6476
Ind. Eng. Chem. Res. 2003, 42, 6476-6493
Processing Pharmaceutical Compounds Using Dense Gas Technology Neil Foster,†,‡ Raffaella Mammucari,† Fariba Dehghani,*,†,‡ Angela Barrett,†,‡ Keivan Bezanehtak,‡ Emma Coen,‡ Gary Combes,‡ Louise Meure,†,§ Aaron Ng,†,‡ Hubert L. Regtop,‡ and Andrian Tandya†,‡ School of Chemical Engineering and Industrial Chemistry, University of New South Wales, Sydney 2052, Australia; Eiffel Technologies Limited, Level 14/50 Market Street, Melbourne, Victoria 3000, Australia; and CRC for Polymers, 32 Business Park Drive, Notting Hill, Victoria 3168, Australia
Dense gas techniques, which utilize the properties of fluids in the vicinity of the critical point, are increasingly being used for the processing of pharmaceuticals. Dense gases are unique solvents that can be used for extractions, chromatographic separations, and chemical syntheses because of their liquidlike solvation power and gaslike mass-transfer properties. The processes can be conducted at moderate temperatures and are thus suitable for many heat-labile compounds such as proteins, biocompatible polymers, and pharmaceuticals. The products formed by densegas processes are generally free of residual solvent. Recent applications of dense gas techniques have focused on micronization; crystallization of high-purity particles; sterilization; and drug formulations, including the formation of liposomes and drug coatings. The following review presents examples of drug extraction, separation, synthesis, sterilization, and particle formation and demonstrates the broad application of dense gases for drug formulation purposes in the pharmaceutical industry. Introduction Dense gases (DGs) have unique properties that make them suitable for various applications such as extractions, reactions, and particle formation processes. In recent years, great interest has been expressed in the field of DG technology in an attempt to find alternative and improved methods of pharmaceutical processing. A substance can generally exist in any of three phases: solid, liquid, or gas. On a pressure-temperature diagram for a pure substance, these regions are clearly defined by phase boundaries, as shown in Figure 1. For all molecules, various phases can coexist up to the critical point. As pressure and temperature increase above the critical point, the liquid and gas phases become indistinguishable. Beyond this point, the substance exists as a supercritical fluid (SCF). In the supercritical region, only a homogeneous medium exists. It is thus possible to construct a path, from A to B, as shown in Figure 1, to induce a phase change from liquid to gas without passing through a distinct phase transition. A substance close to, but not necessarily above, its critical point is referred to as a DG. The properties of DGs can vary widely but are generally intermediate between those of gases and liquids. The density of a DG, such as an SCF, is generally closer to that of conventional liquid solvents and several orders of magnitude higher than that of conventional gases. The comparatively high density accounts for the solvating capabilities of DGs. The density of a DG is also highly sensitive to * To whom correspondence should be addressed. Tel.: +61-2-93854814. Fax: +61-2-93854321. E-mail: f.dehghani@ unsw.edu.au. † University of New South Wales. ‡ Eiffel Technologies Limited. § CRC for Polymers.
Figure 1. Pressure-temperature diagram for a pure substance.
temperature and pressure fluctuations. Because density is an indicator of the solvating power of a DG, the degree of extraction and separation of compounds using DGs can be controlled by simply adjusting the temperature and pressure of the system. The mass-transfer properties of DGs, such as diffusivity and viscosity, are closer to those of conventional gases and enable efficient penetration into solid matrixes and rough surfaces. The enhanced mass-transfer properties of DGs combined with a very low surface tension make DGs advantageous for extraction applications compared to conventional solvents. Carbon dioxide is the most commonly used DG, as it is environmentally benign, nontoxic, nonflammable, noncorrosive, and abundantly available. Carbon dioxide is also poorly miscible with water and is a good solvent for many low- to medium-molecular-weight organic compounds as a result of acid/base, induced dipole, and quadrupole interactions with solutes. The characteristics of CO2, particularly its low critical temperature, make it highly suitable for the processing of many heatsensitive compounds, such as pharmaceuticals. The replacement of toxic and more expensive solvents, such
10.1021/ie030219x CCC: $25.00 © 2003 American Chemical Society Published on Web 10/02/2003
Ind. Eng. Chem. Res., Vol. 42, No. 25, 2003 6477
as chlorofluorocarbons and carbon tetrachloride, with CO2 overcomes concerns regarding solvent residue and solvent waste. The utilization of DGs requires the use of pressure in excess of 40 bar. The need for high-pressure equipment can represent a major drawback in terms of capital investment and, ultimately, in the acceptance and application of DG technology in industry. A major advantage of DG processes is that, typically, no further product purification or separation stages are required. This is advantageous in the manufacture of high-value and specialty chemicals, such as pharmaceuticals, where high product purity is essential. Furthermore, the solubility of compounds in DGs can be increased by the addition of cosolvents, also referred to as entrainers or modifiers. Because most fluids with moderately low critical temperatures (less than 100 °C) are nonpolar, the addition of polar solvents (typically 1-5%) such as methanol and acetone to the DG can increase the solubility of the