrum (IR):
Instrument: infrared absorption spectrometer
Model: ThermoNICOLETis5
Company: Tianjin Inst. of Materia Medica Institute of Analysis
Sample preparation: KBr compressing tablet
3. dsc (DSC):
Instrument: differential thermal analyzer
Model: METTLERTOLEDODSC822e/200
Company: Tianjin Inst. of Materia Medica Institute of Analysis
Temperature range: 40 ~ 250 DEG C
Heat-up rate: 10 DEG C/min
Uncap, nitrogen 40mL/min
embodiment 1
The present embodiment is for illustration of the preparation of ambrisentan DMSO cocrystallization thing of the present invention.
Get 50mL beaker, add 200mg ambrisentan and 1mL methyl-sulphoxide respectively, be heated to 50 DEG C, the ultrasonic solution that makes becomes clarification, adds 1mL water, Temperature fall to 30 DEG C, sufficient standing crystallization.Filter, collect crystal and put into vacuum drying oven, 50 DEG C, vacuum tightness under being the condition of 1000Pa dry 3 hours, obtain ambrisentan DMSO cocrystallization thing.
PXRD analysis is carried out to described cocrystallization thing, represents with 2 θ angles, about 10.62,10.80,12.10,16.06,18.66,19.60,20.26,20.62,21.12,22.26,24.60, there is characteristic peak at 29.58,29.82 places, also 11.00, and 24.14,25.88, there is characteristic peak at 30.10 places; Represent with spacing d value, in spacing d value be respectively
position have characteristic peak, can also in spacing d value be respectively
position have characteristic peak.
embodiment 2
The present embodiment is for illustration of the preparation of ambrisentan DMSO cocrystallization thing of the present invention.
Get 50mL beaker, add 500mg ambrisentan 25mL methyl-sulphoxide respectively, be heated to 40 DEG C, the ultrasonic solution that makes becomes clarification, adds 10mL water, Temperature fall to 15 DEG C, sufficient standing crystallization.Filter, collect crystal and put into vacuum drying oven, 60 DEG C, vacuum tightness under being the condition of 3000Pa dry 3 hours, obtain ambrisentan DMSO cocrystallization thing.
PXRD analysis is carried out to described cocrystallization thing, represents with 2 θ angles, about 10.62,10.80,12.10,16.06,18.66,19.60,20.26,20.62,21.12,22.26,24.60, there is characteristic peak at 29.58,29.82 places, also 11.00, and 24.14,25.88, there is characteristic peak at 30.10 places; Represent with spacing d value, in spacing d value be respectively
position have characteristic peak, can also in spacing d value be respectively
position have characteristic peak.
embodiment 3
The present embodiment is for illustration of the preparation of ambrisentan DMSO cocrystallization thing of the present invention.
Get 50mL beaker, add 1g ambrisentan 10mL methyl-sulphoxide respectively, be heated to 100 DEG C, stir and make solution become clarification, add 3mL water, Temperature fall to 15 DEG C, sufficient standing crystallization.Filter, collect crystal and put into vacuum drying oven, 60 DEG C, vacuum tightness under being the condition of 2000Pa dry 3 hours, obtain ambrisentan DMSO cocrystallization thing.
PXRD analysis is carried out to described cocrystallization thing, represents with 2 θ angles, about 10.62,10.80,12.10,16.06,18.66,19.60,20.26,20.62,21.12,22.26,24.60, there is characteristic peak at 29.58,29.82 places, also 11.00, and 24.14,25.88, there is characteristic peak at 30.10 places; Represent with spacing d value, in spacing d value be respectively
position have characteristic peak, can also in spacing d value be respectively
position have characteristic peak.
embodiment 4
The present embodiment is for illustration of the preparation of ambrisentan DMSO cocrystallization thing of the present invention.
Get 250mL flask, add 5g ambrisentan 100mL methyl-sulphoxide respectively, be heated to 70 DEG C, the ultrasonic solution that makes becomes clarification, adds 10mL water, Temperature fall to 20 DEG C, sufficient standing crystallization.Filter, collect crystal and put into vacuum drying oven, 40 DEG C, vacuum tightness under being the condition of 500Pa dry 5 hours, obtain ambrisentan DMSO cocrystallization thing.
PXRD analysis is carried out to described cocrystallization thing, represents with 2 θ angles, about 10.62,10.80,12.10,16.06,18.66,19.60,20.26,20.62,21.12,22.26,24.60, there is characteristic peak at 29.58,29.82 places, also 11.00, and 24.14,25.88, there is characteristic peak at 30.10 places; Represent with spacing d value, in spacing d value be respectively
position have characteristic peak, can also in spacing d value be respectively
position have characteristic peak.
embodiment 5
The present embodiment is for illustration of the preparation of ambrisentan DMSO cocrystallization thing of the present invention.
