ORIGINAL CONTRIBUTION

Synthesis of poly(p-dioxanone)-based block copolymersin supercritical carbon dioxide

Tianqiang Wang & Yu Liu & Jianyuan Hao

Received: 30 December 2013 /Revised: 8 May 2014 /Accepted: 12 May 2014# Springer-Verlag Berlin Heidelberg 2014

Abstract Poly(p-dioxanone)–poly(ethylene glycol)–poly(p-dioxanone) triblock copolymers (PPDO–PEG–PPDO)were first synthesized by suspension ring-opening polymeri-zation (ROP) of p-dioxanone (PDO) in supercritical carbondioxide (scCO2) using different molecular weights (2–10 K)of poly(ethylene glycol) (PEG) as macroinitiators. White andfine flow powders were successfully obtained when the mo-lecular weight of PEG was below 6 K and its feed contentbelow 20 wt.%. The 1H nuclear magnetic resonance (NMR)result indicated the formation of PPDO–PEG–PPDO blockstructure even in a confined polymerized environment ofparticles. All the powderous samples contained irregularshaped particles that were observed by scanning electronmicroscope (SEM). Except for the copolymer with 10 wt.%PEG10K feed content, the mean particle sizes of otherpowderous samples showed identical values close to 15 μm.This fact was in agreement with the crystallinity of PPDO inthe copolymers measured by differential scanning calorimetry(DSC). The water absorption of these copolymers was alsomeasured, and as compared with PPDO homopolymer, theintroduction of PEG increased the water absorption of thecopolymers. The green and environmentally friendly methoddisclosed in this work is attractive to directly synthesizebiodegradable polymeric particles with potential biomedicalapplications.

Keywords scCO2. PPDO–PEG–PPDO .Microparticles .

Crystallinity . Environmentally friendly

Introduction

Poly(ethylene glycol) (PEG) presents outstanding physico-chemical and biological properties, including hydrophilicity,solubility in water and in organic solvents, lack of toxicity, andabsence of antigenicity and immunogenicity, which allowPEG to be used for many biomedical and biotechnologicalapplications [1, 2]. The hydroxyl end group of PEG could beused to directly conjugate with various drugs to increase thedissolution ability or prolong the circulation time of drugs inblood [3–5]. In sustained drug release fields, PEG could beused to link with polyesters to form amphiphilic diblock ortriblock copolymers, which have the advantage as carriers toprotect the activity of encapsulated protein drugs and modu-late their release profiles. Since the two terminal hydroxylgroups of PEG have equal reactivity towards monomers,PEG can act as a macroinitiator for the ring-openingpolymerization (ROP) of cyclic lactones or lactides toform ABA-type block copolymers. This mechanism ofpolymerization has been studied and clearly demonstratedfor the synthesis of ABA triblock copolymers based onPEG (as B block) and various cyclic monomers such asL-lactide [6], ε-caprolactone [7], glycolide or their mixtures [8](as A block). Poly(p-dioxanone) (PPDO) is a semi-crystalline,biodegradable and biocompatible polymer and has been usedcommercially as suture material with the approval of the Foodand Drug Administration. The complete hydrolysis of PPDOsuture in human body requires 6 months, which is satisfactoryin terms of biosafety as compared with other slow degradablepolyesters. Except for the existence of ester bonds like otheraliphatic polyesters, the unique ether bonds on PPDObackboneendow it with high flexibility and good tensile strength [9].However, PPDO has high crystallinity and high meltingpoint, and could not dissolve in common organic solvent,which impeding its wide applications in biomedical fields.This problem has been addressed by copolymerization of p-dioxanone (PDO) with other cyclic monomers, such as L-lactide, and ε-caprolactone [10, 11].

