EP3328848A1 - Solid forms of ceritinib free base - Google Patents
Solid forms of ceritinib free baseInfo
- Publication number
- EP3328848A1 EP3328848A1 EP16753812.3A EP16753812A EP3328848A1 EP 3328848 A1 EP3328848 A1 EP 3328848A1 EP 16753812 A EP16753812 A EP 16753812A EP 3328848 A1 EP3328848 A1 EP 3328848A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- ceritinib
- free base
- crystalline form
- ray powder
- theta
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention relates to solid forms of 5-chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]-N4-[2-(isopropylsulfonyl)phenyl]-2,4-pyrimidinediamine of formula (I), known as ceritinib, methods of their preparation and use in a dosage form.
Description
Solid forms of ceritinib free base
Field of the invention The invention relates to solid forms of 5-chloro-N2-[2-isopropoxy-5-methyl-4-(4- piperidinyl)phenyl]-N4-[2-(isopropylsulfonyl)phenyl]-2,4-pyrimidinediamine of formula I, known as ceritinib, methods of their preparation and use in a dosage form.
(I)
Ceritinib (CAS no. 1032900-25-6) belongs to the group of anaplastic lymphoma kinase (ALK) inhibitors and is designed for the treatment of lung cancer, incl. non-small cell lung carcinoma. Ceritinib free base was approved under the trade name Zykadia by the European Medicines Agency (EMA) for the treatment of adult patients with non-small cell lung carcinoma (NSCLC) positive for anaplastic lymphoma kinase (ALK), formerly treated with crizotinib.
Background of the Invention Preparation of ceritinib and its isolation was first described in the patent application WO 2008/073687, in Example 7 (compound 66). The patent application WO 2012/082972 described preparation and characterization methods of ceritinib dihydrochloride and two crystalline forms of ceritinib free base (Forms A, B).
Many pharmaceutical solid compounds can exist in various crystalline forms that are considered as polymorphs and hydrates/solvates, having different crystal units and thus different physicochemical properties such as the melting point, solubility, dissolution rate, as well as bioavailability. To distinguish individual solid phases of a compound, several solid-
state analytic methods can be used, e.g. X-ray powder diffraction, solid-state NMR, Raman spectroscopy as well as thermoanalytical methods.
Discovering new solid phases (polymorphs, solvates and hydrates) of an active pharmaceutical ingredient offers an opportunity to select a suitable modification with desired physicochemical properties and processability and to improve the characteristics of the pharmaceutical product. For this reason, there is an obvious need of novel solid forms (polymorphs, solvates, hydrates) of ceritinib.
Summary of the invention
The object of the invention is to provide pharmaceutically acceptable solid forms of ceritinib free base and methods of their preparation. According to the invention, these solid forms of ceritinib of formula I are prepared by crystallization, precipitation or evaporation from a solution of ceritinib in a suitable solvent or mixtures of solvents. The invention provides Crystalline Form 1 of ceritinib free base, exhibiting the following characteristic reflections in the X-ray powder pattern measured by CuKa radiation: 9.9; 18.1 and 25.2 ± 0.2° 2-theta. In some embodiments, Crystalline Form 1 of ceritinib free base is characterized by the following further reflections in the X-ray powder pattern: 7.4; 13.0; 14.7 and 20.8 ± 0.2° 2-theta. In some embodiments, Crystalline Form 1 of ceritinib free base is further characterized by the differential scanning calorimetry curve with the melting point at 130°C.
The invention further provides a method for preparation of Crystalline Form 1 of ceritinib free base, comprising:
a) dissolution of ceritinib in toluene at a temperature in the range from 50°C to the boiling point of the solvent;
b) cooling of the solution;
c) isolation of the separated solid fraction by filtration.
In some embodiments, the solution is filtered before the cooling in step b). In some embodiments, the solution is cooled down to a temperature in the range of -30 to 0°C in step b). In some embodiments, ceritinib is dissolved in the hot state in toluene and then it is rapidly cooled down to a temperature of -30 to 0°C.
The invention further provides Crystalline Form 2 of ceritinib free base, exhibiting the following characteristic reflections in the X-ray powder pattern measured by CuKa radiation: 4.9; 14.4; 22.0 and 25.6 ± 0.2° 2-theta. In some embodiments, Crystalline Form 2 of ceritinib free base is characterized by the following other reflections in the X-ray powder pattern: 9.8; 12.3; 17.0 and 18.9 ± 0.2° 2-theta. In some embodiments, Crystalline Form 2 of ceritinib free base is further characterized by the differential scanning calorimetry curve with the melting point at 96°C.
The invention further provides a method for preparation of Crystalline Form 2 of ceritinib free base, comprising:
a) dissolution of ceritinib in methanol at a temperature in the range from 50°C to the boiling point of the solvent;
b) cooling of the solution;
c) isolation of the separated solid fraction by filtration.
In some embodiments, the solution is filtered before the cooling in step b). In some embodiments, the solution is cooled down to a temperature in the range of -30 to 0°C in step b). In some embodiments, ceritinib is dissolved in the hot state in methanol and then it is rapidly cooled down to a temperature of -30 to 0°C.
