Stable dispersion of solid particles comprising a water-insoluble pyrazine compound

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 salt, prodrug, solvate or crystalline form thereof, in which
• R1 and R2 independently represent a C1-6alkyl group;
• an (amino)C1-4alkyl-group in which the amino is optionally substituted by one or more C1-3alkyl groups;
• an optionally substituted non-aromatic C3-15carbocyclic 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, hydroxy or benzyl;
• 1-adamantylmethyl;
• a group —(CH2)t Het 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 Het represents an aromatic heterocycle optionally substituted by one, two or three groups selected from a C1-5alkyl group, a C1-5alkoxy group or halo;
• or R1 represents H and R2 is as defined above;
• or R1 and R2 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;
• R3 and R4 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 C1-3alkyl group, a C1-3alkoxy 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 and acetyl;
• and
• R5 is H, a C1-3alkyl group, a C1-3alkoxymethyl group, trifluoromethyl, a hydroxyC1-3alkyl group, C1-3alkoxycarbonyl, carboxy, cyano, carbamoyl, mono- or di-C1-3alkylcarbamoyl, acetyl, or hydrazinocarbonyl of formula —CONHNRaRb wherein Ra and Rb are as previously defined for R1 and R2 respectively;
• 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.