CN109336881B - A kind of razaxaban crystal - Google Patents
A kind of razaxaban crystal Download PDFInfo
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- CN109336881B CN109336881B CN201811363494.4A CN201811363494A CN109336881B CN 109336881 B CN109336881 B CN 109336881B CN 201811363494 A CN201811363494 A CN 201811363494A CN 109336881 B CN109336881 B CN 109336881B
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Abstract
The invention belongs to pharmaceutical technology fields, specifically provide a kind of razaxaban formic acid solvent crystal form and its preparation method and application, razaxaban formic acid solvent crystal form prepared by the present invention, relative to existing razaxaban crystal, with preferable chemical stability, and dissolubility with higher and higher bioavilability.
Description
Technical field
The invention belongs to medical synthesis fields, and in particular to a kind of razaxaban crystal and its preparation method and application.
Background technique
Anticoagulation medicine razaxaban (Rivaroxaban), its chemical name is the chloro- nitrogen-of 5- ((5S) -2- oxygen -3- (-
4- (3- oxygen -4- morpholinyl) phenyl) -1,3- oxazolidine -5- base } methyl) -2- thiophene-carboxylic acid amides, molecular formula is
C19H18ClN3O5S, molecular weight 435.88.Structure is as follows:
Razaxaban (Rivaroxaban) is novel anticoagulant of the Bayer AG after research and development in 10 years, is a kind of advanced
Selectivity, the oral drugs of direct inhibiting factor Xa.The endogenous and external source of blood coagulation waterfall can be interrupted by inhibiting factor Xa
Sexual approach inhibits generation and the thrombosis of fibrin ferment.With bioavilability height, treatment spectrum of disease is wide, and dose-effect relationship is stablized,
Convenient oral, the low feature of bleeding risk.From in September, 2008 for the first time Canada listing after, at present the whole world 120 countries obtain
Batch.
There are polycrystalline state forms for razaxaban, and WO2007/039132 discloses crystal form I, crystal form II, crystal form III, nothing at present
Setting, hydrate, NMP and THF solvated compounds crystal form characterize data and their preparation method；CN02292332A report
The APO-A novel crystal forms of razaxaban；EP2573084A1 report razaxaban B1, B2 and crystal form E and each other mutually
The preparation method of conversion；CN104211693A reports IV crystal form of razaxaban.Razaxaban belongs to polycrystalline state compound, different
Razaxaban crystal form there is different stability, physical property, solubility etc., and these properties can directly affect bulk pharmaceutical chemicals
With the stability and bioavilability of preparation.But it still needs further improvement for the dissolubility and stability of existing crystal form.
Summary of the invention
In view of the deficiencies in the prior art, it is an object of the present invention to provide a kind of razaxaban crystal forms；Of the invention is another
One purpose is to provide a kind of preparation method of razaxaban crystal form；Of the invention a further object is provides a kind of razaxaban
Crystal form is preparing the purposes in anticoagulation medicine.
Particular technique content of the invention is as follows:
A kind of razaxaban crystal of such as Formulas I, the lenticular razaxaban is razaxaban formic acid solvent crystal, is made
With Cu-K α radiate, the X-ray diffraction spectrogram indicated with 2 θ at 3.5 ± 0.2 °, 4.8 ± 0.2 °, 7.1 ± 0.2 °, 7.8 ± 0.2 °,
8.9 ± 0.2 °, 9.7 ± 0.2 ° have characteristic peak；
Preferably, the razaxaban crystal is radiated using Cu-K α, the X-ray diffraction spectrogram indicated with 2 θ 3.5 ±
0.2 °, 4.8 ± 0.2 °, 7.1 ± 0.2 °, 7.8 ± 0.2 °, 8.9 ± 0.2 °, 9.7 ± 0.2 °, 13.1 ± 0.2 °, 15.8 ± 0.2 °,
19.5 ± 0.2 °, 22.4 ± 0.2 °, 26.5 ± 0.2 ° have characteristic peak.
Preferably, the razaxaban crystal is radiated using Cu-K α, the X-ray diffraction spectrogram indicated with 2 θ 3.5 ±
0.2 °, 4.8 ± 0.2 °, 7.1 ± 0.2 °, 7.8 ± 0.2 °, 8.9 ± 0.2 °, 9.7 ± 0.2 °, 11.9 ± 0.2 °, 13.1 ± 0.2 °,
14.4 ± 0.2 °, 15.8 ± 0.2 °, 19.5 ± 0.2 °, 19.8 ± 0.2 °, 21.7 ± 0.2 °, 22.4 ± 0.2 °, 25.5 ± 0.2 °,
26.5 ± 0.2 ° have characteristic peak.
