CN103923154B - The eutectic and preparation method of CDB-2914 - Google Patents
The eutectic and preparation method of CDB-2914 Download PDFInfo
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- CN103923154B CN103923154B CN201310015368.0A CN201310015368A CN103923154B CN 103923154 B CN103923154 B CN 103923154B CN 201310015368 A CN201310015368 A CN 201310015368A CN 103923154 B CN103923154 B CN 103923154B
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Abstract
The invention discloses class eutectic of 4,93,20 diketone of diene of the β of 17 α acetoxyl groups of CDB-2914 11 (4 N, N dimethylamino phenyl) 19 norpregnas one and preparation method thereof, and the pharmaceutical formulation containing above-mentioned eutectic.Gained eutectic stability of the invention is good, as medicinal, is produced in preparation with that will not occur the transformation of crystal formation during storing；Preparation method is simple and easy to do, easily realizes large-scale industrial production.
Description
Technical field
The present invention relates to organic chemistry filed and pharmaceutical field, there is provided 17 α of the CDB-2914-β of acetoxyl group-11-(4-
N, N- dimethylamino phenyl) two keto-acids of -19- norpregna -4,9- diene -3,20-（Ⅰ）A class eutectic and preparation method thereof,
And the pharmaceutical formulation containing above-mentioned eutectic.
Background technology
In May, 2009, European Union have approved a kind of novel emergency contraceptive CDB-2914, and the medicine is not only approved can be in nothing
120h (5d) medicine for oral administration after sexual intercourse or contraceptive failure is protected, and emergency contraception effect will not postpone and decline with administration time.Vinegar
Sour Ulipristal be approved so far in global range can after unprotect sexual intercourse or contraceptive failure 120h innerlich anwendens the first mouth
Emergency contraception is taken, with the potential benefit of more unexpected pregnancies can be prevented compared with Levonorgestrel.
Current document CN100354300C, which discloses CDB-2914, two kinds of crystal formations, and one of which is that isopropanol is semi-soluble
Agent compound, fusing point（DSC）About 156 DEG C, another crystal formation fusing point（DSC）About 189 DEG C.
The two kinds of crystal formations the reported at present wherein solvate of isopropanol half, containing substantial amounts of isopropanol, is not suitable for directly making
It is medicinal, simply an intermediate forms in purge process, another fusing point（DSC）189 DEG C of crystal formation, we are making a search
Shi Faxian, after being mixed with pharmaceutical adjunct magnesium stearate, it may occur that crystal transfer phenomenon, influences the stability of the quality of the pharmaceutical preparations, and hard
Fatty acid magnesium is conventional pharmaceutic adjuvant.
Pharmaceutical co-crystals are the medicine branch fields just risen recent years, are had after medicine formation eutectic many excellent
Point, such as increases the stability of drug crystal forms, is formed between active pharmaceutical ingredient and eutectic part after hydrogen bond, can be with water in its structure
The group of molecule formation hydrogen bond is occupied, so as to hinder the effect between medicine and water, reduces the hygroscopicity of medicine, also may be used
With the degraded for the medicine for preventing tool hydrolysis possibility；There is presently no document report for the eutectic morphology of CDB-2914.
The content of the invention
The present invention provides a kind of 17 α of CDB-2914-β of acetoxyl group-11-(4-N, N- dimethylamino phenyl)-19- and gone
The pregnant keto-acids of steroid -4,9- diene -3,20- two of first（Ⅰ）Eutectic.Present invention simultaneously provides the preparation method of above-mentioned eutectic.
The present invention also provides a kind of pharmaceutical formulation, contains above-mentioned eutectic.
The present invention is to be based on the deficiencies in the prior art, using Long carbon chain aliphatic acid or the salt of Long carbon chain aliphatic acid formation as eutectic
Part, develops thermodynamically stable CDB-2914 eutectic.This eutectic stable crystal form in production process, particularly with
When pharmaceutic adjuvant--magnesium stearate is mutually mixed, crystal formation will not change；CDB-2914 eutectic is characterized in：With Long carbon chain aliphatic acid or
Its salt is part formation eutectic, is formed after eutectic, its fusing point（DSC, 10K/min）196~209 DEG C, DSC detections can be increased to
In unimodal.Preparation can be made as bulk drug in CDB-2914 eutectic.
