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Synthesis and Hydrolytic Degradation of Substituted Poly(DL-Lactic Acid)s

Non-substituted racemic poly(DL-lactic acid) (PLA) and substituted racemic poly(DL-lactic acid)s or poly(DL-2-hydroxyalkanoic acid)s with different side-chain lengths, i.e., poly(DL-2-hydroxybutanoic acid) (PBA), poly(DL-2-hydroxyhexanoic acid) (PHA), and poly(DL-2-hydroxydecanoic acid) (PDA) were synthesized by acid-catalyzed polycondensation of DL-lactic acid (LA), DL-2-hydroxybutanoic acid (BA), DL-2-hydroxyhexanoic acid (HA), and DL-2-hydroxydecanoic acid (DA), respectively. The hydrolytic degradation behavior was investigated in phosphate-buffered solution at 80 and 37 °C by gravimetry and gel permeation chromatography. It was found that the reactivity of monomers during polycondensation as monitored by the degree of polymerization (DP) decreased in the following order: LA > DA > BA > HA. The hydrolytic degradation rate traced by DP and weight loss at 80 °C decreased in the following order: PLA > PDA > PHA > PBA and that monitored by DP at 37 °C decreased in the following order: PLA > PDA > PBA > PHA. LA and PLA had the highest reactivity during polymerization and hydrolytic degradation rate, respectively, and were followed by DA and PDA. BA, HA, PBA, and PHA had the lowest reactivity during polymerization and hydrolytic degradation rate. The findings of the present study strongly suggest that inter-chain interactions play a major role in the reactivity of non-substituted and substituted LA monomers and degradation rate of the non-substituted and substituted PLA, along with steric hindrance of the side chains as can be expected.

The molecular weight and comonomer type are crucial parameters for determining the hydrolytic degradation rate and mechanism of poly(lactic acid) [7]. The hydrolytic degradation rate has been found to increase by decreasing the molecular weight and to decrease by incorporating a hydrophilic comonomer.
Interestingly, PDLA is reported to have a stronger interaction with the L-form of phenyl-substituted PLA than with the D-form [55]. However, in spite of numerous studies on the hydrolytic degradation behavior of PLA and PGA and their copolymers [7], few reports can be found for other P(2HB)s. Reported examples for P(2HB) are those of enzymatic and nonenzymatic degradation of poly(lactic acid-co-mandelic acid or phenyllactic acid), which are copolymers with lactic acid units, methyl groups of which are substituted with aromatic groups [56][57][58]. To the best of our knowledge, no report on hydrolytic degradation of PLA homopolymers, methyl groups of which are substituted with other aliphatic groups, has been published so far. In the present study, we synthesized PLA homopolymers, the methyl groups of which are substituted with other aliphatic groups, such as ethyl, butyl, or octyl groups, as well as non-substituted PLA homopolymer ( Figure 1) by a conventional polycondensation method and investigated the hydrolytic degradation behavior of the substituted and non-substituted PLA homopolymers. Here, we used racemic DL-monomers to obtain noncrystallizable substituted and non-substituted PLA homopolymers to exclude the effects of highly ordered structures formed by crystallization during specimen preparation and hydrolytic degradation on hydrolytic degradation behavior.

Materials
Substituted and non-substituted PLA polymers were synthesized by polycondensation or step-growth polymerization of DL-lactic acid (abbreviated as LA, Wako Pure Chemical Industries, Ltd., Tokyo, Japan), DL-2-hydroxybutanoic acid (butyric acid or BA) (Tokyo Chemical Industry Co., Ltd.,  [51,52]. For the synthesis of polymers having number-average molecular weight (M n ) of several thousands for hydrolytic degradation experiments, the second polymerization step was carried out for 24 h. The synthesized polymers from BA, HA, and DA (PBA, PHA, and PDA, respectively) were purified with precipitation with chloroform and methanol/water (v/v = 1/1) as a solvent and non-solvent. The synthesized polymer from LA (PLA) was purified by the same procedure, although acetone was used as the solvent instead of chloroform. The precipitated polymers were dried under reduced pressure for at least 7 days. The purified PLA was a fragile solid, whereas PBA, PHA, and PDA were highly viscous liquids.

