USRE47214EActiveUtility
4-[-2-[[5-methyl-1-(2-naphtalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride polymorphs and solvates

Assignee: ESTEVE LABOR DRPriority: Feb 4, 2010Filed: Feb 4, 2011Granted: Jan 29, 2019
Est. expiryFeb 4, 2030(~3.6 yrs left)· nominal 20-yr term from priority
Inventors:Ramón Berenguer Maimó Jorge Medrano Rupérez Jordi Benet Buchholz Laura Puig Fernandez Laia Pellejà Puxeu
A61P 43/00A61P 9/00C07D 231/22A61K 31/4152A61P 25/00A61P 29/00C07D 413/12A61K 31/4155A61P 25/04
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References
Claims
Abstract

The present invention relates to polymorphs and solvates of the hydrochloride salt of 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine (P027), processes for their preparation, and to pharmaceutical compositions comprising them.
Claims

exact text as granted — not AI-modified
The invention claimed is: 
     
       1. A solid polymorphic or solvated form of the hydrochloride salt of 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine selected from the group consisting of:
 a) a polymorphic phase I form having a X-ray powder diffraction pattern showing characteristic peaks at a reflection angle [2θ in degrees] of about 5.9, 8.1, 11.3, 11.7, 14.2, 15.1, 15.8, 16.3, 16.8, 17.8, 18.1, 18.6, 19.8, 20.9, 21.9, 22.8, 23.0, 23.2, 23.6, 23.9, 24.3, 25.0, 25.1, 28.0, 28.3, 28.6, 29.0, 29.2, 30.7, and 30.9; 
 b) a polymorphic phase II form having a X-ray powder diffraction pattern showing characteristic peaks at a reflection angle [2θ in degrees] of about 5.776, 11.629, 14.558, 15.737, 15.891, 16.420, 16.740, 17.441, 17.635, 18.056, 18.219, 19.232, 19.712, 20.140, 20.685, 21.135, 21.889, 22.108, 22.478, 22.763, 23.219, 23.454, 23.782, 24.689, 25.065, and 25.671; 
 c) a polymorphic phase III form having a X-ray powder diffraction pattern showing characteristic peaks at a reflection angle [2θ in degrees] of about 5.437, 5.714, 10.918, 11.546, 12.704, 13.344, 13.984, 14.505, 15.606, 15.824, 16.164, 16.646, 17.333, 17.837, 18.719, 18.878, 19.236, 19.533, 20.142, 20.689, 21.337, 22.008, 22.929, 23.596, 24.748, 25.064, 25.207, 25.737, and 26.148; 
 d) a polymorphic phase IV form, preferably having a X-ray powder diffraction pattern showing characteristic peaks at a reflection angle [2θ in degrees] of about 5.805, 11.685, 15.559, 15.804, 16.397, 16.879, 17.357, 17.465, 17.621, 19.112, 19.435, 19.923, 21.224, 21.987, 22.167, 22.412, 2.852, 23.059, 23.359, 23.855, 24.092, 25.722, 26.054, 26.649, and 27.780; 
 e) a dioxane solvate having a X-ray powder diffraction pattern showing characteristic peaks at a reflection angle [2θ in degrees] of about 4.734, 9.317, 11.390, 13.614, 14.290, 14.815, 16.211, 16.432, 16.782, 17.741, 18.056, 18.329, 18.724, 19.070, 19.494, 20.436, 20.762, 21.587, 22.000, 22.935, 23.084, 23.551, 23.891, 24.721, and 25.078; and 
 f) a chloroform solvate having a X-ray powder diffraction pattern showing characteristic peaks at a reflection angle [2θ in degrees] of about 11.370, 13.396, 14.048, 15.010, 15.303, 16.117, 16.804, 17.040, 17.830, 18.029, 18.661, 18.859, 19.190, 20.150, 20.434, 21.424, 22.279, 22.871, 23.449, 23.918, 24.343, 24.709, 24.820, 25.459, and 26.199; 
 with the 2θ values being obtained using copper radiation (Cu Kα1  1.54060 Å). 
 
     
     
       2. A process for the preparation of the polymorphic phase I form as defined in  claim 1 , comprising;
 a) dissolving 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride in a suitable solvent, and 
 b) evaporating the solvent. 
 
