A process for the preparation of a stable dispersion of solid particles in an aqueous medium comprising:
- combining
- (a) a first solution comprising a substantially water-insoluble substance which is a compound of Formula I
- or a pharmaceutically acceptable salts, prodrug or solvates thereof, in which
- R1 and R2 independently represent phenyl, thienyl or pyridyl each of which is optionally substituted by one, two or three groups represented by Z;
- Z, independently for each occurrence represents a C1-6alkyl group, a C1-6alkoxy group, hydroxy, halo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, trifluoromethylsulphonyl, nitro, amino, mono- or di-C1-3alkylamino, mono- or di-C1-3alkylamido, C1-3alkylsulphonyl, C1-3alkoxycarbonyl, carboxy, cyano, carbamoyl, mono- or di-C1-3alkyl carbamoyl, sulphamoyl, acetyl or two adjacent carbons may be substituted with the group —O—CH2—CH2—O—;
- and phenyl optionally substituted by one or more of the following:
- C1-6alkyl group, trifluoromethyl, a C1-6alkoxy group, trifluoromethoxy, or halo or two adjacent carbons may be substituted with the group —O—CH2—CH2—O—;
- and
- R3 represents a group —X—Y—NR4R5;
- R4 and R5 independently represent a C1-6alkyl group optionally substituted by a C1-6alkoxy group or trifluoromethoxy;
- an (amino)C1-4alkyl- group in which the amino is optionally substituted by one or more C1-3alkyl groups;
- a non-aromatic C3-15carbocyclic group which is optionally substituted by a C1-3alkoxyC1-3alkyl group;
- a (C3-12cycloalkyl)C1-3alkyl- group;
- a group —(CH2)r(phenyl)s in which r is 0, 1, 2, 3 or 4, s is 1 when r is 0 otherwise s is 1 or 2 and the phenyl groups are optionally independently substituted by one, two or three groups represented by Z;
- naphthyl;
- anthracenyl;
- a saturated 5- to 8-membered heterocyclic group containing one nitrogen and optionally one of the following:
- oxygen, sulphur or an additional nitrogen wherein the heterocyclic group is optionally substituted by one or more C1-3alkyl groups or benzyl;
- 1-adamantylmethyl;
- a group —(CH2)tHet in which t is 0, 1, 2, 3 or 4, and the alkylene chain is optionally substituted by one or more C1-3alkyl groups and either Het represents an aromatic heterocycle optionally substituted by one, two or three groups selected from a C1-6alkyl group, a C1-6alkoxy group, trifluoromethoxy, or halo, or Het represents a saturated 5- to 8-membered heterocyclic group containing one nitrogen and optionally one of the following:
- oxygen, sulphur or an additional nitrogen, wherein the heterocyclic group is optionally substituted by one or more C1-3alkyl groups, hydroxy or benzyl;
- or R4 represents H and R5 is as defined above;
- or R4 and R5 together with the nitrogen atom to which they are attached represent a saturated 5- to 8-membered heterocyclic group containing one nitrogen and optionally one of the following:
- oxygen, sulphur or an additional nitrogen, wherein the heterocyclic group is optionally substituted by one or more C1-3alkyl groups, hydroxy or benzyl;
- X is CO or SO2;
- Y is absent or represents NH or N—C1-3alkyl group;
- a water-miscible organic solvent, and an inhibitor with
- (b) an aqueous phase comprising water and optionally a stabiliser,
- thereby precipitating solid particles comprising the inhibitor and the substantially water-insoluble substance;
- and optionally removing the water-miscible organic solvent;
- wherein:
- (i) the inhibitor is a non-polymeric hydrophobic organic compound that is substantially insoluble in water;
- (ii) the inhibitor is less soluble in water than the substantially water-insoluble substance;
- and
- (iii) the inhibitor is not a phospholipid.