Polymorphs of zaleplon and methods for the preparation thereof
This invention relates to novel crystalline polymorphic forms of zaleplon (N-[3-(3-cyanopyrazolo[1,5a]pyrimidin-7-yl)phenyl]-N-ethylacetamide), methods for the preparation thereof; and their use as anxiolytic. antiepileptic. and sedative-hypnotic agents and skeletal muscle relaxants.
1 . Crystalline polymorph Form 1 of N-[3-(3-cyanopyrazolo(I,5a]pyrimidin-7-yl)phenyl 1-N-ethylacetamide.
2 . A Crystalline polymorph of N-13-(3-eyanopyrarolo[pyrimidin-7-yl)phenyl]-N-ethylacetamide that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 ( ) at about 14.5 and 20.1±0.2° 20.
3 . The crystalline polymorph of claim 2 , wherein the crystalline polymorph further exhibits a characteristic peak at about 10.4±0.2° 20.
4 . The crystalline polymorph of claim 3 , wherein the crystalline polymorph exhibits the characteristic peaks at about 10.4. 14.5. 16.7, 17.2, 18.0. 19.0, 20.1, 20.6, 21.2, 21.9, 22.6. 25.8, 26.6, 27.9. and 29.4±0.2° 20.
5 . The °crystalline polymorph of claim 2 . wherein the crystalline polymorph exhibits an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1
6 . A crystalline polymorph of N-[3-(3-cyanopyrazolo[1,5a]pyrimidin-7-yl)phenyl]-N-ethylacetamide that exhibits a chemical shift in a 13 C Solid State Nuclear Magnetic Resonance spectrum at about 14.3±0.2 ppm.
7 . The crystalline polymorph of claim 6 , wherein the crystalline polymorph further exhibits a chemical shift at about 21.9±0.2 ppm.
8 . The crystalline polymorph of claim 6 , wherein the crystalline polymorph further exhibits a chemical shift at about 167.8±0.2 ppm.
9 . The crystalline polymorph of claim 7 , wherein the crystalline polymorph further exhibits a chemical shift at about 167.8±0.2 ppm.
10 . A crystalline polymorph of N-13-(3-cyanopyrazolo[1,5a1pyrimidin-7-yl)phenyl]-N-ethylacetamide that exhibits a chemical shift in a 13 C Solid State Nuclear Magnetic Resonance spectrum at about 21.9±0.2 ppm.
11 . The crystalline polymorph of claim 10 , wherein the crystalline polymorph further exhibits a chemical shift at about 167.8±0.2 ppm.
12 . A crystalline polymorph N-[3-(3 cyanopyrazolo[1.5a]pyrimidin-7-yl)phenyl]-N-ethylacetamide that exhibits a chemical shift in a 13 C Solid State Nuclear Magnetic Resonance spectrum at about 167.8±0.2 ppm.
13 . The crystalline polymorph of claim 6 , that exhibits chemical shifts in a 13 C Solid State Nuclear Magnetic Resonance spectrum at about 14.3, 21.9, 44.2, 83.5, 113.3, 132.2, 143.9, 146.6, 152.7, and 167.8±0.2 ppm.
14 . A crystalline polymorph of N-[3-(3-cyanopyrazolo[1,5a]pyrimidin-7-yl)phenyl]-N-ethylacetamide that exhibits delta values in a 13 C Solid State Nuclear Magnetic Resonance spectrum of about 7.6, 29.9, 69.2, 99.0, 117.9, 129.6, 132:3, 138.4, and 153.5.
15 . The crystalline polymorph of claim 14 , wherein the crystalline polymorph exhibits a 13 C Solid State Nuclear Magnetic Resonance spectrum substantially the same as that shown in FIG. 2 .
16 . A crystalline polymorph of N-[3-(3-cyanopyrazolo[1.5a1pyrimidin-7-yl)phenyl]-N-ethylacetamide that exhibits a single crystal X-ray crystallographic analysis at 295 K With crystal parameters that are approximately equal to the following:
Parameter
Form I
Space group
P2 1 /c (No. 14)
Cell dimensions
a ({acute over (Å)})
6.9760(5)
b ({acute over (Å)})
25.0623(17)
c ({acute over (Å)})
9.1369(5)
β (°)
100.92(4)
Volume ({acute over (Å)} 3 )
1568.5(5)
Z (Molecules/unit cell)
4
Density (g/cm 3 )
1.293
17 . Crystalline polymorph Form II of N-[3-(3-cyanopyrazolo[1,5a]pyrimidin-7-yl)phenyl]-N-ethylacetamide.
18 . A variable-water hydrate crystalline polymorph of N-[3-(3-cyanopyrazolo[1,5a]pyrimidin-7-yl)phenyl]-N-ethylacetamide
19 . The crystalline polymorph of claim 18 , wherein the polymorph is a hydrate.
