Research paper
Solvent injection as a new approach for manufacturing lipid nanoparticles – evaluation of the method and process parameters

https://doi.org/10.1016/S0939-6411(02)00130-3Get rights and content

Abstract

Lipid nanoparticles (LNP) can be prepared by rapidly injecting a solution of solid lipids in water-miscible solvents or a water-miscible solvent mixture into water. The aim of the present study was to evaluate the potential of this method for the preparation of LNP and the physicochemical characterization of the particles produced by this method. The results show that solvent injection is a potent and versatile approach for LNP preparation. Acetone, ethanol, isopropanol and methanol are suitable solvents in contrast to ethylacetate with which no LNP could be prepared. The obtained particle sizes (z-average) were between 80 and 300 nm depending on the preparation conditions. Up to 96.5% of the employed lipid was directly transformed into LNP. The LNP formation process seems to be diffusion controlled. Physicochemical characterization of the particles by differential scanning calorimetry (DSC), transmission electron microscopy and X-ray diffraction analysis reveals a distinct decrease in crystallinity of the colloidal lipid in comparison to the bulk lipid. Furthermore, DSC analysis of LNP hints at a delayed recrystallization of the colloidal lipid and the presence of two modifications. Therefore, a certain physical instability of the LNP has to be considered.

Introduction

Nanoparticles based on solid lipids have been proposed as a promising alternative colloidal drug delivery system to polymer nanoparticles and liposomes by Westesen [1] and Müller [2]. They combine the advantages of colloidal lipid emulsions with advantages of particles with a solid matrix [3]. Consisting of physiological and biodegradable lipids, lipid nanoparticles (LNP) are suitable for the incorporation of lipophilic, hydrophilic and poorly water soluble drugs within the lipid matrix in considerable amounts [4], [5]. Usually lipids such as dynasan®, witepsol®, compritol® and cetyl palmitate are used as matrix materials.

The standard production method for the preparation of lipid nanodispersions based on solid lipids is high pressure homogenization [6]. Furthermore, LNP can be prepared by precipitation both from microemulsions and emulsions containing organic solvents [7], [8]. The preparation of LNP with these methods involves several critical process parameters like high temperatures, high pressures, toxicologically problematic solvents, high emulsifier concentrations, etc. For example, heat and cavitation cause significant thermodynamical and mechanical stress for the resulting product. In contrast, high emulsifier concentrations and residual solvents are more problematic for the application. Therefore, an alternative production method which is commonly employed for the preparation of liposomes [9] and polymer nanoparticles [10] was investigated for its suitability for the preparation of LNP. This method offers clear advantages over the existing methods such as the use of pharmaceutically acceptable organic solvents, no need for high pressure homogenization, easy handling and a fast production process without technically sophisticated equipment. It is based on lipid precipitation from a dissolved lipid in solution. For this purpose, a solution of the lipid in a water-miscible solvent or a water-miscible solvent mixture is rapidly injected into an aqueous phase with or without surfactant.

Section snippets

Materials

Solid lipids: softisan® 100, softisan® 142, softisan® 154, witepsol® H35 (Condea, D-Witten), cetyl palmitate (Caelo, D-Hilden). Softisan® lipids consist of a triglyceride mixture of natural, saturated, even-numbered and unbranched fatty acids with a chain length from C10 to C18. Softisan® 100 and 142 have melting points of 33.5–35.5 °C and 42–44 °C, respectively. They are also specified as ‘hydrogenated coco-glycerides’ whereas softisan® 154 with a melting point of 53–58 °C is specified as

Method screening

For the preparation of LNP by solvent injection several water-miscible solvents were screened. Acetone, ethanol, isopropanol and methanol were suitable solvents in contrast to ethylacetate with which no LNP could be obtained. LNP preparation with methanol was not examined more closely, as the solubility of lipids in methanol was at least three times lower in comparison to the other solvents and due to the higher toxicity of the solvent. With all the studied solid lipids, i.e. softisan® 100, 142

Conclusion

This study demonstrates that ‘solvent injection’ represents a viable new alternative for preparing LNP. The technique is efficient, versatile and of simple implementation. The particle size can be influenced and controlled by variation of process parameters such as injected solvent, lipid concentrations, injected amount and viscosity. One crucial parameter for the nanoparticle formation process seems to be the diffusion of the solvent from the lipid–solvent phase into the aqueous phase,

Acknowledgements

We like to thank Condea and Phospholipid for kind support with materials.

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