The invention further provides Crystalline Form 2B of ceritinib free base, exhibiting the following characteristic reflections in the X-ray powder pattern measured by CuKa radiation: 5.1; 14.6; 18.0 and 0.2 ± 2° 2-theta. In some embodiments, Crystalline Form 2B of ceritinib free base is characterized by the following further reflections in the X-ray powder pattern: 12.4; 22.1 and 26.0 ± 0,2° 2-theta. In some embodiments Crystalline Form 2B of ceritinib free base is further characterized by the differential scanning calorimetry curve with the melting point at 161 °C. The invention further provides a method for preparation of Crystalline Form 2B of ceritinib free base, comprising:
a) dissolution of ceritinib dihydrochloride in a mixture of one or more solvents and water in the ratio of 3:1 at a temperature in the range from 50 )°C to the boiling point of the mixture of solvents;
b) gradual adding of the base until pH in the range of 11-12 is achieved;
c) gradual adding of an antisolvent (water) to the solution;
d) cooling of the mixture;
e) isolation of the separated solid fraction by filtration;
f) drying of the isolated ceritinib at a temperature in the range of 50 to 55°C under a reduced pressure for at least 12 h.
Methanol, ethanol, 2-propanol, ethyl methyl ketone or their mixtures can be used as the solvent in step a); methanol or ethanol or their mixture are preferably used. In some embodiments, a base is added in step b), selected from the group consisting of Na C03, K2C03, NaHC03, KHC03, aqueous ammonia (NH4OH), NaOH or KOH; preferably a 2M aqueous solution of Na2C03 is used as the base.
The invention further provides Crystalline Form 3 of ceritinib free base, exhibiting the following characteristic reflections in the X-ray powder pattern measured by CuKa radiation: 3.9; 12.1; 17.1 and 20.4 ± 0.2° 2-theta. In some embodiments, Crystalline Form 3 of ceritinib free base is characterized by the following further reflections in the X-ray powder pattern: 5.9; 7.9; 15.8 and 18.6 ± 0.2° 2-theta. In some embodiments, Crystalline Form 3 of ceritinib free base is further characterized by the differential scanning calorimetry curve with the melting point at 80°C.
The invention further provides a method for preparation of Crystalline Form 3 of ceritinib free base, comprising:
a) dissolution of ceritinib in ethanol at a temperature in the range from 50°C to the boiling point of the solvent;
b) cooling of the solution;
c) isolation of the separated solid fraction by filtration.
In some embodiments, the solution is filtered before the cooling in step b). In some embodiments, the solution is cooled down to a temperature in the range of -30 to 0°C in step b). In some embodiments, ceritinib is dissolved in the hot state in ethanol and then it is rapidly cooled down to a temperature of -30 to 0°C.
The invention further provides Crystalline Form 4 of ceritinib free base, exhibiting the following characteristic reflections in the X-ray powder pattern measured by CuKa radiation: 4.9; 14.3 and 21.8 ± 0.2° 2-theta. In some embodiments, Crystalline Form 4 of ceritinib free base is characterized by the following further reflections in the X-ray powder pattern: 12.2; 17.0; 18.0 and 24.3 ± 0.2° 2-theta. In some embodiments, Crystalline Form 4 of ceritinib free base is further characterized by the differential scanning calorimetry curve with the melting point at 72°C.
The invention further provides a method for preparation of Crystalline Form 4 of ceritinib free base, comprising:
a) dissolution of ceritinib in a mixture of ethanol and water comprising 50 to 90 wt. % of ethanol at a temperature in the range from 50°C to the boiling point of the mixture of solvents;
b) cooling of the solution;
c) isolation of the separated solid fraction by filtration.
In some embodiments, the mixture of ethanol and water in step a) contains 75 wt. % of ethanol. In some embodiments, the solution is filtered before the cooling in step b). In some embodiments, the solution is cooled down to a temperature in the range of -30 to 0°C in step b). In some embodiments, ceritinib is dissolved in the hot state in a mixture of ethanol and water containing 50 to 90 wt. % of ethanol and then it is rapidly cooled down to a temperature of-50 to 90°C.
The invention further provides Crystalline Form 5 of ceritinib free base, exhibiting the following characteristic reflections in the X-ray powder pattern measured by CuKa radiation: 5.4; 9.4; 15.1; 16.9 ± 0.2° 2-theta. In some embodiments, Crystalline Form 5 of ceritinib free base is characterized by the following other reflections in the X-ray powder pattern: 12.5, 18.7 and 25.8 ± 0.2° 2-theta. In some embodiments, Crystalline Form 5 of ceritinib free base is further characterized by the differential scanning calorimetry curve with the melting point at 164°C.
The invention further provides a method for preparation of Crystalline Form 5 of ceritinib free base, comprising:
a) dissolution of ceritinib in methanol at a temperature in the range from 50°C to the boiling point of the solvent;
b) cooling of the solution;
c) isolation of the separated solid fraction by filtration;
d) drying of the solid fraction at a temperature in the range from 80 to 120 °C for at least 12 h.
