CZ2016196A3 - Solid forms of Ibrutinib - Google Patents

Abstract

The invention relates to a solid form of 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one of formula I and to preparation methods of crystalline particles with variable morphology. Crystalline form C of ibrutinib free base with the primary particle size smaller than or equal to 120 μm, the ratio of the primary particle size to the cluster size being at least 1:5 and the clusters having the minimum size of 150 μm.

Description

Solid forms of Ibrutinib

Field of technology

The invention relates to solid form 1 - [(3R) -3- [4-Amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] piperidin-1-yl] prop-2 -en-1-one of formula I,

O (I) known as ibrutinib, and methods for preparing crystalline particles with different morphologies.

Prior art

- [(3R) -3- [4-Amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] piperidin-1-yl] prop-2-en-1 -on, which is known as ibrutinib (CAS no. 936563-96-1) and belongs to the group of kinase inhibitors that can be used to treat lymphomas. Ibrutinib has been approved under the tradename Imbruvica by The Food and Drug Administration (FDA) for the treatment of centrocytic lymphoma.

The preparation of this molecule and its isolation by chromatography has been described in WO2008 / 039218. The preparation of crystalline forms of ibrutinib in solvated or unsolvated form has been described in WO 2013/184572, CN 103694241 and WO 2015/145415. The use of ibrutinib in the treatment of lymphomas together with other pharmaceutically active substances has been described in WO 2013/113841 and in WO 2013/155347, which also mentions pharmaceutically acceptable salts of this drug without further description or example of manufacture. In addition to the methods of preparation, WO 2013/184572 also deals with a pharmaceutical composition of crystalline and solvated forms of ibrutinib for oral use and mentions pharmaceutically acceptable salts of this drug without further description or an example of their manufacture. Further use of ibrutinib for the treatment of cancer, inflammatory or autoimmune diseases, together with the description of pharmaceutical compositions with the mention of pharmaceutically acceptable salts without their further description or manufacturing example is mentioned in patent document WO2014 / 004707.

The solubility of crystalline Form A of ibrutinib free base in water is very low, even when using aqueous solutions of different pH. It is clear that new solid forms of this pharmaceutically active substance are needed for the preparation of a dosage form with higher solubility and bioavailability.

The essence of the invention

The dissolution rate of the crystalline forms of the free base ibrutinibu C at a pH of 2 is 0.052 mg · min ^-1 -cm ^'2 while the dissolution rate of the thermodynamically most stable form and the free base is ibrutinibu under identical conditions, 0.017 mg-min-cm'. The present invention relates to the preparation of a crystalline solid form of ibrutinib (Form C) with different sizes of primary particles and their clusters. The morphology of the particles is controlled by process parameters during crystallization. Crystalline Form C of ibrutinib free base can be prepared from methanol solution by crystallization, where by changing the process parameters (solution saturation, temperature, cooling rate, seeding temperature) it is possible to prepare Crystalline Form C of ibrutinib free base in> 90% yield with controlled morphology and primary particle size. from 5 pm to 120 pm. The crystallization yield of ibrutinib Form C described in WO 2008/039218 is 70% with a primary particle size of about 35 μm.

The morphology and primary particle size of crystalline Form C ibrutinib free base also significantly affects the filterability of the suspension during manufacture. It has been found that for crystalline Form C ibrutinib free base with a primary particle size of 120 μm and cluster sizes <600 μm, the filtration time is approximately three times lower than for crystalline Form C ibrutinib free base according to the procedure described in WO2008 / 039218. when the primary particle size was <35 μm. The larger size of the primary particles and clusters also allows for easier handling after filtration of the product and faster achievement of a constant weight during drying of the product. The prepared crystalline Form C ibrutinib free base has suitable physicochemical properties for use in pharmacy and the formulation of new dosage forms.

