Polymorphs of a hydrochloride salt of PN6047
The present invention relates to a hydrochloride salt of 4-[(3-carbamoylphenyl)[1-(1,3-thiazol-5-ylmethyl)piperidin-4-ylidene]methyl]-N,N-dimethylbenzamide (PN6047) and crystalline forms thereof, more specifically Form HCl2 and Form HCl3 of PN6047. The invention also relates to pharmaceutical compositions comprising such polymorphs, to a process for the preparation of these polymorphs, and to the use of these polymorphs in the treatment or prevention of conditions that are mediated by agonism of the δ-opioid receptor, and in particular in the treatment or prevention of pain.
1 . A crystalline HCl salt of PN6047 having a structure:
which is Form HCl2 having an XRPD pattern, obtained with CuKaI-radiation, with at least peaks at °2θ values of 16.5±0.2, 23.3±0.2 and 23.5±0.2.
2 . The crystalline HCl salt of claim 1 , wherein the salt is stable at a relative humidity of 60% at a temperature of 25° C.
3 . The crystalline HCl salt of claim 1 , wherein the salt is stable at a relative humidity of 75% at a temperature of 40° C.
4 . The crystalline HCl salt of claim 1 , wherein the salt is an anhydrate.
5 . The crystalline salt of claim 1 , wherein Form HCl2 has an XRPD pattern, obtained with CuKα1-radiation, with at least peaks at °2θ values of 16.5±0.2, 23.3±0.2 and 23.5±0.2 and one or more of 14.3±0.2, 16.1±0.2, 16.3±0.2 and 20.2±0.2.
6 . The crystalline salt of claim 1 , wherein Form HCl2 has an XRPD pattern, obtained with CuKα1-radiation, substantially as shown in FIG. 1 .
7 . The crystalline HCl salt of claim 1 , wherein Form HCl2 has a DSC curve comprising an endotherm at approximately 228° C.
8 . A crystalline HCl salt of PN6047 having a structure:
which is Form HCl3, having an XRPD pattern, obtained with CuKα-radiation, with at least peaks at °2θ values of 12.8±0.2, 19.1±0.2 and 23.9±0.2.
9 . The crystalline salt of claim 8 , wherein Form HCl3 has an XRPD pattern, obtained with CuKα-radiation, with at least peaks at °2θ values of 12.8±0.2, 19.1±0.2 and 23.9±0.2 and one or more of 10.0±0.2, 25.3±0.2 and 26.3±0.2.
10 . The crystalline salt of claim 8 , wherein Form HCl3 has an XRPD pattern, obtained with CuKα-radiation, substantially as shown in FIG. 2 .
11 . The crystalline HCl salt of claim 8 , wherein Form HCl3 has a DSC curve comprising an endotherm at approximately 167° C.
12 . The crystalline HCl salt of claim 1 , having a crystallinity of greater than about 99%.
13 . A pharmaceutical composition comprising a therapeutically effective amount of a crystalline HCl salt of PN6047 according to claim 1 , in association with one or more pharmaceutically acceptable excipients.
14 . The pharmaceutical composition of claim 13 , wherein the HCl salt of PN6047 is Form HCl2 having a polymorphic purity of at least about 90%.
15 . The pharmaceutical composition of claim 14 , wherein Form HCl2 is substantially free of Form HCl3.
16 . A method of using crystalline HCl salt of PN6047 according to claim 1 in the treatment of pain comprising administering a therapeutically effective amount of the crystalline HCl salt of PN6047 to a patient.
17 . A method of using crystalline HCl salt of PN6047 according to claim 16 , wherein the pain is acute pain, chronic pain, neuropathic pain, cancer pain, visceral pain, diabetic pain, or pain caused by diseases or conditions including rheumatoid arthritis, osteoarthritis, fibromyalgia, migraine and opioid-induced hyperalgesia (OIH).
18 . A process for the preparation of Form HCl2 of PN6047 having a structure:
having an XRPD pattern, obtained with CuKaI-radiation, with at least peaks at 20 values of 16.5±0.2, 23.3±0.2 and 23.5±0.2, comprising the steps of:
a) preparing a solution or a suspension of a HCl salt of PN6047 in a suitable solvent;
b) maintaining stirring until a solid is obtained, or until conversion into Form HCl2 is completed;
c) recovering the solid obtained in step b); and
d) drying the solid under vacuum.
19 . A process for the preparation of Form HCl2 of PN6047 having a structure:
having an XRPD pattern, obtained with CuKaI-radiation, with at least peaks at 20 values of 16.5±0.2, 23.3±0.2 and 23.5±0.2, comprising the steps of:
a) preparing a solution or a suspension of the free base of PN6047 in a suitable solvent;
b) adding a HCl solution to the solution or suspension of step a) to achieve a free base:HCl ratio of about 1:1;
c) maintaining stirring until a solid is obtained, or until conversion into Form HCl2 is completed;
d) recovering the solid obtained in step c); and
e) drying the solid under vacuum.