In some embodiments, the solution is filtered before the cooling in step b). In some embodiments, the solution is cooled down to a temperature in the range of -30 to 0°C in step b). In some embodiments, the separated fraction is dried at 80°C for 72 h.
The invention further provides an amorphous form of ceritmib free base. In some embodiments, the amorphous form of ceritinib free base exhibits a characteristic amorphous halo in the X-ray powder pattern measured by Cu a radiation. In some embodiments, the amorphous form of ceritinib free base is further characterized by a differential scanning calorimetry curve with the glass transition temperature Tg > 65°C.
The invention further provides a method for preparation of an amorphous form of ceritinib free base, comprising:
a) dissolution of ceritinib in acetone at a temperature in the range from 50°C to the boiling point of the solvent;
b) evaporation of the obtained solution.
In some embodiments, the solution is filtered before the evaporation in step b). In some embodiments, ceritinib is dissolved in the hot state in acetone and the obtained solution is evaporated.
The invention further provides the use of Crystalline Form 1, 2, 2b, 3, 4 and/or 5 of ceritinib free base and/or the amorphous form of ceritinib free base for the preparation of a pharmaceutical composition.
The invention further provides a pharmaceutical composition, comprising Crystalline Form 1, 2, 2b, 3, 4 and/or 5 of ceritinib free base and/or the amorphous form of ceritinib free base and at least one pharmaceutically acceptable excipient.
Brief Description of the Drawings
Figure 1: X-Ray powder pattern of ceritinib free base Crystalline Form 1.
Figure 2: X-Ray powder pattern of ceritinib free base Crystalline Form 2.
Figure 3: X-Ray powder pattern of ceritinib free base Crystalline Form 2B.
Figure 4: X-Ray powder pattern of ceritinib free base Crystalline Form 3.
Figure 5: X-Ray powder pattern of ceritinib free base Crystalline Form 4.
Figure 6: X-Ray powder pattern of ceritinib free base Crystalline Form 5.
Figure 7: X-Ray powder pattern of ceritinib free base amorphous form.
Detailed Description of the Invention
Biological availability of active pharmaceutical ingredients greatly depends on whether a crystalline or amorphous product is obtained. An amorphous product is usually more rapidly soluble, it cannot often be obtained in the required quality and it is also often unstable. Conversely, compared to the amorphous form, a crystalline product is often stable, its required purity is easier to achieve and it dissolves more slowly. The problem may be solved by crystalline forms of active pharmaceutical ingredients with a lower melting point, wherein such crystal arrangement guarantees higher solubility of the crystalline form, or by the use of the amorphous form of the active pharmaceutical ingredient. This invention provides solid forms of ceritinib free base in a crystalline form, wherein the obtained crystalline forms exhibit a lower melting point than the known crystalline forms of ceritinib free base, and the amorphous form of ceritinib free base.
The invention provides pharmaceutically acceptable solid forms of ceritinib free base and methods for their preparation. These solid forms of ceritinib can be prepared in adequate ratios and yields with high chemical purity in a crystalline or amorphous form. They can be both anhydrous or non-solvated and in the form of hydrates/solvates of the respective solvents.
The prepared solid forms of ceritinib may have various internal arrangements (polymorphism) with different physicochemical properties depending on the conditions of their preparation.
Preparation of the solid forms of ceritinib of formula I in accordance with the present invention is done by crystallization, precipitation or evaporation from a solution of ceritinib in a suitable solvent or mixtures of solvents. Ketones, esters, ethers, amides, nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water or their mixtures can be used as suitable solvents. Aliphatic Ci-C4 alcohols, substituted aromatic solvents, esters or their mixtures are preferred. The most commonly used solvents are toluene, methanol, ethanol, water or their mixtures.
The resulting product is precipitated or crystallized typically at temperatures in the range of from -30°C to the boiling point of the solvent.
In this invention, the amorphous form of ceritinib free base is preferred, which exhibits higher solubility and biological availability than the corresponding crystalline forms due to its amorphous character. The prepared amorphous form of ceritinib free base exhibits a
sufficiently high glass transition temperature, which makes it sufficiently stable for use in a dosage form.
Of the described preparation processes of crystalline forms of ceritinib free base, the process of preparation from methanol is preferred as the prepared crystalline product exhibits suitable stability for use in the dosage form and is not solvated. Crystalline forms of ceritinib can be prepared and isolated with high chemical purity.
Preparation and isolation of ceritinib was first described in the patent application WO 2008/073687. The patent application WO 2012/082972 described preparation and characterization methods of ceritinib dihydrochloride and two crystalline forms of ceritinib free base (Forms A, B). Ceritinib free base (Form A) was prepared in accordance with the process disclosed in the patent application WO 2012/082972.
Crystalline Form 1 of ceritinib free base is characterized by the reflections presented in Table 1. Table 1 includes reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of Crystalline Form 1 of ceritinib free base with the use of CuKa radiation are: 9.9; 18.1 and 25.2 ± 0.2° 2-theta. Crystalline Form 1 further exhibits the following characteristic reflections: 7.4; 13.0; 14.7 and 20.8 ± 0.2° 2-theta. The X-ray powder pattern is shown in Fig. 1.
