CN103923154A - Eutectic of ulipristal acetate and preparation method thereof - Google Patents
Eutectic of ulipristal acetate and preparation method thereof Download PDFInfo
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- CN103923154A CN103923154A CN201310015368.0A CN201310015368A CN103923154A CN 103923154 A CN103923154 A CN 103923154A CN 201310015368 A CN201310015368 A CN 201310015368A CN 103923154 A CN103923154 A CN 103923154A
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Abstract
The invention discloses a eutectic of ulipristal acetate 17alpha-acetoxy-11beta-(4-N, N-dimethylaminophenyl)-19-norpregna-4, 9-diene-3, 20-dione and a preparation method thereof, as well as a pharmaceutical preparation containing the eutectic. The eutectic obtained by the invention has good stability, and is free of crystal form transformation during preparation production and storage when it is for drug use. The preparation method is simple and practicable, and is easy to realize large-scale industrialized production.
Description
Technical field
The present invention relates to organic chemistry filed and pharmaceutical field, CDB-2914 17 α-acetoxyl group-11 β-(4-N is provided, N-dimethylamino phenyl)-19-norpregna-4,9-diene-3, class eutectic for 20-diketone formula I and preparation method thereof, and the medicinal preparations that contains above-mentioned eutectic.
Background technology
In May, 2009, European Union has ratified a kind of Novel emergency contraceptive bian CDB-2914, this medicine not only get permission can be after unprotect sexual intercourse or contraceptive failure 120h (5d) medicine for oral administration, and emergency contraception effect can not postpone decline with administration time.CDB-2914 be get permission in global range so far can be after unprotect sexual intercourse or contraceptive failure the oral emergency contraception of the first of 120h innerlich anwenden, having can be compared with the potential benefit of the more unexpected gestation of Levonorgestrel prevention.
Document CN100354300C discloses CDB-2914 at present two kinds of crystal formations, and wherein a kind of is Virahol half solvate, approximately 156 ℃ of fusing points (DSC), approximately 189 ℃ of another crystal formation fusing points (DSC).
Two kinds of crystal formations reporting are at present Virahol half solvate wherein, contain a large amount of Virahols, be not suitable for directly doing medicinal, be an intermediate forms in purge process, the crystal formation that another fusing point (DSC) is 189 ℃, we find when making a search, after mixing with pharmaceutical adjunct Magnesium Stearate, can there is crystal conversion phenomenon, affect the stability of the quality of the pharmaceutical preparations, and Magnesium Stearate be conventional pharmaceutical excipient.
Pharmaceutical co-crystals is the Yi Ge medicine branch field of just rising recent years, medicine can have many good qualities after forming eutectic, as increase the stability of drug crystal forms, between active pharmaceutical ingredient and eutectic part, form after hydrogen bond, can to form the group of hydrogen bond occupied with water molecules in its structure, thereby hindered the effect between medicine and water, reduced the water absorbability of medicine, also can prevent the degraded of the medicine of tool hydrolysis possibility; The eutectic morphology of CDB-2914 does not also have bibliographical information at present.
Summary of the invention
The invention provides a kind of CDB-2914 17 α-acetoxyl group-11 β-(4-N, N-dimethylamino phenyl)-19-norpregna-4,9-diene-3, the eutectic of 20-diketone formula I.The present invention provides the preparation method of above-mentioned eutectic simultaneously.
The present invention also provides a kind of medicinal preparations, contains above-mentioned eutectic.
The present invention is based on the deficiencies in the prior art, and the salt that long chain fatty acid or long chain fatty acid form of take is eutectic part, develops thermodynamically stable CDB-2914 eutectic.This eutectic is stable crystal form in preparation process, and while particularly mixing mutually with pharmaceutical excipient Magnesium Stearate, crystal formation can not change; The feature of CDB-2914 eutectic is: take long chain fatty acid or its salt as part forms eutectic, form after eutectic, its fusing point (DSC, 10K/min) can be increased to 196～209 ℃, and DSC detects and is unimodal.CDB-2914 eutectic can be used as bulk drug and makes preparation.
