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Facile preparation of tetra‐polyethylene glycol hydrogel microspheres for drug delivery by cross‐flow membrane emulsification

The purpose of this work was to develop technology for facile, large‐scale production of tetra‐polyethylene glycol (PEG) hydrogel amino‐microspheres to serve as intermediates for injectable microsphere‐drug conjugates produced under cGMP guidelines. Here we developed equipment and procedures utilizing tubular cross‐flow membrane emulsification to produce the amino‐microspheres. The equipment comprised a polyether ether ketone tube containing 1000 evenly spaced pores encased in a cylindrical stainless steel jacket. The dispersed phase – an aqueous solution of two polymerizable tetra‐PEG prepolymers – is delivered into the outer jacket of the assembly by a pulse dampened pump, and the continuous phase – decane and surfactant – is delivered into the bore of the microporous tube from a pressurized tank. As the dispersed phase is pressed through the pores, the continuous phase induces the detachment of small, uniform droplets of ˜60 μm diameter at the mouths of the pores. After collection of the emulsified droplets, they are allowed to self‐polymerize and are then sieved to remove aberrantly small and large particles. The polymerized amino‐microspheres – obtained in ˜70% yield – are well within acceptance specifications, and show excellent injectability. Using this approach, we could prepare about 30 L of swollen amino‐microspheres per day which could be forwarded to production of microsphere‐drug substance under cGMP guidelines.