Table 1
Interplanar spacing [A]
Position [°2Th.] [A]=0.1nm Rel. intensity [%]
7.37 11.988 35.0
7.67 11.518 29.6
9.90 8.926 100.0
12.54 7.055 19.4
13.03 6.791 34.7
14.08 6.285 9.4
14.75 6.003 31.3
15.17 5.835 12.0
18.09 4.901 70.6
19.03 4.661 37.4
19.41 4.570 34.7
19.91 4.456 22.9
20.43 4.344 16.1
20.82 4.263 27.2
21.41 4.148 24.0
22.30 3.984 8.7
23.50 3.782 5.2
24.15 3.682 15.3
24.68 3.605 12.2
25.23 3.528 47.4
25.87 3.442 7.9
26.28 3.389 10.9
26.57 3.352 15.1
27.95 3.190 14.0
29.69 3.007 6.6
34.04 2.632 4.8
The melting point of Crystalline Form 1 of ceritinib free base measured by differential scanning calorimetry (DSC) was 130°C.
Crystalline Form 2 of ceritinib free base is characterized by the reflections presented in Table 2. Table 2 includes reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of Crystalline Form 2 of ceritinib free base measured by CuKa radiation are: 4.9; 14.4; 22.0 and 25.6 ± 0.2° 2-theta. Crystalline Form 2 further exhibits the following characteristic reflections: 9.8; 12.3; 17.0 and 18.9 ± 0.2° 2-theta. The X-ray powder pattern is shown in Fig. 2.
23.04 3.857 2.6
24.37 3.649 3.0
24.80 3.590 2.3
25.64 3.472 7.6
26.61 3.348 2.5
28.42 3.138 4.6
29.13 3.063 3.6
30.70 2.910 1.7
The melting point of Crystalline Form 2 of ceritinib free base measured by differential scanning calorimetry (DSC) was 96°C.
Crystalline Form 2B of ceritinib free base is characterized by the reflections presented in Table 3. Table 3 includes reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of Crystalline Form 2B of ceritinib free base measured by CuKa radiation are: 5.1; 14.6; 18.0 and 0.2 ± 2° 2-theta. Crystalline Form 2B further exhibits the following characteristic reflections: 12.4; 22.1 and 26.0 ± 0,2° 2-theta. The X-ray powder pattern is shown in Fig. 3.
Table 3
Interplanar spacing [A]
Position [°2Th.] [A]=0.1nm Rel. intensity [%]
5.12 17.247 100.0
9.76 9.059 31.2
10.19 8.674 21.6
12.42 7.120 51.3
12.88 6.868 12.1
13.75 6.435 8.5
14.61 6.058 73.1
15.24 5.808 56.8
17.23 5.142 57.6
17.96 4.934 71.4
19.01 4.665 13.4
19.43 4.565 23.8
20.22 4.389 15.4
20.60 4.308 24.2
21.11 4.205 13.5
22.07 4.024 47.6
23.08 3.851 20.0
24.57 3.620 21.4
25.35 3.510 7.7
26.00 3.425 36.9
26.73 3.332 17.1
27.98 3.186 14.9
29.05 3.071 22.7
31.85 2.807 6.8
The melting point of Crystalline Form 2B of ceritinib free base measured by differential scanning calorimetry (DSC) was 161 °C.
Crystalline Form 3 of ceritinib free base is characterized by the reflections presented in Table 4. Table 4 includes reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of Crystalline Form 3 of ceritinib free base measured by CuKa radiation are: 3.9; 12.1; 17.1 and 20.4 ± 0.2° 2-theta. Crystalline Form 3 further exhibits the following characteristic reflections: 5.9; 7.9; 15.8 and 18.6 ± 0.2° 2-theta. The X-ray powder pattern is shown in Fig. 4.
The melting point of Crystalline Form 3 of ceritinib free base measured by differential scanning calorimetry (DSC) was 80°C.
Crystalline Form 4 of ceritinib free base is characterized by the reflections presented in Table 5. Table 5 includes reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of Crystalline Form 4 of ceritinib free base measured by CuKot radiation are: 4.9; 14.3 and 21.8 ± 0.2° 2-theta. Crystalline Form 4 further exhibits the following characteristic reflections: 12.2; 17.0; 18.0 and 24.3 ± 0.2° 2-theta. The X-ray powder pattern is shown in Fig. 5.
Table 5
Interplanar spacing [A] Rel. intensity
Position [°2Th.] [A]=0.1nm [%]
4.91 17.982 100.0
9.50 9.298 11.5
9.77 9.047 12.6
10.02 8.820 9.3
12.20 7.252 19.4
12.65 6.995 4.4
13.64 6.488 7.5
14.34 6.171 40.1
15.01 5.899 21.8
15.41 5.745 7.5
17.02 5.205 29.1
17.96 4.936 23.5
18.78 4.721 5.6
19.13 4.635 7.8
19.87 4.465 6.3
20.44 4.342 8.6
20.89 4.248 4.5
21.81 4.071 14.9
22.60 3.931 4.0
23.05 3.855 4.3
24.30 3.659 7.6
25.80 3.455 6.9
26.62 3.346 3.0
27.70 3.217 5.9
28.28 3.154 4.8
28.75 3.103 7.0
31.56 2.832 2.1
The melting point of Crystalline Form 4 of ceritinib free base measured by differential scanning calorimetry (DSC) was 72°C.
