WO2016127963A1

WO2016127963A1 - Solid forms of palbociclib salts

Info

Publication number: WO2016127963A1
Application number: PCT/CZ2016/000017
Authority: WO
Inventors: Pavel ZVATORA; Ondrej Dammer; Jiri MIKSATKO; Lukas KREJCIK
Original assignee: Zentiva, K.S.
Priority date: 2015-02-11
Filing date: 2016-02-11
Publication date: 2016-08-18
Also published as: CZ201589A3

Abstract

The invention relates to a solid form a salt of palbociclib of formula I with an acid HA in the molar ratio of 1 :1 or 1 :2, the acid HA being selected from the group containing hydrobromic acid, sulphuric acid, oxalic acid, benzenesulfonic acid, salicylic acid, fumaric acid, 2,4-dihydroxybenzoic acid, benzoic acid. Another aspect of the invention is a process of preparing the palbociclib salts.

Description

Solid forms of Palbociclib salts Technical Field The invention relates to solid forms of 6-acetyl-8-cyciopentyl-5-methyl-2-{[5-(l-piperazinyl)- 2^yridinyl]amino}pyrido[2, -d pyrimidin-7(8H)-one of formula I,

(I)

known as palbociclib, and to methods of their preparation.

Background Art

6- Acetyl- 8-cyclopentyl-5 -memyl-2- { [5-( 1 - φ^

d3pyrimidin-7(8H)-one, which is known as palbociclib (CAS no. 571190-30-2) belongs to the group of "cyclin-dependent kinase" (CDK4) inhibitors and is suitable for the treatment of inflammatory diseases, cancer and some vascular diseases. The enzymatic inhibition capability of palbociclib at low concentrations has been published in specialized literature (D.W. Fry et al. J. Biol. Chem. (2001) 16617-16623). Clinical studies with animal models have shown that the free base of palbociclib only exhibits a limited solubility (9 μg ml of water) and biological availability and for this reason it is not suitable for pharmaceutical use. Preparation of this molecule and its isolation in the form of palbociclib hydrochloride is described in the patent document (WO 03/062236). Salts of palbociclib can be prepared by a reaction of the free base of palbociclib with the respective acid in the desired ratio in a suitable solvent. Preparation and characterization of palbociclib mono-isethionate, palbociclib mono- hydrochloride, di-hydrochloride, palbociclib mono-mesylate and di-mesylate and DVS spectrum of palbociclib mono-tosylate are described in the patent document (WO2005/005426). The palbociclib di-hydrochloride salt exhibits a suitable solubility in water, but its physical-chemical properties, especially hygroscopicity, make its use in preparation and formulation of drugs impossible. Some salts of palbociclib exhibit a variable internal structure (polymorphism) depending on the method and conditions of their preparation. The patent document WO 2005/005426 described the following polymorphic forms of palbociclib isethionate: "Form A", "Form B" and "Form D"; and of palbociclib mono-mesylate: "Form A", "Form B", "Form C" and "Form D". However, preparation and isolation of isethionic acid is a relatively demanding process, which, according to the patent document WO 2005/005426, comprises eleven-day long evaporation of the solution with the use of a rotary vacuum evaporator at 50°C. This process is unsuitable for the preparation of this salt in the industrial scale. A patent document (WO 2014/128588) described the following polymorphic forms of palbociclib base.

Although a number of solid forms of palbociclib have been described, it is obvious that some of them do not have suitable physical-chemical characteristics or have a limited solubility and biological availability, or their preparation in the industrial scale is considerably problematic (see the discussion in the patent application WO 2005/005426). The present invention describes preparation of new salts of palbociclib that can be, thanks to their crystalline character, advantageously used for organic synthesis of palbociclib as well as for pharmaceutical composition of new dosage forms.

Disclosure of Invention The invention provides solid forms of palbociclib with inorganic and organic acids and methods of their preparation. These compounds are prepared by a reaction of palbociclib in the basic form with an acid selected from the group containing hydrobromic acid, sulphuric acid, oxalic acid, benzenesulfonic acid, salicylic acid, fumaric acid, 2,4-dihydroxybenzoic acid, benzoic acid in the molar ratio of 1 : 1 or 1 :2 in a suitable solvent or mixtures of solvents.

The prepared solid forms are crystalline and are prepared in a purity corresponding to the demands for their pharmaceutical use in formulation of new dosage forms.

Brief Description of Drawings Figure 1 : X-ray powder pattern of palbociclib hydrobromide (1:1)

Figure 2: DSC record of palbociclib hydrobromide (1:1)

Figure 3: Infrared spectrum of palbociclib hydrobromide (1:1)

Figure 4: X-ray powder pattern of palbociclib sulphate (1:1) Figure 5: DSC record of palbociclib sulphate (1:1)

Figure 6: Infrared spectrum of palbociclib sulphate (1:1)

Figure 7: X-ray powder pattern of palbociclib oxalate (1:1)

Figure 8: DSC record of palbociclib oxalate (1:1)

Figure 9 : Infrared spectrum of palbociclib oxalate (1:1)

Figure 10: ¹HNMR spectrum of palbociclib oxalate (1:1)

Figure 11 : X-ray powder pattern of palbociclib besylate (1:1)

Figure 12: DSC record of palbociclib besylate (1:1)

Figure 13: Infrared spectrum of palbociclib besylate (1:1)

Figure 14: ¹HNMR spectrum of palbociclib besylate (1:1)

Figure 15: X-ray powder pattern of palbociclib salicylate (1 :1)

Figure 16: DSC record of palbociclib salicylate (1 :1)

Figure 17: Infrared spectrum of palbociclib salicylate (1:1)

