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Synthesis, characterization, and degradation of biodegradable poly(mannitol citric dicarboxylate) copolyesters.

INTRODUCTION

The synthesis of biodegradable polymers has emerged as an active area of research interest because of its versatile applications ranging from binders in tablets (1) to plastics for packaging (2), (3). Among the biodegradable polymers, the family of aliphatic polyesters has attracted the interest of many researchers (4-7) because of their excellent biocompatibility, biodegradahility, good thermal, and mechanical properties. The potential applications of such polymers are in drug delivery (8), tissue engineering (9) and are used as bone replacement materials (10), vascular stents (11), sutures and wound dressing (12), (13).

Recently, several polyesters based on diols and carboxylic acids such as poly(l,4-butanediol succinate) (14), poly( 1,3-propylene adipate) (15), poly(ethylene glycol-co-sebacate) (16) have been synthesized and characterized. However, most of these polyesters suffer from poor mechanical or degradation properties. Furthermore, the inability of these polyesters to form to a three-dimensional cross-linked network has hindered their applications. Several efforts have been made in synthesizing new classes of polyesters with versatile properties. For example, poly(l,8-octanediol-co-citrate) (17) and poly(polyol sebacate) (18) were synthesized via melt condensation process. The properties of these polymers can be controlled by tuning the monomer stoichiometry and by adjusting the curing conditions. However, the main disadvantage is the requirement of high temperatures and vacuum for curing the prepolymer. Furthermore, their prolonged degradation time of more than few months hampers their applicability as drug releasing carriers.

In the present work, we have attempted to synthesize a new class of poly(mannitol citric dicarboxylate) [p(MCD)] copolyesters from mannitol, citric acid (CA), and dicarboxylic acids (DAs) such as succinic acid, adipic acid, and sebacic acid. These particular monomers were chosen, because they are inexpensive, nontoxic, and are biocompatible. Thus, we believe that the polymers synthesized from these polymers are also likely to be biocompatible. Furthermore, these polymers have the ability to form well-defined cross-linked 3-D structures, and the final properties of p(MCD) copolymers can be tuned by selecting appropriate monomers and their stoichiometry.

To the best of our knowledge, there is no report on the synthesis and characterization of p(MCD) copolyesters. Thus, the main objective of the work was to synthesize p(MCD) copolyesters by melt condensation under mild conditions without any toxic catalyst. The other objective of the work was to investigate the effect of monomer ratios and the substitution of different DAs on the mechanical, thermal, and the degradation properties of the polymers. The final objective of the study to evaluate the drug-release capabilities of these polymers.

MATERIALS AND METHODS

Materials

Mannitol [molecular weight ([M.sub.w]) = 182.17 g [mol.sup.-1], melting temperature ([T.sub.m]) = 165[degrees]C], CA ([M.sub.w] = 192.12 g [mol.sup.-1], [T.sub.m] = 153[degrees]C), sebacic acid (SA; [M.sub.w] = 202.25 g [mol.sup.-1], [T.sub.m] = 135[degrees]C), adipic acid (AA; [M.sub.w] = 146.14 g [mol.sup.-1], [T.sub.m] = 151[degrees]C), and succinic acid (SuA; [M.sub.w] = 118.1 g [mol.sup.-1] [T.sub.m] = 185[degrees]C) were purchased from Sigma-Aldrich and used without any further purification. Solvents 1, 4-dioxane, ethanol, and DMSO-[d.sub.6], and phosphate buffer pellets were purchased from S.D. Fine Chemicals (India). The dyes, rhodamine B (RB), and Orange G (OG) were obtained from Rolex labs (India).

