Polymorph of rucaparib camsylate

Abstract

The present disclosure may disclose a new crystal form D of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl) methanesulfonic acid salt, preparation method therefor and a medicinal use. Compared to the existing crystalline forms, this new crystalline form has clear advantages with respect to solubility, stability, and the preparation process.

Claims

1. A crystal Form D of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid salt of the formula: ##STR00002## wherein the crystal Form D is characterized by an X-ray powder diffraction pattern comprising characteristic diffraction peaks at angles (°2θ) of 6.0°±0.2 °2θ, 12.0°±0.2 °2θ, and 25.5°±0.2 °2θ; and wherein the X-ray powder diffraction pattern is determined on a diffractometer using CuKα radiation.

2. The crystal Form D of claim 1, wherein the crystal Form D is further characterized by an X-ray powder diffraction pattern comprising additional characteristic diffraction peaks at angles (°2θ) of 18.1°±0.2 °2θ and 22.3°±0.2 °θ.

3. The crystal Form D of claim 1, wherein the crystal Form D is further characterized by an X-ray powder diffraction pattern comprising additional characteristic diffraction peaks at angles (°2θ) of 16.5°±0.2 2θ, 18.1°±0.2 °2θ, 19.3°±0.2 °2θ, 22.3°±0.2 °2θ, and 23.9°±0.2 °2θ.

4. The crystal Form D of claim 1, wherein the crystal Form D is further characterized by an X-ray powder diffraction pattern comprising additional characteristic diffraction peaks at angles (°2θ) of 16.5°±0.2 °2θ, 18.1°±0.2 °2θ, 19.3°±0.2 °2θ, 20.4°±0.2 °2θ, 22.3°±0.2 °2θ, 23.9°±0.2 °2θ, 30.5°±0.2 °2θ, and 31.3°±0.2°2θ.

5. The crystal Form D of claim 1, wherein the crystal Form D is further characterized by an X-ray powder diffraction pattern as depicted in FIG. 1.

6. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the crystal Form D of claim 1 as an active ingredient.

7. A method for treating a cancer in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of the pharmaceutical composition of claim 6.

8. The method of claim 7, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer.

9. A process for the preparation of the crystal Form D of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid salt according to claim 1 of the formula: ##STR00003## wherein the process comprises the following steps: (i) dissolving 8-fluoro-2-4-[(methylamino)methyl]phenyl-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid salt in an organic solvent selected from the group consisting of diethyl oxalate and ethanol, or a mixture thereof, to obtain a solution; (ii) placing the solution obtained in step (i) in an ultrasonic water bath; (iii) adding an antisolvent selected from the group consisting of acetonitrile and 2-butanone, or a mixture thereof, to the solution obtained in step (i), to afford precipitation of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid salt from the solution; and (iv) obtaining the crystal Form D of 8-fluoro-2-4-[(methylamino)methyl]phenyl-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid salt.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is an XPRD pattern of rucaparib camsylate form D. 20 values in unit of degree in accordance with the abscissa. The intensity of diffraction peak as ordinate;

(2) FIG. 2 is a DSC plot of rucaparib camsylate Form D. Temperature in unit of ° C. in accordance with the abscissa. The Heat flow (w/g) as ordinate;

(3) FIG. 3 is a TGA plot of rucaparib camsylate Form D. Temperature in unit of ° C. in accordance with the abscissa. The Weight (%) as ordinate;

(4) FIG. 4 is an XPRD pattern of rucaparib camsylate form D after forced degradation treatment (elevated temperature). 20 values in unit of degree in accordance with the abscissa. The intensity of diffraction peak as ordinate;

(5) FIG. 5 is an XPRD pattern of rucaparib camsylate form D after forced degradation treatment (high humid). 20 values in unit of degree in accordance with the abscissa. The intensity of diffraction peak as ordinate; and

(6) FIG. 6 is an XPRD pattern of rucaparib camsylate form D after forced degradation treatment (light stability). 20 values in unit of degree in accordance with the abscissa. The intensity of diffraction peak as ordinate.

DETAILED DESCRIPTION

(7) The specific embodiments of the present invention are further described in detail below with reference to the drawings and embodiments. The following examples are intended to illustrate the invention, but are not intended to limit the scope of the invention.

(8) The X-ray powder diffraction operation and analysis steps in this patent are as follows:

(9) The Rigaku Ultima IV powder diffractometer was used, which was irradiated with Cu-K(R) (40 kV, 40 mA) at room temperature using a D/tex Ultra detector. The scanning range is from 3° to 45° in the 2θ interval, and the scanning speed is 20°/min.

(10) Measurement differences associated with X-ray powder diffraction analysis results are produced by a variety of factors including: (a) errors in sample preparation (e.g., sample height), (b) instrument error, (c) calibration differences, (d) operator error (including errors that occur when determining peak position), and (e) properties of the substance (e.g., preferred orientation error). Calibration errors and sample height errors often result in displacement of all peaks in the same direction. When using a flat sampler, small differences in sample height will result in large displacements of the XRPD peak position. Systematic studies have shown that a 1 mm sample height difference can result in a 20 peak shift of up to 10. These displacements can be identified from the X-ray diffraction pattern and can be eliminated by compensating for the displacement (using a system calibration factor for all peak position values) or recalibrating the instrument. As described above, the measurement errors from different instruments can be corrected by applying a system calibration factor to make the peak positions consistent.