Get 500mL flask, add 10g ambrisentan 300mL methyl-sulphoxide respectively, be heated to 50 DEG C, the ultrasonic solution that makes becomes clarification, adds 15mL water, Temperature fall to 20 DEG C, sufficient standing crystallization.Filter, collect crystal and put into vacuum drying oven, 40 DEG C, vacuum tightness under being the condition of 500Pa dry 5 hours, obtain ambrisentan DMSO cocrystallization thing.
PXRD analysis is carried out to described cocrystallization thing, represents with 2 θ angles, about 10.62,10.80,12.10,16.06,18.66,19.60,20.26,20.62,21.12,22.26,24.60, there is characteristic peak at 29.58,29.82 places, also 11.00, and 24.14,25.88, there is characteristic peak at 30.10 places; Represent with spacing d value, in spacing d value be respectively
position have characteristic peak, can also in spacing d value be respectively
position have characteristic peak.
embodiment 6
The present embodiment is for illustration of the preparation of ambrisentan DMSO cocrystallization thing of the present invention.
Get 1L flask, add 25g ambrisentan 600mL methyl-sulphoxide respectively, be heated to 60 DEG C, stir and make solution become clarification, add 200mL water, Temperature fall to 15 DEG C, sufficient standing crystallization.Filter, collect crystal and put into vacuum drying oven, 80 DEG C, vacuum tightness under being the condition of 1500Pa dry 5 hours, obtain ambrisentan DMSO cocrystallization thing.
PXRD analysis is carried out to described cocrystallization thing, represents with 2 θ angles, about 10.62,10.80,12.10,16.06,18.66,19.60,20.26,20.62,21.12,22.26,24.60, there is characteristic peak at 29.58,29.82 places, also 11.00, and 24.14,25.88, there is characteristic peak at 30.10 places; Represent with spacing d value, in spacing d value be respectively
position have characteristic peak, can also in spacing d value be respectively
position have characteristic peak, specifically ask for an interview Fig. 1 and Fig. 2.
Carry out IR analysis, its spectrum is about 3428cm
-1, 2947cm
-1, 1721cm
-1, 1289cm
-1, 949cm
-1there is charateristic avsorption band at place, specifically asks for an interview Fig. 3.
Carry out dsc analysis, record its maximum heat absorption and turn brilliant onset temperature and can be 131.99 DEG C, maximum endothermic melting peak onset temperature can be 180 DEG C, specifically asks for an interview Fig. 4.
embodiment 7
The present embodiment is for illustration of the preparation of ambrisentan DMSO cocrystallization thing of the present invention.
Get 3L flask, add 50g ambrisentan 1.5L methyl-sulphoxide respectively, be heated to 100 DEG C, stir and make solution become clarification, add 500mL water, Temperature fall to 20 DEG C, sufficient standing crystallization.Filter, collect crystal and put into vacuum drying oven, 70 DEG C, vacuum tightness under being the condition of 500Pa dry 5 hours, obtain ambrisentan DMSO cocrystallization thing.
PXRD analysis is carried out to described cocrystallization thing, represents with 2 θ angles, about 10.62,10.80,12.10,16.06,18.66,19.60,20.26,20.62,21.12,22.26,24.60, there is characteristic peak at 29.58,29.82 places, also 11.00, and 24.14,25.88, there is characteristic peak at 30.10 places; Represent with spacing d value, in spacing d value be respectively
position have characteristic peak, can also in spacing d value be respectively
position have characteristic peak.
embodiment 8
The present embodiment is for illustration of the preparation of ambrisentan DMSO cocrystallization thing of the present invention.
Get 5L flask, add 100g ambrisentan 3L methyl-sulphoxide respectively, be heated to 100 DEG C, stir and make solution become clarification, add 1L water, Temperature fall to 15 DEG C, sufficient standing crystallization.Filter, collect crystal and put into vacuum drying oven, 80 DEG C, vacuum tightness under being the condition of 300Pa dry 5 hours, obtain ambrisentan DMSO cocrystallization thing.
PXRD analysis is carried out to described cocrystallization thing, represents with 2 θ angles, about 10.62,10.80,12.10,16.06,18.66,19.60,20.26,20.62,21.12,22.26,24.60, there is characteristic peak at 29.58,29.82 places, also 11.00, and 24.14,25.88, there is characteristic peak at 30.10 places; Represent with spacing d value, in spacing d value be respectively
position have characteristic peak, can also in spacing d value be respectively
position have characteristic peak.
embodiment 9
The present embodiment is for illustration of the preparation of the tablet containing ambrisentan DMSO cocrystallization thing of the present invention.
