Crystal Forms of 2--Adenosine
The present invention provides novel crystalline polymorphic forms of 2-cyclohexylmethylidenehydrazino adenosine, also known as binodenoson, methods of making the same, and methods for the manufacture of a pharmaceutical composition by employing such crystal forms, in particular, for the use of binodenoson in a subject, in need thereof, as a pharmacological stress agent to produce coronary vasodilation.
1 . A crystal form of 2-{2-[(cyclohexyl)methylene]hydrazino}adenosine (binodenoson) which crystal form is substantially free of other polymorphic forms of binodenoson and has at least one of the following properties:
(a) an endotherm by differential scanning calorimetry with an extrapolated onset melting temperature in the range of about 139° C. to about 146° C. when heated at 10° C./min;
(b) a X-ray diffraction pattern with characteristic X-ray diffraction peaks at diffraction angles (2θ) of about 5.7±0.2, 10.2±0.2, 14.6±0.2, 19.9±0.2, 21.1±0.2 and 24.6±0.2;
(c) an infrared reflectance spectrum with reflectance bands at about 1668±2 and 1592±2; and
(d) a Raman spectrum with Raman shifts at about 1618±2 and 1593±2 cm −1 .
2 . A crystal form according to claim 1 , which crystal form has characteristic X-ray diffraction peaks at diffraction angles (2θ), and relative intensities (I/I 1 ) of about:
Angle (deg 2θ)
Relative intensity (I/I 1 )
5.7 ± 0.2
100
10.2 ± 0.2
40
11.4 ± 0.2
22
14.4 ± 0.2
21
14.6 ± 0.2
25
15.6 ± 0.2
21
19.9 ± 0.2
38
20.5 ± 0.2
21
20.8 ± 0.2
17
21.1 ± 0.2
29
22.0 ± 0.2
17
24.2 ± 0.2
16
24.6 ± 0.2
27
3 . A crystal form according to claim 1 , which crystal form has all four of the properties (a), (b), (c) and (d).
4 . A crystal form of binodenoson which crystal form is substantially free of other polymorphic forms of binodenoson and has at least one of the following properties:
(a) an endotherm by differential scanning calorimetry with an extrapolated onset melting temperature in the range of about 149° C. to about 154° C. when heated at 10° C./min;
(b) a X-ray diffraction pattern with characteristic X-ray diffraction peaks at diffraction angles (2θ) of about 5.5±0.2, 10.4±0.2, 16.8±0.2, 20.2±0.2 and 26.0±0.2;
(c) an infrared reflectance spectrum with reflectance bands at about 1646±2 and 1598±2 cm −1 ; and
(d) a Raman spectrum with Raman shifts at about 1622±2 and 1588±2 cm −1 .
5 . A crystal form according to claim 4 , which crystal form has characteristic X-ray diffraction peaks at diffraction angles (2θ), and relative intensities of about:
Angle (deg 2θ)
Relative intensity (I/I 1 )
5.5 ± 0.2
100
10.4 ± 0.2
15
16.8 ± 0.2
15
20.2 ± 0.2
18
26.0 ± 0.2
50
6 . A crystal form according to claim 4 , which crystal form has all four of the properties (a), (b), (c) and (d).
7 . A crystal form of anhydrous binodenoson which crystal form is substantially free of other polymorphic forms of binodenoson and has at least one of the following properties:
(a) an endotherm by differential scanning calorimetry with an extrapolated onset melting temperature in the range of about 142° C. to about 145° C. when heated at 10° C./min;
(b) a X-ray diffraction pattern with characteristic X-ray diffraction peaks at diffraction angles (29) of about 5.1±0.2, 7.1±0.2, 8.6±0.2, 9.0±0.2, 17.4±0.2 and 19.0±0.2;
(c) an infrared reflectance spectrum with reflectance bands at about 1669±2 and 1592±2 cm −1 ; and
(d) a Raman spectrum with Raman shifts at about 1617±2 and 1591±2 cm −1 .
8 . A crystal form according to claim 7 , which crystal form has characteristic X-ray diffraction peaks at diffraction angles (2θ), and relative intensities of about:
Angle (deg 2θ)
Relative intensity (I/I 1 )
5.1 ± 0.2
100
7.1 ± 0.2
21
8.6 ± 0.2
21
9.0 ± 0.2
23
10.2 ± 0.2
11
12.0 ± 0.2
13
15.3 ± 0.2
15
17.4 ± 0.2
45
18.0 ± 0.2
16
19.0 ± 0.2
67
23.0 ± 0.2
19
23.5 ± 0.2
17
24.1 ± 0.2
14
9 . A crystal form according to claim 7 , which crystal form has all four of the properties (a), (b), (c) and (d).
10 . A crystal form of anhydrous binodenoson which crystal form is substantially free of other polymorphic forms of binodenoson and has at least one of the following properties:
(a) an endotherm by differential scanning calorimetry with an extrapolated onset melting temperature in the range of about 129° C. to about 133° C. when heated at 10° C./min;
(b) a X-ray diffraction pattern with characteristic X-ray diffraction peaks at diffraction angles (2θ) of about 4.9±0.2, 5.6±0.2, 8.6±0.2, 15.0±0.2, 16.8±0.2, 18.6±0.2, 18.9±0.2, 20.1±0.2, 23.7±0.2 and 24.3±0.2;
(c) an infrared reflectance spectrum with reflectance bands at about 1668±2, 1639±2 and 1591±2 cm −1 ; and
(d) a Raman spectrum with Raman shifts at about 1617±2 and 1591±2 cm −1 .