Example 1

(11) Dissolve 50 mg of rucaparib camsylate in 1 ml of diethyl oxalate, place the solution within bottle in an ultrasonic water bath, and add an anti-solvent acetonitrile under the ultrasonic working environment to produce a precipitate and rucaparib camsylate Form D was obtained.

(12) In the present invention, the rucaparib camsylate form D, the XRPD patterns is shown in FIG. 1 and the diffraction peaks of the XRPD pattern of Form III are listed in the following table:

(13) TABLE-US-00001 2-Theta d(Å) I(Height) % 6.0 14.7651 46.6 12.0 7.3568 100 16.5 5.3749 19.3 18.1 4.9024 46.2 19.3 4.5857 22.1 20.4 4.3499 10.5 22.3 3.9904 40.1 23.9 3.714 17 25.5 3.4902 48.2 30.5 2.9248 14.8 31.3 2.8571 5

(14) A differential scanning calorimetry (DSC) analysis was performed on the crystal Form D in Example 1, using a TA Q2000 differential scanning calorimeter using an N.sub.2 atmosphere at a temperature rising rate of 10° C./min. The DSC plot of Form D is shown in FIG. 2. The melting point of Form D is 276.6° C. (onset temperature). The thermogravimetric (TGA) analysis of the crystal Form D in Example 1 was carried out using a TA Q500 thermogravimetric analyzer using a N.sub.2 atmosphere at a heating rate of 10° C./min. The TGA plot of Form I is shown in FIG. 3.

Example 2

(15) Dissolve 50 mg of rucaparib camsylate in 1 ml of ethanol, place the solution within bottle in an ultrasonic water bath, and add an anti-solvent acetonitrile under the ultrasonic working environment to produce a precipitate and rucaparib camsylate Form D was obtained. The XRPD pattern of the crystal form D obtained in this example is consistent with FIG. 1.

Example 3

(16) Dissolve 50 mg of rucaparib camsylate in 1 ml of ethanol/diethyl oxalate mixture, place the solution within bottle in an ultrasonic water bath, and add an anti-solvent acetonitrile under the ultrasonic working environment to produce a precipitate and rucaparib camsylate Form D was obtained. The XRPD pattern of the crystal form D obtained in this example is consistent with FIG. 1.

Example 4

(17) Dissolve 50 mg of rucaparib camsylate in 1 ml of diethyl oxalate, place the solution within bottle in an ultrasonic water bath, and add an anti-solvent 2-butanone under the ultrasonic working environment to produce a precipitate and rucaparib camsylate Form D was obtained. The XRPD pattern of the crystal form D obtained in this example is consistent with FIG. 1.

Example 5

(18) In order to evaluate the physical stability of the crystal form D, experiments on the stress stability for the crystal form D were performed. The physical stability of the crystal form D under high temperature, high humidity and light stress conditions was investigated. The experimental conditions of the stress stability are as follows:

(19) TABLE-US-00002 Item Conditions Pull point Stress Elevate temperature 60° C. 5, 10 day stability High humidity 92.5% RH 5, 10 day Light stress 4500 lux 5, 10 day

(20) The crystal form D was placed in the above stress conditions. After sampling at the time point, the stability sample was evaluated by XRPD. The results are summarized as follows:

(21) TABLE-US-00003 Initial XRPD Stress condition sample 5 day 10 day pattern Elevate 60° C. Form D Form D Form D FIG. 4 temperature High humidity 92.5% RH Form D Form D Form D FIG. 5 Light stress 4500 lux Form D Form D Form D FIG. 6

(22) The experimental results of stress stability show that the crystal form D is stable under the conditions of high temperature, high humidity and light stress conditions. This indicates that Form D is a very physically stable form and is suitable for drug development.

Example 6

(23) Determination of the solubility of rucaparib camsylate in simulated gastric juice. Weigh about 1 mg of the powder of Form A, Form B, Form C and Form D of rucaparib camsylate in a 2-mL tube, then add 1 mL of simulated gastric juice (Prepared by adding diluted hydrochloric acid 16.4 ml, 800 ml of water and 10 g of pepsin. After shaking, add water to volume of 1000 ml). After shaking the suspension for 20 min, it was filtered through a needle filter to obtain a clear solution. The rucaparib camsylate content in the solution was analyzed by HPLC method.

(24) TABLE-US-00004 Crystal forms of Solubility in SGF rucaparib camsylate Source (mg/mL) Form A Prepared according to 0.10 Form B WO2011098971 0.13 Form C 0.11 Form D Example 1 0.31

(25) From the above results, it can be seen that the crystalline form D of rucaparib camsylate can be rapidly dissolved under low pH conditions, and the solubility at 20 minutes is significantly higher than that of the existing crystalline forms A, B and C. The recommended dose of rucaparib is 600 mg (calculated as rucaparib free base, 300 mg twice daily), and the maximum daily is 1200 mg (calculated by rucaparib free base, 600 mg twice daily). If calculated according to rucaparib camsylate salt, the daily take of the salt will be 1030.9 mg and 2061.8 mg. At such high doses, the compound must be dissolved rapidly in large quantities to ensure that the compound absorbed within the absorption window. For drug that cannot be dissolved in time, it will not be absorbed completely by the body. The unabsorbed drug will be wasted and cause unwanted side effects. The solubility and dissolution rate of new rucaparib camsylate Form D in simulated gastric juice is significantly higher than that of the prior art crystalline form, so that high-dose rucaparib can be fully absorbed, and the better clinical effect obtained at the same dose.