Description of the picture

Figure 1. Raman spectra a) crystalline form A of ibrutinib (according to example 1); b) a suspension of ibrutinib in methanol for 15 min. at 25 ° C; c) a suspension of ibrutinib in methanol for 48 hours at 25 ° C; d) crystalline form F of ibrutinib (according to Example 3); e) a crystalline form of ibrutinib after filtration and drying of the product for 16 hours at 40 ° C and a pressure of 13 kPa; f) crystalline form C of ibrutinib (according to example 2)

Figure 2. SEM image of crystalline Form A of ibrutinib free base (according to Example 1)

Figure 3. X-ray powder recording of crystalline Form A of ibrutinib free base (according to Example 1)

Figure 4. SEM image of crystalline Form C of ibrutinib free base (according to Example 2)

Figure 5. X-ray powder recording of crystalline Form C of ibrutinib free base (according to Example

2)

Figure 6. SEM image of crystalline Form C of ibrutinib free base (according to Example 4)

Figure 7. SEM image of crystalline Form C of ibrutinib free base (according to Example 5)

Figure 8. SEM image of crystalline Form C of ibrutinib free base (according to Example 6)

Figure 9. SEM image of crystalline Form C of ibrutinib free base (according to Example 7)

Detailed description of the invention

The bioavailability of pharmaceutically active substances depends very much on whether the product obtained is crystalline or amorphous. The amorphous product is more rapidly soluble, often cannot be obtained in adequate quality and is also unstable. In contrast, the crystalline product is often stable with easier-to-obtain purity compared to the amorphous form and dissolves more slowly. The solution may be crystalline forms of pharmaceutically active substances with a lower melting point than the corresponding most thermodynamically stable crystalline form, where such a crystal arrangement guarantees a higher solubility of the crystalline form.

The primary particle size and cluster morphology can be controlled by crystallization process parameters such as solution saturation, temperature, cooling rate, seeding temperature.

The size of the primary particles and clusters affects the filtration rate of the suspension during preparation and the time to constant weight during drying of the product.

The present invention provides a process for preparing crystalline Form C of ibrutinib free base in high yields, wherein the obtained crystalline forms show higher solubility than the most thermodynamically stable crystalline Form A of ibrutinib free base free base.

The present invention provides a process for preparing a crystalline solid form of ibrutinib (Form C) with different sizes of primary particles and clusters thereof. Crystalline Form C of ibrutinib free base can be prepared from a methanol solution by crystallization or from a suspension. Process for the preparation of ibrutinib free base form C by dissolving ibrutinib at a concentration of 10 mg / ml to 260 mg / ml at 60 ° C or at a concentration of 90 mg / ml to 260 mg / ml at 60 ° C. The solution is cooled at a rate of 0.1 ° C / min to 3 ° C / min, preferably 0.1 ° C / min to 1 ° C / min. The solution is inoculated at a temperature of from 45 ° C to 0 ° C.

A process for preparing Form C ibrutinib free base comprises obtaining ibrutinib by crystallizing a solution formed by dissolving ibrutinib in methanol at a concentration of 90 mg / ml at 60 ° C, cooling the solution at a rate of 0.3 ° C / min until a temperature of 0 ° C is reached. seeding the solution is carried out by adding 2% of crystalline form C of ibrutinib free base at 25 ° C, the solid being obtained by filtration and drying of the filter cake at 40 ° C, 20 kPa; wherein the drying is applied until a constant weight of product is reached.

The primary particle size and cluster morphology can be controlled by crystallization process parameters such as solution saturation, temperature, cooling rate, seeding temperature.

The size of the primary particles and clusters affects the filtration rate of the suspension during preparation and the time to constant weight during drying of the product.

In the solution, crystalline Form C of ibrutinib free base with a primary particle size <120 μm is preferred, wherein the ratio of primary particle size to cluster size is at least 1: 5 and cluster size is at least 150 μm, and the particles thus prepared were prepared in high yield, good filterability and manipulability in the powder state as well as a short time to reach a constant weight during drying of the product.

The preparation of this molecule and its isolation by chromatography has been described in patent document WQ2008 / 039218. The preparation of crystalline forms of ibrutinib in solvated or unsolvated form has been described in WO2013 / 184572, CN 103694241 and WO 2015/145415. Crystalline forms A, C (morphology I) and F of ibrutinib free base were prepared according to the procedure described in WO2013 / 184572.

It has been found that crystalline Form C of ibrutinib can be prepared by suspending or recrystallizing Forms A, B or mixtures thereof in methanol (see Table 1).