Preferably, the razaxaban crystal is radiated using Cu-K α, and characteristic peak meets x-ray powder as shown in Figure 1
Diffraction spectrogram.
Preferably, the razaxaban crystal, crystallographic parameter is: anorthic system, chiral space group P-1；It is brilliant
Born of the same parents' parameter are as follows: a=9.1107 (6), b=9.4028 (7), c=24.7182 (2), α=96.1124 (6) °, β=94.4983
(6) °, γ=100.8370 (6) °, unit cell volume
A kind of benefit such as Formulas I cuts down the preparation method of his class's crystal, specifically includes the following steps:
Razaxaban crystal form I is added in formic acid, heating stirring to razaxaban crystal form I is completely dissolved, after slow cooling,
Filtering, is placed in small beaker, sealed membrane sealing, pricks hole, volatilizees, crystallizes, and filtering is dried under reduced pressure to obtain razaxaban formic acid solvent
Crystal.
Preferably, the benefit cuts down the preparation method of his class's crystal, 5~20:1 of mass volume ratio of razaxaban and formic acid,
Wherein quality is in terms of mg, and volume is in terms of ml.
Preferably, the benefit cuts down the preparation method of his class's crystal, dissolves by heating temperature are as follows: and 40~80 DEG C, heating time 1
~5h；The temperature that cools down is 0~25 DEG C.
A kind of razaxaban crystal such as Formulas I prepares the application of anticoagulation medicine as active constituent.
A kind of pharmaceutical composition, the composition contains razaxaban crystal of the present invention, and is mixed with other components.
Preferably, pharmaceutical composition of the invention the preparation method is as follows: using standard and conventional technique, make the present invention
Compound in conjunction with solid acceptable on galenic pharmacy or liquid-carrier, and be allowed to arbitrarily with it is acceptable auxiliary on galenic pharmacy
Auxiliary agent and excipient, which combine, is prepared into available dosage form.
Preferably, other components include the other active constituents, excipient, filler, dilution that can be used in combination
Agent, adhesive, disintegrating agent, lubricant etc..
It is further preferred that the diluent is selected from starch, sucrose, dextrin, lactose, microcrystalline cellulose, mannitol, sorbierite
One or more of；Described adhesive is selected from methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxymethyl cellulose
One or more of sodium, ethyl cellulose and povidone；The disintegrating agent is selected from carboxyrnethyl starch sodium, low substituted hydroxy-propyl fiber
One or more of element, cross-linked carboxymethyl cellulose sodium and crospovidone；The lubricant is selected from magnesium stearate, micro mist silicon
One or more of glue, talcum powder and lauryl sodium sulfate.
Preferably, the pharmaceutical composition is tablet, capsule, granule and pill etc..
The confirmation of crystal structure:
X-ray powder diffraction test equipment and test condition in razaxaban crystal form test of the present invention are as follows: Panaco
Empyrean X-ray powder diffraction instrument；Light source copper target, flat samples platform, BBHD input path, PZXCEL optical diffraction, electricity
45kv, electric current 40mA are pressed, divergent slit is 1/4 °, and antiscatter slits are 1 °, and it is 0.04rad, every step gate time that rope, which draws slit,
0.5s, 3~50 ° of scanning range.
Razaxaban crystal form of the present invention TGA/DSC heat analysis test condition are as follows: Mei Tele-support benefit TGA/DSC
Thermal analyzer (model: TGA/DSC3+), dynamic temperature section: 30~250 DEG C, the rate of heat addition: 10 DEG C/min, program segment gas N2,
Flow: 50ml/min, crucible: 40 μ l of aluminium crucible.As shown in Fig. 2, the razaxaban crystal form is detected through TGA/DSC 45.96
There are faint endothermic peak and faint weightlessness at DEG C, is caused by the solvent on razaxaban crystal form surface loses；137.39~
142.46 DEG C have strong endothermic peak and corresponding weightlessness 8.43%, to lose a molecule formic acid；Have at 231.74~233.98 DEG C
Strong endothermic peak is the fusing point of razaxaban crystal form I, so this razaxaban crystal form is razaxaban formic acid solvent crystal.
