(776c) Droplet-Templated Anti-Solvent Spherical Crystallization of Hydrophilic and Hydrophobic Drugs with an in situ Formed Binder

Authors: 
Gu, T., Massachusetts Institute of Technology
Hatton, T. A., Massachusetts Institute of Technology
Khan, S. A., National University of Singapore
Conventional pharmaceutical crystallization processes in batch reactors often lead to broad crystal size distributions with frequent batch-to-batch variations. These crystals subsequently undergo several secondary formulation processes for crystal and dosage uniformity. To consolidate these processes, spherical crystallization is a promising method, which combines crystallization, milling, and granulation into a single unit operation. Droplet-templated spherical crystallization methods have been developed recently to achieve highly monodisperse crystal microspheres with droplet microfluidics and evaporation techniques. We present here a novel droplet-templated anti-solvent spherical crystallization method applicable to both hydrophilic and hydrophobic drugs. In both cases, an alginate hydrogel binder forms in situ simultaneously, effectively encapsulating the drug crystals into highly monodisperse spheres. We study in detail the crystallization and gelation processes with mass transfer modelling, and the characterization of the obtained alginate/drug spheres. While glycine and carbamazepine are used as model hydrophilic and hydrophobic drugs, this method can be generalized to other drugs as well. In particular, this method offers additional benefits such as minimal thermal impact, fast crystallization rates, high drug-binder loading ratios, and high selectivity towards metastable polymorphs.