SYNTHESIS OF HYDROMORPHONE BASE

Abstract

Hydromorphone hydrochloride (I.Math.HCl) is converted into hydromorphone base (I) via hydromorphone monohydrate (I.Math.H.sub.2O).

Claims

1. A process for preparing hydromorphone base (I) comprising: i. suspending or dissolving hydromorphone monohydrate (I.Math.H.sub.2O) in at least an organic solvent, and ii. isolating hydromorphone base (I).

2. The process of claim 1, wherein the organic solvent comprises methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, tert-butanol, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, dichloromethane, acetone, methyl isobutyl ketone, acetonitrile, propionitrile, butyronitrile, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, pentane, cyclopentane, hexane, cyclohexane, heptane, toluene, chloroform, or mixtures thereof.

3. The process of claim 1, wherein the organic solvent comprises a polar organic solvent.

4. The process of claim 3, wherein the polar organic solvent is ethyl acetate.

5. The process of claim 1, wherein the organic solvent comprises a non-polar organic solvent.

6. The process of claim 5, wherein the non-polar organic solvent is toluene.

7. The process of claim 1, wherein the organic solvent is an anhydrous organic solvent.

8. The process of claim 1, wherein the hydromorphone monohydrate (I.Math.H.sub.2O) is suspended or dissolved in step i. at 15-80 C.

9. The process of claim 8, wherein the hydromorphone monohydrate (I.Math.H.sub.2O) is suspended or dissolved in step i. at 20-25 C.

10. The process of claim 9, wherein the hydromorphone monohydrate (I.Math.H.sub.2O) is suspended or dissolved in step i. at 25-35 C.

11. The process of claim 1, wherein isolating step ii. is performed between 5 and 25 C.

12. The process of claim 11, wherein isolating step ii. is performed between 0 and 10 C.

13. Hydromorphone monohydrate (I.Math.H.sub.2O), ##STR00006##

14. The hydromorphone monohydrate (I.Math.H.sub.2O) of claim 13 in a crystalline form comprising a DSC with two endotherms peaks, one at 1124 C. and a second at 2762 C., referred to as Form A.

15. The hydromorphone monohydrate (I.Math.H.sub.2O) crystalline form of claim 13, comprising an FTIR comprising the following peaks: 3547, 2925, 1721, 1377, 973, 7495 cm.sup.1, referred to as Form A.

16. The hydromorphone monohydrate (I.Math.H.sub.2O) crystalline form of claim 13, comprising characterized by an PXRD comprising the following peaks: 11.2 and 15.10.2 degrees 2, referred to as Form A.

17. The hydromorphone monohydrate (I.Math.H.sub.2O) crystalline form of claim 16, comprising an PXRD comprising the following peaks: 11.2, 15.1, and 25.4, 0.2 degrees 2, referred to as Form A.

18. The hydromorphone monohydrate (I.Math.H.sub.2O) crystalline form of claim 17, comprising characterized by an PXRD comprising the following peaks: 11.2, 12.3, 13.9, 15.1, 16.5, 18.9, 19.3, 23.2, 23.6, 24.8, 25.4, 25.7, 28.1, 31.4, and 31.80.2 degrees 2, referred to as Form A.

19. A process for preparing hydromorphone monohydrate (I.Math.H.sub.2O) comprising a) dissolving a hydromorphone salt in a solvent medium comprising water, b) adjusting the pH of the mixture of step a) between 8 and 10, and c) isolating hydromorphone monohydrate (I.Math.H.sub.2O) from the mixture of step b); wherein: step c) is performed between 5 and 25 C.

20. The process of claim 19, wherein the solvent medium comprising water comprises at least 50% water.

21. The process of claim 20, wherein the solvent medium comprising water comprises at least 95% water.

22. The process of claim 19, wherein the pH is adjusted between 8.2 and 9.8.

23. The process of claim 22, wherein the pH is adjusted between 8.8 and 9.2.

24. The process of claim 19, wherein in step b) the pH is adjusted with a weak base.

25. The process of claim 24, wherein the weak base is sodium carbonate, potassium carbonate, caesium carbonate, ammonium hydroxide, methylamine, ethylamine, dimethylamine, diethylamine, triethylamine, diisopropylethylamine, sodium acetate, potassium acetate sodium formate, potassium formate, or mixtures thereof.

