Process for the preparation of polymorph form B of treprostinil diethanolamine salt

Abstract

The invention relates to a robust and reproducible process for the preparation of polymorph form B of treprostinil diethanolamine salt, comprising the following steps: a. treprostinil is dissolved in methanol, b. to the solution of step a) diethanolamine or its methanol solution is added, c. the reaction mixture of step b) is agitated till dissolution, d. when salt formation is completed in step c), first portion of an aprotic solvent is added to the solution, e. the solution of step d) is filtered to remove insoluble impurities, f. the filtrate of step e) is seeded with polymorph form B of treprostinil diethanolamine salt, g. to the crystal suspension obtained in step f) a second portion of the aprotic solvent is added, h. the suspension of step g) is agitated until crystallisation is completed, i. the crystals are separated, washed and dried.

Claims

1. A process for the preparation of polymorph form B of treprostinil diethanolamine salt comprising the following steps: a. treprostinil is dissolved in methanol, b. to the solution of step a) diethanolamine or its solution in methanol is added, c. the reaction mixture of step b) is agitated till dissolution, d. after completion of salt formation in step c) a first portion of aprotic solvent is added to the solution, e. the solution of step d) is filtered, f. the filtrate of step e) is seeded with polymorph form B of treprostinil diethanolamine salt, g. to the crystal suspension obtained in step f), a second portion of the aprotic solvent is added, h. the suspension of step g) is agitated until crystallisation is completed, i. the crystals are separated, washed and dried; wherein ethers, ketone-type solvent, ester-type solvent, or acetonitrile are applied as aprotic solvent.

2. The process according to claim 1, wherein dissolution of treprostinil and diethanolamine is carried out at 25-50° C.

3. The process according to claim 2, wherein dissolution of treprostinil and diethanolamine is carried out at 30-40° C.

4. The process according to claim 1 wherein methyl tertiary-butyl ether is applied as aprotic solvent.

5. A process for the transformation of polymorph form A or the mixture of polymorph forms A and B of treprostinil diethanolamine salt into polymorph form B, comprising the following steps: a. treprostinil diethanolamine salt is dissolved in methanol, b. to the solution of step a) first portion of aprotic solvent is added, c. the solution of step b) is filtered, d. the filtrate of step c) is seeded with polymorph form B of treprostinil diethanolamine salt, e. to the crystal suspension obtained in step d), a second portion of the aprotic solvent is added, f. the suspension of step e) is agitated until crystallisation is completed, g. the crystals are separated, washed and dried; wherein ethers, polar ketone-type solvent, ester-type solvent, or acetonitrile are applied as aprotic solvent.

6. The process according to claim 5, wherein methyl tertiary-butyl ether is applied as aprotic solvent.

7. The process according to claim 5, wherein dissolution of treprostinil and diethanolamine is performed at 25-50° C.

8. The process according to claim 7, wherein dissolution of treprostinil and diethanolamine is performed at 30-40° C.

9. The process according to claim 6, wherein dissolution of treprostinil and diethanolamine is performed at 25-50° C.

10. The process according to claim 1, wherein methyl tertiary-butyl ether, diisopropyl ether, acetone, ethyl acetate, or acetonitrile is applied as aprotic solvent.

11. The process according to claim 5, wherein methyl tertiary-butyl ether, diisopropyl ether, acetone, ethyl acetate, or acetonitrile is applied as aprotic solvent.

12. The process according to claim 2, wherein methyl tertiary-butyl ether, diisopropyl ether, acetone, ethyl acetate, or acetonitrile is applied as aprotic solvent.

13. The process according to claim 3, wherein methyl tertiary-butyl ether, diisopropyl ether, acetone, ethyl acetate, or acetonitrile is applied as aprotic solvent.

