Syntheses and chemical transformations of glycolide and lactide as monomers for biodegradable polymers

https://doi.org/10.1016/j.polymdegradstab.2020.109427Get rights and content

Highlights

  • The structure, physical and thermodynamic properties of glycolide and lactide are discussed.

  • Known methods for the synthesis of diesters from various starting materials are presented.

  • Chemical transformations of glycolide and lactide into valuable compounds are considered.

Abstract

Glycolide and lactide function as the commonly used diester monomers for the preparation of high-molecular weight, degradation-prone (co-)polyesters. Both glycolide and lactide-based polymers are widely used in medicine, pharmaceuticals, the food industry, and additive technologies. This review on the diesters, spanning research from 1833-1854 to the present, encompassing their structural peculiarities, physico-chemical properties, and the range of different methods for obtaining them – including reaction mechanisms – from lactic and glycolic acids, their esters, and halogen derivatives. The review also discusses the chemical transformations of lactide and glycolide (apart from ring-opening polymerization) into valuable organic and high-molecular compounds, such as acrylic acid, nitrogen-containing heterocycles, and functional polymers with novel properties.

Introduction

Biodegradable polymers have applications in biomedicine [1,2] as well as in packaging [3], modern additive technologies [4], and even in agriculture [5]. Biodegradable polymers can either be natural in origin (e.g. polysaccharide-based plastics, polyhydroxyalkanoates) or synthetically made (e.g. poly(lactic acid), polybutylene adipate terephthalate). While the former are in need of extraction or modification processes, the latter type depends on efficient synthesis protocols, either from renewable or fossil feedstock, via certain key monomers. Synthetic polymeric materials that can be prone to biodegradation often include ester, ether, and anhydride bonds. Examples include polymers based on polylactide (PLA), (co)polymers of lactide and glycolide, polydioxanone, poly-ε-caprolactone, and others, some of which already came into view in the second part of the 19th and in the beginning of 20th centuries [6,7]. Polymeric materials based on lactide and glycolide are of outstanding interest: the data on these compounds are presented in a number of review articles and books [8], [9], [10], [11]. Materials based on PLA (= poly(lactic acid)), in essence, the same structure in case of homopolymers) and copolymers of lactide and glycolide are widely used as retention sutures (e.g. Dexon®, Vicryl®, and Panacryl®) [12], [13], [14], as matrices for bone implants (e.g. Bionx Implants®, Innovasive Devices®, Surgical Dynamics®) [15], [16], [17], [18], [19], [20], [21], and as components for targeted drug delivery systems (e.g. Vivitrol®, Zoladex®, Lupron®) [22], [23], [24], [25], [26], [27]. Additionally, they find application in disposable utensils and cups, as fibers in polyester clothing, in packaging, or as filaments for 3d printing [28], [29], [30]. Glycolic and lactic acids serve as the basic units and raw materials for synthesizing PLA and copolymers of lactide and glycolide, with lactic acid currently obtained from renewable feedstock [31]. Direct polycondensation, azeotropic and solid-phase polycondensation, and ring-opening polymerization (ROP) are the most common methods for synthesizing polyesters based on alpha-hydroxy acid units (Fig. 1).

The bifunctional molecules of glycolic and lactic acids (hydroxyl and carboxyl group) can participate both in homo- and copolycondensation reactions to form medium-high molecular weight polymers. However, it is well known that high to very high molecular weight polyesters of lactic and glycolic acids cannot be obtained using direct polycondensation because this type of reaction is reversible. Extreme measures to remove water can be successful, but in general, it remains hard to remove water from the increasingly viscous melt of formed polymers. One can e.g. intensify the removal of condensation water by lowering the pressure, but this leads to side reactions that negatively affect the quality of the final product [32]. Certain authors have proposed a number of direct catalytic methods based on azeotropic and solid-phase polycondensation for the synthesis of PLA with a high molecular weight of 80000-130000 g/mol [33,34] lasting for 20-40 hours. Azeotropic polycondensation is similar to polycondensation per se, but it reduces the systems’ viscosity at high degrees of conversion because the reaction occurs in solution. The synthesis temperature is usually maintained below the melting point of the polymer to decrease the number of depolymerization and transesterification side reactions [35]. The reactions are carried out in various organic solvents that can form azeotropic mixtures with water (e.g. xylene) [36]. Polymers with a molecular weight of more than 100,000 g/mol are obtained in a diphenyl ether medium in the presence of tin (II) compounds [37]. However, it should be noted that the polymers obtained via this method are primarily not suitable for biomedical applications because of the toxicity of used solvents which usually have a high boiling point and cannot be removed from the end product completely.

Solid-phase polycondensation includes two stages: 1) direct polycondensation of hydroxycarboxylic acid solutions at 150-200°C and 2) solid-phase reaction at temperatures between melting point and glass transition temperature [38]. The first stage is accompanied by removal of a solution and condensation water during polycondensation resulting in the formation of low molecular weight prepolymer of hydroxycarboxylic acid. The second stage involves a powdered semi-crystalline prepolymer for the purposes of efficient heat transfer and a fairly high degree of system homogeneity. The processes are carried out in a high vacuum or by purging the system with an inert gas, which increases the molecular weight of the products. Solid-phase polycondensation occurs predominantly in the amorphous regions of systems where all reactive end-groups are spatially accessible.

Along with direct polycondensation, one can also employ the method of elongating the low-molecular weight chains of prepolymers using special agents to obtain high-molecular weight polymers based on lactide and glycolide. Diisocyanates, bis-(2-oxazoles), and bis-(epoxides) are such elongation agents; their reactions with lactic acid prepolymers are shown in Fig. 2a-c respectively [39], [40], [41]. Usually, the ratio of the end groups of these agents and hydroxyl (carboxyl) groups of prepolymers is nearly 1:1. The addition of a chain extension agent allows increasing the molecular weight of the final polymer from 20000 to 250000-300000 g/mol.

