Current issues relating to anti-solvent micronisation techniques and their extension to industrial scales

Journal of Supercritical Fluids 21 (2001) 159– 177 www.elsevier.com/locate/supflu

Current issues relating to anti-solvent micronisation techniques and their extension to industrial scales Russell Thiering, Fariba Dehghani, Neil R. Foster * School of Chemical Engineering and Industrial Chemistry, Uni6ersity of New South Wales, Sydney 2052, Australia Received 8 August 2000; received in revised form 1 May 2001; accepted 14 May 2001

Abstract Realisation of the potential of dense gas anti-solvent precipitation for commercially viable processing of fine chemicals is hindered by our inability to fully exploit the advantages afforded to dense gases. The feasibility of producing dry uniformly sized micronised material using dense gas technology has been well established on a bench scale. However, translating these advantages to an industrial scale remains a challenge for engineers. In this paper, issues specific to the process scale up of dense gas anti-solvent precipitation are discussed. Anti-solvent precipitation is essentially a mixing process and any predictable increase in production rate is impossible without a thorough understanding of the dominant controlling factors. In this paper the dominant process variables, issues such as safety, cleaning, residual solvent concerns, precipitate sizing and product handling are addressed. © 2001 Elsevier Science B.V. All rights reserved. Keywords: Anti-solvent; Precipitation; Scale-up; GAS; Micronisation

1. An introduction to dense gas anti-solvent precipitation Small scale operations are, in general, relatively easy to design and operate. Very often many of the process limitations that are not apparent on the small scale become significant on the large scale, and may even lead to the failure of translating a unit to commercial dimensions. The gas anti-solvent (GAS) and the aerosol solvent extractions system (ASES) are both developing precipitation technologies for which little scale-up * Corresponding author. Fax: + 61-2-9385-5966. E-mail address: [email protected] (N.R. Foster).

methodology currently exists. Hence it is difficult to exploit many of their advantages on a larger scale with any degree of certainty. In this paper a number of issues are raised in relation to the efficient operation of anti-solvent precipitation and some general modelling and scale-up principles for GAS and ASES are noted. The discussion begins with a number of lessons learnt from recent studies on a bench scale in our laboratory. The problems of experimentally quantifying solution supersaturation and the onset and rate of crystal nucleation and growth are outlined. Issues relating to aqueous and carbon dioxide based systems are also noted. A section dealing with the important areas of residual solvent elimi-

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nation and product recovery from a pressurised environment follow this discussion. Such issues have most relevance in a consideration of process scale-up, which is probably dependant more so on these areas than on scale-up heuristics or proportionality rules. The discussion of particulate recovery then leads on to a number of general comments on the scale up of anti-solvent precipitation technology, and some background on the general theoretical fields that need to be incorporated into mathematical models. The paper concludes with a section contrasting the batch GAS and semi-continuous ASES anti-solvent precipitation processes, whilst referring heavily to experimental records.

1.1. A brief o6er6iew of anti-sol6ent precipitation techniques Anti-solvent precipitation techniques exploit the properties of dense gases — a dense gas being a fluid close to or above its critical point (Fig. 1), where the compressibility is high and density changes dramatically with temperature and pressure. In GAS precipitation a dense gas is chosen to operate as an anti-solvent. The anti-solvent is selected so as to be miscible with the solvent and immiscible, or partially so, with the solute of interest. Dissolution of the anti-solvent in the primary solvent leads to a reduction in the bulk density of the solution and hence causes a reduction of the solubility limits of the solute in the expanded solution. At sufficiently high anti-solvent concentrations, precipitation of solute is induced. Two experimental techniques have been designed to take advantage of this procedure; the batch GAS, and the semi-continuous ASES. The GAS (Fig. 2a) process involves the injection of a dense gas anti-solvent into a solution containing the solute of interest (stages 1 and 2). Upon sufficient expansion of the solvent (to the threshold pressure) a precipitate forms (stage 3) after which the anti-solvent/solvent mixture can be flushed out (stage 4). The ASES technique (Fig. 2b) is the reverse mode of operation, where solution is sprayed into the dense gas anti-solvent environment (stage 2). A significant difference

between ASES and GAS is that for the former the solute bearing solution is dispersed through a nozzle and forms an aerosol before the anti-solvent is able to induce precipitation. As well as this the formation of precipitate is continuous, yet the washing and removal of precipitate is performed in a batch wise manner. The ASES process has also been reported by a number of other acronyms, such as PCA, SAS, SEDS and continuous GAS.

1.2. Applications and ad6antages of dense gas precipitation Dense GAS precipitation is promoted as an effective micronisation and fractionation process. The advantage being that it is able to process thermally labile materials and produce discrete

Fig. 1. Phase diagram and the associated trends in the physical properties of a dense gas as temperature increases. Trends are approximated for a reduced pressure of approx. 1.1.

