Important Factors in the Size Reduction of Polymer-Stabilized Drug Particle Suspensions Using High-Pressure Homogenization

Abstract

In recent years, high-pressure homogenization has been used with increasing frequency to reduce the size of pharmaceutical suspensions to the micron, submicron, and nano scales with the goal of increasing the dissolution rate of the drug, and consequently, the in vivo bioavailability. As particle suspensions become smaller in size, increased concentrations of surfactants and stabilizers are required to prevent particle agglomeration. Recently, relatively high concentrations of biocompatible polymers have been used to stabilize suspensions by imparting surface-active steric stability as well as kinetic stability through an increase in suspension viscosity and/or a transition to non-Newtonian rheological properties. While the benefits of stable suspensions are known, little is known about the effect of the high polymer concentration on the actual breakup of the particles in suspension. In this work, designed experiments were used to identify the key parameters that govern the final particle size of a drug suspension following homogenization. In particular, drug loading, operating pressure, and polymer concentration were all found to be statistically significant factors in determining the resulting size of particles in suspension. In addition, it was found that an optimal polymer concentration of 2% (w/w) was required to adequately stabilize the particle suspension while simultaneously avoiding a decrease in homogenizer performance. Concentrations higher than 2% (w/w) resulted in size reduction limitations due to the increased viscosity (>10 cP) and the transition to nonNewtonian behavior.

Mechanistic investigation of biopharmaceutic and pharmacokinetic characteristics of surface engineering of satranidazole nanocrystals

“…Moreover, concentration of Span 20 well beyond its critical micelle concentration results in interaction of surfactant molecules among each other and results in formation of stable self-aggregates of surfactant molecules [32]. Still higher concentration will promote surfactant mediated dissolution of drug particles and Ostwald ripening [33].…”

“…HPMC E-5 also acts as a crystal growth inhibitor and reduces Ostwald ripening [28]. However, further increase in the concentration of HPMC E-5 results in increased viscosity and complex fluid rheology complicating the process of nanosizing [32]. Thus, the results obtained with the use of single stabilizer justifies the need of multiple stabilizer system as a key to the dual problem of incomplete coverage of the particle surface at lower concentrations and Ostwald ripening on storage.…”

Enhanced physical stabilization of fenofibrate nanosuspensions via wet co-milling with a superdisintegrant and an adsorbing polymer

“…The collision rate among the particles, and thus aggregation rate, is lower for more viscous suspensions because of the reduced mobility of the particles, which is also known as viscous dampening [15,18,55]. To be more precise, the collision frequency is inversely proportional to viscosity for perikinetic (Brownian) aggregation and to the square root of viscosity for orthokinetic (turbulent) aggregation [50].…”

Quercetin and 3-O-methylquercetin in vitro skin layers permeation/retention from hydrogels: why only a methoxy group difference determines different behaviors?

“…The concentration employed in the present work (3.0%) has led to an intermediate behavior of non‐newtonian fluid without yield response. Similarly, hydrogels of CS solubilized with acetic acid resulted in pseudoplastic shear thinning fluids that are time‐independent …”

“…Similarly, hydrogels of CS solubilized with acetic acid resulted in pseudoplastic shear thinning fluids that are time-independent. [32][33][34][35]…”