Figure 18: ¹FiNMR spectrum of palbociclib salicylate (1:1)

Figure 19 : X-ray powder pattern of palbociclib fumarate (1:1)

Figure 20: DSC record of palbociclib fumarate (1:1)

Figure 21: Infrared spectrum of palbociclib fumarate (1 :1)

Figure 22: ¹HNMR spectrum of palbociclib fumarate (1 :1)

Figure 23: X-ray powder pattern of palbociclib 2,4-dihydroxybenzoate (1:1) Figure 24 : DSC record of palbociclib 2,4-dihydroxybenzoate (1:1)

Figure 25: Infrared spectrum of palbociclib 2,4-dihydroxybenzoate (1:1) Figure 26: ^[HNMR spectrum of palbociclib 2,4-dihydroxybenzoate (1 :1) Figure 27: X-ray powder pattern of palbociclib benzoate (1 :1)

Figure 28: DSC record of palbociclib benzoate (1:1)

Figure 29: Infrared spectrum of palbociclib benzoate (1 :1)

Figure 30: ¹HNMR spectrum of palbociclib benzoate (1:1)

Figure 31 : X-ray powder pattern of palbociclib mesylate (1:1)

Figure 32: DSC record of palbociclib mesylate (1:1)

Figure 33: Infrared spectrum of palbociclib mesylate (1:1)

Figure 34: ¹HNMR spectrum of palbociclib mesylate (1 :1)

Figure 35: X-ray powder pattern of palbociclib hydrobromide (1:2)

Figure 36: DSC record of palbociclib hydrobromide (1:2)

Figure 37: Infrared spectrum of palbociclib hydrobromide (1:2) Figure 38: X-ray powder pattern of palbociclib sulphate (1:2)

Figure 39: DSC record of palbociclib sulphate (1:2)

Figure 40: Infrared spectrum of palbociclib sulphate (1:2)

Figure 41 : X-ray powder pattern of palbociclib besylate (1 :2)

Figure 42: DSC record of palbociclib besylate (1 :2)

Figure 43: Infrared spectrum of palbociclib besylate (1:2)

Figure 44: ^lHNMR spectrum of palbociclib besylate (1:2)

Figure 45: X-ray powder pattern of palbociclib mesylate (1 :2)

Figure 46: DSC record of palbociclib mesylate (1:2)

Figure 47: Infrared spectrum of palbociclib mesylate (1:2)

Figure 48: ¹HNMR spectrum of palbociclib mesylate (1 :2)

Detailed description of the invention

Although preparation of a salt by a reaction of an acid and base is a well-known method, it is always a problem to obtain the desired salts in the solid phase and in purity corresponding to the demands for their pharmaceutical use. Biological availability greatly depends on whether a crystalline or amorphous product is obtained. An amorphous product is usually more readily 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 purity is easier to achieve and it dissolves more slowly. Mixtures of the amorphous and crystalline solid phase may represent a solution to the problem.

This invention provides a number of salts of palbociclib in the solid phase either or with an admixture of the amorphous form. This invention prefers crystalline forms of palbociclib. The invention provides novel solid forms of palbociclib with hydrobromic acid, sulphuric acid, oxalic acid, benzenesulfonic acid, salicylic acid, fumaric acid, 2.4-dihydroxybenzoic acid and benzoic acid in variable molar ratios. According to the invention, the molar ratios of 1:1 and 1 :2 are preferred.

The novel solid forms of palbociclib with these acids can be prepared in adequate ratios and yields with high chemical purity in a crystalline form, amorphous form, or in a mixture of amorphous and crystalline forms.

These novel solid forms can be both anhydrous and/or non-sol vated and in the form of hydrates/solvates of the respective solvents. The prepared new solid forms of palbociclib may have various internal arrangements (polymorphism) with different physical-chemical properties depending on the conditions of their preparation. For this reason, the invention relates to individual crystals or their mixtures in any ratio.

These novel solid forms are suitable for preparation of palbociclib with a high chemical purity. The preparation of novel solid forms of palbociclib (formula (I)) is achieved by a reaction of the palbociclib base with hydrobromic acid, sulphuric acid, oxalic acid, benzenesulfonic acid, salicylic acid, fumaric acid, 2-4-dihydroxybenzoic acid or benzoic acid. The reaction is conducted in a suitable solvent, which can be ketones, esters, ethers, amides, nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water or their mixtures. Aliphatic -C alcohols, esters or their mixtures are preferred. The most commonly used solvents are methanol, ethanol, water or their mixtures.

The resulting product is precipitated or crystallized, typically at temperatures in the range of -30 °C to the boiling point of the solvent.

The free base of palbociclib was prepared in accordance with the procedure mentioned in the patent document (WO 2014/128588).

The crystalline form of palbociclib hydrobromide (1:1) is characterized by the reflections presented in Table 1. Table 1 includes reflections whose relative intensity value is higher than 1 percent. The characteristic diffraction peaks of palbociclib hydrobromide in accordance with this invention are: 11.5; 14.8; 16.5; 19.1 and 21.9° ± 0.2° 2-theta. The X-ray powder pattern is shown in Fig. 1.

Table 1

Position Interplanar spacing

(°2 Theta) rf(A) [= 0.1 nm] Rel. Intensity (%)

7.50 11.775 10.8

9.03 9.782 8.9

9.58 9.222 20.0

11.47 7.709 56.2

14.79 5.986 30.6

16.47 5.379 30.7

18.08 4.903 11.7

19.13 4.636 79.7

20.75 4.276 19.7 21.92 4.051 100.0

23.33 3.811 19.1

25.18 3.534 15.1

26.64 3.344 17.2

28.95 3.081 5.8

30.70 2.910 10.8

31.31 2.855 6.6

32.29 2.770 5.2

32.72 2.734 5.2

34.40 2.605 5.1

37.62 2.389 5.1

38.80 2.319 4.9

In this case, the melting point of palbociclib hydrobromide (1:1) (Figure 2) is 315°C (DSC). The infrared spectrum of palbociclib hydrobromide (1:1) is shown in Figure 3.

