Santiago Sala

DELOS process: a crystallization technique using compressed fluids. 1. Comparison to the GAS crystallization method

Abstract The depressurization of an expanded liquid organic solution (DELOS) crystallization technique is a new one-step process, which uses a compressed fluid (CF) (e.g. CO 2 ), for the straightforward production of sub-micron- or micron-sized crystalline particles. The driving force of a DELOS crystallization process is the fast, large and extremely homogeneous temperature decrease experienced by a solution, which contains a CF, when it is depressurized from a given working pressure to atmospheric pressure. In contrast to other already reported high-pressure crystallization techniques (RESS, GAS, PCA, PGSS), in a DELOS process the CF behaves as co-solvent over the initial organic solution of the solute to be crystallized. Through a DELOS process it is possible to produce fine powders of a compound provided that a system ‘compound/organic solvent/CF’ in a liquid one-phase state is found. In order to compare DELOS and gas anti-solvent (GAS) procedures, 1,4-bis-( n -butylamino)-9,10-anthraquinone has been crystallized from ‘acetone/CO 2 ’ mixtures by both methods. The crystallization results obtained have been analyzed upon the solubility behavior of 1,4-bis-( n -butylamino)-9,10-anthraquinone in ‘acetone/CO 2 ’ mixtures with different composition. It will be seen how important is the knowledge of the solute solubility behavior in the CO 2 -expanded solvent in order to choose the most convenient crystallization technique (GAS like or DELOS) and the best operational parameters. Finally, it has been experimentally determined which are the operational parameters that control the temperature decrease experienced in a DELOS crystallization. The results obtained have been corroborated through thermodynamic considerations.

Lipid-based nanovesicles for nanomedicine

Molecular self-assembly has enabled the fabrication of biologically inspired, advanced nanostructures as lipid-based nanovesicles (L-NVs). The oldest L-NVs, liposomes, have been widely proposed as potential candidates for drug delivery, diagnostic and/or theranostic applications and some liposome-based drug products have already stepped from the lab-bench to the market. This success is attributed to their ability to encapsulate both hydrophobic and/or hydrophilic molecules, efficiently carry and protect them within the body and finally deliver them at the target site. These positive features are also coupled with high biocompatibility. However, liposomes still present some unsolved drawbacks, such as poor colloidal stability, short shelf-life, restricted and expensive conditions of preparation because of the inherent nature of their fundamental constituents (phospholipids). The new tools available in the self-assembly of controlled molecules have significantly advanced the field of L-NV design and synthesis, and non-liposomal L-NVs have been recently developed; this new generation of nanovesicles can represent a paradigm shift in nanomedicine: they may complement liposomes, showing their advantages and overcoming most of their drawbacks. Clearly, being still young, their rocky way to the clinic first and then to the market has just started and it is still long, but they have all the potentialities to reach their objective target. The purpose of this review is to first present the large plethora of L-NVs available, focusing on this new generation of non-liposomal L-NVs and showing their similarities and differences with respect to their ancestors (liposomes). Since the overspread of a nanomaterial to the market is also strongly dependent on the availability of technological-scale preparation methods, we will also extensively review the current approaches exploited for L-NV production. The most cutting-edge approaches based on compressed fluid (CF) technologies will be highlighted here since they show the potential to represent a game-change in the production of L-NVs, favouring their step from the bench to the market. Finally, we will briefly discuss L-NV applications in nanomedicine, looking also for their future perspectives.

Liposomes and Other Vesicular Systems: Structural Characteristics, Methods of Preparation, and Use in Nanomedicine

Vesicular systems, especially liposomes, have generated a great deal of interest as intelligent materials for the delivery of bioactive molecules since they can be used as sensitive containers that respond to external stimuli, such as pressure, pH, temperature, or concentration changes in the medium, triggering modifications in their supramolecular structure. The control of the nanostructure-particle size and size distribution, membrane morphology, and supramolecular organization-of these self-assembled systems is of profound importance for their application in drug delivery and the discovery of new nanomedicines. This chapter will describe the chemical structure of vesicles and their pharmacological properties, conventional and new vesicle preparation methods and structural characterization, as well as their use in the rational design and fabrication of nanomedicines.