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

The cyclic organic amidine catalyst, 1,8-diazabicyclo[5.4.0]­undec-7-ene (DBU), is gaining 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 the pharmaceutical industry. Currently, commercial PLGA materials are produced via ring-opening copolymerization of lactide and glycolide under the influence of metal catalysts such as tin octoate, and this chemistry has been extensively studied. However, not much is known yet about the details of the newer, 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 intrachain acylation, and DBU deactivation. Predictions of this model in terms of copolymerization rates, repeat unit sequence length distributions in PLGA products, etc., were compared with experimental data available in the literature. This analysis led to the determination of the values of 14 different reaction rate constants; nine of them were previously unknown. As illustrated in the Mayo–Lewis plot presented in the main text, the most striking finding of this study is the 3-orders-of-magnitude difference in the reactivity ratio between the two monomers, lactide (LA, monomer 1) vs glycolide (GL, monomer 2), that is, r₁ (k_p(1,1)¹/k_p(1,2)¹) = 3.37 × 10^–2 and r₂ (k_p(2,2)¹/k_p(2,1)¹) = 13.6, in this DBU-catalyzed process; this result is in contrast to what has previously been reported for tin-catalyzed PLGA polymerization reactions (r₁ = 0.20 and r₂ = 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. We also demonstrate that the kinetic model can be used to design nonconventional, semibatch copolymerization reactors for producing monomer sequence-controlled, “uniform PLGA” products, which have constant monomer sequence characteristics along the chain. Further experimental study is warranted to demonstrate the implementation of the semibatch strategy developed using the kinetic model.