Synthesis and Characterization of Polymers

The synthesis of p(MCD) polymers was carried out by catalyst-free melt-condensation technique (18). Briefly, appropriate amounts of the monomers, as given in Table 1, were taken in a 250-ml three-necked round-bottomed flask maintained at 150[degrees]C. Because succinic acid has a higher melting temperature, the reaction temperature was kept at 180[degrees]C for the synthesis of (MCSu) polymers. The melted monomers were mixed for 1 h under constant supply of nitrogen gas to produce prepolymers as shown in Fig. 1. The resulting prepolymers were then purified by dissolving them in 1,4-dioxane followed by precipitation in double-distilled water. This was then dried under nitrogen atmosphere, and the yield of the reaction was calculated gravimetrically by measuring the weight of the prepoly-mer sample before and after the purification. It was found that the yield is ~75% for all reaction compositions. The prepolymers were then transferred into Teflon petridish to form polymer sheets of ~2~mm thickness. These sheets were kept in oven at 80[degrees]C for 7 days for postpolymerization of the polymers.

[FIGURE 1 OMITTED]
TABLE 1. Composition-thermal, and mechanical properties of the p(MCD)
copolyesters.

          Composition

Polymer       Feed          (1) H       [T.sub.g]     [T.sub.m]
                             NMR     ([degrees])C  ([degrees])C

p(MCS)1       1:1:0.5   1:0.71:0.48          30.5         108.2
p(MCS)2         1:1:1   1:0.72:0.75          29.6         112.5
p(MCS)3       1:1:1.5   1:0.85:1.45          22.1         119.8
p(MCS)4         1:1:2  J: 0.86:1.88          16.5         120.2
p(MCA)1       1:1:0.5   1:0.78:0.51          31.1         114.5
p(MCA)2         1:1:1   1:0.86:0.92          41.8         120.2
p(MCA)3       1:1:1.5   1:0.72:1.44          28.5         122.1
p(MCA)4         1:1:2   1:0.84:2.10          18.5         128.7
p(MCSu)1      1:1:0.5   1.0.89:0.41          36.1         125.5
p(MCSu)2        1:1:1   1:0.72:0.85          58.5         130.7
p(MCSu)3      1:1:1.5   1:0.89:1.21          34.8         132.4
p(MCSu)4        1:1:2   1:0.92:1.62          24.1         137.8

Polymer         E               TS               %
              (MPa)           (MPa)        Elongation

p(MCS)1            53.23           2.60          102.2
          [+ or -] 12.34  [+ or -] 0.51  [+ or -] 16.2

p(MCS)2           193.10           9.78           72.5
          [+ or -] 32.12  [+ or -] 1.23   [+ or -]11.2

p(MCS)3           370.41           8.56           35.8
          [+ or -] 37.84  [+ or -] 0.75   [+ or -] 5.2

p(MCS)4           660.23          12.52           14.2
          [+ or -] 54.20  [+ or -] 2.13   [+ or -] 3.2

p(MCA)1            23.21           2.31           82.3
           [+ or -] 4.21  [+ or -] 0.24   [+ or -]11.2

p(MCA)2            38.48           2.85           65.1
           [+ or -] 6.84  [+ or -] 0.85  [+ or -] 15.2

p(MCA)3            32.44           3.21           71.2
           [+ or -] 8.21  [+ or -] 0.41  [+ or -] 12.5

p(MCA)4            30.21           2.95          101.6
           [+ or -] 4.52   [+ or -]0.14  [+ or -] 21.2

p(MCSu)1           10.25           1.01          140.5
           [+ or -] 5.25  [+ or -] 0.12  [+ or -] 25.2

p(MCSu)2            8.25           2.03          105.2
          [+ or -] 12.21  [+ or -] 0.65  [+ or -] 32.1

p(MCSu)3           24.25           2.25          128.5
           [+ or -] 6.25  [+ or -] 0.38  [+ or -] 28.7

p(MCSu)4           12.25           1.20          180.7
           [+ or -] 4.74  [+ or -] 0.12  [+ or -] 15.4


FTIR Spectroscopy Analysis

The FTIR analysis of the synthesized polymer networks was performed using the FTIR (Perkin Elmer) spectrophotometer. Thin films (<1 mm) of polymers were prepared by dissolving the prepolymer samples in 1,4-dioxane (20% w/w) followed by casting into Teflon pet-ridish and solvent evaporation. These thin films were placed on the KBr crystal and scanned over the range of 4500-500 [cm.sup.-1].