20 . The crystalline polymorph of claim 18 , wherein the crystalline polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 ( ) at about 12.5 and 21.4 0.2° 20
21 . The crystalline polymorph of claim 18 , wherein the crystalline polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 0 at about 12.5 and 21.2±0.2° 20.
22 . The crystalline polymorph of claim 18 , wherein the crystalline polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 0 at about 8.1, 11.0. 12.5: 13.3. 15:0. 16.8. 17.5. 18.0, 21.4, 22.2, 24.5, 25.1, 25.3, 25.7, 26.7. 27.1. 27.7. 28.2. and 30.3 0.2:20
23 . The crystalline polymorph of claim 18 wherein the crystalline polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 0 at about 7.9. 10.6, 12.5. 14.8. 16.4. 16.8. 17.6. 21.2. 23.9, 24.1, 25.2. 25.5. 26.4, 27.0, 27.2, 27.4, and 28.3±0.2° 20.
24 . The crystalline polymorph of claim 18 , wherein the crystalline polymorph exhibits an X-ray powder diffraction pattern substantially the same as that shown in FIG. 6 .
25 . The crystalline polymorph IS. wherein the crystalline polymorph exhibits an X-ray powder diffraction pattern substantially the same as that shown in FIG. 7 .
26 . The crystalline polymorph of claim 18 , wherein the crystalline polymorph exhibits a chemical shift in a 13 C Solid State Nuclear Magnetic Resonance spectrum at about. 13.1 and 23.6±0.2 ppm.
27 . The crystalline polymorph of claim 26 , wherein the crystalline polymorph exhibits chemical shifts in a 13 C Solid State Nuclear Magnetic Resonance spectrum at about 13.2, 23.6, 44.9, 79.0, 111.3. 130.7, 142.7, 145.3. 149.3, 153.1, 171.7. and 173.8±0.2 ppm.
28 . The crystalline polymorph of claim 18 , wherein the crystalline polymorph exhibits a difference between the lowest ppm peak and another peak in a 13 C Solid State Nuclear Magnetic Resonance spectrum of about 10.4 ppm.
29 . The crystalline polymorph of claim 28 , wherein the crystalline polymorph exhibits delta values in a 13 C Solid State Nuclear Magnetic Resonance spectrum of about 10.4, 31.7, 65.8, 98.1, 117.5, 129.5, 132.1, 136.1, 139.9, 158.5, and 160.6 ppm.
30 . The crystalline polymorph of claim 18 , wherein the crystalline polymorph exhibits an X-ray powder diffraction pattern substantially the same as that shown in FIG. 9 .
31 . A crystalline polymorph of N-[3-(3-cyanopyrazolo alpyrimidin-7-yl)phenyl]-N-ethylacetamide that exhibits a single crystal X-ray crystallographic analysis at 150 K with crystal parameters that are approximately equal to the following:
Parameter
Form II
Space group
P2 1 /c (No. 14)
Cell dimensions
a ({acute over (Å)})
11.1896(9)
b ({acute over (Å)})
6.9236(5)
c ({acute over (Å)})
20.986(2)
β (°)
99.089(3)
Volume (Å)
1605.4(4)
Z (Molecules/unit cell)
4
Density (g/cm 3 )
1.300
32 . Crystalline polymorph Form III of N-[3-(3-cyanopyrazolo[1,5a]pyrimidin-7-yl)phenyl]-N-ethylacetanlide.
33 . The crystalline polymorph of claim 18 , wherein the crystalline polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 0 at about 8.0 and 16.2±0.2° 20.
34 . The crystalline polymorph of claim 33 , wherein the crystalline polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 0 at about 8.0, 11.2, 16.2, 17.1, 17.6, 24.3, and 25.1±0.2° 20
35 . The crystalline polymorph of claim 34 , wherein the crystalline polymorph exhibits an X-ray powder diffraction pattern substantially the same as that shown in FIG. 11 .
36 . The crystalline polymorph of claim 18 , wherein the crystalline polymorph exhibits chemical shifts in a 13 C Solid State Nuclear Magnetic Resonance spectrum at about 12.1 and 12.4 0.2 ppm.
37 . The crystalline polymorph of claim 18 , wherein the crystalline polymorph exhibits chemical shifts in a 13 C Solid State Nuclear Magnetic Resonance spectrum at about 22.8 and 25.8±0.2 ppm.
38 . The crystalline polymorph of claim 18 , wherein the crystalline polymorph exhibits a difference between the lowest ppm peak and another peak in a 13 C Solid State Nuclear•Magnetic Resonance spectrum of about 13.7 ppm.