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Fig. 2. Schematic diagram of (a) the GAS process (1 — solution charging; 2 — CO2 injection; 3 — onset of precipitation; 4 — washing) and (b) the ASES process (1 — system pressurization; 2 — solution injection; 3 — washing), along with photos of the associated solution expansion and precipitation.

powders with a defined morphology and narrow particle size distribution [1], more effectively than conventional milling, spray drying and lyophilisation techniques [2]. Dense gases are characterised by densities intermediate to gases and liquids. As well as this, dense gases have a negligible surface tension between the liquid and vapour phases close to the critical point, and allow solutes to exhibit relatively high diffusivities (with respect to the solvent density). These physical properties in combination allow for the generation of extremely

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small uniform particles due to the unusually high supersaturation concentrations that can be induced. The favourable transport properties of dense gases, and the existence of a homogeneous phase in situ, allow for the rapid removal of trace amounts of organic solvent. When carbon dioxide is used as the dense gas, precipitation occurs in a non-oxidising atmosphere at near ambient temperatures and without the need for the application of high shear forces. Hence, dense gas processing is particularly suited to the processing of thermally, chemically or physically unstable material such as biological compounds, chemical intermediates, pharmaceuticals, dyes and even explosives. Of recent interest has been the use of ASES and GAS for the conduct of reactions, where the reaction occurs at the liquid–vapour interface and the product precipitates out of solution. In these systems the progress of reactions normally limited by equilibrium considerations can be changed considerably in dense gas environments. Many promising applications for dense GAS precipitation techniques have been suggested since the early 1980s. These techniques have been primarily applied to the micronisation [3–6] and or simultaneous fractionation [7–12] of difficult to comminute [13,14] or unstable compounds [15,16]. Hence the focus of research has been directed towards applications in coatings [17], semi-conductors [18,19] and pharmaceuticals [20– 26]. More recently these precipitation techniques have been utilised for the encapsulation of microscopic particles [27–32] and the selective precipitation of product from reaction media. Recent review papers [33–36], including one by Reverchon [37], are excellent summaries of the current developments of these research areas. Nearly all of these applications have been restricted to laboratory scale investigations, though, and to date their extension to commercial scales and the relevant scale-up issues have been largely ignored.

2. Laboratory scale studies The ability of the GAS and ASES anti-solvent processes to manipulate precipitate properties by fluctuations in the anti-solvent density is a com-

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monly quoted advantage. Much research involving a wide variety of solutes now shows that the characteristics of products generated by GAS or ASES are quite difficult to modify by changes to the operating parameters. For example, in general, GAS and ASES processing of a material is surprisingly insensitive to variables such as antisolvent density [19,24,29,38], initial solute concentration [39], temperature [1,14] and nozzle geometry. On the other hand, anti-solvent precipitation processes have been able to produce material with some specific properties by altering the rate at which the supersaturation ratio is increased or by altering the co-solvent concentration [5,13,14,24,40,41]. The effects of these above mentioned operating variables still remains poorly defined.

2.1. Solution supersaturation Solution supersaturation or anti-solvent concentration is the driving force for solute precipitation and hence control of it is essential for reproducible particle properties. Variability of the system supersaturation, and therefore precipitate morphology and size, may easily occur in the region where carbon dioxide compressibility is large, it being the same region in which solute nucleation occurs. It is also best to quote experimental results in terms of supersaturation, rather than solution expansion or pressure, as results are more easily correlated to models or compared to other precipitation processes. Control over supersaturation may best be achieved by following a pressurisation profile that maintains a constant supersaturation ratio. Berends et al. [5] estimated the pressurisation rate required to expand a toluene solution with carbon dioxide whilst maintaining a constant supersaturation, by manipulation of the Ny´ vlt [42] theory for crystallisation. The Peng Robinson equation of state for a binary mixture was then used to calculate the equilibrium concentration during the precipitation process. Tai and Cheng [43] have also endeavoured to reproducibly inject anti-solvent in the GAS process by adding anti-solvent into the vapour space above the solution. The rate of solvent expansion may then be simply con-

trolled by the system pressure and liquid phase mixing. In this work the authors investigated a large range of solute/solvent systems. Solution supersaturation is difficult to measure in the GAS or ASES process. Conventional crystallisation studies have incorporated the use of techniques such as refractometry, conductivity, coulometry, densitometry or direct solution sampling [42,44], but none of these methods are readily applicable to GAS or ASES due to high pressure limitations. Unfortunately few procedures for accurately measuring solution supersaturation in pressurised environments on-line exist. In GAS the supersaturation ratio is often simply but inaccurately recorded as the pressurisation rate profile, where as for ASES it is a complex function of solution diffusivities and jet stream fluid dynamics and has never been reported. To date, for GAS precipitation, only system pressure or the expanded phase volume has been recorded and correlated to equilibrium studies of density and molar concentrations. These indirect variables are the easiest to measure but accurate phase equilibrium data is necessary for calculations and the expansion measurements are complicated by the non-equilibrium of the expanding solution. Another technique involves sampling the expanding solution during the precipitation process in order to correlate the observed phase behaviour to the solution supersaturation concentration, but the errors associated with the procedure are high [40].

2.2. Studying particle nucleation and growth Studies of the fundamental mechanisms behind dense gas processing are currently limited by the difficulty of process parameter measurement online. Hence the progression of the precipitation process is difficult to log. Without this information not even the effects of the start up and shut down of the process can be determined. The difficulty of on-line measurement is due to the extremely short time scale in which the precipitation phenomenon takes place. Observations within such a short time frame are further complicated by the practical problems associated with high pressure technology that requires non-intru-

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sive on-line monitoring. One of the few techniques used to monitor ASES has been the visual observation of the precipitation jet stream in a sapphire tube with a macro-lens camera [45,46]. The atomisation of the jet stream was studied and the effect of solvent densities and nozzle designs assessed. The ability to correlate this information with precipitate size and morphology still does not exist, although it is necessary for the design of ASES precipitation vessels. It must be noted that an ASES vessel must be designed so that solute droplets do not impact upon the walls before they are completely dry [47]. To date, a major difficulty in GAS experimentation has been the inability to accurately quantify the onset and rate of precipitate growth in the expanded phase. Such data, detailing the increase in the size and therefore mass of precipitated particles, is necessary for modelling or any theoretical consideration. These observations are most commonly related to the solution expansion or solution supersaturation. The visible onset of nucleation, known as catastrophic nucleation, may or may not indicate the actual point of nucleation, or the upper boundary of the meta-stable supersaturation region. Recently Tai and Cheng [48,49] constructed a GAS apparatus in which the growth rate and growth mechanism can be observed. This procedure used a temperature change to supersaturate an expanded solution but involved the use of a seed crystal that was visible with a low powered microscope. The growth of the seed crystal was calculated optically as a function of time and the supersaturation ratio. The study of homogeneous nucleation in the GAS process, or any pressurised vessel, is complex and the authors have noted that little has been published in this regard. Smedley et al. [50] examined the precipitation of naphthalene dissolved in supercritical carbon dioxide by rapid depressurisation using laser light scattering with a specially designed optical precipitation cell. The design of the cell allowed for the observation of the light extinction at 0° and light scattering at 15°. From this data both the particle size and number distribution could be calculated (within the ranges of 0.2–2.0 mm and 300 − 3 to 3 × 10 − 6 counts/cm − 3).

