Reactive extrusion of pharmaceutical grade PLLA

During the 20th century, degradable aliphatic polyesters have undergone fast and dynamic developments. Nowadays, these materials can be found in several areas of human activities. Originally there have been first designed for the pharmaceutical and medical fields, in particular in surgery and for drug delivery systems. In these domains, polymers are synthesized according to a batch procedure due to the low capacity needed.
This work is dedicated to the optimization of a continuous synthesis of pharmaceutical grade polyesters (e.g. poly-L-lactide, PLLA) by reactive extrusion using a twin screws extruder. This equipment presents several advantages compared to batch reactor such as: absence of solvent, high degree of mixing, easiness of scale-up, and rapid continuous synthesis.
PLLA synthesis by reactive extrusion has been performed adopting a co-rotating twin-screws extruder (diameter=11 mm and L/D ratio=40). A highly active catalyst must be used to reach the target conversion due to the limited residence time. Tin octoate, approved by US Food and Drugs Administration, has been used alone as catalyst considering a catalyst / monomer molar ratio of 1/5000. A polyethylene glycol has been adopted as initiator.
1H.NMR and size exclusion chromatography (SEC) have been adopted to monitor the conversion rate of the monomer and to analyse the mean molecular weights and the corresponding polydispersity.
Static mechanical tests have also carried out to assess the influence of residual monomer within the polymer.
Our optimization study has highlighted that the main challenging aspects were the control of the reaction atmosphere and of the residence time. In the first case, even presence in trace water can competitively initiate the polymerization, but also promote hydrolysis. In order to reach a high monomer conversion (≥ 99 %), the residence time has to be well controlled and extended. This latter parameter is particularly affected by the screw configuration and the use of the protic initiator. In particular, the screw configuration was based on previous studies dedicated to the synthesis of polyesters by reactive extrusion [1, 2]. After synthesis, post-processing step was realized in order to reduce the monomer residue.
Once optimized we have succeeded to reach in a reproducible way high molecular weight PLLA (typically in a range of 50 to 100 KDa) with a high monomer conversion (>96 %) on a time scale of some minutes. Post-polymerization has successfully decreased the residual monomer below 1%. In conclusion, this work provides a continuous and robust process to synthesize pharmaceutical grade PLLA by reactive extrusion.
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