14. The process according to claim 1, wherein the agitation in step h) is at room temperature.

15. The process according to claim 1, wherein a ratio of methanol to aprotic solvent is 1:5 to 1:10.

Description

BRIEF DESCRIPTION OF DRAWINGS/FIGURES

(1) FIG. 1: X-Ray powder diffraction patterns of different polymorph forms of treprostinil diethanolamine salt crystallized from methanol as solvent and different-antisolvents (examples 1 to 6):

(2) 1.1: MeOH/methyl tertiary-butyl ether

(3) 1.2: MeOH/acetone

(4) 1.3: MeOH/ethyl-acetate

(5) 1.4: MeOH/diisopropyl ether

(6) 1.6: MeOH/acetonitrile

(7) “A”: Treprostinil diethanolamine polymorph form A

(8) “B”: Treprostinil diethanolamine polymorph form B

(9) FIG. 2: XRPD pattern of treprostinil diethanolamine salt polymorph form B crystallized from MeOH/methyl tertiary-butyl ether mixture (example 7)

(10) FIG. 3: DSC curve of treprostinil diethanolamine salt polymorph form B crystallized from MeOH/methyl tertiary-butyl ether mixture (peak: 106.56° C., example 7)

(11) FIG. 4: XRPD pattern of treprostinil diethanolamine salt polymorph form B crystallized from MeOH/methyl tertiary-butyl ether mixture (example 8)

(12) FIG. 5: DSC curve of treprostinil diethanolamine salt polymorph form B crystallized from MeOH/methyl tertiary-butyl ether mixture (peak: 106.23° C., example 8)

(13) FIG. 6: XRPD pattern of treprostinil diethanolamine salt polymorph form B crystallized from MeOH/methyl tertiary-butyl ether mixture (example 9)

(14) FIG. 7: DSC curve of treprostinil diethanolamine salt polymorph form B crystallized from MeOH/methyl tertiary-butyl ether mixture (peak: 105.37° C., example 9)

(15) FIG. 8: XRPD pattern of treprostinil diethanolamine salt polymorph form B crystallized from MeOH/methyl tertiary-butyl ether mixture (example 10)

(16) FIG. 9: DSC curve of treprostinil diethanolamine salt polymorph form B crystallized from MeOH/methyl tertiary-butyl ether mixture (peak: 104.91° C., example 10)

(17) FIG. 10: XRPD pattern of treprostinil diethanolamine salt polymorph form B crystallized from MeOH/methyl tertiary-butyl ether mixture (example 11)

(18) FIG. 11: DSC curve of treprostinil diethanolamine salt polymorph form B crystallized from MeOH/methyl tertiary-butyl ether mixture (peak: 106.10° C., example 11)

(19) FIG. 12: XRPD pattern of treprostinil diethanolamine salt polymorph form B crystallized from MeOH/methyl tertiary-butyl ether mixture (Example 12)

(20) FIG. 13: DSC curve of treprostinil diethanolamine salt polymorph form B crystallized from MeOH/methyl tertiary-butyl ether mixture (peak: 107.42° C., example 12)

(21) FIG. 14: XRPD pattern of treprostinil diethanolamine salt polymorph forms A+B crystallized from EtOH/ethyl acetate mixture (example 13)

(22) FIG. 15: DSC curve of treprostinil diethanolamine salt polymorph forms A+B crystallized from EtOH/ethyl acetate mixture (peaks: 103.84° C. and 105.94° C., example 13)

(23) FIG. 16: DSC curve of treprostinil diethanolamine salt polymorph form B crystallized from MeOH/methyl tertiary-butyl ether mixture (peak: 107.34° C., example 14)

(24) FIG. 17: DSC curve of treprostinil diethanolamine salt polymorph form B crystallized from MeOH/water/acetone mixture (peak: 106.56° C., example 15)

(25) FIG. 18: DSC curve of treprostinil diethanolamine salt polymorph form B crystallized from MeOH/methyl tertiary-butyl ether mixture at 40° C. to 50° C. (peak: 106.23° C., example 16)

(26) FIG. 19: XRPD pattern of treprostinil diethanolamine salt polymorph form C crystallized from MeOH/methyl tertiary-butyl ether mixture at −70° C. (example 17)

(27) FIG. 20: DSC curve of treprostinil diethanolamine salt polymorph form C crystallized from MeOH/methyl tertiary-butyl ether mixture at −70° C. (peaks: 87.66° C. and 102.58° C., example 17)

(28) FIG. 21: .sup.13C and .sup.1H NMR data of treprostinil diethanolamine salt acquired at 500 MHz in DMSO

EXAMPLES

Preparation of Treprostinil Diethanolamine Salt (I)