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Of the traditional techniques used for studying crystallisation kinetics only some have application for dense gas precipitation. In general experimental procedures can be divided into direct and indirect methods. Direct methods measure the crystal size as a function of time, where as indirect methods measure other system parameters such as solute concentration to enable calculation of the crystal size. Direct techniques may be visual (travelling microscope, laser diffraction), gravimetric or measurement of the zeta-potential of solution. Indirect techniques are suitable for closed systems and parameters such as refractive index and conductance may be measured to determine the solute concentration. As well as these techniques turbidimetric, thermometric, densiometric, sonic absorption and vapour pressure techniques have also been used to study growth kinetics [42]. Of note is also the point that when measuring particle size with a light scattering technique, data is generated on a volume and not number distribution basis. As a result it is not uncommon in a polydisperse sample for the smaller fraction to be under represented due to the washing out of signal by larger particles. These errors are compounded if light scattering data is represented on a number distribution basis, as it commonly is, as the mathematical conversion from volume to number distribution involves a cubic law and therefore a massive increase in any error associated with the measurement.

2.3. Aqueous systems Many dense gas precipitation systems today incorporate the use of water as a co-solvent or solvent. This is particularly the case for protein systems where protein solubility is increased considerably in the presence of water. York and Hanna [26] were some of the first workers to begin publishing extensively in this area with regard to the SEDS procedure. When exposing an aqueous solution to carbon dioxide the reaction of carbon dioxide with water to produce carbonic acid must be considered. The acidity of the solution will be a function of the carbon dioxide vapour pressure. At high system pressures solution pH may reach values close to

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3.0. The formation of carbonic acid is an equilibrium reaction and is dependent on the carbon dioxide pressure, carbon dioxide solubility and the presence of solute. The effect of carbon dioxide vapour pressure upon the acidity of water has been measured under static conditions with a high pressure glass combination pH electrode (MettlerToledo, Germany) and is reported in Fig. 3. At higher pressures the rate of pH decrease slows and above 100 bar does not drop significantly further [51,52]. In the case of protein precipitation, it is particularly important to consider pH effects. If solution pH drops to a value well away from the protein isoelectric point, denaturation may result, or if solution pH approaches the isoelectric point of the protein (i.e. for acidic isoelectric points) precipitation may actually be induced by surface charge changes, rather than by anti-solvent considerations. It is easy to imagine how in other biological systems that acidification at high carbon dioxide pressures can have a significant influence on the system. For example, in the deactivation of bacteria, a decrease in pH within the cell may actually be more important than the subsequent rapid depressurisation of the sterilisation cell [53].

Fig. 3. Solution pH as a function of carbon dioxide vapour pressure. Results shown for pure water and a 4 g/l solution of soy protein.

3. Residual solvent considerations in biotechnological applications Many of the scale-up issues in anti-solvent precipitation are just as much a consideration of the production of solvent free discrete particles as a consideration of scale-up heuristics and proportionality rules. Therefore the importance of producing solvent free product is addressed here. The purity of dense GAS processed precipitates and the elimination of trace solvents from them has been asserted as one of the major advantages of batch and continuous anti-solvent precipitation over conventional precipitation procedures. However, complete elimination of solvent from the micronised product is not always achieved, especially in the case of protein or polymer micro-particle production. The efficiency of removal of residual solvents therefore limits the application that GAS may have in the pharmaceutical or food technology industry, where much of the current research in protein and polymer micronisation has been focused. In the most extreme case of ineffective particle washing, condensation of solvent during system depressurisation (i.e. during product collection) and hence particle agglomeration will result. Therefore the design of a process must involve consideration of vessel hydrodynamics and process control during the washing phase. System hydrodynamics, filtrate compaction, bed depth, porosity, the mass of carbon dioxide required, sweep volumes and solvent/solute interactions need to be considered. Trace solvent concentrations are primarily a function of the effectiveness of the washing procedure. The washing stage in an anti-solvent precipitation must take place after the precipitation stage to both remove solvent from the vapour space and secondly wash solvent from the product. Washing efficiency may be optimised at large anti-solvent densities, due to improved solvent miscibility, and at high temperatures, due to increased solvent vapour pressure. As well as this, operating the washing stage in a hydrodynamic plug flow regime improves vessel flushing and eliminates ‘dead spots’. Hence a larger narrower vessel is most suitable for batch GAS precipitation, and hydrodynamic considerations such as