NMR Spectroscopic Analysis

(1) H NMR spectra of purified polymer samples were obtained using a Bruker NMR spectroscopy operating at 400 MHz. DMSO-[d.sub.6] was used as the solvent, and TMS was used as the internal reference.

Differential Scanning Calorimetry Analysis

Thermal properties of the polymer like glass transition temperature ([T.sub.g]) and melting temperature ([T.sub.m]) were determined using a differential scanning calorimeter, [DSC823.sup.e] (Mettler Toledo, USA) at a heating rate of 2[degrees]C/ min operating in nitrogen environment. About 5-10 mg of the sample was taken, and the thermograms were recorded between -50 and 200[degrees]C. The glass transition temperatures of the polymers were determined from the inflection point of the thermogram of second heating run.

Mechanical Properties

Tensile tests were carried on dog-bone-shaped polymer strips of the p(MCD) polymers of different composition. Polymer strips were prepared according to ASTM standard D638 (35 X 4 X 2 mm, length X width X thickness), and samples were pulled at a strain rate of 10 mm/min using Universal Testing Machine (S. C. Dey Co., India) attached with 500 N load cell and data acquisition software. All studies were run in triplicate for each polymer synthesized.

Hydrolytic Degradation

The hydrolytic degradation of the p(MCD) polymers was investigated by incubating disc-shaped polymer samples (10 mm in diameter and 2 mm thick) in phosphate buffer solution (PBS) of pH = 7.4 at 37[degrees]C. Samples were taken at regular intervals washed with water followed by incubation in ethanol and drying to constant weight. Incubation in ethanol ensures complete displacement of water from the polymer discs. The spectra taken before and after the immersion in ethanol indicated no change confirming that no alcoholysis occurred.

The extent of degradation was calculated from the initial weight ([W.sub.0]) and the weight at time t ([W.sub.t]) of the polymer sample using the following equation.

% degradation = [W.sub.0] - [W.sub.t]/[W.sub.0] X 100

To investigate the effect of pH on the degradation of the p(MCD) polymers, discs were incubated in the solutions of pH of 5.5, 6.8, and 13. The same procedure was used to determine the extent of degradation.

Evaluation ofp(MCD) Copolyesters as Drug-Delivery Carriers

The applicability of p(MCD) polymers as drug-releasing carriers was evaluated by studying the releasing characteristics from the dye (RB and Orange G)-loaded polymer networks. The prepolymers were dissolved in 1,4-dioxane (20%w/v), and dye (5 wt% of the polymer) was added to polymer solution. The resulting polymer/dye solution was casted into thin sheets using Teflon Petridis and kept in an oven maintained at 80[degrees]C for 7 days. To view the effect of degree of cross linking on the release characteristics, the dye-loaded p(MCSu) sheets were cured at 100[degrees]C and 10 Pa for 1, 2, and 3 days. Discs (10 mm X 1 mm) were punched from polymer/dye composite sheet, and ~200 mg of the discs was wrapped with a nylon mesh and then submerged in the beaker containing 500 ml of 0.1 M PBS (pH = 7.4) maintained at 37[degrees]C. The solution was agitated at 100 rpm, and care was taken to prevent the evaporation of solution. At particular times, samples were withdrawn and analyzed using a Shimadzu UV-1700 UV-vis spectrophotometer. The characteristic wavelengths are 554 nm for RB and 480 nm for acid Orange G. The mass of the dye released was determined from a calibration based on Beer-Lambert law. All studies were carried out in triplicate for each of the polymer that was synthesized.