26. The process of claim 25, wherein the weak base is sodium carbonate.

27. The process of claim 19 wherein hydromorphone salt is hydromorphone hydrochloride (I.Math.HCl).

28. The process of claim 19, wherein step c) is performed between 0 and 10 C.

29. The process according to claim 1, wherein the hydromorphone monohydrate (I.Math.H.sub.2O) is obtained by a) dissolving a hydromorphone salt in a solvent medium comprising water, b) adjusting the pH of the mixture of step a) between 8 and 10, and c)isolating hydromorphone monohydrate (I.Math.H.sub.2O) from the mixture of step b), wherein: step c) is performed between 5 and 25 C.

30. The process according to claim 1, wherein the hydromorphone monohydrate (I.Math.H.sub.2O) ##STR00007##

31. The hydromorphone monohydrate (I.Math.H.sub.2O) of claim 13 for use in therapy.

32. The hydromorphone monohydrate (I.Math.H.sub.2O) for use in claim 31, wherein the therapy is pain management.

Description

DESCRIPTION OF FIGURES

[0051] FIG. 1: FTIR of hydromorphone monohydrate (I.Math.H.sub.2O) Form A prepared in Example 1.

[0052] FIG. 2: DSC of hydromorphone monohydrate (I.Math.H.sub.2O) Form A prepared in Example 1 showing an endotherm peak at 112 C. due to the loss of water and at 276 C. due to the melting of the solid.

[0053] FIG. 3: TGA of hydromorphone monohydrate (I.Math.H.sub.2O) Form A prepared in Example 1 showing a 5.8% drop between 98 C. and 115 C. due to the loss of water. One molecule of water represents a theoretical 5.94% of the molecular weight.

[0054] FIG. 4: FTIR of hydromorphone base (I) prepared in Example 2.

[0055] FIG. 5: DSC of hydromorphone base (I) prepared in Example 2 showing an endotherm peak 275 C.

[0056] FIG. 6: TGA of hydromorphone base (I) prepared in Example 2 showing no loss of water.

[0057] FIG. 7: PXRD of hydromorphone monohydrate (I.Math.H.sub.2O) Form A prepared in Example 1.

[0058] FIG. 8: FTIR of hydromorphone hydrochloride (I.Math.HCl) with the following picks 3029, 2960, 2926, 2584, 1716, 1638, 1621, 1312, 976, 736.

[0059] FIG. 9: FTIR of hydromorphone hydrochloride (MCI), hydromorphone base (I), and hydromorphone monohydrate (I.Math.H.sub.2O) Form A superposed.

DETAILED DESCRIPTION OF THE INVENTION

[0060] The processes are schematically represented in the following scheme:

##STR00004##

[0061] DSC and TGA experiments are performed between 30 and 350 C. at 10 C./min under N.sub.2 flux.

[0062] Embodiment 1. A process for preparing hydromorphone base (I) comprising: [0063] i. suspending or dissolving hydromorphone monohydrate (I.Math.H.sub.2O) in at least an organic solvent, and [0064] ii. isolating hydromorphone base (I).

[0065] Embodiment 2. The process of the previous embodiment, wherein the organic solvent comprises primary, secondary or tertiary alcohols of C.sub.1 to C.sub.8 linear or branched alkanes; C.sub.1 to C.sub.8 linear or branched alkyl esters of C.sub.1 to C.sub.5 linear or branched carboxylic acids; ethers with the same or two different C.sub.1 to C.sub.6-linear or branched chains attached to the oxygen in cyclic or open forms; C.sub.1 to C.sub.8 linear or branched alkanes substituted by 1 to 4 different or same halogen, wherein the halogen is selected from Cl, Br or I; ketones of same or different C.sub.1 to C.sub.8 linear or branched alkanes chains; C.sub.1 to C.sub.5 nitriles; C.sub.5 to C.sub.8 linear, branched or cyclic alkanes; C.sub.1 to C.sub.3 mono, di or tri alkyl substituted C.sub.5 to C.sub.8 aromatic or heteroaromatic compounds; or mixtures thereof.

