Crystallization procedure for obtaining canagliflozin hemihydrate crystals

Abstract

The present invention relates to an improved crystallization procedure to obtain canagliflozin hemihydrate crystals having a narrow particle size distribution by removing a small part of the crystalline suspension in the crystallization vessel from said vessel and subjecting said part to particle size reduction of the formed crystals followed by heating and reintroducting said part of the crystalline suspension again in the crystallization vessel which is kept within a specific temperature range.

Claims

1. A process for preparing canagliflozin hemihydrate crystals comprising the consecutive steps of a) preparing a solution in a crystallization vessel of canagliflozin in a solvent system comprising water in an amount from 0.37 wt % to 1.50 wt % under concentration and temperature conditions which allow the complete dissolution of canagliflozin; b) cooling the said solution to a temperature such that crystallization will start upon addition of a seed crystal; c) seeding the solution of step b) with crystalline canagliflozin hemihydrate; d) cooling the solution of step c) to a temperature ranging from 35 C. to 47 C. in order to obtain a crystalline suspension; e) removing a part of the crystalline suspension from the crystallization vessel in an amount that is less than the entire content and subjecting said part to particle size reduction, heating said part to a temperature higher than the temperature of the crystalline suspension in the crystallization vessel and returning said part back to the crystallization vessel; f) repeating step e) until the entire content of the crystallization vessel has undergone between 0.8 and 100 turnovers; g) isolating the crystals of crystalline canagliflozin hemihydrate thus formed.

2. The process as claimed in claim 1 wherein the solvent system is an organic alkyl ester.

3. The process as claimed in claim 1 wherein canagliflozin in step a) is added to the solvent system in the form of anhydrous canagliflozin.

4. The process as claimed in claim 1 wherein canagliflozin in step a) is added to the solvent system in the form of a hemihydrate or a monohydrate.

5. The process as claimed in claim 3 wherein the temperature in step a) is from 65 C. to 80 C.

6. The process as claimed in claim 5 wherein the temperature in step b) ranges from 50 C. to 64 C.

7. The process as claimed in claim 1 wherein the temperature in step d) ranges from 30 C. to 49 C.

8. The process as claimed in claim 1 wherein the amount of canagliflozin in step a) ranges from 200 g/liter to 500 g/liter.

9. The process as claimed in claim 1 wherein the amount of seeding crystals used in step c) ranges from 0.1 wt % to 1.0 wt %.

10. The process as claimed in claim 1 wherein in step e) the removed part of crystalline suspension that is subjected to particle size reduction, heating and return to the crystallization vessel is in an amount that ranges from 1% to 80%, of the entire content of the crystallization vessel.

11. The process as claimed in claim 9 wherein the number of turnovers in step f) is from 5 to 50.

12. The process as claimed in claim 2 wherein the organic alkyl ester is isopropyl acetate.

13. The process as claimed in claim 5 wherein the temperature in step a) is from 70 C. to 75 C.

14. The process as claimed in claim 6 wherein the temperature in step b) ranges from 52 C. to 60 C.

15. The process as claimed in claim 14 wherein the temperature in step b) ranges from 54 C. to 58 C.

16. The process as claimed in claim 7 wherein the temperature in step d) ranges from 35 C. to 47 C.

17. The process as claimed in claim 16 wherein the temperature in step d) ranges from 38 C. to 45 C.

18. The process as claimed in claim 17 wherein the temperature in step d) ranges from 40 C. to 42 C.

19. The process as claimed in claim 8 wherein the amount of canagliflozin in step a) ranges from 400 g/liter to 500 g/liter.

20. The process as claimed claim 10 wherein in step e) the removed part of crystalline suspension that is subjected to particle size reduction, heating and return to the crystallization vessel is in an amount that ranges from 1% to 70% of the entire content of the crystallization vessel.

21. The process as claimed claim 20 wherein in step e) the removed part of crystalline suspension that is subjected to particle size reduction, heating and return to the crystallization vessel is in an amount that ranges from 2% to 60% of the entire content of the crystallization vessel.

22. The process as claimed claim 21 wherein in step e) the removed part of crystalline suspension that is subjected to particle size reduction, heating and return to the crystallization vessel is in an amount that ranges from 5% to 50% of the entire content of the crystallization vessel.

23. The process as claimed in claim 11 wherein the number of turnovers in step f) is from 10 to 40.

Description

EXAMPLE 1

(1) A solution of canagliflozin (1 mol) in isopropyl acetate (1.0 liter) was heated till 70 C. and filtered over a charcoal filter. The solution was introduced in the crystallization vessel and the amount of water was adjusted to 1.05 wt %.