39 . The crystalline polymorph of claim 18 , wherein the crystalline polymorph exhibits a chemical shift in a 13 C Solid State Nuclear Magnetic Resonance at about 171.6±0.2 ppm.
40 . The crystalline polymorph of claim 39 , wherein the crystalline polymorph exhibits chemical shifts in a 13 C Solid State Nuclear Magnetic Resonance at about 12.1, 12.4, 22.8, 25.8, 44.1, 45.5, 79.0, 81.1, 111.0, 113.4, 131.4, 143.3, 145.7, 149.0, 150.1, 153.0, 155.5, and 171.6±0.2 ppm.
41 . The crystalline polymorph of claim 18 , wherein the crystalline polymorph exhibits a difference between the lowest ppm peak and another peak in a 13 C Solid State Nuclear Magnetic Resonance of about 159.5 ppm.
42 . The crystalline polymorph or claim 41 , wherein the crystalline polymorph exhibits delta values in 13 C Solid State Nuclear Magnetic Resonance spectrum of about 0.3, 10.7. 13.7, 32.0. 33.4. 66.9. 69.0. 98.9. 101.3. 19.3. 131.2. 133.6. 136.9. 138.0. 140.9. 143.4, and 159.5 ppm.
43 . The crystalline polymorph of claim 18 , wherein the crystalline polymorph exhibits an X-ray powder diffraction pattern substantially the same as that shown in FIG. 11 .
44 . The crystalline polymorph of claim 18 , wherein the crystalline polymorph exhibits a 13 C Solid Slate Nuclear Magnetic Resonance spectrum substantially the same as that shown in FIG. 12 .
45 . A pharmaceutical composition comprising a therapeutically effective amount of an anhydrous crystalline polymorph of zaleplon and a pharmaceutically acceptable carrier or diluent.
46 . The pharmaceutical composition of claim 45 , wherein the pharmaceutical composition comprises at least about 90% by weight of Form I of zaleplon, based upon 100% total weight of zaleplon in the pharmaceutical composition.
47 . The pharmaceutical composition of claim 46 , wherein the pharmaceutical composition comprises at least about 95% by weight of Form I of zaleplon, based upon 100% total weight of zaleplon in the pharmaceutical composition.
48 . A pharmaceutical composition comprising a therapeutically effective amount of a hydrate crystalline polymorph of zaleplon and a pharmaceutically acceptable carrier or diluent.
49 . The pharmaceutical composition of claim 48 , wherein the pharmaceutical composition comprises at least about 90% by weight of Form II of zaleplon, based upon 100% total weight of zaleplon in the pharmaceutical composition.
50 . The pharmaceutical composition of claim 49 , wherein the pharmaceutical composition comprises at least about 95% by weight of Form II of zaleplon. based upon 100% total weight of zaleplon in the pharmaceutical composition.
51 . The pharmaceutical composition of claim 48 , wherein the pharmaceutical composition comprises at least about 90% by weight of Form III of zaleplon. based upon 100% total weight of zaleplon in the pharmaceutical composition.
52 . The pharmaceutical composition of claim 51 , wherein the pharmaceutical composition comprises at least about 95% by weight of Form III of zaleplon, based upon 100% total weight of zaleplon in the pharmaceutical composition.
53 . A method of treating anxiety in an animal in need thereof comprising administering an anti-anxiety effective amount of Form I, II, or III of zaleplon or a mixture thereof.
54 . A method of treating epilepsy in an animal in need thereof comprising administering an anti-epilepsy effective amount of Form I, II, or II of zaleplon or a mixture thereof.
55 . A method of inducing a sedative-hypnotic effect in an animal in need thereof comprising administering a sedative-hypnotic effective amount of Form I, II, or III of zaleplon or a mixture thereof.
56 . A method of inducing muscle relaxation in an animal in need thereof comprising administering a skeletal muscle relaxing effective amount of Form I, II. or III of zaleplon or a mixture thereof.
57 . A process for preparing Form 1 of zaleplon comprising:
(i) providing a non-aqueous solution of zaleplon:
(ii) heating the solution to at least about 40° C.: and
(iii) cooling the solution.
58 . A process for preparing Form I of zaleplon comprising:
(i) providing a non-aqueous solution of zaleplon; and
(ii) evaporating the solvent in the solution to yield Form I of zaleplon.
59 . A process for preparing Form I of zaleplon comprising heating one or more of Forms II and III of zaleplon at an effective temperature to yield Form I of zaleplon.
60 . A process for preparing Form II of zaleplon comprising:
(i) dissolving zaleplon in a non-aqueous solvent to form a solution; and
(ii) adding water to the solution.
61 . A process for preparing Form III of zaleplon comprising.
(i) providing a solution containing zaleplon dissolved in an aqueous solvent; and
(ii) evaporating the solvent.