The crystalline form of palbociclib sulphate (1:1) is characterized by the reflections presented in Table 2. Table 2 includes reflections whose relative intensity value is higher than 1 percent. The characteristic diffraction peaks of palbociclib sulphate in accordance with this invention are: 4.1; 9.3; 11.7; 16.2; 17.2 and 21.2° ± 0.2° 2-theta. The X-ray powder pattern is shown in Fig. 4.

Table 2

Position Interplanar spacing

(°2 Theta) rf (A) [= 0.1 nm] Rel. Intensity (%)

4.10 21.560 89.3

6.43 13.732 11.9

8.15 10.836 67.1

9.29 9.509 87.0

11.69 7.565 46.5

14.76 5.996 11.1

16.24 5.453 100.0

16.74 5.292 34.1

17.17 5.162 97.0 18.63 4.759 11.6

21.20 4.187 73.4

22.21 4.000 64.8

23.75 3.743 23.9

26.40 3.374 12.1

26.81 3.323 11.7

27.44 3.248 16.4

28.77 3.100 14.4

30.72 2.908 7.5

In this case, the melting point of palbocichb sulphate (1:1) (Figure 5) is 273°C (DSC).

The infrared spectrum of palbocichb sulphate (1:1) is shown in Figure 6. The crystalline form of palbocichb oxalate (1 :1) is characterized by the reflections presented in Table 3. Table 3 includes reflections whose relative intensity value is higher than 1 percent. The characteristic diffraction peaks of palbocichb oxalate in accordance with this invention are: 4.5; 10.0; 13.8; 17.3; 19.6 and 23. ± 0.2° 2-theta. The X-ray powder pattern is shown in Fig. 7.

Table 3

Position Interplanar spacing

(°2 Theta) rf (A) [= 0.1 nm] Rel. Intensity (%)

4.55 19.424 100.0

6.20 14.240 12.2

7.47 11.827 63.8

10.00 8.842 86.7

12.41 7.125 39.3

13.37 6.618 43.2

13.82 6.402 50.0

14.88 5.949 13.3

17.26 5.135 38.6

17.94 4.940 29.0

18.67 4.750 35.3 19.64 4.517 56.9

20.33 4.365 35.4

21.10 4.207 25.1

23.11 3.845 38.6

23.71 3.750 30.4

25.47 3.495 15.8

27.11 3.286 7.2

28.29 3.152 4.9

29.76 3.000 4.7

In this case, the melting point of palbociclib oxalate (1:1) (Figure 8) is 256°C (DSC).

The infrared spectrum of palbociclib oxalate (1:1) is shown in Figure 9.

Figure 10 shows an example of the 1H NMR spectrum of the prepared palbociclib oxalate (1:1).

The crystalline form of palbociclib besyiate (1:1) is characterized by the reflections presented in Table 4. Table 4 includes reflections whose relative intensity value is higher than 1 percent. The characteristic diffraction peaks of palbociclib besyiate in accordance with this invention are: 9.0; 10.7; 11.9; 15.8; 22.1 and 26.2° ± 0.2° 2-theta. The X-ray powder pattern is shown in Fig. 11.

Table 4

Position Interplanar spacing

(°2 Theta) d (A) [= 0.1 nm] Rel. Intensity (%)

5.03 17.562 25.5

9.02 9.799 44.2

10.12 8.737 12.5

10.69 8.270 45.9

11.29 7.832 21.2

11.92 7.419 34.2

13.01 6.801 12.3

14.76 5.996 30.9

15.76 5.618 52.7

17.08 5.187 10.8 17.88 4.956 21.6

18.17 4.879 23.8

18.57 4.775 27.9

19.54 4.539 8.2

20.40 4.351 7.2

22.06 4.025 100.0

22.77 3.902 24.9

23.05 3,856 24.0

23.61 3.765 11.8

24.05 3.698 12.2

26.20 3.399 18.1

27.70 3.218 5.2

29.92 2.984 12.6

30.77 2.903 10.0

In this case, the melting point of palbociclib besylate (1:1) (Figure 12) is 294°C (DSC).

The infrared spectrum of palbociclib besylate (1:1) is shown in Figure 13.

Figure 14 shows an example of the 1H NMR spectrum of the prepared palbociclib besylate (1 :1).

The crystalline form of palbociclib salicylate (1:1) is characterized by the reflections presented in Table 5. Table 5 includes reflections whose relative intensity value is higher than 1 percent. The characteristic diffraction peaks of palbociclib salicylate in accordance with this invention are: 6.9; 11.7; 13.9; 16.9; 21.8 and 26.2° ± 0.2° 2-theta. The X-ray powder pattern is shown in Fig. 15.

Table s

Position Interplanar spacing

(°2 Theta) rf (A) [= 0.1 nm] Rel. Intensity (%)

6.94 12.720 55.5

10.14 8.716 93.2

11.00 8.036 42.5

11.75 7.529 92.8

12.30 7.188 14.8

13.03 6.790 17.5 13.91 6.362 89.6

15.54 5.699 13.9

16.12 5.495 36.1

16.87 5.252 59.6

18.29 4.847 49.6

19.56 4.534 10.1

20.63 4.302 69.0

21.79 4.076 100.0

22.34 3.976 44.0

23.75 3.744 59.2

24.96 3.565 20.8

26.23 3.395 72.7

27.10 .287 10.3

28.12 3.171 18.2

30.67 2.913 12.8

32.49 2.754 8.8

33.31 2.687 6.6

34.89 2.570 6.2

In this case, the melting point of palbociclib salicylate (1:1) (Figure 16) is 258°C (DSC).

