WO2016165650A1 - Co-crystal of olaparib and urea and preparation method therefor - Google Patents

Abstract

Disclosed are a co-crystal of olaparib and urea and a preparation method therefor. Specifically disclosed is a co-crystal form A, and an X-ray powder diffraction pattern of this crystal form has characteristic peaks at points where 2theta value is 17.4°±0.2°, 20.7°±0.2°, 10.5°±0.2°. The disclosed co-crystal has better stability, lower hygroscopicity and higher solubility as compared to existing olaparib free alkali crystal forms.

Description

Eutectic of urapa and urea and preparation method thereof Technical field

The invention relates to a eutectic of olaparib and urea, a preparation method and use thereof.

Background technique

Olaparib was first developed by the British biotechnology company KuDOS Pharmaceuticals Co., Ltd. In 2005, after the acquisition of KuDOS, AstraZeneca continued to develop Olapani for the treatment of ovarian cancer. On December 19, 2014, Olapani was approved by the FDA in the United States. It is the first FDA-approved targeted drug for ovarian cancer patients with BRCA mutations. It is suitable for patients who have previously undergone chemotherapy. It has been shown in preclinical models that olaparib is the first oral poly ADP ribose polymerase (PARP) inhibitor that utilizes defects in the DNA repair pathway to preferentially kill cancer cells. The chemical name of olapanib is 4-[3-(4-cyclopropanecarbonyl-piperazine 1-carbonyl)-4-fluoro-benzyl]-2H-pyridazin-1-one, which has the structure of formula (I) Shown as follows:

KuDOS (Kudos) Pharmaceutical Co., Ltd. discloses the free base form A of olaparib in patent CN101528714B, and the free base form L of olaparib is disclosed in CN101821242B. In addition, there are no other crystal patents that disclose Olapani. However, the solubility of the free base crystal form listed in Olapani is low, and it is necessary to find a crystal form with high solubility to improve the absorption efficiency of the drug.

Based on this, the inventors of the present invention have developed a eutectic of olaparib, which solves the problem of low solubility of the free base crystal form. A eutectic is a crystal containing two molecules in the same crystal structure. The role between the two molecules is non- Covalent bonds (such as hydrogen bonds, π-π conjugates, halogen bonds, etc.). The formation of drug eutectic does not destroy the covalent bond of the active ingredient of the drug, and has the opportunity to improve the crystallization and physicochemical properties of the drug itself, such as bioavailability (Pharmaceut. Res. 23 (8), 2006, pp. 1888-1897). .), Stability and Process Developability (Int. J. Pham. 320, 2006, pp. 114-123.), a new choice for pharmaceutical solid formulations.

The eutectic stability provided by the invention is good, and the wettability is low. Compared with the crystal form in the prior art, the solubility is improved, which is beneficial to improving the bioavailability of the drug, and is important for improving the efficacy and safety of the drug.

Summary of the invention

The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a eutectic of olrapani and urea with high solubility and good stability.

Preferably, the eutectic of olrapani and urea provided by the present invention has the structural formula shown in formula (II).

Specifically, the eutectic provided by the present invention is named as eutectic crystal form A, and its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 17.4°±0.2°, 20.7°±0.2°, and 10.5°±0.2°.

Further, the eutectic crystal form A provided by the present invention has an X-ray powder diffraction pattern having one or more of 2theta values of 21.1°±0.2°, 24.6°±0.2°, and 12.2°±0.2°. Characteristic peaks.

Preferably, the eutectic crystal form A provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2theta values of 21.1°±0.2°, 24.6°±0.2°, and 12.2°±0.2°.

Further, the present invention provides a eutectic crystal form A having an X-ray powder diffraction pattern at a 2theta value. One or more of 9.2°±0.2°, 15.0°±0.2°, and 23.4°±0.2° have characteristic peaks.

Preferably, the eutectic crystal form A provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2theta values of 9.2°±0.2°, 15.0°±0.2°, and 23.4°±0.2°.

According to a particular and preferred aspect of the invention, the X-ray powder diffraction pattern of eutectic crystal form A is substantially as shown in FIG. Further, a total of 26 diffraction peaks were shown in the X-ray powder diffraction pattern, and the positions and relative peak intensities of these diffraction peaks are shown in Table 1 or Table 2, in which the peak position was varied within a range of 0.2°.