RESULTS AND DISCUSSION

Synthesis and Characterization of the Polymers

All p(MCD) copolyesters were synthesized by melt condensation of monomers based on the schematic represented in Fig. 1. Based on the monomers used for the reaction, the polymers were categorized into three groups namely, poly(mannitol citric succinate) [p(MCSu)], poly (mannitol citric adipate) [p(MCA)], and poly(mannitol citric sebacate) [p(MCS)]. Several compositions of p(MCD) polymers were synthesized (see Table 1).

Figure 2 shows the FTIR spectra of representative p(MCD) polymers. A strong absorbance peak at 1740 [cm.sup.-1] corresponding to ester groups (C=0) (14) confirms the formation of polyesters. The peaks centered at 2854-2969 [cm.sup.-1] were assigned to methylene (--C[H.sub.2]--) groups (14), (19) for the DAs and observed in all the spectra of p(MCD) copolyesters. The broad stretch at 3475 [cm.sup.-1] was attributed to the stretching vibration of the hydrogen-bonded carboxyl and hydroxy! groups (20). The unreacted carboxyl groups from CA, SA, AA, and SuA were observed at 1300 [cm.sup.-1] (21).

[FIGURE 2 OMITTED]

The compositions of all the synthesized polymers were determined from (1) H NMR spectra. Figure 3a-c depicts the (1) H NMR spectra of representative p(MCD) polymers p(MCS)2, p(MCA)2, and p(MCSu)2, respectively. The peaks from the mannitol appeared at 3.5-5.5 ppm (17) due to central and terminal methylene units. The multiple peaks around at 2.8 ppm (22) were attributed to the proton in the - C[H.sub.2]-- group from CA. The protons from methylene units of DA showed peaks at 1.3, 1.6, and 2.3 ppm (23) depending upon the presence of SA/AA/SuA. The compositions of the p(MCD) polymers were computed from the peak integrals of corresponding monomers.

DSC Analysis

The DSC analysis of all the synthesized polymers was carried out to obtain the thermal properties such as [T.sub.g] and [T.sub.m], as shown in Table 1. The thermograms of the second heating run of the representative p(MCD) polymers are shown in Fig. 4. It can be observed that the glass transition temperature of the polymers follows the order: p(MCS) < p(MCA) < p(MCSu). This can be attributed the number of methylene (--C[H.sub.2]--) units from SA (n = 8), AA (n = 4), and SuA (n = 2), where n is the number of methylene units. As the number of methylene units increases, the [T.sub.g] decreases due to increased chain/segment mobility. Therefore, the [T.sub.g] of p(MCS) polymers decreased with the increase in the SA content. It was hypothesized that all the condensable functional groups in the monomers reacted completely if the monomers were reacted in 1:1:1 ratio. However, in other cases, some amount of unreacted hydroxyl and carboxyl groups is present in the polymer, and this hypothesis is supported by FTIR studies. The presence of these unreacted pendant groups increases the free volume resulting in the decrease of glass transition temperature (24). Therefore, the [T.sub.g] of p(MCA) and p(MCSu) polymers was lower compared to p(MCA)2 and p(MCSu)2, respectively.

[FIGURE 4 OMITTED]

Mechanical Properties

The results of the tensile testing of the p(MCD) polymers are summarized in Table 1. The Young's modulus (E) of the polymers ranges from 10.25 [+ or -] 5.25 MPa to 660.23 [+ or -] 54.20 MPa with tensile strength (TS) ranging from 1.01 [+ or -] 0.12 MPa to 12.52 [+ or -]2.13 MPa. The %elon-gation at break varies between 14.2 [+ or -] 3.2 and 140.7 [+ or -] 15.4. Figure 5 depicts the typical stress-strain curves of the synthesized p(MCD) polymers. Based on the Young's modulus, the polymers were categorized into two groups as shown in Fig. 5a and b. It can be observed that among the three DA-based copolymers, sebacic acid based copolymers show higher Young's modulus and TS. Furthermore, the Young's modulus and TS of the p(MCS) polymers increased with sebacic acid content mainly due to increased intermolecular bonding resulting from close packing of SA units in the polymer matrix. A similar trend was reported for the mechanical properties of PPS (18), and POCS (25) polymers. The Young's modulus and TS of p(MCA)2 and p(MCSu)2 polymers were observed to be higher than other polymers in the respective group. This can be attributed to the presence of unreacted hydroxyl and carboxyl groups in the polymer that tend to decrease the strength of intermolecular bonding, thereby decreasing the Young's modulus and TS.

