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Kinetics of the hydrolytic degradation of poly(lactic acid)
Polymer Degradation and Stability 97 (2012) 2460e2466
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Polymer Degradation and Stability journal homepage: www.elsevier.com/locate/polydegstab
Kinetics of the hydrolytic degradation of poly(lactic acid) F. Codari a, S. Lazzari a, M. Soos a, G. Storti a, M. Morbidelli a, D. Moscatelli b, * a b
Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland Dipartimento di Chimica, Materiali e Ingegneria Chimica “Giulio Natta”, Politecnico di Milano, 20131 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history: Received 24 February 2012 Received in revised form 12 June 2012 Accepted 18 June 2012 Available online 29 June 2012
The hydrolysis of water soluble PLA oligomers of different chain lengths and chirality was investigated at acidic pH and temperatures in the range from 40 to 120 C. The time evolution of the concentrations of all oligomers was measured by HPLC and the corresponding degradation rates were evaluated for each specific chain length. In agreement with the preferential chain end scission mechanism suggested in the literature, the ester groups were classified as a (chain end esters) and b (backbone esters). A kinetic model was developed from the resulting kinetic scheme and it was found to well reproduce the concentration values of all different oligomers during degradation as a function of time. The corresponding rate constants kad and kbd were estimated over the whole temperature range, with activation energies of 73 and 58 kJ/mol and pre-exponential factors of 8.21$107 and 1.77$105 l/mol/h, respectively. It is seen that the faster hydrolysis of the ester groups close to the carboxylic and hydroxyl chain end groups (a) with respect to those inside the polymer chain (b) is mainly due to the largely different preexponential factors. This steric effect can be explained considering that the water approach is favoured by the hydrophilic nature of the chain end groups compared to the hydrophobic character of the polymer backbone. No dependence of kad and kbd on chiral composition was found, suggesting that the differences reported earlier in the literature are due to the effect of crystallinity on diffusion phenomena rather than to different reactivity of the two stereoisomers. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: Biopolymers Degradation kinetics Hydrolysis Chirality Poly(lactic acid)
1. Introduction In the past years, poly(lactic acid) (PLA) gained significant interest as hydrolytically degradable, non-toxic material for carriers and devices used for drug delivery medical applications. Degradation studies have been performed in different systems of interest, such as nano and microparticles [1], as well as tablets and suture threads [2,3]. Hydrolytic degradation affects mechanical properties and erosion mechanism of the devices, thus strongly influencing release and targeting of the drug [4]. Moreover, its excellent environmental compatibility combined with good mechanical properties makes PLA one of the most attractive candidates to replace non-biodegradable oil-based synthetic polymers in large scale production of consumables [5,6]. Thus, degradation kinetics is also interesting in the chemical industry for the polymer production and its final composting. In general, polymer degradation is the result of the interplay between chemical hydrolysis and water and oligomer diffusion [7,8]. To decouple these effects, and thus to
* Corresponding author. via Mancinelli 7, 20131 Milano, Italy. Tel.: þ39 (0)2 2399 3135; fax: þ39 (0)2 2399 3180. E-mail address: [email protected] (D. Moscatelli). 0141-3910/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.polymdegradstab.2012.06.026
evaluate the hydrolytic degradation kinetics in the chemical regime, degradation has been carried out in solution [9e14]. Hydrolytic degradation rate of PLA is a strong function of pH, which can affect both the degradation mechanism and kinetics. In particular, at neutral and basic pH it was found that degradation occurs preferentially through backbiting reactions, although a minor contribution of random scission hydrolysis was observed [9,12]. At acidic pH it was shown that the hydrolysis proceeds through a preferential scission of the polymer end groups. In particular, the scission kinetic constant of the terminal groups (Fig. 1) was found to be 10 times larger than that of the internal esters [11,15]. The same result was obtained by Batycky et al. [16], who found that the difference in reaction rate between terminal and backbone esters is 4 fold. Similar findings were reported by de Jong et al. [9], who however did not evaluate the two degradation kinetic constants. On the other hand, Belbella et al. studied the degradation of PLA nanospheres concluding that the degradation mechanism is random chain scission [17]. Other parameters affecting the degradation hydrolysis are temperature, molecular weight and chain stereo-configuration. Different studies have been reported in the literature suggesting Arrhenius-dependent kinetics, with activation energies in the order of 40e100 kJ/mol [18e20]. In contrast, Lyu et al. and Han et al.
F. Codari et al. / Polymer Degradation and Stability 97 (2012) 2460e2466
Fig. 1. Definition of a- and b-ester groups along a PLA chain composed by n repeating units.
reported that the degradation kinetic constant follows a VogeleTammaneFulcher (VTF) temperature dependence [21,22]. The dependence of the degradation rate constant upon the polymer molecular weight was investigated suggesting that the hydrolysis constant decreases with increasing molecular weight [23]. On the other hand, Maniar et al. reported that the rate of hydrolysis among the homologous series of oligomers increases as the molecular weight increases [24]. Furthermore, chain stereo-configuration, i.e. enantiomer composition, plays an important role, the degradation being faster the lower the crystallinity. For example, a maximum in hydrolysis rate was found for a racemic polymer with an L/ D composition equal to 50/50 mol% [25]. The aim of this work is to develop a reliable kinetic model for PLA degradation in acidic conditions. This way, we try to clarify some of the issues listed above and in particular to identify: (i) the degradation kinetic scheme, (ii) the influence of molecular weight, (iii) the dependence upon temperature and (iv) the effect of chain stereo-configuration. The degradation experiments were carried out at pH 2, starting from oligomers of different chain lengths (n ¼ 2e9) and chiral compositions (50% DL and 100% LL) within the temperature range 40e120 C. As such, the experimental results cover conditions of interest for both biomedical as well as chemical applications. The considered oligomers are short enough to ensure complete solubility at all examined conditions. In fact, as reported in a previous work in which a detailed description of oligomers degradation in time has been characterized through HPLC, oligomers with less than 10 lactic acid units are fully soluble in water at pH ¼ 2 [26]. After employing the aforementioned HPLC characterization, the obtained data were simulated considering different reaction mechanisms, namely random chain scission and preferential chain end scission. Due to the wide experimental range of temperature considered, a reliable evaluation of the different activation energies was possible along with a convincing elucidation of the degradation mechanism. 2. Experimental part 2.1. Materials L lactic acid 90% reagent grade and DL-lactic acid purum were supplied by Acros Organics and Fluka, respectively. HPLC grade acetonitrile and orthophosphoric acid, used for the HPLC analysis, were purchased from Fluka. Copper(II) sulphate anhydrous 98% was supplied by Acros Organics. All reagents were used as received without any further purification.
