Review
Design and process aspects of laboratory scale SCF particle formation systems

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Abstract

Consistent production of solid drug materials of desired particle and crystallographic morphologies under cGMP conditions is a frequent challenge to pharmaceutical researchers. Supercritical fluid (SCF) technology gained significant attention in pharmaceutical research by not only showing a promise in this regard but also accommodating the principles of green chemistry. Given that this technology attained commercialization in coffee decaffeination and in the extraction of hops and other essential oils, a majority of the off-the-shelf SCF instrumentation is designed for extraction purposes. Only a selective few vendors appear to be in the early stages of manufacturing equipment designed for particle formation. The scarcity of information on the design and process engineering of laboratory scale equipment is recognized as a significant shortcoming to the technological progress. The purpose of this article is therefore to provide the information and resources necessary for startup research involving particle formation using supercritical fluids. The various stages of particle formation by supercritical fluid processing can be broadly classified into delivery, reaction, pre-expansion, expansion and collection. The importance of each of these processes in tailoring the particle morphology is discussed in this article along with presenting various alternatives to perform these operations.

Introduction

The central role of solvents in the processing of pharmaceutical materials is widely accepted since the origin of modern pharmaceutical processing. It is only in the recent past that the adverse effects of the residual solvents from both processing and environmental standpoints have been recognized. Strict regulations on the use of organic solvents and their residual level in the end products form a major limitation to the traditional processing techniques. In an effort to reduce the use of volatile organics, search for alternative techniques of material processing developed as a new facet to pharmaceutical research. Supercritical fluid (SCF) technology is an outcome of such research with particular emphasis in the green synthesis and particle formation. Particle formation using supercritical fluids involves minimal or no use of organic solvents, while the processing conditions are relatively mild. In contrast to the conventional particle formation methods, where a larger particle is originally formed and then comminuted to the desired size, SCF technology involves growing the particles in a controlled fashion to attain the desired morphology. The adverse effects originating from the energy imparted to the system to bring about size reduction can thus be circumvented. Typical among the adverse events are the formation of non-crystalline domains, phase changes in the physical form, high surface energy and static charge and occasional chemical degradation. Growing particles from a solution in a controlled fashion, on the other hand, means that the rigid solid particle, once formed, does not have to undergo the thermal and mechanical stresses. This feature makes supercritical fluid technology amenable to produce biomolecules and other sensitive compounds in their native pure state.

Growing demands on the particle and crystalline morphologies of pharmaceutical actives and excipients, coupled with the limitations of current methods, brought wide attention to SCF technology (York, 1999). The technology is rapidly evolving, as reflected by the number of modified processes reported since its inception. These include static supercritical fluid process (SSF) (Lindsay and Omilinsky, 1992), rapid expansion of supercritical solutions (RESS) (Matson et al., 1987), particles from gas-saturated solutions (PGSS) (Weidner et al., 1995), gas antisolvent process (GAS) (Gallagher et al., 1989), precipitation from compressed antisolvent (PCA) (Bodmeier et al., 1995), aerosol solvent extraction system (ASES) (Bleich et al., 1993), supercritical antisolvent process (SAS) (Bertucco et al., 1996), solution enhanced dispersion by supercritical fluids (SEDS) (York and Hanna, 1995) and supercritical antisolvent process with enhanced mass transfer (SAS-EM) (Gupta and Chattopadhyay, 2001). Refer Table 1 and Fig. 1 to distinguish various processes and to identify the critical attributes controlling the particle morphology. Adaptations to the above generic processes also exist, among which the notable ones are ferro micron mix (Mandel, 2002), carbon dioxide-assisted aerosolization (Sellers et al., 2001, polymer liquefaction using supercritical solvation (Shine and Gelb, 1998) and biorise (Carli et al., 1999) technologies. While it is not the intent of this article to dwell on the subtle differences in the above techniques, it serves as an efficient means of following the chronological developments of the technology as new understanding emerged. Further, the existence of so many closely related patents serves as a testimonial to the current interest in SCF particle formation and the restrictions on the freedom to operate.

