AMORPHOUS SOLID COMPOSITION CONTAINING A PYRAZOLE-3-CARBOXAMIDE IN AMORPHOUS FORM AND STABILISING CARRIERS
The invention relates to a pyrazole-3-carboxamide in amorphous form, to an amorphous solid solution containing the same, and more generally to pharmaceutical composition containing the same
1 . A pyrazole-3-carboxamide derivative in amorphous form, selected from:
N-piperidino-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxamide, which exhibits a glass transition temperature of between 60° C. and 90° C., and in that its X-ray diffractogram shows the presence of a halo and the absence of diffraction peaks; and
N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, which exhibits a glass transition temperature of between 65° C. and 95° C., and in that its X-ray diffractogram shows the presence of a halo and the absence of diffraction peaks.
2 . The pyrazole-3-carboxamide derivative according to claim 1 , which is N-piperidino-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxamide.
3 . The pyrazole-3-carboxamide derivative according to claim 1 , which is N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide.
4 . An amorphous solid solution comprising a pyrazole-3-carboxamide derivative selected from:
N-piperidino-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxamide; and
N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide;
or a salt thereof in amorphous form; and
one or more excipients themselves in amorphous form.
5 . The solid solution according to claim 4 , wherein the pyrazole-3-carboxamide derivative is N-piperidino-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxamide, or a salt thereof in amorphous form.
6 . The solid solution according to claim 4 , wherein the pyrazole-3-carboxamide derivative is N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, or a salt thereof in amorphous form.
7 . The solid solution according to claim 4 , wherein the stabilizing excipient is selected from the group consisting of pharmaceutically acceptable acids, polyols and a polymer excipient.
8 . The solid solution according to claim 4 , wherein the stabilizing excipient is selected from the group consisting of pharmaceutically acceptable:
methacrylate copolymers,
vinyl homopolymers and copolymers,
polydextroses,
cellulosic polymers,
chemically modified starches,
pectins,
chitin derivatives,
polymers of natural origin,
polyalkylene oxides, and
polyethylene glycols.
9 . The solid solution according to claim 7 , wherein the stabilizing excipient is in an amount such that the total number of moles of stabilizing excipients is at least equal to the number of moles of amorphous pyrazole-3-carboxamide derivative.
10 . The solid solution according to claim 4 , wherein the stabilizing excipient is one or more pharmaceutically acceptable acid.
11 . The solid solution according to claim 10 , wherein the total number of acid functions of the pharmaceutically acceptable acid excipient is at least equal to the number of molecules of amorphous pyrazole-3-carboxamide derivative.
12 . The solid solution according to claim 7 , wherein one stabilizing excipient is citric acid or fumaric acid.
13 . The solid solution according to claim 7 , wherein the stabilizing excipient is a polyol.
14 . The solid solution according to claim 7 , wherein the stabilizing excipient is a polymer.
15 . The solid solution according to claim 14 , wherein the number of monomer unit of the stabilizing polymer excipient is at least equal to the number of moles of amorphous pyrazole-3-carboxamide derivative.
16 . The solid solution according to claim 15 , wherein the polymer has a glass transition temperature above 75° C.
17 . The solid solution according to claim 15 , wherein the polymer is selected from the group consisting of: methacrylate copolymer, vinyl homopolymer and vinyl copolymer.
18 . The solid solution according to claim 17 , wherein the stabilizing polymer excipient is selected from the group consisting of: the basic butyl methacrylate copolymer, the methacrylic acid/methyl methacrylate (1:1) copolymer, the methacrylic acid/methyl methacrylate (1:2) copolymer and the methacrylic acid/ethyl acrylate (1:1) copolymer.
19 . The solid solution according to claim 17 , wherein the stabilizing excipient is the methacrylic acid/methyl methacrylate (1:1) copolymer or the methacrylic acid/ethyl acrylate (1:1) copolymer.
20 . A process for preparing the amorphous solid solution according to claim 4 , comprising:
dissolving the pyrazole-3-carboxamide derivative according to claim 4 in amorphous form or in crystalline form and the stabilizing excipient in an appropriate solvent in order to form a liquid solution, and removing the solvent.
21 . A process for preparing the amorphous solid solution according to claim 4 , comprising:
treating a mixture of the pyrazole-3-carboxamide derivative according to claim 4 in crystalline or amorphous form and the stabilizing excipient either by melting and rapid cooling, or by injection molding, or by extrusion.
22 . A process for preparing the amorphous solid solution according to claim 4 , comprising:
milling together a mixture of pyrazole-3-carboxamide derivative according to claim 4 in crystalline or amorphous form and the stabilizing excipient.
23 . A pharmaceutical composition comprising the amorphous solid solution according to claim 4 .
24 . The pharmaceutical composition according to claim 23 suitable for oral administration.