CN116554255A - Preparation method and pharmaceutical composition of ulipristal acetate crystal form A - Google Patents
Preparation method and pharmaceutical composition of ulipristal acetate crystal form A Download PDFInfo
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- CN116554255A CN116554255A CN202310817792.0A CN202310817792A CN116554255A CN 116554255 A CN116554255 A CN 116554255A CN 202310817792 A CN202310817792 A CN 202310817792A CN 116554255 A CN116554255 A CN 116554255A
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- China
- Prior art keywords
- ulipristal acetate
- preparation
- crystal form
- ketone solvent
- ulipristal
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- OOLLAFOLCSJHRE-ZHAKMVSLSA-N ulipristal acetate Chemical group C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(OC(C)=O)C(C)=O)[C@]2(C)C1 OOLLAFOLCSJHRE-ZHAKMVSLSA-N 0.000 title claims abstract description 66
- 239000013078 crystal Substances 0.000 title claims abstract description 60
- 229960000499 ulipristal acetate Drugs 0.000 title claims abstract description 57
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 150000002576 ketones Chemical class 0.000 claims abstract description 14
- 238000003756 stirring Methods 0.000 claims abstract description 9
- 239000012043 crude product Substances 0.000 claims abstract description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000002441 X-ray diffraction Methods 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 4
- 238000000634 powder X-ray diffraction Methods 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003433 contraceptive agent Substances 0.000 description 2
- 230000002254 contraceptive effect Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000000583 progesterone congener Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 230000000708 anti-progestin effect Effects 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 239000003418 antiprogestin Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940096118 ella Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- YGSFNCRAZOCNDJ-UHFFFAOYSA-N propan-2-one Chemical compound CC(C)=O.CC(C)=O YGSFNCRAZOCNDJ-UHFFFAOYSA-N 0.000 description 1
- 229940075993 receptor modulator Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229960000200 ulipristal Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention belongs to the field of pharmaceutical chemistry, and discloses a preparation method and a pharmaceutical composition of ulipristal acetate crystal form A, wherein the preparation method comprises the following steps: under the condition of room temperature, the crude product of ulipristal acetate is dissolved in a ketone solvent, slowly added into water containing seed crystals under the condition of stirring, filtered and dried to obtain the ulipristal acetate crystal form A. The method has the advantages of simple operation, good repeatability and high yield, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method and a pharmaceutical composition of ulipristal acetate crystal form A.
Background
Ulipristal acetate is an orally active, selective progestogen receptor modulator that acts by high affinity binding to the human progestogen receptor and has the chemical structure:
。
presently, ulipristal acetate tablets (trade name: ella) have been marketed in the united states and europe, primarily for use as an emergency contraceptive for unprotected sexual life or within 5 days after known or suspected contraceptive failure.
The crystalline form has a large influence on the properties of the drug. Volume 35, 12, in the medical guide 2016, 1340-1347, discloses various forms of ulipristal acetate, of which forms A, D, G and K are considered to be relatively stable forms, wherein forms D, G and K are solvates and form a is a non-solvate, the most thermodynamically stable clinically acceptable form. However, it is very difficult to obtain a single crystal form a, for example, the ulipristal acetate prepared by various methods in patent US5929262 and CN102675395A, CN1753905A, CN102675395A is a mixed crystal of crystal form a and crystal form C, and the ulipristal acetate prepared by the method disclosed in patent CN102344478a is crystal form C. Only patent CN104418930B discloses a preparation method of a crystal form a with higher purity at present. The crystal forms disclosed in other patents or documents are mostly mistaken as purer crystal forms, but the mixed crystal of the crystal form A and the crystal form C or the crystal form C is obtained in practice. Therefore, the preparation of the relatively pure crystal form A of ulipristal acetate has great difficulty. The inventors tried to repeat the preparation method of patent CN104418930B, found that the method has not only poor repeatability, large solvent amount (30-60 volume), low yield, but also difficult industrial scale-up production. In practical operation, it is found that, as ulipristal acetate is a poorly water-soluble compound, the solubility in alcohol solvents is not large, and the more the amount of anti-solvent water is, the more the amount of alcohol-water mixed solvent is needed for ulipristal acetate. The inventor found that in the practical operation process of reproducing the embodiment of CN104418930B, the dissolution is difficult to reproduce by adopting the temperature rise of the alcohol aqueous solution with a certain proportion, and the filtered 'mechanical impurities' contain most of the difficult-to-dissolve ulipristal acetate, so that the final yield is less than 30%. Further researches show that the crystal form A can be transformed after being heated in alcohol water with a certain proportion above 45 ℃ for a long time, and the cooling rate can have a larger influence on the purity of the crystal form in the steps of subsequent cooling and the like. In addition, due to the fact that ulipristal acetate is easily degraded into impurities such as demethylated ulipristal acetate under the condition of high temperature. The process of heating and dissolving for crystal transformation has higher risk for impurity control of ulipristal acetate.