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these are fundamental to any vessel design. Debenedetti and Reid [54] commented on the laminar or turbulent flow regimes that may occur during the use of supercritical fluids. Washing efficiency in the GAS process has also been improved by performing the operation in the two phase region with a vapour and liquid anti-solvent present [40]. The concentration of organic in the precipitation vessel rapidly decreased by sequentially filling it with a liquid anti-solvent and then flushing it out. Using this technique, residual organic that was preferentially dissolved in the liquid phase was removed under a plug flow regime, unlike washing with supercritical carbon dioxide. Lower residual solvent concentrations are easier to produce in ASES processing by maintaining a large excess of anti-solvent with respect to the solution stream. As a result the concentration of residual solvent in the precipitation vessel is lower at all times, and particle agglomeration is reduced. The difficulty of eliminating solvent from a precipitate product is a function of the solute/solvent affinity with respect to its interaction with the anti-solvent and the spacial complexity of the precipitate. In the case of polymers and proteins, where both factors are significant, the residual solvent concentrations in the precipitate can also be expected to be high. Thiering et al. [40] noted the effect of increasing the amount of carbon dioxide anti-solvent used during the washing of residual DMSO from lysozyme precipitates. Washing with 70 g of anti-solvent (35 °C, 86 bar) yielded a residual dimethylsulphoxide concentration of up to 120 000 ppm, whereas washing with 350 g reduced the concentration to 300 ppm. Note that the mass of protein washed here was typically less than 0.1 g and that the anti-solvent ratio was exceptionally large, due to the relatively large volume in the precipitation vessel (60 ml) that needed to be flushed. Bleich and Mu¨ ller [30] and Ruchatz et al. [55] made similar observations with polylactic acid precipitated from methylene chloride by ASES. In these studies the residual solvent concentration was reduced to 30 and 100 ppm, respectively. Despite the lengthy times taken to wash these products ASES and GAS are still more rapid

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compared with conventional drying techniques. The reduction of methylene chloride in poly(lactic acid) takes days or even weeks for vacuum drying [55]. In some cases solvent may even be incorporated into the crystal lattice [6]. In these cases, due to the high solvent/crystal affinity, extended washing times, high temperatures and excessive volumes of dense anti-solvent are typically required to remove solvent from the product. The injection of a co-solvent into the carbon dioxide stream wash solution may also further reduce traces of poorly soluble or tightly bound solvents. For example ethanol may be added to carbon dioxide in order to help remove water which may be present in a system. In the lysozyme precipitation that was studied by Thiering et al. [40] 5 wt.% ethanol was used to help remove traces of DMSO solvent which was tightly bound within the protein structure by hydrogen bonds [40]. For the same wash volumes the residual DMSO concentration was decreased fourfold. As the recycling of anti-solvent is essential to the economical operation of the ASES or GAS processes [56], the presence of residual solvents in this stream needs to be addressed. Under pressure the carbon dioxide phase may contain a significant concentration of solvent. Depressurisation or cooling may well cause solvent condensation, which needs to be collected before recompression to avoid mechanical difficulties. Activated carbon absorption or a scrubber may be alternatives to a depressurisation or cooling of the carbon dioxide recycle stream. An example of this is in the use of a water scrubber to extract caffeine from its carbon dioxide rich phase in the coffee decaffeination process.

4. Recovery of a fine precipitate The issue of precipitate recovery from a pressurised environment is not a trivial matter, especially where the product is sub-micron, valuable or non-benign. The ability of anti-solvent precipitation to produce uniform particles within the micron size range and smaller has been emphasised as a major advantage in recent GAS and ASES development. However, the continuous and

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efficient recovery of these fine particles has remained an on going problem and a major concern in any efforts to scale up precipitation technology. In this section the importance of on-line recovery of precipitate is discussed and a number of methods for overcoming operational difficulties are proposed. Efficient removal of precipitate is important in both GAS and ASES. Continuous or semi-continuous removal has two main advantages. Firstly it reduces any product degradation due to exposure to solvents present in the carbon dioxide rich phase. The presence of solid product in the precipitation vessel over extended periods of time may lead to solution ripening or aggregation by solute bridging between previously discrete particles. In the case of ASES it allows for smoother long term operation as it prevents the need for start-up and shut down complications during spraying and the need to depressurise the whole system during powder recovery. In ASES the production vessel is also typically large due to the need to prevent jet impingement on the vessel surface. The requirements of the GAS and ASES processes for the continual removal of product are slightly different. ASES induced precipitate needs to be recovered from a pressurised carbon dioxide rich fluid phase whereas GAS induced precipitate is present as a suspension in an expanded solution. Current procedures involve the depressurisation of the precipitation vessel to allow access to the particulate material caught inside. At present most ASES and GAS experimentalists trap the solid product on filtration devices in the outlet stream. This technique is both time and anti-solvent intensive and the metal membranes or frits are prone to blocking with time. In the case of protein or polymer precipitation, where the precipitate is compressible, the caking of filters makes filtration an even more difficult task. On a larger scale, blocked filters are a major safety issue and vessel depressurisation to unblock them is also a costly task. An alternative has been suggested by Sieber and Zehnder [57], who utilised a special ball valve (the details of which were not given) that enabled continuous product recovery from the ASES process.