Crystalline Form 5 of ceritinib free base is characterized by the reflections presented in Table 6. Table 6 includes reflections whose relative intensity value is higher than 1%. The characteristic diffraction peaks of Crystalline Form 5 of ceritinib free base measured by CuKa radiation are: 5.4; 9.4; 15.1; 16.9 ± 0.2° 2-theta. Crystalline Form 5 further exhibits the following characteristic reflections: 12.5, 18.7 and 25.8 ± 0.2° 2-theta. The X-ray powder pattern is shown in Fig. 6. Table 6
27.87 3.198 10.0
28.52 3.127 19.6
29.64 3.011 3.7
30.50 2.929 5.1
The melting point of Crystalline Form 5 of ceritinib free base measured by differential scanning calorimetry (DSC) was 164°C.
The X-ray powder pattern of the amorphous form of ceritinib free base is shown in Figure 7. The glass transition temperature of amorphous form of ceritinib free base measured by differential scanning calorimetry (DSC) was 65°C.
The solid forms of ceritinib free base prepared in accordance with this invention can be used for the preparation of pharmaceutical compositions, especially solid dosage forms, e.g. tablets or capsules. Such pharmaceutical compositions can contain at least one excipient from the group of fillers (e.g. lactose), binders (e.g. microcrystalline cellulose), disintegrants (e.g. sodium salt of croscarmellose), lubricants (e.g. magnesium stearate), surfactants etc. Ceritinib free base can be mixed with the above mentioned excipients, screened through a sieve and the resulting mixture can be tabletted or filled into capsules. The tablets can be further coated with common coating compounds, e.g. polyvinyl alcohol or polyethylene glycol. The term "room temperature" refers, for the purposes of the text below and above, to the temperature range from 22 to 26°C.
The invention is clarified in a more detailed way using the examples below. These examples, which illustrate the preparation of solid forms of ceritinib, only have an illustrative character and do not restrict the scope of the invention in any respect.
Experimental part X-ray powder diffraction
The diffractograms were obtained using an X'PERT PRO MPD PANalytical powder diffractometer, used radiation CuKa (λ=1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40° 2Θ, increment: 0.01° 2Θ at the dwell time at a reflection of 0.5 s, the measurement was carried out with a flat sample with the area/thickness of 10/0.5 mm. For the correction of the primary array 0.02 rad Soller slits, a 10mm mask and a 1/4° fixed anti-
dispersion slit were used. The irradiated area of the sample is 10 mm, programmable divergence slits were used. For the correction of the secondary array 0.02 rad Soller slits and a 5.0 anti-dispersion slit were used. Differential Scanning Calorimetry (DSC)
The records of the solid crystalline forms of ceritinib were measured with the use of a DSC Pyris 1 device by Perkin Elmer. The sample charge in a standard Al pot was between 2.5-3 mg and the heating rate was 10°C/min. The temperature program that was used consists of 1 min of stabilization at the temperature of 0°C and then of heating up to 300°C at the heating rate of 10°C/min. As the carrier gas 4.0 N2 was used at the flow of 20 ml/min.
The record of the amorphous solid form of ceritinib was measured using a Discovery DSC device made by TA Instruments. The sample charge in a standard Al pot (40 xL) was between 4-5 and 5 mg and the heating rate was 5°C/min. The temperature program that was used consists of 1 min of stabilization at the temperature of 0°C and then of heating up to 250°C at the heating rate of 5°C/min (amplitude = 0.8°C and period = 60 s). As the carrier gas 5.0 N2 was used at the flow of 50 ml/min.
Examples
Crystalline ceritinib free base (Form A) was prepared in accordance with the process disclosed in the patent application WO 2012/082972.
The crystalline form of ceritinib dihydrochloride was prepared in accordance with the method disclosed in the patent application PV 2015-613.
Example 1
Preparation of Crystalline Form 1 of ceritinib free base in toluene
Crystalline free base of 5-chloro-iV2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]-N4-[2- (isopropylsulfonyl)phenyl]-2,4-pyrimidinediamine (Form A) in the amount of 90 mg was dissolved in 0.3 ml of toluene at 110°C. The obtained solution was filtered in the hot state and rapidly cooled down to -20°C. The separated solid fraction was stored at this temperature for 3 days. The separated solid fraction was filtered. The obtained product was left to dry at the atmospheric pressure at the room temperature for 48 hours. Yield 87 mg. X-ray powder pattern in Fig. 1. Melting point in accordance with DSC 130°C.
Example 2
Preparation of Crystalline Form 2 of ceritinib free base in methanol
Crystalline free base of 5-chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]-N4-[2- (isopropylsulfonyl)phenyl]-2,4-pyrimidinediamine (Form A) in the amount of 95 mg was dissolved in 1.2 ml of methanol at 65°C. The obtained solution was filtered in the hot state and rapidly cooled down to -20°C. The separated solid fraction was stored at this temperature for 3 days. The separated solid fraction was filtered. The obtained product was left to dry at the atmospheric pressure at the room temperature for 48 hours. Yield 92 mg. X-ray powder pattern in Fig. 2. Melting point in accordance with DSC 96°C.