Therefore, the ulipristal acetate crystal form A prepared by the prior art has the technical problems of large solvent volume, low yield, poor repeatability and difficult industrial production, and specifically comprises the following problems: 1) The actual reproduction yield is far lower than the yield disclosed in the patent publication, and at least the crystallization conditions are difficult to realize, the operation is not easy, and the repeatability and the reproducibility are not good; 2) The rate of cooling may affect the purity of the resulting form a; 3) The long-time heating of the seed crystal a may turn into mixed crystals, and ulipristal acetate is easily hydrolyzed into other impurities by heating (journal 2014, 45 (12), 1176 of the chinese medical industry); 4) The volume of the solvent is large, which is not beneficial to industrial large-scale production and is not environment-friendly.
Therefore, the preparation method of the ulipristal acetate crystal form A needs to be improved to overcome the technical problems in the prior art. The inventors have made extensive studies and found an improved process for preparing ulipristal acetate form a.
Disclosure of Invention
In order to overcome the technical problems in the prior art, the invention aims to provide a preparation method of ulipristal acetate crystal form A. This process is an improvement over the process for the preparation of CN 104418930B. The method can obtain single ulipristal acetate crystal form A, is simple to operate, good in repeatability and high in yield, and is suitable for industrial production.
In order to achieve the purpose of the invention, the following implementation technical scheme is provided.
In one embodiment, the preparation method of the ulipristal acetate crystal form A comprises the steps of dissolving crude ulipristal acetate in ketones at room temperature, slowly adding the crude ulipristal acetate into water containing seed crystals under stirring, filtering, and drying to obtain the ulipristal acetate crystal form A, wherein the X-diffraction powder pattern of the crystal form A is 9.04 in 2 theta value、11.30、11.59、11.85、14.40、15.10、15.77、16.39、16.89、17.10、17.26、17.93、18.94、20.33、24.19±0.2 o There is a characteristic peak.
Preferably, in the preparation method of the present invention, the mass volume ratio of the ulipristal acetate to the ketone solvent is 1: (5-10) g/ml, more preferably 1: (5-8).
Preferably, according to the preparation method of the invention, the volume ratio of the ketone solvent to water is 1:3 to 1:1, more preferably 1: 2-1: 1.
preferably, the preparation method of the present invention, the ketone solvent is selected from one or more of acetone, butanone and methyl isobutyl ketone.
Preferably, according to the preparation method of the present invention, the seed crystal is used in an amount of 0.01 to 0.03 times, preferably 0.02 to 0.03 times, the mass of ulipristal acetate.
On the other hand, the invention also provides a pharmaceutical composition which contains the ulipristal acetate crystal form A prepared by the preparation method and a pharmaceutically acceptable carrier.
The invention also provides application of the ulipristal acid crystal form A prepared by the preparation method in preparation of medicines for antiprogestins or antiglucocorticoids.
In a specific embodiment, the invention relates to a preparation method of ulipristal acetate crystal form A, which comprises the following steps: under the condition of room temperature, the crude product of ulipristal acetate is dissolved in ketone solvent with the volume of 6-8 times, and under the condition of stirring, the crude product of ulipristal acetate is slowly added into water containing 0.02-0.03 times (the crude product of ulipristal acetate) of seed crystal, and the crystal form A of ulipristal acetate is obtained after filtering and drying. The obtained ulipristal acetate has X-diffraction powder pattern of crystal form A with 2 theta value of 9.04, 11.30, 11.59, 11.85, 14.40, 15.10, 15.77, 16.39, 16.89, 17.10, 17.26, 17.93, 18.94, 20.33, 24.19+ -0.2 o There is a characteristic peak.
