AGGLOMERATION BEHAVIOR AND MODIFICATION OF SPHERICAL CRYSTALLIZATION PROCESS OF PHARMACEUTICALS BY THE EMULSION-SOLVENT-DIFFUSION METHOD AND PROPOSED CLOSED-CIRCUIT BATCH SYSTEM

Agglomeration mechanism of the spherical crystallization of a water soluble drug by the emulsion solvent diffusion method was investigated with a mixed system of two or three partially miscible solvents, i.e., bridging liquid-poor solvent system or good solvent-bridging liquid-poor solvent system. When bridging liquid (or plus good solvent) solution of the drug was poured into poor solvent (= dispersing medium) under agitation, quasi emulsion droplets of bridging liquid or good solvent were produced. The diffusion of bridging liquid or good solvent from the emulsion droplet into the dispersing medium induced the crystallization of drug, which was clearly monitored by an X-ray diffraction analysis. Seeding the drug crystals to the system enhanced the solidification of emulsion droplets, resulting improved agglomeration. The agglomerated crystals had the most thermodynamically stable crystalline form. Both hydrophilic and hydrophobic polymers could be coprecipitated into the agglomerated crystals to modify the physicochemical properties of raw crystals of the drug. A closed circuit batch operation system was proposed to use repeatedly the dispersing medium recovered after each operation for industrialization.