According to still another specific aspect of the present invention, a total of 34 diffraction peaks are shown in the X-ray powder diffraction pattern of the eutectic crystal form A. The positions of the diffraction peaks and the relative peak intensities are shown in Table 3, wherein the peak position is 0.2. ° range changes.

Preferably, the eutectic crystal form A shows an endothermic heat peak at 170 ± 2 ° C in a spectrum measured by differential scanning calorimetry.

Preferably, the eutectic crystal form A is shown by thermogravimetric analysis as being heated to 120 ± 2 ° C with a weight loss gradient of about 1.8%.

According to the present invention, the eutectic crystal form A can be obtained by reacting olaparib and urea in one or more solvent systems of alcohols, ketones, alkyl nitriles, and cyclic ethers. The alcohol solvent is preferably ethanol, the ketone solvent is preferably acetone, and the alkyl nitrile solvent is preferably acetonitrile or a cyclic ether solvent, preferably tetrahydrofuran or 1,4-dioxane.

Another object of the present invention is to provide a method for preparing eutectic of olrapani and urea, which comprises olaparib and urea in one of alcohols, ketones, alkylnitrile and cyclic ethers. The reaction is carried out in a plurality of solvent systems, and is obtained by a crystallization method including, but not limited to, volatilization, stirring or cooling.

Further, the alcohol solvent is preferably ethanol, and the ketone solvent is preferably acetone.

According to a specific and preferred aspect of the present invention, the mixed system containing olrapani, urea and solvent is subjected to multiple heating and constant temperature cooling operations, and solid precipitation, filtration, washing and drying are carried out to obtain the eutectic crystal of the present invention. Type A. Preferably, the solvent is ethanol or acetone or a combination of the two. Preferably, the olaparib free base is the original It is dissolved in the solvent, and urea is added to obtain the mixed system containing olaparib, urea and a solvent. The heating constant temperature cooling operation refers to heating the system to a set higher temperature than room temperature, then thermostating for a set time, and finally cooling to a lower temperature set below room temperature. The set higher temperature may be, for example, 40 to 80 ° C, preferably 50 to 70 ° C, more preferably 55 to 65 ° C, and a specific higher temperature value is about 60 ° C. The set lower temperature may be, for example, -5 to 18 ° C, preferably -5 to 10 ° C, more preferably -5 to 5 ° C, and most preferably 0 to 5 ° C. The rate of heating may be from 0.5 to 3 ° C/min, preferably from 1 to 2 ° C/min. The rate of temperature drop may be from 0.1 to 1 ° C/min, preferably from 0.3 to 0.6 ° C/min. The constant temperature period is preferably 5 hours or longer, more preferably 8 hours or longer, further preferably 9 hours or longer, more preferably 9 to 12 hours, specifically, for example, 10 hours. The number of times of the heating constant temperature cooling operation is preferably 2 to 4 times, and most preferably 3 times.

According to a particularly preferred embodiment of the invention, the higher temperature is 40 to 80 ° C, the lower temperature is -5 to 18 ° C, and the constant temperature is 5 hours or longer. In a further preferred embodiment, the higher temperature is 55 to 65 ° C, the lower temperature is 0 to 5 ° C, and the constant temperature is 9 to 11 hours.

Another object of the present invention is to provide a pharmaceutical composition comprising a co-crystal of olaparib and urea, and at least one pharmaceutically acceptable excipient, and a method of using the same for treating cancer. A method of treating cancer includes administering to a cancer patient an effective amount of the pharmaceutical composition.

According to the present invention, the cancer includes, but is not limited to, melanoma, pancreatic cancer, ovarian cancer, breast cancer, lymphoma, lung cancer, and the like.

The beneficial effects of the invention are:

The olapani and urea provided by the invention have good eutectic stability and low hygroscopicity, and no special drying conditions are needed in the preparation process, which simplifies the preparation and post-treatment process of the medicine, and is easy for industrial production. Moreover, the moisture content remains basically unchanged under different humidity conditions, which is convenient for long-term storage of medicines and has strong economic value.

The eutectic ratio of olaparib and urea provided by the present invention is free crystal form disclosed in patent CN101528714B The higher solubility of A is beneficial to improve the absorption efficiency of the drug and improve the bioavailability of the drug, which is of great significance for improving the efficacy and safety of the drug.