The above preparation method of ulipristal acetate form a according to the invention, wherein the seed crystal is obtained by the method of example 1 of CN104418930B, is incorporated by reference in its entirety.
The term "volume amount" means that the volume amount of the solvent is a multiple of the mass of the solute, for example, 5 to 10 times the volume amount means that the volume amount (L or ml) of the ketone solvent is 5 to 10 times the mass (kg or g) of the solute ulipristal acetate.
The preparation method provided by the invention can be used for obtaining single ulipristal acetate crystal form A, is simple to operate, saves energy consumption, has good repeatability and high yield, and is suitable for industrial production.
The specific advantages are as follows:
1. the yield is high and is basically more than 90 percent;
2. the patent repeatability is good (the solubility of the crystal form A in water is beneficial to the stability of the crystal form A), and the anti-dissolution agent can always keep the crystal seeds and the precipitated crystal form in relatively more water;
3. the solution and the dripping are carried out at room temperature, the operation is easy, and hydrolysis impurities are not easy to generate in the aspect of impurities;
4. the volume of the solvent is relatively small, the waste water is less, the environment is protected, the crystallization is carried out at room temperature, the heating is not needed, the energy consumption is saved, the operation is easy, and the industrial large-scale production is easy.
Drawings
FIG. 1 is an XRPD pattern for ulipristal acetate form A obtained in example 1.
Detailed Description
The following examples are representative of the methods for preparing ulipristal acetate form a, for further explanation and understanding of the essence of the invention, but are not intended to limit the scope of the invention.
EXAMPLE 1 preparation of form A
Under the condition of room temperature, 500g of crude ulipristal acetate is added into 3L of acetone for dissolution, under the condition of stirring, the crude ulipristal acetate is slowly added into 3L of water containing 10g of seed crystal, the solution is filtered, and vacuum reduced pressure drying is carried out at 45-50 ℃ to obtain 453g of ulipristal acetate crystal form A, and the yield is 90.6%.
The X-ray powder diffraction pattern (XRPD pattern) of the resulting ulipristal acetate form a was measured using a Cu target X-ray powder diffractometer, see figure 1, with the 2 theta values and relative intensities I% of the characteristic peaks shown in table 1,
TABLE 12 theta values and relative intensity I% for ulipristal acetate form A
EXAMPLE 2 preparation of form A
300g of crude ulipristal acetate is added into 2.4L of acetone for dissolution at room temperature, slowly added into 2.5L of water containing 9g of seed crystal under stirring, filtered, and dried under vacuum and reduced pressure at 45-50 ℃ to obtain 279g of ulipristal acetate crystal form A with the yield of 93.0%. The X-ray powder diffraction pattern (XRPD pattern) of the resulting form a was measured and substantially in accordance with figure 1.
EXAMPLE 3 preparation of form A
200g of crude ulipristal acetate is added into 1L of butanone for dissolution at room temperature, slowly added into 3L of water containing 2g of seed crystal under stirring, filtered, and dried under vacuum and reduced pressure at 45-50 ℃ to obtain 191g of ulipristal acetate crystal form A with the yield of 95.5%.
EXAMPLE 4 preparation of form A
300g of crude ulipristal acetate is added into 1.5L of prepared ketone mixed solvent (V) Acetone (acetone) ：V Methyl isobutyl ketone =2:1), slowly adding into 2L of water containing 4g of seed crystal under stirring, filtering, and vacuum drying at 45-50 ℃ under reduced pressure to obtain 282g of ulipristal acetate crystal form A with the yield of 94.0%.
EXAMPLE 5 preparation of form A
Under the condition of room temperature, 500g of crude ulipristal acetate is added into 3.5L of methyl isobutyl ketone for dissolution, and under the condition of stirring, the crude ulipristal acetate is slowly added into 10.5L of water containing 12g of seed crystal, and is filtered, vacuum reduced pressure dried at 45-50 ℃ to obtain 482g of crystal form A ulipristal acetate, and the yield is 96.4%.
