Investigation of the Mechanisms and Kinetics of DBU-Catalyzed PLGA Copolymerization via a Full-Scale Population Balance Analysis
Investigation of the Mechanisms and Kinetics of DBU-Catalyzed PLGA Copolymerization via a Full-Scale Population Balance Analysis
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DOI：
10.1021/acs.iecr.1c03096
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发表时间：
2021-10
影响因子：
4.2
通讯作者：
Samruddhi Patil;Jin-Bok Yoo;You-Yeon Won
中科院分区：
文献类型：
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作者：
Samruddhi Patil;Jin-Bok Yoo;You-Yeon Won
1，8-二氮杂双环[5.4.0]Undec-7-ene(DBU)是一种新型的环状有机酰胺催化剂，用于合成可生物降解的脂肪族聚酯，如聚(乳酸-乙醇酸共聚)(PLGA)。PLGA是制药工业中最成功的聚合物给药材料之一。目前，商品化的PLGA材料主要是在辛酸锡等金属催化剂的作用下，丙交酯和乙交酯开环共聚而成，并得到了广泛的研究。然而，关于DBU催化的较新的PLGA聚合反应的细节还不是很清楚。本研究旨在解决这一差距。在这项研究中，建立了一个完整的动力学群体平衡模型，该模型考虑了所有可能的共聚反应，包括通过活化醇和亲核攻击途径引发、自繁殖和交叉繁殖、通过链间和链内酰化结合以及DBU失活。将该模型在共聚速率、PLGA产物中重复单位序列长度分布等方面的预测与文献中的实验数据进行了比较。这一分析导致确定了14个不同反应速率常数的值；其中9个以前是未知的。如正文中的马约-刘易斯图所示，本研究最引人注目的发现是，在这个DBU催化过程中，丙交酯(LA，单体1)与乙交酯(GL，单体2)之间的竞聚率相差3个数量级，即r1(≡kp(1，1)1/kp(1，2)1)=3.37×10-2andr2(≡kp(2，2)1/kp(2，1)1)=13.6.这一结果与以前报道的锡催化PLGA聚合反应(r1=0.20和r2=2.8)相反。这一结果的一个重要含义是，用普通的间歇反应过程几乎不可能生产出单体序列分布均匀的DBU催化的PLGA共聚物。我们还证明，该动力学模型可用于设计非常规、半间歇共聚反应器，以生产具有恒定单体序列特征的、单体顺序可控的“均匀PLGA”产品。有必要进行进一步的实验研究，以证明利用动力学模型开发的半批处理策略的实施。
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(≡kp(1,1)1/kp(1,2)1) = 3.37 × 10–2andr2(≡kp(2,2)1/kp(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 andr2= 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.