[0066] Embodiment 3. The process of any of the previous embodiments, wherein the organic solvent comprises methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, tert-butanol, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, dichloromethane, acetone, methyl isobutyl ketone, acetonitrile, propionitrile, butyronitrile, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, pentane, cyclopentane, hexane, cyclohexane, heptane, toluene, chloroform, or mixtures thereof.

[0067] Embodiment 4. The process of any of the previous embodiments, wherein the organic solvent comprises ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl isobutyl ketone, dichloromethane, methanol, ethanol, propanol, isopropanol, 1-butanol, isobutanol, tert-butanol, pentane, hexane, heptane, toluene, methyl tert-butyl ether, diethyl ether, or mixtures thereof.

[0068] Embodiment 5. The process of any of the previous embodiments, wherein the organic solvent comprises ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl isobutyl ketone, methanol, heptane, toluene, methyl tert-butyl ether, or mixtures thereof.

[0069] Embodiment 6. The process of any of the previous embodiments, wherein the organic solvent comprises ethyl acetate, isopropyl acetate, methyl isobutyl ketone, heptane, toluene, methyl tert-butyl ether, or mixtures thereof.

[0070] Embodiment 7. The process of any of the previous embodiments, wherein the organic solvent comprises a polar organic solvent.

[0071] Embodiment 8. The process of the previous embodiment, wherein the polar organic solvent comprises methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, tert-butanol, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, dichloromethane, acetone, methyl isobutyl ketone, acetonitrile, propionitrile, butanenitrile, or mixtures thereof.

[0072] Embodiment 9. The process of the previous embodiment, wherein the organic solvent comprises a polar protic organic solvent.

[0073] Embodiment 10. The process of the previous embodiment, wherein the polar protic organic solvent comprises methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, tert butanol, or mixtures thereof.

[0074] Embodiment 11. The process of embodiment 8, wherein the organic solvent comprises a polar aprotic organic solvent.

[0075] Embodiment 12. The process of the previous embodiment, wherein the polar aprotic organic solvent comprises methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, dichloromethane, acetone, methyl isobutyl ketone, acetonitrile, propionitrile, butanenitrile, or mixtures thereof.

[0076] Embodiment 13. The process of any of the embodiments 1 to 6, wherein the organic solvent comprises a non-polar organic solvent.

[0077] Embodiment 14. The process of the previous embodiment, wherein the non-polar organic solvent comprises diethyl ether, 1,4-dioxane, methyl tert-butyl ether, pentane, cyclopentane, hexane, cyclohexane, heptane, toluene, chloroform, or mixtures thereof.

[0078] Embodiment 15. The process of any of the previous embodiments, wherein the organic solvent comprises less than 5% of water.

[0079] Embodiment 16. The process of the previous embodiment, wherein the organic solvent comprises less than 3% of water.

[0080] Embodiment 17. The process of the previous embodiment, wherein the organic solvent comprises less than 2% of water.

[0081] Embodiment 18. The process of the previous embodiment, wherein the organic solvent comprises less than 1% of water.

[0082] Embodiment 19. The process of the previous embodiment, wherein the organic solvent comprises less than 0.1% of water.

[0083] Embodiment 20. The process of the previous embodiment, wherein the organic solvent comprises less than % of water.

[0084] Embodiment 21. The process of the any of the previous embodiments, wherein the organic solvent is an anhydrous organic solvent.

[0085] Embodiment 22. The process of any of the previous embodiments, wherein the hydromorphone monohydrate (I.Math.H.sub.2O) is suspended or dissolved in step i. at 15-80 C.

[0086] Embodiment 23. The process of the previous embodiment, wherein the hydromorphone monohydrate (I.Math.H.sub.2O) is suspended or dissolved in step i. at 25-50 C.

[0087] Embodiment 24. The process of the previous embodiment, wherein the hydromorphone monohydrate (I.Math.H.sub.2O) is suspended or dissolved in step i. at 25-35 C.

[0088] Embodiment 25. The process of any of the embodiments 1 to 22, wherein the hydromorphone monohydrate (I.Math.H.sub.2O) is suspended or dissolved in step i. at 20-25 C.