DRAWINGS

Figure 1 is an XRPD pattern of eutectic crystal form A;

2 is a DSC chart of eutectic crystal form A;

Figure 3 is a TGA diagram of eutectic crystal form A;

Figure 4 is a DVS diagram of eutectic crystal form A;

Figure 5 is a DVS diagram of the free base crystal form A in the patent CN101528714B;

Figure 6 is a ¹ H NMR chart of eutectic crystal form A.

detailed description

The invention is further illustrated by the following examples, but is not intended to limit the scope of the invention. Improvements in the method of preparation and use of the apparatus may be made by those skilled in the art within the scope of the claims, and such modifications are also considered to be within the scope of the invention. Therefore, the scope of the invention should be determined by the appended claims.

In the following examples, the test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer; the powder of olaparib is obtained by a commercially available method.

The abbreviations used in the present invention are explained as follows:

XRPD: X-ray powder diffraction

DSC: Differential Scanning Calorimetry

TGA: Thermogravimetric analysis

The X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer. The method parameters of the X-ray powder diffraction described in the present invention are as follows:

X-ray reflection parameters: Cu, Kα

Kα1

:1.540598;Kα2

:1.544426

Kα2/Kα1 intensity ratio: 0.50

Voltage: 45 volts (kV)

Current: 40 milliamps (mA)

Scan range: from 3.0 to 40.0 degrees

The differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q200. The method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:

Scanning rate: 10 ° C / min;

Protective gas: nitrogen.

The thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000. The method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:

Scanning rate: 10 ° C / min;

Protective gas: nitrogen.

Example 1

Preparation of Olapani and Urea Eutectic Form A:

10.0 mg of olaparib free base (amorphous) was dissolved in 0.6 mL of ethanol, 11.8 mg of urea was added, and the mixture was heated to 60 ° C at a heating rate of 1.0 ° C / min, stirred at 60 ° C for 600 min, and then at 0.37 ° C / The cooling rate of min was lowered to 5 ° C, and the above heating and cooling process was repeated three times. After the reaction was completed, it was filtered, and the obtained solid was washed with ethanol, dried, and the solid was collected. Upon examination, the solid obtained in this example was a eutectic crystal form A, and its XRPD pattern is shown in Fig. 1, and its X-ray powder diffraction data is shown in Table 1. Its DSC chart is shown in Fig. 2, its TGA chart is shown in Fig. 3, and its ¹ H NMR chart is shown in Fig. 6.

The eutectic products of olaparib and urea prepared by the above method have the following 1H NMR identification data as follows:

^{1 H NMR (400MHz, DMSO)} δ12.57 (s, 1H), 8.26 (d, J = 7.8Hz, 1H), 7.97 (d, J = 7.9Hz, 1H), 7.89 (t, J = 6.9Hz, 1H), 7.83 (t, J = 7.5 Hz, 1H), 7.44 (dd, J = 8.2, 5.3 Hz, 1H), 7.37 (d, J = 5.5 Hz, 1H), 7.24 (t, J = 9.1 Hz, 1H), 4.33 (s, 2H), 3.59 (t, J = 60.4 Hz, 6H), 3.26 - 3.08 (m, 2H), 1.97 (s, 1H), 0.73 (t, J = 7.0 Hz, 4H).

Table 1

2theta	d interval	strength%
6.66	13.26	7.31
9.21	9.60	1.89
10.50	8.42	3.50
12.20	7.25	3.96
13.34	6.64	1.29
15.00	5.90	2.17
17.41	5.09	22.35
18.51	4.79	1.72
18.66	4.75	1.24
20.10	4.42	1.96
20.67	4.30	9.65
21.10	4.21	2.38
22.23	4.00	100.00
22.29	3.99	50.88
23.45	3.79	1.95
24.56	3.62	4.74
25.18	3.53	1.45
26.24	3.39	0.82
26.90	3.31	0.53
29.58	3.02	2.83
30.30	2.95	1.17
31.68	2.82	0.27
32.94	2.72	0.54
33.69	2.66	0.52
35.51	2.53	1.80
37.06	2.42	1.08

Example 2

Preparation method of co-crystal of olaparib and urea: 101.9 mg of olaparib free base dissolved in 3.0 mL of ethanol 98.7mg of urea was added, heated to 60 ° C at a heating rate of 1.0 ° C / min, stirred at 60 ° C for 600 min, then cooled to 5 ° C at a cooling rate of 0.37 ° C / min, repeating the above heating and cooling process three times, the reaction is over After filtration, the resulting solid was washed with ethanol and dried.