(1R,2R,3aS,9aS)-2-[2-Hydroxy-1-[3(S)-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1H-benz[f]inden-5-yloxy] acetic acid diethanolamine salt

Example 1 (JIM-562/1)

(29) 1 g of treprostinil (II) is dissolved in 4 ml of methanol at room temperature. To the solution 0.3 g of diethanolamine (IV) is added and the reaction mixture is agitated at 35±5° C. for half an hour, then 15 ml of methyl tertiary-butyl ether (TBME) is added. The solution is filtered, seeded with approx. 10 mg of polymorph form B crystals, the suspension is agitated at room temperature for 2 hours and then 20 ml of methyl tertiary-butyl ether is added dropwise. Agitation is continued at room temperature for 16-24 hours, then the crystals are filtered off, washed and dried in vacuum at 45±5° C.

(30) Yield: 1.15 g (91%), colorless crystals, corresponding to polymorph form B.

Example 2 (JIM-562/2)

(31) 1 g of treprostinil (II) is dissolved in 4 ml of methanol at room temperature. To the solution 0.3 g of diethanolamine (IV) is added and the reaction mixture is agitated at 35±5° C. for half an hour, then 15 ml of acetone is added, the solution is filtered, seeded with approx. 10 mg of polymorph form B crystals, agitated at room temperature for 2 hours, then 30 ml of acetone is added dropwise. The suspension is agitated at room temperature for 16-24 hours, then the crystals are filtered off, washed, and dried in vacuum at 45±5° C.

(32) Yield: 0.92 g (73%), colorless crystals, corresponding to polymorph form B.

Example 3 (JIM-562/3)

(33) 1 g of treprostinil (II) is dissolved in 4 ml of methanol at room temperature. To the solution 0.3 g of diethanolamine (IV) is added and the reaction mixture is agitated at 35±5° C. for half an hour, then 15 ml of ethyl acetate is added, the solution is filtered, seeded with approx. 10 mg of polymorph form B crystals, agitated at room temperature for 2 hours, then 20 ml of ethyl acetate is added dropwise. The suspension is agitated at room temperature for 16-24 hours, then the crystals are filtered off, washed, and dried in vacuum at 45±5° C.

(34) Yield: 1.16 g (92%), colorless crystals, corresponding to polymorph form B.

Example 4 (JIM-562/4)

(35) 1 g of treprostinil (II) is dissolved in 6 ml of methanol at room temperature. To the solution 0.3 g of diethanolamine (IV) is added, the reaction mixture is agitated at 35±5° C. for half an hour, then 10 ml of diisopropyl ether (DIPE) is added, the solution is filtered, seeded with approx. 10 mg of polymorph form B crystals, agitated at room temperature for 2 hours and then 20 ml of diisopropyl ether is added dropwise. The suspension is agitated at room temperature for 16-24 hours, then the crystals are filtered off, washed and dried in vacuum at 45±5° C.

(36) Yield: 1.20 g (95%), colorless crystals, corresponding to polymorph form B.

Example 5 (JIM-562/5)

(37) 1 g of treprostinil (II) is dissolved in 6 ml of methanol at room temperature. To the solution 0.3 g of diethanolamine (IV) is added, the reaction mixture is agitated at 35±5° C. for half an hour, then 10 ml of toluene is added, the solution is filtered, seeded with approx. 10 mg of polymorph form B crystals, agitated at room temperature for 2 hours and then 30 ml of toluene is added dropwise. No crystallisation occurred.

Example 6 (JIM-562/6)

(38) 1 g of treprostinil (II) is dissolved in 4 ml of methanol at room temperature. To the solution 0.3 g of diethanolamine (IV) is added, the reaction mixture is agitated at 35±5° C. for half an hour, then 15 ml of acetonitrile is added, the solution is filtered, seeded with approx. 10 mg of polymorph form B crystals, agitated at room temperature for 2 hours an then 20 ml of acetonitrile is added dropwise. The suspension is agitated at room temperature for 16-24 hours, then the crystals are filtered off, washed, and dried in vacuum at 45±5° C. Yield: 1.15 g (91%), colorless crystals, corresponding to polymorph form B.