[0089] Embodiment 26. The process of the previous embodiment, wherein the hydromorphone monohydrate (I.Math.H.sub.2O) is suspended or dissolved in step i. at room temperature.

[0090] Embodiment 27. The process of any of the previous embodiments, wherein isolating step ii. is performed between 5 and 25 C.

[0091] Embodiment 28. The process of any of the previous embodiments, wherein the isolating step ii. is performed between 5 and 15 C.

[0092] Embodiment 29. The process of any of the previous embodiments, wherein the isolating step ii. is performed between 0 and 10 C.

[0093] Embodiment 30. The process of any of the embodiments 1 to 29 or 76 to 88, wherein the hydromorphone monohydrate (I.Math.H.sub.2O) is prepared according to embodiments 47 to 67.

[0094] Embodiment 31. The process of any of the embodiments 1 to 29 or 76 to 88, wherein the hydromorphone monohydrate (I.Math.H.sub.2O) is the hydromorphone monohydrate (I.Math.H.sub.2O) as described in embodiments 36 to 43 or 68 to 75.

[0095] Embodiment 32. A crystalline form of hydromorphone base (I) having a DSC endothermic peak at 2752 C.

[0096] Embodiment 33. The crystalline form of hydromorphone base (I) of the previous embodiment characterized by an FTIR comprising the following peaks 3361, 2924, 2797, 1727, 1502, 1314, 9465 cm.sup.1.

[0097] Embodiment 34. A pharmaceutical composition comprising a crystalline form of hydromorphone base (I) as described in any of the embodiments 32 to 33, together with at least one pharmaceutically acceptable excipient.

[0098] Embodiment 35. A crystalline form of hydromorphone base (I) as described in any of the embodiments 32 to 33 or the pharmaceutical composition as described in embodiment 34 for use in the treatment of pain.

[0099] Embodiment 36. Hydromorphone monohydrate (I.Math.H.sub.2O).

##STR00005##

[0100] Embodiment 37. The hydromorphone monohydrate (I.Math.H.sub.2O) of the previous embodiment which is to be considered that does not encompass the isotopically labelled derivatives.

[0101] Embodiment 38. The hydromorphone monohydrate (I.Math.H.sub.2O) of the previous embodiment, wherein the non-majoritarian isotopes represent less than 5% in mole percent.

[0102] Embodiment 39. The hydromorphone monohydrate (I.Math.H.sub.2O) of the previous embodiment, wherein the less abundant isotopes represent less than 3% in mole percent.

[0103] Embodiment 40. The hydromorphone monohydrate (I.Math.H.sub.2O) of any of the embodiments 36 to 39, wherein deuterium represents less than 0.1% of the hydrogen isotopes in mole percent.

[0104] Embodiment 41. A hydromorphone monohydrate (I.Math.H.sub.2O) of any of the embodiments 36 to 40 in a crystalline form characterized by an FTIR substantially such as that in FIG. 1.

[0105] Embodiment 42. The hydromorphone monohydrate (I.Math.H.sub.2O) crystalline Form A of any of the embodiments 36 to 41 characterized by an FTIR comprising the following peaks: 3547, 2925, 1721, 1377, 973, 7495 cm.sup.1.

[0106] Embodiment 43. The hydromorphone monohydrate (I.Math.H.sub.2O) crystalline Form A of the previous embodiment characterized by a DSC with two endotherms peaks, one at 1124 C. and a second at 2762 C.

[0107] Embodiment 44. Hydromorphone monohydrate (I.Math.H.sub.2O), as described in embodiments 36 to 43, for use in the preparation of hydromorphone base (I).

[0108] Embodiment 45. A pharmaceutical composition comprising a hydromorphone monohydrate (I.Math.H.sub.2O) as described in any of the embodiments 36 to 43, together with at least one pharmaceutically acceptable excipient.

[0109] Embodiment 46. A hydromorphone monohydrate (I.Math.H.sub.2O) as described in any of the embodiments 36 to 43 or the pharmaceutical composition as described in embodiment 45 for use in the treatment of pain.