4.1. ASES On an industrial scale, particle separation from fumes is a result of the gravitational, centrifugal or electrostatic forces imparted to the particles. Particle separation in ASES is essentially the same physical process, except that it operates under pressure. In Fig. 4 the size ranges for which various separation techniques may be employed are shown graphically and compared to the typical size ranges of products produced by ASES and GAS. In Fig. 4 gravitational settling chambers, which have large space requirements, can be noted to only be suitable for particles greater than 200 micron. Cyclones have a higher efficiency and are suitable for particle separation down to approx. 5 micron. Collection efficiency depends on particle size and the circulation velocity at the vessel perimeter. Cyclonic separation devices may also be used in conjunction with scrubbers, where the vessel walls are wet or an inert fluid is sprayed into the gas stream to concentrate the particulate material. The particles may then be recovered in a liquid suspension, which is easy withdrawn through a sampling valve. Wet walled cyclones lead to an improvement in entrainment but are still limited to \ 5 micron [58]. Electrical forces may be used to further enhance the separation of fumes. Electrostatic precipitators operate by charging the particles and then displacing them within an electric field. The particulate matter must be periodically removed from the electrodes. The efficiency of electrostatic separation is primarily a function of the resistivity of the dust particles and, of course, the particle size. Hence generalisations about the suitability of electrostatic separation of ASES produced particles cannot be made [59]. Electrostatic units may also be coupled with cyclones, where the vessel walls are charged. Applying a charge of 10 kV/cm to an electrostatic precipitator has been shown to enable 50–80% removal of 1–2 micron particles. Without an electric charge cyclone efficiency dropped to below 10%. High efficiency air filters may also be used to separate micron sized solids from a vapour stream. Final stage filters give very high separa-

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Fig. 4. Size range of dense gas precipitated material and operating ranges of conventional dust extraction equipment.

tion efficiencies (\ 99.97 +% for 0.3 mm) for even submicron fumes (Table 1). The principle types of high efficiency filters are the HEPA (high efficiency particulate air) and ULPA (ultra low penetration) filters. A disadvantage of HEPA filters being that gas flow rates are limited to 0.03 m/s, and they are bulky units of considerable thickness, more designed for gas cleaning than particle recovery. Electrostatic precipitators are suitable for similar sized particles, but may more importantly operate at much higher flow rates [60].

4.2. GAS In the GAS process, separation of a dry solid product from a suspension is difficult for small sized particles. Particles below 5 micron are no longer influenced by the fluid shear and do not move outside the flow streamlines. Hence collection of this material is most efficiently achieved if it is allowed to first aggregate before it is filtered or settles from solution. In fact the extremely small size of the precipitate formed in a dense GAS process intrinsically leads to agglomeration of particles [19]. Often in the GAS process aggregation is encouraged by increasing the anti-solvent mole fraction to concentrations higher than

the point of initial precipitation. Large anti-solvent concentrations enhance the interaction between particle surface forces. Note that for the particle size ranges typical in anti-solvent precipitation, increased agitation will not significantly influence aggregation as aggregation is predominantly perikinetic1, and therefore too small to carry a momentum imparted to them by the fluid hydrodynamics. Aggregates may be broken up after they have been removed from the pressure vessel by the many conventional techniques available such as ultrasonics or acceleration in an air stream. The subsequent break up of aggregates should in most cases be straightforward as perikinetically grown aggregates are not densely packed. Thiering et al. [40] noted that submicron sized lysozyme particles precipitated from DMSO by the GAS process aggregated at high solution expansions and settled out solely under gravity. The recovered lysozyme aggregates were later successfully dispersed by ultrasound. Another precipitate separation technique was described by Thiering et al. [61] who withdrew a suspension of the precipitated material 1 Perikinetic aggregation is relevant to particles experiencing Brownian motion.

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Table 1 Comparison of air filter efficiencies [84] Filter type

I II III

Efficiency

Low Moderate High (HEPA) Extreme

from the precipitation vessel with a pressure rated centrifugal cell (50 barg). The pressure cell was then fitted to a centrifuge and later depressurised without disturbing the settled material. The procedure was efficient for particles greater than 5 micron in diameter. Work by Weider et al. [62], on the precipitation of fine polyethyleneglycol particles, involved the combination of a number of separation systems. They claimed that the continued use of a gravitational settler, high efficiency cyclone and an electrostatic precipitator was effective in separating the product from the gas stream (Fig. 5). Little information was provided on the system efficiency or yield and no comment was made with regards to the on-line removal of product from the pressurised environment, and the control of pressure within it.

4.3. Further comments on aggregation The significant advantage of GAS and ASES as homogenous precipitation procedures for the production of particles of a narrow size distribution is of no relevance if aggregation occurs within the system. As GAS and ASES product is in the micron size range and aggregation is considerable, it is often the cluster size and not the primary particle size that needs to be considered. If the clusters are broken up by mechanical force this too needs to be quantified before the precipitate product can be considered seriously for its potential industrial application [63]. Aggregation is especially pertinent in biotechnological or pharmaceutical applications where dissolution rate or the rate of particle diffusion is a major function of particle size.

Removal efficiency (%) for 0.3 (mm)

1.0 (mm)

10 (mm)

0–2 10–40 45–85 \99.97

10–30 40–70 75–99 99.99

90–98 98–99 99.9 100

Aggregation of precipitate is not always detrimental, and is often desirable as far as precipitate separation is concerned. The coagulation of particles to larger agglomerates improves the efficiency of any solid separation process. There are two requirements for the coagulation of particles. Firstly, they must come into contact and secondly the inter-particle adhesion forces must be sufficient for the aggregates to retain their structural integrity. The cohesion of particles may be due to either van der Waals or coulombic adhesion forces and, if wet, also capillary forces. The strength of the van der Waals force is a function of particle size and shape, whereas the magnitude of the coulombic force is a function of particle surface charge, and capillary forces are a function of fluid surface tension and particle shape. Particles may be transported through a fluid by their inertia or via their molecular diffusion, that

Fig. 5. Polyethyleneglycol precipitate collection apparatus [62].