T. Wang :Y. Liu : J. HaoState Key Laboratory of Electronic Films and Integrated Devices,School of Microelectronics and Solid State Electronics, Universityof Electronic Science and Technology of China, Chengdu,Sichuan 610054, China

J. Hao (*)School ofMicroelectronics and Solid State Electronics, University ofElectronic Science and Technology of China, Number 4, Section 2,Jianshe North Road, Chengdu 610054, Chinae-mail: jyhao@uestc.edu.cn

Colloid Polym SciDOI 10.1007/s00396-014-3275-z

Recently, amphiphilic triblock copolymers composed ofPPDO and PEG were synthesized by ROP of PDO monomerinitiated through dihydroxyl-terminated PEG in the presenceof stannous 2-ethylhexanoate [Sn(Oct)2] as a catalyst [12–14].Yang et al. [13] synthesizedABA type poly(p-dioxanone)–poly(ethylene glycol)–poly(p-dioxanone) (PPDO–PEG–PPDO)block copolymers using PEG with different molecular weightsas macroinitiators. Wang et al. [14] also synthesized PPDO–PEG–PPDO copolymers and presented the release behavior oflevonorgestrel loaded into the copolymers. However, the solu-bility of PPDO–PEG–PPDO synthesized by bulk polymeriza-tion is somewhat like that of the PPDO homopolymer, which isdifficult to process into particulate form by solvent method andimpedes many biomedical applications.

We describe the use of scCO2 as a benign solvent for thesuspension copolymerization of PEG and PDO and directlyobtain PPDO–PEG–PPDO particles. Above the critical pointof 73.8 bar and 31.1 °C, CO2 possesses a liquid like density,making it a potential nontoxic solvent for many chemicalsynthesis and fabrication processes [15–17]. In biomedicalfields, scCO2 may act as a nontoxic replacement for manycommon organic solvents to produce biomedical materialscontaining labile molecules without bioactivity being compro-mised. It has been shown by many groups that the addition ofa suitable stabilizer to polymerization conducted in scCO2

facilitates the synthesis of well-defined morphological prod-ucts. Biocompatible and biodegradable polymeric particles,such as poly(ε-caprolactone) (PCL) [18, 19], poly(L-lactide)(PLLA) [20], poly(glycolide) (PGA) [21] and PPDO [22]have been produced by polymerization in scCO2 in situ. Wefound that the success of acquiring particulate polymerizationproducts relied on the high crystallinity of the homopolymerswhich could not be plasticized by scCO2. So far there are fewreports about production of biodegradable copolymer particlesvia direct polymerization in scCO2.

In this work, a series of PPDO–PEG–PPDO copolymerparticles containing different molecular weights of PEG andcompositions were synthesized firstly in scCO2 using poly(ε-caprolactone)–poly(perfluoroether)– poly(ε-caprolactone)(PCL–PFPE–PCL) as the stabilizer, and their morphology,thermal and crystalline behaviors and water absorptions werealso studied.

Experimental

Materials

PEG2K, 4 K, 6 K and 10 K (with molecular weights of 2,4, 6, and 10 K) were purchased from Kelong ChemicalFactory (Chengdu, China), and dried under reduced pres-sure at 50 °C for 24 h before use. ε-Caprolactone (Aldrich,99 %) was dried over CaH2 at room temperature for 48 h

and distilled under reduced pressure. Telechelic dihydroxylterminated poly(perfluoroether) (PFPE) was supplied bySolvay (registered name Fluorolink D10H). The ROP cat-alyst, Sn(Oct)2 (Aldrich) was degassed before use. Researchgrade CO2, 99.999 % purity, was supplied by GuangzhouPuyuan Gas Limited Company. Other reagents were usedas received.

Synthesis of PDO and the scCO2 soluble PCL–PFPE–PCLstabilizer

PDO was synthesized by well established procedures fromethylene glycol and chloroacetic acid and purified by repeatedrecrystallization from ethyl acetate to achieve a purity of over99.5 % [23].

The stabilizer synthesis was adapted from that of Pilatiet al. [24] beginning with the ROP of ε-caprolactone fromthe terminal hydroxyl groups of the “CO2-philic” PFPEmacromonomer, in accordance with the activated chain endmechanism proposed by Duda et al. [25]. The structure of thestabilizer is shown in Scheme 1.