[0110] Embodiment 47. A process for preparing hydromorphone monohydrate (I.Math.H.sub.2O) comprising [0111] a) dissolving a hydromorphone salt in a solvent medium comprising water, [0112] b) adjusting the pH of the mixture of step a) between 8 and 10, and [0113] c) isolating hydromorphone monohydrate (I.Math.H.sub.2O) from the mixture of step b).

[0114] Embodiment 48. The process of the previous embodiment, wherein the hydromorphone salt is hydromorphone hydrochloride (I.Math.HCl), sulphate, 1,4-benzendicarboxylate, 1,1,1-trifluoromethansulfonate, 1-hydroxy-2-naphthalenecarboxylate, 3-hydroxy-2-naphthalenecarboxylate, -methyl-4-[(2-oxocyclopentyl)methyl]benzeneacetate, 2,4-difluoro-4-hydroxy[1,1,1-biphenyl]-3-carboxylate, 4,5-diphenyl-2-oxazolepropanoate, -methyl-3-phenoxybenzeneacetate, 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate, 2-fluoro--methyl[1,1-biphenyl]-4-acetate, -methyl-4-(2-thienylcarbonyl)benzeneacetate, (1Z)-5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetate, 3-benzoyl--methylbenzeneacetate, 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetate, (S)-6-methoxy--methyl-2-naphthaleneacetate, 2-naphthalenesulfonate, butanedioate, (2E)-2-butenedioate, (2Z)-2-butenedioate, 2-hydroxy-1,2,3-propanetricarboxylate, 4-methylbenzenesulfonate, 2-hydroxypropanoate, benzoate, borate, dodecanoate, ethanedioate, pentanoate, hydrobromide, (2R,3R)-2,3-dihydroxybutanedioate, phosphate, acetate, (9Z)-9-octadecenoate, 2,3-dimethyl-4-[[(4-methylphenyl)sulfonyl]oxy]benzenesulfonate, 4-[[(2,3-dimethylphenyl)sulfonyl]oxy]benzenesulfonate, 4-[[(4-methylphenyl)sulfonyl]oxy]benzenesulfonate, 4-[(phenylsulfonyl)oxy]benzenesulfonate, or 3-hydroxy-2,6-dimethylbenzenesulfonate.

[0115] Embodiment 49. The process of the previous embodiment, wherein the hydromorphone salt is hydromorphone hydrochloride (I.Math.HCl).

[0116] Embodiment 50. The process of embodiment any of the embodiments 47 to 49, wherein the solvent medium comprising water comprises at least 50% water.

[0117] Embodiment 51. The process of the previous embodiment, wherein the solvent medium comprising water comprises at least 75% water.

[0118] Embodiment 52. The process of the previous embodiment, wherein the solvent medium comprising water comprises at least 85% water.

[0119] Embodiment 53. The process of the previous embodiment, wherein the solvent medium comprising water comprises at least 95% water.

[0120] Embodiment 54. The process of embodiment any of the embodiments 47 to 53, wherein the pH is adjusted between 8.2 and 9.8.

[0121] Embodiment 55. The process of the previous embodiment, wherein the pH is adjusted between 8.4 and 9.6.

[0122] Embodiment 56. The process of the previous embodiment, wherein the pH is adjusted between 8.6 and 9.4.

[0123] Embodiment 57. The process of the previous embodiment, wherein the pH is adjusted between 8.8 and 9.2.

[0124] Embodiment 58. The process of any of the embodiments 47 to 57, wherein step c) is performed between 5 and 25 C.

[0125] Embodiment 59. The process of the previous embodiment, wherein step c) is performed between 5 and 15 C.

[0126] Embodiment 60. The process of the previous embodiment, wherein step c) is performed between 2 and 12 C.

[0127] Embodiment 61. The process of the previous embodiment, wherein step c) is performed between 0 and 10 C.

[0128] Embodiment 62. The process of any of the embodiments 47 to 61, wherein the pH is adjusted with a base.

[0129] Embodiment 63. The process of the previous embodiment, wherein the base is a weak base.

[0130] Embodiment 64. The process of the previous embodiment, wherein the weak base is selected from sodium carbonate, potassium carbonate, caesium carbonate, ammonium hydroxide, methylamine, ethylamine, dimethylamine, diethylamine, triethylamine, diisopropylethylamine, sodium acetate, potassium acetate sodium formate, potassium formate, or mixtures thereof.