The infrared spectrum of palbociclib salicylate (1 :1) is shown in Figure 17.

Figure 18 shows an example of the 1H NMR spectrum of the prepared palbociclib salicylate (1:1).

The crystalline form of palbociclib fumarate (1 :1) is characterized by the reflections presented in Table 6. Table 6 includes reflections whose relative intensity value is higher than 1 percent. The characteristic diffraction peaks of palbociclib fumarate in accordance with this invention are: 5.1; 7.6; 12.9; 17.8 and 24.9° ± 0.2° 2-theta. The X-ray powder pattern is shown in Fig. 19.

Table 6

Position Interplanar spacing

(°2 Theta) <*(A) [= 0.1 nm] Rel. Intensity (%) 4.27 20.665 18.6

5.10 17.322 100.0

7.63 11.577 23.2

8.87 9.962 4.7

9.29 9.513 6.5

11.54 7.661 14.2

12.93 6.844 19.7

14.67 6.034 5.9

15.36 5.766 14.0

15.85 5.586 12.4

17.41 5.090 24.8

17.79 4.981 26.3

18.87 4.698 13.5

19.27 4.603 18.0

20.02 4.431 4.5

21.74 4.084 5.0

23.61 3.766 12.1

24.87 3.578 22.4

25.78 3.453 6.1

28.57 3.122 3.5

In this case, the melting point of palbociclib fumarate (1 :1) (Figure 20) is 197°C (DSC).

The infrared spectrum of palbociclib fumarate (1:1) is shown in Figure 21.

Figure 22 shows an example of the 1H NMR spectrum of the prepared palbociclib fumarate (1:1).

The crystalline form of palbociclib 2,4-dihydroxybenzoate (1:1) is characterized by the reflections presented in Table 7. Table 7 includes reflections whose relative intensity value is higher than 1 percent. The characteristic diffraction peaks of palbociclib 2,4- dihydroxybenzoate in accordance with this invention are: 6.3; 10.6; 12.7; 16.4; 19.2 and 21.3° ± 0.2° 2-theta. The X-ray powder pattern is shown in Fig. 23.

Table 7

Position Interplanar spacing

(°2 Theta) d(A) [= 0.1 nm] Rel. Intensity (%) 6.33 13.953 100.0

9.29 9.516 8.1

10.56 8.373 35.3

11.33 7.803 22.6

11.92 7.421 14.4

12.72 6.956 29.9

16.36 5.414 59.2

18.04 4.913 12.4

18.66 4.752 10.3

19.16 4.629 24.9

19.64 4.517 10.4

21.30 4.168 11.5

22.57 3.936 6.1

23.77 3.741 9.8

24.19 3.676 10.2

24.66 3.607 5.0

25.63 3.473 4.6

26.34 3.381 8.6

28.32 3.149 6.8

29.35 3.041 12.4

In this case, the melting point of palbociciib 2,4-dihydroxybenzoate (1:1) (Figure 24) is 214°C (DSC).

The infrared spectrum of palbociciib 2,4-dihydroxybenzoate (1:1) is shown in Figure 25.

Figure 26 shows an example of the 1H NMR spectrum of the prepared palbociciib 2,4- dihydroxybenzoate (1:1).

The crystalline form of palbociciib benzoate (1:1) is characterized by the reflections presented in Table 8. Table 8 includes reflections whose relative intensity value is higher than 1 percent. The characteristic diffraction peaks of palbociciib benzoate in accordance with this invention are: 4.1; 8.8; 14.0; 18.9; 21.6 and 23.8° ± 0.2° 2-theta. The X-ray powder pattern is shown in Fig. 27.

Table 8

Position Interplanar spacing Rel. Intensity (%) (°2 Theta) d(A) [= 0.1 nm]

4.12 21.445 64.0

8.24 10.718 49.3

8.81 10.028 100.0

10.18 8.679 8.6

10.80 8.189 11.8

11.55 7.657 9.5

12.31 7.182 37.4

14.02 6.311 66.5

15.10 5.864 7.2

15.89 5.573 7.7

16.74 5.292 15.9

17.14 5.170 12.1

18.47 4.799 45.4

18.87 4.698 50.1

19.28 4.599 36.3

20.49 4.331 9.2

21.60 4.110 46.9

22.63 3.925 8.2

23.25 3.823 11.2

23.81 3.734 68.6

25.34 3.512 6.6

27.14 3.283 6.7

28.17 3.166 10.7

29.402 3.035 10.5

30.806 2.90011 6.8

In this case, the melting point of palbociclib benzoate (1:1) (Figure 28) is 221°C (DSC). The infrared spectrum of palbociclib benzoate (1:1) is shown in Figure 29.

Figure 30 shows an example of the 1H NMR spectrum of the prepared palbociclib benzoate (1 :1). The crystalline form of palbociclib mesylate (1:1) is characterized by the reflections presented in Table 9. Table 9 includes reflections whose relative intensity value is higher than 1 percent. The characteristic diffraction peaks of palbociclib mesylate in accordance with this invention are: 9.9; 13.4; 19.4 and 21.6° ± 0.2° ± 0.2° 2-theta. The X-ray powder pattern is shown in Fig. 31.

Table 9

In this case, the meltmg point of palbociclib mesylate (1:1) (Figure 32) is 312°C (DSC).

The infrared spectrum of palbociclib mesylate (1 : 1) is shown in Figure 33. Figure 34 shows an example of the 1H NMR spectrum of the prepared palbociclib mesylate (1:1).