Polymerization procedure in scCO2

Polymerization (Scheme 2) was conducted in a 100-ml stain-less steel autoclave with a pressure relief valve. Heating wasprovided via an oil bath, and pressure and temperature weremonitored on a digital display control rack. The contents ofthe reactor were stirred with a Teflon stir bar controlled by amagnetic stir plate. The high-pressure reactor is schematizedin Fig. 1. Predetermined 0.5 g PEG was added into a flame-dried autoclave. The reactor was evacuated and purged withnitrogen several times. Then the reactor was immersed into atemperature-adjusted oil bath at 70 °C. After the added PEGwas melted, 0.5 ml catalyst (3.2 g Sn(Oct)2 in 10 ml toluene)was added. One hour later, when PEG macroinitiator wasformed, 4.5 g PDO and 0.5 g stabilizer were charged intothe reactor. The reactor was then closed and connected to aCO2 feed pump, which supplied CO2 until the reactor reachedthe desired polymerization pressure. Following pressurization,the reactor was heated to the desired reaction temperature. Allpolymerizations were conducted in scCO2 at 241 bar and70 °C for a total of 24 h. The stirrer bar was set to a stirringrate of 350 rpm. The reactor was then cooled to room temper-ature (23 °C), and CO2 was vented through the pressure reliefvalve.

Measurements

The scanning electron microscopy (SEM) images of parti-cles were obtained from an FEI INSPECTF apparatus andmeasured at 10 kV after being coated with a thin layer ofsputtered gold.

Colloid Polym Sci

The particle size and distribution were characterized by alaser diffraction particle size analyzer (Horiba LA-920).

The intrinsic viscosities ([η]) of the resulting poly-mers were measured in phenol/1,1,2,2-tetrachloroethane(1:1 v/v) solutions using an Ubbelohde viscosimeterthermostated at 25 °C, and all of the solutions were filteredbefore measurement.

The proton nuclear magnetic resonance (1H NMR) spectrawere recorded on a 400-MHz 1H NMR spectrometer (BrukerAV-300), using tetramethylsilane as an internal reference andCDCl3 as the solvent.

Differential scanning calorimetry (DSC) analysis was per-formed on a TA Q20 DSC system over a temperature rangefrom 20 to 130 °C at heating and cooling rates of 10 °C/min.

Water absorption: PPDO–PEG–PPDO copolymer powderswere immersed in distilled water at 37 °C for 24 h, and thentaken out; the surplus surface water removed by filter paper.Water absorption was calculated according to the followingequation:

Water absorption %ð Þ ¼ m1 � m2ð Þ=m2 � 100%;

where m1 and m2 are the weights of wet and dry samples,respectively.

Results and discussion

Solubility of the stabilizer in scCO2

The solubility of this stabilizer were examined by Daniel et al.at 80 °C and 241 bar in scCO2, the stabilizer was observed to

be soluble under these conditions, demonstrating its CO2-philicity at least up to loadings of 0.006 g/ml, which isequivalent to that used during our polymerization reactionsin the 120-ml autoclave [20]. However, PEG and PDO werefound to be insoluble under these conditions, as was Sn(Oct)2.Thus, the polymerization must proceed via a suspensionmechanism, which involves the direct conversion of monomerdroplets in the continuous scCO2 phase to solid polymerparticles.

