Continuous processing of paclitaxel polymeric micelles.

A continuous polymeric micelle processing platform was successfully developed, which eliminated batch-to-batch variation in critical quality attributes (for example, size and polydispersity that are typically associated with batch processing). A continuous precipitation process was achieved via coaxial turbulent jet in co-flow technology allowing precise control of particle size with average particle size in the range 15 to 70 nm and low polydispersity. Critical relationships between material attributes (e.g., block copolymer design), process parameters (e.g., polymer concentration, organic to aqueous flow rate ratios, and temperature), and critical quality attributes (e.g., size and polydispersity) of the polymeric micelles were realized via multiple designs of experiments studies. Both polymer molecular weight and concentration were shown to influence the micelle polydispersity index. Notably, higher molecular weight polymer required higher processing temperatures to produce monodispersed particles and were generally of larger size. Using optimized conditions, paclitaxel polymeric micelles that are qualitatively and quantitatively equivalent to commercial Genexol PM were produced, exhibiting comparable quality attributes including particle size, size distribution, morphology, drug loading, release characteristics, and stability. Lastly, a dynamic light scattering method was adapted to determine the critical micelle concentration and aggregation number of the block copolymers, providing useful information about the raw material.