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Controlling morphology of active pharmaceutical ingredients (APIs) during crystallization/precipitation is essential for pharmaceutical development since the pharmaceutical powder properties such as solubility, flowability, and dissolution rates are morphology dependent. The objective of this work was to understand the morphological evolution of a poorly water-soluble antifungal drug, griseofulvin (GF), during liquid antisolvent (LAS) precipitation in the presence of ultrasound and additives. GF was found to precipitate as hierarchical structures in the presence of different additives and in the absence of ultrasound. An umbrella-like morphology was observed when hydroxypropyl methylcellulose was used, hexagonal particles elongated along the central axis were obtained in the presence of Tween 80, and the use of polyvinylpyrrolidone yielded long needle-like particles. The most fascinating morphology was observed in the case of bovine serum albumin and no ultrasound, where the GF particles precipitated as six-branched hierarchical structures. Interestingly, the morphology of 6-month-old GF particles reveals that the outline of the overall morphology of initial unfilled skeletons resembled the bipyramidal morphology that would form when particles are completely filled/fused due to Ostwald ripening. The size of GF particles typically varied from 30 to 50 μm when no ultrasound was used. Time-resolved scanning electron microscopy (SEM) studies imply that interesting morphologies of GF particles observed in the absence of ultrasound could be the result of aggregation and fusion of a large number of small particles formed in the beginning of the precipitation process. These smaller particles fuse to form primary bipyramidal particles which then undergo diffusion-limited growth through Ostwald ripening and secondary nucleation on specific particle faces due to selective adsorption of additives depending on the functional groups present on those particular faces. In contrast to the no ultrasound situation, the use of ultrasound along with the additives resulted in the formation of completely filled octahedron/bipyramidal GF particles irrespective of the additive used. These particles were significantly smaller with sizes ranging from 4 to 6 μm. Use of ultrasound improves micromixing and alters the particle growth mechanism from diffusion limited to integration controlled resulting in smaller and well-formed GF particles.

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The focus of this work is to understand the polymorphic behavior of curcumin crystallized from two different organic solvents by liquid antisolvent (LAS) precipitation carried out in a semibatch mode. LAS precipitation of curcumin from ethanol yielded the metastable (orthorhombic) Form 3, while acetonitrile led to the precipitation of stable (monoclinic) Form 1. These polymorphic crystal structures mirrored clustering of curcumin molecules in the respective organic solutions determined using in situ Raman spectroscopy. The presence of strong CH•••O bonds in acetonitrile solution indicated interactions between curcumin molecules through the phenolic end groups. On the other hand, parallel stacking of curcumin molecules was favored in ethanol solution due to stronger solute−solvent interactions at the polar end groups. These observations are consistent with the results obtained from density function theory (DFT) calculations and molecular dynamics (MD) simulations. Accordingly, with acetonitrile interacting weakly with the solute molecules, curcumin−curcumin interactions through the phenolic ends were promoted, in turn, favoring formation of Form 1. Stronger interaction between ethanol and curcumin led to relaxation of solute molecules into parallel stacked clusters, thereby favoring Form 3. Furthermore, the solvatochromic effect of curcumin exhibited in these solvents was related to solvent-induced conformations and, in turn, nucleation of curcumin crystal polymorphs.

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