Formation of polymer particles with supercritical fluids: A review
Introduction
Interest in supercritical fluids and their potential use for process improvements has significantly increased in the past decade. These fluids, the properties of which can be tuned by changing the fluid density between those of liquid and gases, have been adopted or are being explored as: (a) alternative solvents for classical separation processes such as extraction, fractionation, adsorption, chromatography, and crystallization, (b) as reaction media as in polymerization or depolymerization, or (c) simply as reprocessing fluid as in production of particles, fibers, or foams. Some of the extraction processes such as decaffeination, and some polymerization and foaming processes have become commercial. Particle formation will most likely be the next major commercial application area that uses supercritical fluids.
The particle formation technology that uses supercritical fluids has evolved in many different forms during the last 20 years. Several review articles have already appeared in the literature [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]. A wide variety of organic and inorganic materials have been processed in the form of particles, fibers, films, and foams, employing the supercritical fluids as solvents or as antisolvents. Supercritical fluids were used as solvents, for example, to crystallize a supercritical fluid-soluble compound [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], or as non-solvents to precipitate supercritical fluid-insoluble materials [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54]. In some cases, these fluids were employed as cosolvents or coantisolvents along with an organic liquid solvent to produce particles with a targeted morphology [31]. The versatile operating conditions that are possible with supercritical fluids and their mixtures, provide the flexibilities in controlling the size of the particles that span from microns to nanometers. Indeed, the recent advances in these techniques are opening new horizons for the supercritical fluid technology in the area of particle design by extending the utilization domain to nanotechnology-based applications.
Among the various organic and inorganic compounds that have been processed with supercritical fluids, polymers have been of special interest and significance. A variety of polymers including polyolefins [14], fluoropolymers [25], polyamides [37], and biopolymers [45] have been explored. A range of protocols and flow arrangements and their influence on the particle size and shapes have been reported. General observations from these studies have been that the external shape of the resulting particles is relatively insensitive to process variables, and that the particle morphology depends more strongly on the properties of the polymer itself. For example, if the polymer is semicrystalline such as polyesters, particles are found to be spherical [46], and if molecules have stiff chains such as polyamides, fibrous forms are likely to be formed [37]. It remains a challenge to design for a specific particle shape and size in “any” targeted range for “every” type of polymer. Even though many forms of particles may be generated, finding their niche use areas presents another challenge. Therefore, the knowledge that is being generated is shifting more towards those applications where polymer particles that are produced have more clearly identifiable use areas, such as the case with pharmaceutical applications. In this respect, the more attractive polymers are the biopolymers. Particles of various biodegradable polymers have been produced for applications of drug delivery, or for use in agricultural and biological applications [8]. An important objective of the particle formation with biopolymers is to encapsulate a biologically active ingredient in the polymer matrix to be used for a controlled release of the compound to a targeted location. Two approaches are common, one is the formation of pure biopolymer particle which is then impregnated with the active ingredients, and the other is the coproduction of the polymer and other active ingredients. Many technical methods were developed to control the concentration of the active compounds inside the polymer particles. The variation of experimental conditions and contacting mechanism between supercritical fluids and liquid solutions that contain polymers and biologically active compounds result in different loading efficiencies in the polymer particles. The key challenge in these techniques is to successfully impregnate the active ingredient into polymeric matrix at a target concentration, or when coproduced, to overcome the segregated particle formation of the two components upon their coprecipitation.
The objective of the present review is to provide a critical account of the current state of formation of particles from polymers with a special focus on pharmaceutical applications. This is the first comprehensive review that is specifically devoted to particle formation from polymers. We first briefly describe the various supercritical particle formation technologies that have been developed, and then survey the previously published review articles on the supercritical particle formation processes that cover processing of not only polymers but also other organic and inorganic materials. Next, we present a review of the recent technical papers on polymer particle production with an emphasis on developments in the last 4 years. The review is presented in subsections according to the type of polymer particles generated, and the role of supercritical fluids in the experimental technology used. The review describes the recent advances made in the formation of particles from pure polymers, followed by coprocessing of polymers with non-polymeric materials. The focus is more on the practical applications, especially the pharmaceutical applications of this technology. Articles on chemical reaction-based particle formation such as particle formation in polymerization under supercritical conditions were excluded from the review. Even though the focus is on pharmaceutical applications of polymer particles, we hope that this review demonstrates the significant strides that are being made in the supercritical fluid-based particle formation technology for the downstream processing of polymer products in general.
Section snippets
Summary of supercritical particle formation methodologies
Twenty years of usage of supercritical fluids in the particle formation technology has given birth to a number of modified processes that use different nucleation and growth mechanisms of precipitating particles. These are summarized in Table 1 and are briefly described in the following sections.
Previous review articles
Several review articles on supercritical fluid-based particle formation technology have been published during the past decade. These are listed in Table 2. These reviews have concentrated either on a particular experimental technique or on a specific type of material being processed. A survey of these earlier review articles is of value since their appearance, in some measure, correlates with the expansion of interest in the relevant technology within academic institutions and industry. They
Formation of particles from pure polymers
The small size particles of a pure polymer find use in chromatographic applications, as solid adsorbents, as standards for particle sizers and counters, as catalytic support materials, and in other applications where uniformly distributed polymer microparticles are needed. Production of micro- or nanoparticles of polymers using supercritical technology is especially attractive for providing alternative solutions to various problems encountered in traditional techniques. For example, the
Formation of polymer particles containing active ingredients
The successful production of microspheres of pure biopolymers has fueled the interest in generation of polymer particles containing active ingredients that can be used for controlled release applications. Additives such as pharmaceuticals, cosmetics, and agricultural chemicals can be incorporated into the biopolymer particles in order to achieve the delivery of these active ingredients to a targeted location in a controlled manner either by a diffusional process or by degradation of the host
Concluding observations and future trends
This review which covered the recent articles published during 2000–2003 clearly is not and was not meant to be exhaustive. Since the initial submission of this manuscript several new reviews on the broader aspects of particle formation has appeared in the literature [84], [85], [86]. The studies included in the present and in these other reviews have addressed a variety of issues such as particle size reduction, narrowing the particle size distribution, creation of homogeneous particle
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