11 . A crystal form according to claim 10 , which crystal form has characteristic X-ray diffraction peaks at diffraction angles (2θ), and relative intensities of about:
Angle (deg 2θ)
Relative intensity (I/I 1 )
4.9 ± 0.2
100
5.6 ± 0.2
49
7.0 ± 0.2
28
8.6 ± 0.2
39
10.0 ± 0.2
26
15.0 ± 0.2
37
16.8 ± 0.2
41
17.2 ± 0.2
36
18.6 ± 0.2
47
18.9 ± 0.2
43
19.6 ± 0.2
39
19.7 ± 0.2
40
20.1 ± 0.2
47
21.5 ± 0.2
27
23.7 ± 0.2
37
24.3 ± 0.2
38
12 . A crystal form according to claim 10 , which crystal form has all four of the properties (a), (b), (c) and (d).
13 . A crystal form of anhydrous binodenoson which crystal form is substantially free of other polymorphic forms of binodenoson and has at least one of the following properties:
(a) an endotherm by differential scanning calorimetry with an extrapolated onset melting temperature in the range of about 178° C. to about 183° C. when heated at 10° C./min;
(b) a X-ray diffraction pattern with characteristic X-ray diffraction peaks at diffraction angles (2θ) of about 8.0±0.2, 8.5±0.2, 10.8±0.2, 12.1±0.2, 15.4±0.2, 17.1±0.2, 18.6±0.2, 19.6±0.2 and 20.3±0.2;
(c) an infrared reflectance spectrum with reflectance bands at about 1672±2, 1650±2 and 1589±2 cm −1 ; and
(d) a Raman spectrum with Raman shifts at about 1625±2 and 1589±2 cm −1 .
14 . A crystal form according to claim 13 , which crystal form has characteristic X-ray diffraction peaks at diffraction angles (2θ), and relative intensities of about:
Angle (deg 2θ)
Relative intensity (I/I 1 )
7.9 ± 0.2
91
8.0 ± 0.2
92
8.5 ± 0.2
55
10.7 ± 0.2
30
10.8 ± 0.2
30
12.1 ± 0.2
32
14.6 ± 0.2
30
15.4 ± 0.2
100
16.3 ± 0.2
40
17.1 ± 0.2
40
17.7 ± 0.2
36
18.6 ± 0.2
68
19.6 ± 0.2
57
20.2 ± 0.2
78
20.3 ± 0.2
79
21.0 ± 0.2
38
26.2 ± 0.2
53
15 . A crystal form according to claim 13 , which crystal form has all four of the properties (a), (b), (c) and (d).
16 . A crystal form of anhydrous binodenoson which crystal form is substantially free of other polymorphic forms of binodenoson and has at least one of the following properties:
(a) an endotherm by differential scanning calorimetry with an extrapolated onset melting temperature in the range of about 183° C. to about 188° C. when heated at 10° C./min;
(b) a X-ray diffraction pattern with characteristic X-ray diffraction peaks at diffraction angles (2θ) of about 4.2±0.2, 8.5±0.2, 10.5±0.2, 12.8±0.2, 16.1±0.2, 20.6±0.2 and 23.5±0.2;
(c) an infrared reflectance spectrum with reflectance bands at about 1647±2, 1595±2 and 1582±2 cm −1 ; and
(d) a Raman spectrum with Raman shifts at about 1627±2 and 1595±2 cm −1 .
17 . A crystal form according to claim 16 , which crystal form has characteristic X-ray diffraction peaks at diffraction angles (2θ), and relative intensities of about:
Angle (deg 2θ)
Relative intensity (I/I 1 )
4.2 ± 0.2
100
8.5 ± 0.2
47
10.5 ± 0.2
33
12.8 ± 0.2
26
16.1 ± 0.2
77
19.7 ± 0.2
26
20.6 ± 0.2
63
21.6 ± 0.2
29
23.5 ± 0.2
95
28.3 ± 0.2
27
18 . A crystal form according to claim 16 , which crystal form has all four of the properties (a), (b), (c) and (d).
19 . A method for the manufacture of a pharmaceutical composition by employing a crystal form according to any one of claims 1 to 18 , for the use of binodenoson in a subject, in need thereof, as a pharmacological stress agent to produce coronary vasodilation.
20 . A method of producing coronary vasodilation in a subject, in need thereof, comprising:
(a) incorporating an effective amount of a crystal form according to any one of claims 1 to 18 in an aqueous carrier suitable for parenteral administration to form a pharmaceutical composition;
(b) if required, reconstituting the pharmaceutical composition to form a pharmaceutical composition suitable for parenteral administration; and
(c) administering the pharmaceutical composition to the subject to produce coronary vasodilation.
21 . A method of assessing a coronary artery disease in a subject, in need thereof, comprising:
(a) dissolving an effective amount of a crystal form according to any one of claims 1 to 18 in an aqueous solution suitable for parenteral administration to form a pharmaceutical composition;
(b) if required, reconstituting the pharmaceutical composition to form a pharmaceutical composition suitable for parenteral administration;
(c) administering the pharmaceutical composition to the subject to produce coronary vasodilation; and
(d) detecting a coronary artery disease in the subject.