Thermodynamics of aqueous solutions containing poly (N-isopropylacrylamide) and vitamin C

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Abstract

Using vitamin C as a model drug we focus our attention to the experimental and theoretical investigation of swelling equilibria of ternary system made from water, cross-linked poly (N-isopropylacrylamide) and vitamin C. This contribution aims to the prediction of the amount of drug uptake by the hydrogel using a thermodynamic model and independent experimental information, like the demixing behavior of linear polymer in water and in aqueous vitamin C solutions as well as the solubility of vitamin C in water. As theoretical approach a combination of the Koningsveld–Kleintjens model for the Gibbs energy of mixing and the affine network theory for the elasticity of the gel is applied. The model shows an excellent performance in the prediction of the degree of swelling as function of vitamin C concentration and in the amount of drug in the hydrogel. Only for the calculation of the temperature dependency two parameters must be refitted slightly in order to achieve quantitative agreement with the experimental data. From the experimental point of view some hysteresis effects, growing with increasing vitamin C concentration are found, especially in the transformation range.

Introduction

Hydrogels, because of their low toxicity, good biocompatibility and ability to release the entrapped solutes when dispersed in the aqueous medium, are considered as excellent ‘carriers’ for a variety of pharmacological agents ranging from small molecular weight compounds to macromolecules [1], [2], [3], [4], [5], [6]. Their use for controlled and prolonged drug release systems permits modulation of the drug release, with the release rate of entrapped solute depending on many factors such as chain mobility, cross-linking density, crystallinity degree, swelling degree, drug solubility in the polymer [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. The knowledge of the swelling behavior as well as models for correlating and predicting drug loading are important for the application as controlled drug delivery systems. The properties of a hydrogel are the result of the interplay of intermolecular interactions between the chains of the polymer network and the surrounding liquid and elastic forces acting on the cross-linked polymer chains. For this reason models combining the Gibbs energy of mixing and a network theory are often used to model the swelling behavior (i.e. [12], [13]).

The classical examples for non-ionic hydrogel having hydrophilic groups are hydrogels made from cross-linked poly (N-isopropylacrylamide) (PNIPAM). Hydrogels can be applied for several biomedical purposes [1], [2], [3], [4], [5], [6], i.e. controlled drug delivery systems, wound dressing, coating of biosensors, soft tissue substitution (artificial muscles or blood vessels) and contact lenses.

Linear polymers based on PNIPAM show in water a lower critical solution temperature (LCST) [14]. The occurrence of the LCST determines the temperature dependence of the swelling behavior. Hydrogels made from PNIPAM swell at lower temperature and shrink at higher temperature. For these hydrogels Hirokawa and Tanaka [14] found a discontinuous phase transition close to 305.15 K. The phase transition can be utilized for the release or deliver substances, which have been previously absorbed into the gel, at these specific temperatures. In the literature [3], [15], [16], [17], [18], [19] the application of hydrogels made from PNIPAM for drug delivery purposes was studied, experimentally. Coughlan et al. [17], [18] recognized the important role of the polymer network properties. The investigations included the use in pulsatile drug delivery and the protein delivery (i.e. [19]). Uludag et al. [19] figured out the high potential for retention of therapeutic proteins at an application site, where tissue regeneration is desired. The potential of application of PNIPAM for tissue engineering was also studied in the literature [20], [21], [22], [23], [24], [25], [26], [27].

The swelling behavior of chemically cross-linked PNIPAM in water [28], [29], [30], [31], in solvent mixtures [28], [29], [32], [33], [34], [35], [36], [37] and in salt solutions [38], [39], [40], [41] was studied extensively. Recently [31], the possibility to predict the swelling equilibria of PNIPAM-hydrogels in pure water based on the Koningsveld–Kleintjens model [42] in combination with a network model (affine network model [43] or phantom network model [44]), where the model parameter were obtained by independent experimental data, like demixing behavior of the linear polymer in water, is discussed. The model predicts the swelling behavior as function of the temperature qualitatively correctly, however in order to achieve quantitative agreement with the experimental data, two parameters must be changed slightly [31]. A similar approach, based on a different thermodynamic model, was also suggested in the literature [45], [46], [47].

In order to study the possibility to predict the drug loading by the hydrogel a model drug, namely vitamin C (l-ascorbic acid), is selected. Usually, the drug loading is modeled using correlation equations based on experimental data [48] and not on thermodynamic models. The vitamin C delivery using hydrogels were studied in the literature [49], [50], [51], [52], [53] for different polymers forming the hydrogel.

In this contribution we focus our attention to describing the phase as well as the swelling equilibrium, simultaneously. Emphasis will be given to the loading of hydrogels with water-soluble drugs. In order to reach our goal the influence of temperature and vitamin C concentration on the swelling equilibrium of PNIPAM-hydrogels, on the drug loading and on the phase separation behavior of the network building polymer was investigated experimentally and theoretically. The present work aims to the prediction of vitamin C uptake based on the Koningsveld–Kleintjens model [42] in combination with the affine network theory [43], where the model parameter should be obtained from independent experimental findings, like phase equilibria measurements.

Section snippets

Experimental

The non-ionic, cylindrical PNIPAM-hydrogels used in the work were prepared from N-isopropylacrylamide (NIPAM) acting as monomer, N,N′-methylenbisacrylamide (MBA) acting as cross-linker by radical polymerization. In our investigations we take vitamin C as model drug. Some information about the used chemicals are collected in Table 1.

The preparation of the hydrogels was performed, like suggested by Xu [54] and described in the literature [31]. The obtained hydrogels were characterized by the mass

Swelling behavior

Following Maurer and Prausnitz [12] the phase equilibrium between a liquid phase (I) and a coexisting gel phase (II) can be modeled using the following equations:μiI(T,pI,njI)=μiII(T,pI,njII)+viIIAmVIITwhere T is the absolute temperature, μi the chemical potential of the substance i, pI the pressure of the liquid phase, ni the number of moles of the substance i, viII the molar volume of the substance i in the gel phase, Am the Helmholtz energy of the elastic network and vII the volume of the

Swelling equilibria

In order to study the influence of the third component on the swelling behavior, first the swelling equilibrium is measured as function of temperature at a constant vitamin C concentration in the liquid phase. The experimental results are plotted in Fig. 2. The measurement of the degree of swelling was repeated two times, where the deviation between these experimental results was smaller than 7%.

The hydrogel will shrink significantly over a relatively narrow temperature range and loses its

Conclusion

The aim of this work was to describe the swelling equilibrium in aqueous solution of vitamin C. Therefore, swelling experiments in water and aqueous solutions of vitamin C are performed. A dramatic and sometimes discontinuous volume change can be induced by continuous and small variation of the surrounding conditions such as temperature. The violent change is near its critical point, which is analogous to the lower critical solution temperature of the corresponding polymer solution. For this

Acknowledgment

The authors thank the Max-Buchner Science Foundation for financial support.

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