[0131] Embodiment 65. The process of the previous embodiment, wherein the weak base is selected from sodium carbonate, potassium carbonate, caesium carbonate, ammonium hydroxide, triethylamine, diisopropylethylamine, sodium acetate, potassium acetate, sodium formate, potassium formate, or mixtures thereof.

[0132] Embodiment 66. The hydromorphone monohydrate (I.Math.H.sub.2O) crystalline Form A of any of the embodiments 36 to 46 characterized by a PXRD comprising the following peaks: 11.2 and 15.10.2 degrees 2, referred to as Form A.

[0133] Embodiment 67. The hydromorphone monohydrate (I.Math.H.sub.2O) crystalline Form A of the previous embodiment characterized by a PXRD comprising the following peaks: 11.2, 15.1, and 25.40.2 degrees 2, referred to as Form A.

[0134] Embodiment 68. The hydromorphone monohydrate (I.Math.H.sub.2O) crystalline Form A of the previous embodiment characterized by a PXRD comprising the following peaks: 11.2, 15.1, 16.5, 25.4, and 25.70.2 degrees 2, referred to as Form A.

[0135] Embodiment 69. The hydromorphone monohydrate (I.Math.H.sub.2O) crystalline Form A of the previous embodiment characterized by a PXRD comprising the following peaks: 11.2, 12.3, 15.1, 16.5, 25.4, and 25.70.2 degrees 2, referred to as Form A.

[0136] Embodiment 70. The hydromorphone monohydrate (I.Math.H.sub.2O) crystalline Form A of the previous embodiment characterized by a PXRD comprising the following peaks: 11.2, 12.3, 15.1, 16.5, 23.2, 25.4, and 0.2 degrees 2, referred to as Form A.

[0137] Embodiment 71. The hydromorphone monohydrate (I.Math.H.sub.2O) crystalline Form A of the previous embodiment characterized by a PXRD comprising the following peaks: 11.2, 12.3, 13.9, 15.1, 16.5, 23.2, 24.8, 25.4, 25.7, and 28.10.2 degrees 2, referred to as Form A.

[0138] Embodiment 72. The hydromorphone monohydrate (I.Math.H.sub.2O) crystalline Form A of the previous embodiment characterized by a PXRD comprising the following peaks: 11.2, 12.3, 13.9, 15.1, 16.5, 18.9, 19.3, 23.2, 24.8, 25.4, and 28.10.2 degrees 2, referred to as Form A.

[0139] Embodiment 73. The hydromorphone monohydrate (I.Math.H.sub.2O) crystalline Form A of the previous embodiment characterized by a PXRD comprising the following peaks: 11.2, 12.3, 13.9, 15.1, 16.5, 18.9, 19.3, 23.2, 23.6, 24.8, 25.4, 25.7, 28.1, 31.4, and 31.80.2 degrees 2, referred to as Form A.

[0140] Embodiment 74. The process of any of the embodiments 1 to 31, wherein the organic solvent comprises ethyl acetate, toluene, or mixtures thereof.

[0141] Embodiment 75. The process of the previous embodiment, wherein the organic solvent comprises ethyl acetate.

[0142] Embodiment 76. The process of embodiment 74, wherein the organic solvent comprises toluene.

[0143] Embodiment 77. The process of any of the embodiments 1 to 31 or 74 to 76, wherein the hydromorphone monohydrate (I.Math.H.sub.2O) is suspended or dissolved in step i. from 30 min to 48 h.

[0144] Embodiment 78. The process of the previous embodiment, wherein the hydromorphone monohydrate (I.Math.H.sub.2O) is suspended or dissolved in step i. from 1 h to 36 h.

[0145] Embodiment 79. The process of the previous embodiment, wherein the hydromorphone monohydrate (I.Math.H.sub.2O) is suspended or dissolved in step i. from 1.5 h to 24 h.

[0146] Embodiment 80. The process of the previous embodiment, wherein the hydromorphone monohydrate (I.Math.H.sub.2O) is suspended or dissolved in step i. from 1.5 h to 12 h.