The salt that long chain fatty acid or long chain fatty acid form, refer to be under normal temperature and pressure long chain fatty acid or its salt of solid form, preferably carbonatoms is 12 to 22, more preferably stearic acid (octadecanoic acid), palmitinic acid (hexadecanoic acid), eicosanoic acid (arachic acid), the preferred Magnesium Stearate of form of salt, calcium stearate.
After the salt that long chain fatty acid or long chain fatty acid form mixes with CDB-2914, just can automatically, slowly produce eutectic, but prepared by preferred CDB-2914 and the part mode of DL or molten clearly rear recrystallization in solvent.
2～10% of the usage quantity preferred CDB-2914 weight of the salt that long chain fatty acid or long chain fatty acid form during as part.
Be appreciated that thus the eutectic that the invention provides a kind of CDB-2914, its physical property is more stable than CDB-2914, can be used as medicinal, in preparation production and storage process, can there is not the transformation of crystal formation, keeping the stable of preparation crystal formation, is the prerequisite that the quality of the pharmaceutical preparations is stable, and the preparation method of eutectic of the present invention is simple and easy to do, easily realize large-scale industrial production, and there is great commercial application value.
By the embodiment by some specific examples representatives, again foregoing of the present invention is described in further detail below, but this should be interpreted as to the scope of the above-mentioned theme of the present invention is only confined to following embodiment.
Accompanying drawing explanation
Fig. 1 is the DSC figure of embodiment 1 gained CDB-2914 eutectic
Fig. 2 is the X-diffractogram of embodiment 1 gained CDB-2914 eutectic
Fig. 3 is the DSC figure of embodiment 2 gained CDB-2914 eutectics
Fig. 4 is the X-diffractogram of embodiment 2 gained CDB-2914 eutectics
Fig. 5 is the DSC figure of embodiment 3 gained CDB-2914 eutectics
Fig. 6 is the DSC figure of embodiment 4 gained CDB-2914 eutectics
Fig. 7 is the DSC figure of embodiment 11 CDB-2914s and the experiment of pharmaceutical excipient Magnesium Stearate consistency
Fig. 8 is the DSC figure of embodiment 11 CDB-2914 eutectics and the experiment of pharmaceutical excipient Magnesium Stearate consistency
Embodiment
Embodiment 1
CDB-2914 50g, 2.5g stearic acid, adds in the dehydrated alcohol of 500ml, is heated to 70 ℃ ~ 80 ℃, molten clear, adds water 1000ml, separates out solid, and 80 ℃ are stirred 20 minutes, filter, appropriate hot wash; Dry, obtain 50 grams of white solids.Fusing point detects: 198～202 ℃; DSC(10K/min) 202.79 ℃ as figure (1), XRPD is as figure (2).
Embodiment 2
Ulipristal acetate 50g, Magnesium Stearate: 5g(10%), and water 2000ml, return stirring is 8 hours together.Be down to normal temperature, filter, dry; Obtain 49 grams of white powders.Fusing point detects: 196～198 ℃; DSC(10K/min) 202.8 ℃ as figure (3), XRPD is as figure (4).
Embodiment 3
CDB-2914 0.5g, 25mg calcium stearate, adds in the dehydrated alcohol of 5ml, is heated to 70 ℃ ~ 80 ℃, molten clear, adds water 10ml, separates out solid, and 80 ℃ are stirred 20 minutes, filter, appropriate hot wash; Dry, obtain 0.5 gram of white solid.Fusing point detects: 198～202 ℃; DSC(10K/min) 203.2 ℃ as figure (5).
Embodiment 4
CDB-2914 0.5g, 25mg palmitinic acid, adds in the dehydrated alcohol of 5ml, is heated to 70 ℃ ~ 80 ℃, molten clear, adds water 10ml, separates out solid, and 80 ℃ are stirred 20 minutes, filter, appropriate hot wash; Dry, obtain 0.5 gram of white solid.Fusing point detects: 199～203 ℃, and 203.5 ℃ of DSC as figure (6).