Upon examination, the solid obtained in this example was Form A, and the X-ray powder diffraction data thereof is shown in Table 2.

Table 2

2theta	d interval	strength%
3.19	27.69	3.95
6.66	13.28	17.03
9.21	9.60	14.41
10.48	8.44	23.01
12.20	7.25	16.21
13.34	6.64	4.44
14.99	5.91	11.75
17.41	5.09	80.90
18.49	4.80	13.15
18.65	4.76	8.79
19.54	4.54	3.32
20.11	4.42	7.32
20.66	4.30	50.82
21.08	4.21	20.78
23.43	3.80	10.94
24.18	3.68	4.12
24.56	3.62	20.51
25.15	3.54	10.06
26.23	3.40	6.73
26.92	3.31	2.25
27.65	3.23	4.14
29.56	3.02	12.32
30.26	2.95	9.71
32.94	2.72	2.59
33.69	2.66	3.30
37.04	2.43	8.81

Example 3

Preparation of olapani and urea eutectic:

10.0 mg of olaparib free base (amorphous) was dissolved in 0.6 mL of acetone, and 10.8 mg of urea was added to add After heating at a heating rate of 1.0 ° C / min to 60 ° C, stirring at 60 ° C for 600 min, cooling (cooling rate 0.37 ° C / min) to 5 ° C, repeat the above heating and cooling process three times, after the reaction is filtered, the resulting solid is washed with ethanol Dry, cool to room temperature and collect solids.

Upon examination, the solid obtained in this example was identical to the crystal form obtained in Example 1, and was a eutectic crystal form A, and its X-ray powder diffraction data is shown in Table 3.

table 3

2theta	d interval	strength%
6.66	13.27	20.43
9.21	9.61	5.31
10.50	8.42	11.34
12.21	7.25	12.27
13.35	6.63	4.90
15.00	5.91	9.33
17.42	5.09	70.03
17.99	4.93	8.66
18.50	4.80	5.88
19.57	4.54	17.94
20.14	4.41	17.07
20.69	4.29	40.92
20.95	4.24	21.27
22.24	4.00	100.00
23.45	3.79	35.47
24.20	3.68	11.50
24.61	3.62	40.84
25.06	3.55	19.08
25.83	3.45	8.99
26.25	3.40	21.52
26.92	3.31	2.58
27.65	3.23	1.87
28.46	3.14	8.85
29.32	3.05	25.61
29.57	3.02	10.60

30.30	2.95	5.67
30.66	2.92	2.26
31.68	2.82	3.65
32.89	2.72	4.79
33.72	2.66	3.40
34.17	2.62	3.16
35.52	2.53	6.99
37.10	2.42	7.77
38.25	2.35	2.84

Example 4

Comparative study on the wettability of free base crystal form A in eutectic crystal form A and patent CN101528714B:

10 mg of the eutectic crystal form A of the present invention and the free base crystal form A of the patent CN101528714B were respectively subjected to dynamic moisture adsorption (DVS) test, and then XRPD was sampled. The results are shown in Table 4. The DVS pattern of the eutectic crystal form A is shown in Fig. 4, and the DVS of the free base crystal form A in the patent CN101528714B is shown in Fig. 5.

The results show that the weight gain of the eutectic crystal form A of the present invention is lower than the free base crystal form A in the patent CN101528714B at 25 ° C, 80% and 95% relative humidity, indicating the eutectic crystal form A of the present invention. Less wettability.

Table 4

Defining the characteristics of wettability and the definition of moisture-wetting weight gain (Guidelines for the Chinese Pharmacopoeia 2010 Edition Appendix XIX J Drug Wetness Test):

Deliquescence: absorb enough water to form a liquid

Very hygroscopic: the wetting weight gain is not less than 15%

Humidity: Wet weight gain is less than 15% but not less than 2%

Slightly wettability: wetting gain is less than 2% but not less than 0.2%

No or almost no wettability: wetting gain is less than 0.2%

Example 5

Comparative study on the solubility of free base crystal form A in eutectic crystal form A and patent CN101528714B:

The eutectic crystal form A prepared by the present invention and the free base crystal form A of CN101528714B were respectively prepared into a saturated solution by using SGF (simulated artificial gastric juice) of pH 1.8 and pH 6.5 FaSSIF (artificial intestinal juice under fasting state) for 1 hour. After 4 hours, the content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC). The experimental results are shown in Table 4.