Technique:
Cocrystallization thing and auxiliary material are crossed 100 mesh sieves respectively for subsequent use.The cocrystallization thing first getting recipe quantity mixes with polyvinylpolypyrrolidone, add Microcrystalline Cellulose, the lactose of recipe quantity more successively, fully mix, then add the 2% hypromellose aqueous solution and prepare softwood in right amount, 20 mesh sieves are granulated, 55 DEG C of drying about 1h, the whole grain of 18 mesh sieve, finally add Magnesium Stearate to mix, compressing tablet after mensuration active constituent content.
embodiment 10
The present embodiment is for illustration of the preparation of the capsule containing ambrisentan DMSO cocrystallization thing of the present invention.
Technique:
Cocrystallization thing and auxiliary material are crossed 100 mesh sieves respectively for subsequent use.The cocrystallization thing first getting recipe quantity mixes with croscarmellose sodium, add Microcrystalline Cellulose, the lactose of recipe quantity more successively, fully mix, then add the 10% PVP K30 aqueous solution and prepare softwood in right amount, 20 mesh sieves are granulated, 55 DEG C of drying about 1h, the whole grain of 18 mesh sieve, finally add Magnesium Stearate and talcum powder mixes, encapsulated after measuring active constituent content.
test example 1
This test example is for measuring the solubleness of ambrisentan DMSO cocrystallization thing of the present invention.
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, be heated to 20 DEG C in a water bath.Dropwise 120g(0.44mol is added in 20 minutes) (2S)-2-hydroxy-3-methoxy-3,3-henyl propionic acid is dissolved in 750mlN, the solution of dinethylformamide.Then, in 20 minutes, dropwise adding 90.3g(0.48mol) 4,6-dimethyl-2-(methylsulfonyl)-pyrimidines are dissolved in 500mlN, the solution of dinethylformamide, stir gained mixture 17 hours.The water of 3000ml and the citric acid of 800ml2M is added in mixture.The dichloromethane extraction reaction mixture of use 2000ml three times, then uses the organic phase that dried over sodium sulfate gained merges, 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, dry, obtain the crystal of needle-like.Be its ambrisentan crystal formation I.
The ambrisentan DMSO cocrystallization thing that precision to take in embodiment 6 preparation is about 10mg and ambrisentan crystal formation I is as a comparison about 10mg, be placed in 100ml measuring bottle respectively, add deionized water and be about 60ml, jolting about 20 minutes, add deionized water and be diluted to scale, shake up, getting supernatant liquor at 200-400nm place mensuration maximum wavelength is 263nm, measures obtained the maximum absorption (ABS) at this wavelength.The results are shown in following table 1.
The solubility test data of table 1 different crystal forms
| Sample | Sample (mg) | Concentration (mg/ml) | ABS absorption value |
| DMSO cocrystallization thing of the present invention | 10.5 | 0.105 | 1.292 |
| Ambrisentan crystal formation I (contrast) | 10.4 | 0.104 | 0.722 |
Data from upper table 1, ambrisentan DMSO cocrystallization thing of the present invention is higher relative to the solubleness of ambrisentan crystal formation I as a comparison, both nearly one times of differences, illustrate that cocrystallization thing of the present invention has good solubility, and this is conducive to the bioavailability improving effective constituent.
test example 2
This test example is for measuring the stability of ambrisentan DMSO cocrystallization thing of the present invention.
Ambrisentan DMSO cocrystallization thing of the present invention and ambrisentan crystal formation I are as a comparison carried out influence factor test, places 10 days at illumination 4500LX or high temperature 60 DEG C respectively, compared outward appearance, impurity number and total impurities with 0 day.
Be below chromatographic condition and the instrument of HPLC mensuration:
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 DEG C
Instrument:
ThermoAS1000 automatic sampler
SeriesIII liquid phase pump
Spectia100 UV-detector
LabAlliance Chinese chromatographic working station
1. light durability test
The ambrisentan DMSO cocrystallization thing of preparation in embodiment 6 and ambrisentan crystal formation I as a comparison are evenly shared in unlimited culture dish respectively, thickness≤5mm, adjustable range, intensity of illumination is made to be 4500 ± 500Lx, detect respectively at 5 days and sampling in 10 days, and contrast with the result of 0 day.The results are shown in Table 2.
Table 2 light durability testing data
Note: temperature variation 22-26 DEG C, relative humidity variations 45-56%.
