(T1330-11-75) Stabilizing High Salt Content Suspensions with Colloidal Microcrystalline Cellulose and Xanthan

Purpose: Suspension formulations are an important class of pharmaceutical dosage forms. To successfully develop a patient-centric and stable suspension formulation, it is critical to properly select suspending agents that can provide key functionalities. Requirements include a gel-like network to enable uniform dispersion of drug particles and retention of a uniform formulation over extended periods of storage, a thixotropic property to ensure user friendly administration of the suspension, and an optimal viscosity profile for convenient handling, as well as an appealing sensory experience. Colloidal microcrystalline cellulose (cMCC) is a co-processed excipient of microcrystalline cellulose and sodium carboxymethyl cellulose (NaCMC). cMCC exhibits several key properties and functionalities and is an ideal suspending aid. For example, it forms a strong gel-like network, is thixotropic, remains stable over a wide range of temperatures, and provides a pleasant mouthfeel. However, the suspending properties of cMCC may be compromised when a suspension has high salt contents. Therefore, protective colloids are usually added to maintain the suspending properties of cMCC in formulations with high ionic strength. Xanthan has been recommended as the most effective protective colloid for cMCC. The objective of this study was to show the proper use of xanthan as a protective colloid for cMCC in a high salt suspension environment. Avicel® RC-591 was selected to represent cMCC and GRINDSTED^â Xanthan Clear 80 PRM was chosen to represent xanthan. Liquid model suspensions of paracetamol with calcium chloride (CaCl₂) salt were prepared and evaluated in terms of their rheological and stability properties.

Methods: As shown in Table 1, five paracetamol model suspensions were prepared. In formulations F1 to F4, Avicel® RC-591 was the only suspending aid used. CaCl₂ levels were varied from 0% (control) to 1.5%. In formulation F5, which contains the highest level of CaCl₂ (1.5%), GRINDSTED^â Xanthan Clear 80 PRM was added as protective colloidal besides Avicel® RC-591 as suspending aid. To prepare the formulations, a dispersion of Avicel® RC-591 in water was first activated at 24000 rpm using an IKA inline high shear mixer, followed by the addition of other ingredients under agitation with a propeller mixer at 900 rpm. Finally, deionized water was added under agitation to obtain a total volume of 1000 mL. Rheological and stability tests were performed on all samples at pre-determined time points of 24 hours (initial) and after one, two, and four weeks of storage at room temperature (about 25 °C). Rheological properties were analyzed with a TA-Instruments DHR3 rheometer using a 50 mm parallel geometry with a 1.8 mm gap size at 20 °C. Stability of suspensions was monitored using a Turbiscan Lab instrument and reported as so-called Turbiscan Stability Index (TSI).

Results: Figure 1 shows the TSI of the five formulations over the pre-determined storage time. Avicel RC-591 demonstrated excellent suspending capability for formulation that contains no CaCl₂ (F1). The suspension was very stable during the 4-week long storage with a TSI rating “A+”. However, as the CaCl₂ concentration increased gradually from 0.5% to 1.5%, the suspensions became less stable, with TSI dropping to “B”, “C” and “D” even at the first week of storage for F2, F3, and F4, respectively. Figure 2 displays the suspensions’ visual appearance after 4 weeks of storage, clearly showing more phase separation and flocculation in formulations with high CaCl₂ concentration. The root cause for this instability was coordination of the bivalent calcium ions to NaCMC. The latter is an anionic polymer which is critical for cMCC to maintain its colloidal form and thus stabilizing functionality. However, the addition of GRINDSTED^â Xanthan Clear 80 PRM in the formulation with the highest CaCl₂ concentration (1.5%) significantly improved the suspension’s stability. Thus, formulation F5 obtained the TSI rating “A” after a 4-week storage period and did not show phase separation. Xanthan was therefore proven to be a great protective colloid, which enabled the formulation of stable suspensions even with very high salt contents.

Conclusion: Avicel® cMCC is a very effective suspending agent that provides stable and strong suspending capability. Yet, its functionality can be limited in high salt environments, especially with divalent cations like calcium. In this situation, protective colloids like GRINDSTED® Xanthan PRM should be added to maintain and improve the suspending properties of Avicel® cMCC. Thus, xanthan is an effective protective colloid to ensure stability of cMCC suspensions in challenging formulations.

References: 1. Comparison of commonly used pharmaceutical suspending agents, AAPS PharmSci poster 2021.
2. pH impact on the suspension capability of colloidal MCC, AAPS PharmSci poster 2022.

Table 1. Formulation details

Figure 1. Turbiscan Stability Index of suspensions during storage

Figure 2. Suspension appearance after 4-week storage