Basic Concepts

Lactides and e-caprolactone can be polymerized according to cationic, anionic, and pseudoanionic mechanisms. The mechanisms and kinetics of these processes have been investigated in detail [9-30]. All of these processes have to be carried out in organic media at anhydrous conditions because in ionic and pseudoionic polymerizations compounds with labile protons (e.g., water and alcohols) act as termination and/or chain transfer agents. Thus, all procedures developed for more than a century for emulsion and/or dispersion polymerizations carried out in water cannot be used for the analogous polymerizations of the above-mentioned cyclic esters.

There are two ways of stabilizing suspensions of colloidal particles: electrostatic and steric [31]. Repulsive forces between particles with the same electric charge are responsible for electrostatic stabilization. However, this type of interaction is possible only in media with very high dielectric constant (like water). In a majority of organic media the relatively (in relation to water) low dielectric constant reduces dissociation of ions, and in effect the ionic double layer at the surface of microspheres is too thin to induce strong repulsive forces at sufficiently long interparticle distances. Thus, steric stabilization is the only method suitable for synthesis of polyester microparticles. Steric stabilization results from desolvation and reduction of conformational freedom of molecular, oligo-mer, or polymer segments in overlapping interfacial layers of microspheres coming in close contact. Positive changes of free energy related to decreased distance between particles manifest themselves as repulsive forces.

When we begun our studies on dispersion polymerization of e-caprolactone and lactides, very little was known about these processes. The literature contained a report on a patent to Union Carbide (from 1972) for the synthesis of polyester microspheres by ring-opening polymerization and many important issues were not clear [32]. For our studies we selected anionic and pseudoanionic polymerizations as the methods of choice. In recent years both types of polymerization of cyclic esters in solution and in bulk were investigated comprehensively in many (including ours) laboratories and main features of these processes were established [14-29]. Briefly, anionic polymerizations of e-caprolactone could be initiated with alkali metal alcoholates. Monomer addition proceeds by nucleophilic attack of alcoholate anion onto carbonyl carbon atom in monomer molecule followed with acyl-oxygen bond scission and regeneration of alcoholate anion (cf. Scheme 1). However, it is necessary to remember that alcoholate active centers may also participate in side inter- and intramolecular transesterifi-cation reactions shown in Scheme 2. Intermolecular transesterification results in

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broadening of molecular weight distribution of synthesized polymer whereas intermolecular transesterification results in formation of cyclics [18,33-37].

Detailed kinetic studies revealed that in polymerizations with less reactive active centers (e.g., in pseudoanionic polymerization with aluminum alkoxide active centers) rate constants of the side transesterification reactions are much more strongly reduced than rate constants of propagation [18,37-40]. Propagation in pseudoanionic polymerization proceeds with coordination of monomer molecule with aluminum alkoxide active center followed with monomer insertion (cf. Scheme 3 illustrating propagation in pseudoanionic polymerization of e-caprolactone initiated with diethylaluminum ethoxide). Pseudoanionic polymerizations are especially interesting because reduction of transesterification reactions often allows for practically complete monomer conversion before side reactions can have any effect on molecular weight and molecular weight distribution of synthesized polymer. Therefore, this type of polymerization has been chosen to begin our discussion on dispersion polymerization of e-caprolactone.

Polymerizations of lactides were usually initiated with stannous octoate [tin(II) 2-ethoxyhexanoate]. For many years the mechanism of initiation and propagation in this system remained obscure. Recently, Duda and Penczek found that in polymerizations initiated with stannous octoate, protic impurities (e.g., traces of water or alcohols) act as coinitiators and active centers contain tin-alkoxide groups [28,41,42]. Studies of dispersion polymerization of lactides were carried out using tin octoate and tin alkoxides as initiators.