Razaxaban crystal form of the present invention X-ray single crystal diffraction test condition are as follows: XtaLAB Synergy of science
X-ray single crystal diffractometer；Light source copper target, temperature 293K, voltage 50kv, electric current 1mA, collection method are Orthogonal Method, sweep time
45min.Data collection is carried out using Cu-ka target ray scanning, further progress structure elucidation obtains X-ray single crystal diffraction figure
(SXRD), as shown in Figure 2.Its cell parameter be a=9.1107 (6), b=9.4028 (7), c=24.7182 (2), α=
96.1124 (6) °, β=94.4983 (6) °, γ=100.8370 (6) °, unit cell volumeFrom SXRD Fig. 3
In as can be seen that the razaxaban of a molecule contains the formic acid of a molecule in a structure cell, so judging that this crystal form cuts down sand for benefit
Class's formic acid solvent crystal form.
The 1. main peak XRD razaxaban formic acid solvent crystal I of table
Compared with prior art, present invention has an advantage that
1) razaxaban formic acid solvent crystal I provided by the present invention in water, 0.01mol/L hydrochloric acid, pH4.5 acetic acid
Be significantly higher than existing razaxaban crystal with the solubility in pH6.8 phosphate buffer, so as under gastric acid environment more
Adequately dissolution, to improve drug effect.
2) razaxaban formic acid solvent crystal I provided by the present invention either has under solid-state or solution state
There is preferable chemical stability, so as to preferably store.
3) the tablet medicine Fast Stripping of razaxaban formic acid solvent crystal I preparation provided by the present invention, so as to
Enough quick actings, inhibit generation and the thrombosis of fibrin ferment.
4) animal test results are shown: the tablet of razaxaban formic acid solvent crystal I preparation provided by the present invention can
Rat tail bleeding time and amount of bleeding are obviously increased, anticoagulant effect is significant.
Detailed description of the invention
Fig. 1: the X-ray powder diffraction pattern of razaxaban formic acid solvent crystal I.
Fig. 2: razaxaban formic acid solvent crystal I DSC-TGA figure.
Fig. 3: razaxaban formic acid solvent crystal I ORTEP figure.
Fig. 4: razaxaban formic acid solvent crystal I hydrogen bond figure.
Specific embodiment
Beneficial effects of the present invention are now further described by following embodiment, embodiment is only used for the purpose of illustration,
It does not limit the scope of the invention, while the obvious change and modification that those of ordinary skill in the art are made according to the present invention
It is also contained within the scope of the invention.
Prepared all samples crystallographic parameter all having the same and X-ray powder diffraction spectrogram in embodiment 1-5.
Embodiment 1:
1g razaxaban crystal form I is added in 100ml formic acid, the razaxaban formic acid solution of 10mg/ml is configured to, is heated
To 70 DEG C, stirring 2h razaxaban crystal form I is completely dissolved, and to after 10 DEG C, filtering is placed in small beaker, sealed membrane slow cooling
Hole is pricked in sealing, and volatilization crystallizes 3 days, and filtering, 50 DEG C are dried under reduced pressure to obtain razaxaban formic acid solvent crystal I.Yield:
98.1%, HPLC purity: 99.95%.
Embodiment 2:
1g razaxaban crystal form I is added in 50ml formic acid, the razaxaban formic acid solution of 20mg/ml is configured to, is heated
To 80 DEG C, stirring 2h razaxaban crystal form I is completely dissolved, and to after 25 DEG C, filtering is placed in small beaker, sealed membrane slow cooling
Hole is pricked in sealing, and volatilization crystallizes 2 days, and filtering, 50 DEG C are dried under reduced pressure to obtain razaxaban formic acid solvent crystal I.Yield:
96.2%, HPLC purity: 99.93%.
Embodiment 3:
1g razaxaban crystal form I is added in 200ml formic acid, the razaxaban formic acid solution of 5mg/ml is configured to, is heated
To 40 DEG C, stirring 2h razaxaban crystal form I is completely dissolved, and to after 0 DEG C, filtering is placed in small beaker slow cooling, sealed membrane envelope
Mouthful, hole is pricked, volatilization crystallizes 5 days, and filtering, 50 DEG C are dried under reduced pressure to obtain razaxaban formic acid solvent crystal I.Yield: 95.7%,
HPLC purity: 99.91%.
