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 - 18 . (canceled)
19 . A method for the manufacture of a pharmaceutical composition by employing a crystal form according to claim 4 , 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 claim 4 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) incorporating an effective amount of a crystal form according to claim 4 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;
(c) administering the pharmaceutical composition to the subject to produce coronary vasodilation; and
(d) detecting a coronary artery disease in the subject.
22 . A method for the manufacture of a pharmaceutical composition by employing a crystal form according to claim 1 , for the use of binodenoson in a subject, in need thereof, as a pharmacological stress agent to produce coronary vasodilation.
23 . A method of producing coronary vasodilation in a subject, in need thereof, comprising:
(a) incorporating an effective amount of a crystal form according to claim 1 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.
24 . A method of assessing a coronary artery disease in a subject, in need thereof, comprising:
(a) incorporating an effective amount of a crystal form according to claim 1 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;
(c) administering the pharmaceutical composition to the subject to produce coronary vasodilation; and
(d) detecting a coronary artery disease in the subject.