Design and mechanism of agglomeration of aspirin crystals in pure solvents

Abstract

Agglomeration with improved flowability for platy crystals is desirable in pharmaceutical downstream processing. The formation of agglomerates in pure solvents without the aid of bridging liquids is a convenient and low-cost method compared with complex spherical crystallization. In this work, the adhesion free energies between aspirin crystals in six solvents were calculated using Lifshitz-van der Waals acid-base theory to screen suitable solvents for agglomeration. The maximum stirring rate for agglomeration was determined by adhesion forces and dispersion forces. Then the agglomerates of plate-shaped aspirin were successfully prepared in acetone, methanol, ethanol, 2-propanol, and ethylene glycol without additives by simple cooling crystallization. The interactions between solvent and crystal surfaces were also used to explain the outcomes. A feasible mechanism for the agglomeration process of platy crystals was elucidated, involving the adhesion of dominant crystal facets at the beginning. The effect of stirring rate, cooling rate, and initial supersaturation on agglomeration degree and particle size of aspirin agglomerates were studied. The obtained aspirin agglomerates under the optimal conditions exhibited a uniform particle size distribution, a high agglomeration degree, and superior flowability.