     
     
       3. The process according to  claim 2 , wherein 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride is dissolved at a temperature ranging from room temperature to 120° C. and/or the solvent is evaporated at a temperature ranging from −21° C. to 60° C. 
     
     
       4. A process for the preparation of the polymorphic phase I form as defined in  claim 1 , comprising mixing a solution comprising 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride with a suitable antisolvent. 
     
     
       5. The process according to  claim 4 , wherein the mixing is performed at a temperature ranging from room temperature to 90° C. 
     
     
       6. The process according to  claim 4 , wherein the mixing is performed by a liquid-liquid diffusion or a gas-liquid diffusion. 
     
     
       7. The process according to  claim 2 , further comprising adding water to the solution. 
     
     
       8. A process for the preparation of the polymorphic phase I form as defined in  claim 1 , comprising preparing a suspension comprising 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride. 
     
     
       9. The process according to  claim 8 , wherein the suspension is maintained at a temperature ranging from room temperature to 80° C. 
     
     
       10. A process for the preparation of the polymorphic phase II form as defined in  claim 1 , comprising:
 a) dissolving the hydrochloride salt of 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine in water in the presence of catalytic amounts of poly(vinyl alcohol), and 
 b) evaporating the water. 
 
     
     
       11. A process for the preparation of the polymorphic phase III form as defined in  claim 1 , comprising:
 a) dissolving the hydrochloride salt of 4-[(2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine in water or acetone in the presence of catalytic amounts of poly(ethylene glycol), and 
 b) evaporating the water or the acetone; 
 
       or comprising:
 a) dissolving the hydrochloride salt of 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine in water in the presence of catalytic amounts of poly(ethylene glycol), and 
 b) adding diisopropyl ether as antisolvent. 
 
     
     
       12. A process for the preparation of the polymorphic phase IV form as defined in  claim 1 , comprising:
 a) dissolving the hydrochloride salt of 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine in chloroform in the presence of catalytic amounts of a polymer selected from the group consisting of: polyvinyl pyrrolidone, poly(acrylic acid), polypropylene, poly(styrene-co-divinylbenzene), poly(tetrafluoroethylene), poly(vinyl alcohol), polyacrylamide and poly(methyl methacrilate methacrylate), and 
 b) adding diisopropyl ether as antisolvent. 
 
     
     
       13. A process for the preparation of the dioxane solvate as defined in  claim 1 , comprising:
 a) solvent drop grinding comprising:
 a) charging the hydrochloride salt of 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine together with catalytic quantities of dioxane to a ball mill container; and 
 b) grinding; or 
 
 b) crystallization from a hot saturated solution of dioxane. 
 
     
     
       14. A process for the preparation of the chloroform solvate as defined in  claim 1 , comprising:
 a) dissolving the hydrochloride salt of 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine in chloroform in the presence of catalytic amounts of a polymer selected from the group consisting of poly(ethylene glycol), polyvinyl pyrrolidone, poly(acrylic acid), nylon 6/6, polypropylene, poly(tetrafluoroethylene), poly(vinyl acetate), poly(vinyl alcohol), polyacrylamide and polysulfone; and 
 b) either evaporating the chloroform or crystallizing in a hot saturated solution of chloroform. 
 
     
     
       15. A process for the preparation of the phase I form of the hydrochloride salt of 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine of  claim 1  comprising heating the polymorphic phase II form, polymorphic phase III form, polymorphic phase IV form, dioxane solvate or chloroform solvate. 
     
     
       16. A process for the preparation of phase I form of the hydrochloride salt of 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine comprising the step of heating crystalline forms phase II, phase III and/or phase IV of this compound at a temperature between 140° C. and 170° C. 
     
     
       17. A pharmaceutical composition comprising the solid form defined in  claim 1 . 
     
     
       18. The solid polymorphic or solvated form of  claim 1  which is
 a polymorphic phase I form having a X-ray powder diffraction pattern showing characteristic peaks at a reflection angle [2θ in degrees] of about 5.9, 8.1, 11.3, 11.7, 14.2, 15.1, 15.8, 16.3, 16.8, 17.8, 18.1, 18.6, 19.8, 20.9, 21.9, 22.8, 23.0, 23.2, 23.6, 23.9, 24.3, 25.0, 25.1, 28.0, 28.3, 28.6, 29.0, 29.2, 30.7, and 30.9, 
 with the 28 values being obtained using copper radiation (CU Kα1  1.54060 Å). 
 
