Abstract. The aim of this review paper is to compare the potential of various techniques developed for production of homogenous, stable liposomes. Traditional techniques, such as Bangham, detergent depletion, ether/ethanol injection, reverse-phase evaporation and emulsion methods, were compared with the recent advanced techniques developed for liposome formation. The major hurdles for scaling up the traditional methods are the consumption of large quantities of volatile organic solvent, the stability and homogeneity of the liposomal product, as well as the lengthy multiple steps involved. The new methods have been designed to alleviate the current issues for liposome formulation. Dense gas liposome techniques are still in their infancy, however they have remarkable advantages in reducing the use of organic solvents, providing fast, single-stage production and producing stable, uniform liposomes. Techniques such as the membrane contactor and heating methods are also promising as they eliminate the use of organic solvent, however high temperature is still required for processing.

Dense gas techniques, which utilize the properties of fluids in the vicinity of the critical point, are increasingly being used for the processing of pharmaceuticals. Dense gases are unique solvents that can be used for extractions, chromatographic separations, and chemical syntheses because of their liquidlike solvation power and gaslike mass-transfer properties. The processes can be conducted at moderate temperatures and are thus suitable for many heat-labile compounds such as proteins, biocompatible polymers, and pharmaceuticals. The products formed by densegas processes are generally free of residual solvent. Recent applications of dense gas techniques have focused on micronization; crystallization of high-purity particles; sterilization; and drug formulations, including the formation of liposomes and drug coatings. The following review presents examples of drug extraction, separation, synthesis, sterilization, and particle formation and demonstrates the broad application of dense gases for drug formulation purposes in the pharmaceutical industry.

A new dense gas process for the formation of liposomes has been developed: depressurization of an expanded solution into aqueous media (DESAM). The technique provides a fast and simple process for bulk liposome formation. As an alternative to current dense gas technologies, the DESAM process reduces the pressure requirements for liposome formation. Liposomes with diameters between 50 and 200 nm were formed. For all samples produced using ethanol as the solvent, the average effective diameter ranged from 119 to 207 nm. When chloroform was used as the solvent, the average effective diameter increased to 387 nm. The residual solvent volume fraction in the liposomal product was less than 4% v/v, which is approximately one-quarter of the value reported for some other dense gas liposome formation methods. The liposomal samples were stored after formation at 5 degrees C for up to 8 months, with the average effective diameter and polydispersity increasing by only 13% and 7%, respectively, indicating high stability of the formulations.