Exploring the physical short-term stability of naproxen suspensions: The impact of stabilizer and stabilizer concentration on the particle size profiles

Surfactants are typically used as solubility enhancers of drug compounds but also as stabilizers during the preparation of nano- and microsuspensions. In this context, their solubilizing properties may inadvertently alter the particle size over time, potentially affecting the drug release profile. Therefore, selecting appropriate stabilizers with optimal affinity to prevent particle agglomeration and stabilization concentration is crucial to ensure the physical stability and efficacy of the suspension. For that reason, the present study explored naproxen suspensions prepared with dual centrifugation while stabilized with polysorbate 20, poloxamer 188, or a combination of both to determine the importance of stabilizer/drug affinity and drug solubility in the presence of the surfactants. The thermodynamic solubility of naproxen in the presence of polysorbate 20 was almost eight times higher than in the presence of poloxamer 188. The increased solubility induced by polysorbate 20 seemed to impact the size of naproxen particles just after milling due to excess surfactant present in the suspensions, i.e., a minimum concentration of stabilizer seemed to exist just after milling where the preferable concentration should be kept above 0.75% and below 2.00% (w/v) to obtain the smallest size distribution. In contrast to this, indications towards improved physical stability with time was observed for suspensions which contained excess surfactant. By combining both surfactants, the sizes of naproxen particles just after milling did not increase at higher stabilization concentrations while it was also possible to use lower concentrations of poloxamer 188 to decrease the sizes of naproxen particles. Naproxen particles were generally unstable during 28 days of storage at 40 °C and an increase in particle size distribution was observed every week of measurement when stabilized with polysorbate 20 and poloxamer 188. Yet, improved physical stability profiles were obtained when polysorbate 20 and poloxamer 188 were combined, when compared to suspensions stabilized with the individual surfactants, indicating a stabilization synergism between the two surfactants for naproxen suspensions during the short-term evaluation. In general, the study showed that the stabilizer concentration needed to obtain a smaller particle size after milling was not sufficient and it did not lead to the most stable suspensions while the lack of solubilization capacity of the stabilizer was a poor predictor for physical stability of naproxen suspensions.