     
     
       19. The solid polymorphic or solvated form of  claim 1  which is
 a polymorphic phase II form having a X-ray powder diffraction pattern showing characteristic peaks at a reflection angle [2θ in degrees] of about 5.776, 11.629, 14.558, 15.737, 15.891, 16.420, 16.740, 17.441, 17.635, 18.056, 18.219, 19.232, 19.712, 20.140, 20.685, 21.135, 21.889, 22.108, 22.478, 22.763, 23.219, 23.454, 23.782, 24.689, 25.065, and 25.671, 
 with the 2θ values being obtained using copper radiation (Cu Kα1  1.54060 Å). 
 
     
     
       20. The solid polymorphic or solvated form of  claim 1  which is
 a polymorphic phase III form having a X-ray powder diffraction pattern showing characteristic peaks at a reflection angle [2θ in degrees] of about 5.437, 5.714, 10.918, 11.546, 12.704, 13.344, 13.984, 14.505, 15.606, 15.824, 16.164, 16.646, 17.333, 17.837, 18.719, 18.878, 19.236, 19.533, 20.142, 20.689, 21.337, 22.008, 22.929, 23.596, 24.748, 25.064, 25.207, 25.737, and 26.148, 
 with the 2θ values being obtained using copper radiation (Cu Kα1  1.54060 Å). 
 
     
     
       21. The solid polymorphic or solvated form of  claim 1  which is
 a polymorphic phase IV form, preferably having a X-ray powder diffraction pattern showing characteristic peaks at a reflection angle [2θ in degrees] of about 5.805, 11.685, 15.559, 15.804, 16.397, 16.879, 17.357, 17.465, 17.621, 19.112, 19.435, 19.923, 21.224, 21.987, 22.167, 22.412, 2.852, 23.059, 23.359, 23.855, 24.092, 25.722, 26.054, 26.649, and 27.780, 
 with the 2θ values being obtained using copper radiation (Cu Kα1  1.54060 Å). 
 
     
     
       22. The solid polymorphic or solvated form of  claim 1  which is
 a dioxane solvate having a X-ray powder diffraction pattern showing characteristic peaks at a reflection angle [2θ in degrees] of about 4.734, 9.317, 11.390, 13.614, 14.290, 14.815, 16.211, 16.432, 16.782, 17.741, 18.056, 18.329, 18.724, 19.070, 19.494, 20.436, 20.762, 21.587, 22.000, 22.935, 23.084, 23.551, 23.891, 24.721, and 25.078, 
 with the 2θ values being obtained using copper radiation (Cu Kα1  1.54060 Å). 
 
     
     
       23. The solid polymorphic or solvated form of  claim 1  which is
 a) a chloroform solvate having a X-ray powder diffraction pattern showing characteristic peaks at a reflection angle [2θ in degrees] of about 11.370, 13.396, 14.048, 15.010, 15.303, 16.117, 16.804, 17.040, 17.830, 18.029, 18.661, 18.859, 19.190, 20.150, 20.434, 21.424, 22.279, 22.871, 23.449, 23.918, 24.343, 24.709, 24.820, 25.459, and 26.199, 
 with the 2θ values being obtained using copper radiation (Cu Kα1  1.54060 Å). 
 
     
     
       24. A pharmaceutical composition comprising the solid form defined in  claim 18 . 
     
     
       25. A pharmaceutical composition comprising the solid form defined in  claim 19 . 
     
     
       26. A pharmaceutical composition comprising the solid form defined in  claim 20 . 
     
     
       27. A pharmaceutical composition comprising the solid form defined in  claim 21 . 
     
     
       28. A pharmaceutical composition comprising the solid form defined in  claim 22 . 
     
     
       29. A pharmaceutical composition comprising the solid form defined in  claim 23 . 
     
     
       30. A solid form of the hydrochloride salt of 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at about 19.8 and 29.0. 
     
     
       31. The solid form of claim 30, having an X-ray powder diffraction pattern further comprising a peak, in terms of 2-theta, at about 16.3, 17.8, 21.9, and 22.8. 
     
     
       32. The solid form of claim 30, having an X-ray powder diffraction pattern further comprising a peak, in terms of 2-theta, at about 5.9, 8.1, 11.3, 11.7, 14.2, 15.1, 15.8, 16.8, 18.1, 18.6, 20.9, 23.0, 23.2, 23.6, 23.9, 24.3, 25.0, 25.1, 28.0, 28.3, 28.6, 29.2, 30.7, and 30.9. 
     
