NEW CRYSTALLINE FORM AND ACETIC ACID ADDUCTS OF PALBOCICLIB

Abstract

The present invention relates to an adduct of palbociclib, a method of preparing the same, as well as a pharmaceutical composition comprising the same.

Claims

1. Palbociclib acetic acid adduct.

2. Palbociclib acetic acid adduct according to claim 1, having characteristic X-ray powder diffraction peaks at 8.7, 10.0, 11.6, 13.4 and 19.1 degrees 2 (0.2 degrees 2).

3. Palbociclib acetic acid adduct according to claim 1, having one or more further characteristic X-ray powder diffraction peak(s) at 4.5, 7.8, 16.1, 17.4 and/or 21.7 degrees 2 (0.2 degrees 2).

4. Palbociclib acetic acid adduct according to claim 1, having characteristic X-ray powder diffraction peaks at 9.2, 10.9, 13.1, 13.8 and 23.0 degrees 2 (0.2 degrees 2).

5. Palbociclib acetic acid adduct according to claim 1, having one or more further characteristic X-ray powder diffraction peak(s) at 4.6, 17.0, 19.5, 20.0 and/or 21.5 degrees 2 (0.2 degrees 2).

6. Palbociclib acetic acid adduct according to claim 1, wherein palbociclib and acetic acid are present in a molar ratio between 1:1.25 and 1.25:1.

7. Method for preparing palbociclib acetic acid adduct according to claim 1 comprising the steps of a) providing palbociclib b) dissolving palbociclib from step a) in aqueous acetic acid c) isolating palbociclib acetic acid adduct.

8. Palbociclib in crystalline form having characteristic X-ray powder diffraction peak(s) at 6.0, 10.9, 12.8, 16.3 and 19.7 degrees 2 (0.2 degrees 2).

9. Palbociclib according to claim 8, having one or more further characteristic X-ray powder diffraction peak(s) at 6.6, 19.4, 22.0, 22.5 and/or 26.6 degrees 2 (0.2 degrees 2).

10. Method for preparing palbociclib according claim 8 comprising the steps of a) providing palbociclib and/or protected palbociclib b) dissolving palbociclib from step a) in aqueous acetic acid or mineral acid c) optionally isolating palbociclib acetic acid adduct d) optionally dissolving palbociclib acetic acid adduct in water e) adding the solution from step b) or the solution from step d) to an aqueous, alkaline solution f) isolating palbociclib in crystalline form.

11. Method for preparing palbociclib according claim 8 comprising the steps of a) providing palbociclib and/or protected palbociclib b) dissolving palbociclib from step a) in an organic acid, preferably capable of deprotecting the protected palbociclib, c) optionally isolating palbociclib acetic acid adduct according to any one of claims 1 to 6 d) optionally dissolving palbociclib acetic acid adduct in water e) adding the solution from step b) or the solution from step d) to an aqueous, alkaline solution f) isolating palbociclib in crystalline form.

12. Method according to claim 10, wherein the aqueous, alkaline solution contains an inorganic, alkaline substance, preferably selected from sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate.

13. Pharmaceutical composition comprising palbociclib acetic acid adduct according to claim 1, and further at least one pharmaceutical acceptable excipient.

14. Compound according to claim 1 for use in the treatment of cancer, preferably for the use in the treatment of breast cancer.

15. Method for treating and/or preventing cancer, preferably for treating or preventing breast cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to claim 1.

Description

EXAMPLES

[0153] Starting Material

[0154] Palbociclib Form A as described in WO 2014/128588 A1 was used as starting material.

Example 1

Palbociclib Acetic Acid Adduct Form 1

[0155] Palbociclib (1.72 g) was dissolved in a mixture of glacial acetic acid (5 mL) and deionized water (5 mL). The solution was filtered through a folded filter and the solvents were removed on a rotary evaporator at 85 mbar/90 C. bath temperature. The resulting solid was triturated to a powder, which was further dried on the rotary evaporator at 85 mbar/90 C. bath temperature for 4 h. A yellow-brown powder was obtained.

[0156] Yield: 1.47 g (75%)

[0157] XRPD: 1.sup.st priority reflections 8.7, 10.0, 11.6, 13.4 and 19.12 2.sup.nd priority reflections 4.5, 7.8, 16.1, 17.4 and 21.72

[0158] .sup.1H-NMR (CD.sub.3OD/D.sub.2O 1:1.13 [v/v]) [ ppm]: 1.66 (m, 2H, CH), 1.81-2.02 (m, 7H, CH+CH.sub.3COO), 2.27 (m, 2H, CH), 2.35 (s, 3H, CH.sub.3), 2.49 (s, 3H, CH.sub.3), 3.33 (m, 4H, piperazine-CH.sub.2), 3.38 (m, 4H, piperazine-CH.sub.2), 5.87 (quintet, 1H, J=8.9 Hz, CH), 7.51 (dd, 1H, J.sub.1=9.2 Hz, J.sub.2=2.9 Hz, pyridine-CH), 7.94 (d, 1H, J=9.0 Hz, pyridine-CH), 8.05 (d, 1H, J=2.7 Hz, pyridine-CH), 8.93 (s, 1H, pyrimidine-CH)

