The homogeneous, cyclic organic amidine catalyst, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), has gained popularity for its use in the synthesis of biodegradable aliphatic polyesters such as poly(lactic-co-glycolic acid) (PLGA). PLGA is one of the most successful polymeric drug delivery materials in pharmaceutical industry. However, not much is known yet about the details of the DBU-catalyzed PLGA polymerization reactions. The present study is intended to address this gap. For this investigation, a full-scale kinetic population balance model was developed that takes into account all possible reactions of the copolymerization, including initiation via activated alcohol and nucleophilic attack pathways, self- and cross-propagation, combination via inter- and intra-chain acylation, and DBU deactivation. Predictions of this model in terms of copolymerization rates, monomer sequence length distributions in PLGA products, etc. were compared with experimental data from our own work and also with those available in the literature. This analysis led to the determination of the values of all (16 different) reaction rate constants that were previously unknown. As illustrated in the Mayo-Lewis plot shown below, the most striking finding of this study is the four-orders-of-magnitude difference in reactivity ratio between the two monomers, lactide (L) vs. glycolide (G), that is, rL ≡ kLL/kLG ≈ 3.6 × 10-3 and rG ≡ kGG/kGL ≈ 12.4 in this DBU-catalyzed process; this result is in contrast to what has previously been reported for tin-catalyzed PLGA polymerization reactions (rL ≈ 0.20 and rG ≈ 2.8). An important implication of this result is that it is practically impossible to produce DBU-catalyzed PLGA copolymers with uniform monomer sequence distributions using an ordinary batch reaction process. In this presentation, we will also discuss how the kinetic model can be used to design non-conventional copolymerization reactors for producing monomer sequence-controlled, uniform PLGA products.

Investigation of the Detailed Mechanisms of DBU-Catalyzed PLGA Copolymerization via a Full-Scale Population Balance Analysis

ACS Spring Meeting 2021

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