(T1130-03-15) Investigations on Formulation and Process Effects on Avicel^® RC-591 Rheological Performance in Suspensions

Purpose: Avicel^® RC-591, a co-processed excipient composed of Microcrystalline Cellulose (MCC) and Carboxymethylcellulose Sodium, is also known as dispersible cellulose or colloidal MCC which is widely used in pharmaceutical suspensions as an efficient suspending agent. Suspensions made with colloidal MCC Avicel^® RC-591 possess a unique rheological combination of thixotropy with excellent yield values and low viscosity. The excipient provides advantages of unrivaled suspension stability with good aesthetic qualities such as pourability and accurate dosage. Viscosity, thixotropy and yield stress, are the three key parameters describing a suspension’s rheological flow properties. In the present study, we investigated the effects of formulation and process parameters on Avicel^® RC-591 suspension’s rheological flow properties with a rotational rheometer.

Methods: Development of rheological evaluation methods: A 1.2% Avicel^® RC-591 suspension was prepared with high shear activation process as test sample. All samples were tested after standing for 24 hours, undisturbed. Appropriate rheological evaluation methods were developed with Brookfield DVNext rheometer. Effects of Avicel^® RC-591 concentration. The effects of concentration of Avicel^® RC-591’s on rheological properties were assessed at two levels 1.2%w/v and 1.5%w/v. The suspension samples (600ml) were formulated by a high shear activation process wherein the samples were sheared at 15000rpm for 15minutes with IKA T25 high-shear mixer. Effects of high shear force in activation of Avicel RC^® 591: Two activation process parameters, high shear time and high shear speed, were studied separately. Avicel^® RC-591 suspensions (600ml) 1.2% were activated with different high shear force as per below specifications. 1. 1.5minutes, 10 minutes, 20 minutes and 30 minutes@15000rpm. 2. 10000rpm, 15000rpm and 20000rpm @10 minutes. Effects of addition of polyols: Sorbitol was evaluated as a polyol at 30% (w/v) usage level at two stages of addition, before and after 1.2% Avicel^® RC-591’s activation. Control sample, a 1.2% Avicel^® RC-591 suspension was activated with same process parameters. Effects of protective colloids against low pH and divalent cations on Avicel^® RC-591 suspensions: Two commonly recommended protective colloids sodium carboxymethylcellulose (CMC-Na) and Xanthan gum were added separately after the activation of 1.2% Avicel^® RC-591suspension. Two use levels of protective colloids corresponding to 20% and 30% of Avicel^® RC-591 concentration were studied. The protection potential was assessed as a measure of flocculation by polarizing microscopy to evaluate and rheological performance by a rotational viscometer. The two conditions for evaluation were: 1. Low pH using citric acid monohydrate. 2. Divalent cations introduced by high concentration calcium chloride (90mmol/L)

Results: All the three rheological parameters had an obvious nonlinear rise with the increase of Avicel^® RC-591 concentration (Figure 1). The three rheological parameters decrease with the extension of shearing time and speed (Figure 2). Adding sorbitol decreased the three rheological parameters significantly, especially addition of sorbitol after Avicel^® RC-591 activation (Figure 3). CMC-Na had a better protection than xanthan gum at both low pH and high divalent cation conditions. An interesting finding was that CMC-Na decreased the yield stress.

Conclusion: The present work investigated the influence of Avicel^® RC-591 suspension formulation and process parameters on its rheological performance with a simple cost-saving rheology measurement method. This would facilitate pharmaceutical formulation R&D scientists to explore the efficiency of Avicel^® RC 591 as an efficient suspending agent.

References: 1. Characterisation of the interactive properties of microcrystalline cellulose-carboxymethyl cellulose hydrogels, G.H. Zhao, N. Kapur, B. Carlin, E. Selinger, J.T. Guthrie, International Journal of Pharmaceutics, 415 (2011) 95– 10
2. Rheological characterization of microcrystalline cellulose/sodiumcarboxymethyl cellulose hydrogels using a controlled stress rheometer: part I, Varmas S. Rudraraju, Christy M. Wyandt, International Journal of Pharmaceutics, 292(2005)53-61
3. Rheological characterization of microcrystalline cellulose/sodiumcarboxymethyl cellulose hydrogels using a controlled stress rheometer: part Ⅱ, Varmas S. Rudraraju, Christy M. Wyandt, International Journal of Pharmaceutics, 292(2005)63-73

Acknowledgements: The authors would like to thank James Du from International Flavors and Fragrances Inc. (IFF) for providing excipient support and technical guidance.


Figure 1: Avicel® RC-591 suspension rheological evaluation at different usage level


Figure 2: Avicel® RC-591 suspension rheological evaluation at different high shear time


Figure 3: Avicel® RC-591 suspension rheological evaluation different addition stage of sorbitol