Suspension polymerization of PPDO–PEG–PPDOcopolymers in scCO2

PPDO–PEG–PPDO triblock copolymers with different mo-lecular weights of PEG (PEG2K, PEG4K, PEG6K, andPEG10K) and contents of PEG6K were synthesized viaROP of PDO monomer initiated by PEG macroinitiator withPCL–PFPE–PCL as stabilizer. The mechanism of bulk poly-merization has been studied and clearly demonstrated for thesynthesis of ABA triblock copolymer based on PEG andPDO. Because there is a possibility of ROP of PDO initiatedby moisture in the system besides PEG, the feed order ofreactants is crucial for the control of formation of blockcopolymers. In our work, the initiator PEG was first addedin the reactor, and after it became melted and thoroughlyreacted with Sn(Oct)2 to form PEG macroinitiator, the mono-mer PDOwas then added to allow the block copolymerizationproceeding predominantly. The typical 1H NMR spectrum(Fig. 2) of PEDO4K exhibits two sharp and distinct singletscentered at 4.18 and 3.65 ppm and two equally intense tripletsat d 4.35 and 3.81 ppm. The singlet resonance at 3.65 ppmcorresponds to the –O-CH2CH2-O– unit of PEG segment. Thesinglet resonance at 4.18 ppm and triplet resonances at 4.35and 3.81 ppm correspond to –O-CH2-O–, –O-CH2CH2-OCO– and –O-CH2CH2-OCO– units of PPDO segments,respectively. It is worth noting that additional peaks atpositions 4.29–4.33 ppm (d′ in Fig. 2) and 3.70–3.76 ppm(c′ in Fig. 2) also emerge and correspond to the resonancesof methylene groups in the block connecting unit of –O-CH2CH2-O–PPDO and the terminal unit of –O-CH2-O-CH2CH2-OH. This information indicates that block copoly-merization indeed proceeded between the PEG segment andPDO monomer in scCO2. Furthermore, the intensity ofresonance at 3.65 ppm is linearly increased with the content

HO CF2O CF2CF2O CF2O CF2CH2 OHx y

Fluorolink D10H

D10H OO

O

(CO)CH3H3C(OC)O

O

O

m n

End-capped PCL-PFPE-PCL

Scheme 1 Chemical structure ofend-capped PCL–PFPE–PCLstabilizer

Scheme 2 Suspension polymerization of PPDO–PEG– PPDO copoly-mers in scCO2

Colloid Polym Sci

of PEG, which implies the substantial increase in hydrophi-licity of the copolymer.

The relevant characterization data of the copolymers,which were named as PEDO2K, PEDO4K, PEDO6K, andPEDO10K in terms of the different molecular weights ofPEG, were listed in Table 1. Table 1 shows that the conver-sions of PDO are relatively low, due to the presence ofequilibrium between polymerization and depolymerizationfor this monomer. The free energy change of polymerizationfor PDO is less negative compared with other monomers suchas LA and GA. The [η] of copolymers were determined bycapillary viscosity measurements using an Ubbelohde vis-cometer and solutions of copolymer samples in phenol/1,1,2,2-tetrachloroethane (2:3 w/w) at 25 °C. The inherentviscosity of the copolymers with 10 wt.% PEG feed content

increases with the increase of molecular weight of PEG. Forthe copolymers containing PEG6K, the inherent viscositydecreases as the content of the PEG increases. When thefeed content of PEG is fixed, the one with higher molecularweight shows lower molar content of hydroxyl groups, Sothat for each copolymer chain there will be more PDOsegments. In the same way, if the molecular weight ofPEG is fixed, higher feed content means higher molarcontent of hydroxyl groups, so that for each copolymerchain there will be less PDO segments. These changes inmolecular weight of the copolymers are in accordance withthe block copolymerization mechanism between PEG andthe PDO monomer, indicating PPDO–PEG–PPDO blockstructure really formed even in a microenvironment of thepolymerized droplets in scCO2.