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Next, the oligomers were separated through semi-preparative HPLC, using the analytical procedure described in the next section. Namely, the polymer samples were dissolved in acetonitrile at high concentration (0.4 g/l) and narrow fractions of oligomers were collected. Finally, the degradation kinetics of the individual oligomers was investigated. The polycondensation reactions were carried out without catalyst for 10 h at 150 C in a round bottomed glass flask under nitrogen flow. The reaction temperature was set low enough to limit the formation of side products, such as cyclic compounds [27]. The resulting polymers exhibited relatively broad molecular weight distribution (polydispersity of 1.7), and number average molecular weight close to 500e600 Da. It is worth noting that the oligomers collected by gradient semipreparative HPLC are dissolved in solutions with different acetonitrileewater compositions. In order to avoid any error due to the presence of the organic solvent, all the collected samples were diluted in water acidified with phosphoric acid (pH ¼ 2), to the same volume fraction of acetonitrile equal to about 3% (the acetonitrile content was measured by gas chromatography as described in the ESI). This concentration of acetonitrile was selected because appeared to affect the degradation kinetics at negligible extent, as reported in detail in the ESI. After dilution, the oligomer concentration is low enough to avoid any backward reaction and high enough to be easily detected by HPLC. The hydrolysis reaction of each individual oligomer was investigated at different temperatures in closed glass vials heated by means of an electrical oven (accuracy 3 C). While the degradation of L-LA oligomers was studied in a temperature range from 40 to 120 C, DL-LA oligomers hydrolysis was investigated between 40 and 60 C. The degradation products were characterized by RPHPLC analysis. Samples were collected at different times during the hydrolysis reaction and once more characterized by HPLC as described above. To investigate the occurrence of racemization reactions, the same samples were also analysed by chiral chromatography. 2.3. Reverse phase HPLC analysis The concentration of the polymer chains of any given length in a polymer sample was measured by gradient HPLC following the procedure detailed in a previous work for LL polymers [26]. As reported in the ESI, the calibration factors were found to be independent on the oligomer stereo configuration, and thus the same procedure is applied for all species. The analysis was carried out using an Agilent 1200 series apparatus, equipped with 2 Agilent Eclipse XDB C18 columns (3.9 mm 150 mm, particle size 3.5 mm) and UV detector (constant wavelength at 210 nm). The mobile phase was a mixture of water and acetonitrile, acidified with phosphoric acid (0.1% v/v). Column oven temperature was 40 C and mobile phase flow rate was 1 mL/min. A gradient operating mode was applied, with the following gradient profile: initial adsorbing conditions with mobile phase at 98% v/v water; after 2 min, the acetonitrile concentration was ramped linearly to 60% v/ v in 25 min; then, it was changed to 100% v/v and maintained constant for 5 min and finally back to 98% v/v water in a step change.
2.2. PLA oligomer synthesis, separation and degradation
2.4. Chiral HPLC analysis
PLA oligomers with chain lengths n ¼ 2e9 were synthesized and collected following a two-step procedure: low molecular weight PLA samples were produced by bulk melt polymerization starting from L-lactic acid and a mixture of D and L lactic acid (50% mol/mol).
The separation of the isomers of L and D lactic acids has been carried out using a Chirex 3126 (D)-penicillamin (Phenomenex) column (length 150 mm, internal diameter 4.6 mm and 5 mm particles) mounted on the same HPLC apparatus described above. A
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mixture of Copper(II) sulfate 3 mM was used as eluent at flow rate of 1 ml/min. As shown in Fig. 2a, the elution times of the two isomers were identified by injection of L-LA and the racemic mixture of D and L-LA. Since the chromatogram of the racemic mixture showed that the ratio between the areas of the two isomers is equal to 1, the same calibration factors were used for both species. 3. Results and discussion The hydrolytic degradation kinetics of PLA has been investigated as a function of oligomer chain length, temperature and chiral composition. As described in Section 2, oligomer mixtures were fractionated by HPLC, and the collected oligomers were separately degraded at acidic conditions (pH ¼ 2) and different temperatures (from 40 to 120 C). As an example, the chromatograms of the initial pentamer, LA5, and its degradation products after 6 h of reaction are shown in Fig. 3. Given the calibration factors, the concentration profiles of the initial oligomer and its degradation products have been evaluated as a function of time as shown in Fig. 4. In order to verify that pH was constant during all reactions, a preliminary test was run by adding L-LA to an aqueous H3PO4 solution at pH 2. The concentration of LA was 0.01 mol/l, i.e. 5 times larger than the maximum value measured after the hydrolysis of
Fig. 3. HPLC chromatograms at (a) t ¼ 0 and (b) 6 h for the hydrolysis of L-LA5 at 80 C.
the longest oligomer investigated. No change in pH was found, thus confirming that pH remains practically constant during all the considered hydrolysis reactions. It is worth noting that, since the experiments are in batch mode, the first order moment of the molecular weight distribution (i.e. the total number of monomer units) is constant. For all experiments in this work this condition was fulfilled with an error of 2%. This number provides a reliable estimate of the experimental error for all data reported in this work.
Fig. 2. Chiral HPLC chromatogram of: (a) L lactic acid (dashed line) and DL lactic acid (solid line) monomers; (b) degradation products of LL (dashed line) and DL (solid line) oligomers with chain length equal to 5 after 40 h. Degradation experiments performed at 60 C.
Fig. 4. Oligomer concentrations as a function of time during the degradation of L-LA5 at 80 C. Experimental results: C5 (,), C4 (*), C3 (þ), C2 (B), C1 ().
F. Codari et al. / Polymer Degradation and Stability 97 (2012) 2460e2466
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In the following we discuss all the collected results: while the results for the LL oligomers cover the entire temperature range mentioned above, the effect of chirality is analysed in a narrower temperature range (40e60 C). 3.1. The random chain scission mechanism (RCS) According to this reaction mechanism the degradation of a PLA oligomer with chain length n occurs by hydrolysis of the ester bonds along the polymer backbone which exhibit the same reactivity whatever their position. Due to the high dilution of the sample in water, the hydrolysis reaction can be considered irreversible and the corresponding scheme becomes: kd
LAn þ W / LAi þ LAni
(1)
where LAn indicates an oligomer with chain length n, kd the hydrolysis rate constant and W a water molecule. The material balance of the generic n-th oligomer, detailed in [28], is: N X dCn Cf ðn 1Þkd CW Cn ¼ 2kd CW dt
(2)
f ¼ nþ1
where Cn is the concentration of the species with chain length n and CW the concentration of water. This last species, being present in large excess, is considered constant in time. In all experiments, the initial conditions were evaluated by HPLC after dilution of the selected oligomer and a few minutes of temperature conditioning in the oven at the selected temperature. Therefore, the degradation process never started from a solution of the pure oligomer but from the set of initial concentrations measured by HPLC, which therefore accounts for trace amounts of shorter oligomers formed during the sample pre-treatment. Focussing on the major component in the system (the initial oligomer), its material balance reduces to the consumption term and can be integrated in time leading to:
ln
Cn Cn0
Fig. 5. Natural logarithm of the concentration ratios during the degradation at (a) 40 C and (b) 100 C of L-oligomers with different chain lengths (C8 (◄), C6 (>), C4 (-), C2 (B)).
!
