Identification of critical process parameters and its interplay with nanosuspension formulation prepared by top down media milling technology – A QbD perspective

Abstract

The purpose of this study was to optimize the process parameters of a poorly soluble drug by top down media milling process using different polymer systems. Process parameters including agitation rate (RPM), size of grinding media and drug content were studied through a Quality by Design (QbD) approach, using three different polymeric stabilizers (HPMC 3 cps, PVP K-30 and HPC-EXF) with the addition of Vitamin E TPGS as a surface active agent. From the statistical analysis, the RPM of the media milling was determined to be the most significant process parameter with respect to influence on particle size. The effects of varying the size of grinding media or drug content were not found to be as significant as the effects of RPM. Finally, the polymeric stabilizer played an important role in the production of nanoparticles. Among the different polymers, HPMC stabilized systems demonstrated superior results with regards to the consistency in producing successful nanoparticles and inhibition of crystal growth during storage. This study established the interplay among the formulation parameters in order to select the design space, which helped us in the identification and rank ordering of critical and noncritical variables related to the quality attributes of nanosuspension formulation during the early phase of product development.

Influence of Critical Parameters of Nanosuspension Formulation on the Permeability of a Poorly Soluble Drug through the Skin—A Case Study

“…Finally, the use of HPMC K100 along with vitamin E TPGS could have a synergistic effect in stabilizing the highly energized crystals. Similar observation from Vitamin E TPGS was reported in the past (26,27).…”

Parenteral nanosuspensions: a brief review from solubility enhancement to more novel and specific applications

“…Ghosh et al 89 have studied the effect of different polymeric stabilizers (HPMC, polyvinyl pyrrolidone, and HPC) on process parameter associated variabilities in size and polydispersity of nanosuspension. They used the quality by design (QbD) approach and found that the type of polymeric stabilizers plays an important role in the production of the nano range particles.…”

“…Overall results revealed that the choice of stabilizer to be used is a key factor along with the concentration to be used in the successful development of stable nanosuspension. Authors reported steric stabilization and hydrogen bond making tendency of polymer, responsible for better stabilization effect 89 .…”

Sub-100nm drug particle suspensions prepared via wet milling with low bead contamination through novel process intensification

“…Enhanced breakage kinetics can reduce milling time required, energy consumption, and even bead wear, which can be achieved by proper selection of the milling parameters such as bead size, bead loading, drug loading, rotor speed, and suspension flow rate. Influence of these parameters on the final drug particle size has been studied previously through experiments (Afolabi et al, 2014;Cerdeira et al, 2011;Ghosh et al, 2011;Ghosh et al, 2013;Ghosh et al, 2012;Monteiro et al, 2013;Singare et al, 2010;Singh et al, 2011). However, the influence of these parameters on breakage kinetics leading to sub-100 nm drug particles with reduced energy consumption and low bead wear has not been addressed.…”