Copolymerization of 2-hydroxyethyl acrylate and 2-hydroxyethyl

1. Copolymerization of 2-hydroxyethyl acrylate and 2-hydroxyethyl methacrylate: Controlling the water content of hydrogels Alfonso Ramirez and W. Tandy Grubbs, Stetson University, Department of Chemistry, Unit 8271, DeLand, FL 32720, wgrubbs@stetson.edu Introduction Results Results (continued) Results (continued) Hydrogels are polymer that are insoluble in aqueous solution, yet they are capable of absorbing large amounts of water.1 Hydrogels can be found in many consumer products; disposable diapers, incontinence pads, and bandages. More recently, hydrogels are finding use in a medical applications.2 In particular, hydrogels based upon 2-hydroxyethyl methacrylate (HEMA) have been found to exhibit remarkable biocompatibility; HEMA is used to make commercial soft contact lenses and has been studied as an artificial tissue. Controlled drug delivery represents one of the more promising fields of application for HEMA hydrogels. The ability of water to permeate, diffuse through the hydrated gels, and carry away an imbedded drug has been demonstrated in several case studies.3-5 Widespread application of HEMA hydrogels as drug delivery vehicles has not be realized because of mechanical instabilities that arises during water absorption.6,7 Attempts to enhance the mechanical stability of these systems by incorporating various cross-linkers in the polymer formulation have led to an undesired decrease in water absorption.6,7 An alternate approach to preparing HEMA based hydrogels with controlled water absorption tendencies is presented here. HEMA is randomly copolymerized with 2-hydroxyethyl acrylate (HEA) – the monomers associated with this work are shown in Figure 1. Alone, the HEA homopolymer exhibits a much higher tendency to absorb water; the percentage water absorption of HEA is nearly 600% in comparison to HEMA homopolymer which exhibits 84% water absorption. To perform quantitative FTIR analysis on a copolymer formulation, one must first identify an absorption peak that is distinct to one homopolymer (preferably at wavenumbers higher than 1000 cm-1) which has an isosbestic point to each side. An inspection of Figure 4 reveals that the C-H deformation peak at 1484 cm-1 is amenable to such analysis (the region around this peak is illustrated in Figure 5). This peak is due to the –CH3 group in HEMA. Integration of the area under this peak between 1456 cm-1 and 1515 cm-1 and subtraction of the baseline absorption of poly-HEA in this region yielded the mole fraction of HEMA in each copolymer. The 100% anhydrous HEMA homopolymer is highly brittle, whereas the 100% HEA homopolymer is elastic and sticky to touch. The mechanical properties of the copolymers vary between these two extremes. The mechanical stability of the hydrogels decreases upon swelling in water, and the degradation is more pronounced as the percentage HEA in the copolymer increases. Results from the percentage water absorption measurements for the five hydrogels are illustrated in Figure 2, revealing a marked increase in water absorption as increasing amounts of HEA are incorporated into the polymer. After drying these copolymer formulations in a vacuum oven, they are difficult to re-dissolve in standard solvents (the samples remain insoluble even after sonication at elevated temperatures in DMF or DMSO). Consequently, attempts to characterize the copolymer composition of these polymers by traditional solution-phase NMR and IR methods have not been successful. We have had some preliminary success in recording infrared spectra of these formulations by mounting a small amount of dry polymer (or copolymer) against an attenuated total reflection (ATR) sampling crystal (purchased from PIKE Technologies). The PIKE MIRacleTM ATR sampling attachment is illustrated below in Figure 3. Since the HEMA and HEA monomers only differ structurally by a –CH3 group (see Figure 1), the IR spectra are only expected to exhibit substantial spectral differences in the C-H stretching and deformation regions (Illustrated in Figures 4 and 5). Figure 5: Expanded view of the C-H deformation region. The peak at 1484 cm-1 arises from the –CH3 group in HEMA. Figure 2: Percentage water absorption as a function