Crystalline, anhydrous forms of oxymorphone hydrochloride
View Patent ↗Crystalline, anhydrous hydrochloride salts of 4,5α-epoxy-3,14-dihydroxy-17-methylmorphinan-6-one (oxymorphone) are disclosed and three polymorphic forms of these salts are reported. The invention further relates to a method for the production of such salts, a pharmaceutical composition comprising an effective amount of such a salt as a medicament and for the treatment and/or prevention of pain.
1. A crystalline, anhydrous hydrochloride salt of 4,5α-epoxy-3,14-dihydroxy-17-methylmorphinan-6-one according to formula (I):
wherein the hydrochloride salt exhibits an X-ray powder diffractogram wherein peaks are observed at a grouping of peaks selected from the group consisting of A and B:
A) at (±0.2 in 2θ): 9.2, 12.7, 13.8, 14.7, 15.3, 16.2, 17.1, 19.0, 19.9, 20.6, 21.7, 24.6, 31.9 and 34.6; and
B) (±0.2 in 2θ): 6.0, 12.1, 13.1, 13.6, 15.3, 16.5, 22.4, 22.6, 24.1 and 29.8,
and wherein the hydrochloride salt is stable at room temperature.
2. The hydrochloride salt according to claim 1 , wherein the melting or sublimation temperature, defined as the peak temperature in a differential scanning calorimetry measurement at a heating rate of 10° C./minute, is ≥250° C.
3. A method for the preparation of a crystalline, anhydrous hydrochloride salt of 4,5α-epoxy-3,14-dihydroxy-17-methylmorphinan-6-one of formula (I) according to claim 1 , comprising the steps of:
providing a hydrate hydrochloride salt of 4,5α-epoxy-3,14-dihydroxy-17-methylmorphinan-6-one of formula (I); and
heating to a temperature of ≥130° C. to ≤210° C.
4. The method according to claim 3 , further comprising the step of grinding the hydrate hydrochloride salt of 4,5α-epoxy-3,14-dihydroxy-17-methylmorphinan-6-one of formula (I) prior to heating.
5. The method according to claim 3 , wherein the heating is conducted during a hot-melt extrusion process.
6. A pharmaceutical composition comprising an effective amount of a crystalline, anhydrous hydrochloride salt of 4,5α-epoxy-3,14-dihydroxy-17-methylmorphinan-6-one of formula (I) according to claim 1 .
7. A method of treating and/or inhibiting pain in a patient in need of such treatment, said method comprising administering to said patient an effective amount therefor of a crystalline, anhydrous hydrochloride salt of 4,5α-epoxy-3,14-dihydroxy-17-methylmorphinan-6-one of formula (I) according to claim 1 .
8. The pharmaceutical composition of claim 6 , wherein the effective amount of a crystalline, anhydrous hydrochloride salt of 4,5α-epoxy-3,14-dihydroxy-17-methylmorphinan-6-one is from about 0.05 mg/kg to about 500 mg/kg of body weight of a patient.
9. The pharmaceutical composition of claim 6 , wherein the composition is a delayed release composition.
10. The pharmaceutical composition of claim 6 , wherein the composition is a controlled release composition.
11. The pharmaceutical composition of claim 6 , wherein the composition is used with at least one other pharmaceutical active substance.
12. A method of treating pain in a subject in need thereof, said method comprising administering to said subject an analgesically effective amount of the crystalline, anhydrous hydrochloride salt of 4,5α-epoxy-3,14-dihydroxy-17-methylmorphinan-6-one of formula (I) according to claim 1 .
13. The hydrochloride salt according to claim 1 , wherein the melting or sublimation temperature, defined as the peak temperature in a differential scanning calorimetry measurement at a heating rate of 10° C./minute, is from about 280° C. to about 290° C.