Formoterol tartrate process and polymorph
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.
1. A highly pure (R,R)-formoterol L-tartrate composition that exhibits a differential scanning calorimetry pattern substantially the same as the differential scanning calorimetry pattern shown in FIG. 8 and obtained by a process comprising crystallizing a first polymorph (C) of (R,R)-formoterol L-tartrate from aqueous isopropyl alcohol, 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;
said first polymorph 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.
2. The composition of claim 1 , wherein said (R,R)-formoterol L-tartrate is 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 polymorph (A) of (R,R)-formoterol L-tartrate.