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Claims for Patent: 6,472,563

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Claims for Patent: 6,472,563

Title: Formoterol tartrate process and polymorph
Abstract:A method of preparation of a highly pure salt of R,R-formoterol L-tartrate is disclosed. The process provides the most thermodynamically stable polymorph by recrystallization of a novel polymorph.
Inventor(s): Tanoury; Gerald J. (Hudson, MA), Senanayake; Chris H. (Shrewsbury, MA), Kessler; Donald W (Groton, MA)
Assignee: Sepracor Inc. (Marlborough, MA)
Application Number:10/037,183
Patent Claims: 1. A process for the preparation of highly pure (R,R)-formoterol L-tartrate comprising crystallizing a first polymorph (C) of (R,R)-formoterol L-tartrate from aqueous isopropyl alcohol, said first polymorph having peaks at the diffraction degrees with the intensity shown below in an X-ray powder diffraction pattern:

2. A process according to claim 1 wherein said first polymorph is crystallized from isopropyl alcohol:water in a two stage process whereby said first polymorph is first dissolved in 50% (v/v) isopropyl alcohol:water at 50-55.degree. C. and then immediately crystallized by seeding and addition of sufficient isopropyl alcohol to adjust to 25% (v/v)isopropyl alcohol:water.

3. A process according to claim 1 wherein: (a) 1 part by weight of said first polymorph is dissolved, by warming, in a mixture of about 2 parts by weight isopropyl alcohol and about 2.5 parts by weight water; (b) from 1.5 to 4 additional parts by weight of isopropyl alcohol are added; (c) said solution is cooled; and (d) (R,R)-formoterol L-tartrate is separated from said solution.

4. 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.degree. C., first polymorph (C) having peaks at the diffraction degrees with the intensity shown below in an X-ray powder diffraction pattern:

and said second polymorph (B) having peaks at the diffraction degrees with the intensity shown below in an X-ray powder diffraction pattern:

5. A process according to claim 4 wherein 1 part by weight (in grams) of said second polymorph is slurried at 45-50.degree. C. in 2.7 to 3.1 parts by volume (in milliliters) of a mixture of about 3.6 parts by weight of isopropyl alcohol, about 1 part by weight of toluene and about 0.5 parts by weight of water until the (R,R)-formoterol L-tartrate is >98% first polymorph (C).

6. 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.degree. 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:

said second polymorph (B) having peaks at the diffraction degrees with the intensity shown below in an X-ray powder diffraction pattern:

and said third polymorph (A) having peaks at the diffraction degrees with the intensity shown below in an X-ray powder diffraction pattern:

7. (R,R)-formoterol L-tartrate in the form of a crystalline solid comprising at least 95% of a first polymorph (C) having peaks at the diffraction degrees with the intensity shown below in an X-ray powder diffraction pattern:

8. (R,R)-formoterol L-tartrate in the form of a crystalline solid consisting of greater than 99.5% by weight of formoterol L-tartrate at least 95% in the polymorphic form of a thermodynamically stable third polymorph (A) of (R,R)-formoterol L-tartrate, said polymorph (A) having peaks at the diffraction degrees with the intensity shown below in an X-ray powder diffraction pattern:

9. A method for preventing bronchoconstriction or inducing bronchodilation in a mammal comprising administering to said mammal a therapeutically effective amount of the solid R,R-formoterol L-(+)-tartrate of claim 8.

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the solid R,R-formoterol L-(+)-tartrate of claim 8.

11. An aerosol pharmaceutical composition according to claim 10.

12. An oral pharmaceutical composition according to claim 10.

13. An oral pharmaceutical composition according to claim 12 in the form of a tablet, capsule or syrup.

14. A dry powder pharmaceutical composition for inhalation according to claim 10.
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