From the data in table 2, ambrisentan DMSO cocrystallization thing of the present invention is compared with ambrisentan crystal formation I, increase less at illumination rear impurity number, total impurities amount increases less, and this illustrates that ambrisentan DMSO cocrystallization thing of the present invention is more good to the stability of illumination.
2. thimble test
The ambrisentan DMSO cocrystallization thing of preparation in embodiment 6 and ambrisentan crystal formation I are as a comparison positioned in sealed junction crystal glass bottle respectively, are placed in 60 DEG C of thermostatic drying chambers, detect respectively at 5 days and sampling in 10 days, and contrast with the result of 0 day.The results are shown in Table 3.
Table 3 thimble test data
From the data in table 3, ambrisentan DMSO cocrystallization thing of the present invention is compared with ambrisentan crystal formation I, impurity number under the high temperature conditions increases less, and total impurities amount increases less, and this illustrates that ambrisentan DMSO cocrystallization thing of the present invention is more good to the stability of high temperature.
Although present invention has been description to a certain degree, significantly, under the condition not departing from the spirit and scope of the present invention, can carry out the suitable change 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 equivalent replacement of described each factor.
Claims (14)
1. an ambrisentan DMSO cocrystallization thing, is characterized in that, in the X-ray powder diffraction spectrum that described cocrystallization thing uses Cu-K α radiation to obtain, represents with 2 θ angles, 10.62,10.80,12.10,16.06,18.66,19.60,20.26,20.62,21.12,22.26,24.60,29.58, there is characteristic peak at 29.82 places, also 11.00, and 24.14, there is characteristic peak at 25.88,30.10 places, and described X-ray powder diffraction spectrum as shown in Figure 1.
2. cocrystallization thing according to claim 1, is characterized in that, the infrared absorption spectrum of described cocrystallization thing is at 3428cm
-1, 2947cm
-1, 1721cm
-1, 1289cm
-1, 949cm
-1there is charateristic avsorption band at place, and the infrared absorption spectrum of described cocrystallization thing as shown in Figure 3.
3. cocrystallization thing according to claim 1 and 2, it is characterized in that, described cocrystallization thing is at 40 ~ 250 DEG C, temperature rise rate 10 DEG C/min, uncap, under the condition of nitrogen 40mL/min environment, recording its maximum heat absorption, to turn brilliant onset temperature be 131.99 DEG C, and maximum endothermic melting peak onset temperature is 180 DEG C.
4. prepare a method for the ambrisentan DMSO cocrystallization thing according to any one of claims 1 to 3, it is characterized in that, described method comprises:
1) be 1:5 ~ 50 according to the weight ratio of ambrisentan and methyl-sulphoxide, ambrisentan be dissolved in methyl-sulphoxide, be heated to 40 ~ 100 DEG C, adopt and to stir or ultrasonic power makes solution clarify, obtain the dimethyl sulfoxide solution of ambrisentan;
2) add water in the dimethyl sulfoxide solution of the ambrisentan obtained to step 1), wherein the volume ratio of methyl-sulphoxide and water is 1 ~ 20:1, is cooled to less than 30 DEG C, place crystallization, collecting by filtration crystal, vacuum-drying 3 ~ 5 hours at 40 ~ 80 DEG C, obtains ambrisentan DMSO cocrystallization thing.
5. method according to claim 4, is characterized in that, in step 1), the weight ratio of described ambrisentan and methyl-sulphoxide is 1:10 ~ 30.
6. method according to claim 4, is characterized in that, in step 1), is heated to 50 ~ 70 DEG C.
7. the method according to any one of claim 4 to 6, is characterized in that, step 2) in, the volume ratio of methyl-sulphoxide and water is 3 ~ 10:1.
8. the method according to any one of claim 4 to 6, is characterized in that, step 2) in, be cooled to 15 ~ 30 DEG C.
9. the method according to any one of claim 4 to 6, is characterized in that, step 2) in, vacuum drying vacuum tightness is 300 ~ 3000Pa.
10. a pharmaceutical composition, is characterized in that, described pharmaceutical composition includes the ambrisentan DMSO cocrystallization thing according to any one of claims 1 to 3 of effective amount.
11. pharmaceutical compositions according to claim 10, is characterized in that, described pharmaceutical composition is solid orally ingestible.
12. pharmaceutical compositions according to claim 11, is characterized in that, described solid orally ingestible is tablet, capsule or granule.
13. pharmaceutical compositions according to claim 12, is characterized in that, described tablet is dispersible tablet, enteric coated tablet, chewable tablet or orally disintegrating tablet.
The purposes of ambrisentan DMSO cocrystallization thing according to any one of 14. claims 1 to 3 in the medicine for the preparation for the treatment of pulmonary hypertension or high blood pressure disease.
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