Embodiment 4:
1g razaxaban crystal form I is added in 33ml formic acid, the razaxaban formic acid solution of 30mg/ml is configured to, is heated
To 75 DEG C, stirring 3h razaxaban crystal form I is completely dissolved, and to after 30 DEG C, filtering is placed in small beaker, sealed membrane slow cooling
Hole is pricked in sealing, and volatilization crystallizes 2 days, and filtering, 50 DEG C are dried under reduced pressure to obtain razaxaban formic acid solvent crystal I.Yield:
92.6%, HPLC purity: 99.70%.
Embodiment 5:
1g razaxaban crystal form I is added in 20ml formic acid, the razaxaban formic acid solution of 50mg/ml is configured to, is heated
To 40 DEG C, stirring 2h razaxaban crystal form I is completely dissolved, and to after 25 DEG C, filtering is placed in small beaker, sealed membrane slow cooling
Hole is pricked in sealing, and volatilization crystallizes 2 days, and filtering, 50 DEG C are dried under reduced pressure to obtain razaxaban formic acid solvent crystal I.Yield:
90.7%, HPLC purity: 99.52%.
Embodiment 6: the preparation method of the tablet containing razaxaban formic acid solvent crystal I
(1) prescription
| Ingredient | Inventory |
| Razaxaban formic acid solvent crystal I | According to razaxaban meter 2g |
| Microcrystalline cellulose | 8 |
| Lactose | 5.58 |
| Croscarmellose sodium | 0.6 |
| Hydroxypropyl methylcellulose | 0.6 |
| Lauryl sodium sulfate | 0.1 |
| Magnesium stearate | 0.12 |
| It is made altogether | 200 |
(2) prepared by tablet
Tabletting is carried out using following technique.Pretreatment: razaxaban is micronized, spare.Binder is prepared: preparing 8%
Hydroxypropyl methylcellulose aqueous solution, it is spare.Premix: razaxaban, microcrystalline cellulose, lactose, cross-linked carboxymethyl cellulose are weighed
Sodium, lauryl sodium sulfate are uniformly mixed.Granulation: softwood processed, the granulation of 20 meshes.It is dry: 55~60 DEG C of dryings.Whole grain: 20 mesh
Sieve whole grain.Total mix: it is uniform that magnesium stearate total mix is added.Tabletting: diameter 6mm scrobicula stamping.
Bioavilability experiment: influence of the razaxaban formic acid solvent crystal I to rat Hemorrhage Model
(1) material
1. drug
I, (include razaxaban specification is 10.0mg to razaxaban piece (visiing auspicious appropriate), and Bayer Pharma AG production is criticized
Number BXHEB31), when administration, is dissolved to the stomach-filling liquid of required concentration using polyethylene glycol 400-ethyl alcohol-water (3: 1: 1), presses respectively
According to 2.5mgkg-1·d-1、1mg·kg-1·d-1Dosage stomach-filling.
II, investigational agent, the tablet including razaxaban γ cyclodextrin crystal obtained in comparative example 5 preparation, administration
When using polyethylene glycol 400-ethyl alcohol-water (3: 1: 1) be dissolved to the stomach-filling liquid of required concentration, respectively according to 2.5mgkg-1·d-1、1mg·kg-1·d-1Dosage stomach-filling.
III, investigational agent, the tablet including razaxaban formic acid solvent crystal I obtained in embodiment 1 preparation, administration
When using polyethylene glycol 400-ethyl alcohol-water (3: 1: 1) be dissolved to the stomach-filling liquid of required concentration, respectively according to 2.5mgkg-1·d-1、1mg·kg-1·d-1Dosage stomach-filling.
2. animal
Wistar rat, cleaning grade, male and female dual-purpose, 250~300g, Beijing Vital River Experimental Animals Technology Co., Ltd.
It provides, animal productiong licensing SCXK (capital) 2012-0001.