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Table 2 Rate of diffusion of dust in air Particle diameter (mm)

10

Diffusion coefficient (cm2/s)

2.4×10−8

is, Brownian motion. Only particles larger than 5 micron are able to experience inertial displacement. Inertial displacement occurs when the shear forces imparted by the fluid to the particle are great enough to allow it to move across the streamlines. Hence the rate of aggregation of large particles often increases in turbulent streams, where the likelihood of collision increases. Such aggregation has been termed orthokinetic aggregation. On the other hand, particles smaller than about 1 micron are unable to pass across streamlines and hence are not influenced by the intensities at which a suspension is agitated. Such particles only collide and aggregate due to their molecular diffusion, and this process is called perikinetic aggregation. If particle mobility is calculated from Stoke’s Law as a function of particle diameter, it becomes apparent that the diffusion coefficients are a strong function of particle size (Table 2). The diffusion of particles may be enhanced if their net charge is non zero and they are exposed to an electric field. 5. Issues relating to process scale-up

5.1. What is industrial scale? Traditionally in the chemical industry, the terms commercial and ’large’ scale raise connotations of vessels and reactors capable of processing tonnes of material per day. However, dense GAS precipitation processes have generally not been promoted as viable processing techniques for the production of bulk chemicals. Dense gas technology is more appropriately applied to the specialty chemical industry; for example in pharmaceuticals, food technology, encapsulations, semi-conductors and in specialty chemical reactions. What then is meant by the terms, large or industrial scale, when used to describe GAS or ASES precipitation processes?

1

0.1

2.7×10−7

6.1×10−6

0.01

0.001

4.0×10−4

3.8×10−2

Consider a process to produce a fine pharmaceutical with a market value of hundreds to tens of thousands of dollars per gramme, which is realistic for human therapeutic agents, enzymes for research or diagnosis, monoclonal antibodies, hormones and so on. It is also not uncommon for therapeutic enzymes to approach many hundreds of thousands of dollars per gramme. The market value of some of the products processed in this work is given below (Table 3). A realistic assumption of annual production rate for some of these compounds would be in the order of 0.1–2 tonne per annum. For a continuous GAS plant this translates to a production rate of 10–230 g/h, which is a rate easily achievable using a bench scale apparatus. For example Gilbert et al. [64] have discussed the use of a 2 l precipitation vessel which was able to process 80 g/h. Hence for high value added fine chemicals, bench scale continuous GAS is synonymous with industrial scale. Realistically, though, it may often be more economical and wiser to invest capital in larger continuous GAS precipitation rigs and operate them as multi-purpose units, producing a range of several different products. For a similar production rate of 0.1–2 tonne per annum, using batch GAS, it is estimated that a vessel 1.5– 25 l in volume would be required (calculated assuming a precipitation yield of 100% from a 5 mg/ml solution with a 30 min processing cycle time). Therefore batch GAS precipitation on a commercial scale requires considerable extenTable 3 Some of the specialty chemicals used in this work (2000) Product

Value (US$/g)

Insulin, human recombinant Hypericin Deoxyribonuclease I, bovine

1800 90 000 18 000

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sion from a laboratory apparatus after the optimum operating conditions have been defined, especially if the working solution is dilute.

5.2. Scale-up considerations Scale-up or translation is the redesigning of a process to accommodate higher product throughputs, which may or may not necessarily involve an increase in reactor or vessel size. In fact, successful scale-up is the determination of the most compact, economical and efficient design for a specific process. Before scale-up is possible, the controlling or dominant factors in the process must be determined and the effect of scale on the mechanism understood. Vessel scale affects volume processes, such as anti-solvent precipitation, much more than surface or interface limited processes, such as GAS. Additionally, mixing processes with large density differences or multiple phases are difficult to scale. In a further complication, the dominant mechanism, the physical properties, the hydrodynamics and many other variables may all change independently upon an increase in scale. This section does not attempt to provide a detailed account of scale-up rules for high pressure processes, but instead some of the important considerations are noted. GAS and ASES are essentially mixing processes. The rate at which anti-solvent is mixed homogeneously into solution affects the rate of change of the solution supersaturation, and hence the nature of the nucleation and growth of the precipitate. Therefore the vapour– liquid mixing is the primary property that affects precipitate size, morphology and quality. Scale-up of mixing dependant processes must be based upon whichever of the following factors is the dominant mechanism; the mixing geometry, flow patterns (both mechanical and convective), residence times, micromixing, multiple phase mass transfer coefficients, interfacial areas, chemical effects and power load. Ideally upon scale-up the process should be mixed efficiently enough so that it becomes kinetically limited and hence controlled by the process variables such as temperature and pressure.

It is important to consider how the GAS process changes with scale as it is a volume dependant process that is hard to represent on a small scale. Such surface area to volume considerations are a common difficulty in scale-up. For example a linear scale-up factor of 10 will result in a 103 volumetric increase. Thus in the case of GAS, where end effects are very important (i.e. because the vapour–liquid interfacial area effects mass transfer), direct linear scale-up does not accurately represent the process. It should also be noted that the heats due to mixing, compression and depressurisation will scale-up in proportion to volume. Often on scale-up, massive internals are added to a vessel to account for such added heat transfer difficulties. The prepressurisation of the GAS precipitator with an inert gas is a convenient way of by passing these heat transfer considerations [65]. Another issue will also be the formation of significant amounts of precipitate at high pressures. Scale-up considerations in ASES are slightly different, as the controlling variable in ASES is the droplet size. The droplet size, along with vapour pressure and diffusivities will affect the rate of droplet swelling, due to anti-solvent diffusion into the solution, or droplet evaporation, due to solvent diffusion into the anti-solvent. Jet atomisation processes may be scaled up using some dimensionless groupings such as the Reynolds, Weber, Ohnesorge, Capillary or Bond numbers. As jet hydrodynamics are controlling, the simplest scale-up option remains a modular design, where nozzle characteristics are identical to the laboratory scale unit and the atomisation chamber increases to accommodate a larger number of nozzles. Product collection would occur in a pressure lock (Fig. 6a) or in a series of collection vessels arranged in series (Fig. 6b) — the advantage being that the actual precipitation process, which is critical to product quality, remains continuous, whereas the product separation system which is not as critical remains batch-wise. It is also necessary to note that ASES is fundamentally more suited than GAS precipitation to large scale operation, as the liquid–vapour mixing intensity can still be maintained at larger scales than GAS precipitation. Both the GAS and ASES