[0159] DSC: endotherms (onset T):186 C., 261 C., 275 C. (FIG. 4)

[0160] As can be seen from the TGA-thermogram in FIG. 5 acetic acid evaporates between 100 and 220 C. at a heating rate of 10 C./min. The observed weight loss amounted to 11.7%, wherein the theoretical value for 1:1 stoichiometry (palbociclib: acetic acid) is 11.8%. The results of dynamic vapor sorption measurements are shown in FIG. 6. The weight curves feature no steps which would be indicative for the formation of stoichiometrically defined hydrated forms, and the sample weight after the measurement was almost unchanged (0.5%). The diffractogram after DVS measurement was practically identical with the initial one.

Example 2

Palbociclib Acetic Acid Adduct Form 2

[0161] Palbociclib (7 g) was dissolved in a mixture of glacial acetic acid (20 mL) and water (20 mL). The solution was filtered through a folded filter and the solvents were removed on a rotary evaporator at 60 mbar/50 C. bath temperature. The remaining solid was further dried 12 h at room temperature under fine vacuum (rotary vane pump, approx. 0.001 mbar) and further at 80 C./8 mbar 24 hours. A yellow powder was obtained.

[0162] Yield: 7.4 g (93%))

[0163] XRPD: 1.sup.st priority reflections 9.2, 10.9, 13.1, 13.8 and 23.02 2.sup.nd priority reflections 4.6, 17.0, 19.5, 20.0 and 21.52

[0164] DSC: endotherms (onset T):162 C., 260 C. (FIG. 7)

[0165] As it can be seen from the TGA-thermogram in FIG. 8 acetic acid evaporates between 120 and 220 C. at a heating rate of 10 C./min. The observed weight loss amounted to 11.2%.

Example 3

Palbociclib in Crystalline Form

[0166] Palbociclib acetic acid solvate (250 mg) was dissolved in deionized water (9 mL). The clear solution was added dropwise within 7 minutes to a mixture of aqueous 1N NaOH solution (0.6 mL) and deionized water (8 mL) at room temperature under magnetic stirring. A yellow solid precipitated immediately. The mixture was further stirred for 15 min, then it was stored 2 hours at room temperature without stirring. The solid was isolated by filtration, washed with deionized water (220 mL) and dried 3 hours in open atmosphere at room temperature, then 1 hour in dynamic vacuum (2 mbar) at room temperature. A yellow powder was obtained.

[0167] Yield: 156 mg (71%)

Example 3

Palbociclib in Crystalline Form

[0168] Palbociclib (5 g) was dissolved in glacial acetic acid (20 mL). Deionized water (20 mL) was added and the solution was filtered through a folded filter. The clear solution was added dropwise to aqueous 1N NaOH solution (384 mL) under stirring at room temperature. A yellow solid precipitated immediately. After complete addition, the mixture was further stirred for 30 minutes. The solid was then isolated by filtration, washed with deionized water (230 mL) and dried in dynamic vacuum (5 mbar) at room temperature for 2 days. A yellow powder was obtained.

[0169] Yield: 4.6 g (92 %)

Example 3

Palbociclib in Crystalline Form

[0170] Palbociclib (0.5 g, 1.1 mmol) was stirred 10 min at room temperature (23 C.) in a mixture of water (5 mL) and 1.12 mL 1N HC1 (1.0 equivalent). The essentially clear solution was filtered through a folded filter. The filtrate was initially clear, but turns slightly turbid within 5 minutes. This suspension was added dropwise to a mixture of 1N NaOH (1.3 mL) and water (5 mL) under stirring at RT (23 C.). A yellow solid precipitated, the mixture was further stirred for 30 minutes, then stored at room temperature (23 C.) for 1 hour. The solid was isolated by filtration, washed with water, and dried at 2 mbar/room temperature (23 C.) for 2 hours.

[0171] Yield: 254 mg (51%).

Example 3

Palbociclib in Crystalline Form by Use of Protected Palbociclib as Educt

[0172] 4-[6-(6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester hydrochloride (Boc-protected palbociclib hydrochloride) (1.0 g, 1.7 mmol) was suspended in a mixture of water (5 ml) and acetic acid (4 ml). 0.83 ml of HCl 32% solution (8.6 mmol, 5.0 eq.) were added dropwise, the mixture was heated to 70 C. and stirred for 2.5 hours (until completion). After cooling to 50 C., 10 ml of water were added followed by 3.4 ml of an aqueous 2N NaOH solution. The yellow solution was cooled to 23 C. (room temperature), filtered through a 1 m filter and added dropwise within 5 min to an aqueous 2N NaOH solution (37.8 mL) at 23 C. (room temperature) under magnetic stirring. A yellow solid precipitated immediately. The mixture was further stirred for 15 min, then it was stored for 20 min at 23 C. (room temperature) without stirring. The solid was isolated by filtration, washed with deionized water (320 mL) and dried at 50 C/10 mbar for 72 h to give a yellow solid.

