WO2013013595A1

WO2013013595A1 - Crystal of 17α-acetoxy-11β-(4-n,n-dimethylaminophenyl)-19-norpregna-4,9-dien- 3,20-dione and preparation process thereof

Info

Publication number: WO2013013595A1
Application number: PCT/CN2012/078909
Authority: WO
Inventors: 安晓霞; 吕峰; 申淑匣
Original assignee: 上海希迈医药科技有限公司; 江苏希迪制药有限公司
Priority date: 2011-07-22
Filing date: 2012-07-20
Publication date: 2013-01-31
Also published as: CN102344478A; CN102344478B

Abstract

Disclosed are a crystal of 17α-acetoxy-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-dien-3,20- dione, and the preparation process thereof. The crystal substantially has the powder X-ray diffraction pattern shown in Fig. 1. The preparation process of the crystal comprises providing an organic solvent solution of a CDB-2914 raw material, with the solution temperature being 30 - 55°C; reducing the temperature to 20 - 30°C, and adding an anti-solvent; and further reducing the temperature to 0 - 10 °C and crystallizing for 2 - 7 hours.

Description

Crystalline of 17α-acetoxy-11β-(4-anthracene-yttrium-dimethylaminophenyl)-19-norpregnathene-4,9-diene-3,20-dione and preparation thereof Method

Technical field

The present invention relates to 17α-acetoxy-11β-(4-indole-indole-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione (CDB-2914) A new type of crystal and a preparation method thereof. Background technique

CDB-2914 (Uliprisnil acetate), molecular formula C ₃ QH ₃₇ NO4, molecular weight 475.634, CAS number 126784-99-4, chemical name: 17α-acetoxy-11β-(4-Ν, Ν-dimethyl Aminophenyl)-19-norpregna-4,9-diene-3,20-dione, its chemical structural formula is as follows:

CDB-2914 is an emergency contraceptive drug jointly developed by the National Institute of Child Health and Human Development and the French H A Pharmaceutical Company. CDB-2914 (trade name ELLA) was approved in Europe in May 2009 and first in the UK, Germany and France on October 1. On August 13, 2010, the US Food and Drug Administration (FDA) approved the ELLA listing application.

In the patent US 4,954,490, the compound CDB-2914 and its synthesis method are disclosed.

Another method of synthesizing CDB-2914 is disclosed in U.S. Patent 5,929,262. In this patent, the final product obtained by the method described in Example 7 is described as a product in the form of a yellow crystal (referred to as Form A) having a melting point between 183 and 185 °C.

A crystalline form of CDB-2914 isopropanol hemisolvate (referred to as Form B) and a process for its preparation are disclosed in Chinese Patent No. 1,753,905. The DSC of this isopropanol hemisolvate crystal form showed a characteristic absorption peak at 156 °C. The isocratic characteristic peak of isopropanol hemisolvate crystal form 2 and its corresponding intensity (%) are shown in Table 1: Table 1

In addition, CN 1753905 also discloses XRD and DSC data for CDB-2914 Form A in US 5,929,262. The DSC plot of this Form A shows a characteristic absorption peak at 189 °C. The 2 特征 characteristic peak of Form A and the corresponding intensity (%) are shown in Table 2:

Table 2

The crystalline form 异丙 (isopropanol hemisolvate) is a solvate with poor thermal stability; the crystalline form has a low solubility and is not very stable. Summary of the invention

In order to overcome the above-mentioned drawbacks of the prior art, it is an object of the present invention to provide a novel crystal of CDB-2914 (referred to as Form C) and a process for its preparation.

The crystal of CDB-2914 of the present invention basically has the powder X-ray diffraction pattern shown in Fig. 1. Further, the crystal of CDB-2914 of the present invention basically has a DSC chart shown in Fig. 2, an IR chart shown in Fig. 3, and a TGA spectrum shown in Fig. 4.