XRPD of form a obtained by the method of examples 2-5 was determined as in example 1 and its XRPD characteristics substantially in accordance with figure 1 over the error range.
The above embodiments are exemplary, and any simple modification and variation made within the spirit of the invention falls within the scope of the invention.
Claims (10)
1. A preparation method of ulipristal acetate crystal form A comprises the following steps: under the condition of room temperature, the crude product of ulipristal acetate is dissolved in a ketone solvent, and is slowly added into water containing seed crystals under the condition of stirring, filtered and dried, thus obtaining the ulipristal acetate crystal form A.
2. The preparation method of claim 1, wherein the mass-volume ratio of the ulipristal acetate to the ketone solvent is 1: (5-10) g/ml.
3. The preparation method of claim 2, wherein the mass-volume ratio of the ulipristal acetate to the ketone solvent is 1: (5-8) g/ml.
4. The preparation method according to claim 1, wherein the volume ratio of the ketone solvent to water is 1: 3-1:1.
5. The process according to claim 4, wherein the volume ratio of ketone solvent to water is 1: 2-1: 1.
6. the process of claim 1, wherein the form a has an X-ray diffraction powder pattern with 2 theta values of 9.04, 11.30, 11.59, 11.85, 14.40, 15.10, 15.77, 16.39, 16.89, 17.10, 17.26, 17.93, 18.94, 20.33, 24.19±0.2 o There is a characteristic peak.
7. The process according to any one of claims 1 to 5, wherein the ketone solvent is one or more selected from the group consisting of acetone, butanone and methyl isobutyl ketone.
8. The method according to claim 1, wherein the amount of the seed crystal is 0.01-0.03 times of the mass of ulipristal acetate.
9. The method according to claim 8, wherein the amount of the seed crystal is 0.02-0.03 times of the mass of ulipristal acetate.
10. A pharmaceutical composition comprising ulipristal acetate crystalline form a prepared by the method of any of claims 1-9 and a pharmaceutically acceptable carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310817792.0A CN116554255A (en) | 2023-07-05 | 2023-07-05 | Preparation method and pharmaceutical composition of ulipristal acetate crystal form A |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310817792.0A CN116554255A (en) | 2023-07-05 | 2023-07-05 | Preparation method and pharmaceutical composition of ulipristal acetate crystal form A |
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|---|---|---|---|
| CN202310817792.0A Pending CN116554255A (en) | 2023-07-05 | 2023-07-05 | Preparation method and pharmaceutical composition of ulipristal acetate crystal form A |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875629A (en) * | 2012-10-10 | 2013-01-16 | 苏州康润医药有限公司 | Synthetic method of ulipristal acetate |
| CN104418930A (en) * | 2013-08-23 | 2015-03-18 | 四川海思科制药有限公司 | High-purity ulipristal acetate |
| US20150246943A1 (en) * | 2012-09-28 | 2015-09-03 | Aska Pharmaceutical Co., Ltd. | Crystalline polymorphic form of ulipristal acetate |
| CN105294808A (en) * | 2015-09-28 | 2016-02-03 | 国家卫生计生委科学技术研究所 | Ulipristal acetate crystal G type substance as well as preparation method, composition and applications thereof |
-
2023
- 2023-07-05 CN CN202310817792.0A patent/CN116554255A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150246943A1 (en) * | 2012-09-28 | 2015-09-03 | Aska Pharmaceutical Co., Ltd. | Crystalline polymorphic form of ulipristal acetate |
| CN102875629A (en) * | 2012-10-10 | 2013-01-16 | 苏州康润医药有限公司 | Synthetic method of ulipristal acetate |
| CN104418930A (en) * | 2013-08-23 | 2015-03-18 | 四川海思科制药有限公司 | High-purity ulipristal acetate |
| CN105294808A (en) * | 2015-09-28 | 2016-02-03 | 国家卫生计生委科学技术研究所 | Ulipristal acetate crystal G type substance as well as preparation method, composition and applications thereof |
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