¼ ðn 1Þkd CW t
(3)
and the rate coefficient kd for each individual oligomer is readily evaluated from the experimental data independently of the degradation kinetics of the other species. The experimental data corresponding to Equation (3) are shown in Fig. 5 at two selected temperatures and for four oligomers of different length. The linearity of the experimental data supports the assumption of negligible autocatalytic effect: despite the increase of the concentration of carboxylic groups during degradation, no change in the reaction rate is observed in the studied temperature range. This means that at constant, acidic pH of the solution, the dissociation of the carboxylic groups is irrelevant and non-detectable, in agreement with the results reported in the literature for ester hydrolysis in the presence of an additional acid [10]. The corresponding values of the constants, kd, estimated for each chain length are reported in Fig. 6 and Table 1. It is seen that, contrary to the assumption of RCS mechanism, the value of the rate constant kd changes with the oligomer chain length. In particular, it is larger for shorter chains and becomes almost independent of the chain length for oligomers longer than 7 repeating units. 3.2. The preferential chain end scission mechanism (PCES) In order to overcome the difficulties of the RCS mechanism discussed above, a model accounting for the different reactivity of the ester groups depending on their position along the chain was
Fig. 6. kd,n of L-oligomers estimated at different temperature as a function of chain length: (a) - 80 C, C 100 C and A 120 C; (b) - 40 C, C 50 C and A 60 C.
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Table 1 Values of hydrolysis rate constant of L-oligomers, kd,n, estimated at 40, 50, 60, 80, 100 and 120 C (l/mol/h). Chain length
kd,n . 105 (40 C)
kd,n . 105 (50 C)
kd,n . 105 (60 C)
kd,n . 102 (80 C)
kd,n . 102 (100 C)
kd,n . 102 (120 C)
2 3 4 5 6 7 8 9
8.5 6.0 4.4 4.0 3.3 3.2 2.6 e
23.4 18.1 12.2 11.1 8.5 8.5 6.6 e
45.4 31.7 23.8 29.7 17.2 15.1 13.5 e
0.28 0.13 0.10 0.07 0.07 0.04 0.05 0.05
0.75 0.44 0.32 0.26 0.21 0.17 0.19 0.16
2.30 1.69 1.18 0.86 0.69 0.65 0.75 0.55
adopted based on the observation of Shih [11]. In particular, according to the Preferential Chain End Scission mechanism (PCES), two types of ester groups with different reactivity were postulated: a-esters, the groups close to hydroxyl or carboxyl chain end groups, and b-esters, all the other ester groups in the polymer chain backbone as sketched in Fig. 1. Accordingly, the following expression of the overall degradation rate constant, kd,n, for a generic oligomer of length n can be proposed:
kd;n ¼
2kad þ ðn 3Þkbd n1
n3
(4)
This equation is a simple average of the two rate constants weighed on the corresponding number of reacting sites. It is worth noticing that Equation (4) predicts the same qualitative behaviour identified experimentally (Fig. 6): as the chain length increases, the ratio between the numbers of a and b esters along the chain backbone decreases and, therefore, the impact of kad (corresponding to the most reactive groups) on the overall degradation constant becomes smaller and smaller. For long enough chains, kd,n becomes practically constant and equal to kbd . Of course, such expression applies to chain lengths larger than 2: the linear dimer is an exception since, due to the close vicinity of the chain end groups, it could in principle exhibit different reaction rate constant, kd,2 (evaluated through Equation (3)). In this frame, the hydrolysis reactions of oligomers longer than 2 units are sketched as follows: kad
LAn þ W / LA1 þ LAn1 kbd
LAn þ W / LAni þ LAi
n3 n3
(5)
i ¼ 2; 3::; n 2
(6)
Table 2 Values of the kinetic rate constants kad and kbd at 80, 100 and 120 C (l/mol/h). T C
kad 105 l/mol/h
kbd 105 l/mol/h
40 50 60 80 100 120
4.5 12 22.5 84 355 1450
2 8 11.8 34 123 355
of the previous RCS mechanism. The values of kad and kbd at each temperature were estimated by fitting the experimental data of oligomers longer than two and they are listed in Table 2. The value of the overall average relative error was about 13%. As expected, kad is larger than kbd in agreement with the key assumption underlying the PCES mechanism. Both kad and kbd conform to Arrhenius temperature dependence as shown in Fig. 7, with activation energies equal to 73 and 58 kJ/mol and preexponential factors of 8.21$107 and 1.77$105 l/mol/h, respectively. These values are within the range of 40e100 kJ/mol where previous values reported in the literature are also included [18e20,23,29], while the observation that the degradation rate constant follows a VogeleTammaneFulcher (VTF) temperature dependence is not confirmed [21,29]. From the Arrhenius plots in Fig. 7 it is seen that the difference between kad and kbd is due to the large difference between the preexponential factors more than to that between the activation energies (larger in the case of a ester bonds). Similar conclusions have been reached for the ester bonds hydrolysis in acidic conditions [30]: the corresponding activation energy (involving two transition states) is in fact only slightly affected by the atoms surrounding the ester bond, while the steric effect is predominant in discriminating the reactivity in different solvents. In the specific case under examination, the larger probability of hydrolysis of the a ester groups can be attributed to the presence of two hydrophilic chain end groups (carboxylic and hydroxyl) enhancing the rate of hydrolysis of the ester groups close to them. Finally, the predictions of two models based on the RCS and PCES kinetic mechanisms, respectively, are compared to the concentration values of the various oligomers as a function of time for a selected reaction in Fig. 8. As expected, no difference between RCS and PCES models is observed for the longest oligomers. However, the PCES model gives better predictions for shorter oligomers. It is worth noticing that by looking only at the monomer consumption kinetics it would not be possible to discriminate between these two models.
The corresponding material balances, derived in [28], are: N X dCn Cf 2kad Cw Cn ¼ 2kad Cnþ1 Cw þ 2Cw kbd dt f ¼ nþ2
b
ðn 3Þkd Cw Cn
(7)
n3
while for shorter oligomers, the following specific balances are considered: N X dC1 Cf ¼ 2kd;2 Cw C2 þ 2Cw kad dt
(8)
N X dC2 Cf kd;2 Cw C2 ¼ 2kad C3 Cw þ 2Cw kbd dt
(9)
f ¼3
f ¼4
The PCES mechanism involves only three parameters, kd,2, kad and kbd , instead of the multiple chain length specific rate coefficients
Fig. 7. Arrhenius plot of kad (,) and kbd (>) for LL (open symbols) and symbols) oligomers.
DL
(solid
F. Codari et al. / Polymer Degradation and Stability 97 (2012) 2460e2466
3.3. Effect of chiral composition The dependence of the degradation kinetics upon the chiral composition of the oligomers was investigated experimentally in
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the temperature range from 40 to 60 C by studying the degradation kinetics of racemic DL oligomers. The DL polymer samples were produced by polycondensation of a mixture of D and L lactic acid 50% w/w, as reported in Section 2.
Fig. 8. Concentration profiles of the different oligomers during degradation at 100 C of L-LA8. Symbols: experimental data; lines: RCS (dashed) and PCES (continuous line) models.