     
       33. A process for the preparation of the solid form as defined in claim 30, comprising; a) dissolving 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride in a suitable solvent, and b) evaporating the solvent. 
     
     
       34. The process according to claim 33, wherein 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride is dissolved at a temperature ranging from room temperature to 120° C. and/or the solvent is evaporated at a temperature ranging from −21° C. to 60° C. 
     
     
       35. A process for the preparation of the solid form as defined in claim 30, comprising mixing a solution comprising 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride with a suitable antisolvent. 
     
     
       36. The process according to claim 35, wherein the mixing is performed at a temperature ranging from room temperature to 90° C. 
     
     
       37. The process according to claim 35, wherein the mixing is performed by a liquid-liquid diffusion or a gas-liquid diffusion. 
     
     
       38. The process according to claim 33, further comprising adding water to the solution. 
     
     
       39. A process for the preparation of the solid form as defined in claim 30, comprising preparing a suspension comprising 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride. 
     
     
       40. The process according to claim 39, wherein the suspension is maintained at a temperature ranging from room temperature to 80° C. 
     
     
       41. A solid form of the hydrochloride salt of 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at about 15.7, 17.4, and 18.1. 
     
     
       42. The solid form of claim 41, having an X-ray powder diffraction pattern further comprising a peak, in terms of 2-theta, at about 17.6 and 22.1. 
     
     
       43. The solid form of claim 41, having an X-ray powder diffraction pattern further comprising a peak, in terms of 2-theta, at about 5.8, 11.6, 14.56, 15.9, 16.4, 16.7, 17.4, 18.2, 19.2, 19.7, 20.1, 20.7, 21.1, 21.9, 22.5, 22.8, 23.2, 23.5, 23.8, 24.7, 25.1, and 25.7. 
     
     
       44. A process for the preparation of the solid form as defined in claim 41, comprising: a) dissolving the hydrochloride salt of 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine in water in the presence of catalytic amounts of poly(vinyl alcohol), and b) evaporating the water. 
     
     
       45. A solid form of the hydrochloride salt of 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at about 15.8, 18.9 and 26.2. 
     
     
       46. The solid form of claim 45, having an X-ray powder diffraction pattern further comprising a peak, in terms of 2-theta, at about 16.2, 17.8, 18.7, and 23.6. 
     
     
       47. The solid form of claim 45, having an X-ray powder diffraction pattern further comprising a peak, in terms of 2-theta, at about 5.4, 5.7, 10.9, 11.5, 12.7, 13.3, 14.0, 14.5, 15.6, 16.6, 17.3, 19.2, 19.5, 20.1, 20.7, 21.3, 22.0, 22.9, 24.7, 25.1, 25.2, and 25.7. 
     
     
       48. A process for the preparation of the solid form as defined in claim 45, comprising: a) dissolving the hydrochloride salt of 4-[(2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine in water or acetone in the presence of catalytic amounts of poly(ethylene glycol), and b) evaporating the water or the acetone; or comprising: a) dissolving the hydrochloride salt of 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine in water in the presence of catalytic amounts of poly(ethylene glycol), and b) adding diisopropyl ether as antisolvent. 
     
     
       49. A solid form of the hydrochloride salt of 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at about 11.7, 19.1, 23.4, and 24.1. 
     
     
       50. The solid form of claim 49, having an X-ray powder diffraction pattern further comprising a peak, in terms of 2-theta, at about 15.6, 16.4, 16.9, 17.6, and 22.0. 
     
     
       51. The solid form of claim 49, having an X-ray powder diffraction pattern further comprising a peak, in terms of 2-theta, at about 5.8, 15.8, 17.4, 17.5, 19.4, 19.9, 21.2, 22.2, 22.4, 22.9, 23.1, 23.9, 24.1, 25.7, 26.1, 26.6, and 27.8. 
     
     
       52. A process for the preparation of the solid form as defined in claim 49, comprising: a) dissolving the hydrochloride salt of 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine in chloroform in the presence of catalytic amounts of a polymer selected from the group consisting of: polyvinyl pyrrolidone, poly(acrylic acid), polypropylene, poly(styrene-co-divinylbenzene), poly(tetrafluoroethylene), poly(vinyl alcohol), polyacrylamide and poly(methyl methacrylate), and b) adding diisopropyl ether as antisolvent. 
     