Specifically, the crystal of CDB-2914 according to the present invention is subjected to powder X-ray diffraction at 2Θ

4.801. , 6.339°, 8.294°, 9.593°, 12.691°, 13.362°, 18.628°, 22.476°, 26.857. There are characteristic peaks; DSC spectrum shows a large absorption peak between 178~194 °C, the peak value is about 186.46 °C; the IR spectrum shows the wave number is 1662, 1610, 1560, 1518, 1458, 1438, 1369, 1349, 1255, 1233, 1202, 1169, 1148, 1092, 1062, 1016, 961, 948, 860, 826, 790, 770, 698, 670, 592, 528, and 494 cm- ¹ have absorption peaks; TGA spectra are shown at 20 There is no obvious weight loss step at ~200 °C.

A method for preparing a crystal of the CDB-2914, comprising the steps of:

a) Dissolving CDB-2914 raw material with an organic solvent, the dissolution temperature is 30~55 ° C (preferably 40~55 ° C); b) cooling to 20~30 ° C (preferably 20~25 ° C), adding anti Solvent

c) Continue to cool down to 0 to 10 ° C (preferably 5 to 7 ° C) and perform crystallization for 2 to 7 hours (preferably 2 to 3 hours).

The CDB-2914 starting material is any known crystal form.

The ratio of the CDB-2914 raw material to the organic solvent is 5~15 ml of organic solvent for the lg CDB-2914 raw material.

The anti-solvent is added in an amount of 2 to 30 ml of lg CDB-2914 starting material.

The organic solvent is a common organic solvent such as acetone, methanol, ethanol, n-butanol, isopropanol or ethyl acetate, and is preferably acetone.

The anti-solvent is water, n-hexyl hydrazine, n-heptane, isopropyl ether or methyl tert-butyl ether, and is preferably water. The crystal of CDB-2914 of the present invention, the XRD pattern of the crystal comprising 3 or more of the 2 Θ values selected from the group consisting of 4.801 ± 0.2. , 6.339±0.2. , 8.294 ± 0.2 °, 9.593 ± 0.2. , 12.691 ± 0.2. , 13.362 ± 0.2. , 18.628 ± 0.2. , 22.476 ± 0.2. And 26.857 ± 0.2. .

In another preferred embodiment, the differential scanning calorimetry (DSC pattern) of the crystal has a characteristic endothermic peak at 178 to 194 °C.

In another preferred embodiment, the crystals have substantially the DSC pattern shown in Fig. 2.

In another preferred embodiment, the crystallized product is prepared as follows, the method comprising the steps of: a) dissolving the CDB-2914 raw material with an organic solvent, and having a dissolution temperature of 30 to 55 ° C;

b) cooling to 20~30 ° C, adding anti-solvent;

c) Continue to cool down to 0~10 °C, and crystallization for 2 to 7 hours to obtain amorphous form of CDB-2914.

In another preferred embodiment, the ratio of the raw material of the CDB-2914 to the organic solvent is 5 to 15 ml of an organic solvent for the lg CDB-2914 raw material;

And / or the anti-solvent is added in an amount of lg CDB-2914 raw material is added 2~30ml;

In another preferred embodiment, the organic solvent is acetone, methanol, ethanol, n-butanol, isopropanol or Ethyl acetate, preferably acetone;

And / or the anti-solvent is water, n-hexyl, n-heptane, isopropyl ether or methyl tert-butyl ether, preferably water.

The pharmaceutical composition of the present invention, the composition comprising:

(a) a crystalline material according to the invention;

(b) a pharmaceutically acceptable carrier or excipient. The crystal of CDB-2914 provided by the invention (referred to as crystal form C) has the advantages of good thermal stability (decompression at 140 ° C for 8 hours, crystal form unchanged), stable storage, and good solubility, etc. It is suitable for preparation into a pharmaceutical preparation. In addition, the preparation method provided by the invention can obtain crystals of CDB-2914 with high yield (quality yield can reach more than 90%) and high purity (HPLC purity can reach 99.5%), and has simple operation and scale Advantages of implementation. DRAWINGS

Figure 1 is an XRPD spectrum of the crystal of CDB-2914 of the present invention;

Figure 2 is a DSC spectrum of the crystal of CDB-2914 of the present invention;

Figure 3 is an IR spectrum of the crystal of CDB-2914 of the present invention;

Figure 4 is a TGA spectrum of the crystal of CDB-2914 of the present invention. detailed description

The present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Example 1

Add 50 mL of acetone to lO.Og CDB-2914 (Form A), heat to 50 ° C, stir to completely dissolve the solid; cool to 25 ° C, slowly add 50 mL of water with stirring; then cool to 5~ At 10 ° C, crystals were precipitated, and after crystallization for 6 hours, it was filtered; and dried under reduced pressure at 60 ° C for 12 hours to obtain 9.7 g of white crystals, mass yield of 97%, and HPLC purity of 99.5%.

