Development of agomelatine nanocomposite formulations by wet media milling

• Published in: European journal of pharmaceutical sciences Vol. 166; p. 105979
• Main Authors: Vardaka, Elisavet, Ouranidis, Andreas, Nikolakakis, Ioannis, Kachrimanis, Kyriakos
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.11.2021
• Subjects: Acetamides; Agomelatine; Dissolution; Drug Compounding; Nanocomposites; Nanocrystals; Nanoparticles; Nanosuspension stabilizer; Particle informatics; Particle Size; Solubility; Suspensions; Wet media milling; Agomelatine; Nanocrystals; Wet media milling; Nanosuspension stabilizer; Dissolution; Particle informatics
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2021.105979

•Stable agomelatine nanosuspensions were produced by wet milling in presence of HPC.•Particle size depends on stabilizer concentration in a manner affected by the mill rotation speed.•Agomelatine (form I) undergoes a polymorphic transition to form II during milling.•Solid state modeling reveals agomelatine polymorphs’ mechanical anisotropy.•Nanocomposite formulation exhibits greatly enhanced dissolution. Nanocrystal formulations of the BCS class II agomelatine, were developed by wet media milling. The most suitable stabilizer was identified and effects of process and formulation variables on the nanocrystal size and ζ-potential were evaluated employing a Box-Behnken experimental design. The optimized nanosuspensions were dried and subsequently evaluated for redispersibility and physicochemical properties. Computational simulation of solid state properties was applied to rationalize crystal fracture. It was found that low viscosity hydroxypropylcellulose with sodium dodecyl sulfate is the most suitable stabilizer. Stabilizer concentration exerts a statistically significant effect on particle size, which depends on the mill's rotation speed. The milling process induces a polymorphic transition to form II, which could affect size reduction kinetics. The solidified nanosuspensions’ redispersibility is deteriorating progressively with storage time, with only minor differences between drying methods, retaining enhanced dissolution rate. Crystal lattice simulations suggest high mechanical anisotropy of form I crystals, which could be an additional reason for fast particle size reduction prior to the polymorphic transformation. Wet media milling, combined with a suitable drying method, can be an efficient technique for the production of stable nanocrystals of agomelatine. Particle informatics methods can enhance our understanding of the mechanisms responsible for agomelatine's nanocomminution. [Display omitted]