Lipase-catalyzed synthesis of aliphatic polyesters via copolymerization of lactide with diesters and diols

Abstract

Aliphatic lactate-bearing copolyesters were successfully synthesized via copolymerization of L-lactide (LLA) with diesters and diols using Candida antarctica lipase B (CALB) as the catalyst. The resultant copolymers had a M_w up to 38,000 Da with M_w/M_n between 1.5 and 2.0, and contained L-lactate units (up to 53 mol%), C₆–C₁₂ diester units, and C₄–C₆ alkylene units in the polymer chains. The lactate repeat units were present primarily as lactate–lactate diads in the polymers. The LLA-diester-diol copolymers were purified in good yield (70–85%) and all purified copolymers were optically active. Hydrolytic degradation study shows that LLA-diethyl adipate-1,6-hexanediol (LLA-DEA-HD) copolymers are degradable polymers as the molecular weight (M_w) of the copolymer with 53% lactate units decreased by ∼70% upon incubation in PBS solution under physiological conditions (37 °C, pH of 7.4) for 80 days. The LLA-diester-diol copolymers are thermally stable up to at least 300 °C with the temperature of maximum degradation rate ranging from 380 to 410 °C. The copolymers exhibit a wide range of physical properties (e.g., from white solid to wax and liquid) depending on their structure and composition. In particular, the LLA-DEA-HD and LLA-DEA-1,4-butanediol copolymers with ∼50 mol% lactate units are colorless, viscous liquids at ambient temperature. Biodegradable liquid polymers are potentially useful biomaterials for drug delivery to treat ocular ailments because of their good compatibility with sensitive soft tissues.

Introduction

Lactate-containing polyesters are a family of biodegradable materials with important biomedical applications, which typically consist of lactate units or a mixture of lactate and lactone (e.g., glycolide, ε-caprolactone) units in the polymer chains [1], [2], [3]. In particular, poly(L-lactide) (PLLA), poly(D,L-lactide) (PDLLA), and poly(L-lactide-co-glycolide) (PLGA) have been widely used as raw materials to construct various medical devices including sutures, screws, meniscus staples, tacks, plates, meshes, and spinal cages for clinic applications. These polymeric materials are currently produced via ring-opening polymerization of lactides or ring-opening copolymerization of lactides with lactones using an organometallic catalyst [4], [5], [6]. However, in these processes, the metal contents in the polymer products need to be minimized in order to meet the requirement for the polymers to serve as medical grade materials.

In the past two decades, enzymes (particularly lipases) have been successfully employed for synthesis of polyesters, polycarbonates, and poly(carbonate-co-esters) with a wide variety of molecular structures [7], [8], [9], [10], [11]. Comprehensive reviews are available on enzyme-catalyzed ring-opening polymerization of lactones [12], [13], [14], [15], [16], [17] and cyclic carbonates [18], [19], [20], polycondensation between diacids (or diesters) and diols [21], [22], [23], polymerization of hydroxy acids [21], [24], polycondensation of organic carbonates with diols [25], [26], [27] or organic carbonates with diesters and diols [28], [29], copolymerization of lactone with diester and diol [30], [31], [32], [33], and copolymerization of lactone with organic carbonate and diol [34], [35]. In contrast to chemical processes, the enzymatic synthesis methods have several distinct advantages that include mild reaction conditions, high tolerance of functional groups, higher catalyst selectivity, and resultant high purity of products that are also metal-free.

Despite the large number of enzymatic polymers disclosed in literature, only limited number of reports were found on synthesis of polylactides and copolymers bearing lactate units. It is particularly challenging to incorporate polar, short chain monomers into copolymer chains [36], [37]. Enzymatic polylactides were first prepared via ring-opening polymerization of lactides using lipase PS, porcine pancreatic lipase, and Candida cylindracea lipase as catalysts (3–29% polymer yield after 7 days) [38], [39]. Addition of ethylene glycol as an initiator was found to promote poly(L-lactide) synthesis [40]. When polyols were employed as initiators, branched polylactides were formed [41]. Syntheses of poly(L-lactide-co-glycolide) and poly(DL-lactide-co-glycolide) were disclosed using lipase PS as the catalyst (no yield reported) [42]. Copolymerization of lactides with trimethylene carbonate in the presence of porcine pancreatic lipase generated poly(lactide-co-trimethylene carbonates) in 6–40% yield after 7 days [43]. Candida antarctica lipase B (CALB) has also been evaluated as a catalyst for lactide polymerization. At mild reaction conditions (50–70 °C), CALB was an active catalyst for polymerization of D-lactide, but not L-lactide [44]. Oligomers were formed during CALB-catalyzed copolymerization of ε–caprolactone with DL-lactide [45].

In this work, lipase-mediated synthesis of aliphatic copolyesters bearing lactate units is achieved via copolymerization of lactide with diesters and diols. The polymer molecular weights were measured by gel permeation chromatography (GPC), and the polymer structures were characterized by ¹H and ¹³C NMR spectroscopy. The thermal properties of the copolymers were analyzed by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The hydrolytic degradation rate of a representative L-lactide-diester-diol copolymer was also investigated. To the best of our knowledge, enzymatic synthesis of copolyesters comprising of lactate, diester, and alkylene units via copolymerization of lactide with diesters and diols has not been reported previously. In addition, this synthesis method allows preparation of a number of biodegradable polyesters from various renewable monomers including L-lactide, adipates or succinates, 1,4-butanediol, and 1,6-hexanediol [46].