The crystalline form of palbociclib hydrobromide (1:2) is characterized by the reflections presented in Table 10. Table 10 includes reflections whose relative intensity value is higher than 1 percent. The characteristic diffraction peaks of palbociclib hydrobromide in accordance with this invention are: 9.4; 11.5; 16.3; 19.2; 20.4 and 22.0° ± 0.2° 2-theta. The X-ray powder pattern is shown in Fig. 35.

Table 10

Position Interplanar spacing

(°2 Theta) d(A) [= QA nm] Rel. Intensity (%)

6.43 13.733 22.3

8.67 10.193 38.6

9.36 9.441 100.0

11.55 7.659 20.8

12.70 6.965 12.1

13.75 6.435 6.8

14.87 5.954 21.9

15.97 5.544 30.0

16.33 5.423 61.3

17.23 5.142 12.6

19.22 4.613 44.8

20.43 4.343 40.6

21.99 4.038 34.7

23.35 3.806 12.2

24.24 3.669 11.2

25.32 3.515 24.1

27.13 3.284 25.7

27.54 3.236 20.9

28.26 3.156 10.1

32.26 2.773 12.2

32.83 2.726 18.2

5.92 14.928 60.1

In this case, the melting point of palbociclib hydrobromide (1:2) (Figure 36) is 207°C (DSC). The infrared spectrum of palbociclib hydrobromide (1 :2) is shown in Figure 37.

The crystalline form of palbociclib sulphate (1 :2) is characterized by the reflections presented in Table 11. Table 11 includes reflections whose relative intensity value is higher than 1 percent. The characteristic diffraction peaks of palbociclib sulphate in accordance with this invention are: 3.1; 9.1; 12.6; 16.0; 20.1 and 26.6° ± 0.2° 2-theta. The X-ray powder pattern is shown in Fig. 38.

Table 11

In this case, the melting point of palbociclib sulphate (1:2) (Figure 39) is 283°C (DSC).

The infrared spectrum of palbociclib sulphate (1 :2) is shown in Figure 40. The crystalline form of palbociciib besyiate (1:2) is characterized by the reflections presented in Table 12. Table 12 includes reflections whose relative intensity value is higher than 1 percent. The characteristic diffraction peaks of palbociciib besyiate in accordance with this invention are: 6.3; 8.2; 11.4; 14.3; 17.8 and 20.6° ± 0.2° 2-theta. The X-ray powder pattern is shown in Fig. 41.

Table 12

In this case, the melting point of palbociciib besyiate (1 :2) (Figure 42) is 283°C (DSC).

The infrared spectrum of palbociciib besyiate (1 :2) is shown in Figure 43.

Figure 44 shows an example of the ^!H NMR spectrum of the prepared palbociciib besyiate (1:2). The crystalline form of palbociclib mesylate (1:2) is characterized by the reflections presented in Table 13, Table 13 includes reflections whose relative intensity value is higher than 1 percent. The characteristic diffraction peaks of palbociclib mesylate in accordance with this invention are: 6.9; 9.7; 13.9; 16.6 and 19.6° ± 0.2° 2-theta. The X-ray powder pattern is shown in Fig. 45.

Table 13

In this case, the melting point of palbociclib mesylate (1 :1) (Figure 46) is 302°

The infrared spectrum of palbociclib mesylate (1 :2) is shown in Figure 47.

Figure 48 shows an example of the 1H NMR spectrum of the prepared palbociclib mesylate (1:2). The invention is clarified in a more detailed way using the working examples below. These examples, which illustrate the preparation of the novel solid forms of palbociclib in accordance with the invention, only have an illustrative character and do not restrict the scope of the invention in any respect.

Experimental part

X-ray powder diffraction

The diffraction patterns 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° 20, increment: 0.0 Γ 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. 0.02 rad Soller slits, a 10mm mask and a 1/4° fixed anti-dispersion slit were used for the correction of the primary array. The irradiated area of the sample is 10 mm, programmable divergence slits were used. 0.02 rad Soller slits and a 5.0 anti-dispersion slit were used for the correction of the secondary array.

Infrared spectroscopy

ATR (ZnSe - single reflection) infrared spectra of the powder samples were measured with an infrared spectrometer (Nicolet Nexus, Thermo, USA) equipped with a DTGS KBr detector, in the measurement range of 600-4000 cm^"1 and the spectral resolution of 4.0 cm^"1. The data were obtained at 64 spectrum accumulations. The OMNIC 6.2 software was used to process the spectra.

Differential Scanning Calorimetry (DSC)

The DSC records were measured using a Discovery DSC device made by TA Instruments. The sample charge in a standard Al pot (40 μΤ) was 4-5 mg and the heating rate was 10°C/min. The temperature program that was used consists of 30 min of stabilization at the temperature of 30°C and then of heating up to 350°C at the heating rate of 5°C/min (Amplitude = 0.8°C and Period = 60 s). 5.0 N₂ at the flow rate of 50 ml/min was used as the carrier gas. ^}HNMR

1H NMR spectroscopy at 250 MHz by Bruker Avance 250 was used for the structural characterization. As the solvent deuterated D6-dimethyl sulfoxide was used and the measurements were carried out at the temperature of 303 K. trimethylsilane (TMS) was used as the internal reference with 0.00 ppm.

Examples

Example 1

The free base of palbociclib was prepared in accordance with the procedure mentioned in the document WO 2014/128588.