Taking a crystal sample of CDB-2914 obtained in this example, a radiation source having a wavelength aj of 1.5460 angstroms (A) and a wavelength α ₂ of 1.54439 angstroms (A), the intensity ratio α ₂ is 0.5, 40 kV and Powder X-ray Diffraction (XRPD) measured in a Dedye-Scherrer INEL CPS-120 device with 30 mA current intensity The spectrum is shown in Fig. 1. It can be seen from Fig. 1 that the crystal of the obtained CDB-2914 is 4.801°, 6.339°, 8.294 at 2Θ. , 9.593. , 12.691. , 13.362°, 18.628. , 22.476°, 26.857. There are characteristic peaks, and their specific characteristics are shown in Table 3:

table 3

Take the crystal sample of CDB-2914 prepared in this example, and in a closed container, pass a nitrogen stream of 50 ml/min at a temperature of 20 to 320 ° C, and the heating rate is 10 ° C / min, in DSC Q 2000. (TA company) The differential scanning calorimetry (DSC) spectrum measured in the equipment is shown in Figure 2. It can be seen from Figure 2 that the crystal of CDB-2914 produced has a ratio between 178 and 194 °C. The large absorption peak has a peak of about 186.46 °C. Taking the crystal sample of CDB-2914 prepared in this example, the infrared absorption spectrum (IR) spectrum measured in PE Spectrum RX equipment after tableting with potassium bromide at 24 and 40% humidity is shown in the figure. 3, wherein KBr blank is a blank control, as can be seen from Figure 3: The crystals of CDB-2914 produced are at wave numbers of 1662, 1610, 1560, 1518, 1458, 1438, 1369, 1349, 1255, 1233, There are absorption peaks at 1202, 1169, 1148, 1092, 1062, 1016, 961, 948, 860, 826, 790, 770, 698, 670, 592, 528 and 494 cm- ¹ .

A sample of the crystal of CDB-2914 prepared in this example was passed through a 100 ml/min nitrogen stream in a closed vessel at a temperature of 20 to 320 ° C at a heating rate of 10 ° C/min. (TA company) The thermogravimetric analysis (TGA) spectrum measured in the equipment is shown in Fig. 4. It can be seen from Fig. 4 that the crystal of CDB-2914 produced has no obvious weight loss step at 20~200 °C. , indicating that the crystal is an solvate. Example 2

Add 5.0 mL of acetone to 5.0 g of CDB-2914 (isopropanol hemisolvate), heat to 55 V, stir to completely dissolve the solid; cool down to 20 ° C, slowly add 60 mL of water with stirring; then cool to 5 At ~10 ° C, crystals were precipitated, and after crystallization for 5 hours, it was filtered; and dried under reduced pressure at 60 ° C for 12 hours to obtain 4.7 g of white crystals, mass yield of 94%, and HPLC purity of 99.5%.

The XRPD spectrum, DSC spectrum, IR spectrum and TGA spectrum of the crystal of CDB-2914 prepared in this example are shown in Figs. 1 to 4 . Example 3

Add 15mL of acetone to 2.0g CDB-2914 (Form A), heat to 45 ° C, stir to completely dissolve the solid; cool down to 30 ° C, slowly add 30mL of water under stirring; then cool down to 5~10 At °C, crystals were precipitated, and after crystallization for 3 hours, it was filtered; dried under reduced pressure at 60 ° C for 12 hours to obtain 1.8 g of white crystals, mass yield of 90%, HPLC purity of 99.54%.