(39) Powder X-ray diffractograms of the treprostinil diethanolamine salts prepared as described in examples 1-6 are demonstrated in FIG. 1

Example 7

(40) 70 g of treprostinil (II) is dissolved in 280 ml of methanol at 25±5° C. To the solution 20.73 g of diethanolamine (IV) is added and the reaction mixture is agitated at 35±5° C. for half an hour, then 1050 ml of methyl tertiary-butyl ether (TBME) is added. The solution is filtered into an apparatus equipped with stirrer, seeded with approx. 700 mg of polymorph form B crystals and agitated at room temperature for 2 hours, then 1400 ml of methyl tertiary-butyl ether is added dropwise. Agitation is continued at room temperature for 16-24 hours, then the crystals are filtered off, washed and dried in vacuum at 45±5° C.

(41) Yield: 87.2 g (98%), colorless crystals, corresponding to polymorph form B.

(42) DSC curve is shown in FIG. 3, X-ray powder diffractogram in FIG. 2.

(43) .sup.13C and .sup.1H NMR data of treprostinil diethylamine salt are demonstrated in FIG. 21.

Example 8

(44) 1 g of treprostinil (II) is dissolved in 4 ml of methanol at 25±5° C. To the solution 0.3 g of diethanolamine (IV) is added and the reaction mixture is agitated at 35±5° C. for half an hour, then 15 ml of methyl tertiary-butyl ether (TBME) is added. The solution is filtered into an apparatus fitted with stirrer, seeded with approx. 10 mg of polymorph form B crystals and agitated at room temperature for 2 hours, then 20 ml of methyl tertiary-butyl ether is added dropwise. Agitation is continued at room temperature for 16-24 hours, then the crystals are filtered off, washed and dried in vacuum at 45±5° C.

(45) Yield: 1.15 g (91%), colorless crystals, corresponding to polymorph form B.

(46) DSC curve is shown in FIG. 5, X-ray powder diffractogram in FIG. 4.

Example 9

(47) 1 g of treprostinil (II) is dissolved in 4 ml of methanol at 25±5° C. To the solution 0.3 g of diethanolamine (IV) is added and the reaction mixture is agitated at 35±5° C. for half an hour, then 15 ml of methyl tertiary-butyl ether (TBME) is added. The solution is filtered into an apparatus fitted with stirrer, seeded with approx. 10 mg of polymorph form B crystals and agitated at room temperature for 2 hours, then 25 ml of methyl tertiary-butyl ether is added dropwise. Agitation is continued at room temperature for 16-24 hours, then the crystals are filtered off, washed and dried in vacuum at 45±5° C.

(48) Yield: 1.15 g (91%), colorless crystals, corresponding to polymorph form B.

(49) DSC curve is shown in FIG. 7, X-ray powder diffractogram in FIG. 6.

Example 10

(50) 1 g of treprostinil (II) is dissolved in 4 ml of methanol at 25±5° C. To the solution 0.3 g of diethanolamine (IV) is added and the reaction mixture is agitated at 35±5° C. for half an hour, then 15 ml of methyl tertiary-butyl ether (TBME) is added. The solution is filtered into an apparatus fitted with stirrer, seeded with approx. 10 mg of polymorph form B crystals and agitated at room temperature for 2 hours, then 29 ml of methyl tertiary-butyl ether is added dropwise. Agitation is continued at room temperature for 16-24 hours, then the crystals are filtered off, washed and dried in vacuum at 45±5° C.

(51) Yield: 1.16 g (92%), colorless crystals, corresponding to polymorph form B.

(52) DSC curve is shown in FIG. 9, X-ray powder diffractogram in FIG. 8.

Example 11

(53) 1 g of treprostinil (II) is dissolved in 4 ml of methanol at 25±5° C. To the solution 0.3 g of diethanolamine (IV) is added and the reaction mixture is agitated at 35±5° C. for half an hour, then 15 ml of methyl tertiary-butyl ether (TBME) is added. The solution is filtered into an apparatus fitted with stirrer, seeded with approx. 10 mg of polymorph form B crystals and agitated at room temperature for 2 hours, then 9 ml of methyl tertiary-butyl ether is added dropwise. Agitation is continued at room temperature for 16-24 hours, then the crystals are filtered off, washed and dried in vacuum at 45±5° C.

(54) Yield: 1.02 g (81%), colorless crystals, corresponding to polymorph form B.