Table 1: Polymorphic transformation of crystalline forms of ibrutinib in methanol suspension (3 weeks at 35 ° C)

The starting crystalline form or mixture of crystalline forms of ibrutinib Final crystalline form after filtration and drying (XRPD) Form A Form C Form B Form C Form A + Form B Form C Form A + Form C Form C Form B + Form C Form C Form A + Form B + Form C Form C

By Raman spectroscopy, it was found that the preparation of crystalline Form C of ibrutib first results in the crystalline Form F of ibrutinib, which is described in WO2008 / 039218 as a methanol solvate, and its desolvation produces crystalline Form C, see Raman spectra in Figure 1.

The characteristic diffraction peaks of crystalline Form A of ibrutinib free base using CuKα radiation are: 5.7; 13.6; 16.1; 18.9; 21.3 and 21.6 ± 0.1 ° 2-theta. The melting point of crystalline Form A of ibrutinib free base is 154 ° C according to DSC. The SEM image of morphology and particle size is shown in Figure 2. Reproduction of the procedure described in the patent application (WO2013 / 184572) gave a powder material with a primary particle size (max. Feret) of <15 μm in the absence of clusters with 80% crystallization yield. An example of an X-ray powder recording is shown in Figure 3.

The characteristic diffraction peaks of crystalline Form C of ibrutinib free base using CuKα radiation are: 7.0; 14.0; 15.7; 18.2; 19.1; 19.5; 20.3; 22.1; 22.9 ± 0.1 ° 2-theta. The melting point of crystalline Form C of ibrutinib free base is 134 ° C according to DSC. An image of the morphology and size of the primary particles from the SEM is shown in Figure 4. By reproducing the procedure described in the patent application (WO2008 / 039218) a powder material with a primary particle size (max. Feretes) <35 μm was obtained without the presence of clusters with 70% crystallization yield. An example of an X-ray powder recording is shown in Figure 5.

Figure 6 is an image of the morphology and size of the primary particles and cluster of crystalline Form C ibrutinib from SEM. The particles were prepared according to the procedure described in Example 4. Figure 7 is an image of the morphology and size of the primary particles and cluster of crystalline Form C ibrutinib from SEM. The particles were prepared according to the procedure described in Example 5. Figure 8 is an SEM image of the morphology and size of the primary particles and cluster of crystalline Form C ibrutinib. The particles were prepared according to the procedure described in Example 6. Figure 9 is an SEM image of the morphology and size of the primary particles and cluster of crystalline Form C ibrutinib. The particles were prepared according to the procedure described in Example 7.

The prepared crystalline ibrutinib Form C particles showed different filtration resistance depending on the size of the primary particles or clusters (see Table 2).

Table 2: Resistance of prepared particles of crystalline ibrutinib form C to filtration

morphology size of primary particles (max. feret) cluster size (max. feret) filtration time AND <35 pm individual particles 169 s II <5 pm <150 pm 24 s III <30 pm <300 pm 82 s IV <20 pm <100 pm 181 s IN <120 pm <600 pm 55 s

The invention is further elucidated in the following examples. These examples, which illustrate the preparation of the novel solid forms of ibrutinib according to the invention, are purely illustrative and do not limit the scope of the invention in any way.

Experimental part

R TG powder diffraction

Diffractograms were obtained on a powder diffractometer X'PERT PRO MPD PANalytical, used CuKa radiation (λ = 1.542 Å), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40 ° 20, step size: 0.01 ° 20 while maintaining a reflection of 0.5 s, the measurement was performed on a flat sample with an area / thickness of 10 / 0.5 mm. 0.02 rad Soller diaphragm, 10 mm mask, and 1/4 ° fixed anti-scatter diaphragm were used to correct the primary beam. The irradiated area samples 10 mm, programmable divergence screens were used. 0.02 rad Soller diaphragm and 5.0 mm anti-scatter diaphragm were used to correct the secondary beam.

Differential Scanning Calorimetry (DSC)

Melting points of the prepared solid forms of ibrutinib were measured on a Discovery DSC from TA Instruments. The sample load into a standard AI crucible (40 μL) was between 4-5 mg and a heating rate of 5 ° C / min. The temperature program that was used consists of 1 stabilization minute at 0 ° C and then heating to 220 ° C at a heating rate of 5 ° C / min (Amplitude = 0.8 ° C and Period = 60s). 5.0 N2 with a flow rate of 50 ml / min was used as the carrier gas.