[0147] Embodiment 81. The process of the previous embodiment, wherein the hydromorphone monohydrate (I.Math.H.sub.2O) is suspended or dissolved in step i. from 1.5 h to 6 h.

[0148] Embodiment 82. The process of the previous embodiment, wherein the hydromorphone monohydrate (I.Math.H.sub.2O) is suspended or dissolved in step i. from 1.5 h to 4 h.

[0149] Embodiment 83. The process of embodiment 79, wherein the hydromorphone monohydrate (I.Math.H.sub.2O) is suspended or dissolved in step i. from 4 h to 24 h.

[0150] Embodiment 84. The process of the previous embodiment, wherein the hydromorphone monohydrate (I.Math.H.sub.2O) is suspended or dissolved in step i. from 8 h to 24 h.

[0151] Embodiment 85. The process of the previous embodiment, wherein the hydromorphone monohydrate (I.Math.H.sub.2O) is suspended or dissolved in step i. from 12 h to 24 h.

[0152] Embodiment 86. The process of the previous embodiment, wherein the hydromorphone monohydrate (I.Math.H.sub.2O) is suspended or dissolved in step i. from 17 h to 22 h.

Examples

[0153] Test 1. Powder X-Ray Diffraction Analysis (PXRD) Analysis are Performed as Follows:

[0154] Sample preparation: In order to acquire a powder diffraction pattern of the obtained solid, approximately 20 mg of the samples were prepared in a standard sample holder using two foils of polyacetate.

[0155] Data acquisition: Powder diffraction patterns were acquired on a Bruker D8 Advance Series 2Theta/Theta powder diffraction system using CuK1-radiation (1.54060 ) in transmission geometry. The system is equipped with a V{hacek over (A)}NTEC-1 single photon counting PSD, a Germanium monochromator, a ninety positions auto changer sample stage, fixed divergence slits and radial soller.

[0156] Programs used: Data collection with DIFFRAC plus XRD Commander V.2.5.1 and evaluation with High Score Plus 4.9 (Malvern Panalytical).

[0157] Measurement conditions: The samples were measured at room temperature in a range from 4 to 40 in degrees 2 in a 1 hour measurement, using an angular step of 0.033 and a time per step of 2930.45 s.

Example 1. Preparation of Hydromorphone Monohydrate (I.Math.H.SUB.2.O) from Hydromorphone Hydrochloride (I.Math.HCl)

[0158] 1.002 g (3.11 mmol) of I.Math.HCl was dissolved in 10 mL of water under nitrogen stream and cooled to 0/10 C. 0.278 g (2.62 mmol) of sodium carbonate was portionwise added under stirring to adjust pH to 9.0. The mixture was stirred for 3 h at 0/10 C. The resulting suspension was filtered, the solid was washed with cold water and dried at 50 C. under vacuum (55 mbar). 0.774 g (82% yield) of I.Math.H.sub.2O was obtained.

[0159] FTIR (FIG. 1): 3547, 2925, 1721, 1377, 973, 749 cm.sup.1.

[0160] DSC endotherm at 112 C. & 276 C., loss of water and I endotherm respectively, as shown in FIG. 2.

[0161] TGA 5.8%, loss of water between 98 C. and 115 C., as shown in FIG. 3.

[0162] MW I.Math.H.sub.2O: 303.36.

[0163] MW H.sub.2O: 18.02.

[0164] I.Math.H.sub.2O has a 5.94% of water.

[0165] PXRD Form A, as shown in FIG. 7 with the following peaks:

