Melt-extruded solid dispersions containing an apoptosis-inducing agent

A process for preparing a solid dispersion, comprising:

• (a) subjecting to elevated temperature (i) an active pharmaceutical ingredient (API) that comprises a compound of Formula I
• where:
• R1 is halo;
• R1 and R2 are H or are independently methyl or methoxy;
• R1 and R4 are independently methyl or methoxy if R1 and R2 are H, or are H if R1 and R2 are independently methyl or methoxy;
• A1 and A2 are each independently CH or N;
• R5 is C1-4 alkyl or haloalkyl, C1-4 alkylsulfonyl or haloalkylsulfonyl, halo, nitro or cyano;
• X is —O— or —NH—;
• Y is —(CH2)n— where n is 0, 1, 2 or 3;
• and
• R6 is an unsubstituted or substituted 3- to 7-membered carbocyclic or heterocyclic ring as defined herein, or is NR7R8;
• wherein, if R6 is NR7R8, R7 and R8 are each independently H or R9—(CH2)m— groups, no more than one of R7 and R8 being H, where each R9 is independently a 3- to 7-membered carbocyclic or heterocyclic ring, optionally substituted with no more than two Z1 groups as defined below, and each m is independently 0 or 1;
• and
• wherein, if R6 is a substituted carbocyclic or heterocyclic ring, substituents thereon are no more than two Z1 groups and/or no more than one Z2 group, Z1 groups being independently selected from (a) C1-4 alkyl, C2-4 alkenyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, C1-4 alkylsulfonyl, C1-4 alkylsulfonylamino, C1-4 alkylcarbonyl, C1-4 alkylcarbonylamino and C1-4 alkylcarboxy, each optionally substituted with one or more substituents independently selected from halo, hydroxy, C1-4 alkoxy, amino, C1-4 alkylamino, di-(C1-4 alkyl)amino and cyano, (b) halo, (e) hydroxy, (f) amino and (g) oxo groups, and Z2 being (i) a further 3- to 6-membered carbocyclic or heterocyclic ring, optionally substituted with no more than two Z1 groups as defined above, or (ii) NR7R8 where R7 and R8 are as defined above;
• or a pharmaceutically acceptable salt thereof, (ii) a pharmaceutically acceptable water-soluble polymeric carrier and (iii) a pharmaceutically acceptable surfactant to provide an extrudable semi-solid mixture;
• (b) extruding the semi-solid mixture;
• and
• (c) cooling the resulting extrudate to provide a solid matrix comprising the polymeric carrier and the surfactant and having the compound or salt thereof dispersed in an essentially non-crystalline form therein.

A process for preparing a solid dispersion, comprising:

• (a) subjecting to elevated temperature (i) an active pharmaceutical ingredient (API) that comprises a compound of Formula I
• where:
• R0 is halo;
• R1 and R2 are H or are independently methyl or methoxy;
• R3 and R4 are independently methyl or methoxy if R1 and R2 are H, or are H if R1 and R2 are independently methyl or methoxy;
• A1 and A2 are each independently CH or N;
• R5 is C1-4 alkyl or haloalkyl, C1-4 alkylsulfonyl or haloalkylsulfonyl, halo, nitro or cyano;
• X is —O— or —NH—;
• Y is —(CH2)n— where n is 0, 1, 2 or 3;
• and
• R6 is an unsubstituted or substituted 3- to 7-membered carbocyclic or heterocyclic ring as defined herein, or is NR7R8;
• wherein, if R6 is NR7R8, R7 and R8 are each independently H or R9—(CH2)m— groups, no more than one of R7 and R8 being H, where each R9 is independently a 3- to 7-membered carbocyclic or heterocyclic ring, optionally substituted with no more than two Z1 groups as defined below, and each m is independently 0 or 1;
• and
• wherein, if R6 is a substituted carbocyclic or heterocyclic ring, substituents thereon are no more than two Z1 groups and/or no more than one Z2 group, Z1 groups being independently selected from (a) C1-4 alkyl, C2-4 alkenyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, C1-4 alkylsulfonyl, C1-4 alkylsulfonylamino, C1-4 alkylcarbonyl, C1-4 alkylcarbonylamino and C1-4 alkylcarboxy, each optionally substituted with one or more substituents independently selected from halo, hydroxy, C1-4 alkoxy, amino, C1-4 alkylamino, di-(C1-4 alkyl)amino and cyano, (b) halo, (e) hydroxy, (f) amino and (g) oxo groups, and Z2 being (i) a further 3- to 6-membered carbocyclic or heterocyclic ring, optionally substituted with no more than two Z1 groups as defined above, or (ii) NR7R8 where R7 and R8 are as defined above;
• or a pharmaceutically acceptable salt thereof, (ii) a pharmaceutically acceptable water-soluble polymeric carrier and (iii) a pharmaceutically acceptable surfactant to provide an extrudable semi-solid mixture;
• (b) extruding and calendering the semi-solid mixture;
• and
• (c) cooling the resulting extrudate to provide a solid matrix comprising the polymeric carrier and the surfactant and having the compound or salt thereof dispersed in an essentially non-crystalline form therein.