Scanning Electron Microscope (SEM)

Electron microscope images were obtained using a MIRA II instrument, Tescan, Czech Republic, 2006. The cathode was a W fiber with an inserted voltage of 7 kV with a YAG scintillation detector located in the optical axis under the pole piece of the objective (BSE). The measurement was performed in a high vacuum. The sample was applied to carbon tape and Pt plated in a vacuum sprayer before measurement.

Determination of dissolution rate by true dissolution method

The dissolution rate was measured on an Agilent 708-DS dissolution instrument. Right dissolution disks with a surface available to dissolve 0.125 cm ² were prepared using a Specac press. The pressing time was 30 seconds under a pressing pressure of 1 ton. Dissolution was performed in 500 ml of pH 2 solution (10 mM HCl), at a constant rate of 100 RPM. Samples were taken at 5 minute intervals and the concentration of dissolved ibrutinib was determined using an Agilent Cary 60 UV / Vis spectrophotometer at 274 nm.

Raman spectroscopy

Raman spectra were measured on a Broker RFS 100 / S instrument. Wavelength of laser source 1064 nm. Measurements were performed with an accumulation of 64 scans with a resolution of 4 cm ^-1 .

Measurement of resistance of prepared particles during filtration

The filtration rate was determined by measuring the time of solvent flow through the prepared filter cake. The filter cake was prepared by weighing an appropriate amount of dried crystalline ibrutinib particles after sample preparation. The weighed particles were washed on a frit of defined dimensions with 20 ml of water. The filter cake thus prepared was characterized by measuring the height, and the filtration resistance was determined by measuring the flow time of 25 ml of water. All samples were measured under identical conditions.

Examples of a specific embodiment Example 1

Preparation of ibrutinib Form A

Ibrutinib free base (Form A) was prepared according to the procedure described in the patent (WO2008 / 039218). An image of the morphology and particle size from the SEM is shown in Figure 2. An example of an X-ray powder record is shown in Figure 3.

Example 2

Preparation of ibrutinib form C (morphology I)

Ibrutinib free base (Form C) was prepared according to the procedure described in the patent (WO2008 / 039218). An image of the morphology and particle size from the SEM is shown in Figure 4. An example of an X-ray powder record is shown in Figure 5.

Example 3

Preparation of ibrutinib Form F

Ibrutinib free base (Form F) was prepared according to the procedure described in the patent (WO2008 / 039218).

Example 4

Preparation of ibrutinib form C (morphology II)

- [(3R) -3- [4-Amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] piperidin-1-yl] prop-2-ene- 1-one (4 g, 9.08 mmol) was charged to the reactor and this portion was suspended in 61 mL of methanol. The resulting suspension was heated to 60 ° C for 10 min with stirring (250 rpm). The solution thus obtained was then cooled at a rate of 3 ° C / min to 5 ° C and subsequently cooled at a rate of 0.3 ° C / min to -7 ° C. At 0 ° C, the solution was seeded with 5% of crystalline Form C of ibrutinib prepared in Example 1. The suspension obtained was filtered and the solid was dried in a vacuum oven at 40 ° C and 13 kPa. A solid crystalline product of ibrutinib (Form C) was obtained. An image of the prepared product from SEM is shown in Figure 6. In this way, particles with approximately spherical clusters with a size <150 μm and with a primary particle size <5 μm were prepared. Crystallization yield 3.91 g (93%).

Example 5

Preparation of ibrutinib form C (morphology III)

- [(3R) -3- [4-Amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] piperidin-1-yl] prop-2-ene- 1-one (4.1 g, 9.31 mmol) was charged to the reactor and quenched with 50 mL of methanol. The resulting suspension was heated to 60 ° C for 10 min with stirring (125 rpm). The solution thus obtained was then cooled at a rate of 3 ° C / min to 40 ° C and subsequently cooled at a rate of 1 ° C / min to -7 ° C. At 35 ° C, the solution was seeded with 5% of crystalline Form C of ibrutinib prepared in Example 1. The suspension obtained was filtered and the solid was dried in a vacuum oven at 40 ° C and 13 kPa. A solid crystalline product of ibrutinib (Form C) was obtained. A picture of the prepared product from SEM is shown in the picture

7. In this way, particles with approximately spherical clusters with a size <300 μm and with a primary particle size <30 μm were prepared. Crystallization yield 4.05 g (94%).