Embodiment 5
CDB-2914 0.5g, 25mg magnesium palmitate, adds in the dehydrated alcohol of 5ml, is heated to 70 ~ 80 ℃, molten clear, adds water 10ml, separates out solid, and 80 ℃ are stirred 20 minutes, filter, appropriate hot wash; Dry, obtain 0.5 gram of white solid.Fusing point detects: 199～203 ℃.
Embodiment 6
CDB-2914 0.5g, 25mg eicosanoic acid, adds in the dehydrated alcohol of 5ml, is heated to 70 ~ 80 ℃, molten clear, adds water 10ml, separates out solid, and 80 ℃ are stirred 20 minutes, filter, appropriate hot wash; Dry, obtain 0.5 gram of white solid.Fusing point detects: 197～202 ℃.
Embodiment 7
CDB-2914 0.5g, 25mg eicosanoic acid magnesium, adds in the dehydrated alcohol of 5ml, is heated to 70 ~ 80 ℃, molten clear, adds water 10ml, separates out solid, and 80 ℃ are stirred 20 minutes, filter, appropriate hot wash; Dry, obtain 0.5 gram of white solid.Fusing point detects: 197～202 ℃.
Embodiment 8
CDB-2914 0.5g, the acid of 10mg dodecyl, adds in the dehydrated alcohol of 5ml, is heated to 70 ~ 80 ℃, molten clear, adds water 10ml, separates out solid, and 80 ℃ are stirred 20 minutes, filter, appropriate hot wash; Dry, obtain 0.5 gram of white solid.Fusing point detects: 197～202 ℃.
Embodiment 9
CDB-2914 0.5g, 10mg stearic acid, adds in the dehydrated alcohol of 5ml, is heated to 70 ℃ ~ 80 ℃, molten clear, adds water 10ml, separates out solid, and 80 ℃ are stirred 20 minutes, filter, appropriate hot wash; Dry, obtain 0.5 gram of white solid.Fusing point detects: 198～202 ℃.
Embodiment 10
Medicinal preparations
46 grams of CDB-2914 eutectics (embodiment mono-product)
180 grams of Microcrystalline Celluloses (weighting agent)
27 grams of sodium starch glycolatees (disintegrating agent)
3 grams of micropowder silica gels (glidant)
1.5 grams of Magnesium Stearates (lubricant)
Preparation technology
Main ingredient is crossed 200 mesh sieves, and weighting agent, disintegrating agent are crossed 80 mesh sieves, and the weighting agent, the disintegrating agent that take recipe quantity mix, then the main ingredient of recipe quantity is mixed according to the equivalent method of progressively increasing with it, the glidant and the lubricant that add recipe quantity, after mixing, compressing tablet and get final product.
Embodiment 11
Auxiliary material consistency experiment contrast:
1g CDB-2914 (DSC, 189 ℃) and 50mg Magnesium Stearate are mixed, add 0.5ml water-wet, 80 ℃ of oven dry; DSC detects as figure (7), has located peak except original 189 ℃, and part has converted 202 ℃ to, and crystal formation conversion has occurred;
1g CDB-2914 eutectic (DSC, 202.8 ℃, embodiment 1 product) and 50mg Magnesium Stearate are mixed, add 0.5ml water-wet, 80 ℃ of oven dry; DSC detects 204 ℃ as figure (8), and crystal formation conversion does not occur.
Embodiment 12
The influence factor contrast experiment of CDB-2914 and eutectic:
CDB-2914 high temperature test result (60 ℃)
Result shows, this product is placed 10 days under 60 ℃ of conditions, and CDB-2914 related substance slightly increases, and CDB-2914 eutectic related substance is substantially constant, illustrates that eutectic is more stable under hot conditions.