BathOil

Pump Stirrer

P/T Vent

CO2

Fig. 1 Schematic apparatus forsuspension polymerization

Fig. 2 1H NMR spectrum ofPEDO4K copolymer

Colloid Polym Sci

Particle morphology and size distributions of PPDO–PEG–PPDO copolymers

The copolymerization proceeds via a suspension mechanism,which involves the direct conversion of monomer/PEG mix-ture droplets in the continuous scCO2 phase to copolymerparticles. For suspension polymerization in scCO2, the mor-phology of the products is known to be sensitive to the rate ofstirring and amount of stabilizer during the reaction. Thus inorder to highlight how the composition affects the final prod-uct morphology, the stirring rate and the content of the stabi-lizer are fixed the same to all experiments. In the absence ofstabilizer, PPDO homopolymer is obtained as a hard, white,aggregated solid block. This morphology is very similar tothat obtained by conventional bulk polymerization at thistemperature. In the presence of 10 % (w/w, based on totalweight of PEG and PDO) stabilizer, PPDO and most of thePPDO–PEG–PPDO copolymers were obtained after ventingas a fine, free-flowing powder (Table 1 and Fig. 3), in com-parison with the aggregated solid usually encountered in theabsence of a stabilizer. PPDO and the PPDO–PEG–PPDOcopolymers are not wildly used in pharmaceutical fields,owing to their insolubility in common organic solvents suchas methylene chloride or acetone and difficulty to process intoparticles. In this work, we are able to directly produce pow-dery PPDO–PEG–PPDO copolymer particles by suspensioncopolymerization in scCO2.

For PPDO homopolymer particles, the morphology is ir-regular and rough (Fig. 4a). This is consistent with a powdersuspension polymerization in which the product polymer isnot well plasticized by its monomer in the polymerized drop-lets [26]. When copolymerization of PDO with PEG, themorphology of the resultant particles is not improved(Fig. 4b–f), which means the interaction between the product

polymer and the monomer not changed much by the intro-duction of PEG. When the feed content of PEG is fixed at10 wt.% and the molecular weight of PEG is below 6 K, theparticle size of the products (15–20 μm) shows no obviouschange with the increase of PEG molecular weight (Fig. 5).However for PEDO10K, the product displays a much largerparticle size of 70–100 μm as compared with other productswith the same 10 wt.% PEG feed content (Fig. 5). This casemay be ascribed to the much higher [η] value of PEDO10Kand thereby higher viscosity of the polymerized droplets thattend to agglomerate before being solidified by crystallinityand form coarse particles. For the series of PEDO6K products,the powdery products could only be acquired when the feedcontent of PEG6K is below 20 wt.%. If it reaches a high valueas 30wt.% (PEDO6K-3), the final product is in an aggregated,block form. Since PEG6K was in a molten state under the

Table 1 Suspension polymerization of PPDO–PEG–PPDO copolymers in scCO2

Sample a PDO (feed)(wt.%)b

PDO (NMR)(wt.%)c

Yield(%)d

[η](dl/g)e

Morphologyf

PPDO 100 100 75 0.56 Fine powder

PEDO2K 90 75.6 73 0.36 Fine powder

PEDO4K 90 84.3 77 0.41 Fine powder

PEDO6K 90 80.9 75 0.64 Fine powder

PEDO6K-2 80 72.5 71 0.55 Fine powder

PEDO6K-3 70 61.3 >80 0.41 Aggregated

PEDO10K 90 73.5 72 0.78 Course powder

a Synthesized at 70 °C and 24 MPa for 24 h with 5 g of the monomers, 0.09 ml of Sn(Oct)2, and 10 % (w/w) PCL–PFPE–PCL stabilizerb Amount of PPDO in the feedstockc Amount of PPDO units in the polymer chain, as determined by 1H NMRdDetermined gravimetrically. The yields were estimated for aggregated samplese [η] was measured in phenol/1,1,2,2-tetrachloroethane (1:1 v/v) at 25 °Cf Appearance of the product directly from the autoclave

Fig. 3 Image of PPDO–PEG–PPDO fine powder obtained by suspen-sion polymerization in scCO2

Colloid Polym Sci

Fig. 4 SEM images of copolymer particles produced by suspension polymerization in scCO2: a PPDO; b PEDO2K; c PEDO4K; d PEDO6K; ePEDO6K-2; f PEDO10K

Colloid Polym Sci

reaction conditions, the high percentage of PEG6K inPEDO6K-3 implied a low crystallinity portion of PPDO overthe whole volume of the polymerized droplets, which couldnot be fully hardened. Thus, when the stirring was stoppedand CO2 was released, the sticky product would coagulate andwas thus collected in an aggregated and block form.