(2) The solution in the crystallization vessel was stirred, cooled to 54 C., seeded with canagliflozin hemihydrate crystals (1.13 g, 0.25 w/w %) and stirred for 15 minutes. The crystallization suspension in the crystallization vessel was cooled to 42 C. using a linear cooling profile and kept at 40 C.

(3) Then an amount of the crystallization suspension was pumped (1600 mL/min) through a high shear mill (Dispax-Reactor type DR 2000/20 from IKA-Werke GmbH & Co. KG in Germany with a 2P milling disk), heated with a hot heat exchanger to a temperature of 55 C. and returned to the crystallization vessel. The high shear milling, heating, and pumping back into the crystallization vessel was performed for 2 hours and then stopped.

(4) The crystallisation suspension was stirred for 15 minutes and then cooled to 20 C. while simultaneously dosing isopropylacetate (1.116 liter) the canagliflozin hemihydrate crystals were isolated by filtration, washed with isopropyl acetate and dried under vacuum.

(5) For canaglifozin hemihydrate the graphical representation of the particle size distribution obtained by a classical cooling crystallisation process can be found in FIG. 3. The particle size distribution of canaglifozin hemihydrate obtained after performing the crystallization procedure of Example 1 is represented in FIG. 4. As can be seen by comparing both particle size distribution figures, the particle size distribution of crystalline canaglifozin hemihydrate obtained using process of the present invention does not show the presence of a double distribution and has a narrower particle size distribution.

EXAMPLE 2

(6) A solution of canagliflozin (1 mol) in isopropyl acetate (1.0 liter) was heated till 72 C. and filtered over a charcoal filter. The solution was introduced in the crystallization vessel and the amount of water was adjusted to 1.05 wt %.

(7) The solution in the crystallization vessel was stirred, cooled to 56 C., seeded with canagliflozin hemihydrate crystals (1.13 g, 0.25 w/w %) and stirred for 15 minutes.

(8) The crystallization suspension in the crystallization vessel was cooled to 42 C. using a linear cooling profile and kept at 42 C.

(9) Then an amount of the crystallization suspension was pumped (1600 mL/min) through a high shear mill (Dispax-Reactor type DR 2000/20 from IKA-Werke GmbH & Co. KG in Germany with a 2P or 4M milling disk), heated with a hot heat exchanger to a temperature of 53 C. and returned to the crystallization vessel. The high shear milling, heating, and pumping back into the crystallization vessel was performed for 2 hours and then stopped.

(10) The crystallisation suspension was stirred for 15 minutes and then cooled to 18 C. while simultaneously dosing isopropylacetate (1.116 liter) the canagliflozin hemihydrate crystals were isolated by filtration, washed with isopropyl acetate and dried under vacuum.

EXAMPLE 3

(11) A solution of canagliflozin (1.25 mol) in isopropyl acetate (1.0 liter) was heated till 72 C. and filtered over a charcoal filter. The solution was introduced in the crystallization vessel and the amount of water was adjusted to 1.10 wt %.

(12) The solution in the crystallization vessel was stirred, cooled to 56 C., seeded with canagliflozin hemihydrate crystals (1.27 g, 0.25 w/w %) and stirred for 15 minutes.

(13) The crystallization suspension in the crystallization vessel was cooled to 42 C. using a linear cooling profile and kept at 42 C.

(14) Then an amount of the crystallization suspension was pumped (1600 mL/min) through a high shear mill (Dispax-Reactor type DR 2000/20 from IKA-Werke GmbH & Co. KG in Germany with a 2P and 4M milling disk), heated with a hot heat exchanger to a temperature of 55 C. and returned to the crystallization vessel. The high shear milling, heating, and pumping back into the crystallization vessel was performed for 2 hours and then stopped.

(15) The crystallisation suspension was stirred for 15 minutes and then cooled to 18 C. while simultaneously dosing isopropylacetate (1.116 liter) the canagliflozin hemihydrate crystals were isolated by filtration, washed with isopropyl acetate and dried under vacuum.

EXAMPLE 4

(16) A solution of canagliflozin (1 mol) in isopropyl acetate (1.0 liter) was heated till 70 C. and filtered over a charcoal filter. The solution was introduced in the crystallization vessel and the amount of water was adjusted to 1.10 wt %.

(17) The solution in the crystallization vessel was stirred, cooled to 56 C., seeded with canagliflozin hemihydrate crystals (1.13 g, 0.25 w/w %) and stirred for 15 minutes.