     
       53. A solid form of the hydrochloride salt of 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at about 14.8 and 22.0, wherein the solid form is a dioxane solvate. 
     
     
       54. The solid form of claim 53, having an X-ray powder diffraction pattern further comprising a peak, in terms of 2-theta, at about 18.7 and 19.1. 
     
     
       55. The solid form of claim 53, having an X-ray powder diffraction pattern further comprising a peak, in terms of 2-theta, at about 4.7, 9.3, 11.4, 13.6, 14.3, 16.2, 16.4, 16.8, 17.7, 18.1, 18.3, 19.5, 20.4, 20.8, 21.6, 22.9, 23.1, 23.6, 23.9, 24.7, and 25.1. 
     
     
       56. A process for the preparation of the solid form as defined in claim 53, comprising: a) solvent drop grinding comprising: a) charging the hydrochloride salt of 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine together with catalytic quantities of dioxane to a ball mill container; and b) grinding; or b) crystallization from a hot saturated solution of dioxane. 
     
     
       57. A solid form of the hydrochloride salt of 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at about 22.3 and 25.5, wherein the solid form is a chloroform solvate. 
     
     
       58. The solid form of claim 57, having an X-ray powder diffraction pattern further comprising a peak, in terms of 2-theta, at about 11.4, 15.0, and 26.2. 
     
     
       59. The solid form of claim 57, having an X-ray powder diffraction pattern further comprising a peak, in terms of 2-theta, at about 13.4, 14.0, 15.3, 16.1, 16.8, 17.0, 17.8, 18.0, 18.7, 18.9, 19.2, 20.2, 20.4, 21.4, 22.9, 23.4, 23.9, 24.3, 24.7, and 24.8. 
     
     
       60. A process for the preparation of the solid form as defined in claim 57, comprising: a) dissolving the hydrochloride salt of 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine in chloroform in the presence of catalytic amounts of a polymer selected from the group consisting of poly(ethylene glycol), polyvinyl pyrrolidone, poly(acrylic acid), nylon 6/6, polypropylene, poly(tetrafluoroethylene), poly(vinyl acetate), poly(vinyl alcohol), polyacrylamide and polysulfone; and b) either evaporating the chloroform or crystallizing in a hot saturated solution of chloroform. 
     
     
       61. A solid form of the hydrochloride salt of 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine selected from the group consisting of:
 (a) a polymorphic phase I form having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at about 19.8 and 29.0;   (b) a polymorphic phase II form having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at about 15.7, 17.4, and 18.1;   (c) a polymorphic phase III form having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at about 15.8, 18.9, and 26.2;   (d) a polymorphic phase IV form having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at about 11.7, 19.1, 23.4, and 24.1;   (e) a dioxane solvate having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at about 14.8 and 22.0; and   (f) a chloroform solvate having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at about 22.3 and 25.5.   
     
     
       62. A process for the preparation of the polymorphic phase I form of the hydrochloride salt of 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine of claim 61 comprising heating the polymorphic phase II form, polymorphic phase III form, polymorphic phase IV form, dioxane solvate or chloroform solvate. 
     
     
       63. A process for the preparation of phase I form of the hydrochloride salt of 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine of claim 61, comprising the step of heating crystalline forms phase II, phase III and/or phase IV of this compound at a temperature between 140° C. and 170° C. 
     
     
       64. A pharmaceutical composition comprising the solid form defined in claim 30. 
     
     
       65. A pharmaceutical composition comprising the solid form defined in claim 41. 
     
     
       66. A pharmaceutical composition comprising the solid form defined in claim 45. 
     
     
       67. A pharmaceutical composition comprising the solid form defined in claim 49. 
     
     
       68. A pharmaceutical composition comprising the solid form defined in claim 53. 
     
     
       69. A pharmaceutical composition comprising the solid form defined in claim 57. 
     
     
       70. The solid form of claim 30, wherein the solid form is polymorphic phase I form. 
     
     
       71. The solid form of claim 41, wherein the solid form is polymorphic phase II form. 
     
     
       72. The solid form of claim 45, wherein the solid form is polymorphic phase III form. 
     
     
       73. The solid form of claim 49, wherein the solid form is polymorphic phase IV form.
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