Incorporation of small quantities of surfactants as a way to improve the rheological and diffusional behavior of carbopol gels

Abstract

This paper analyzes the effects of Tween 80, Pluronic F-127, sodium dodecylsulfate (SDS), and benzalkonium chloride on the macro and microviscosity of Carbopol^® 934NF (0.25–0.50 g/dl) pharmaceutical gels. Carbopol/surfactant interactions, which were reflected in changes in the intrinsic viscosity of the polymer and in shifts of IR spectra bands of films, considerably modified the rheological properties of the gel (flow and oscillatory rheometry) and the diffusion coefficients of polystyrene particles (dynamic light scattering, DLS). At pH 4, any surfactant at a concentration of 0.01 g/dl promoted interpolymer connections producing an open three-dimensional network with maximum viscous and elastic moduli, which does not disturb the diffusive movement of polystyrene particles. An increase in non-ionic surfactant (0.05–0.50 g/dl) gradually decreased viscosity and elasticity since there were more surfactant molecules to surround each carbopol particle, forming intrapolymeric micelles and breaking the interpolymer connections. This macroscopic effect is, however, not reflected in a decrease but in an increase in microviscosity (estimated by DLS) owing to the formation of larger carbopol/surfactant aggregates and free micelles that contribute significantly to the obstruction of the diffusional path. Both ionic surfactants decreased macroviscosity owing to ionic aggregation (benzalkonium chloride) or increase in ionic strength (mainly SDS), while the repercussion on the diffusion of polystyrene particles was dramatically different, and was hindered (due to the carbopol/surfactant aggegates) or enhanced (due to the shrinking of carbopol microgels), respectively. At pH 7.4, the ionization of the carboxylic groups produced an expansion of the polymer chains accompanied by a huge increase in viscosity and elasticity and a decrease in diffusion coefficients in comparison with those obtained at pH 4. The effects of the surfactants were similar to those observed at pH 4 but less intense. Chloramphenicol release studies (Franz–Chien cells) revealed that 0.01 g/dl surfactant did not affect the diffusion while a change in pH dramatically altered the process. The results show that by choosing the appropriate proportion of the most suitable surfactant, it is possible to modulate the flow behavior, elastic properties, and diffusional microenvironment of carbopol gels, without losing the pH-dependent gelling ability, which could improve the suitability of carbopol gels for drug delivery through different routes.

Introduction

Aqueous polymeric dispersions are very useful as platforms in drug delivery since they can resist the physiological stress caused by skin flexion, blinking, and mucociliar movement; adopting the shape of the application area and controlling the drug release [1], [2], [3]. Some of these systems combine gelling in situ behavior with high fluidity at the moment of administration: the low viscosity makes application easy, but later the temperature, pH, or ionic strength conditions of the application site cause its behavior to become viscous [2], [4].

The incorporation of small amounts of surfactants into a polymeric dispersion can dramatically alter the polymer conformation and the viscosity of the dispersion. Aggregation processes can appear as a consequence of hydrophobic interactions between the non-polar surfactant tail and the polymer backbone, electrostatic interactions between the polar heads of the surfactant and the charged groups of the polymer, or both [5]. Usually, the importance of the aggregation effects on the rheological properties of the mixture depends strongly on the relative proportion of both components showing, for a given system, very different and even opposite effects [6]. Surfactants can also greatly modify the responsiveness of temperature-sensitive polymers. These effects were reported for cellulose ethers [7], poloxamer-co-acrylic acid [8], or poly(N-isopropylacrylamide) [9].

The rheological parameters provide information useful for predicting the in vivo behavior of polymer dispersions [10], [11]. However, most of the studies of the influence of surfactants on the rheological properties of liquid or semisolid polymer-based formulations focus on the stability of low polymer concentration suspensions or emulsions, to which surfactants are added as wetting agents or to prevent microbiological growth [12]. There is an important lack of information about the effects of surfactants on the rheological properties of pharmaceutical gels, into which surfactants are frequently incorporated to modulate the drug release rate or promote the drug flux through the cellular membranes [13]. In addition to the effects on the bulk properties of the gel, it is foreseeable that polymer–surfactant interactions dramatically alter the microenvironment in which the solute diffusion occurs. The formation of polymer–surfactant aggregates or free micelles could modify the size of the water-filled regions or the mobility of the polymer chains. A reduction in the gel free volume or an increase in the path length due to obstructions restrict the diffusive movement of the drug and decrease the drug release rate [14]. In polymer dispersions or in surfactant solutions separately, it has been shown that the effects of the polymer concentration or the surfactant [15], [16], [17], [18] on the macroscopic flow properties of the system do not necessarily correlate with the effects on diffusion, which means that it is necessary to take the microviscosity of the medium into account.

Carbopol^® is very useful as a major component of drug delivery gel systems for buccal [19], transdermic [20], ocular [4], rectal [21], and nasal [10] applications. The physical properties of the carbopol gels, the time they remain on the application area, and the drug release rate are extremely sensitive to the presence and concentration of additives [22]. The pH-induced gelling in situ capability and the control of drug release can be improved by addition of cellulose ethers [4] or polyvinylpyrrolidone [23], which causes structural changes that increase viscosity. In two recent papers [24], [25], the influence of some nonionic surfactants on the viscosity of carbopol dispersions was evaluated for high concentrations of Tween 80 and Pluronic F-127, using continuous flow measurements. The shear stress applied can have the important drawback of breaking the aggregates or dissolving the entanglement of the polymer, leading to loss of information about the structure of the systems. Nevertheless, both studies revealed strong changes in the gel strength caused by the surfactants and their important practical repercussions. No references were found regarding the microviscosity of carbopol/surfactant systems.

This paper reports on the analysis of the interactions and the effects exerted by the addition of small amounts of surfactants of different nature and low toxicities [26] (two non-ionic: Tween 80 and Pluronic F-127; and two ionic: sodium dodecylsulfate (SDS) and benzalkonium chloride) on the macro and microrheological properties and pH-responsiveness of Carbopol^® 934 gels. We evaluated the behavior of carbopol-surfactant systems when the polymer is non-ionized (acidic) or completely ionized (neutral conditions). To obtain information about viscous and elastic behavior under shear conditions closer to the physiological, flow viscometry and oscillatory rheometry were used [11], [27], while information about the microstructure of the gels was obtained from probe particle diffusion using dynamic light scattering. Diffusion assays using chloramphenicol, as a model drug, were also carried out. The final aim was to establish what possibilities the incorporation of small quantities of surfactants may offer in the modulation of the rheological and diffusional behavior of the gels with a view to applying them to the different commonly used routes of delivery.