Spherulitic Growth Strategy for Agitation-Induced Formation of Spherical Amoxicillin Sodium Products

In industrial crystallization, spherical crystals have gained increasing interest due to their excellent physicochemical properties, such as high bulk density, flowability, stability, etc. However, their formation mechanism is still not well understood and is often oversimplified. In this work, spherical amoxicillin sodium crystals were obtained via a spherulitic growth strategy. It was found that agitation immediately after the addition of crystal seeds was critical for inducing radial noncrystallographic branching and spherulite formation of amoxicillin sodium. Without agitation during the aging period after seed addition, only discrete rod-shaped crystals were obtained. The formation mechanism of amoxicillin sodium spherulites was studied using process analytical technology (PAT) tools, including focused beam reflectance measurement (FBRM) and particle video microscope (PVM). The result was indicative of a three-step morphological evolution process: formation of polycrystalline agglomerates, noncrystallographic branching, and spherulite growth. During this process, agitation immediately after seed addition could help to solute diffusion and induce the agglomeration of small crystals that result from secondary nucleation. The polycrystalline agglomerates serve as the cores for further noncrystallographic branching and growth. On this basis, a new spherulitic growth strategy was proposed by the large addition of crystal seeds as the growth substrates of new branching and spherulite growth. High agitation rates during the aging period can increase the mass ratio of spherulites, and high initial supersaturation can promote branching. Compared with the discrete rod-shaped crystals, spherulites self-regulate the final size greatly up to three times and have a higher bulk density as well as much lower hygroscopicity.