A scale-up strategy for the synthesis of chitosan derivatives used in micellar nanomedicines

Nanomedicines have been increasingly investigated and used by pharmaceutical industry due to their potential in solving various public health problems. However, standardizing and approving nanomedicines remains a significant challenge, as the translation from the laboratory to the market is still limited. These constraints are due to a lack of reproducibility and standardization of procedures, small batch sizes due to inability to scale-up, or the associated production costs as a result of the production methods chosen.

Highlights

Copolymers synthesized at bench scale were produced by a continuous manufacturing method at an industrial pilot batch;

The physicochemical characteristics of copolymers were maintained after the industrialization process;

The industrialization process decreased the manufacturing time and improved the yield of the synthesis;

Polymeric micelles maintained their stability and characteristics during 6 months stored at −20 °C.

In this work, two chitosan derivatives, methoxypolyethylene glycol-chitosan (mPEG-CS) and methoxypolyethylene glycol-chitosan-oleic acid (mPEG-CS-OA), produced at the lab scale were implemented in a pharmaceutical industry to achieve the scale-up production using cross flow filtration (CFF). The two copolymers were shown to be capable of retaining their physicochemical properties when produced in larger batch sizes, with reduced production time and increased yield. Also, both chitosan derivatives presented no in vitro cytotoxicity independent of the method of production.

Furthermore, after scale-up, polymeric micelles produced from mPEG-CS-OA were tested for storage stability, demonstrating that micelles remained stable at – 20 °C for at least 6 months. This study demonstrated the feasibility of producing polymers and polymeric micelles closer to the bedside due to their suitability for GMP production.

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Article information: Andreia Almeida, Nazende Günday-Türeli, Bruno Sarmento, A scale-up strategy for the synthesis of chitosan derivatives used in micellar nanomedicines, International Journal of Pharmaceutics, Volume 609, 2021. https://doi.org/10.1016/j.ijpharm.2021.121151.