(2) method: influence of the razaxaban to rat tail bleeding time and amount of bleeding
Wistar rat, half male and half female are randomly divided into 7 groups by weight, i.e., control group (1 group), visit auspicious appropriate group (2 groups),
Razaxaban γ cyclodextrin group (2 groups), razaxaban formic acid solvent crystal I group (2 groups), every group 10.Visit auspicious appropriate group (2
Group), razaxaban γ cyclodextrin group (2 groups), razaxaban formic acid solvent crystal I group (2 groups), dosage is respectively 2.5,
1.0mg/kg, control group give isometric solvent, and administered volume is 1mL/100g weight.After 1.5h is administered in rat, adopt
With docking method measurement bleeding time and amount of bleeding, i.e., after rat tails cleaning and sterilizing, away from cutting rat-tail tail point portion 5mm at, so
The surface of a wound is placed in 37 DEG C of water-bath physiological saline of 1mL afterwards, records the time bled from docking portion to stopping, as bleeding time；
By protein content in colorimetric method for determining physiological saline, rat amount of bleeding is calculated.
(3) result: influence of the razaxaban to rat tail bleeding time and amount of bleeding
Rat is given visit auspicious appropriate, razaxaban γ cyclodextrin group, razaxaban formic acid solvent crystal I group after, dock out
There is different degrees of extension in the blood time, wherein giving the rat of the tablet of razaxaban formic acid solvent crystal I preparation, breaks
Tail bleeding time and more other two groups of amount of bleeding significantly extend and improve.It the results are shown in Table 2.
Influence of the 2 different crystal forms razaxaban of table to rat tail bleeding time and amount of bleeding
This experiment passes through the detection to rat tail bleeding time and amount of bleeding, the results showed that administration 2.5mg/Kg,
When 1.0mg/Kg, the tablet of razaxaban formic acid solvent crystalline substance I body preparation is given, rat bleeding time and amount of bleeding are than giving
It visits auspicious appropriate, razaxaban γ cyclodextrin tablet the rat bleeding time and amount of bleeding extends and improve 28%~59%, show this
The razaxaban formic acid solvent crystal I of invention preparation can effectively inhibit thrombin activity and thrombosis, with higher
Bioavilability.
Comparative example 1
Razaxaban crude product 10g is added in 50ml anhydrous formic acid, is heated with stirring to 30 DEG C, is filtered after clarification completely,
Obtain clear solution.150ml ethyl acetate, stirring and crystallizing are added dropwise into filtrate；Mixture, which is cooled to room temperature, to be placed in ice-water bath
Stirring and crystallizing 2h；Filtering.Filter cake is dried under reduced pressure in 45~55 DEG C to constant weight, obtains 9.2g white solid i.e. crystal form.Yield: 88%,
Purity: 97.8%.
Comparative example 2
2g razaxaban (crystal form I) is suspended in 13g formic acid, heating water bath mixture obtains solution to about 55 DEG C.Add
Enter 55g acetonitrile, mixture is cooled to room temperature, is then stored in suspension in refrigerator (+4 DEG C) overnight.Crystal is separated by filtration,
It is dried in vacuo (about 20mbar) overnight.Yield 1.6g, yield 72.4%: purity: 96.4%.
Comparative example 3
Razaxaban formic acid crystal 0.5g made from comparative example 2 is suspended in water, is stirred at room temperature about 1 hour, to
The NaOH solution of 1.25ml (1.2eq) 1M is added in suspension, 16h is stirred at room temperature in mixture, filters, and washes solid, takes out
15min is filtered, colourless wet crystalline solid is obtained, is razaxaban dihydrate.HPLC purity: 97.4%.
Comparative example 4
4.5g (10.32mmmol) razaxaban polymorphic I (HPLC purity: 99.6%) is dissolved in 9.5ml 2,2,2- tri-
In fluoroethanol (70~80 DEG C), 1.29g (10.15mmol) oxalic acid dihydrate is added in Xiang Shangshu hot solution.By solution in the temperature
Lower stirring 5min, reaction stirred is cooled to room temperature, and after 4h, filtration product is simultaneously dry with infrared lamp, and it is white to obtain 3.5g (64%)
Color solid is razaxaban-oxalic acid (1:1) eutectic.Purity: 97.5%.168-169 DEG C of fusing point.
Comparative example 5
1.56g (3.58mmol) razaxaban crystal form I is dissolved in 70-80 DEG C of 2,2,2 tfifluoroethyl alcohol (17.1ml) and distillation
In the mixed solution of water (3.6ml), 4.68g (3.61mmol) γ cyclodextrin is added into hot solution, stirs 5min in this temperature,
18ml methanol is added dropwise, mixture continues to stir 10min, then cool to room temperature.After for 24 hours, precipitated product is filtered to obtain.Yield
72.3%, HPLC purity: 93.9.