Hydrolytic Degradation
Hydrolytic degradation of each sample (20 mg) was performed using the purified polymers in 100 mL of phosphate-buffered solution (pH 7.4) at 80 °C or 37 °C. After hydrolytic degradation, the samples were rinsed with fresh distilled water, soaked in fresh distilled water for 1 h, soaked for another 3 h in a new batch of fresh distilled water, and then dried under reduced pressure for at least 7 days. Although the polymerization and hydrolytic degradation were performed once in the present study, the subsequent investigations indicated similar dependences of the rates of polymerization [at fixed catalyst concentrations (mol%) and under atmospheric pressure] and hydrolytic degradation on the monomer type.

Measurements
The respective weight and number-average molecular weights (M w and M n , respectively) of polymers were evaluated in chloroform at 40 °C by a Tosoh (Tokyo, Japan) GPC system with two TSK gel columns (GMH XL ) using polystyrene standards. Therefore, the molecular weights are relative to polystyrene.

Synthesis
In the first polymerization step, each monomer was polymerized by polycondensation to yield its oligomers at 130 °C at atmospheric pressure for 5 h to have a sufficiently high molecular weight not to be removed under reduced pressure in the second polymerization step. In the second polymerization step, thus formed oligomers were further polymerized by polycondensation under reduced pressure at 130 °C for 24 h [50,51]. Figure 2 shows the changes in molecular weight distribution curves of PLA, PBA, PHA, and PDA during the second polymerization under reduced pressure. As seen, whole curves shifted to a higher molecular weight with the second polymerization. Table 1 and Figure 3 show are DP before and after polymerization, respectively, and DP b for the first polymerization step is one.
As seen in Table 1 and Figure 3, the DP and DP a − DP b of polymers after the first polymerization step    3.05 13.7 9.8 (13.7-3.9) a) M n and M w are the number-and weight-average molecular weights, respectively. b) DP b and DP a are DP before and after polymerization, respectively. The actual calculation is shown in the parentheses.        Table 2 and Figure 6 show M n , DP estimated from M n , and molecular weight distribution (M w /M n ) of PLA, PBA, PHA, and PDA during hydrolytic degradation. The degradation rate was calculated according to the following equation [59]:

Hydrolytic Degradation at 80 °C
where DP(t 2 ) and DP(t 1 ) are DP values at degradation times of t 2 and t 1 , respectively.       Weight loss (%) Figure 8 shows the molecular weight distribution curves of PLA, PBA, PHA, and PDA before hydrolytic degradation (0 day) and after hydrolytic degradation at 37 °C for 28 days. Figure 9

Discussion
The hydrolytic degradation rate is known to vary with molecular and highly ordered structures and material shapes [1][2][3][4][5][6][7]60]. In the present study, amorphous poly(DL-2-hydroxyalkanoic acid)s were used to eliminate the effects of highly ordered structures such as crystallinity. The molecular weight, the structures of terminal groups, and material shape are crucial for the hydrolytic degradation [60]. All the poly(DL-2-hydroxyalkanoic acid)s were synthesized by the same method and, therefore, the structures of terminal groups should be identical. For precise comparisons of the hydrolytic degradation rates of although the highest hydrophobicity of PDA with the longest octyl side groups may help in the removal of water molecules during polymerization but disturbs the approach of water molecules during hydrolytic degradation. As stated in a review article [60], hydrophilicity and inter-chain interactions, which can be monitored by water absorption and glass transition temperature, will affect the rates of polymerization and hydrolytic degradation. However, these two indicators could not be measured in the present study due to the low molecular weights of the synthesized polymers. Further detailed studies using the polymers with high and similar molecular weights are required to investigate exact causes for the different reactivities of polymers.

Conclusions
The reactivity of monomers during polycondensation monitored by DP decreased in the following order: LA > DA > BA > HA, whereas the hydrolytic degradation rate traced by DP and weight loss at 80 °C decreased in the following order: PLA > PDA > PHA > PBA and that monitored by DP at 37 °C decreased in the following order: PLA > PDA > PBA > PHA. LA and PLA had the highest reactivity during polymerization and degradation rate, respectively, followed by DA and PDA; BA, HA, PBA, and PHA had the lowest reactivity and degradation rates. The findings of the present study strongly suggest that not only the steric hindrance of the side chains but also the inter-chain interaction determine the reactivity of the non-substituted and substituted LA monomers and the hydrolytic degradation rate of the non-substituted and substituted PLA.