Example 2

Preparation of palbociclib hydrobromide (1:1)

100.2 mg (2.23-10^"4 mol) of 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(l-piperazinyI)-2- pyridinyl]amino}pyrido[2_s3-d]pyrimidin-7(8H)-one (palbociclib) was charged into a 25 ml flask and suspended in 5 ml of methanol. 37.7 mg (2.23 -10^"4 mol) of hydrobromic acid (48%) was added to this suspension. The resulting suspension was left to be stirred in a magnetic stirrer at the room temperature for 4 hours. The remaining solvent was evaporated in a vacuum drier at the room temperature, the pressure of 20 kPa (200 mBar) for 16 hours. The crystalline product was subjected to final drying at 30 to 40°C. Yield 137.5 mg (99%). Melting point 315°C (DSC). XRPD: Fig. 1.

Example 3

Preparation of palbociclib sulphate (1:1)

100.9 mg (2.25-10^"4 mol) of 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(l-piperazinyl)-2- pyridinyl]amino}pyrido[2,3-d3pyrimidin-7(8H)-one (palbociclib) was charged into a 25 ml flask and suspended in 5 ml of methanol. 23.0 mg (2.25· 10^" mol) of sulphuric acid (96%) was added to this suspension. The resulting suspension was left to be stirred in a magnetic stirrer at the room temperature for 4 hours. The remaining solvent was evaporated in a vacuum drier at the room temperature, the pressure of 20 kPa (200 mBar) for 16 hours. The crystalline product was subjected to final drying at 30 to 40°C. Yield 123.7 mg (99%). Melting point 273°C (DSC). XRPD: Fig. 4. Example 4

Preparation of palbociclib oxalate (1 :1)

100.1 mg (2.24-10^"4 mol) of 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(l-piperazinyI)-2- pyridinyl]ammo}pyrido[2,3-d]pyrim^ (palbociclib) was charged into a 25 ml flask and suspended in 7.5 ml of methanol. 28.5 mg (2.24· 10^"4 mol) of oxalic acid (99%) was added to this suspension. The resulting suspension was left to be stirred in a magnetic stirrer at the room temperature for 4 hours. The remaining solvent was evaporated in a vacuum drier at the room temperature, the pressure of 20 kPa (200 mBar) for 16 hours. The crystalline product was subjected to final drying at 30 to 40°C. Yield 128.2 mg (99%). Melting point 256°C (DSC). XRPD: Fig. 7.

Example 5

Preparation of palbociclib besylate (1:1)

100 mg (2.23-10^"4 mol) of 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(l-piperazinyl)-2- pyridinyl]amino}pyrido[2_J3-d]pyrimidin-7(8H)-one (palbociclib) was charged into a 25 ml flask and suspended in 5 ml of methanol. 35.7 mg (2.23· 10^"4 mol) of benzenesulfonic acid (99%) was added to this suspension. The resulting suspension was stirred in a magnetic stirrer at the room temperature for 4 hours. The remaining solvent was evaporated in a vacuum drier at the room temperature, the pressure of 20 kPa (200 mBar) for 16 hours. The crystalline product was subjected to final drying at 30 to 40°C. Yield 135.3 mg (99%). Melting point 294°C (DSC). XRPD: Fig. 11.

Example 6

Preparation of palbociclib salicylate (1:1)

100.4 mg (2.24-10^"4 mol) of 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(l-piperazinyl)-2- pyridmyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one (palbociclib) was charged into a 25 ml flask and suspended in 5 ml of methanol. 31.3 mg (2.24· 10^"4 mol) of salicylic acid (99%) was added to this suspension. The resulting suspension was stirred in a magnetic stirrer at the room temperature for 4 hours. The remaining solvent was evaporated in a vacuum drier at the room temperature, the pressure of 20 kPa (200 mBar) for 16 hours. The crystalline product was subjected to final drying at 30 to 40°C. Yield 131.4 mg (99%). Melting point 258°C (DSC). XRPD: Fig. 15. Example 7

Preparation of palbociclib fumarate (1 :1)

100.4 mg (2.24-10^"4 mol) of 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(l-piperazinyl)-2- pyridiny^aminoipyridop^^pyrimidm^SHJ-o e (palbociclib) was charged into a 25 ml flask and suspended in 5 ml of methanol. 34.9 mg (2.25-10^"4 mol) of fumaric acid (99 %) was added to this suspension. The resulting suspension was stirred in a magnetic stirrer at the room temperature for 4 hours. The remaining solvent was evaporated in a vacuum drier at the room temperature, the pressure of 20 kPa (200 mBar) for 16 hours. The crystalline product was subjected to final drying at 30 to 40°C. Yield 136 mg (99%). Melting point 214°C (DSC). XRPD: Fig. 19.

Example 8

Preparation of palbociclib 2,4-dihydroxybenzoate (1:1)

100.6 mg (2.25-10^"4 mol) of 6-acetyl-8-cyclopentyl-5-me l-2-{[5-(l-piperazinyl)-2- pyridinyl3ammo}pyrido[2,3-d]pyrimidin-7(8H)-one (palbociclib) was charged into a 25 ml flask and suspended in 5 ml of methanol. 26.4 mg (2.25· 10^"4 mol) of 2-4-dihydroxybenzoic acid (99 %) was added to this suspension. The resulting suspension was stirred in a magnetic stirrer at the room temperature for 4 hours. The remaining solvent was evaporated in a vacuum drier at the room temperature, the pressure of 20 kPa (200 mBar) for 16 hours. The crystalline product was subjected to final drying at 30 to 40°C. Yield 126,7 mg (99%). Melting point 197°C (DSC). XRPD: Fig. 23.