TABLE-US-00001 Angle (2) Rel. Intensity (%) d Value () 5.6 0.4 15.87 8.5 1.3 10.35 11.2 36.6 7.86 11.9 2.6 7.45 12.3 70.7 7.18 13.0 81.9 6.83 13.9 17.9 6.37 14.2 5.3 6.23 15.1 100 5.84 16.5 26.7 5.37 17.2 2.2 5.15 17.9 56.1 4.94 18.7 0.6 4.75 18.9 6 4.69 19.3 7.6 4.59 20.0 6.6 4.44 20.2 1.3 4.39 21.0 2.2 4.24 21.7 0.1 4.09 22.5 7 3.94 23.2 58.9 3.84 23.6 3.6 3.77 23.8 2.6 3.73 24.4 5.3 3.65 24.8 22.1 3.59 25.4 3.2 3.5 25.7 8.7 3.46 26.1 4.2 3.41 26.8 2.2 3.32 27.2 1.1 3.27 28.1 10 3.17 28.6 7.2 3.12 29.7 0.5 3.01 30.2 1.3 2.96 30.8 1.9 2.9 31.4 4.2 2.85 31.8 4.9 2.81 32.1 3.3 2.79 33.1 2.3 2.7 34.2 1.2 2.62 34.9 4.6 2.57 35.4 3 2.53 36.1 0.6 2.49 36.8 1.4 2.44 37.5 0.3 2.4 37.8 1.1 2.38 38.3 0.7 2.35 38.5 0.6 2.33 39.3 1.2 2.29 39.7 3.8 2.27

Example 2: Preparation of Hydromorphone Base (I) from Hydromorphone Monohydrate (I.Math.H.SUB.2.O) in Ethyl Acetate

[0166] 0.306 g of I.Math.H.sub.2O (1.00 mmol) was suspended in 1.5 mL of anhydrous ethyl acetate at 20/25 C. under nitrogen stream for 2 h. After cooling to 0/10 C. for 1 h, the resulting suspension was filtered and the solid washed twice with 1 mL of cold ethyl acetate. The solid was dried at 50 C. under vacuum to obtain 0.257 g (89% yield) of I.

[0167] FTIR (FIG. 4): 3361, 2924, 2797, 1727, 1502, 1314, 946 cm.sup.1.

[0168] DSC at 275 C., as shown in FIG. 5.

Example 3: Preparation of Hydromorphone Base (I) from Hydromorphone Monohydrate (I.Math.H.SUB.2.O) in a Battery of Solvents

[0169] 0.100 g of hydromorphone monohydrate (I.Math.H.sub.2O) (0.33 mmol) was suspended in 0.5 mL of the anhydrous solvent listed in the table below at 20/25 C. under nitrogen stream for 2 h. After cooling to 0/10 C. for 1 h, the resulting suspension was filtered, and the solid was washed four times with 0.5 mL of the respective cold solvent. The solid was dried at 50 C. under vacuum. Results are reported in the following table:

TABLE-US-00002 solvent yield hydromorphone purity Isopropyl acetate 69% Mixture of monohydrate and base form Methyl tert-butyl ether 67% Mixture of monohydrate and base form Tetrahydrofuran 48% base form Methanol 40% base form Heptane 72% Mixture of monohydrate and base form Toluene 71% Mixture of monohydrate and base form Methyl isobutyl ketone 64% base form with traces of monohydrate form

Example 4. Preparation of Hydromorphone Monohydrate (I.Math.H.SUB.2.O) from Hydromorphone Hydrochloride (I.Math.HCl)

[0170] 2.0 g (6.23 mmol) of I.Math.HCl were dissolved in 20 mL of water under nitrogen stream and cooled to 0/10 C. Sodium carbonate (0.766 g, 7.22 mmol) was portionwise added at 0/10 C. under stirring to adjust pH to 9.0. The mixture was stirred for 2.5 h at 0/10 C. The resulting suspension was filtered and the solid was washed several times with cold water to completely remove NaCl. The solid was dried at 50 C. under vacuum (55 mbars) to obtain 1.754 g (92.8% yield) of I.Math.H.sub.2O. The FTIR matches with the monohydrate obtained in Example 1.

Example 5: Preparation of Hydromorphone Base (I) from Hydromorphone Monohydrate (I.Math.H.SUB.2.O) in Toluene

[0171] 0.898 g of I.Math.H.sub.2O (2.96 mmol) were suspended in 4.5 mL of toluene at 30/35 C. under nitrogen stream for 19 h. After cooling to 0/10 C. for 1 h, the resulting suspension was filtered and the solid washed twice with 2 mL of toluene. The solid was dried at 50 C. under vacuum to obtain 0.788 g (88% yield) of I. The FTIR matches with the hydromorphone base (I) obtained in Example 2.

REFERENCES

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