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The occurrence of racemization during polycondensation has been excluded by analysing the degradation products of LL and DL oligomers through analytical chiral chromatography. As an example, the chromatograms obtained in the case of LA5 hydrolysis are shown in Fig. 2b. While in case of degradation of the LL oligomer only the peak of L-LA is found, L-LA and D-LA peaks with similar areas are found for the DL oligomer. This finding suggests that configurational rearrangements during polycondensation and hydrolysis are negligible. Following the same procedure applied above for the LL oligomers, the degradation rate constants of DL oligomers, kad and kbd , compatible with the PCES model have been evaluated by fitting experimental data of the corresponding degradation reaction. The resulting values of rate constants are compared in Fig. 7 with those of the LL oligomers: all values are quite similar whatever the examined stereo-configuration, thus suggesting that the chiral composition does not affect the degradation kinetic to any significant extent. Experimental data obtained by studying the hydrolytic degradation of macroscopic devices suggested that hydrolysis reactions are strongly influenced by the isomer composition [18]. For example, Fukuzaki et al. [25] pointed out that the hydrolytic degradation of PLA plates is faster the larger the amount of D-LA. The highest rate of hydrolysis rate was found for a racemic PLA with L/D composition equal to 50/50 mol% [25]. This apparent contradiction can be explained by considering the role of mass transport resistances which are most likely the rate determining step in the degradation of macroscopic objects. Since the degradation kinetics is a function of the local water concentration in the polymer object [8,31], and water diffusion is strongly affected by the crystallinity of the polymer, crystalline and amorphous PLA devices degrade with rather different characteristic times. Thus, DL polymers with a majority of amorphous domains enhances water uptake and therefore degrades faster than LL ones. However, when transport limitations are removed, as it is the case of the aqueous solutions considered in this work, it is found that the degradation rate constants are not affected by the stereo-configuration of the reacting chains. 4. Conclusions A comprehensive study of the hydrolysis kinetics of water soluble PLA oligomers in solution was carried out at temperatures in the range 40e120 C and acidic pH conditions for various chain lengths, ranging from 2 to 9 repeating units. First, degradation experiments starting from single oligomers were performed. It was found that oligomers shorter than a critical chain length, equal to seven, exhibit larger degradation rates than longer ones, while, above this threshold length, the reactivity becomes independent of chain length. These findings are compatible with the assumption that the ester groups along the PLA chain are classified as a- and b-ester, the first ones being the ester groups close to the hydroxyl and carboxyl chain end groups and the second ones all the others, i.e. the so called preferential chain end scission mechanism. Based on this assumption a relation is developed for evaluating the hydrolysis rate constant of oligomers of any length as a function of two parameters only, i.e. the hydrolysis rate constants of the ester groups a and b (kad and kbd ). For the special case of the dimer, the corresponding kinetic constant of hydrolysis is evaluated directly from experimental data. This model can be applied to predict the hydrolysis of
polymer chains of any length. Activation energies of 73 and 58 kJ/ mol and a pre-exponential factors of 8.21$107 and 1.77$105 l/mol/ h have been estimated for kad and kbd , respectively. All experimental data are reproduced with an average relative error of about 13%. The obtained data indicate that the higher reactivity of the ester groups close to the chain end groups, with respect to those inside the oligomer chain, has to be attributed to a favourable steric effect caused by the hydrophilic nature of the chain end groups more than to a difference in the activation energies. Finally, it was shown that the hydrolysis kinetics is not affected by chirality suggesting that the differences reported in the literature in the degradation of macroscopic objects are most probably due to mass transport resistances in turn due to different degrees of crystallinity in the polymer matrix. Appendix A. Supplementary data Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.polymdegradstab.2012.06.026. References [1] Stevanovic M, Uskokovic D. Current Nanoscience 2009;5(1):1e14. [2] Vert M, Li SM, Spenlehauer G, Guerin P. Journal of Materials Science-Materials in Medicine 1992;3(6):432e46. [3] Arosio P, Busini V, Perale G, Moscatelli D, Masi M. Polymer International 2008; 57(7):912e20. [4] Alexis F. Polymer International 2005;54(1):36e46. [5] Garlotta D. Journal of Polymers and the Environment 2001;9(2):63e84. [6] Nampoothiri KM, Nair NR, and John RP. Bioresource Technology; 101(22):8493e8501. [7] Grayson ACR, Cima MJ, Langer R. Biomaterials 2005;26(14):2137e45. [8] von Burkersroda F, Schedl L, Gopferich A. Biomaterials 2002;23(21):4221e31. [9] de Jong SJ, Arias ER, Rijkers DTS, van Nostrum CF, Kettenes-van den Bosch JJ, Hennink WE. Polymer 2001;42(7):2795e802. [10] Siparsky GL, Voorhees KJ, Miao FD. Journal of Environmental Polymer Degradation 1998;6(1):31e41. [11] Shih C. Journal of Controlled Release 1995;34(1):9e15. [12] van Nostrum CF, Veldhuis TFJ, Bos GW, Hennink WE. Polymer 2004;45(20): 6779e87. [13] Schliecker G, Schmidt C, Fuchs S, Wombacher R, Kissel T. International Journal of Pharmaceutics 2003;266(1e2):39e49. [14] Zhang XC, Wyss UP, Pichora D, Goosen MFA. Journal of Bioactive and Compatible Polymers 1994;9(1):80e100. [15] Shih C. Pharmaceutical Research 1995;12(12):2036e40. [16] Batycky RP, Hanes J, Langer R, Edwards DA. Journal of Pharmaceutical Sciences 1997;86(12):1464e77. [17] Belbella A, Vauthier C, Fessi H, Devissaguet JP, Puisieux F. International Journal of Pharmaceutics 1996;129(1e2):95e102. [18] Makino K, Arakawa M, Kondo T. Chemical & Pharmaceutical Bulletin 1985; 33(3):1195e201. [19] Tsuji H. Biomaterials 2003;24(4):537e47. [20] Weir NA, Buchanan FJ, Orr JF, Farrar DF, Dickson GR. Proceedings of the Institution of Mechanical Engineers Part H-Journal of Engineering in Medicine 2004;218(H5):321e30. [21] Lyu SP, Schley J, Loy B, Lind D, Hobot C, Sparer R, et al. Biomacromolecules 2007;8(7):2301e10. [22] Han XX, Pan JZ, Buchanan F, Weir N, and Farrar D. Acta Biomaterialia; 6(10):3882e3889. [23] Schliecker G, Schmidt C, Fuchs S, Kissel T. Biomaterials 2003;24(21):3835e44. [24] Maniar ML, Kalonia DS, Simonelli AP. Journal of Pharmaceutical Sciences 1991;80(8):778e82. [25] Fukuzaki H, Yoshida M, Asano M, Kumakura M. European Polymer Journal 1989;25(10):1019e26. [26] Codari F, Moscatelli D, Storti G, and Morbidelli M. Macromolecular Materials and Engineering;295(1):58e66. [27] Keki S, Bodnar I, Borda J, Deak G, Zsuga M. Journal of Physical Chemistry B 2001;105(14):2833e6. [28] Dotson NA. Polymerization process modeling. New York [etc.]: VCH; 1996. [29] Mohd-Adnan AF, Nishida H, Shirai Y. Polymer Degradation and Stability 2008; 93(6):1053e8. [30] Bender ML. Journal of the American Chemical Society 1951;73(4):1626e9. [31] Wiggins JS, Hassan MK, Mauritz KA, Storey RF. Polymer 2006;47(6):1960e9.