(18) The crystallization suspension in the crystallization vessel was cooled to 42 C. using a linear cooling profile and kept at 42 C.

(19) Then an amount of the crystallization suspension was pumped (1600 mL/min) through a high shear mill (Dispax-Reactor type DR 2000/20 from IKA-Werke GmbH & Co. KG in Germany with 2P, 4M and 6F milling disks), heated with a hot heat exchanger to a temperature of 55 C. and returned to the crystallization vessel. The high shear milling, heating, and pumping back into the crystallization vessel was performed for 2 hours and then stopped.

(20) The crystallisation suspension was stirred for 15 minutes and then cooled to 18 C. while simultaneously dosing isopropylacetate (1.116 liter) the canagliflozin hemihydrate crystals were isolated by filtration, washed with isopropyl acetate and dried under vacuum.

EXAMPLE 5

(21) A solution of canagliflozin (1 mol) in isopropyl acetate (1.0 liter) was heated till 70 C. and filtered over a charcoal filter. The solution was introduced in the crystallization vessel and the amount of water was adjusted to 1.15 wt %.

(22) The solution in the crystallization vessel was stirred, cooled to 58 C., seeded with canagliflozin hemihydrate crystals (1.13 g, 0.25 w/w %) and stirred for 15 minutes. The crystallization suspension in the crystallization vessel was cooled to 42 C. using a linear cooling profile and kept at 42 C.

(23) Then an amount of the crystallization suspension was pumped (1600 mL/min) through a high shear mill (Dispax-Reactor type DR 2000/20 from IKA-Werke GmbH & Co. KG in Germany with a 2P milling disk), heated with a hot heat exchanger to a temperature of 57 C. and returned to the crystallization vessel. The high shear milling, heating, and pumping back into the crystallization vessel was performed for 2 hours and then stopped.

(24) The crystallisation suspension was stirred for 15 minutes and then cooled to 18 C. while simultaneously dosing isopropylacetate (1.116 liter) the canagliflozin hemihydrate crystals were isolated by filtration, washed with isopropyl acetate and dried under vacuum.

EXAMPLE 6

(25) A suspension of the MTP inhibitor (+)-phenyl-(4-{4-[(4-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperidin-1-yl)-acetic acid methyl ester (204 g, 0.357 mol) in isopropanol (1781 mL) was heated till 75 C. The solution in the crystallization vessel was stirred, cooled to 67 C., seeded with MTP crystals (1.5 g, 0.5 w/w %) and stirred for 2 hours. The crystallization suspension in the crystallization vessel was cooled to 58 C. using a nonlinear cooling profile of 1.5 hours. Then an amount of the crystallization suspension was pumped (1600 mL/min) through a high shear mill (Dispax-Reactor type DR 2000/20 from IKA-Werke GmbH & Co. KG in Germany with a 2P and 4M milling disk), heated with a hot heat exchanger to a temperature of 63 C. and returned to the crystallization vessel. The high shear milling, heating (successively 63 C., 60 C. and 57 C.), and pumping back into the crystallization vessel was performed for 3 hours 20 minutes while cooling nonlinearly to 20 C.

EXAMPLE 7

(26) A suspension of the MTP inhibitor (+)-phenyl-(4-{4-[(4-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperidin-1-yl)-acetic acid methyl ester (204 g, 0.357 mol) in isopropanol (1781 mL) was heated till 75 C. The solution in the crystallization vessel was stirred, cooled until spontaneous crystallization occurs. Heat up until stirrable (68 C.). The crystallization suspension in the crystallization vessel was cooled to 58 C. using a nonlinear cooling profile of 1.5 hours. Then an amount of the crystallization suspension was pumped (1600 mL/min) through a high shear mill (Dispax-Reactor type DR 2000/20 from IKA-Werke GmbH & Co. KG in Germany with a 2P and 4M milling disk), heated with a hot heat exchanger to a temperature of 63 C. and returned to the crystallization vessel. The high shear milling, heating (successively 63 C., 60 C. and 57 C.), and pumping back into the crystallization vessel was performed for 3 hours 20 minutes while cooling nonlinearly to 20 C.

DESCRIPTION OF THE DRAWINGS

(27) FIG. 1: comparison of equipment set-up of prior art process of WO-2011/003976 and the improves set-up using an externally placed shearing machine and a hot heat exchanger

(28) FIG. 2: narrowing of particle size distribution by combining particle size reduction and heating

(29) FIG. 3: particle size distribution of canagliflozin hemihydrate at the start of Example 1

(30) FIG. 4: particle size distribution of canagliflozin hemihydrate at the end of Example 1