Example 6

Preparation of ibrutinib Form C (Morphology IV) 1 - [(3R) -3- [4-Amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] piperidin-1-yl] Prop-2-en-1-one (4 g, 9.08 mmol) was charged to the reactor and quenched with 50 mL of methanol. The resulting suspension was heated to 60 ° C for 10 min with stirring (65 rpm). The solution thus obtained was then cooled at a rate of 1 ° C / min to 40 ° C and subsequently cooled at a rate of 1 ° C / min to -7 ° C. At 35 ° C, the solution was seeded with 5% of crystalline Form C of ibrutinib prepared in Example 1. The suspension obtained was filtered and the solid was dried in a vacuum oven at 40 ° C and 13 kPa. A solid crystalline product of ibrutinib (Form C) was obtained. A picture of the prepared product from SEM is shown in the picture

8. In this way, particles with approximately spherical clusters with a size <100 μm and with a primary particle size <20 μm were prepared. Crystallization yield 3.95 g (94%).

Example 7

Preparation of ibrutinib Form C (Morphology V) 1 - [(3R) -3- [4-Amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] piperidin-1-yl] prop -2-en-1-one (4 g, 9.08 mmol) was charged to the reactor and quenched with 50 mL of methanol. The resulting suspension was heated to 60 ° C for 10 mm with stirring (250 rpm). The solution thus obtained was then cooled at a rate of 0.333 ° C / min to 0 ° C. At 25 ° C, the solution was seeded with 5% of crystalline Form C ibrutinib prepared in Example 1. The resulting suspension was allowed to stir for 24 hours at 0 ° C, then the suspension was filtered and the solid was dried in a vacuum oven at 40 ° C. and a pressure of 13 kPa. A solid crystalline product of ibrutinib (Form C) was obtained. An image of the prepared product from SEM is shown in Figure 9. In this way, particles with approximately spherical clusters with a size <600 μm and with a primary particle size <120 μm were prepared. Crystallization yield 3.78 g (90%).

Claims (10)

Patent claims A process for the preparation of crystalline Form C of ibrutinib free base, characterized in that it is prepared by crystallization from methanol. Process for the preparation of crystalline Form C of ibrutinib free base according to claim 1, characterized in that it is prepared from a suspension of ibrutinib, wherein ibrutinib is dissolved at a concentration of 10 mg / ml to 260 mg / ml at 60 ° C. Process for the preparation of crystalline form C of ibrutinib free base according to claim 2, characterized in that ibrutinib is dissolved at a concentration of 90 mg / ml to 260 mg / ml at 60 ° C. Process for the preparation of Form C ibrutinib free base according to claims 1 and 3, characterized in that the solution is cooled at a rate of 0.1 ° C / min to 3 ° C / min. Process for the preparation of crystalline Form C of ibrutinib free base according to claim 4, characterized in that the solution is cooled at a rate of 0.1 ° C / min to 1 ° C / min. Process for the preparation of ibrutinib free base form C according to claims 1, 2 and 3, characterized in that the solution is inoculated at a temperature of from 45 ° C to 0 ° C. Process for the preparation of ibrutinib free base form C according to claims 1, 2, 3 and 6, characterized in that ibrutinib is obtained by crystallization of a solution formed by dissolving ibrutinib in methanol at a concentration of 90 mg / ml at 60 ° C, cooling the solution. .3 C / min until a temperature of 0 DEG C. is reached, the solution is seeded by adding 2% of crystalline form C of ibrutinib free base at 25 DEG C., the solid is obtained by filtration and drying of the filter cake at 40 DEG C., 20 kPa; wherein the drying is applied until a constant weight of product is reached. 8. Crystalline Form C ibrutinib free base consists of clusters wherein the ratio of primary particle size to cluster size is at least 1: 5 and the cluster size is at least 150 μm. Crystalline Form C of ibrutinib free base preparable according to claim 7. The crystalline Form C of ibrutinib free base prepared according to claim 7 is formed by clusters wherein the ratio of the primary particle size to the cluster size is at least 1: 5 and the cluster size is at least 150 μm.