Example 3
Preparation of Crystalline Form 2B of ceritinib free base
The crystalline form of 5-chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]-iV4-[2- (isopropylsulfonyl)phenyl]-2,4-pyrimidine diamine dihydrochloride was prepared according to the method disclosed in the patent application WO 2012/082972. 500 mg of this substance was dissolved in 0.3 ml of methanol, 1.2 ml of ethanol and 0.5 ml of water at 55°C. Under stirring at 55°C, a 2M aqueous solution of Na2C03 was gradually added to the obtained solution until pH 12 was achieved (1.5 ml of 2M Na2C03 was used). The obtained suspension was stirred for 1 h. Subsequently, 2.5 ml of water was added to the the suspension and being stirred, the mixture was cooled down to the room temperature and at this temperature it was further stirred for 20 h. The separated solid fraction was filtered and washed with water. The obtained product was dried at the temperature of 55°C and the pressure of 30 kPa for 22 h. 412 mg of the product was obtained in the form of a white powder. X-ray powder pattern in Fig. 3. Melting point in accordance with DSC 161 °C.
Example 4
Preparation of Crystalline Form 2B of ceritinib free base
The crystalline form of 5-chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]-N4-[2- (isopropylsulfonyl)phenyl]-2,4-pyrimidinediamine dihydrochloride in the amount of 500 mg was dissolved in 1.5 ml of 2-propanol and 0.5 ml of water at 55°C. Under stirring at 55°C, a
2M aqueous solution of Na2C03 was gradually added to the obtained solution until pH 12 was achieved (1.5 ml of 2M Na2C03 was used). The obtained suspension was stirred for 1 h. Subsequently, 2.5 ml of water was added to the suspension and being stirred, the mixture was cooled down to the room temperature and at this temperature it was further stirred for 20 h. The separated solid fraction was filtered and washed with water. The obtained product was dried at the temperature of 55°C and the pressure of 30 kPa for 22 h. 418 mg of the product was obtained in the form of a white powder. The X-ray powder pattern and melting point according to DSC were in conformity to the records measured for Form 2B in Example 3.
Example 5
Preparation of Crystalline Form 2B of ceritinib free base
The crystalline form of 5-chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]-iV4-[2- (isopropylsulfonyl)phenyl]-2,4-pyrimidinediamine dihydrochloride in the amount of 500 mg was dissolved in 1.5 ml of ethyl methyl ketone and 0.5 ml of water at 55°C. Under stirring at 55°C, a 2M aqueous solution of Na2C03 was gradually added to the obtained solution until pH 12 was achieved (1.5 ml of 2M Na2C03 was used). The obtained suspension was stirred for 1 h. Subsequently, 2.5 ml of water was added to the suspension and being stirred, the mixture was cooled down to the room temperature and at this temperature it was further stirred for 20 h. The separated solid fraction was filtered and washed with water. The obtained product was dried at the temperature of 55°C and the pressure of 30 kPa for 22 h. 416 mg of the product was obtained in the form of a white powder. The X-ray powder pattern and melting point according to DSC were in conformity to the records measured for Form 2B in Example 3.
Example 6
Preparation of Crystalline Form 2B of ceritinib free base
The crystalline form of 5-chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]-iV4-[2- (isopropylsulfonyl)phenyl]-2,4-pyrimidinediamine dihydrochloride in the amount of 30 mg was dissolved in 90 ml of ethanol and 30 ml of water at 55°C. Under stirring at 55°C, a 2M aqueous solution of Na2C03 was gradually added to the obtained solution until pH 11-12 was achieved (90 ml of 2M Na2C03 was used). The obtained suspension was stirred for 1 h. Subsequently, 150 ml of water was added to the the suspension and being stirred, the mixture
was cooled down to the room temperature and at this temperature it was further stirred for 1 h. The separated solid fraction was filtered and washed.
Example 7
Preparation of Crystalline Form 3 of ceritinib free base in ethanol (99%)
Crystalline free base of 5-chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]-N4-[2- (isopropylsulfonyl)phenyl]-2,4-pyrimidinediamine (Form A) in the amount of 92.5 mg was dissolved in 1.2 ml of ethanol (99.8 %) at 65°C. The obtained solution was filtered in the hot state and rapidly cooled down to -20°C. The separated solid fraction was stored at this temperature for 3 days. The separated solid fraction was filtered. The obtained product was left to dry at the atmospheric pressure at the room temperature for 48 hours. Yield 89.3 mg. X- ray powder pattern in Fig. 4. Melting point in accordance with DSC 80°C.
Example 8
Preparation of Crystalline Form 4 of ceritinib free base in ethanol (75%)
Crystalline free base of 5-chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]-N4-[2- (isopropylsulfonyl)phenyl]-2,4-pyrimidinediamine (Form A) in the amount of 89.1 mg was dissolved in 2 ml of ethanol (75 %) at 65°C. The obtained solution was filtered in the hot state and rapidly cooled down to -20°C. The separated solid fraction was stored at this temperature for 3 days. The separated solid fraction was filtered. The obtained product was left to dry at the atmospheric pressure at the room temperature for 48 hours. Yield 85 mg. X-ray powder pattern in Fig. 5. Melting point in accordance with DSC 72°C.
