Solid-state forms of Regadenoson, their use and preparation

Patent metadata

Field	Value
Publication number	US-11535644-B2
Application number	US-202016948659-A
Country	US
Kind code	B2
Filing date	Sep 28, 2020
Priority date	Mar 29, 2018
Publication date	Dec 27, 2022
Grant date	Dec 27, 2022

Abstract

The invention relates to a crystalline methanol or dimethyl sulfoxide solvated form of regadenoson and an anhydrous polymorph of regadenoson. The invention is also directed to the preparation of the methanol or dimethyl sulfoxide solvated and anhydrous solid-state forms of regadenoson. In particular, the invention relates to the preparation of the anhydrous polymorph of regadenoson in a stable form from the dimethyl sulfoxide solvated form of regadenoson, which preparation is purifiable and scalable.

First claim

The invention claimed is:

1. A compound which is a crystalline methanol or dimethyl sulfoxide solvate of regadenoson.

2. The compound of claim 1 which is the methanol solvate of regadenoson.

3. The compound of claim 2 wherein the methanol solvate of regadenoson is Form I of methanol solvate of regadenoson, which as a single crystal is monoclinic, C2 a=20.2462 Å b=6.9115 Å c=44.061 Å, α=90°, β=99.98°, γ=90°, unit Cell Volume is about 6072.24 Å 3 and having at least 2 or more X-ray powder diffraction peaks selected from about 9.1, 13.0, 14.3, 17.3, 18.2, 20.8, 24.6 and 25.5° 2θ, as measured by CuKα radiation.

4. The compound of claim 2 wherein the methanol solvate of regadenoson is Form II of methanol solvate of regadenoson, having at least 2 or more X-ray powder diffraction peaks selected from about 10.2, 12.2, 16.2, 17.9, 21.7, 26.3 and 27° 2θ, as measured by CuKα radiation and having one to three thermal event(s) selected from about 190.9° C., 205.3° C., and 277.6° C.

5. The compound of claim 1 which is the dimethyl sulfoxide solvate of regadenoson.

6. The compound of claim 5 wherein the dimethyl sulfoxide solvate of regadenoson is Form I of dimethyl sulfoxide solvate of regadenoson, which as a single crystal is orthorhombic, P2 1 2 1 2 1 , a=4.9676 Å b=9.203 Å c=45.667 Å, α=90° β=90° γ=90°, unit Cell Volume is about 2087.68 Å 3 and having at least 2 or more X-ray powder diffraction peaks selected from about 15.6, 19.5, 20.4 and 25.4° 2θ, as measured by CuKα radiation and having one to two thermal event(s) selected from about 143.0° C. and 251.6° C.

7. The compound of claim 5 wherein the dimethyl sulfoxide solvate of regadenoson is Form II of dimethyl sulfoxide solvate of regadenoson, which as a single crystal is triclinic, P1 a=4.904 Å b=9.1144 Å c=22.849 Å, α=84.130° β=99.979° γ=89.89′7°, unit Cell Volume is about 1013.57 Å 3 and having at least 2 or more X-ray powder diffraction peaks selected from about 3.9, 10.1, 10.9, 16.0, 20.3 and 25.9°.

8. A compound which is a crystalline Form I of anhydrous regadenoson having at least 2 or more X-ray powder diffraction peaks selected from about 5.0, 13.7, 24.0 and 27.0° 2θ, as measured by CuKα radiation or having a thermal event at about 250.8° C.

9. A process for the preparation of the Form I of methanol solvate of regadenoson of claim 3 , comprising: (a) dissolving regadenoson in methanol to form a saturated methanol solution of regadenoson; and (b) evaporating slowly the methanol solution of regadenoson to yield the Form I of methanol solvate of regadenoson.

10. A process for the preparation of the Form I of dimethyl sulfoxide solvate of regadenoson of claim 6 , comprising: (a) dissolving regadenoson in dimethyl sulfoxide (about 100:1—wt(mg) RDN :v(mL) DMSO ) to form a solution of regadenoson in dimethyl sulfoxide, (b) adding acetone to the solution of regadenoson in dimethyl sulfoxide (about 2:1—v Ace :v DMSO ), (c) stirring the resultant solution of step (b) for about 18-20 h at about room temperature and then for about 48 h with cooling to precipitate the Form I of DMSO solvate of regadenoson.

11. A process for the preparation of the Form I of dimethyl sulfoxide solvate of regadenoson of claim 6 , comprising: (a) dissolving regadenoson in dimethyl sulfoxide (about 100:1—wt(mg) RDN :v(mL) DMSO ) to form a solution of regadenoson in dimethyl sulfoxide, (b) adding methanol or ethyl acetate to the solution of regadenoson in dimethyl sulfoxide (about 1.5:1—v MeOH :v DMSO ) or (.about.1:1—v EtOAc :v DMSO ), (c) stirring the resultant solution of step (b) for about 72 h at about room temperature, and (d) drying the resultant solution of step (c) under reduced pressure with warming at about 50° C. to yield the Form I of DMSO solvate of regadenoson.

12. A process for the preparation of the Form II of dimethyl sulfoxide solvate of regadenoson of claim 7 , comprising: (a) dissolving regadenoson in dimethyl sulfoxide (about 210:1—wt(mg) RDN :v(mL) DMSO ) at 50° C. to form a solution of regadenoson in dimethyl sulfoxide, (b) adding ethyl acetate to the solution of regadenoson in dimethyl sulfoxide (about 1:3—v DMSO :v EtOAc ), (c) stirring the resultant solution of step (b) at about room temperature for about 18-20 h to yield a precipitate, and (d) filtering the precipitate, washing the filtered precipitate with ethyl acetate (about 1:1—v DMSO :v EtOAc ) and drying the washed precipitate under vacuum at about 45° C. to yield the Form II of DMSO solvate of regadenoson.

13. A process for the preparation of the Form I of anhydrous regadenoson of claim 8 comprising: (a) dissolving regadenoson in dimethyl sulfoxide (about 250:1—wt(mg) RDN :v(mL) DMSO ) at about 50° C. to form a solution of regadenoson in dimethyl sulfoxide, (b) adding sequentially ethyl acetate (about 1:1—V DMSO :v EtOAc ), seeds of Form II of DMSO solvate of RDN (about 1:0.04—wt RDN :wt RDNseed ), and ethyl acetate (about 1:4—v DMSO :v EtOAc ) to the solution of regadenoson in dimethyl sulfoxide while maintaining the temperature at about 50° C., (c) discontinuing the heating, and stirring the resultant solution of step (b) for about 5 hrs to yield a precipitate, and (d) filtering the precipitate, and drying under vacuum at about 60° C. to yield the Form I of anhydrous regadenoson.

Assignees

• Johnson Matthey Plc
• Macfarlan Smith Ltd

Inventors

• Kavuru Padmini

Classifications

• C07H19/167 Primary

  with ribosyl as the saccharide radical · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07H19/19 Primary

  with arabinosyl as the saccharide radical · CPC title