(W0930-12-83) Effect of Methylcellulose on Suspensions Based on Various Mixing Procedures and Temperature

Purpose: There are several key factors that play a role during the development of a pharmaceutical suspension. These factors include, but are not limited to, the suspension system, the recipe/mixing procedure, the particle size of the active pharmaceutical ingredient (API), rheology, and stability. A suspension system is typically comprised of several suspending agents working in tandem. One such agent is methylcellulose, a polymer which can be found in a wide range of pharmaceutical applications and exhibits characteristics that helps define a suspension’s rheology and viscosity. The objective of this study was to showcase the effects methylcellulose imparts on suspensions when produced under different mixing procedures and temperature. Suspension prototypes were formulated using methylcellulose and evaluated based on phase separation, particle size distribution (PSD) of the API, and viscosity.

Methods: The methylcellulose used in this study was METHOCEL™ A15C. A clear, lump-free solution can be formed with METHOCEL™ A15C by heating water to 65°C and cooling down to room temperature (RT) with continuous mixing. Three formulation trials were conducted following this 65°C/RT method with the details listed out in Table 1. Only the percentage of METHOCEL™ A15C varied between the formulation trials – all other ingredients remained constant. To measure the PSD of the formulation trials, 1ml samples (as received) were dispersed in a Microtrac S3500 Laser Diffraction PSA with DI water until the obscuration of the laser’s path met ISO 13320-2020 standards. The instrument then conducted triplicate measurements and averaged the results. The viscosity (Figure 1) was measured at RT using a Brookfield DV2T LV viscometer. Phase separation was monitored over 1 month at RT. Trials 1 – 3 were mixed by first heating purified water to a minimum of 65°C using a hot plate and stir bar. METHOCEL™ A15C powder was added into the purified water and mixed at speeds of up to 900 revolutions per minute (rpm) until all powder was fully dissolved. Gellan gum was mixed in next and dissolved. For trials 1 & 3, Bismuth Subsalicylate (API) was mixed into the solution as it was cooling with continuous mixing. Solution was homogenized at RT using a Silverson L5M-A Laboratory Mixer for 15 minutes at no more than 5,000rpm. For trial 2, API mixed into the solution did not have continuous mixing and solution was homogenized at 35°C for 10 minutes at no more than 3,000rpm.

Results: From trials 1 – 3, it is significant to note that the homogenization temperature, speed, and duration vastly affected the final appearance and homogeneity of the prototype suspensions (Table 1). Trials 1 and 3 remained homogenous for 1 month at RT while trial 2 exhibited initial separation overnight and complete separation after 5 days at RT. Continuous mixing was not maintained for trial 2 and the solution was not properly cooled to RT before homogenization. This led to trial 2 displaying complete separation after 5 days. The importance of temperature’s effect on viscosity was additionally highlighted. Trial 3 was formulated with less METHOCEL™ A15C compared to trial 1, but the mixing parameters remained the same. However, trial 2 contained the same quantities as trial 1 but was mixed with different parameters and did not cool to RT nor have continuous mixing before the homogenization step. Resulting viscosity differences (Figure 1) between trial 2 when compared to 1 & 3 showcases how temperature results in different viscosity measurements. PSD results (Figure 2) were high in micron size due to equipment limitation. Further studies and testing are needed to optimize the Bismuth Subsalicylate’s particle size during the homogenization process for the next phase of this study.

Conclusion: Although trials 1 & 2 contained the same amounts of METHOCEL™ A15C, the difference in mixing parameters resulted in complete separation of the suspension in trial 2 and a difference in viscosity measurements. Temperature and mixing played a key role during the formation of the suspension system. Trial results indicate there should be continuous mixing of the purified water and METHOCEL™ A15C until the solution has achieved room temperature. Otherwise, any API addition and further mixing will result in improper suspensions and lead to stability concerns.

References: Arora K, Vats V, Verma PK. A Review on Pharmaceutical Suspension and Its Advancement. Ann Clin Case Rep. 2022; 7: 2321.
ISSN: 2474-1655.

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Table 1. Formulation Trial 1 - 3 Details

Figure 1. Formulation Trial 1 - 3 Viscosity

Figure 2. Formulation Trial 1 - 3 Particle Size Distribution