For dispersion polymerizations of e-caprolactone and lactides it was necessary to choose a medium that would be a solvent for monomer and initiator and a nonsolvent for the corresponding polymer. Unfortunately, because no pure solvent suitable for anionic and/or pseudoanionic polymerization fulfilled the above-mentioned requirements, mixed solvents were used as reaction media. Polymerizations of lactides were carried out in heptane/1,4-dioxane 4:1 (v/v) mixtures, whereas for polymerizations of e-caprolactone the most suitable mixture was heptane/1,4-dioxane 9:1 (v/v) [43].

Surface-active compound providing steric stabilization of poly(e-caprolac-tone) and poly(lactide) microspheres was designed taking into account both chemical composition of polymers in microspheres and properties of the reaction media. It was assumed that the necessary properties could have poly(dode-

CH3CH2 \

i chjch/

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ch3ch1 \

o chjchi \



cyl acrylate) with poly(e-caprolactone) grafts [43]. Poly(dodecyl acrylate) is highly soluble in heptane and heptane/1,4-dioxane mixtures, and thus should form the sterically stabilizing layer, whereas poly(e-caprolactone) could act as an anchor binding poly(dodecyl acrylate) onto the surface of microspheres (cf. Scheme 4).


Poly(dodecyl acrylate)-g-poly(e-caprolactone) was synthesized by radical co-polymerization of dodecyl acrylate and poly(e-caprolactone) methacrylate macro-monomer. Synthesis of macromonomer and its copolymerization with dodecyl acrylate is illustrated in Scheme 5. A brief description (based on Ref. 43) is given below. Hydroxyl-terminated poly(e-caprolactone) was synthesized by polymerization of e-caprolactone (14.2 g, 0.125 mmol) initiated with (CH3CH2)2-AlOCH2CH3 (0.785 g, 6 mmol). Polymerization was carried out for 8 h at 20°C in 145 mL of dry tetrahydrofuran (THF) in a sealed ampoule into which (before sealing) all reagents were introduced under vacuum conditions. Thereafter, ampoule was opened and active centers were killed by addition of acetic acid (fourfold excess with respect to initiator). Polymer was precipitated into cold (-30°C methanol); after isolation it was dissolved in chloroform and purified from aluminum acetate by column chromatography. Eventually, the hydroxyl-


terminated poly(e-caprolactone) was reprecipitated into cold methanol, isolated, and dried to the constant weight. The molecular weight of obtained polymer [gel permeation chromatography (GPC), calibration with poly(e-caprolactone) samples with narrow molecular weight distribution] was Mn = 3090. A sample (4.7 g) of hydroxyl-terminated poly(e-caprolactone) (1.5 mmol of hydroxyl groups), 0.21 g of methacryloil chloride (2 mmol) reacted in the presence of 0.41 g of triethylamine in 5 mL of dry toluene for 48 h. After filtration of triethylamine hydrochloride, poly(e-caprolactone) methacrylate macromonomer was precipitated into cold methanol and dried at room temperature under high


vacuum, with a yield of 3 g (64%), Mn = 3000 (Mw/Mn = 1.19). The structure of poly(e-caprolactone) methacrylate macromonomer was determined by 1H NMR [-CH2CH2CH2CH2CH2OC(O)-(t) 4.06, -CH2CH2CH2CH2CH2OC(O)-(t) 2.33, -CH2CH2CH2CH2CH2OC(O)-(m) 1.64, -CH2CH2CH2CH2CH2OC(O)-(m) 1.38, -CH2CH2CH2CH2CH2OC(O)-C(CH3)=CH2 5.55 and 6.08].

