Regulating mass transfer via transient interfacial phase for controlled crystallization of cilostazol spherulite in miscible systems

Controlling crystallization in fully miscible solvent systems remains challenging due to the absence of stable interfaces and the resulting rapid interdiffusion of solutes. This leads to poorly regulated mass transfer and uncontrolled nucleation behavior, limiting the ability to engineer particle properties. Here, we report a crystallization strategy based on the formation of a transient interfacial phase induced by glycyrrhizic acid (GA) in an ethanol–water miscible system. This dynamic phase acts as a temporary mass transfer regulator, reducing molecular diffusion and modifying local supersaturation evolution during cilostazol (CLZ) crystallization. The presence of this interfacial modulation alters crystallization kinetics, leading to a shift from uncontrolled nucleation to regulated pathway involving delayed nucleation and selective crystal growth. As a result, uniform spherulitic particles with narrow size distribution (2.13 μm, PDI = 0.103) are obtained. These particles show improved flowability, higher aerosol deposition efficiency (45%), and enhanced dissolution behavior. In situ analysis and molecular simulations indicate that crystallization behavior is strongly coupled with transient mass transfer resistance at the interface. The improved particle properties can be directly attributed to controlled transport and crystallization kinetics under interfacial modulation. This work demonstrates a general approach to regulate crystallization in miscible systems via dynamic control of interfacial transport, providing a process-oriented strategy for particle engineering of poorly soluble compounds.