compounds by several orders of magnitude. The addition of cosolvents can also improve solute selectivity for extraction applications.1 Stahl and Schilz first reported the potential of DG processing in pharmaceutical applications in their work involving the extraction of natural lipophilic substances from plants.2 Since then, the application of DGs in the processing of pharmaceutical compounds has received increasing interest, primarily due to the ability to utilize a nontoxic solvents such as carbon dioxide (CO2), as well as the ability to operate at mild temperatures and with minimal use of organic solvents. Numerous recent studies have focused on the precipitation of pharmaceutical compounds by employing DGs as antisolvents. The advantages of utilizing DGs for the processing of pharmaceuticals are mainly due to the tuneable solvating strength and transport property characteristics of these fluids. The extraction of valuable constituents from natural materials, such as cholesterol and lipids from animal fats or chemotherapeutic drugs and antitumor compounds from plant materials, has been carried out using DGs. The success of DG extraction in the field of pharmaceuticals has been reflected by the development of industrial plants and increased research interest. An example of an industrial plant that utilizes dense CO2 for the processing of fine chemicals and pharmaceutical intermediates is the Thomas Swan and Co. plant in the U.K. This plant has been successfully operated at a capacity of 1000 kg/h of CO2 and at pressures up to 500 bar.3 Dense CO2 has also been employed to sterilize bioactive products for food and medicine.4,5 As regulatory authorities are placing greater emphasis on environmental and health issues in production processes, DG technology provides an environmentally benign alternative to numerous existing processes. In the pharmaceutical industry, for which product specifications are extremely stringent, DG technology provides both technically and commercially feasible alternatives to conventional processes. Furthermore, DG technology has the potential to add novel and unique features to the product, resulting in benefits to product characteristics, formulations, and patient compliance. Currently, the pharmaceutical industry is facing the challenge of drug formulation involving active ingredients with low solubilities, high toxicities, low stabilities, and short in vivo half-lives. The characteristics of these newly developed drugs, combined with
Figure 2. Schematic diagram of the dense gas extraction process.
the interest in advanced drug-delivery devices, provide increasing potential for DG technology in the pharmaceutical industry. Dense gas technology might facilitate the development of significant improvements in the efficiency of both currently marketed drugs and new therapeutic entities. Extraction/Fractionation of Therapeutic Agents Currently, extraction in the food industry is the most developed application of DG technology, with an estimated 10% yearly growth in the number of industrial plants.6 Significant factors behind this growth are environmental driving forces, such as the need to eliminate organic solvents and the request for highquality products. A schematic diagram of a typical DG extraction process is presented in Figure 2. The feed is contacted with the DG in the extractor, where the desired component is dissolved and removed by the DG. In the separator, the solvent is separated from the solute by modifying the temperature and/or pressure to produce a pure extract stream. The solvent is then recycled to the extractor after being compressed back to DG conditions. Extraction, fractionation, and purification of complex mixtures of plant materials are performed with DG solvents, resulting in highly pure therapeutic compounds. The therapeutic use of DG extracts covers a range of categories such as anti-HIV, antimalarial, antifungal, and cardiotonic applications.7 Extraction with DGs can also provide drug precursors. An example is diosgenin, a precursor in the preparation of pregnenolone and progesterone, which can be extracted from a tuber, Dioscorea nipponica, by means of dense CO2.7 Sterilization of Pharmaceutical Products Conventional sterilization techniques include autoclaving, exposure to radiation, and extreme heat. Many therapeutic compounds and biopolymers are sensitive to heat, oxidation, pH, γ-rays, or exposure to ethylene oxide gas. Therefore, there is a demand for a novel sterilization technique that has the potential to overcome such limits for application in areas such as controlled-release drug delivery and implantation. The use of dense CO2 as a process medium can produce sterilized products requiring no separate sterilization stages. Sterilization processes involving dense CO2 can inactivate both gram-positive and gram-nega-
6478 Ind. Eng. Chem. Res., Vol. 42, No. 25, 2003
tive bacteria at mild temperatures without degrading organic compounds.5 Foods and beverages, as well as dried blood and plasma, have been sterilized by dense CO2.8 The parameters that determine the inactivating effect of DG processes are temperature, pressure, and the presence of water.9 By adjusting the process variables, it has been possible to adapt the treatment to the inactivation of many microorganisms without the use of irradiation or organic solvents. The technique has been applied to the sterilization of contaminated samples of biocompatible polymers such as poly(lactic-co-glycolic acid) (PLGA) and poly(lactic acid) (PLA).9 These two polymers are widely used as drug carriers, surgical sutures, and a biodegradable base in tissue-engineering applications. Sterilization of PLGA and PLA from a variety of bacteria was achieved by exposure to dense CO2 at temperatures less