Example 9

Preparation of palbociclib benzoate (1:1)

100.2 mg (2.24-10"¹ mol) of 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(l-piperazinyl)-2- pyridinyl]ammo}pyrido[2₎3-d]pyrimidin-7(8H)-one (palbociclib) was charged into a 25 ml flask and suspended in 5 ml of methanol. 27.6 mg (2.25· 10^"4 mol) of benzoic acid (99 %) was added to this suspension. The resulting suspension was stirred in a magnetic stirrer at the room temperature for 4 hours. The remaining solvent was evaporated in a vacuum drier at the room temperature, the pressure of 20 kPa (200 mBar) for 16 hours. The crystalline product was subjected to final drying at 30 to 40°C. Yield 127.5 mg (99%). Melting point 221°C (DSC). XRPD: Fig. 27. Example 10

Preparation of palbociclib mesylate (1 :1)

100.5 mg (2.25-10^"4 mol) of 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(l-piperazinyl)-2- pyridinyl]arriino}pyrido[2_J3-d]pyrimidm-7(8/^ (palbociclib) was charged into a 25 ml flask and suspended in 5 ml of methanol. 21.8 mg (2.25-10^" mol) of methanesulfonic acid (99 %) was added to this suspension. The resulting suspension was stirred in a magnetic stirrer at the room temperature for 4 hours. The remaining solvent was evaporated in a vacuum drier at the room temperature, the pressure of 20 kPa (200 mBar) for 16 hours. The crystalline product was subjected to final drying at 30 to 40°C. Yield 122.1 mg (99%). Melting point 312°C (DSC). XRPD: Fig. 31.

Example 11

Preparation of palbociclib hydrobromide (1 :2)

100 mg (2.23-10^"4 mol) of 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(l-piperazinyl)-2- pyridinyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one (palbociclib) was charged into a 25 ml flask and suspended in 5 ml of methanol. 75.3 mg (4.47- 10^"4 mol) of hydrobromic acid (48%) was added to this suspension. The resulting suspension was stirred in a magnetic stirrer at the room temperature for 4 hours. The remaining solvent was evaporated in a vacuum drier at the room temperature, the pressure of 20 kPa (200 mBar) for 16 hours. The crystalline product was subjected to final drying at 30 to 40°C. Yield 174.6 mg (99%). Melting point 207°C (DSC). XRPD: Fig. 31.

Example 12

Preparation of palbociclib sulphate (1 :2)

100.2 mg (2.24-10^"4 mol) of 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(l-piperazinyl)-2- pyridinyl]amino}pyrido[2,3-d]pyimidin-7(8H)-one (palbociclib) was charged into a 25 ml flask and suspended in 5 ml of methanol. 45.7 mg (4.48· 10^"4 mol) of sulphuric acid (96%) was added to this suspension. The resulting suspension was stirred in a magnetic stirrer at the room temperature for 4 hours. The remaining solvent was evaporated in a vacuum drier at the room temperature, the pressure of 20 kPa (200 mBar) for 16 hours. The crystalline product was subjected to final drying at 30 to 40°C. Yield 145.5 mg (99%). Melting point 283°C (DSC). XRPD: Fig. 34. Example 13

Preparation of palbociclib besylate (1 :2)

100.3 mg (2.24-10^"4 mol) of 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(l-piperazinyl)-2- pyridmyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one (palbociclib) was charged into a 25 ml flask and suspended in 5 ml of methanol. 71.6 mg (4.48· 10^"4 mol) of benzenesulfonic acid (99%) was added to this suspension. The resulting suspension was stirred in a magnetic stirrer at the room temperature for 4 hours. The remaining solvent was evaporated in a vacuum drier at the room temperature, the pressure of 20 kPa (200 mBar) for 16 hours. The crystalline product was subjected to final drying at 30 to 40°C. Yield 171.2 mg (99%). Melting point 283°C (DSC). XRPD: Fig. 37.

Example 14

Preparation of palbociclib mesylate (1 :2)

100.2 mg (2.24-10^"4 mol) of 6-acetyl-8-cyclopentyI-5-methyl-2-{[5-(l-piperazinyl)-2- pyridinyl]ammo}pyrido[2,3-d]pyrimidin-7(8H)-one (palbociclib) was charged into a 25 ml flask and suspended in 5 ml of methanol. 43.5 mg (4.48* 10^"4 mol) of methanesulfonic acid (99%) was added to this suspension. The resulting suspension was stirred in a magnetic stirrer at the room temperature for 4 hours. The remaining solvent was evaporated in a vacuum drier at the room temperature, the pressure of 2 kPa (200 mBar) for 16 hours. The crystalline product was subjected to final drying at 30 to 40°C. Yield 143.2 mg (99%). Melting point 302°C (DSC). XRPD: Fig. 45.

Claims

1. Solid forms of a salt of palbociclib of formula I with an acid HA in the molar ratio of 1 :1 or 1:2, wherein the acid HA is selected from the group containing hydrobromic acid, sulphuric acid, oxalic acid, benzenesulfonic acid, salicylic acid, fumaric acid, 2,4-dihydroxybenzoic acid and benzoic acid.

(I)

2. A salt according to claim 1, of palbociclib with hydrobromic acid in the solid phase.

3. The salt of palbociclib with hydrobromic acid according to claim 2 in a crystalline form, which exhibits the following characteristic reflections in the X-ray powder pattern with the use of CuKot radiation: 11.5; 14.8; 16.5; 19.1 and 21.9° + 0.2° 2-theta.

4. The salt of palbociclib with hydrobromic acid according to claim 3 in a crystalline form, which exhibits the peak maximum at the temperature of 315°C in the differential scanning calorimetry - the DSC record.

5. A salt according to claim 1, of palbociclib with sulphuric acid in the solid phase.

6. The salt of palbociclib with sulphuric acid according to claim 5 in a crystalline form, which exhibits the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 4.1; 9.3; 11.7; 16.2; 17.2 and 21.2° ± 0.2° 2-theta.