(55) DSC curve is shown in FIG. 11, X-ray powder diffractogram in FIG. 10.

Example 12

(56) 1 g of treprostinil (II) is dissolved in 4 ml of methanol at 25±5° C. To the solution 0.3 g of diethanolamine (IV) is added and the reaction mixture is agitated at 35±5° C. for half an hour, then 15 ml of methyl tertiary-butyl ether (TBME) is added. The solution is filtered into an apparatus fitted with stirrer, seeded with approx. 10 mg of polymorph form B crystals and agitated at room temperature for 2 hours, then 5 ml of methyl tertiary-butyl ether is added dropwise. Agitation is continued at room temperature for 16-24 hours, then the crystals are filtered off, washed and dried in vacuum at 45±5° C.

(57) Yield: 0.95 g (75%), colorless crystals, corresponding to polymorph form B.

(58) DSC curve is shown in FIG. 13, X-ray powder diffractogram in FIG. 12.

Example 13

(59) 1 g of treprostinil (II) is dissolved in 5 ml of ethanol at room temperature. To the solution 0.3 g of diethanolamine (IV) is added and the reaction mixture is agitated at 35±5° C. for half an hour, then 15 ml of ethyl acetate is added, the solution is filtered, seeded with approx. 10 mg of polymorph form B crystals, agitated at room temperature for 2 hours, then 20 ml of ethyl acetate (EtOH:EtOAc=1:7) is added dropwise. The suspension is agitated at room temperature for 16-24 hours, then the crystals are filtered off, washed and dried in vacuum at 45±5° C.

(60) Yield: 1.1 g (87%), colourless crystals, mixture of polymorph forms A and B.

(61) DSC curve is shown in FIG. 15, X-ray powder diffractogram in FIG. 14.

Example 14

(62) 1 g of treprostinil diethanolamine salt (I, mixture of polymorph forms A and B) is dissolved in 4 ml of methanol at 35±5° C. To the homogenous solution 15 ml of methyl tertiary-butyl ether is added at room temperature and the mixture is seeded with approx. 10 mg of polymorph form

(63) B crystals, agitated at room temperature for 2 hours, then 20 ml of methyl tertiary-butyl ether is added dropwise. Agitation is continued at room temperature for 16-24 hours, then the crystals are filtered off, washed and dried in vacuum at 45±5° C.

(64) Yield: 1.23 g (97%), colorless crystals, corresponding to polymorph form B.

(65) DSC curve is shown in FIG. 16.

Example 15

(66) 0.5 g of treprostinil diethanolamine salt is dissolved in a mixture of 2 ml of methanol and 0.6 ml of water at room temperature. To the homogenous solution 20 ml of acetone is dropped at room temperature, the opalescent solution is seeded with approx. 5 mg of polymorph form B crystals, agitated at room temperature for 2 hours, then 10 ml of acetone is added dropwise. After 20 hours of agitation the crystals are filtered off, washed and dried in vacuum at 45±5° C.

(67) Yield: 0.39 g (61%), colorless crystals, corresponding to polymorph form B.

(68) DSC curve is shown in FIG. 17.

Example 16

(69) 0.5 g of treprostinil diethanolamine salt is dissolved in 2 ml of methanol at 45±5° C. To the homogenous solution 20 ml of methyl tertiary-butyl ether is added at 45±5° C. and the mixture is seeded with approx. 5 mg of polymorph form B crystals. The opalescent solution is cooled to room temperature. After 20 hours of agitation the crystals are filtered off, washed and dried in vacuum at 45±5° C.

(70) Yield: 0.55 g (87%), colorless crystals, corresponding to polymorph form B.

(71) DSC curve is shown in FIG. 18.

Example 17

(72) 0.5 g of treprostinil diethanolamine salt is dissolved in 5 ml of methanol at −70° C. To the homogenous solution 30 ml of methyl tertiary-butyl ether is added at −70° C. and the mixture is seeded with approx. 5 mg of polymorph form B crystals. After 2 hours of agitation the opalescent solution is allowed to warm to room temperature. The not well filterable crystals are filtered off, washed and dried in vacuum at 45±5° C.

(73) Yield: 0.31 g (49%), corresponding to polymorph form C.

(74) DSC curve is shown in FIG. 20, X-ray powder diffractogram in FIG. 19.