of percentage of 2-hydroxyethyl acrylate monomer in the polymer. Error bars are standard deviations based upon at least 3 trials. The relative amounts of HEMA/HEA were determined by quantitative ATR-FTIR measurements, discussed below. Conclusion Figure 3: The MIRacle ATR-FTIR sampling attachment – purchased from PIKE Technologies (www.pike.com).. Figure 1: 2-hydroxyethyl methacrylate (HEMA) and 2-hydroxyethyl acrylate (HEA) monomers ________________________________________________________ The percent water in most biological tissues is approximately 80%, in line with the 84% value measured here for the HEMA homopolymer. The results presented in Figure 1 show that the percent water absorption in HEMA-HEA co-polymers can be tuned upward substantially from the 80% range by incorporating HEA into the formulation. The ability to improve the inherent water absorption tendency of a HEMA system will be important in biological applications where a crosslinker has been utilized to improve the mechanical stability of the swollen gel. Since many crosslinkers are hydrophobic in nature (derivatives of ethylene glycol dimethacrylate are often used), their incorporation in the hydrogel can cause an undesirable decrease in water absorption capability. This undesired effect can be offset by including an appropriate amount of HEA in the crosslinked HEMA hydrogel. Future studies will address this issue. During synthesis, we have noted that the reactivity of the HEA monomer is about three times as fast as the HEMA monomer. Consequently, a 50/50 (by volume) reaction mixture of these monomers will not necessarily give rise to equal molar amounts of the two monomers in the final copolymer. Therefore, some method should be employed to determine the actual monomer composition of the products. A series of HEMA-HEA random copolymers have been prepared and characterized in terms of their water absorption tendencies. Results suggest that this system holds promise as biocompatible hydrogel systems. Future studies will address the effect of adding a crosslinking agent (to improve the mechanical properties of the swollen gel), while maintaining an approximate 80% percent water absorption in the system. Experimental Materials. 2-hydroxyethyl methacrylate (HEMA, 99%, Fluka), 2-hydroxyethyl acrylate (HEA, >97%, Fluka), ,’-azo-bis-isobutryo-nitrile (AIBN, Kodak), tetrahydrofuran (THF, >99%, Aldrich), and dimethylformamide (DMF, 99.8%, Aldrich). Synthesis. Hydrogels were prepared by combining HEMA and HEA in the reaction vessel according to the following percentages of HEMA (by volume): 0, 25, 50, 75, and 100% HEMA. 20 mL of DMF, 15 mL of monomer(s) solution, and 20 mg of AIBN were combined in a sealed flask, the solution was purged with N2 for 5 minutes, and then random polymerization was carried out at 70 C until the reaction mixture became visibly viscous. The polymer was then precipitated in THF, and washed with several fresh volumes of THF. The hydrogels were subsequently dried at 40 C in a vacuum oven for 2 weeks. Characterization. The percentage water absorption was determined by weighing samples before and after soaking the polymer samples in distilled water for 3 days. Infrared spectroscopic investigations were carried out on the dry hydrogels using a Perkin-Elmer Spectrum One FTIR in conjunction with a MIRacleTM attenuated total reflection (ATR) attachment (PIKE Technologies). References 1. Kopecek, J. Nature (London)2002, 417, 388. 2. Nguyen, K. and West, J. Biomaterials 2002, 23, 4307. 3. Qiu, Y. and Park, K. Adv. Drug Delivery Rev. 2001, 46, 125. 4. Brazel, C. and Peppas, N. Polymer1999, 40, 3383. 5. Peppas, N. and Scott, R. Biomaterials1999, 20, 1371. 6. Barnes, A., Corkhill, P. and Tighe, B. Polymer1988, 29, 2191. 7. Mequanint, K. and Sheardown, H. J. Biomater. Sci. Polymer Edn.2005, 16, 1303. Acknowledgements Figure 4: Comparison of ATR-FTIR spectra for the HEMA and HEA homopolymers and the various copolymer formulations. The ATR correction has been applied to these spectra and each has been normalized to the C-O stretching band at 1072 cm-1. This work was funded in part by the National Science foundation (DMR-0215407). Special thanks to Amy Luce who carried out some of the preliminary measurements in the HEMA-HEA system.