7. The salt of palbociclib with sulphuric acid according to claim 6 in a crystalline form, which exhibits the peak maximum at 273 °C in the DSC record.

8. A salt according to claim 1, of palbociclib with oxalic acid in the solid phase.

9. The salt of palbociclib with oxalic acid according to claim 8 in a crystalline form, which exhibits the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 4.5; 10.0; 13.8; 17.3; 19.6 and 23.1° + 0.2° 2-theta.

10. The salt of palbociclib with oxalic acid according to claim 9 in a crystalline form, which exhibits the peak maximum at 256°C in the DSC record.

11. A salt according to claim 1, of palbociclib with benzenesulfonic acid in the solid phase.

12. The salt of palbociclib with benzenesulfonic acid according to claim 11 in a crystalline form, which exhibits the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 9.0; 10.7; 11.9; 15.8; 22.1 and 26.2° + 0,2° 2-theta.

13. The salt of palbociclib with benzenesulfonic acid according to claim 12 in a crystalline form, which exhibits the peak maximum at 294°C in the DSC record.

14. A salt according to claim 1, of palbociclib with salicylic acid in the solid phase.

1 . The salt of palbociclib with salicylic acid according to claim 14 in a crystalline form, which exhibits the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 6.9; 11.7; 13.9; 16.9; 21.8 and 26.2° ± 0.2° 2-theta.

16. The salt of palbociclib with salicylic acid according to claim 15 in a crystalline form, which exhibits the peak maximum at 258°C in the DSC record.

1 . A salt according to claim 1 , of palbociclib with fumaric acid in the solid phase.

18. The salt of palbociclib with fumaric acid according to claim 17 in a crystalline form, which exhibits the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 5.1; 7.6; 12.9; 17.8 and 24.9° ± 0.2° 2-theta.

19. The salt of palbociclib with fumaric acid according to claim 18 in a crystalline form, which exhibits the peak maximum at 197°C in the DSC record.

20. A salt according to claim 1, of palbociclib with 2-4-dihydroxybenzoic acid in the solid phase.

21. The salt of palbociclib with 2,4-dihydroxybenzoic acid according to claim 20 in a crystalline form, which exhibits the following characteristic reflections in the X-ray powder pattern with the use of Cu a radiation: 6.3; 10.6; 12.7; 16.4; 19.2 and 21.3° ± 0.2° 2-theta.

22. The salt of palbociclib with 2,4-dihydroxybenzoic acid according to claim 21 in a crystalline form, which exhibits the peak maximum at 214°C in the DSC record.

23. A salt according to claim 1, of palbociclib with benzoic acid in the solid phase.

24. The salt of palbociclib with benzoic acid according to claim 23 in a crystalline form, which exhibits the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 4.1; 8.8; 14.0; 18.9; 21.6 and 23.8° ± 0.2° 2-theta.

25. The salt of palbociclib with benzoic acid according to claim 24 in a crystalline form, which exhibits the peak maximum at 221°C in the DSC record.

26. A salt according to claim 1, of palbociclib with two molar equivalents of hydrobromic acid in the solid phase.

27. The salt of palbociclib with two molar equivalents of hydrobromic acid according to claim

26 in a crystalline form, which exhibits the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 9.4; 11.5; 16.3; 19.2; 20.4° + 0.2° 2-theta.

28. The salt of palbociclib with two molar equivalents of hydrobromic acid according to claim

27 in a crystalline form, which exhibits the peak maximum at 207°C in the DSC record.

29. A salt according to claim 1, of palbociclib with two molar equivalents of sulphuric acid in the solid phase.

30. The salt of palbociclib with two molar equivalents of sulphuric acid according to claim 29 in a crystalline form, which exhibits the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 3.1; 9.1; 12.6; 16.0; 20.1 and 26.6° ± 0.2° 2- theta.

31. The salt of palbociclib with two molar equivalents of sulphuric acid according to claim 30 in a crystalline form, which exhibits the peak maximum at 283 °C in the DSC record.

32. A salt according to claim 1, of palbociclib with two molar equivalents of benzenesulfonic acid in the solid phase.

33. The salt of palbociclib with two molar equivalents of benzenesulfonic acid according to claim 32 in a crystalline form, which exhibits the following characteristic reflections in the X- ray powder pattern with the use of CuKa radiation: 6.3; 8.2; 11.4; 14.3; 17.8 and 20.6° ± 0.2° 2-theta.

34. The salt of palbociclib with two molar equivalents of benzenesulfonic acid according to claim 33 in a crystalline form, which exhibits the peak maximum at 283°C in the DSC record.

35. A process of preparing the solid forms of palbociclib of formula I with acids, according to claims 1, 2, 5, 8, 11, 14, 17, 20, 23, 26, 29 and 32, comprising mixing of the basic form of 6- acetyI-8-cycIopentyl-5 -methyl-2- { [5-(l -piperazmyl)-2-pyridmyl]amino }pyrido [2,3 - d]pyrimidin-7(8H)-one, palbociclib of formula I, with an acid HA, wherein the acid HA is selected from the group containing hydrobromic acid, sulphuric acid, oxalic acid, benzenesulfonic acid, salicylic acid, fumaric acid, 2,4-dihydroxybenzoic acid and benzoic acid, in a suitable solvent or a mixture of solvents.

36. The process according to claim 35, characterized in that the solvent is selected from the group containing ketones, esters, ethers, amides, nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water and their mixtures.

37. The process according to claim 36, characterized in that the solvent is selected from aliphatic C1-C4 alcohols, esters or their mixtures, preferably the solvent being methanol, ethanol, water or their mixtures.