[FIGURE 5 OMITTED]

It is evident from the tensile testing results that the mechanical properties of the p(MCD) polymers can be controlled simply either by changing the composition or substituting different dicarboxylic units. It is also evident that the p(MCD) polymers cover a wide range of mechanical properties that can be useful for a variety of biomedical application. For example, the Young's modulus of cancellous bone and cortical bone is 50-100 MPa and 17-20 GPa (26), respectively. This indicates the potential use of p(MCS) polymers for bone tissue engineering and orthopedic applications. Similarly, the p(MCA) and p(MCSu) polymers exhibit the mechanical properties comparable with that of different tissues such as skin (27), cartilage (28) cardiovascular tissue (27), and, therefore, could be potentially developed for soft tissue-engineering applications.

Hydrolytic Degradation

The biodegradability of the synthesized copolyesters was assessed by performing hydrolytic degradation tests in PBS (pH = 7.4) at 37[degrees]C and monitoring the weight loss of the samples. Figure 6a-c represents the hydrolytic degradation profiles of the p(MCS), p(MCA), and p(MCSu) copolyesters, respectively. The half-life of the polymers was plotted as a function of ratio of DA to CA (see Fig. 7) to compare the extent of biodegradability of the polymers within and among the groups. It can be observed that among the three groups, p(MCS) polymers were degraded at much slower rate compared to p(MCSu) and p(MCA). And at any given copolyester composition, the extent of biodegradability follows the order: p(MCSu) > p(MCA) > p(MCS), which is consistent with the number of methylene units in the dicarboxylic unit. It is widely known that resistance to the penetration water molecules into the vicinities of ester bonds increases with the presence of more hydrophobic methylene units in the polymer chain (18), (25), This indicates that the order of the rate of degradation of these polymers is consistent with previous studies. The half-life of the p(MCS) polymers increased with SA content, whereas the half-life was maximum for p(MCA)2, and p(MCSu)2 in case of p(MCA) and p(MCSu) polymers,. This can be attributed to decrease in the crystallinity due of the presence of unreacted pendant carboxyl, hydroxyl groups, and the catalytic effect of the carboxyl group.

[FIGURE 6 OMITTED]

[FIGURE 7 OMITTED]

Poly(lactic acid) (PLA) and poly(glycolic acid) (PGA) and their copolymers have been extensively used as bio-materials because of their excellent biocompatibility and variable degradability. The degradation rates and the physical/chemical properties of the material can be varied by adjusting the chirality of the lactic acid units (29-31). The degradation is catalyzed by the carboxyl end groups formed by chain cleavage (32), (33). Carboxylic acid functionality significantly increased the hydrolytic degradation rate in poly(D.L-lactide) polymers (34) and in polyhydroxy-alkanoates (35).

The effect of pH on the hydrolytic degradation of p(MCD) polymers was investigated by degrading representative polymer samples from each group in solutions of pH 5.5, 6.8, and 13, and the degradation profiles are shown in Fig. 8. It can be observed that the degradation of polymers increases with the pH of the solution mainly due to increased cleavage of ester bonds by the OH[TM] ions. Thus, hydrolytic cleavage seems to be favored in the basic media. In case of polymers like PLA, PGA, and their copolymers, increased degradation is observed in acidic media(29), (30) while in case of polyesters like poly(polyol sebacates) (18) and poly(diol citrates) (17), the degradation is favored in the basic media. The extent of degradation increased with pH, but the order of degradability remained the same, that is, p(MCSu)2 > p(MCA)2 > p(MCS).

