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Rheology

Rheological behavior of hydrogels in depedence on concentration of the polymer and type of neutralizing agent
H.-M. Petri1, S. Popovic2, M. Zirkovic2 1 Gebrder HAAKE GmbH, R. Augusto Farinha 45, 05594-000 So Paulo, Brazil 2 ICN Yugoslavia, Institute, November 29111, 11000 Belgrade, Yugoslavia

Introduction In the development of bioadhesive gel the concentration of the bio(muco)adhesive polymer agent is an important factor for the preformulation. Rheological characteristics of bioadhesives are known to be important contributions to bio(muco)adhesive performance. The strength and duration of adhesive bonds depend on degree of chain entanglement between two viscoelastic gels (hydrogel and mucin) and the type of interaction, influenced by the neutralizing agent, when placed in contact [1]. The purpose of the present work was to investigate the influence of concentration of the hydrogel and of the neutralizing agent on the rheological behavior of the product. Methods High molecular weight components in a polymeric system contribute strongly to rheological properties. The influence of low molecular weight components is normally much less, if they do not have special characteristics:

Creep/Recovery: The creep test is a static method for determining the viscoelastic behavior of a sample. A constant stress is applied to the test material and the resulting strain is measured. Zero shear viscosity and elastic deformation/compliance can be calculated, upon other parameters. Creep tests can be performed to calculate the viscous and elastic components of a viscoelastic sample, and also to simulate real-life controlled stress phenomena such as sedimentation and sagging. Information about e.g. shelf life of products can be obtained. Frequency Sweep: Delivers information about the elastic and viscous behavior of the samples at different frequencies/application speeds without breaking the structures within the sample. For gels results a typical plateau, i.e. only a weak dependence of elastic modulus G and loss modulus G on the frequency. G is a measure for the gel strength. Stress Ramp: For the determination of the breaking point of the gels, there are two different methods which deliver information within reasonable time spans: The first one is the continuous increase of the applied stress with time (stress ramp). Stresses below the break-up of structures of the sample cause

Strong variations of rheological parameters can be achieved with material that changes the mechanism of interactions between the molecules, e.g. agents of different gel forming capacity. To distinguish the influence of polymer concentration and different neutralizing agents, a complete rheological characterization was performed with the samples at 23C:

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V187-E only small deformations. With bigger stresses, the interactions between the molecules are overcome and much higher deformation results. Assuming the validity of the Hookean law below the breaking point, one may evaluate: = G ( = shear stress, G = spring modulus, = deformation) log = log G + log <==> log = - log G + 1*log A double logarithmic plot of (log ) versus (log ) should exhibit a slope of approximately one. Above the breaking point, much steeper slopes are expected. The stress at the transition between the two regions may be interpreted as yield point [2]. Stress Sweep: The second possibility to determine the stability of a gel is the performance of a stress sweep in the oscillation mode. The increase of the stress amplitude applied to the sample leads to a constant storage
Segment type Creep Recovery Frequency Sweep Stress Ramp Stress Sweep Segment Time 5 min 5 min -3 min --

modulus G within the so called linear viscoelastic region and a significant decrease of G for bigger stresses. As the sample is not deformed continuously in one direction, the stress sweep is less destructive in comparison to the stress ramp and therefore the stresses necessary for breaking up the structures are normally slightly bigger.
The creep and recovery tests and the stress ramps were performed within one jobstream to optimize the reproducibility and comparability of the sample preparation. Because of the destruction of the sample with the final determination of the yield stress, the oscillation stress sweep was performed separately. Drying up of the samples during the measurement was avoided by covering the edge with a low viscosity mineral oil which was supposed neither to solve components of the sample nor to have a significant influence on the measurement results. The main items of the procedure are shown in the following table: Table 1: Measurement parameters for the rheological characterization of the hydrogels Specifications shear stress = 10 Pa shear stress = 0 Pa 10 to 0.036 Hz, autostrain = 0.01 5 to 1000 Pa 5 to 1000 Pa, 1 Hz at a constant temperature of 23C ( 0.1C), controlled by a liquid circulator, model F6C25 (Gebr. HAAKE GmbH, Karlsruhe, Germany).