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Polymer Degradation and Stability journal homepage: www.elsevier.com/locate/polydegstab
Kinetics of the hydrolytic degradation of poly(lactic acid) F. Codari a, S. Lazzari a, M. Soos a, G. Storti a, M. Morbidelli a, D. Moscatelli b, * a b
Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland Dipartimento di Chimica, Materiali e Ingegneria Chimica “Giulio Natta”, Politecnico di Milano, 20131 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history: Received 24 February 2012 Received in revised form 12 June 2012 Accepted 18 June 2012 Available online 29 June 2012
The hydrolysis of water soluble PLA oligomers of different chain lengths and chirality was investigated at acidic pH and temperatures in the range from 40 to 120 C. The time evolution of the concentrations of all oligomers was measured by HPLC and the corresponding degradation rates were evaluated for each specific chain length. In agreement with the preferential chain end scission mechanism suggested in the literature, the ester groups were classified as a (chain end esters) and b (backbone esters). A kinetic model was developed from the resulting kinetic scheme and it was found to well reproduce the concentration values of all different oligomers during degradation as a function of time. The corresponding rate constants kad and kbd were estimated over the whole temperature range, with activation energies of 73 and 58 kJ/mol and pre-exponential factors of 8.21$107 and 1.77$105 l/mol/h, respectively. It is seen that the faster hydrolysis of the ester groups close to the carboxylic and hydroxyl chain end groups (a) with respect to those inside the polymer chain (b) is mainly due to the largely different preexponential factors. This steric effect can be explained considering that the water approach is favoured by the hydrophilic nature of the chain end groups compared to the hydrophobic character of the polymer backbone. No dependence of kad and kbd on chiral composition was found, suggesting that the differences reported earlier in the literature are due to the effect of crystallinity on diffusion phenomena rather than to different reactivity of the two stereoisomers. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: Biopolymers Degradation kinetics Hydrolysis Chirality Poly(lactic acid)
1. Introduction In the past years, poly(lactic acid) (PLA) gained significant interest as hydrolytically degradable, non-toxic material for carriers and devices used for drug delivery medical applications. Degradation studies have been performed in different systems of interest, such as nano and microparticles [1], as well as tablets and suture threads [2,3]. Hydrolytic degradation affects mechanical properties and erosion mechanism of the devices, thus strongly influencing release and targeting of the drug [4]. Moreover, its excellent environmental compatibility combined with good mechanical properties makes PLA one of the most attractive candidates to replace non-biodegradable oil-based synthetic polymers in large scale production of consumables [5,6]. Thus, degradation kinetics is also interesting in the chemical industry for the polymer production and its final composting. In general, polymer degradation is the result of the interplay between chemical hydrolysis and water and oligomer diffusion [7,8]. To decouple these effects, and thus to
* Corresponding author. via Mancinelli 7, 20131 Milano, Italy. Tel.: þ39 (0)2 2399 3135; fax: þ39 (0)2 2399 3180. E-mail address: [email protected] (D. Moscatelli). 0141-3910/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.polymdegradstab.2012.06.026
evaluate the hydrolytic degradation kinetics in the chemical regime, degradation has been carried out in solution [9e14]. Hydrolytic degradation rate of PLA is a strong function of pH, which can affect both the degradation mechanism and kinetics. In particular, at neutral and basic pH it was found that degradation occurs preferentially through backbiting reactions, although a minor contribution of random scission hydrolysis was observed [9,12]. At acidic pH it was shown that the hydrolysis proceeds through a preferential scission of the polymer end groups. In particular, the scission kinetic constant of the terminal groups (Fig. 1) was found to be 10 times larger than that of the internal esters [11,15]. The same result was obtained by Batycky et al. [16], who found that the difference in reaction rate between terminal and backbone esters is 4 fold. Similar findings were reported by de Jong et al. [9], who however did not evaluate the two degradation kinetic constants. On the other hand, Belbella et al. studied the degradation of PLA nanospheres concluding that the degradation mechanism is random chain scission [17]. Other parameters affecting the degradation hydrolysis are temperature, molecular weight and chain stereo-configuration. Different studies have been reported in the literature suggesting Arrhenius-dependent kinetics, with activation energies in the order of 40e100 kJ/mol [18e20]. In contrast, Lyu et al. and Han et al.
F. Codari et al. / Polymer Degradation and Stability 97 (2012) 2460e2466
Fig. 1. Definition of a- and b-ester groups along a PLA chain composed by n repeating units.
reported that the degradation kinetic constant follows a VogeleTammaneFulcher (VTF) temperature dependence [21,22]. The dependence of the degradation rate constant upon the polymer molecular weight was investigated suggesting that the hydrolysis constant decreases with increasing molecular weight [23]. On the other hand, Maniar et al. reported that the rate of hydrolysis among the homologous series of oligomers increases as the molecular weight increases [24]. Furthermore, chain stereo-configuration, i.e. enantiomer composition, plays an important role, the degradation being faster the lower the crystallinity. For example, a maximum in hydrolysis rate was found for a racemic polymer with an L/ D composition equal to 50/50 mol% [25]. The aim of this work is to develop a reliable kinetic model for PLA degradation in acidic conditions. This way, we try to clarify some of the issues listed above and in particular to identify: (i) the degradation kinetic scheme, (ii) the influence of molecular weight, (iii) the dependence upon temperature and (iv) the effect of chain stereo-configuration. The degradation experiments were carried out at pH 2, starting from oligomers of different chain lengths (n ¼ 2e9) and chiral compositions (50% DL and 100% LL) within the temperature range 40e120 C. As such, the experimental results cover conditions of interest for both biomedical as well as chemical applications. The considered oligomers are short enough to ensure complete solubility at all examined conditions. In fact, as reported in a previous work in which a detailed description of oligomers degradation in time has been characterized through HPLC, oligomers with less than 10 lactic acid units are fully soluble in water at pH ¼ 2 [26]. After employing the aforementioned HPLC characterization, the obtained data were simulated considering different reaction mechanisms, namely random chain scission and preferential chain end scission. Due to the wide experimental range of temperature considered, a reliable evaluation of the different activation energies was possible along with a convincing elucidation of the degradation mechanism. 2. Experimental part 2.1. Materials L lactic acid 90% reagent grade and DL-lactic acid purum were supplied by Acros Organics and Fluka, respectively. HPLC grade acetonitrile and orthophosphoric acid, used for the HPLC analysis, were purchased from Fluka. Copper(II) sulphate anhydrous 98% was supplied by Acros Organics. All reagents were used as received without any further purification.