Long carbon chain aliphatic acid or the salt of Long carbon chain aliphatic acid formation, refer to the Long carbon chain fat in solid forms under normal temperature and pressure
Acid or its salt, preferably carbon number are 12 to 22, more preferably stearic acid（Octadecanoid acid）, palmitic acid（Hexadecanoic acid）、
Arachidic acid（Arachic acid）, the preferred magnesium stearate of form, the calcium stearate of salt.
Long carbon chain aliphatic acid or the salt of Long carbon chain aliphatic acid formation just can be automatically, slowly after being mixed with CDB-2914
Produce eutectic, but it is prepared by the mode that preferably CDB-2914 and part are recrystallized after DL or dissolved clarification in a solvent.
Long carbon chain aliphatic acid or the salt of Long carbon chain aliphatic acid formation are used as the preferred CDB-2914 of usage amount during part
The 2~10% of weight.
It is thus understood that the invention provides a kind of eutectic of CDB-2914, its physical property is than CDB-2914 more
It is stable, it can be produced at preparation with that will not occur the transformation of crystal formation during storing as medicinal, keep the steady of preparation crystal formation
It is fixed, it is the stable necessary condition of the quality of the pharmaceutical preparations, the preparation method of eutectic of the present invention is simple and easy to do, easily realizes large-scale industry
Metaplasia is produced, and is provided with great commercial application value.
Make further below by way of the above as the embodiment representated by some instantiations again to the present invention
Describe in detail, but this should not be interpreted as to the scope of above-mentioned theme of the invention and be limited only to following embodiment.
Brief description of the drawings
Fig. 1 schemes for the DSC of the gained CDB-2914 eutectic of embodiment 1
Fig. 2 is the X- diffraction patterns of the gained CDB-2914 eutectic of embodiment 1
Fig. 3 schemes for the DSC of the gained CDB-2914 eutectic of embodiment 2
Fig. 4 is the X- diffraction patterns of the gained CDB-2914 eutectic of embodiment 2
Fig. 5 schemes for the DSC of the gained CDB-2914 eutectic of embodiment 3
Fig. 6 schemes for the DSC of the gained CDB-2914 eutectic of embodiment 4
Fig. 7 is that the DSC of the CDB-2914 of embodiment 11 and pharmaceutic adjuvant--magnesium stearate compatibility experiments schemes
Fig. 8 is that the DSC of the CDB-2914 eutectic of embodiment 11 and pharmaceutic adjuvant--magnesium stearate compatibility experiments schemes
Embodiment
Embodiment 1
In CDB-2914 50g, 2.5g stearic acid, the absolute ethyl alcohol for adding to 500ml, 70 DEG C ~ 80 DEG C are heated to, it is molten
Clearly, water 1000ml is added, solid is separated out, 80 DEG C are stirred 20 minutes, filtering, appropriate hot wash；Dry, obtain white solid 50
Gram.Fusing point is detected：198~202 DEG C；DSC（10K/min）202.79 DEG C such as figure（1）, XRPD is as schemed（2）.
Embodiment 2
Ulipristal acetate 50g, magnesium stearate：5g（10%）, water 2000ml, together return stirring 8 hours.It is down to normal temperature,
Filtering, is dried；Obtain 49 grams of white powders.Fusing point is detected：196~198 DEG C；DSC（10K/min）202.8 DEG C such as figure（3）,
XRPD is as schemed（4）.
Embodiment 3
In CDB-2914 0.5g, 25mg calcium stearate, the absolute ethyl alcohol for adding to 5ml, 70 DEG C ~ 80 DEG C are heated to, it is molten
Clearly, water 10ml is added, solid is separated out, 80 DEG C are stirred 20 minutes, filtering, appropriate hot wash；Dry, obtain white solid 0.5
Gram.Fusing point is detected：198~202 DEG C；DSC（10K/min）203.2 DEG C such as figure（5）.