Experimental Instrument The measurements were performed on a controlled stress rheometer RS150 (Gebr. HAAKE GmbH, Karlsruhe, Germany). A parallel plate geometry was used (diameter: 35 mm, gap: 1mm) to perform the measurements with a minimum possible destruction of the samples. The measurements were performed

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Materials Bioadhesive gel agents: Carbopol 934P (Goodrich, USA; comm. avail. carboxy methyl cellulose) Neutralizing agents: triethanolamine TEA, NaOH (USP/NF) Humectant: propylene glycol (USP/NF) Gel Preparation Gels were made by dispersion of 1%, 3% and 6% Carbopol (w/w) in redistilled water while continuously stirring with a rotary stirrer at 750 rpm for 45, 90, and 120 min. At unchanged stirring speed, first propylene glycol (3g/100g of gel) and then the neutralizing agent was added.

Results and Discussion Dependence on the polymer concentration (samples with 1, 3, and 6% Carbopol 934P (samples no. 1, 2, 3)) The influence of the polymer component on the rheological behavior of the gel is clearly shown in all results: With increasing content of the Carbopol component the elastic parts of the gel increases. The creep tests show a considerably smaller elastic deformation of the sample with the highest polymeric content (Fig. 1). The calculated zero shear viscosities increase slightly with Carbopol percentage 6 6 6 (1.31 10 Pas 1.34 10 Pas 2.08 10 Pas) which means that an increasing stability and a longer shelf life could be expected.

Figure 1: Creep and recovery results for different Carbopol concentration The frequency sweep shows the gel-like behavior of G and G [3]. The moduli are nearly independent of frequency. The viscosity increases with the content of

Carbopol as the gel strength (which may be related to G and explained with the number of net points) does (Fig. 2). Figure 2: Frequency sweeps for different Carbopol concentrations

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The stability of the gels develops in the same direction as before: Higher Carbopol concentration means a wider linear viscoelastic range (Fig. 3) and higher yield stress (Fig.4).

Figure 3: Stress sweeps for different Carbopol concentrations

Figure 4: Stress ramps and yield point evaluation for different Carbopol concentrations Dependence on the neutralizing agent (samples no. 6 (TEA), 8 (NaOH); Carbopol concentration 1% Different neutralizing agents can exhibit different gelation mechanisms. The type of interactions within the junction zones (net points) can be different. The diagrams show, that the influence on the rheological parameters is not very strong. The frequency and stress sweeps are practically identical for the two neutralizing agents. On the base of these tests one may assume, that the gel strength is approximately the same and depends only on the polymeric component (Fig. 5).

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Figure 5: Frequency sweeps for different neutralizing agents Nevertheless, the yield stress determination shows differences between the neutralizing agents, the break-up of the structures is influenced by them (Fig. 6).

Figure 6: Stress ramps and yield point evaluation for different neutralizing agents

Figure 7: Creep and recovery test results for different neutralizing agents

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The most signifcant differences can be seen in the creep and recovery tests: The network built up with TEA seems to be the more stable one in terms of shelf life: the elastic deformation is smaller than for NaOH and the zero shear viscosity calculated from the 6 6 creep curves is higher (9 10 Pas 5 10 Pas), which implies a longer shelf life of the product (Fig. 7). Conclusion Rheological characteristics of bioadhesives vary with the concentration of the polymer component and the type of neutralization agent. The network strength and stability increases with the Carbopol concentration. The shelf life does not depend significantly on the polymer concentration. Triethylamine

forms slightly more stable networks with Carbopol than NaOH. The shelf life, nevertheless, is significantly better for TEA, as the higher zero shear viscosity shows. The results of the rheological investigations show the possibility to design ideal hydrogels varying concentration or neutralizing agents of the preformulation. Literature [1] M.D. de Vries, H.E. Bodde, J. Biomed. Mater. Res. 22, 1988: 1023-1032 [2] G. Schramm, A Practical Approach to Rheology and Rheometry, 1994, Gebr. HAAKE GmbH, Karlsruhe, Germany [3] S. Popovic, H.M. Petri, M. Zirkovic, Second Central European Symposium on Pharmaceutical Tecnology, Belgrade, Yugoslavia 1997

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