(T1230-12-71) pH Impact on the Suspension Capability of Colloidal MCC

Purpose: There are multiple excipients included in a pharmaceutical suspension to ensure a uniform and stable drug product with pleasant taste and mouthfeel. A suspending agent, protective colloid and viscosifier are commonly applied as critical functional components. Colloidal microcrystalline cellulose (cMCC), a co-processed excipient of microcrystalline cellulose and sodium carboxymethyl cellulose (NaCMC), is well established as an effective suspending agent for pharmaceutical suspensions. Because of several key properties and functionalities, cMCC is an ideal suspending aid: it forms a gel-like network, is thixotropic, remains stable over a wide range of temperatures, and provides superior mouthfeel. However, the suspending properties of cMCC may be compromised when a suspension requires a pH lower than 4. Therefore, protective colloids are usually added to maintain the suspending properties of cMCC at low pH. Xanthan and NaCMC have been recommended as most effective protective colloids for cMCC. The objective of this study was to show the proper use of Xanthan and NaCMC as protective colloid for cMCC in a typical low pH pharmaceutical suspension. Avicel® RC-591 was selected to represent cMCC and was combined with GRINDSTED^â Xanthan Clear 80 PRM and/or the NaCMC TEXTURECEL^TM 2000 PA 07. Liquid model suspensions of ibuprofen were prepared and evaluated regarding their rheological properties and stability.

Methods: Table 1 shows the formulation details. For study I, two ibuprofen model suspensions with pH~3.5 were prepared. For study II, three ibuprofen model suspensions with pH~2.7 were prepared. In all formulations, the Avicel® RC-591 water dispersion was activated through in-line high shear at 24000 rpm, followed by the addition of other ingredients under agitation with propeller mixer at 900 rpm. Finally, deionized water was added under agitation to obtain a total volume of 1000 mL. Microscopy analysis was performed on all suspensions using a Nikon Eclipse Ci Microscope to verify uniformity of the suspension. After 24 hours of rest at room temperature, the “set-up” viscosity of each suspension was measured using a Brookfield RVT viscometer. Rheological analysis was also performed with a TA-Instruments DHR3 rheometer using a 50 mm parallel geometry with a 1.8 mm gap size at 20 °C. Rheological and Turbiscan stability tests were utilized to evaluate the suspending performance and stability of the suspensions at pre-determined time points of 24 hours (initial) and after one, two, and four weeks of storage at room temperature (about 25 °C).

Results: In study I, a pH of around 3.5 was set in the ibuprofen model suspensions. F1 contained only Avicel® RC-591, while F2 contained Avicel® RC-591 and TEXTURECEL^TM 2000 PA 07 as protective colloid. The thixotropic profiles (Figure 1) along with other rheological data clearly indicated that the suspension with only Avicel® RC-591 was unstable. Thus, F1 showed flocculation, lost its thixotropic property and possessed an unstable gel-like structure. With addition of TEXTURECEL^TM 2000 PA 07 as protective colloid in F2, the suspension was able to maintain its thixotropic property, gel-like structure, and was also stable during storage for four weeks. In study II, the pH of the ibuprofen model suspensions was lowered further to around 2.7, considered as an extreme low pH condition. F3 contained only Avicel® RC-591. F4 contained Avicel® RC-591 and protective colloid GRINDSTED® Xanthan Clear 80 PRM. F5 contained Avicel® RC-591 and both GRINDSTED® Xanthan Clear 80 PRM and TEXTURECEL^TM 2000 PA 07 at a 50/50 mass ratio. As shown in Figure 2, the global Turbiscan Stability Index (TSI) of F3 was “C”, indicating the suspension with only Avicel® RC-591 was not stable. The addition of Xanthan or combination of Xanthan/NaCMC improved significantly on the stability with a TSI rating “A” for F4 and “B” for F5. Xanthan was proven to be a great protective colloid which is particularly effective at extreme low pH conditions.

Conclusion: Although Avicel® cMCC is a very effective suspending agent that provides stable and strong suspending capability, its functionality may be limited at low pH. Therefore, protective colloids should be added to maintain and improve the suspending properties of Avicel® cMCC at low pH. Depending on the pH of the suspension, either TEXTURECEL^TM NaCMC or/and GRINDSTED® Xanthan PRM can be selected as the protective colloid. Study results indicate that GRINDSTED® Xanthan PRM is more effective than TEXTURECEL^TM NaCMC at extreme low pH environments.


Table 1. Formulation details


Figure 1. Thixotropy of suspensions F1-F2 upon storage


Figure 2. Turbiscan Stability Index of suspensions F3-F5 after storage for 4 weeks