Formoterol tartrate process and polymorph

A process for the preparation of a first polymorph (C) of (R,R)-formoterol L-tartrate comprising stirring a slurry of a second polymorph (B) of (R,R)-formoterol L-tartrate in water, isopropyl alcohol and from 13% to 75% by weight toluene at 40-55° C., first polymorph (C) having peaks at the diffraction degrees with the intensity shown below in an X-ray powder diffraction pattern:

• Peak number 2-Theta Intensity 1 6.4 100.0 2 9.0 14.4 3 11.1 14.8 4 12.4 13.9 5 12.9 19.7 6 13.5 19.5 7 14.0 15.1 8 15.0 19.7 9 15.4 16.9 10 15.7 18.1 11 16.3 12.8 12 17.5 64.9 13 19.4 47.3 14 19.9 44.8 15 21.3 29.3 16 22.3 31.5 17 22.9 35.8 18 24.1 80.0 19 24.7 17.6 20 25.5 11.3 21 26.0 15.6 22 26.8 9.1 23 27.4 8.5 24 28.4 10.8 25 29.0 8.5 26 30.5 8.1 27 32.7 10.9 28 34.2 7.9 29 35.7 9.3 30 36.4 6.6 31 37.3 7.9 32 37.8 9.1 33 39.3 10.0 34 39.6 11.4 35 41.1 5.7 36 42.3 4.7.
• and said second polymorph (B) having peaks at the diffraction degrees with the intensity shown below in an X-ray powder diffraction pattern:
• peak number 2-Theta Intensity 1 6.7 29.8 2 7.7 23.9 3 8.5 76.8 4 9.9 24.1 5 11.6 23.7 6 12.2 35.9 7 13.0 24.8 8 13.7 32.7 9 16.4 32.9 10 17.3 99.1 11 19.4 47.9 12 20.6 100.0 13 22.1 72.8 14 22.7 70.2 15 23.5 29.1 16 23.9 25.0 17 24.5 22.8 18 25.4 35.8 19 25.5 39.8 20 26.3 48.0 21 27.4 25.7 22 28.6 28.6 23 29.5 20.5 24 30.9 20.1 25 33.0 19.5 26 37.2 22.1 27 38.6 20.1 28 40.9 19.7 29 41.7 20.0 30 44.3 20.0.

A process for the preparation of a third polymorph (A) of (R,R)-formoterol L-tartrate comprising:

• (a) stirring a slurry of a second polymorph (B) of (R,R)-formoterol L-tartrate in water, isopropyl alcohol and toluene at 40-55° C. to produce a first polymorph (C) of (R,R)-formoterol L-tartrate;
• (b) crystallizing said first polymorph (C) of (R,R)-formoterol L-tartrate from aqueous isopropyl alcohol to produce a third polymorph (A) of (R,R)-formoterol L-tartrate;
• and
• (c) separating said third polymorph (A) of (R,R)-formoterol L-tartrate from aqueous isopropyl alcohol,
• said first polymorph (C) having peaks at the diffraction degrees with the intensity shown below in an X-ray powder diffraction pattern:
• Peak number 2-Theta Intensity 1 6.4 100.0 2 9.0 14.4 3 11.1 14.8 4 12.4 13.9 5 12.9 19.7 6 13.5 19.5 7 14.0 15.1 8 15.0 19.7 9 15.4 16.9 10 15.7 18.1 11 16.3 12.8 12 17.5 64.9 13 19.4 47.3 14 19.9 44.8 15 21.3 29.3 16 22.3 31.5 17 22.9 35.8 18 24.1 80.0 19 24.7 17.6 20 25.5 11.3 21 26.0 15.6 22 26.8 9.1 23 27.4 8.5 24 28.4 10.8 25 29.0 8.5 26 30.5 8.1 27 32.7 10.9 28 34.2 7.9 29 35.7 9.3 30 36.4 6.6 31 37.3 7.9 32 37.8 9.1 33 39.3 10.0 34 39.6 11.4 35 41.1 5.7 36 42.3 4.7
• said second polymorph (B) having peaks at the diffraction degrees with the intensity shown below in an X-ray powder diffraction pattern:
• peak number 2-Theta Intensity 1 6.7 29.8 2 7.7 23.9 3 8.5 76.8 4 9.9 24.1 5 11.6 23.7 6 12.2 35.9 7 13.0 24.8 8 13.7 32.7 9 16.4 32.9 10 17.3 99.1 11 19.4 47.9 12 20.6 100.0 13 22.1 72.8 14 22.7 70.2 15 23.5 29.1 16 23.9 25.0 17 24.5 22.8 18 25.4 35.8 19 25.5 39.8 20 26.3 48.0 21 27.4 25.7 22 28.6 28.6 23 29.5 20.5 24 30.9 20.1 25 33.0 19.5 26 37.2 22.1 27 38.6 20.1 28 40.9 19.7 29 41.7 20.0 30 44.3 20.0
• and said third polymorph (A) having peaks at the diffraction degrees with the intensity shown below in an X-ray powder diffraction pattern:
• peak number 2-Theta Intensity 1 8.8 33.1 2 9.3 33.4 3 12.1 58.1 4 12.4 60.6 5 14.2 30.9 6 15.2 87.4 7 15.5 82.8 8 16.8 69.8 9 18.9 39.6 10 19.7 41.1 11 20.8 40.6 12 22.5 38.8 13 23.0 59.9 14 23.7 100.0 15 25.6 55.9 16 26.8 37.2 17 28.6 25.6 18 30.9 37.2 19 36.1 28.0 20 38.1 25.0 21 39.1 22.7 22 41.5 21.3 23 43.3 20.9