Example 9
Preparation of Crystalline Form 5 of ceritinib free base
Crystalline free base of 5-chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]-iV4-[2- (isopropylsulfonyl)phenyl]-2,4-pyrimidinediamine (Form A) in the amount of 190 mg was dissolved in 2.5 ml of methanol at 65°C. The obtained solution was filtered in the hot state and rapidly cooled down to -20°C. The separated solid fraction was stored at this temperature for 3 days. The separated solid fraction was filtered. The obtained product was left to dry at the atmospheric pressure at the temperature of 80°C for 72 h. Yield 183 mg. X-ray powder pattern in Fig. 6. Melting point in accordance with DSC 164°C.
Example 10
Preparation of amorphous ceritinib free base
Crystalline free base of 5-chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]-N -[2- (isopropylsulfonyl)phenyl]-2,4-pyrimidinediamine (Form A) in the amount of 90 mg was dissolved in 6.9 ml of acetone at 56°C. The obtained solution was filtered in the hot state and evaporated on a rotary vacuum evaporator at 40°C and the pressure of 2 kPa for 30 min. Yield 89 mg. X-ray powder pattern in Fig. 7. Glass transition temperature according to DSC 65°C.
Claims
1. Crystalline Form 1 of ceritinib free base, exhibiting the following characteristic reflections in the X-ray powder pattern measured by CuKa radiation: 9.9; 18.1 and 25.2 ± 0.2° 2-theta.
2. Crystalline Form 1 of ceritinib free base according to claim 1, characterized by the following further reflections in the X-ray powder pattern: 7.4; 13.0; 14.7 and 20.8 ± 0.2° 2-theta.
3. Crystalline Form 1 of ceritinib free base according to claims 1 and 2, characterized by a differential scanning calorimetry curve with the melting point at 130°C.
4. A method for preparation of Crystalline Form 1 of ceritinib free base defined in claims 1 to 3, characterized in that it comprises:
a) dissolution of ceritinib in toluene at a temperature in the range from 50°C to the boiling point of the solvent;
b) cooling of the solution;
c) isolation of the separated solid fraction by filtration.
5. Crystalline Form 2 of ceritinib free base, exhibiting the following characteristic reflections in the X-ray powder pattern measured by CuKa radiation: 4.9; 14.4; 22.0 and 25.6 ± 0.2° 2-theta.
6. Crystalline Form 2 of ceritinib free base according to claim 5, characterized by the following further reflections in the X-ray powder pattern: 9.8; 12.3; 17.0 and 18.9 ± 0.2° 2-theta.
7. Crystalline Form 2 of ceritinib free base according to claims 5 to 6, characterized by a differential scanning calorimetry curve with the melting point at 96°C.
8. A method for preparation of Crystalline Form 2 of ceritinib free base defined in claims 5 to 7, characterized in that it comprises:
a) dissolution of ceritinib in methanol at a temperature in the range from 50°C to the boiling point of the solvent;
b) cooling of the solution;
c) isolation of the separated solid fraction by filtration.
9. Crystalline Form 2B of ceritinib free base, exhibiting the following characteristic reflections in the X-ray powder pattern measured by Cu a radiation: 5.1; 14.6; 18.0 and 0.2 ± 2° 2-theta.
10. Crystalline Form 2B of ceritinib free base according to claim 9, characterized by the following further reflections in the X-ray powder pattern: 12.4; 22.1 and 26.0 ± 0.2° 2- theta.
11. Crystalline Form 2B of ceritinib free base according to claims 9 and 10, characterized by a differential scanning calorimetry curve with the melting point at 161°C.
12. A method for preparation of Crystalline Form 2B of ceritinib free base defined in claims 9 to 11, characterized in that it comprises:
a) dissolution of ceritinib dihydrochloride in a mixture of one or more solvents and water in the ratio of 3:1 at a temperature in the range from 50 °C to the boiling point of the mixture of solvents;
b) gradual adding of the base until pH in the range of 11 to 12 is achieved;
c) gradual adding of an antisolvent to the solution;
d) cooling of the mixture;
e) isolation of the separated solid fraction by filtration;
f) drying of the isolated ceritinib at a temperature in the range of 50 to 55 °C under a reduced pressure for at least 12 h;
wherein the solvent in step a) is selected from the group that consists of methanol, ethanol, 2-propanol, ethyl methyl ketone and their mixtures; preferably, methanol ethanol or their mixture is selected and the antisolvent in step c) is water.
13. The method for preparation of Crystalline Form 2B of ceritinib free base according to claim 12, characterized in that Na2C03, K2C03, NaHC03, KHC03, NF^OH, NaOH or KOH is used as the base in step b); a 2M aqueous solution of Na2C03 is preferably used as the base.
