Optimization of self-nanoemulsifying formulations for weakly basic lipophilic drugs: role of acidification and experimental design

Abstract

Formulators face great challenges in adopting systematic approaches for designing self-nanoemulsifying formulations (SNEFs) for different drug categories. In this study, we aimed to build-up an advanced SNEF development framework for weakly basic lipophilic drugs, such as cinnarizine (CN). First, the influence of formulation acidification on CN solubility was investigated. Second, formulation self-emulsification in media with different pH was assessed. Experimentally designed phase diagrams were also utilized for advanced optimization of CN-SNEF. Finally, the optimized formulation was examined using cross polarizing light microscopy for the presence of liquid crystals. CN solubility was significantly enhanced upon external and internal acidification. Among the various fatty acids, oleic acid-based formulations showed superior self-emulsification in all the tested media. Surprisingly, formulation turbidity and droplet size significantly decreased upon equilibration with CN. The design was validated using oleic acid/ Imwitor308/Cremophor El (25/25/50), which showed excellent self-nanoemulsification, 43-nm droplet size (for CN-equilibrated formulations), and 88 mg/g CN solubility. In contrast to CN-free formulations, CN-loaded SNEF presented lamellar liquid crystals upon 50% aqueous dilution. These findings confirmed that CN-SNEF efficiency was greatly enhanced upon drug incorporation. The adopted strategy offers fast and accurate development of SNEFs and could be extrapolated for other weakly basic lipophilic drugs. Uniterms: Self-nanoemulsifying formulations/solubility. Cinnarizine/lipophilic drugs. Acidification/ experimental design. Solubility enhancement.

Evaluation of Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) for Poorly Water-Soluble Talinolol: Preparation, in vitro and in vivo Assessment

“…It is common that weakly base compounds (pKa > 8) have high solubility in acidic conditions (stomach media) and low in neutral and or basic conditions (intestinal media), as they can be converted into uncharged molecule in neutral and or basic conditions (Shahba et al, 2016). Therefore, basic drugs might dissolve completely in the stomach, maintain drug in solubilized form and later precipitate in the intestine due to sudden changes in pH (pH shift to higher) and/or extensive dilution of excipients.…”

“…Solubility and dissolution is primarily the rate limiting factors for oral bioavailability of many drugs. There have been a variety of formulation strategies designed over the past two decades to improve drug solubility to enhance the rate and extent of drug absorption from the GIT (Shahba et al, 2012, 2016, 2017; Devraj et al, 2013; Mohsin et al, 2016).…”

<p>Self-nanoemulsifying ramipril tablets: a novel delivery system for the enhancement of drug dissolution and stability</p>

“…The formulations were diluted at a ratio of 1:1,000 v/v (formulation: distilled water) and mixed for 1 minute before analysis. The droplet size distribution and zeta potential of the diluted formulation were measured using the Zetasizer (Nano ZS, Germany) particle size and zeta potential analyzer 15…”

Stabilization benefits of single and multi-layer self-nanoemulsifying pellets: A poorly-water soluble model drug with hydrolytic susceptibility

“…Based on the recent optimization studies [ 28 ], the liquid SNEDDS was prepared by mixing the components: OL/I308/Cr-El (25/25/50). The formulation components were heated if nesseccary to ensure complete melting and homogeneity.…”