[0173] Yield: 684 mg (89.3%)

[0174] The following data are identical in Examples 3, 3, 3 and 3

[0175] XRPD: 1.sup.st priority reflections 6.0, 10.9, 12.8, 16.3 and 19.72 2.sup.nd priority reflections 6.6, 19.4, 22.0, 22.5 and 26.642

[0176] .sup.1H-NMR (DMSO-D.sub.6) [ ppm]: 1.57 (m, 2H, CH), 1.75 (m, 2H, CH), 1.86 (m, 2H, CH), 2.23 (m, 2H, CH), 2.29 (s, 3H, CH.sub.3), 2.40 (s, 3H, CH.sub.3), 2.83 (m, 4H, piperazine-CH.sub.2), 3.04 (m, 4H, piperazine-CH.sub.2), 5.80 (quintet, 1H, J=8.9 Hz, CH), 7.42 (dd, 1H, J.sub.1=9.0 Hz, J.sub.2 =3.1 Hz, pyridine-CH), 7.82 (d, 1H, J=9.0 Hz, pyridine-CH), 8.02 (d, 1H, J=2.7 Hz, pyridine-CH), 8.93 (s, 1H, pyrimidine-CH), 10.05 (s, 1H, NH)

[0177] DSC: endotherms (onset T): 98 C., 271 C. (FIG. 9)

[0178] The DSC thermogram features two endothermic peaks at 103 C. (onset: 98 C.) and 272 C. (onset 271 C.). In the DSC thermogram the peak at 103 C. does not correspond to loss of residual water. In fact cyclic DSC measurements (FIG. 10) indicate that this peak corresponds to a reversible transformation. The TGA thermogram (FIG. 11) shows only a marginal weight loss of 0.2% until 200 C. Hence, the product is an anhydrous form.

[0179] Results of dynamic vapor sorption measurements are shown in FIG. 12. There are no clear steps in the weight curves which would be indicative for the formation of stoichiometrically defined hydrates. The maximum water uptake was 1.3% and the sample weight after the measurement was almost unchanged (0.2%). The diffractogram after DVS measurement was practically identical with the initial one.

[0180] Results

[0181] Solubility:

[0182] Solubilities of palbociclib acetic acid adduct Form 1, present palbociclib in crystalline form and palbociclib Form A in aqueous solvents at 37 C. are shown in the following Table 1.

TABLE-US-00003 TABLE 1 Solubilities of different palbociclib forms in aqueous solvents at 37 C. Palbociclib Palbociclib in acetic acid present crys- Palbociclib adduct Form 1 talline Form Form A 15 60 15 60 15 60 min min min min min min Water 34.9 36.3 0.0 0.0 0.0 0.0 0.01M HCl 41.4 42.0 4.2 4.3 3.1 3.0 20 mM NaOAc/HOAc 15.9 16.0 16.2 15.0 12.4 11.7 50 mM KH.sub.2PO.sub.4 8.1 5.0 0.1 0.1 0.0 0.0

[0183] Form A and present crystalline palbociclib are insoluble in water and in 50 mM KH.sub.2PO.sub.4 solution. In 20 mM NaOAc/HOAc solution and in 0.01M HCl they are sparingly soluble, whereby present crystalline palbociclib is slightly better soluble in both cases. In contrast, palbociclib acetic acid adduct Form 1 shows good solubility in water and in 0.01M HCl.

[0184] Solubilities of palbociclib acetic acid adduct Form 1, present crystalline palbociclib and palbociclib Form A in different organic solvents aqueous solvents at 23 C. (room temerature) are shown in the follwing Table 2.

TABLE-US-00004 TABLE 2 Solubilities of different palbociclib forms in organic solvents at 23 C. (room temperature) Palbociclib Palbociclib in present Palbociclib acetic acid crystalline form Form A adduct Form 1 methanol 1.2 0.5 Acetone 0.5 0.2 chloroform 86.1 48.7 7.3 dimethyl sulfoxide 4.0 1.5

[0185] The solubility of present palbociclib in crystalline form in chloroform, methanol, acetone, and DMSO is 1.8 to 2.7 times higher than for Form A.

[0186] Summary

[0187] A method for the preparation of palbociclib in crystalline form has been achieved. The solubility of palbociclib in crystalline form in aqueous solvents is comparable to that of Form A. However, the solubility of palbociclib in crystalline form in four examined organic solvents is 1.8 to 2.7 times higher than the one of palbociclib Form A. Further, new palbociclib acetic acid adduct Form 1 and Form 2 were prepared, which can be used as an intermediate in the formation of palbociclib in crystalline form. The palbociclib acetic acid adduct Form 1 and Form 2 is a crystalline solid, which is well soluble in water and in 0.01M HCl.