A common feature in all the above particle formation techniques is the function of SCF as a reprecipitation aid. The basic advantages like rapid and uniform nucleation of solute(s) remain the same in all the processes, although the mode and mechanism of particle precipitation varies depending on the manner in which the SCF is used to precipitate particles. Essentially, all the abovementioned techniques can be classified depending on whether the SCF is used as (i) a solvent, e.g. RESS (ii) a solute, e.g. PGSS and (iii) an antisolvent, e.g. SAS. Refer to Table 1 and Fig. 1 for further details of this classification. Solubilization, plasticization and diffusion properties of supercritical fluids are utilized in static supercritical fluid process, RESS and PGSS processes. On the other hand, rapid mass transport between SCF and the continuous phase carrying the material to be processed is of interest while dealing with the antisolvent precipitation processes.

Carbon dioxide is regarded as a favorable processing medium and is the commonly used SCF for pharmaceutical applications. It is generally regarded as safe (GRAS), chemically inert, non-flammable, inexpensive, has a low critical temperature and pressure and exhibits solubilization and plasticization effects that can be varied continuously by moderate changes in pressure and temperature. The solvent properties of supercritical carbon dioxide are reported to resemble those of hexane, toluene, isopentane and methylene chloride depending on the pressure and temperature conditions of the fluid (see Fig. 2) (Hyatt, 1984, Dandge et al., 1985, Dobbs et al., 1987, Ting et al., 1993). From a feasibility standpoint, compounds exhibiting significant solubility behavior in the SCF of interest are most suitable for RESS process (for example, lipophilic compounds with low molecular weight and high vapor pressure for SC CO2). PGSS is ideal for processing low melting compounds that exhibit negligible interaction with the SCF and more importantly, significant thermal stability. Antisolvent processes, on the other hand provide more flexibility in choosing the precipitation conditions through the use of solvents and solvent mixtures and by manipulating the solvent extraction conditions of SCF. Excepting ferro micron mix (Mandel, 2002), PGSS (Mura and Pozzoli, 1995) and SEDS (Bonner, 2000) processes, which have been scaled up to the tune of producing 1 t particulate solids per year, the progress with other techniques is by far only limited to the research laboratories. For the purposes of clarity in this manuscript, lab-scale and pilot-scale particle formation systems are distinguished on the basis of their product throughputs. Lab-scale systems typically produce few grams of particulate solids per hour while the throughput of pilot scale systems are of the order of few kilograms per hour.

Scale-up of RESS process is limited by the poor solubilities of many pharmaceutical actives and excipients in commonly used supercritical fluids. While a semi-pilot scale particle production of saquinavir was demonstrated in a Roche patent (Bausch and Hidber, 2001), the solute throughputs are still prohibitively low to earn commercial value for RESS scale-up. Antisolvent processes, on one hand provide more flexibility in the variety of compounds that can be processed. The downside however stems from the agglomeration of the particles containing un-extracted residual solvents. Means of containing the agglomeration to retain the original particle characteristics have been the subject of interest in several closely related patents (Sievers and Karst, 1997, Kulshreshtha et al., 1998, Schmitt, 1998, Hanna and York, 2001, Pace et al., 2001, Merrified and Valder, 2000, Gupta and Chattopadhyay, 2002) and form the scope of GAS, PCA, ASES, SAS, SEDS and SAS-EM processes. Associated scale-up issues with the various antisolvent processes have been extensively covered in a recent publication by Thiering (Thiering et al., 2001). While large inroads remain to be made, the potential for SCF technology appears immense as reflected by the wide gamut of pharmaceutical applications reported to date. Further, the appearance of a number of reviews on this subject in the recent pharmaceutical literature is a testimony to its potential. (Subramaniam et al., 1997, York, 1999, Kompella and Koushik, 2001, Jung and Perrut, 2001, Tan and Borsadia, 2001). Table 2 summarizes the various applications of supercritical fluid technologies in pharmaceutical material processing. The initiatives of major pharmaceutical industries in tapping this potential through acquisitions or co-developmental work with diverse supercritical research groups are illustrated in Table 3.