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Next, the oligomers were separated through semi-preparative HPLC, using the analytical procedure described in the next section. Namely, the polymer samples were dissolved in acetonitrile at high concentration (0.4 g/l) and narrow fractions of oligomers were collected. Finally, the degradation kinetics of the individual oligomers was investigated. The polycondensation reactions were carried out without catalyst for 10 h at 150 C in a round bottomed glass flask under nitrogen flow. The reaction temperature was set low enough to limit the formation of side products, such as cyclic compounds [27]. The resulting polymers exhibited relatively broad molecular weight distribution (polydispersity of 1.7), and number average molecular weight close to 500e600 Da. It is worth noting that the oligomers collected by gradient semipreparative HPLC are dissolved in solutions with different acetonitrileewater compositions. In order to avoid any error due to the presence of the organic solvent, all the collected samples were diluted in water acidified with phosphoric acid (pH ¼ 2), to the same volume fraction of acetonitrile equal to about 3% (the acetonitrile content was measured by gas chromatography as described in the ESI). This concentration of acetonitrile was selected because appeared to affect the degradation kinetics at negligible extent, as reported in detail in the ESI. After dilution, the oligomer concentration is low enough to avoid any backward reaction and high enough to be easily detected by HPLC. The hydrolysis reaction of each individual oligomer was investigated at different temperatures in closed glass vials heated by means of an electrical oven (accuracy 3 C). While the degradation of L-LA oligomers was studied in a temperature range from 40 to 120 C, DL-LA oligomers hydrolysis was investigated between 40 and 60 C. The degradation products were characterized by RPHPLC analysis. Samples were collected at different times during the hydrolysis reaction and once more characterized by HPLC as described above. To investigate the occurrence of racemization reactions, the same samples were also analysed by chiral chromatography. 2.3. Reverse phase HPLC analysis The concentration of the polymer chains of any given length in a polymer sample was measured by gradient HPLC following the procedure detailed in a previous work for LL polymers [26]. As reported in the ESI, the calibration factors were found to be independent on the oligomer stereo configuration, and thus the same procedure is applied for all species. The analysis was carried out using an Agilent 1200 series apparatus, equipped with 2 Agilent Eclipse XDB C18 columns (3.9 mm 150 mm, particle size 3.5 mm) and UV detector (constant wavelength at 210 nm). The mobile phase was a mixture of water and acetonitrile, acidified with phosphoric acid (0.1% v/v). Column oven temperature was 40 C and mobile phase flow rate was 1 mL/min. A gradient operating mode was applied, with the following gradient profile: initial adsorbing conditions with mobile phase at 98% v/v water; after 2 min, the acetonitrile concentration was ramped linearly to 60% v/ v in 25 min; then, it was changed to 100% v/v and maintained constant for 5 min and finally back to 98% v/v water in a step change.
2.2. PLA oligomer synthesis, separation and degradation
2.4. Chiral HPLC analysis
PLA oligomers with chain lengths n ¼ 2e9 were synthesized and collected following a two-step procedure: low molecular weight PLA samples were produced by bulk melt polymerization starting from L-lactic acid and a mixture of D and L lactic acid (50% mol/mol).
The separation of the isomers of L and D lactic acids has been carried out using a Chirex 3126 (D)-penicillamin (Phenomenex) column (length 150 mm, internal diameter 4.6 mm and 5 mm particles) mounted on the same HPLC apparatus described above. A
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mixture of Copper(II) sulfate 3 mM was used as eluent at flow rate of 1 ml/min. As shown in Fig. 2a, the elution times of the two isomers were identified by injection of L-LA and the racemic mixture of D and L-LA. Since the chromatogram of the racemic mixture showed that the ratio between the areas of the two isomers is equal to 1, the same calibration factors were used for both species. 3. Results and discussion The hydrolytic degradation kinetics of PLA has been investigated as a function of oligomer chain length, temperature and chiral composition. As described in Section 2, oligomer mixtures were fractionated by HPLC, and the collected oligomers were separately degraded at acidic conditions (pH ¼ 2) and different temperatures (from 40 to 120 C). As an example, the chromatograms of the initial pentamer, LA5, and its degradation products after 6 h of reaction are shown in Fig. 3. Given the calibration factors, the concentration profiles of the initial oligomer and its degradation products have been evaluated as a function of time as shown in Fig. 4. In order to verify that pH was constant during all reactions, a preliminary test was run by adding L-LA to an aqueous H3PO4 solution at pH 2. The concentration of LA was 0.01 mol/l, i.e. 5 times larger than the maximum value measured after the hydrolysis of
Fig. 3. HPLC chromatograms at (a) t ¼ 0 and (b) 6 h for the hydrolysis of L-LA5 at 80 C.
the longest oligomer investigated. No change in pH was found, thus confirming that pH remains practically constant during all the considered hydrolysis reactions. It is worth noting that, since the experiments are in batch mode, the first order moment of the molecular weight distribution (i.e. the total number of monomer units) is constant. For all experiments in this work this condition was fulfilled with an error of 2%. This number provides a reliable estimate of the experimental error for all data reported in this work.
Fig. 2. Chiral HPLC chromatogram of: (a) L lactic acid (dashed line) and DL lactic acid (solid line) monomers; (b) degradation products of LL (dashed line) and DL (solid line) oligomers with chain length equal to 5 after 40 h. Degradation experiments performed at 60 C.
Fig. 4. Oligomer concentrations as a function of time during the degradation of L-LA5 at 80 C. Experimental results: C5 (,), C4 (*), C3 (þ), C2 (B), C1 ().
F. Codari et al. / Polymer Degradation and Stability 97 (2012) 2460e2466
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In the following we discuss all the collected results: while the results for the LL oligomers cover the entire temperature range mentioned above, the effect of chirality is analysed in a narrower temperature range (40e60 C). 3.1. The random chain scission mechanism (RCS) According to this reaction mechanism the degradation of a PLA oligomer with chain length n occurs by hydrolysis of the ester bonds along the polymer backbone which exhibit the same reactivity whatever their position. Due to the high dilution of the sample in water, the hydrolysis reaction can be considered irreversible and the corresponding scheme becomes: kd
LAn þ W / LAi þ LAni
(1)
where LAn indicates an oligomer with chain length n, kd the hydrolysis rate constant and W a water molecule. The material balance of the generic n-th oligomer, detailed in [28], is: N X dCn Cf ðn 1Þkd CW Cn ¼ 2kd CW dt
(2)
f ¼ nþ1
where Cn is the concentration of the species with chain length n and CW the concentration of water. This last species, being present in large excess, is considered constant in time. In all experiments, the initial conditions were evaluated by HPLC after dilution of the selected oligomer and a few minutes of temperature conditioning in the oven at the selected temperature. Therefore, the degradation process never started from a solution of the pure oligomer but from the set of initial concentrations measured by HPLC, which therefore accounts for trace amounts of shorter oligomers formed during the sample pre-treatment. Focussing on the major component in the system (the initial oligomer), its material balance reduces to the consumption term and can be integrated in time leading to:
ln
Cn Cn0
Fig. 5. Natural logarithm of the concentration ratios during the degradation at (a) 40 C and (b) 100 C of L-oligomers with different chain lengths (C8 (◄), C6 (>), C4 (-), C2 (B)).
!