Comparative example 6
The solvent-laden razaxaban crude product (residual moisture content) of 2120g is suspended in 12kg acetic acid, is heated to
110~115 DEG C.Stirring acquired solution 10min is cooled to 20 DEG C after solution clarification filtration at this temperature.With suction
The product for filtering out precipitating, it is dry with acetic acid and water washing, obtain 1783g, yield 92.9%, purity: 93.7%.Fusing point: 230 DEG C.
Stability test
Study on the stability of the razaxaban formic acid crystal in solution state
The razaxaban formic acid dissolution of crystals Yu Shuizhong that Example is prepared, is placed in 25 DEG C for razaxaban solution
Environment in, stability of the razaxaban formic acid crystal under solution state is investigated, every two hours sampling and testings wherein impurity
Content, test result is shown in Table 3.
Stability test result of the 3 razaxaban aminic acid crystal of table under solution state
Known existing razaxaban crystal form, the content of total impurities is all as the extension of dissolution time is in increase tendency.Through
Test learns that for razaxaban formic acid crystalloid solution of the invention in 25 DEG C of environment, the purity and total impurities content of sample are equal
It does not substantially change；And 1 crystal form of comparative example to 6 crystal form of comparative example under identical condition, the content of total impurities is continuous
Increase, it can be seen that, compared to existing razaxaban crystal form, razaxaban formic acid crystal prepared by the present invention is in solution shape
There is preferable stability under state.
3.2 razaxaban temperature and humidity and exposure experiments to light
The razaxaban formic acid solvent compound crystal I that Example is prepared, referring to Chinese Pharmacopoeia bulk pharmaceutical chemicals and medicine
The method of the stability test guideline of object preparation investigates the stability of razaxaban formic acid dissolved compound crystal, test knot
Fruit is shown in Table 4.
Stability test result of the 4 razaxaban formic acid crystal of table under illumination, high temperature and super-humid conditions
Learn that the razaxaban formic acid crystal that the present invention is prepared is under conditions of illumination, high temperature and high humidity through test
Obvious variation do not occur for its purity, appearance, and 1 crystal form of comparative example to 6 crystal form of comparative example in identical experiment condition
Its lower purity is greatly reduced, and impurity content has obvious raising, that is, rotten situation occurs, it is seen that present invention preparation
Razaxaban formic acid crystal compared to existing crystal form have preferable chemical stability.
Dissolubility test
With reference to State Food and Drug Administration's import drugs registered standard.The preparation of acetate buffer: 2.99g is taken
Sodium acetate is placed in 1000ml water, adds 1.66ml glacial acetic acid and the 10%SDS solution of 20ml, with sodium hydroxide or glacial acetic acid tune
PH value is saved to 4.5 ± 0.1.900ml is dissolution medium.
Solubility of the measurement embodiment in water and difference pH solution respectively.Respectively measure 900ml medium (water,
0.01mol/L HCl solution, the acetate buffer solution of pH4.5, pH6.8 PBS) in cillin bottle, excessive drug is added, will be western
Woods bottle sealing is set 37 DEG C of constant temperature water baths and is stirred 1 hour, through 0.45 μm of membrane filtration, subsequent filtrate is taken to distinguish at the wavelength of 250nm
Absorbance is measured, its solubility is calculated by the absorbance of testing standard reference substance.
The solubility (μ g/ml) of 5 razaxaban formic acid crystal of table in different media
This experimental result is confirmed to be dissolved in different pH solution with the razaxaban aminic acid crystal of the application method preparation
Degree is above other crystal forms.It is verified, the application crystal forms obtained by various methods better than crystal form I, crystal form II, crystal form III, it is amorphous,
Hydrate, the crystal form of NMP, THF solvated compounds, crystal form B1, crystal form B2, crystal form E, APO-A crystal form and γ cyclodextrin crystal form.
Dissolution test
Dissolution determination
After embodiment product is prepared tablet according to former triturate prescription, measurement dissolution.
80 meshes are crossed, powder 10mg after sieving are weighed respectively, according to two annex XC second of " Chinese Pharmacopoeia " version in 2010
Method (paddle method) device, dissolution medium are respectively 900ml water, revolving speed 75rpm, and 37 DEG C of temperature.Respectively at 5,10,15,30,45min
2ml is sampled, sample crosses 0.22 μm of filter membrane, and sample introduction calculates dissolution rate in HPLC.It the results are shown in Table 6.