than 60 °C, without modification of the polymer structure.9 Castor et al. describes a method for the inactivation of viruses, without denaturation of blood proteins, using DGs other than CO2.10 Inactivation is achieved by exposing the blood-derived samples, which contain the virus, to near-critical or supercritical nitrous oxide, chlorodifluoromethane, ethylene, ethane, or propane. Modifiers, such as ethanol, methanol, acetone, and ethylene glycol, have also been added to the fluid. The authors claim that the process is particularly advantageous for the inactivation of viruses associated with blood-borne illnesses, such as HIV.10 The synergistic effects of dense CO2 and other sterilization methods have been tested in an attempt to inactivate highly resistant microorganisms, such as spores, at mild operating conditions. Dense gas technology was shown to have a synergistic effect on all species examined, including bacteria and spores, when combined with radiation and pulsed electric fields.11,12 Fages et al. and Castor et al. found inactivation efficiencies comparable to those of traditional methods.13,14 The advantage of using DGs in sterilization processes, compared to traditional methods, has been demonstrated in the sterilization of foods, beverages, and pharmaceuticals. The possibility of processing thermally and hydrolytically sensitive materials, such as biopolymers and proteins, at mild and easily controlled conditions makes the application of dense CO2 technology especially advantageous for drug-delivery devices and implants. Supercritical Fluid Chromatography Supercritical fluid chromatography (SFC) is a separation technique that bridges the gap between gas chromatography (GC) and liquid chromatography (LC). The nondestructive separation by SFC of a broad spectrum of components, ranging from volatile components to macromolecules, places it at an advantage compared to other methods of chromatography. However, the analysis of polar and very volatile molecules remains the domain of LC and GC, respectively. The mild temperatures required for the separation, combined with the ease of separation of components, make SFC ideal for the collection of residue-free fractions. The improved resolution gained from using SFC is directly related to the tunability of the eluent density and system temperature. The improved mass transfer of DGs and faster response to changes in system conditions provide for shorter separation times and, hence, higher throughput
efficiencies. Thus, SFC provides a unique and efficient tool for both analytical and preparative separation techniques. Considerable research and development of SFC for analytical purposes has been achieved in the past decade, as several reviews indicate.15-18 The most popular mobile phase for SFC, CO2, has been applied to the separation of many drugs and metabolites.19 The use of cosolvents is common because of the low solubility of most polar compounds in dense CO2. Even so, the overall consumption of organic solvent is dramatically reduced. The cosolvent provides an extra degree of tunability, which can further reduce processing time and/or improve resolution. The study by Thienpont et al., on the separation of the four stereoisomers of the antifungal drug itraconazole with liquid CO2, achieved a reduction of more than 40% in processing time, without loss of selectivity, compared to the conventional HPLC technique.20 The simplification of the SFC method from a three-stage gradient method to an isocratic method also yielded a 60% reduction in organic solvent requirements. Packedcolumn SFC has been demonstrated to be more efficient than conventional HPLC for both analytical and preparative processing. The use of combinatorial chemistry for drug discovery requires a significant amount of analysis. Berger and Wilson conducted studies using a packed-column SFC on a wide number of compounds and found that packed-column SFC was between 5 and 10 times faster than conventional HPLC.21 On the preparative scale, the SFC technique has been used for the analysis of pharmaceuticals and natural therapeutic products.22 Yaku and Morishita investigated the separation of a range of steroids and chiral products using SFC on a number of column packings.23 They showed that column packing provided a very sensitive parameter for obtaining optimum separation and retention times. Wang et al. used a packed-column, semipreparative SFC system with mass-spectrometer-directed fraction collection for purifying pharmaceutical compounds.24 Testing of the system with modified dense CO2 achieved an average yield of 77%.24 The inclusion of a mass spectrometer unit in preparative SFC is of great assistance in combinatorial chemistry analysis and in the isolation of therapeutic products from complex natural matrixes. The extraction and purification of eicosapentaneoic acid/ester from polyunsaturated oils has been performed on both laboratory- and pilot-scale SFC columns.25 Pettinello et al. scaled up the process from a 2-4-g unit to 300-400-g loading on a 5-L column.25 Selectivities were typically 5% lower and yields of the eicosapentaneoic acid/ester product were 10% lower than those obtained on the smaller scale. Perrut et al. used simulated moving-bed chromatography (SMBC) in combination with a packed-bed column to provide a continuous separation technique.26 An overall yield of 62% product, consisting of 92% eicosapentaneoic acid/ester, was obtained from the outlet of the SMBC. Chromatographic methods for the fractionation of products are viable for products with annual capacities of 0.1-1 ton. The commercial scale production of active enantiomers as therapeutic agents is in this range, and the high value of the products renders this process ideally suited to the use of SCF.