¼ ðn 1Þkd CW t
(3)
and the rate coefficient kd for each individual oligomer is readily evaluated from the experimental data independently of the degradation kinetics of the other species. The experimental data corresponding to Equation (3) are shown in Fig. 5 at two selected temperatures and for four oligomers of different length. The linearity of the experimental data supports the assumption of negligible autocatalytic effect: despite the increase of the concentration of carboxylic groups during degradation, no change in the reaction rate is observed in the studied temperature range. This means that at constant, acidic pH of the solution, the dissociation of the carboxylic groups is irrelevant and non-detectable, in agreement with the results reported in the literature for ester hydrolysis in the presence of an additional acid [10]. The corresponding values of the constants, kd, estimated for each chain length are reported in Fig. 6 and Table 1. It is seen that, contrary to the assumption of RCS mechanism, the value of the rate constant kd changes with the oligomer chain length. In particular, it is larger for shorter chains and becomes almost independent of the chain length for oligomers longer than 7 repeating units. 3.2. The preferential chain end scission mechanism (PCES) In order to overcome the difficulties of the RCS mechanism discussed above, a model accounting for the different reactivity of the ester groups depending on their position along the chain was
Fig. 6. kd,n of L-oligomers estimated at different temperature as a function of chain length: (a) - 80 C, C 100 C and A 120 C; (b) - 40 C, C 50 C and A 60 C.
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Table 1 Values of hydrolysis rate constant of L-oligomers, kd,n, estimated at 40, 50, 60, 80, 100 and 120 C (l/mol/h). Chain length
kd,n . 105 (40 C)
kd,n . 105 (50 C)
kd,n . 105 (60 C)
kd,n . 102 (80 C)
kd,n . 102 (100 C)
kd,n . 102 (120 C)
2 3 4 5 6 7 8 9
8.5 6.0 4.4 4.0 3.3 3.2 2.6 e
23.4 18.1 12.2 11.1 8.5 8.5 6.6 e
45.4 31.7 23.8 29.7 17.2 15.1 13.5 e
0.28 0.13 0.10 0.07 0.07 0.04 0.05 0.05
0.75 0.44 0.32 0.26 0.21 0.17 0.19 0.16
2.30 1.69 1.18 0.86 0.69 0.65 0.75 0.55
adopted based on the observation of Shih [11]. In particular, according to the Preferential Chain End Scission mechanism (PCES), two types of ester groups with different reactivity were postulated: a-esters, the groups close to hydroxyl or carboxyl chain end groups, and b-esters, all the other ester groups in the polymer chain backbone as sketched in Fig. 1. Accordingly, the following expression of the overall degradation rate constant, kd,n, for a generic oligomer of length n can be proposed:
kd;n ¼
2kad þ ðn 3Þkbd n1
n3
(4)
This equation is a simple average of the two rate constants weighed on the corresponding number of reacting sites. It is worth noticing that Equation (4) predicts the same qualitative behaviour identified experimentally (Fig. 6): as the chain length increases, the ratio between the numbers of a and b esters along the chain backbone decreases and, therefore, the impact of kad (corresponding to the most reactive groups) on the overall degradation constant becomes smaller and smaller. For long enough chains, kd,n becomes practically constant and equal to kbd . Of course, such expression applies to chain lengths larger than 2: the linear dimer is an exception since, due to the close vicinity of the chain end groups, it could in principle exhibit different reaction rate constant, kd,2 (evaluated through Equation (3)). In this frame, the hydrolysis reactions of oligomers longer than 2 units are sketched as follows: kad
LAn þ W / LA1 þ LAn1 kbd
LAn þ W / LAni þ LAi
n3 n3
(5)
i ¼ 2; 3::; n 2
(6)
Table 2 Values of the kinetic rate constants kad and kbd at 80, 100 and 120 C (l/mol/h). T C
kad 105 l/mol/h
kbd 105 l/mol/h
40 50 60 80 100 120
4.5 12 22.5 84 355 1450
2 8 11.8 34 123 355
of the previous RCS mechanism. The values of kad and kbd at each temperature were estimated by fitting the experimental data of oligomers longer than two and they are listed in Table 2. The value of the overall average relative error was about 13%. As expected, kad is larger than kbd in agreement with the key assumption underlying the PCES mechanism. Both kad and kbd conform to Arrhenius temperature dependence as shown in Fig. 7, with activation energies equal to 73 and 58 kJ/mol and preexponential factors of 8.21$107 and 1.77$105 l/mol/h, respectively. These values are within the range of 40e100 kJ/mol where previous values reported in the literature are also included [18e20,23,29], while the observation that the degradation rate constant follows a VogeleTammaneFulcher (VTF) temperature dependence is not confirmed [21,29]. From the Arrhenius plots in Fig. 7 it is seen that the difference between kad and kbd is due to the large difference between the preexponential factors more than to that between the activation energies (larger in the case of a ester bonds). Similar conclusions have been reached for the ester bonds hydrolysis in acidic conditions [30]: the corresponding activation energy (involving two transition states) is in fact only slightly affected by the atoms surrounding the ester bond, while the steric effect is predominant in discriminating the reactivity in different solvents. In the specific case under examination, the larger probability of hydrolysis of the a ester groups can be attributed to the presence of two hydrophilic chain end groups (carboxylic and hydroxyl) enhancing the rate of hydrolysis of the ester groups close to them. Finally, the predictions of two models based on the RCS and PCES kinetic mechanisms, respectively, are compared to the concentration values of the various oligomers as a function of time for a selected reaction in Fig. 8. As expected, no difference between RCS and PCES models is observed for the longest oligomers. However, the PCES model gives better predictions for shorter oligomers. It is worth noticing that by looking only at the monomer consumption kinetics it would not be possible to discriminate between these two models.
The corresponding material balances, derived in [28], are: N X dCn Cf 2kad Cw Cn ¼ 2kad Cnþ1 Cw þ 2Cw kbd dt f ¼ nþ2
b
ðn 3Þkd Cw Cn
(7)
n3
while for shorter oligomers, the following specific balances are considered: N X dC1 Cf ¼ 2kd;2 Cw C2 þ 2Cw kad dt
(8)
N X dC2 Cf kd;2 Cw C2 ¼ 2kad C3 Cw þ 2Cw kbd dt
(9)
f ¼3
f ¼4
The PCES mechanism involves only three parameters, kd,2, kad and kbd , instead of the multiple chain length specific rate coefficients
Fig. 7. Arrhenius plot of kad (,) and kbd (>) for LL (open symbols) and symbols) oligomers.
DL
(solid
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3.3. Effect of chiral composition The dependence of the degradation kinetics upon the chiral composition of the oligomers was investigated experimentally in
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the temperature range from 40 to 60 C by studying the degradation kinetics of racemic DL oligomers. The DL polymer samples were produced by polycondensation of a mixture of D and L lactic acid 50% w/w, as reported in Section 2.
Fig. 8. Concentration profiles of the different oligomers during degradation at 100 C of L-LA8. Symbols: experimental data; lines: RCS (dashed) and PCES (continuous line) models.
