Controlled Crystallization Enables Facile Fine-Tuning of Physical-Chemical Properties of Nicergoline Toward Easier Processability.

Background/Objectives: Crystallization is a key process in the manufacturing of active pharmaceutical ingredients (APIs), as it significantly affects the physical and chemical properties of the final product. Nicergoline, a clinically relevant ergot derivative, was chosen as a model compound to investigate how different crystallization strategies affect particle attributes. The objective of this study was to compare controlled and uncontrolled crystallization techniques and evaluate their impact on the physicochemical properties of nicergoline. Methods: Nicergoline was crystallized using controlled methods, including sonication-induced and seeding-induced crystallization, and uncontrolled methods, namely cubic and linear cooling, as well as acetone evaporation. The resulting powders were characterized by using a range of physicochemical techniques to assess particle morphology, size distribution, agglomeration behavior, and surface properties. Results: Uncontrolled crystallization methods produced particles prone to agglomeration, resulting in a broader particle size distribution ranging from 8 to 720 µm and heterogeneous surface characteristics. In contrast, controlled crystallization generated more uniform particles with reduced agglomeration and narrower particle size distributions. Among the evaluated methods, sonocrystallization provided the most effective control over particle size and morphology, demonstrated by a narrow size distribution ranging from 16 to 39 µm which correlated with improved flowability and surface energy. Conclusions: The study demonstrates that the choice of crystallization method significantly influences the structural and physicochemical properties of nicergoline. These findings highlight the importance of method selection for tailoring API properties to enhance downstream processing and product quality.