The XRPD spectrum, DSC spectrum, IR spectrum of the crystal of CDB-2914 prepared in this example

The TGA spectrum is shown in Figures 1 to 4. Example 4

Add 5.0 mL of methanol to 5.0 g of CDB-2914 (isopropanol hemisolvate), heat to 40 V, stir to completely dissolve the solid; cool down to 25 ° C, slowly add 70 mL of water with stirring; then cool down After 5 to 10 ° C, crystals were precipitated, and after crystallization for 7 hours, it was filtered; and dried under reduced pressure at 60 ° C for 12 hours to obtain 4.6 g of white crystals, mass yield of 92%, and HPLC purity of 99.58%.

The XRPD spectrum, DSC spectrum, IR spectrum and TGA spectrum of the crystal of CDB-2914 prepared in this example are shown in Figs. 1 to 4 . Example 5

Add 5.0mL of ethanol to 5.0g CDB-2914 (Form A), heat to 50 ° C, stir to completely dissolve the solid; cool down to 25 ° C, slowly add 100 mL of water under stirring; then cool to 5 ~ 10 At °C, crystals were precipitated, and after crystallization for 5 hours, it was filtered; dried under reduced pressure at 60 ° C for 12 h to obtain 4.64 g of white crystals, mass yield of 92.8%, and HPLC purity of 99.25%.

The XRPD spectrum, DSC spectrum, IR spectrum and TGA spectrum of the crystal of CDB-2914 prepared in this example are shown in Figs. 1 to 4 . Example 6

Add 5.0 mL of isopropanol to 5.0 g of CDB-2914 (isopropanol hemisolvate), heat to 40 ° C, stir to completely dissolve the solid; cool down to 20 ° C, slowly add 75 mL of isopropyl ether with stirring Then, the temperature was lowered to 0 to 5 ° C, crystals were precipitated, and after crystallization for 6 hours, it was filtered; and dried under reduced pressure at 60 ° C for 12 hours to obtain 4.52 g of white crystals, mass yield was 90.4%, and HPLC purity was 99.27%.

The XRPD spectrum, DSC spectrum, IR spectrum and TGA spectrum of the crystal of CDB-2914 prepared in this example are shown in Figs. 1 to 4 . Example 7

Add 5.0 mL of n-butanol to 5.0 g of CDB-2914 (Form A), heat to 55 ° C, stir to completely dissolve the solid; cool to 20 ° C, slowly add 100 mL of methyl tert-butyl ether with stirring Then, the temperature was lowered to 0 to 5 ° C, crystals were precipitated, and after crystallization for 7 hours, it was filtered; and dried under reduced pressure at 60 ° C for 12 hours to obtain 4.59 g of white crystals, mass yield of 91.8%, and HPLC purity of 99.44%.

The XRPD spectrum, DSC spectrum, IR spectrum and TGA spectrum of the crystal of CDB-2914 prepared in this example are shown in FIGS. 1 to 4. Example 8 Add 5.0 mL of ethyl acetate to 5.0 g of CDB-2914 (Form A), heat to 30 ° C, stir to completely dissolve the solid; cool down to 20 ° C, slowly add 70 mL of hexamethylene under stirring; then cool down to 5 to 10 ° C, crystals were precipitated, and after crystallization for 2 hours, it was filtered; dried under reduced pressure at 60 ° C for 12 h to obtain 4.65 g of white crystals, mass yield of 93%, HPLC purity of 99.50%.

The TGA spectrum is shown in Figures 1 to 4. Example 9

Add 5.0 mL of ethyl acetate to 5.0 g of CDB-2914 (isopropanol hemisolvate), heat to 50 ° C, stir to completely dissolve the solid; cool to 25 ° C, slowly add 50 mL of isopropyl ether with stirring Then, the temperature was lowered to 5 to 10 ° C, and crystals were precipitated, and after crystallization for 7 hours, the mixture was filtered; and dried under reduced pressure at 60 ° C for 12 hours to obtain 4.55 g of white crystals. The mass yield was 91.0%, and the HPLC purity was 99.15%.