Given the commercialization of SCF technology in the extraction of coffee, hops, flavors etc. and in analytical chromatography, the majority of the currently available off-the-shelf SCF instrumentation is designed for extraction purposes. Only a few selective vendors appear to be in the early stages of manufacturing equipment specific to particle formation (Table 4). A general practice however, as reflected from the reported publications and patents, is to reconfigure a commercially available system specific to the end use. It is the purpose of this article to provide such information and resources necessary for startup research involving particle formation using supercritical fluids. The various stages of supercritical particle formation can be broadly classified into delivery, reaction, pre-expansion, expansion and collection and SCF recycling. The importance of each of these processes from the standpoint of tailoring the particle morphology is discussed in the following sections while also providing various alternatives to perform these operations. Issues on the safety are an integral part of any high-pressure operation and are addressed in the final section of this manuscript.

Section snippets

Supercritical fluid delivery

The critical point for any pure substance is defined by the temperature and pressure coordinates, above which no physical distinction exists between the liquid and gaseous states. Substances above the critical point are referred to as ‘supercritical fluids’. In contrast to the other transitions of state, the phase change from the liquid or gaseous state to the supercritical fluid state is not a first-order phenomenon, although most physical and transport properties change abruptly around the

Processing

The processing vessel (also called as pressure vessel or a reaction vessel) is where the supercritical fluid is brought in contact with the material(s) to be processed. Essential requirements for a processing vessel are chemical inertness, ability to withstand the operating temperature and pressure conditions and ASME-specified design. Several designs of the pressure vessels are currently available and in general are distinguished by the type of closures. Different closures vary in the nature

Pre-expansion

The composition and phase of the supercritical solution from which particles precipitate is found to have a major effect on the particle morphology in RESS and PGSS processes and is controlled during the pre-expansion stage (Weidner et al., 1996, Helfgen et al., 2000). Independent control of the temperature and pressure during the pre-expansion stage is therefore critical in these processes. Additionally, the phase changes in the supercritical solutions, which often lead to plugging of the

Spray configurations

In supercritical fluid particle formation, the fluids are expanded through a restriction device in a controlled fashion. Two critical aspects of rapid expansion that are of interest in the context of controlling particle morphologies are: (i) the supersaturation profile of solutes as temperature, pressure, phase and composition changes during the expansion (thermodynamics) and (ii) mechanical shear that a particle undergoes in the subsonic and supersonic regions of the expanding supercritical

Particle collection

Retaining the original characteristics of the particles produced by supercritical fluid process is as critical as forming the particles and constitutes the particle collection step. This step is critical in that the distinct characteristics of the particles can be completely lost owing to a poor collection technique (Turk, 1999). Although it is recognized that the issues of particle collection will become more apparent during the process scale-up, very little research has been directed toward

Recycling

The commercial viability of a technology depends not only on its scientific virtues but also on the cost of instrumentation and operation. High-pressure operations with such sensitivity as supercritical fluids require sophisticated control systems for precision and safety. Apparently, the associated costs of building such instrumentation are high. The capital costs for building a developmental non-cGMP supercritical fluid plant capable of processing 20 kg/day are estimated to be 2 million

Safety

In a recent publication (Lucas et al., 2003), Lucas et al. have presented an excellent treatise on the safety aspects of supercritical processing in general and extraction in specific. The authors have not only laid out the potential areas of hazard while dealing with SCF equipment, but also performed a model-based safety analysis. While the above work should be treated as a primary reference in developing the safety guidelines, the present discussion attempts to specifically cover aspects

Summary

Current advances in pharmaceutical research have not only contributed to the discovery of various new technologies but also identified the potential limitations of the conventional techniques of material processing. Among the different nascent technologies currently under investigation, supercritical fluid-aided particle formation is reported to operate under relatively mild conditions making the process amenable to sensitive molecules, enzymes, proteins and other macromolecules (Yeo et al.,

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