ROP of cyclic dimers of glycolic and lactic acids (glycolide and lactide) is the preferable and industrially most common method for obtaining high-molecular weight PLA and copolymers of lactide and glycolide. It can be controlled well and it is not accompanied by the formation of low-molecular weight by-products or water. ROP allows one to steer target properties of polymerization products such as molecular weight, polydispersity, stereoregularity (to a degree catalyst-dependent), and others [42], [43], [44]. This reaction can be carried out in the melt, in solution, and in suspension in the presence of catalysts based on organic and inorganic compounds. Among the latter, tin and aluminum carboxylates and alkoxides have been intensely studied [10,[45], [46], [47]]. Currently, there are ROP catalysts based on compounds with nontoxic biogenic metal atoms such as calcium, magnesium, zinc, and iron [48], [49], [50], [51], metal-free organic compounds [52], and enzymes [53].

Although a large number of studies on the ROP of glycolide and lactide there exist, there are significantly fewer academic studies with a focus on the properties and synthesis of the cyclic diesters. They appear to be scattered among separate articles, book sections on PLA and copolymers of lactide and glycolide, and patents. The overwhelming majority of these have not been compiled into a coherent review article or a monograph even though glycolide and lactide remain the only raw materials for preparing high-molecular weight polylactide/glycolides. Recently, Sels and Dusselier and coworkers have published a review article considering certain methods of lactide synthesis, purification, and chirality monitoring conditions [54]. The work emphasizes a novel single-stage liquid-phase method proposed by the authors for lactide synthesis in the presence of shape-selective zeolites as catalysts and compare it to polycondensation/backbiting routes (step 1 and 2) as well as some gas-phase direct routes in patents [55]. Nevertheless, other methods of lactide synthesis are of considerable interest, as are approaches to the synthesis of glycolide, another cyclic diester, along with the physical, thermodynamic, and chemical properties of both monomers.

This review presents an overview of the physical, structural, and chemical properties of these cyclic diesters and on the methods for obtaining glycolide and lactide as initial monomers for further synthesizing valuable hydrolysis-prone or biodegradable polyester polymers. The review considers mechanistic approaches to the methods of obtaining glycolide and lactide, in particular, from the depolymerization of the related oligomers of hydroxycarboxylic acids and to the racemization of lactide as an optically active cyclic diester. In addition, we discuss approaches for the chemical modification of the diesters in the light of new functional polymers based on them.

Section snippets

Glycolide (and polyglycolide)

Glycolide, the cyclic diester of glycolic acid (1,4-dioxane-2,5-dione), is a white crystalline substance. It is soluble in benzene, toluene, ethyl acetate, chloroform, tetrahydrofuran, acetone, alcohols, and other organic solvents. The melting point of glycolide is 85°C and it sublimates at 80-84°C and 133.3 Pa. Glycolide can be polymerized and may participate in copolymerization reactions with certain heterocyclic monomers [56]. Having crystallized glycolide from a number of solvents, Schmitt

Methods of syntheses of glycolide and lactide

Cyclic diesters of glycolic and lactic acids are classically obtained 1) by depolymerizing oligomers of the related hydroxycarboxylic acids [102], [103], [104] or oligomers based on alkyl lactates using a catalyst (the sources provide no data on the synthesis of glycolide from alkyl glycolate-derived oligomers) [105,106] and 2) by cyclizing the salts of halogen-derived hydroxycarboxylic acids with alkali and alkaline earth metals [107], [108], [109]. As a rule, the synthesis of diesters is

Chemical transformations of lactide and glycolide

Structural features and physico-chemical properties of lactide and glycolide pre-determine the route of their chemical reactions both with retention and opening of the diester cycles. Studies on the chemical properties of lactide are widely reported in the literature, which is probably linked to its applicability as a monomer for the production of biodegradable polymers. Epimerization and halogenation belong to the chemical transformations of lactide that are not accompanied by ring-opening. On

Conclusions

This review focuses on lactide and glycolide that serve as valuable monomers in the preparation of high-molecular weight biodegradable polyesters, which are widely used mainly in biomedicine and (PLA) packaging. The review considers the peculiarities of diesters’ structure, their physical properties, methods of synthesizing, and also transforming them into different functional compounds. Lactide, glycolide, as well as polymers and copolymers based on them, are still of interest among

Insights

Glycolide and lactide are representatives of the same homologous series of cyclic diesters of hydroxycarboxylic acids, however, their properties, methods of synthesis, and reactivity during modification are significantly different. These differences are mainly associated with the structural features of diesters. Due to the presence of asymmetric methine carbon atoms in the molecules of lactic acid and lactide, they exist in the form of several optical isomers, and methyl groups that create

Outlook

Glycolide and lactide are the key monomers necessary to obtain high molecular weight PLA or PGA polymers, therefore the increasing annual demand for biodegradable polymers, especially PLA, will increase studies in the field of both the polymers themselves and the starting monomers. From the point of view of unsolved questions in the field of physical chemistry of cyclic diesters, the study of the thermodynamic characteristics of meso-lactide looks attractive. Among the studies devoted to the

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgment

This research is supported by the Tomsk State University Competitiveness Improvement Program (no. 8.2.04.2020) and by the Russian Foundation for Basic Research (no. 18-33-00534). M.D. acknowledges KU Leuven Internal Funds for support. We also thank Prof. Anatoly Filimoshkin for kindly help in the discussion of some sections of the review.

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