Preparation of Agglomerated Crystals for Direct Tabletting and Microencapsulation by the Spherical Crystallization Technique with a Continuous System

Abstract

Adhesive and cohesive properties of chlorpromazine hydrochloride (CP) crystals were modified to improve their powder processing, e.g., direct tabletting and microencapsulation, by agglomeration. Moreover, sustained-released gelling microcapsules of CP were devised to prolong the pharmacological effect. The spherical crystallization technique was applied to prepare agglomerates for direct tabletting and microencapsulation to use them as core materials. The ethanolic solution dissolving CP was poured into a stirred cyclohexane, yielding spherically agglomerated crystals. The resultant agglomerates were free-flowing and easily packable spheres with average diameters of 200 to 1000 µm. The agglomerates reserved the high compressibility of the original powder having a small particle size (14 µm). The compression behavior represented by Heckel’s equation suggested that the agglomerates were disintegrated to individual primary crystals at low compression pressures, and then they were closely repacked and plastically deformed at higher pressures. After agglomeration, microencapsulation was continuously performed in the same batch by a phase separation method. Coacervate droplets produced by pouring cyclohexane into a dichloromethane solution, dissolving poly vinyl acetate as a coating polymer, were added to the crystallization system under stirring, to prepare the microcapsules. By filling the microcapsules in gelatin hard capsules or tabletting them, their drug release rates became retarded compared with the physical mixture treated in the same way, having the same formulation as the microcapsules. This phenomenon was due to the gelation of poly vinyl acetate of the microcapsules in the dissolution medium, whose glass transition temperature is very low. This novel sustained-release dosage form is termed “gelled microcapsules.”