Process for crystallizing nalmefene hydrochloride
The application is directed to an efficient process for crystallizing nalmefene hydrochloride in a hydrated form from an aqueous hydrochloric acid solution (or a mixture) with a high yield.
1 . A process for crystallizing nalmefene hydrochloride, said process comprising:
mixing a source of nalmefene, water and hydrochloric acid to provide a substantially homogeneous mixture, wherein the hydrochloric acid is present in said substantially homogeneous mixture in an amount sufficient to achieve a final molarity of about 3 M to about 4 M; and
crystallizing said nalmefene hydrochloride from said substantially homogeneous mixture to provide a heterogenous mixture comprising crystalline hydrated form of nalmefene hydrochloride in an acidic aqueous continuous phase.
2 . The process of claim 1 , further comprising filtering said substantially homogeneous mixture to remove trace impurities prior to said crystallizing.
3 . The process of claim 1 , further comprising isolating a crystalline form of nalmefene hydrochloride from said heterogeneous mixture.
4 . The process of claim 1 , wherein said process comprises:
mixing said source of nalmefene in water or aqueous hydrochloric acid at an elevated temperature to obtain a substantially homogeneous mixture; and
crystallizing nalmefene hydrochloride by adding concentrated hydrochloric acid to said substantially homogeneous mixture in an amount sufficient to achieve a final molarity of the hydrochloric acid of from about 3 M to about 4 M, thus providing a heterogeneous mixture comprising a crystalline hydrated form of nalmefene hydrochloride in an acidic aqueous continuous phase.
5 . The process of claim 4 , wherein about 1 ml to about 5 ml of an acidic aqueous continuous phase is provided for every gram of said source of nalmefene.
6 . The process of claim 4 , further comprising filtering said substantially homogeneous mixture to remove trace solid impurities.
7 . The process of claim 4 , wherein said concentrated hydrochloric acid is added to said substantially homogeneous mixture in an amount to achieve a final molarity of about 3.5 M.
8 . The process of claim 1 , wherein said process comprises:
mixing said source of nalmefene in about 3 M to about 4 M hydrochloric acid at an elevated temperature to obtain a substantially homogeneous mixture; and
cooling said substantially homogeneous mixture or allowing said substantially homogeneous mixture to cool to a reduced temperature to provide a heterogeneous mixture comprising crystalline hydrated form of nalmefene hydrochloride in an acidic aqueous continuous phase,
wherein about 1 ml to about 5 ml of an acidic aqueous continuous phase is provided for every gram of said source of nalmefene.
9 . The process of claim 4 , wherein said crystalline hydrated form of nalmefene hydrochloride is isolated from said heterogeneous mixture.
10 . The process of claim 1 , wherein said source of nalmefene is nalmefene free base.
11 . The process of claim 1 , wherein said source of nalmefene is an acid salt of nalmefene.
12 . The process of claim 11 , wherein said source of nalmefene is nalmefene hydrochloride.
13 . The process of claim 12 , wherein said source of nalmefene is a hydrated form of nalmefene hydrochloride.
14 . The process of claim 13 , wherein said hydrated form of nalmefene hydrochloride is nalmefene hydrochloride monohydrate or nalmefene hydrochloride dihydrate.
15 . The process of claim 4 , wherein said source of nalmefene is dissolved at a temperature of from about 50° C. to about 90° C.
16 . The process of claim 4 , further comprising allowing said substantially homogeneous mixture to cool to a reduced temperature.
17 . The process of claim 16 , further comprising cooling said mixture to about 0 to 5° C., and isolating said crystalline hydrated form of nalmefene hydrochloride by filtration.
18 . The process of claim 17 , further comprising steps of washing said isolated crystalline hydrated form of nalmefene hydrochloride with 3 M hydrochloric acid, and drying.
19 . The process of claim 1 , wherein said crystalline hydrated form of nalmefene hydrochloride is crystalline nalmefene hydrochloride monohydrate.
20 . The process of claim 1 , wherein said crystalline hydrated form of nalmefene hydrochloride is crystalline nalmefene hydrochloride dihydrate.