Stationary phase: using octadecylsilane chemically bonded silica as filler
Mobile phase: -60% water of 40% acetonitrile
Flow velocity: 1.0ml/min
Detection wavelength: 250nm
Column temperature: 25 DEG C
Dissolution percentage amounts/the % of the different razaxaban crystal form tablets of table 6 in water
The Dissolution of Tablet of the preparation of crystal form obtained by the application is higher than the Dissolution of Tablet of other crystal forms preparation.It is verified to be higher than
Crystal form I, crystal form II, crystal form III, crystal form IV, crystal form B1, crystal form B2, crystal form E, amorphous, APO-A crystal form, malonic acid eutectic,
Hydrate, NMP and THF solvated compounds.
Claims (10)
1. a kind of razaxaban crystal of such as Formulas I, which is characterized in that the lenticular razaxaban is razaxaban formic acid solvent
Change crystal, radiated using Cu-K α, the X-ray diffraction spectrogram indicated with 2 θ at 3.5 ± 0.2 °, 4.8 ± 0.2 °, 7.1 ± 0.2 °,
7.8 ± 0.2 °, 8.9 ± 0.2 °, 9.7 ± 0.2 ° have characteristic peak；
Formulas I.
2. razaxaban crystal as described in claim 1, which is characterized in that radiated using Cu-K α, the X-ray indicated with 2 θ
Diffraction spectrogram at 3.5 ± 0.2 °, 4.8 ± 0.2 °, 7.1 ± 0.2 °, 7.8 ± 0.2 °, 8.9 ± 0.2 °, 9.7 ± 0.2 °, 13.1 ±
0.2 °, 15.8 ± 0.2 °, 19.5 ± 0.2 °, 22.4 ± 0.2 °, 26.5 ± 0.2 ° have characteristic peak.
3. razaxaban crystal as described in claim 1, which is characterized in that radiated using Cu-K α, the X-ray indicated with 2 θ
Diffraction spectrogram at 3.5 ± 0.2 °, 4.8 ± 0.2 °, 7.1 ± 0.2 °, 7.8 ± 0.2 °, 8.9 ± 0.2 °, 9.7 ± 0.2 °, 11.9 ±
0.2 °, 13.1 ± 0.2 °, 14.4 ± 0.2 °, 15.8 ± 0.2 °, 19.5 ± 0.2 °, 19.8 ± 0.2 °, 21.7 ± 0.2 °, 22.4 ±
0.2 °, 25.5 ± 0.2 °, 26.5 ± 0.2 ° have characteristic peak.
4. razaxaban crystal as described in claim 1, which is characterized in that radiated using Cu-K α, characteristic peak meets such as figure
X-ray powder diffraction spectrogram shown in 1.
5. razaxaban crystal according to any one of claims 1-4, which is characterized in that its crystallographic parameter is: three is tiltedly brilliant
System, chiral space group P-1；Cell parameter are as follows: a=9.1107 (6), b=9.4028 (7), c=24.7182 (2), α=
96.1124 (6) °, β=94.4983 (6) °, γ=100.8370 (6) °, unit cell volume V=6358.6 (2)3。
6. the preparation method of razaxaban crystal as described in claim 1, which is characterized in that specific preparation step include: by
Razaxaban crystal form I is added in formic acid, and heating stirring to razaxaban crystal form I is completely dissolved, and after slow cooling, filtering is placed in
In small beaker, sealed membrane sealing pricks hole, volatilizees, crystallizes, and filtering is dried under reduced pressure to obtain razaxaban formic acid solvent crystal.
7. the preparation method of razaxaban crystal as claimed in claim 6, which is characterized in that the mass body of razaxaban and formic acid
Product is than being 5~20: 1, and wherein quality is in terms of mg, and volume is in terms of ml.
8. the preparation method of razaxaban crystal as claimed in claim 6, which is characterized in that dissolving by heating temperature is 40~80
DEG C, heating time is 1~5h；The temperature that cools down is 0~25 DEG C.
9. a kind of pharmaceutical composition, which is characterized in that it is brilliant that the composition contains any razaxaban of claim 1-5
Body, and it is mixed with other components.
10. pharmaceutical composition as claimed in claim 9, which is characterized in that the pharmaceutical composition is oral solid formulation,
For the oral solid formulation using any razaxaban crystal of claim 1-5 as effective component, being equipped with pharmacy can
The additive of receiving is prepared.
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