[FIGURE 8 OMITTED]

Evaluation of p(MCD) Copolyesters as Drug-Delivery Carriers

The representative polymers p(MCS)2, p(MCA)2, and p(MCSu)2 were chosen to investigate the drug release characteristics of the p(MCD) copolyesters. The release experiments were conducted with two model compounds (dyes), RB and Orange G (OG) with nearly the same molecular weight (MW). These were RB (MW = 442.5 g/ mol, solubility in water = 1 mg/ml) and Orange G (MW = 452.38 g/mol, solubility in water = 103.6 mg/ml), which are hydrophobic and hydrophilic model compounds, respectively. The structurally important features of the dyes are that RB is cationic and has tertiary diamines, while Orange G is anionic and has the sulfonic acid moiety. These ionizable groups have a large impact on the intrapolymer matrix environmental pH, which will dictate the solubility of the monomer, which is a primary factor in the erosion of the polymer.

The release profile of RB and OG from the polymer discs is shown in Fig. 9a-c. The release of the two dyes from p(MCA)2 and p(MCSu)2 was almost complete within a few hours, while the release of the dyes from p(MCS)2 occurred over days. The release profiles of RB and OG from the polymer matrices can be attributed to many factors such as polymer-dye interactions, solubility of the compounds in the degradation medium, intrapoly-mer pH, and water ingression into polymer matrix (36). Because of the hydrophobic nature, RB would be expected to be more soluble in hydrophobic p(MCA)2 and p(MCS)2 than OG. Consequently, a rapid release of OG and nearly linear release of RB was observed. Similar results were obtained in the case of release of RB and acid Orange 8 from polyanhydrides (29), wherein a complete initial burst of acid Orange 8 was observed while a linear release of RB was observed. In contrast, slower release of OG compared to RB was observed from p(MCSu)2, this can be explained by hypothesizing that the release of RB increases the intrapolymer pH, which enhanced the degradation of polymer.

[FIGURE 9 OMITTED]

Figure 10 shows the effect of degree of crosslinking of p(MCSu)2 on the release of RB. The increase in the curing time significantly lowered the release rate of the RB mainly due to increased resistance to water penetration into the polymer matrix. From the results of the dye-release experiments, it can be observed that the release of the compounds can be effectively controlled by appropriately choosing the polymer or by adjusting the curing conditions. Therefore, the p(MCD) polymers could be expected to useful for rapid delivery as well as sustained release of the drugs.

[FIGURE 10 OMITTED]

CONCLUSIONS

The synthesis and characterization of three different p(MCD) copolyesters, namely, p(MCS), p(MSA), and p(MCSu) of various compositions were carried out, The effect of monomer and stoichiometry of the monomers on the mechanical, thermal, and degradation properties was investigated. Among the p(MCD) polymers, p(MCS) polymers were found to have better mechanical properties compared to the p(MCA) and p(MCSu) polymers of the same composition. The hydrolytic degradation of the polymers follows the order: p(MCSu) > p(MCA) > p(MCSu), and this order was attributed to the number of hydrophobic methylene units. The p(MCD) polymers were evaluated for their applicability as drug-delivery carriers and found to have versatile drug-delivery characteristics. The low cost of the monomers, ease of synthesis, and the tunable properties of p(MCD) make them suitable for a wide range of biomedical applications.

ACKNOWLEDGMENTS

The corresponding author thanks the Department of Science and Technology, India for the Swarnajayanthi Fellowship.

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Sasikiran Pasupuleti, Anusha Avadanam, Giridhar Madras

Department of Chemical Engineering, Indian Institute of Science, Bangalore 560012

Correspondence to: Giridhar Madras; e-mail: giridhar@chemeng.iisc.emet.in

Contract grant sponsor: Department of Biotechnology, India.

DOI 10.1002/pen.21965

Published online in Wiley Online Library (wileyonlinelibrary.com).

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