The use of SCFs or dense gases has been recently widened to the processing of pharmaceuticals. In this chapter, we will focus on the techniques that can be used for the formation of drug-loaded polymer particles. For more general information about material processing with SCFs, particle formation, SCF extraction, or other applications of SCF, some landmark reviews or books [8,16-18,21-25] are recommended.
Production of particles by rapid expansion of SC solutions (RESS) relies on the fact that the solvent strength of an SCF can be dramatically reduced by altering its pressure. Depending on the nature of solutes and operating conditions, the RESS process can produce very small and nearly monodispersed particles. The first publication dealing with the formation of particles from SC solutions was published in 1879 , where the formation of "snow" by a sudden pressure reduction of a binary solution was reported. Surprisingly, the potentiality of processing difficult to comminute solids by decompression of an SC solution was not highlighted until the early 1980s .
As presented in Fig. 3, the RESS process consists of dissolving the material to be powdered in an SCF, then expanding the SC solution through a nozzle into a low-pressure chamber. Due to the simplicity of its concept, RESS allows the production of solvent-free particles within a single-step operation and can be implemented in a simple way. The SC solution is obtained by passing a preheated SCF through an extraction vessel previously loaded with the solute(s) to be processed. If the precipitation of a mixture of solutes (e.g., drug and polymer carrier) is desired, the extraction unit is loaded with multiple solutes , or multiple extraction vessels are used with a subsequent mixing of SC solutions [9,29]. The mixing of SC solutions from multiple extraction units makes it possible to control the content of each component in the expanded SC solution. On the other hand, the use of a single extraction vessel packed with multiple components means that the particle composition is governed by equilibrium solubilities in the extraction vessel. The expansion capillaries, or fine-diameter orifices of the nozzles, typically have a diameter ranging from 5 to 200 pm. To avoid phase separation, solute precipitation, and plugging related to cooling effects, the nozzle has to be heated. The low-pressure chamber can be set either at the atmospheric pressure, or at an intermediate pressure between
atmospheric and preexpansion pressure, or even at a vacuum pressure. The main process parameters that influence the particulate product morphology were identified; these are the temperature and pressure in the extraction unit and in the precipitation vessel, the nozzle geometry and diameter, the nature of solute-solvent interaction, and the nature of the solute to be precipitated. Depending on these parameters, various solid shapes and morphologies are obtained, from fine powders to needles, or even thin films if the SC solution is expanded onto a surface . Agglomeration of the discrete particles and difficulties encountered for their collection were often reported for the RESS process. The final particulate product is dry and solvent-free, which eliminates any further purification step usually needed with conventional liquid solvent-based processes. Micrometer-sized particles are typically obtained with the RESS process. However, some authors reported the production of nanometric powder of pure compounds as cholesterol or benzoic acid .
The flow pattern and nucleation process of RESS were investigated [9,15, 28,32-36]. If the phase change from the SC to the gas state takes place in the nozzle and in the supersonic free jet after the nozzle, the nucleation process is extremely rapid, with a particle nucleation and growth time estimated to be much less than 10-5 s . The expansion of the SC solution leads to high supersaturation, nucleation and consequently to the formation of particles. Cooling rates of 109K/s and supersaturations of about 105-108 were calculated using a modeling of the pressure and temperature changes along the expansion pathway .
Particle size reduction was the primary application of RESS, displaying major advantages over conventional processes, either mechanical (grinding, milling) or wet (crystallization from solution). As frequently reported [21,22,3739], RESS has been applied to a wide variety of pure materials including pharmaceuticals, polymers, dyes, and inorganic compounds. The RESS process requires compounds to precipitate to be soluble enough in the SCF. However, most pharmaceutical compounds exhibit solubilities below 0.1 wt% under mild processing conditions [38,39].
Polymer RESS processing was described in the first comprehensive study of RESS . Using propylene as the SCF, polypropylene was changed from rough-surfaced spheres of 30 pm to fibrous particles with multiple branches and high aspect ratios (about 50 pm length and 2-3 pm diameter). As shown in Table 2, various polymers were then processed using RESS. The Batelle Institute's detailed pioneer work on RESS processing of polymers [9,40,41] has demonstrated that this process can be used to produce solvent-free polymer powders with various morphologies ranging from micrometer-sized spherical particles to fibers of 100-1000 pm length. These experiments involved drastic operating conditions, such as high preexpansion temperature of 350°C and the use of flammable low molecular weight alkanes as SC solvents to overcome the low solubility of most polymers in SC CO2.
All of these studies made it possible to foresee the opportunity offered by RESS to produce intimate mixtures of materials with a controlled morphology in a single processing step. RESS has been considered for the engineering of biodegradable polymer particles with the ultimate goal of producing drug-loaded polymer particles. However, most of the polymers used in therapeutic applications (e.g., for sustained release) are not reasonably soluble in SC CO2.
The wide variety of bioerodible polymer particle morphologies that can be produced by RESS has been illustrated by the processing of polycaprolactones (PCLs). PCLs were found to be insoluble in SC CO2, but were soluble in SC chlorodifluoromethane . Depending on the preexpansion temperature and pressure, as well as L/D ratio of the orifices, various morphologies of polycapro-lactone particles were obtained from fine-diameter particles to high aspect ratio fibers. Using cloud point measurements for chlorodifluoromethane/polymer systems, the product morphology was found to be dependent on the degree of saturation upstream of the expansion nozzle . It was shown that a process whose operating conditions lead to a phase separation in the expansion device results in a precipitation time scale over microseconds only. The nuclei formed during the early stages of phase separation are then frozen, and submicrometer particles are produced. Conversely, the occurrence of fibers is related to a phase separation over tens of seconds in the entry region of the orifice. Thus, it appears that RESS dynamics can be used to control the shape morphology of polymer precipitates. This feature is illustrated with the precipitation of poly(l-lactic acid) (l-PLA) from a CHClF2 SC solution, where tuning the operating conditions for a microsecond phase separation resulted in the formation of practically spherical particles with a diameter ranging from 0.2 to 0.6 pm .
The RESS processing of the poly(hydroxy acids) l-PLA, poly(d,l-lactic acid) (dl-PLA), and poly(glycolic acid) (PGA) with CO2 as the SC solvent was also reported . Commercial l-PLA (Mw = 5500 g/mol, Mw/Mn = 2.0) were found to be soluble in SC CO2, with a solubility of 0.05 wt %. The solubility was increased up to 0.37 wt % with the addition of 1 wt % of acetone as entrainer. The polydispersity of l-PLA has a significant impact on the formation of polymeric microspheres by the RESS process. The SC solvent preferentially extracts low molecular weight l-PLA , thereby affecting the molecular weight and polydispersity of the processed polymer. Starting from commercial polydisperse l-PLA, the molecular weight of extracted and precipitated polymer varies during the course of the RESS experiment. The low molecular weight l-PLA were first extracted and formed a viscous low glass transition temperature precipitate. After sufficient preconditioning, the molecular weight of the extracted l-PLA was found to be 2000-3000 g/mol (starting from Mw = 5500 g/
TABLE 2 Polymers and Composite Drug/Polymer Particles Processed with RESS or w-RESS
Results and comments
Poly(vinyl chloride) and potassium iodide
Poly(methyl methacrylate) (PMMA)
Poly(heptadecafluorodecyl acrylate) Poly-l-lactic acid and poly(d,l-lactic acid) (l-PLA and dl-PLA) l-PLA
cyclohexanol 98:2 v/v Pentane
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