CDB-2914 strong illumination test-results (4500Lx ± 500Lx)
Result shows, CDB-2914 is placed 10 days under the condition of illumination 4500Lx ± 500Lx, and related substance obviously increases, and the increment of CDB-2914 eutectic related substance is obviously less than normal compared with CDB-2914, illustrates that eutectic is more stable under illumination condition.
Liquid phase chromatogram condition: measuring according to high performance liquid chromatography (two appendix V D of Chinese Pharmacopoeia version in 2010), is weighting agent with octadecylsilane chemically bonded silica; With acetonitrile-water (containing 0.03% triethylamine, being 5.0(60:40 with phosphorus acid for adjusting pH) for moving phase; Flow velocity is 1.0ml/min; Detection wavelength is 306nm, and number of theoretical plate calculates and should be not less than 5000 by CDB-2914 peak.Regulate detection sensitivity, make the peak height of principal constituent chromatographic peak be about 5～10% of full range; Precision measures need testing solution 20 μ l again, and injection liquid chromatography, records need testing solution color atlas to 4 times of principal constituent peak retention time respectively.
Claims (11)
1.17 α-acetoxyl group-11 β-(4-N, N-dimethylamino phenyl)-19-norpregna-4,9-diene-3, the eutectic of 20-diketone formula I, is characterized in that:
A, eutectic part are the salt that long chain fatty acid or long chain fatty acid form;
B, eutectic melting point (DSC 10K/min) are at 196～209 ℃.
2. eutectic according to claim 1, is characterized in that the salt carbonatoms of described long chain fatty acid or its formation is 12 to 22.
3. eutectic according to claim 2, is characterized in that the salt that described long chain fatty acid or long chain fatty acid form refers to that hexadecanoic acid is palmitinic acid or its salt.
4. eutectic according to claim 2, is characterized in that the salt that described long chain fatty acid or long chain fatty acid form refers to that octadecanoic acid is stearic acid or its salt.
5. eutectic according to claim 2, is characterized in that the salt that described long chain fatty acid or long chain fatty acid form refers to that arachic acid is eicosanoic acid or its salt.
6. eutectic according to claim 1, is characterized in that described eutectic part is that octadecanoic acid is stearic acid.
7. eutectic according to claim 1, is characterized in that described eutectic part is that Dolomol is Magnesium Stearate.
8. a preparation method for eutectic according to claim 2, is characterized in that: the ratio of the shared compound weight of eutectic part is 2～10%.
9. the preparation method of eutectic according to claim 8, is characterized in that: by compound (I) and 2～10% stearic acid, with dissolve with ethanol, under stirring, adds water, separates out solid, and dry, obtain eutectic.
10. the preparation method of eutectic according to claim 8, is characterized in that: by compound (I) and 2～10% Magnesium Stearate, water, stirs together, more than 5 hours, filters, dry, obtains eutectic.
11. 1 kinds of medicinal preparationss, is characterized in that containing the eutectic described in good grounds claim 1～10.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN117903050A (en) * | 2024-03-15 | 2024-04-19 | 中国药科大学 | Aripiprazole co-crystal and pharmaceutical composition and application thereof |
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| CN102727457B (en) * | 2011-04-08 | 2014-05-28 | 华润紫竹药业有限公司 | A stable ulipristal preparation |
| CN102675395B (en) * | 2012-04-17 | 2014-04-30 | 常州市第四制药厂有限公司 | Polycrystal forms of ulipristal acetate and preparation method thereof |
| FR2997627B1 (en) * | 2012-11-08 | 2015-01-16 | Hra Pharma Lab | CO-MICRONIZATION PRODUCT COMPRISING ULIPRISTAL ACETATE |
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| CN117903050A (en) * | 2024-03-15 | 2024-04-19 | 中国药科大学 | Aripiprazole co-crystal and pharmaceutical composition and application thereof |
| CN117903050B (en) * | 2024-03-15 | 2024-05-17 | 中国药科大学 | Aripiprazole co-crystal and pharmaceutical composition and application thereof |
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