14. Crystalline Form 3 of ceritinib free base, exhibiting the following characteristic reflections in the X-ray powder pattern measured by CuKa radiation: 3.9; 12.1 ; 17.1 and 20.4 ± 0.2° 2-theta.
15. Crystalline Form 3 of ceritinib free base according to claim 14, characterized by the following further reflections in the X-ray powder pattern: 5.9; 7.9; 15.8 and 18.6 ± 0.2° 2-theta.
16. Crystalline Form 3 of ceritinib free base according to claims 14 to 15, characterized by a differential scanning calorimetry curve with the melting point at 80°C.
17. A method for preparation of Crystalline Form 3 of ceritinib free base defined in claims 14 to 16, characterized in that it comprises:
a) dissolution of ceritinib in ethanol at a temperature in the range from 50 °C to the boiling point of the solvent;
b) cooling of the solution;
c) isolation of the separated solid fraction by filtration.
18. Crystalline Form 4 of ceritinib free base, exhibiting the following characteristic reflections in the X-ray powder pattern measured by CuKa radiation: 4.9; 14.3 and 21.8 ± 0.2° 2-theta.
19. Crystalline Form 4 of ceritinib free base according to claim 18, characterized by the following further reflections in the X-ray powder pattern: 12.2; 17.0; 18.0 and 24.3 ± 0.2° 2-theta.
20. Crystalline Form 4 of ceritinib free base according to claims 18 and 19, characterized by a differential scanning calorimetry curve with the melting point at 72°C.
21. A method for preparation of Crystalline Form 4 of ceritinib free base defined in claims 18 to 20, characterized in that it comprises:
a) dissolution of ceritinib in a mixture of ethanol and water comprising 50 to 90 wt. % of ethanol at a temperature in the range from 50°C to the boiling point of the mixture of solvents;
b) cooling of the solution;
c) isolation of the separated solid fraction by filtration.
22. Crystalline Form 5 of ceritinib free base, exhibiting the following characteristic reflections in the X-ray powder pattern measured by CuKa radiation: 5.4; 9.4; 15.1; 16.9 ± 0.2° 2-theta.
23. Crystalline Form 5 of ceritinib free base according to claim 22, characterized by the following further reflections in the X-ray powder pattern: 12.5, 18.7 and 25.8 ± 0.2° 2- theta.
24. Crystalline Form 5 of ceritinib free base according to claims 22 to 23, characterized by a differential scanning calorimetry curve with the melting point at 164°C.
25. A method for preparation of Crystalline Form 5 of ceritinib free base defined in claims 22 to 24, characterized in that it comprises:
a) dissolution of ceritinib in methanol at a temperature in the range from 50°C to the boiling point of the solvent;
b) cooling of the solution;
c) isolation of the separated solid fraction by filtration;
d) drying of the solid fraction at a temperature in the range from 80 to 120°C for at least 12 hours.
26. The amorphous form of ceritinib free base.
27. The amorphous form of ceritinib free base according to claim 26, exhibiting a characteristic amorphous halo in the X-ray powder pattern measured by CuKa radiation.
28. The amorphous form of ceritinib free base according to claims 26 and 27, characterized by a differential scanning calorimetry curve with the glass transition temperature Tg of 65 °C.
29. A method for preparation of the amorphous form of ceritinib free base defined in claims 26 to 28, characterized in that it comprises:
a) dissolution of ceritinib in acetone at a temperature in the range from 50°C to the boiling point of the solvent;
b) evaporation of the obtained solution.
30. Use of a solid form of ceritinib free base defined in any one of the preceding claims for the preparation of a pharmaceutical composition.
31. A pharmaceutical composition, characterized in that it contains a solid form of ceritinib free base defined in any one of the preceding claims and at least one pharmaceutically acceptable excipient.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CZ2015-522A CZ2015522A3 (en) | 2015-07-28 | 2015-07-28 | Solid forms of the free base of ceritinib |
| CZ2015-743A CZ2015743A3 (en) | 2015-10-21 | 2015-10-21 | Solid forms of the free base of ceritinib |
| PCT/CZ2016/000082 WO2017016529A1 (en) | 2015-07-28 | 2016-07-28 | Solid forms of ceritinib free base |
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| Publication Number | Publication Date |
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| EP3328848A1 true EP3328848A1 (en) | 2018-06-06 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP16753812.3A Withdrawn EP3328848A1 (en) | 2015-07-28 | 2016-07-28 | Solid forms of ceritinib free base |
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| WO (1) | WO2017016529A1 (en) |
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| EP3453708B8 (en) | 2010-12-17 | 2022-03-16 | Novartis AG | Process for the preparation of 5-chloro-n2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-n4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine di-hydrochloride |
| CN112645929B (en) * | 2019-10-11 | 2022-03-11 | 苏州泽璟生物制药股份有限公司 | Polymorphs of isopropylsulfonylphenylpyrimidines or salts thereof |
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| AU2007333394C1 (en) | 2006-12-08 | 2011-08-18 | Novartis Ag | Compounds and compositions as protein kinase inhibitors |
| EP3453708B8 (en) | 2010-12-17 | 2022-03-16 | Novartis AG | Process for the preparation of 5-chloro-n2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-n4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine di-hydrochloride |
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