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The occurrence of racemization during polycondensation has been excluded by analysing the degradation products of LL and DL oligomers through analytical chiral chromatography. As an example, the chromatograms obtained in the case of LA5 hydrolysis are shown in Fig. 2b. While in case of degradation of the LL oligomer only the peak of L-LA is found, L-LA and D-LA peaks with similar areas are found for the DL oligomer. This finding suggests that configurational rearrangements during polycondensation and hydrolysis are negligible. Following the same procedure applied above for the LL oligomers, the degradation rate constants of DL oligomers, kad and kbd , compatible with the PCES model have been evaluated by fitting experimental data of the corresponding degradation reaction. The resulting values of rate constants are compared in Fig. 7 with those of the LL oligomers: all values are quite similar whatever the examined stereo-configuration, thus suggesting that the chiral composition does not affect the degradation kinetic to any significant extent. Experimental data obtained by studying the hydrolytic degradation of macroscopic devices suggested that hydrolysis reactions are strongly influenced by the isomer composition [18]. For example, Fukuzaki et al. [25] pointed out that the hydrolytic degradation of PLA plates is faster the larger the amount of D-LA. The highest rate of hydrolysis rate was found for a racemic PLA with L/D composition equal to 50/50 mol% [25]. This apparent contradiction can be explained by considering the role of mass transport resistances which are most likely the rate determining step in the degradation of macroscopic objects. Since the degradation kinetics is a function of the local water concentration in the polymer object [8,31], and water diffusion is strongly affected by the crystallinity of the polymer, crystalline and amorphous PLA devices degrade with rather different characteristic times. Thus, DL polymers with a majority of amorphous domains enhances water uptake and therefore degrades faster than LL ones. However, when transport limitations are removed, as it is the case of the aqueous solutions considered in this work, it is found that the degradation rate constants are not affected by the stereo-configuration of the reacting chains. 4. Conclusions A comprehensive study of the hydrolysis kinetics of water soluble PLA oligomers in solution was carried out at temperatures in the range 40e120 C and acidic pH conditions for various chain lengths, ranging from 2 to 9 repeating units. First, degradation experiments starting from single oligomers were performed. It was found that oligomers shorter than a critical chain length, equal to seven, exhibit larger degradation rates than longer ones, while, above this threshold length, the reactivity becomes independent of chain length. These findings are compatible with the assumption that the ester groups along the PLA chain are classified as a- and b-ester, the first ones being the ester groups close to the hydroxyl and carboxyl chain end groups and the second ones all the others, i.e. the so called preferential chain end scission mechanism. Based on this assumption a relation is developed for evaluating the hydrolysis rate constant of oligomers of any length as a function of two parameters only, i.e. the hydrolysis rate constants of the ester groups a and b (kad and kbd ). For the special case of the dimer, the corresponding kinetic constant of hydrolysis is evaluated directly from experimental data. This model can be applied to predict the hydrolysis of
polymer chains of any length. Activation energies of 73 and 58 kJ/ mol and a pre-exponential factors of 8.21$107 and 1.77$105 l/mol/ h have been estimated for kad and kbd , respectively. All experimental data are reproduced with an average relative error of about 13%. The obtained data indicate that the higher reactivity of the ester groups close to the chain end groups, with respect to those inside the oligomer chain, has to be attributed to a favourable steric effect caused by the hydrophilic nature of the chain end groups more than to a difference in the activation energies. Finally, it was shown that the hydrolysis kinetics is not affected by chirality suggesting that the differences reported in the literature in the degradation of macroscopic objects are most probably due to mass transport resistances in turn due to different degrees of crystallinity in the polymer matrix. Appendix A. Supplementary data Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.polymdegradstab.2012.06.026. References [1] Stevanovic M, Uskokovic D. Current Nanoscience 2009;5(1):1e14. [2] Vert M, Li SM, Spenlehauer G, Guerin P. Journal of Materials Science-Materials in Medicine 1992;3(6):432e46. [3] Arosio P, Busini V, Perale G, Moscatelli D, Masi M. Polymer International 2008; 57(7):912e20. [4] Alexis F. Polymer International 2005;54(1):36e46. [5] Garlotta D. Journal of Polymers and the Environment 2001;9(2):63e84. [6] Nampoothiri KM, Nair NR, and John RP. Bioresource Technology; 101(22):8493e8501. [7] Grayson ACR, Cima MJ, Langer R. Biomaterials 2005;26(14):2137e45. [8] von Burkersroda F, Schedl L, Gopferich A. Biomaterials 2002;23(21):4221e31. [9] de Jong SJ, Arias ER, Rijkers DTS, van Nostrum CF, Kettenes-van den Bosch JJ, Hennink WE. Polymer 2001;42(7):2795e802. [10] Siparsky GL, Voorhees KJ, Miao FD. Journal of Environmental Polymer Degradation 1998;6(1):31e41. [11] Shih C. Journal of Controlled Release 1995;34(1):9e15. [12] van Nostrum CF, Veldhuis TFJ, Bos GW, Hennink WE. Polymer 2004;45(20): 6779e87. [13] Schliecker G, Schmidt C, Fuchs S, Wombacher R, Kissel T. International Journal of Pharmaceutics 2003;266(1e2):39e49. [14] Zhang XC, Wyss UP, Pichora D, Goosen MFA. Journal of Bioactive and Compatible Polymers 1994;9(1):80e100. [15] Shih C. Pharmaceutical Research 1995;12(12):2036e40. [16] Batycky RP, Hanes J, Langer R, Edwards DA. Journal of Pharmaceutical Sciences 1997;86(12):1464e77. [17] Belbella A, Vauthier C, Fessi H, Devissaguet JP, Puisieux F. International Journal of Pharmaceutics 1996;129(1e2):95e102. [18] Makino K, Arakawa M, Kondo T. Chemical & Pharmaceutical Bulletin 1985; 33(3):1195e201. [19] Tsuji H. Biomaterials 2003;24(4):537e47. [20] Weir NA, Buchanan FJ, Orr JF, Farrar DF, Dickson GR. Proceedings of the Institution of Mechanical Engineers Part H-Journal of Engineering in Medicine 2004;218(H5):321e30. [21] Lyu SP, Schley J, Loy B, Lind D, Hobot C, Sparer R, et al. Biomacromolecules 2007;8(7):2301e10. [22] Han XX, Pan JZ, Buchanan F, Weir N, and Farrar D. Acta Biomaterialia; 6(10):3882e3889. [23] Schliecker G, Schmidt C, Fuchs S, Kissel T. Biomaterials 2003;24(21):3835e44. [24] Maniar ML, Kalonia DS, Simonelli AP. Journal of Pharmaceutical Sciences 1991;80(8):778e82. [25] Fukuzaki H, Yoshida M, Asano M, Kumakura M. European Polymer Journal 1989;25(10):1019e26. [26] Codari F, Moscatelli D, Storti G, and Morbidelli M. Macromolecular Materials and Engineering;295(1):58e66. [27] Keki S, Bodnar I, Borda J, Deak G, Zsuga M. Journal of Physical Chemistry B 2001;105(14):2833e6. [28] Dotson NA. Polymerization process modeling. New York [etc.]: VCH; 1996. [29] Mohd-Adnan AF, Nishida H, Shirai Y. Polymer Degradation and Stability 2008; 93(6):1053e8. [30] Bender ML. Journal of the American Chemical Society 1951;73(4):1626e9. [31] Wiggins JS, Hassan MK, Mauritz KA, Storey RF. Polymer 2006;47(6):1960e9.