Solid dispersions containing an apoptosis-inducing agent

1. A process for preparing a solid dispersion, comprising:

(a) dissolving in a suitable solvent (i) an active pharmaceutical ingredient (API) comprising a compound of Formula I

where:

R 0 is halo;

R 1 and R 2 are H or are independently methyl or methoxy;

R 3 and R 4 are independently methyl or methoxy if R 1 and R 2 are H, or are H if R 1 and R 2 are independently methyl or methoxy;

A l and A 2 are each independently CH or N;

R 5 is C 1-4 alkyl or haloalkyl, C 1-4 alkylsulfonyl or haloalkylsulfonyl, halo, nitro or cyano;

X is —O— or —NH—;

Y is —(CH 2 ) n —where n is 0, 1, 2 or 3; and

R 6 is an unsubstituted or substituted 3- to 7-membered carbocyclic or heterocyclic, or is NR 7 R 8 ;

wherein, if R 6 is NR 7 R 8 , R 7 and R 8 are each independently H or R 9 —(CH 2 ) m — groups, no more than one of R 7 and R 8 is H, each R 9 is independently a 3- to 7-membered carbocyclic or heterocyclic ring, optionally substituted with no more than two Z 1 groups as defined below, and each m is independently 0 or 1; and

wherein, if R 6 is a substituted carbocyclic or heterocyclic ring, substituents thereon are no more than two Z 1 groups and/or no more than one Z 2 group, Z 1 groups being independently selected from the group consisting of (a) C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonylamino, C 1-4 alkylcarbonyl C 1-4 alkylcarbonylamino and C 1-4 alkylcarboxy, each optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, C 1-4 alkoxy, amino, C 1-4 alkylamino, di-(C 1-4 alkyl)amino and cyano, (b) halo, (e) hydroxy, (f) amino and (g) oxo groups, and Z 2 being (i) a further 3- to 6-membered carbocyclic or heterocyclic ring, optionally substituted with no more than two Z 1 groups as defined above, or (ii) NR 7 R 8 where R 7 and R 8 are as defined above;

or a pharmaceutically acceptable salt thereof, (ii) at least one pharmaceutically acceptable water-soluble polymeric carrier and (iii) at least one pharmaceutically acceptable surfactant; and

(b) removing the solvent to provide a solid matrix comprising the at least one pharmaceutically acceptable water-soluble polymeric carrier and the at least one pharmaceutically acceptable surfactant and having the compound or a pharmaceutically acceptable salt thereof dispersed in an essentially non-crystalline form therein.

2. The process of claim 1 , wherein the API comprises a compound of Formula I or a pharmaceutically acceptable salt thereof in parent-compound form; and the process further comprises adding a pharmaceutically acceptable acid before removing the solvent.

3. The process of claim 1 , wherein the solvent is removed under heat and/or vacuum.

4. The process of claim 1 , wherein the solvent is removed by rotary evaporation or by spray-drying.

5. The process of claim 1 , wherein the solvent comprises one or more of methanol, ethanol, acetone, tetrahydrofuran and dichloromethane.

6. The process of claim 1 , wherein the solvent comprises a dichloromethane/methanol or THF/water mixture.

7. The process of claim 1 , wherein no more than about 5% of the compound of Formula I or the pharmaceutically acceptable salt thereof in the solid matrix is crystalline as observed by X-ray diffraction analysis.

8. The process of claim 1 , wherein no more than about 2% of the compound of Formula I or the pharmaceutically acceptable salt thereof in the solid matrix is crystalline as observed by X-ray diffraction analysis.

9. The process of claim 1 , wherein no more than about 1% of the compound of Formula I or the pharmaceutically acceptable salt thereof in the solid matrix is crystalline as observed by X-ray diffraction analysis.

10. The process of claim 1 , wherein API is 4-(4-4{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-y1]methyl}piperazin-1-yl)-N-({ 3 -nitro-4- [(tetrahydro-2H-pyran-4-ylmethyl)amino] phenyl}sulfonyl)-2-(1H-pyrrolo [2,3 -]pyridin-5-yloxy)benzamide or a pharmaceutically acceptable salt thereof.

11. The process of claim 10 , wherein the pharmaceutically acceptable water-soluble polymeric carrier is a copovidone.

12. The process of claim 11 , wherein the pharmaceutically acceptable surfactant is a polysorbate.