Embodiment 4
In CDB-2914 0.5g, 25mg palmitic acid, the absolute ethyl alcohol for adding to 5ml, 70 DEG C ~ 80 DEG C are heated to, dissolved clarification,
Water 10ml is added, solid is separated out, 80 DEG C are stirred 20 minutes, filtering, appropriate hot wash；Dry, obtain 0.5 gram of white solid.
Fusing point is detected：199~203 DEG C, 203.5 DEG C of DSC is as schemed（6）.
Embodiment 5
In CDB-2914 0.5g, 25mg magnesium palmitate, the absolute ethyl alcohol for adding to 5ml, 70 ~ 80 DEG C are heated to, dissolved clarification,
Water 10ml is added, solid is separated out, 80 DEG C are stirred 20 minutes, filtering, appropriate hot wash；Dry, obtain 0.5 gram of white solid.
Fusing point is detected：199~203 DEG C.
Embodiment 6
In CDB-2914 0.5g, 25mg arachidic acid, the absolute ethyl alcohol for adding to 5ml, 70 ~ 80 DEG C are heated to, dissolved clarification, plus
Enter water 10ml, separate out solid, 80 DEG C are stirred 20 minutes, filtering, appropriate hot wash；Dry, obtain 0.5 gram of white solid.It is molten
Point detection：197~202 DEG C.
Embodiment 7
In CDB-2914 0.5g, 25mg arachidic acid magnesium, the absolute ethyl alcohol for adding to 5ml, 70 ~ 80 DEG C are heated to, dissolved clarification,
Water 10ml is added, solid is separated out, 80 DEG C are stirred 20 minutes, filtering, appropriate hot wash；Dry, obtain 0.5 gram of white solid.
Fusing point is detected：197~202 DEG C.
Embodiment 8
CDB-2914 0.5g, 10mg dodecyl acid, in the absolute ethyl alcohol for adding to 5ml, are heated to 70 ~ 80 DEG C, molten
Clearly, water 10ml is added, solid is separated out, 80 DEG C are stirred 20 minutes, filtering, appropriate hot wash；Dry, obtain white solid 0.5
Gram.Fusing point is detected：197~202 DEG C.
Embodiment 9
In CDB-2914 0.5g, 10mg stearic acid, the absolute ethyl alcohol for adding to 5ml, 70 DEG C ~ 80 DEG C are heated to, dissolved clarification,
Water 10ml is added, solid is separated out, 80 DEG C are stirred 20 minutes, filtering, appropriate hot wash；Dry, obtain 0.5 gram of white solid.
Fusing point is detected：198~202 DEG C.
Embodiment 10
Pharmaceutical formulation
CDB-2914 eutectic（The product of embodiment one）46 grams
Microcrystalline cellulose（Filler）180 grams
Sodium carboxymethyl starch（Disintegrant）27 grams
Superfine silica gel powder（Glidant）3 grams
Magnesium stearate（Lubricant）1.5 gram
Preparation technology
Main ingredient crosses 200 mesh sieves, and filler, disintegrant cross 80 mesh sieves, and filler, the disintegrant mixing for weighing recipe quantity are equal
It is even, then the main ingredient of recipe quantity is well mixed with it according to the equivalent method of progressively increasing, the glidant and lubricant of recipe quantity is added, mixed
After closing uniformly, tabletting is produced.
Embodiment 11
Auxiliary material compatibility experiments are contrasted：
1g CDB-2914s (DSC, 189 DEG C) and 50mg magnesium stearates are mixed, the wetting of 0.5ml water, 80 DEG C of bakings is added
It is dry；DSC detections are as schemed（7）, except having peak at original 189 DEG C, 202 DEG C are partly had been converted into, there occurs that crystal formation is changed；
By 1g CDB-2914 eutectics（DSC, 202.8 DEG C, the product of embodiment 1）Mix, add with 50mg magnesium stearates
0.5ml water is soaked, 80 DEG C of drying；DSC detects 204 DEG C as schemed（8）, do not occur crystal formation conversion.
Embodiment 12
The influence factor contrast experiment of CDB-2914 and eutectic：
CDB-2914 hot test result（60℃）
As a result show, this product is placed 10 days under the conditions of 60 DEG C, the relevant material of CDB-2914 slightly has increase, acetic acid crow
The relevant material of Li Sita eutectics is basically unchanged, and illustrates that eutectic is more stable under the high temperature conditions.
