Droplet‐Templated Antisolvent Spherical Crystallization of Hydrophilic and Hydrophobic Drugs with an in situ Formed Binder

Abstract

This study presents a novel droplet-templated antisolvent spherical crystallization method applicable to both hydrophilic and hydrophobic drugs. In both cases, an alginate hydrogel binder forms in situ, concurrently with the crystallization process, effectively binding the drug crystals into monodisperse spheres. This study presents a detailed process description with mass transfer modeling, and with characterization of the obtained alginate/drug spheres in terms of morphology, composition, and drug loading. Although glycine and carbamazepine are used as model hydrophilic and hydrophobic drugs, this method is easily generalized to other drugs, and offers several benefits such as minimal thermal impact, fast crystallization rates, high drug-binder loading ratios, and high selectivity toward metastable polymorphs.

Recent progress in antisolvent crystallization

“…In addition, in order to screen the valuable pathways to optimize the process and achieve energy and cost saving, determination of kinetics and thermodynamics in antisolvent crystallization is also necessary. Moreover, several coupled techniques, such as supercritical fluid, 14 spherical crystallization, [15][16][17] microchannel reactor, 18,19 membrane distillation, 20,21 etc., are also applied in antisolvent crystallization to optimize the product properties.…”

Continuous Embedded Droplet Printing in Yield‐Stress Fluids for Pharmaceutical Drug Particle Synthesis

“…[ 23 ] Batch methods can struggle to produce uniform spherical particles, and instead often result in granules of agglomerated crystals that may have irregular shapes or wide size distributions. [ 24 ] Microfluidic emulsion approaches to spherical crystallization have provided significant improvements in terms of morphology, [ 25–27 ] and also synergize with a broader movement of pharmaceutical manufacturing towards continuous processes due to their advantages in terms of flexibility in production scale, more consistent product quality, and increased efficiency. [ 23,28,29 ] However, even in microfluidic platforms, crystalline particles often still have noticeable deviations from sphericity due to the deforming effects of viscous drag, [ 1 ] and unintended nucleation and aggregation can occur when droplets come into contact with each other or solid surfaces.…”

Membrane-Assisted Antisolvent Crystallization: Interfacial Mass-Transfer Simulation and Multistage Process Control

“…Antisolvent crystallization is an essential separation and purification technology in the manufacturing of fine chemicals , and pharmaceutical crystals. − By avoiding high-temperature operations, antisolvent crystallization is suitable for heat-sensitive materials with low energy consumption. − Also, the final product can be easily regulated by adjusting the operating parameters − and solution/antisolvent system. , While the traditional approach of antisolvent crystallization usually involves batch droplets and mixing of the antisolvent, this operation commonly induces a local high supersaturation degree and explosive nucleation, which easily result in broad crystal size distribution and undesired particle morphology. − The mixing rate and supersaturation distribution cannot meet the stable nucleation requirement of the scale-up operation . Thus, the accurate mass transfer and supersaturation control at the antisolvent–solvent mixing interface are the eternal concerns to hinder the exceeding local supersaturated concentration and explosive nucleation. − …”