Thermal analysis and crystallinity of PPDO–PEG–PPDOcopolymers

A series of PPDO–PEG–PPDO copolymers with differentcompositions were analyzed by DSC (Fig. 6). The DSC firstheating and subsequent heating curves (performed at10 °C/min) of the copolymers are shown in Fig. 6a and c. Itcan be seen from the DSC heating scans, two groups ofmelting peaks representing PEG and PPDO components,respectively, appeared for all the copolymers. For the firstheating scans, the Tm of the copolymers for both PEG andPPDO components are very close to the values for the homo-polymers (Tm of PEG is 57 °C) [14], and change slightly withPEG molecular weight and composition. However for thesecond heating scans, the Tm of PPDO blocks decreasesgreatly for the copolymers as compared with that for thehomopolymer. This fact is further evidence that the PPDO–PEG–PPDO block structure was really formed. The presenceof PEG block hindered the crystallization of PPDO blocks,leading to the formation of less perfect crystals if crystalliza-tion took place under an inadequate condition (cooling at arate of 10 °C). Furthermore, the PEG block in the PEDO6Kcopolymer shows two melting peaks for both heating scans.Since PPDO blocks first crystallized in the copolymer sam-ples, the crystalline domains could also impede the subsequent

crystallization of PEG block. When the PEG6K feed contentincreases to 30 wt.%, the volume of isolated amorphousPEG6K domains can be much greater than that restrictedwithin PPDO crystalline domains, thus creating appropriateconditions for homogeneous nucleation. The coexistence ofboth homogeneous and heterogeneous nucleation gave rise totwo types of crystals with different perfectness and meltingpeaks.

Figure 6b shows DSC cooling scans of the copolymers andPPDO homopolymer from 120 °C. The crystallization tem-perature for the PPDO homopolymer is about 58 °C, and afterintroduction of PEG, the crystallization temperature and theintensity of the peak for the copolymers decrease at the sametime. As we all know that the PEG segment disturbs theregularity of the polymer chains, the crystallization behaviorof PPDO blocks was thus suppressed, leading to the decreasedcrystallization temperature for the copolymers.

The relevant DSC data are listed in Table 2. The degree ofcrystallinity, Xc, of the PPDO and PEG components for thecopolymers can be calculated according to the followingrelation:

X c ¼ ΔH f = w�ΔH f;100%

� �;

where ΔHf,100% and ΔHf indicate the heats of fusion for a100 % crystalline PPDO or PEG homopolymer and the co-polymer, respectively; w is the weight fraction of PPDO orPEG components in the copolymer [27]. To calculate Xc,PPDO

and Xc,PEG, the literature value of ΔHf,100%=14.4 KJ/mol and219 J/g were used, respectively. Table 2 shows that, for theoriginal samples, the Xc,PPDO of the copolymers (from the firstheating scans) with 10 wt.% PEG feed content varies slightly

Fig. 5 Particle size distributionsof copolymer samples

Colloid Polym Sci

Fig. 6 DSC first heating scans(a), subsequent cooling scans (b)and second heating scans (c) forthe copolymer samples