CDB-2914 strong illumination result of the test（4500Lx±500Lx）
As a result show, CDB-2914 is placed 10 days under conditions of illumination 4500Lx ± 500Lx, relevant material is obvious
Increase, CDB-2914 eutectic is substantially less than normal compared with CDB-2914 about the increment of material, illustrates eutectic in illumination condition
Under it is more stable.
Liquid phase chromatogram condition：According to high performance liquid chromatography（Two D of annex V of Chinese Pharmacopoeia version in 2010）Determine, with 18
Alkyl silane bonded silica gel is filler；With acetonitrile-water（It is 5.0 with phosphorus acid for adjusting pH containing 0.03% triethylamine（60：40）For
Mobile phase；Flow velocity is 1.0ml/min；Detection wavelength is 306nm, and number of theoretical plate is calculated by CDB-2914 peak to be not less than
5000.Detection sensitivity is adjusted, the peak height for making principal component chromatographic peak is about the 5~10% of full scale；Precision measures test sample again
The μ l of solution 20, are injected separately into liquid chromatograph, 4 times of record need testing solution chromatogram to principal component peak retention time.
Claims (10)
1. a kind of eutectic of CDB-2914, it is characterised in that：
A, eutectic part are the salt of Long carbon chain aliphatic acid or the formation of Long carbon chain aliphatic acid；
B, the detection under conditions of DSC is with 10K/min, eutectic melting point are 196~209 DEG C.
Described Long carbon chain aliphatic acid or its salt carbon number formed are 12 to 22.
2. eutectic according to claim 1, it is characterised in that described Long carbon chain aliphatic acid or Long carbon chain aliphatic acid is formed
Salt refer to hexadecanoic acid i.e. palmitic acid or its salt.
3. eutectic according to claim 1, it is characterised in that described Long carbon chain aliphatic acid or Long carbon chain aliphatic acid is formed
Salt refer to octadecanoid acid i.e. stearic acid or its salt.
4. eutectic according to claim 1, it is characterised in that described Long carbon chain aliphatic acid or Long carbon chain aliphatic acid is formed
Salt refer to arachic acid i.e. arachidic acid or its salt.
5. eutectic according to claim 1, it is characterised in that described eutectic part is octadecanoid acid i.e. stearic acid.
6. eutectic according to claim 1, it is characterised in that described eutectic part is Dolomol i.e. magnesium stearate.
7. a kind of eutectic according to claim 1, it is characterized in that：The ratio of CDB-2914 weight is shared by eutectic part
2~10%.
8. the preparation method of eutectic according to claim 3, it is characterized in that：By CDB-2914 and 2~10% tristearin
Acid, is dissolved with ethanol, under stirring, adds water, separates out solid, is dried, is obtained eutectic.
9. the preparation method of eutectic according to claim 3, it is characterized in that：By CDB-2914 and 2~10% stearic acid
Magnesium, water is stirred together, more than 5 hours, is filtered, and is dried, is obtained eutectic.
10. a kind of pharmaceutical formulation, it is characterized in that containing the eutectic described in good grounds any one of claim 1~7.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102675395A (en) * | 2012-04-17 | 2012-09-19 | 常州市第四制药厂有限公司 | Polycrystal forms of ulipristal acetate and preparation method thereof |
| CN102727457A (en) * | 2011-04-08 | 2012-10-17 | 北京紫竹药业有限公司 | A stable ulipristal preparation |
| CN104902928A (en) * | 2012-11-08 | 2015-09-09 | Hra医药实验室 | Co-micronisation product comprising ulipristal acetate |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102727457A (en) * | 2011-04-08 | 2012-10-17 | 北京紫竹药业有限公司 | A stable ulipristal preparation |
| CN102675395A (en) * | 2012-04-17 | 2012-09-19 | 常州市第四制药厂有限公司 | Polycrystal forms of ulipristal acetate and preparation method thereof |
| CN104902928A (en) * | 2012-11-08 | 2015-09-09 | Hra医药实验室 | Co-micronisation product comprising ulipristal acetate |
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