Table 4

From the above comparison results, it can be seen that after standing for 1 hour in SGF, the urea eutectic crystal form A of the present invention has higher solubility than the patent free base crystal form A after 4 hours; it is placed in FaSSIF for 4 hours. The urea eutectic crystal form A of the present invention has a higher solubility.

The above embodiments are merely illustrative of the technical concept and the features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the present invention and to implement the present invention, and the scope of the present invention is not limited thereto. Equivalent variations or modifications made in accordance with the spirit of the invention are intended to be included within the scope of the invention.

Claims (17)

1. A eutectic of a compound of formula (I) with urea.

   
2. The eutectic according to claim 1, wherein the eutectic structural formula is as shown in formula (II).

   
3. The eutectic according to claim 1 or 2, comprising a eutectic crystal form A, characterized in that the X-ray powder diffraction pattern of the eutectic crystal form A has a value of 17.4 ° ± 0.2 °, 20.7 ° ± 0.2 Characteristic peak at °, 10.5 ° ± 0.2 °.
4. The eutectic according to claim 3, characterized in that the X-ray powder diffraction pattern of the eutectic crystal form A is also in the 2theta value of 21.1 ° ± 0.2 °, 24.6 ° ± 0.2 °, 12.2 ° ± 0.2 ° One or more of them have characteristic peaks.
5. The eutectic according to claim 4, wherein the eutectic crystal form A has an X-ray powder diffraction pattern at a 2theta value of 21.1 ° ± 0.2 °, 24.6 ° ± 0.2 °, and 12.2 ° ± 0.2 °. Has a characteristic peak.
6. The eutectic according to any one of claims 3 to 5, wherein the X-ray powder diffraction pattern of the eutectic crystal form A is also 9.2 ° ± 0.2 °, 15.0 ° ± 0.2 One or more of °, 23.4 ° ± 0.2 ° has characteristic peaks.
7. The eutectic according to claim 6, wherein the eutectic crystal form A has an X-ray powder diffraction pattern at a value of 9.2 ° ± 0.2 °, 15.0 ° ± 0.2 °, and 23.4 ° ± 0.2 °. Has a characteristic peak.
8. A method for preparing a eutectic according to any one of claims 1 to 7, characterized in that olaparib and urea are in an alcohol, a ketone, an alkylnitrile or a cyclic ether. The reaction in one or more solvent systems is obtained by volatilization, stirring or cooling.
9. The production method according to claim 8, wherein the alcohol solvent comprises ethanol, and the ketone solvent comprises acetone.
10. A method for preparing a eutectic according to any one of claims 1 to 7, characterized in that the mixed system containing olrapani, urea and solvent is subjected to multiple heating and constant temperature cooling operations, and solid Precipitation, filtration, washing, drying, that is, eutectic crystal form A, the heating constant temperature cooling operation refers to heating the system to a set higher temperature than room temperature, then constant temperature for a set time, and finally cooling To a lower temperature set below room temperature.
11. The production method according to claim 10, wherein the solvent is ethanol or acetone or a combination of the two.
12. The preparation method according to claim 10, wherein the higher temperature is 40 to 80 ° C, the lower temperature is -5 to 18 ° C, and the constant temperature is 5 hours or longer.
13. The preparation method according to claim 12, wherein the higher temperature is 55 to 65 ° C, the lower temperature is 0 to 5 ° C, and the constant temperature is 9 to 11 hours.
14. The preparation method according to any one of claims 10 to 13, characterized in that the number of times of the heating constant temperature cooling operation is 2 times, 3 times or 4 times.
15. A pharmaceutical composition comprising the eutectic according to any one of claims 1 to 7 and a pharmaceutically acceptable excipient.
16. A method of treating cancer, comprising: administering to a cancer patient an effective amount of the pharmaceutical composition of claim 15.
17. Use of the eutectic according to any one of claims 1 to 7 for the preparation of a medicament for treating cancer.

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