ABSTRACT
The key concept of antisolvent precipitation is the decrease of solubility in solvent-nonsolvent mixtures. Taking advantage of the poor solubility of many compounds in CO2, the use of compressed CO2 as antisolvent was rapidly developed for processing polymers and opened the route for composite formulation. This chapter first introduces the compressed CO2 antisolvent concept based on the relevant phase equilibria (CO2-solvent mixture, solubility of a species in CO2+solvent, ternary diagram of a polymer-CO2-solvent system) and describes the key features of the two versions of the process known as gaseous antisolvent (GAS) and supercritical antisolvent (SAS). The second part of the article sorts out examples of composites produced by GAS and SAS as coprecipitation of two components (drug-polymer powders), precipitation of one
compound on a slurry (polymer-inorganic spheres or fibers, drug-excipient powders) and coprecipitation on slurry (drug-polymer-inorganic ternary hybrids). 6.1 IntroductionCoating or encapsulation of particles is of great interest in pharmaceutical, agrochemical, food, and cosmetic industries since it enables the tailoring of surface or bulk properties of the material. With many molecules poorly soluble in compressed CO2, the concept of using compressed CO2 as antisolvent was developed in the 1995s to bypass the restriction of rapid expansion of supercritical solutions (RESS) to the few molecules soluble enough in CO2 to be economically viable. The CO2 antisolvent process offers hence solutions for formulating CO2 nonsoluble compounds. In antisolvent approach, the compound(s) to precipitate is initially dissolved in an organic solvent and a nonsolvent for the solute is further mixed with the solution. The key concept is the decrease of solubility of the compound in the formed solvent-antisolvent mixtures compared to its solubility in neat solvent. Compared to RESS, the extend of the solubility shift induced by a CO2 antisolvent is less pronounced than the shift induced by the depressurization encountered in RESS, so, antisolvent techniques are prone to produce larger sizes of particles than RESS [1]. Precipitation by an antisolvent, compressed or not, obeys to general laws of crystallization. The control of particle size goes along with the control of the supersaturation level, that is, the knowledge of the solubility variation with the solvent-antisolvent composition and of the time and space scales at which supersaturation is obtained and crystallization develops (mixing scales of solvent and antisolvent). Compared to conventional precipitation carried out at atmospheric pressure, the interest of the compressed antisolvent resides in the rapidity at which supersaturation can be obtained due to the higher mass and thermal diffusivities in fluids compared to liquids. As postprocessing advantage, the elimination of solvent from the precipitated material is realized in situ by a flow of CO2; by designing a one-pot process, it avoids the multiple filtration and drying steps detrimental to the product integrity and to the technician’s health. Two variants of antisolvent techniques were developed, the gaseous antisolvent (GAS) in which CO2 is added initially as a gas to
the solution, with, as a consequence, pressurization of the medium; and the supercritical antisolvent (SAS) in which the solution is directly injected in a compressed CO2 maintained at desired pressure. The operating lines of the two variants in the pressure-composition diagram are very different, as illustrated in Fig. 6.1, so that different sizes of particles or composites can be obtained [2]. MPC
Figure 6.1 Operating lines of SAS and GAS in a solvent-CO2 liquid-vapor phase diagram showing the evolution of the mixture composition when CO2 is added to the solvent. In GAS, the pressure increases as well. In SAS that proceeds by injection of the solution in CO2, the pressure is fixed. Composites described in this chapter incorporate mostly a polymer in their formulation. Processing or coprocessing polymers by the SAS technique is not as “easy” as single processing molecules of low molecular weight. Polymer behavior in dense fluids has been reviewed by Kiran in 2009 [3]. First, CO2 might interact strongly with polymers, especially with the amorphous ones. The great solubility of CO2 in the polymer phase can result in plasticization and agglomeration of the final product. Secondly, polymers in solution exhibit a peculiar behavior since their chains can behave as independent entities at dilute concentration or are capable of entangling with one another when more concentrated. The increased viscosity of the polymer melt with concentration makes atomization more difficult. Combined to a precipitation in presence of CO2 that occurs by liquid-liquid phase split, various morphologies ranging from particles to fibers can be formed, especially with SAS. Moreover, in the case of coprocessing, the polymer and the molecule might not be soluble in the same solvent, so a mixture of solvent could be necessary for the composite production.