Colloid Polym Sci

with PEG molecular weight. This similarity in crystallinityexplains the slight variation of particle size for the copolymerproducts with different molecular weights of PEG. In case ofPEDO10K, it was the viscosity of the polymerized dropletsrather than the crystallinity of the copolymer that led to thesignificant increase of particle size. For the series of PEDO6Kcopolymers, the Xc,PPDO drops obviously when the feed con-tent of PEG increases to 20 wt.%, indicating the hindrance ofPEG on crystallinity of PPDO. Surprisingly, however, with afurther increase of PEG feed content to 30 wt.%, the Xc,PPDO

increases significantly to the value close to that for PPDOhomopolymer. In view of crystallinity, this fact seems to becontradictory to the failure of PEDO6K-3 product acquired ina powdery form. A possible reason may be due to the differ-ence in crystallization behavior of the copolymer in a limitedmicroenviroment as compared with that in an aggregated,block form. Owing to the strong hindrance of PEG on PPDOcrystallization, the initial polymerized droplets for PEDO6K-3may have low crystallinity, which could not be fully solidifiedand tend to merge into large aggregates. However, post-crystallization may continue if the dispersed droplets weremerged and the restriction of space for crystallization wasliberated, resulting in the increase of crystallinity for the finalproduct.

Figure 7 shows the XRD spectra for the PEDO particlesacquired in scCO2. In the spectra, the appearance of twoBragg peaks at 21.95° and 23.90° correspond to the charac-teristic peaks for PPDO segments and confirm the crystallinephase derived from the PPDO component. The characteristicpeaks representing PEG component are not clearly observed,due to the low content and low crystallinity of PEG in thecopolymers. The variation of intensity of PPDO peaks isrelated to the crystallinity of the copolymers as well as thesample amount for measurements.

Mechanism for generation of PPDO–PEG–PPDO particlesin scCO2

As we all know that scCO2 can swell and plasticize amor-phous polymers,so to generate powderous polymer productusing scCO2 technology, the polymer must be able tocrystallize and be resistant to the plasticizing effect ofscCO2. In our work, PPDO is semi-crystalline polymerand has very high melting point (109 °C) that allows thesolidification of the particles in scCO2. So it is possible toacquire PPDO homopolymer particles by suspension poly-merization in scCO2. However, although PEG is a semi-crystalline polymer, it is in a molten state under the reac-tion conditions (70 °C, 241 bar) due to its low meltingpoint (<60 °C). Thus, the addition of PEG to form PPDO–

Table 2 Thermal properties of PPDO–PEG–PPDO copolymers derived from DSC analysis

Sample PPDO PEDO2K PEDO4K PEDO6K PEDO6K-2 PEDO6K-3 PEDO10K

Tm (°C) PPDO1st 107.6 109.9 107.8 108.7 105.4 110.3 111.1

PPDO2st 104.4 93.7 97.7 92.3 102.4 98.5 101.6

PEG1st – 59 55.24 55 52.5 43.3/56 54.9

PEG2st – 43.4 46.7 45.7 48.2/52 41.7/48.9 49.0

ΔH (J/g) PPDO1st 90.73 73.16 81.91 77 52.44 58.36 73.91

PPDO2st 77.57 36.78 62.03 38.8 40.83 35.05 47.95

PEG1st – 3.5 6.92 7.51 3.32 9.92 6.87

PEG2st – 4.3 3.37 5.01 1.50 10.28 2.71

Xc (%) PPDO1st 76.9 75.0 75.3 73.8 56.1 73.8 78.0

PPDO2st 64.6 37.7 57.0 37.2 43.7 44.3 50.6

PEG1st – 6.5 20.1 18.0 5.5 11.7 11.8

PEG2st – 7.9 9.8 12.0 2.5 12.1 4.7

1st and 2st represents the first heating and second heating of DSC. Tm,ΔH, and Xc are the melting temperature, enthalpy and the degree of crystallinity ofthe polymer samples