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taneously with regard to the fluid mechanics, which are generally multi-component and multiphase. Crystallisation rate, particle size distribution, width of the meta-stable region, the suspension characteristics, solute and solvent composition and solvent diffusivity and density all vary with respect to time and anti-solvent concentration. Currently no model is able to adequately describe growth kinetics over a large supersaturation concentration range in conventional systems [66], let alone under the novel conditions of dense gas precipitation. To date models have been correlative rather than predictive. Four general areas need to be considered in order to mathematically characterise these crystallisation processes: “ the ternary phase behaviour and properties of the solute/solvent/anti-solvent system [8,45,67– 70]; “ the fluid dynamics; in GAS the particle suspension and vapour/liquid contacting; in ASES the mixing in the expanding jet-stream [27,28,45,46,71,72]; “ the nucleation rate [66,73]; “ the growth rate [5,14,42,48,72,74–76].

5.3. Current pilot plant research

Fig. 6. Larger scale conceptual design for ASES, with (a) pressure lock and (b) modular precipitate separation units.

procedures are mixing processes, and in GAS, sparging induces liquid–vapour mixing. On a larger scale mixing in a GAS vessel may be increased by the addition of a mechanical mixer, but mixers in large pressure vessels becomes troublesome. The need to quantitatively and qualitatively characterise GAS and ASES crystallisation in order to scale it up to a production process is obvious. Ideally a mathematical model should be capable of accounting for the hydrodynamics, supersaturation concentration, solvent evaporation rate and the anti-solvent diffusion effects. Heat and mass transfer must be considered simul-

The successful scale-up of an experimental or bench scale procedure is usually dependent upon the existence of a good model. No model has yet been successfully applied to either the ASES or GAS process as relatively little is still known about the nature of dense gas anti-solvent precipitation. A fundamental understanding of the thermodynamic and kinetic phenomena is necessary for the consistent production of high quality product and to increase the certainty of scale-up success to an acceptable level. Scale-up can be simplified by a modular design incorporating a series of smaller volume vessels. In GAS the vessel size is limited by fluid dynamics, which in turn controls the ability of a system to rapidly reach phase equilibrium as well as the efficiency of the precipitate washing procedure. An interesting multi-stage GAS separator was trialed by Shishikura et al. [7,77] and consisted of a series of precipitation vessels that sequentially step up pressure, precipitating different solutes in

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each vessel. A modular design is also well suited to the ASES process as this micronisation technique relies on the ability of a fine nozzle to atomise a stream under controlled conditions. The processing of large volumes of solution could be achieved by using a series of nozzle systems. Although no comprehensive model exists, considerable effort recently has been invested in the design and development of scaled up GAS and ASES precipitation processes [64,72,78,79]. Such pilot scale units contain a single vessel for the formation and drying of precipitate and another vessel for anti-solvent recovery. Temperature and pressure control is used to allow the anti-solvent to be recycled. The actual design of these scaledup units differs very little from the bench scale experimental units discussed in earlier sections and no comments are made on the techniques used for precipitate washing and recovery. The economics of a 250 l ASES crystallisation plant have been estimated from a 10 l bench scale model by Weber et al. [79]. The product yield and plant capacity were calculated from the model and major economic considerations such as capital investment, tax and operating costs were considered. A 250 l plant was estimated to produce a product competitive with existing fine chemical processes. King et al. [80] provides some useful information of the costing of high pressure chemical equipment such as compressors.

6. Batch GAS or semi-continuous ASES precipitation? Both the ASES and GAS precipitation processes are capable of generating uniform micron sized precipitate, yet they differ on a number of counts, including the ease with which they may be scaled-up. For a specific process the choice of whether to precipitate with GAS or ASES is as much a consideration of the cost of the precipitation chamber (which is larger in ASES), the safety requirements, cleaning and maintenance concerns (due to abrasion by solids) as it is the control over the precipitation process and the final product morphology. In a recent paper Perrut [81] discussed a number of maintenance and cleaning

matters in larger scale apparatus and these are not considered further here. Instead both the batch GAS and semi-continuous ASES process are compared, in order to gain a more complete understanding of anti-solvent precipitation. To date little research has compared these two experimental techniques which are the two operating extremes of dense gas precipitation. Even if GAS, for example, is an appropriate precipitation technique on a laboratory scale there is no guarantee that it will be the most appropriate anti-solvent process on a larger scale. Traditionally in supercritical carbon dioxide processing, unit operations have been batch wise, which in many cases results in limited versatility. As well, in the case where solid material must be handled, difficulties are encountered during the loading or recovery of the solids from a pressurised vessel. As a result anti-solvent precipitation processes are often single stage batch or at best semi-continuous. Supercritical batch processes (GAS) are disadvantaged by the large processing times required to load, pressurise, depressurise and unload the vessel and also the high energy costs and equipment wear caused by frequent pressure cycling. The ASES process has generated interest due to its ability to create finer precipitates and its apparently straightforward inclusion into continuous commercial scale processes. However, even though the solution is fed continuously into a recycled anti-solvent phase, no simple procedure exists for separating the precipitate on-line. The GAS and ASES procedures differ in the ease with which they may be controlled. The rate of change of solution supersaturation in ASES is so rapid that in practice changing the relative rates of anti-solvent and solvent diffusion, by altering system temperature or pressure cannot easily control it. On the other hand, in the batch process the solution supersaturation may be accurately controlled. The commercialisation of the GAS process is driven by the ease with which process parameters can be controlled and the generation of higher product yields. Yeo et al. [24] used the ASES and GAS processes to precipitate a substituted para-linked aromatic polyamide. The GAS process produced