Poly(e-caprolactone) methacrylate (2.5 g), dodecyl acrylate (10 g), and azoi-sobutyronitrile (0.135 g) were dissolved in 15 mL of toluene and placed in an ampoule. After removal of air from the mixture by the freeze-thaw method, the ampoule was sealed off. Polymerization was carried out at 70°C for 72 h. Thereafter, polymer solution was diluted with 100 mL of toluene, precipitated into methanol, and isolated poly(dodecyl acrylate)-g-poly(e-caprolactone) was dried under high vacuum, with a yield of 9.5 g (76%). In NMR spectrum of copolymer the signals of -CH3 groups of dodecyl acrylate (t) were at 0.87, but signals of —CH2 groups of dodecyl acrylate overlapped with signals of -CH2

groups of poly(e-caprolactone) grafts. The molecular weight of copolymer, determined by osmometry, was 49,000. Integration of a signal of CH3 groups of poly(dodecyl acrylate) units and signal of -CH2CH2COO groups of poly(e-caprolactone) allowed determination of molar fraction of poly(e-caprolactone) monomeric units that for synthesized copolymer was f(e-caprolactone) = 0.25. Knowledge of the molecular weight of poly(e-caprolactone) macromonomer (Mn = 3000), of poly(e-caprolactone)-g-poly(dodecyl acrylate) (Mn = 49,000), and the molar fraction of poly(e-caprolactone) allowed calculation of the average number of poly(e-caprolactone) grafts per copolymer macromolecule [NG = Mn(copolymer) f(e-caprolactone)/Mn(poly(e-caprolactone], which for described copolymer was 4.1.

Proper selection of initial concentrations of initiator [(CH3CH2)2AlOCH2CH3] and monomer (e-caprolactone) allowed one to obtain hydroxyl-terminated poly(e-caprolactone) (block for grafts in copolymer) with Mn ranging from 1200 to 8800 [44]. Poly(e-caprolactone)-g-poly(dodecyl acrylate) copolymers with molar fraction of poly(e-caprolactone) kept in the relatively narrow range from 0.19 to 0.24 were obtained using the above-mentioned macromonomers. The molecular weight of copolymers varied from 22,000 to 50,000 and the average number of poly(e-caprolactone) grafts from 0.6 to 6.9. It has to be noted that for these copolymers critical concentrations of micellization were strongly dependent on their composition. The lowest ones from 2 to 3 g/L were observed for copolymers with the ratio Mn[poly(e-caprolactone)]/Mn [poly(e-caprolac-tone)-g-poly(dodecyl acrylate)] in the range 1.5-2.6.


A. Poly(t-caprolactone) Microspheres

An example of a recipe for synthesis of poly(e-caprolactone) microspheres by dispersion ring-opening pseudoanionic polymerization of e-caprolactone (based on description in Ref. 43) is given below. Polymerization of 5.55 g (50 mmol) of e-caprolactone initiated with 0.1 g (0.77 mmol) of (CH3CH2)2AlOCH2CH3 was carried out in a mixture (100 mL) of dry (dried over sodium-potassium alloy) heptane and 1,4-dioxane (9:1; v:v) containing 0.22 g of poly(dodecyl acrylate)-g-poly(e-caprolactone) (molecular weight of copolymer Mn[poly(dode-cyl acrylate)-g-poly(e-caprolactone)] = 49,000, molecular weight of poly(e-caprolactone) grafts M„[poly(e-caprolactone)] = 3000, average number of po-ly(e-caprolactone) grafts per copolymer molecule NG = 4.1). All reagents were charged into reaction vessel under vacuum conditions. Polymerization was carried out under argon at room temperature for 1 h. Thereafter, propagation was stopped by addition of 2.3 g (30 mmol, about tenfold molar excess with respect to substituents on Al) of CH3CH2COOH in 100 mL of heptane. After sedimentation under gravitational forces, microspheres were washed (resuspended in fresh portions of heptane and isolated by sedimentation) 10 times. Diameter and diameter polydispersity index [determined from scanning electron microscopy (SEM) images] of these microspheres were Dn = 630 nm and Dw/Dn = 1.038, respectively. GPC measurements [columns calibrated using poly(e-caprolactone) samples with narrow molecular weight distribution] revealed that Mn of polyester in microspheres was 8200 and polydispersity parameter Mw/Mn was 1.11. Tonomet-ric studies confirmed these findings, yielding Mn = 10,000.

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