Fig. 7 XRD spectra for the copolymer particles acquired in scCO2

Colloid Polym Sci

PEG–PPDO block structure will decrease both the volumeof crystalline portion as well as the crystallizability of thepolymerized droplets. Thus, at a high PEG6K feed contentof 30 wt.%, the polymerized droplets of PEDO6K-3 couldnot be fully solidified and tend to agglomerate and form anaggregated block (Fig. 8). Besides crystallization behavior,the presence of PEG can also affect the molecular weightof the copolymers. The triblock structure of PPDO–PEG–PPDO determines that in theory, the molecular weight ofthe copolymers is proportional to PEG molecular weight ifthe feed content of PEG is fixed and the effect of residualmoisture on polymerization could be neglected. This trendhas been roughly reflected in the [η] values in Table 1. Ata fixed PEG feed content of 10 wt.%, the copolymer basedon PEG10K has the highest [η] value of 0.78. Thus, thepolymerized droplets of PEDO10K must be very stickybefore being fully solidified and has high tendency toaggregate with each other, leading to production of coarseparticles (Fig. 8). In contrast, other copolymers productswith the same PEG feed content of 10 wt.%, but lowermolecular weights of PEG (2 K, 4 K, 6 K) could retaindispersed state and form fine particles (Fig. 8).

Water absorption of PPDO–PEG–PPDO copolymers

The incorporation of hydrophilic PEG into hydrophobicPPDO can increase the hydrophilicity of the polymer, whichis beneficial as drug release carrier to enhance the loading

Disaggregation

Aggregation

Disaggregation

Aggregation

PEG+PDO phase + scCO2 phase

(Stirring)Predispersion

PDO+PEG

(6K-3, 10K)

PDO+PEG

(2k,4k, 6k, 6K-2)

Polymerized

droplets

Polymerized

droplets

Fig. 8 Illustration of particleformation process andmorphology by suspensionpolymerization in scCO2

Fig. 9 Effect of PEG molecular weight and content on water absorptionbehavior of the copolymers measured at 37 °C

Colloid Polym Sci

amount of hydrophilic drugs, such as peptides or pro-teins, and protect the activity of sensitive molecules [28].Due to the high water affinity of PEG, the presence ofPEG could also enhance the water adsorption of thecopolymers, and therefore modulate the drug release behaviorof the carriers.

The water absorption of the copolymers with differentmolecular weights of PEG and PPDO homopolymer areshown in Fig. 9. The water absorption of PPDO homopolymeris quite lower (9.52 %) than the copolymers containing PEG.For the copolymers with a fixed 10 wt.% PEG feed content,the water absorption of the copolymers also increases with theincrease of PEG molecular weight. For example, the waterabsorption of the copolymer increases from 14.3 % forPEDO2K to 63.5 % for PEG10K. At the same time, whenthe feed content of PEG6K increases from 10 wt.% to30 wt.%, the water absorption of the copolymers also in-creases obviously. The increase of water absorption of thecopolymers is ascribed to the existence of hydrophilic PEGsegments in the amorphous domains. Thewater molecules canpenetrate into the amorphous phase more easily if the copol-ymers containing a high PEG content or low PEG molecularweight.

Conclusion

PPDO–PEG–PPDO triblock copolymer particles with dif-ferent molecular weights and contents of PEG can besynthesized directly via suspension polymerization ofPDO using different molecular weights of PEG as macro-initiators and Sn(Oct)2 as a catalyst. The stabilizer iseffective to stabilize the polymerized droplets and allowthe formation of fine resorbable microparticles in a “onepot” procedure in scCO2. The molecular weight and con-tent of PEG have effects on the intrinsic viscosities, ther-mal and crystalline behaviors, and water absorption of thecopolymers, Because of the similar Xc,PDO of the copoly-mers with low molecular weight PEG (2–6 K), the meanparticle size is very close. The incorporation of hydrophilicPEG into hydrophobic PPDO increases the hydrophilicity ofthe polymer microparticles, which is beneficial as drug releasecarrier to enhance the loading amount of hydrophilic drugs forfuture work. The development of a simple, adaptable, andenvironmentally friendly method for the production of biode-gradable microparticles used in biomedical fields will drawmore and more attention.

Acknowledgments This work was supported by the National NaturalSciences Fund of China (No. 30970725, No. 51273034), the OpeningProject of the State Key Laboratory of Polymer Materials Engineering(Sichuan University, KF201201) and the Fundamental Research Fundsfor the Central Universities.

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