Study of arginine hydrochloride and hydroxypropyl cellulose as stabilizers of Naproxen nanosuspensions

The objective of this study was to formulate Naproxen nanosuspensions at drug concentrations of up to 300 mg/ml using ball milling and to investigate the effect of arginine hydrochloride as a primary stabilizer. Hydroxypropyl cellulose (HPC) and arginine hydrochloride as co-stabilizers were also investigated. The nanosuspensions were prepared at different arginine hydrochloride/polymer weight ratios. Particle size of the suspensions studied was measured by the N4MD coulter submicron particle size analyzer. The feasibility of converting liquid nanosuspensions into a dry product was assessed using lyophilization. Stability of the nanosuspensions was assessed by particle size and zeta potential changes.;To further study the effect of arginine hydrochloride as a primary stabilizer without using HPC, addition of arginine hydrochloride and increased milling time were investigated. The result showed that after ball milling for 4 hours, arginine hydrochloride by itself at a concentration between 1.5-3% w/v can produce 100 mg/ml Naproxen nanosuspensions with a mean particle size in the range of 400-600 nm, and at a concentration between 3-5% w/v can produce 300 mg/ml Naproxen nanosuspensions with a mean particle size in the range of 400-600 nm. However, when these stable nanosuspensions containing only arginine hydrochloride were lyophilized, the addition of 3-5% w/v trehalose as a cryoprotectant for 100 mg/ml and 300 mg/ml of nanosuspensions, respectively, was required to improve redispersability.;Presence of arginine hydrochloride caused a slight increase in negative values of zeta potential of Naproxen nanosuspensions. However, HPC significantly reduced the zeta potentials of the system to a value close to zero. The results of zeta potential and the two-week stability study indicated that arginine hydrochloride either did not adsorb onto the surface of Naproxen particles to a significant degree, or was not able to change the zeta potential significantly; therefore, it might stabilize the system through a combination of electrostatic and a steric effects. Stabilization of nanosuspensions by HPC appeared to occur through a steric hindrance mechanism. Additionally, it was found that other variables such as drug particle size and 10 mM citrate/HCl buffer had no effect on the zeta potentials.;Keywords: Hydroxypropylcellulose, Arginine hydrochloride, Nanosuspensions, Zeta potentials, Naproxen, Poorly soluble drug, Stabilizer IV;In the study of the effect of arginine hydrochloride as a primary stabilizer, the results indicated that arginine hydrochloride levels less than 0.8% w/v were not able to help reduce particle size below one micron. Therefore, HPC was also added to the system to study the additive effect between hydroxypropyl cellulose (HPC) and arginine hydrochloride as stabilizers. HPC was added to increase suspension stability, presumably by a steric repulsion mechanism. However, when the Naproxen concentration was increased from 100 to 300 mg/ml, 1% w/v HPC was not able to provide good stabilization. Arginine hydrochloride was found to increase the stabilization efficiency of 1% w/v HPC by preventing flocculation as observed visually. When the HPC level was increased to 4% w/v, it was able to stabilize the nanosuspensions for 2 weeks and thereby could maintain the mean size diameter of the suspensions without the presence of arginine hydrochloride. Furthermore, stable nanosuspensions containing both HPC and arginine hydrochloride were successfully lyophilized without the use of additional cryoprotectants.