Chen, Hongbo2020-11-172020-11-172020-07https://hdl.handle.net/11299/217172University of Minnesota Ph.D. dissertation.July 2020. Major: Pharmaceutics. Advisor: Changquan Sun. 1 computer file (PDF); 263 pages.Spherical crystallization, a particle engineering technique, has been commonly used to modify the size and shape of particles to enhance the micromeritics properties of a powder and facilitate tablet formulation development. By identifying the key factors affecting the generation of spherical agglomerates and the underlying mechanism, spherical agglomerates with optimal size, shape and density can be obtained, presenting excellent flowability, tabletability and dissolution. The goals of this thesis work include: (i) prepare and evaluate the properties of the spherical agglomerates of drugs using the two main methods including spherical agglomeration (SA) and quasi-emulsion solvent diffusion (QESD) , (ii) explore high drug loading direct compression tablet formulations enabled by the spherical crystallization technique, (iii) develop a spherical cocrystallization technique to simultaneously improve the manufacturability and dissolution of drugs, and (iv) reduce the punch sticking propensity via a polymer assisted QESD method. To successfully prepare the spherical agglomerates, it is crucial to select a solvent system-based phase diagram. Spherical agglomerates of a model API, ferulic acid (FA), via a QESD process presented exceptional flowability and tabletability. Such spherical FA crystals enabled the development of a direct compression tablet formulation containing 99% of the API. Spherical griseofulvin agglomerates prepared by a SA process, exhibited not only good flowability but also excellent tabletability. The unexpected profoundly improved tabletability was attributed to a micro porous structure of primary crystals, due to an in-situ solvation and desolvation during the SA process, which enhanced the plasticity of the agglomerates. For low water-soluble drugs, spherical crystallization of more soluble cocrystals, i.e., spherical cocrystallization, is an enabling technology to simultaneously improve the manufacturability and dissolution and enable the development of high drug loading tablet formulation. Moreover, spherical agglomerates of celecoxib obtained via a polymer assisted QESD process not only showed substantially improved tabletability and flowability but also significantly reduced punch-sticking propensity. A thin layer of polymer coating onto the agglomerates surface, confirmed by SEM and XPS analysis, explains the reduced punch sticking propensity due to the physical barrier of polymer between the drug and punch.enflowquasi-emulsion solvent diffusionspherical cocrystallizationSpherical crystallizationtabletThesis or Dissertation