The XRPD spectrum, DSC spectrum, IR spectrum and TGA spectrum of the crystal of CDB-2914 prepared in this example are shown in Figs. 1 to 4 . Example 10 Stability Experiment

The crystals of CDB-2914 obtained in the above examples were dried under reduced pressure at 140 ° C for 8 hours and then dried under vacuum for 15 hours. The sample was analyzed by XRPD, DSC, IR and TGA. The crystal form of the product after heat treatment did not change. The XRPD spectrum, DSC spectrum, IR spectrum and TGA spectrum are shown in Figure 1 to Figure 4. The crystal of CDB-2914 produced was thermally stable. Example 11 Solubility test

An excess of known crystals (Form A) and a sample of the new crystals (Form C) of the present invention were taken and added to 0.5 ml of water, respectively, and then dispersed and dissolved by ultrasonic operation for several minutes (about 3 minutes). After standing at room temperature for 30 min, the supernatant was separated by centrifugation; the concentration of the sample in the supernatant (defined as apparent solubility) was determined by HPLC, and the results are shown in Table 4.

Table 4 Solubility test results

Sample apparent solubility (mg/ml)

Crystalline (Form C) 0.000250

Crystalline (Form A) 0.000125 As can be seen from Table 4, the new crystal (crystal form C) of CDB-2914 of the present invention has a solubility which is twice as high as that of the known crystal form (crystal form A), and has excellent solubility. Example 12 Pharmaceutical Composition

Take 100 g of the new crystal of CDB-2914 prepared in any of Examples 1 to 9 (Form C), and 4 times the weight

Claims

Rights request

1. A 17α-acetoxy-11β-(4-indole-indole-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione (CDB-2914) The crystal of the film is characterized by having substantially the powder X-ray diffraction spectrum shown in Fig. 1.

The crystal of CDB-2914 according to claim 1, which has substantially the DSC chart shown in Fig. 2, the IR pattern shown in Fig. 3, and the TGA spectrum shown in Fig. 4.

3. A method of preparing a crystal of CDB-2914 according to claim 1, comprising the steps of:

a) dissolving CDB-2914 raw material with an organic solvent, the dissolution temperature is 30~55 ° C;

b) cooling to 20~30 ° C, adding anti-solvent;

c) Continue to cool down to 0~10 °C and perform crystallization for 2~7 hours.

The method for producing a crystal of CDB-2914 according to claim 3, wherein the material of the CDB-2914 is any known crystal form.

The method for producing a crystal of CDB-2914 according to claim 3, wherein the ratio of the raw material of the CDB-2914 to the organic solvent is 5 to 15 ml of an organic solvent for the raw material of lg CDB-2914.

The method for preparing a crystal of CDB-2914 according to claim 3, wherein the anti-solvent is added in an amount of 2 to 30 ml of the raw material of lg CDB-2914.

The method for producing a crystal of CDB-2914 according to claim 3, wherein the organic solvent is acetone, methanol, ethanol, n-butanol, isopropanol or ethyl acetate.

The method for producing a crystal of CDB-2914 according to claim 3, wherein the anti-solvent is water, n-hexyl, n-heptane, isopropyl ether or methyl tert-butyl ether.

9. A 17α-acetoxy-11β-(4-indole-indole-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione (CDB-2914) The crystal of the crystal, characterized in that the XRD pattern of the crystal includes 3 or more 2 选自 values selected from the group consisting of: 4.801 ± 0.2°, 6.339 ± 0.2°, 8.294 ± 0.2°, 9.593 ± 0.2° , 12.691 ± 0.2 °, 13.362 ± 0.2 °, 18.628 ± 0.2 °, 22.476 ± 0.2 ° and 26.857 ± 0.2 °.

The crystal according to claim 9, wherein the differential scanning calorimetry (DSC chart) of the crystal has a characteristic endothermic peak at 178 to 194 °C.

The crystal according to claim 9, wherein the crystal is obtained as follows, the method comprising the steps of: a) dissolving CDB-2914 raw material with an organic solvent, the dissolution temperature is 30~55 ° C;

b) cooling to 20~30 ° C, adding anti-solvent;

c) Continue to cool down to 0~10 °C, crystallization for 2~7 hours, to obtain amorphous of CDB-2914

12. A pharmaceutical composition, characterized in that the composition comprises:

(a) the crystal of any one of claims 1 to 2 or 9 to 11;

(b) a pharmaceutically acceptable carrier or excipient.