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particles with a high degree of sphericity, whereas ASES produced fibrous polymer. The different hydrodynamic events in both processes were used to explain this significant difference in morphology. In the ASES process the shear forces of the solution jet caused an alignment of the polymer chains, whereas in the GAS precipitation vessel the solution was poorly agitated and polymer alignment remained random. Steckel et al. [82] and Gallagher-Wetmore et al. [20] studied the precipitation of the steroid dexamethasone, using both techniques and observed surprising differences in morphology due to hydrodynamics. The GAS process was able to produce discrete micron sized particles, whereas a film precipitated on the vessel walls in the ASES process. Although the solvents differed in these studies it is important to note that despite the formation of discrete particles, the shear forces involved can dramatically change the morphology of precipitates and a discrete or free flowing product may not necessarily result. The ability of ASES to produce finer particles than is possible with GAS, is often considered an advantage of the process, and is for example supported by the precipitation of para-hydroxybenzoic acid (p-HBA) from methanol, acetone or ethyl acetate [6]. In each solvent the size of the crystalline precipitate produced by ASES was smaller than that formed by GAS, which was in turn smaller than that produced by conventional solvent evaporation (Fig. 7). For example p-HBA precipitated from ethyl acetate by ASES was 100 times smaller than those produced by GAS. Such conclusions drawn from the study of low molecular weight molecules cannot be extended to systems precipitating macromolecules, such as proteins or polymers. A study of insulin precipitation from dimethylsulphoxide by Yeo et al. [3] shows the opposite trend in particle size. The average size of the spherically precipitated protein was approximately doubled in the ASES process. The large driving force in the ASES process that produces fine particles may not be significant for macromolecules such as protein. Thiering et al. [83] also found the size of insulin

and was that size

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myoglobin precipitated by ASES and GAS not significantly different. It was observed the ASES product had a relatively broader distribution and was more irregular and

Fig. 7. Examples of the morphology of p-HBA precipitated by (a) solvent evaporation at RTP (scale: 25 mm), (b) the GAS process (scale: 25 mm) and, (c) ASES process (scale: 25 mm).

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amorphous than that precipitated at more moderate rates of solution expansion. Similarly Benedetti et al. [1] observed this trend in particle size by precipitating HYAFF-11 polymer from a dimethylsulphoxide solution with carbon dioxide. Polymer was precipitated with a narrow particle size distribution and average diameter of 0.4 mm by the GAS process, whereas ASES precipitated polymer had an average diameter of 18 mm and a broad size distribution. GAS and ASES have also been used as separation and co-precipitation techniques. Chang et al. [12] attempted to separate b-carotene from carotene oxidation products. ASES proved to be a much more efficient separation process than GAS, which generated separation factors of 7.34 and 2.17, respectively. The result is surprising, as precipitate purity is typically poorer at larger crystal growth rates. Under conditions closer to a thermodynamic equilibrium the b-carotene molecules should preferentially associate and precipitate as a purer solid. Yeo et al. [3] studied the co-precipitation of aromatic polyamide and lithium chloride in N,Ndimethylacetamide, and noted the opposite phenomenon. In the ASES process the polymer and salt was precipitated as an intimate mixture due to the rate of precipitate growth. The precipitate was a viscous, paste-like material. GAS precipitation was unable to co-precipitate the polymer and salt as the polymer was preferentially precipitated at significantly lower solution expansions than the salt.

7. Conclusions Liquid–liquid anti-solvent precipitation processes have been used in the chemical, petroleum, food, cosmetic and petrochemical industries for many decades as both separation and purification processes. A fundamental understanding of the mechanics and kinetics of these processes has been essential to their development and design. GAS and ASES are specialised dense gas precipitation techniques that have recently been developed. By using them it is possible to produce

monodisperse micron and submicron particles for application in many technical applications; that is as absorbents, chromatographic packing, ion exchange media, pharmaceuticals, cosmetics, food processing, photographic substances, dyes, lacquer as well as explosives. GAS and ASES have also been used as separation or purification techniques where solutes are selectively precipitated or recycle streams are cleared of impurity, such as in the pharmaceutical industry where recycled solvent must be monitored for its purity. These dense gas anti-solvent techniques are favoured by their ability to control particle characteristics such as shape, size, internal structure (i.e. solvent inclusions), and residual solvent concentration, but little is still known about the fundamental mechanics of the processes. The recent extension of dense gas precipitation techniques into the micronisation of ceramic and superconductor precursors, pigments and pharmaceuticals has opened up exciting new avenues of research. Dense GAS techniques have also recently been used for the preparation of membranes and the purification of drugs, especially crystallisation separations. Reactions are now being studied in expanded gases to take advantage of the tunable solvent power of these fluids to maximise the differences between the reactant and product solubilities. The rapid development of dense gas precipitation has not only been hindered by its capital intensive nature, as often stated, but also by the lack of suitable design procedures or models. Questions concerning the control over particle size, the concentration of residual solvent and precipitate agglomeration have still not been fully addressed. Specific challenges regarding the ASES process include the characterisation of a sprayed solution and its influence on precipitate morphology. Ideally a continuous production capability is being sought for dense gas precipitation processes in order to improve process control and reproducible product quality. A truly continuous antisolvent precipitation process has not yet been developed that allows for the continued removal of precipitate from a pressurised vessel on a production scale.

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