Ind. Eng. Chem. Res., Vol. 42, No. 25, 2003 6479
Isomer and Enantiomer Separation using Dense CO2 It is known that the enantiomers or optical isomers of a given chemical compound can interact differently in organisms, sometimes with deleterious effects. The (S) isomeric form of the drug thalidomide, for example, is a strong teratogen, whereas the (R) form has been claimed to cause no such side effects. Hence, the purification of enantiomers is of prime importance in the pharmaceutical industry.27 The varying levels of toxic pharmacological activity and medical effectiveness of different isomers have also encouraged recent research into chiral pharmaceuticals. For example, pharmacological studies have confirmed that only (S)ibuprofen provides therapeutic relief, and yet ibuprofen has previously been sold as a racemate.28 Dense gases have been successfully used as substitutes for conventional solvents in the common industrial method of diastereomeric crystallization.29-31 Diastereomeric crystallization involves the addition of a secondary chiral salting agent to a mixture of isomers, which results in the formation of diastereomers. The difference in solubilities of the two diastereomers can be utilized in SCF processes to preferentially extract one of the chiral products. Simandi et al. investigated the effects of temperature and pressure of CO2 and time on the separation efficiency of the mixture pair of cis-(()chrysanthemic acid using the resolving agent (S)-(-)2-benzylamino-1-butanol.32 The pressure, and hence density, had a large effect on the yield but not the product enantioselectivity. In another study, a mixture of racemic (()-cis-permethric acid was resolved using (R)-(+)-R-phenylethylamine, and a second matrix of racemic (()-trans-permethric acids was resolved with (S)-(+)-2-benzylaminobutan-1-ol.33 A maximum enantiomeric excess (e.e.) of 75% (-)-cis-permethric acid was reported for the former extraction, and 89% e.e. (+)trans-permethric acid was reported for the latter extraction. The purification of structural isomer mixtures can also be achieved with DGs. The structural isomers of hydroxybenzoic acid (HBA) provide a good case study in selective DG extraction techniques. The solubility of o-HBA is typically 2 orders of magnitude greater than that of p-HBA. Despite the significant enhancement in p-HBA solubility when extracted from a 50:50 o-HBA/ p-HBA mixture, selective extraction of an equimolar o-HBA/p-HBA mixture with SC CO2 at 328 K and 150200 bar yields a product in excess of 99.5% o-HBA.34 Several investigations into supercritical SMBC have demonstrated significant separation efficiencies.35-37 Depta et al. used cis/trans isomers of phytol as the model compounds for a supercritical SMBC and were able to achieve purities of both isomers exceeding 99%.37 A solute loading of 16 g/h was processed by the unit, considerably larger than the loading used at the preparative SFC scale, with a purity of the recovered chiral isomers consistently in excess of 98%. Selectivity in Pharmaceutical Synthesis and Purification with Dense CO2 An important aspect of pharmaceutical synthesis is achieving the product purity requirement in the minimal number of steps. The synthesis and purification processes in the pharmaceutical industry are often numerous and complex. The presence of impurities can
result from incomplete reactions, side reactions producing byproducts, or residual solvent in the product. Supercritical fluids provide a unique environment for reactions and separations, because the solvent can be easily removed and the product recovered by reducing the system pressure. Conversion can be improved in equilibrium-limited reactions by utilizing the solubility limitations of DG systems.38-40 Blanchard et al. showed that the equilibrium conversion in the esterification of acetic acid with ethanol could be increased from 63% in neat solution to 72% in CO2 at 333 K and 59 bar.40 The use of enzymes in the pharmaceutical industry for reaction and transformation purposes is attracting a significant amount of research.41-43 Work such as that by Overmeyer et al. is of particular interest to the pharmaceutical industry.43 Overmeyer et al. demonstrated that it was possible to achieve a 61% e.e. from a racemate feed of ibuprofen in dense CO2 over Novozym. However, a 99% e.e. was obtained for the transformation of (R,S)-1-phenylethanol to (S,S)-1phenylethanol using the same system. A number of studies have already demonstrated that rates and selectivity for enzyme-catalyzed reactions can be enhanced in supercritical media.41-43 Wang et al. synthesized D,L-R-tocopherol by the condensation of trimethylhydroquinone with isophytol in both dense CO2 and dense N2O.44 Both media were found to present a viable alternative to the conventional process in terms of product yield (up to 89% recorded in dense N2O) and product separation. Another example of DGs providing advantages over conventional methods is demonstrated in the synthesis of amines. These materials provide reaction pathways to pharmaceutical intermediates and traditionally require the use of hazardous azide reagents. The ammonolyses of esters was found by Wang et al. to proceed in dense NH3 (165 °C, 260 bar) with yields of up to 96%.45 By comparison, the reaction did not proceed in conventional media and ran very slowly with considerable byproducts in solutions of 25% NH4OH. The use of dense NH3 effectively removed a reaction step in the overall process and increased the yield and efficiency. The initial investigations of homogeneous hydrogenations used dense CO2 as both the reactant and the solvent to produce pharmaceutical raw materials such as formic acid, methanol, formamide, and ethanol.46-49 Jessop et al. demonstrated the esterification of formic acid in a single-stage process to methyl formate and achieved turn-over numbers (TONs ) moles of product/moles of catalyst) an order of magnitude higher and equilibrium yields greater than any reported for the ester synthesis.50 These results were achieved at 323 K, significantly lower than the temperatures of 373-448 K used in prior studies in conventional solutions.51-53 These results suggest that high-value chiral syntheses might benefit from the increased reaction rates provided by a dense CO2 medium. The dominant effect of solvent polarity and density on the hydrogenation reaction was reported by Combes et al. and Jessop et al. in experiments with DGs.54,55 Wang et al. considered the asymmetric homogeneous hydrogenation of 2-(4-fluorophenyl)-3-methylbut-2-enoic acid to a pharmaceutical intermediate in dense CO2.56 In this system, the enantioselectivity depended on the H2 partial pressure, varying from 63 to 84% enantiomeric excess as the H2 pressure was increased from 180 to 260 bar. The results in the CO2 system were compa-
6480 Ind. Eng. Chem. Res., Vol. 42, No. 25, 2003
rable to the 93% enantiomeric excess (e.e.) and almost total conversion in neat methanol. The synthesis of a β-hydroxyester intermediate for the drug Xenical was found to proceed significantly more rapidly in a liquid melt of CO2 and the reactant when compared to the reaction in methanol. An enantioselectivity of 98% and a conversion of 99% were achieved. The improved masstransfer characteristics of the CO2/reactant melt were suggested to be responsible for the improved synthesis results. From the previous examples, it is clear that CO2 might have a deleterious effect on a reaction or produce significant benefits. Dense gases can provide the means to realize a single-stage reaction and separation operation in an integrated process while removing impurities through improved reaction control. Simultaneous Synthesis and Product Purification The optimal synthesis process is one that produces a product of required purity in the minimal number of steps. The production of the nonsteroidal antiinflammatory drug copper indomethacin (Cu-Indo) from dimethylformamide (DMF) solution using dense CO2 provides a good process case study.57 Cu-Indo is currently synthesized in DMF and precipitated using ethanol as an antisolvent. The product subsequently undergoes repeated washing and filtering stages for purification. The process is costly in terms of solvent consumption, product loss, and time. Warwick et al. used a CO2-expanded DMF solution for the synthesis of Cu-Indo. The reactants, indomethacin and copper acetate, and the byproduct, acetic acid, are soluble in expanded DMF, whereas the product is poorly soluble. The fast kinetics of the reaction in conventional media meant that the impact of the CO2-expanded environment was predominantly upon improvements in product purification and recovery yields. The purity of Cu-Indo produced with CO2 was consistently higher (from 5 to 45%) than that using ethanol over a range of Cu-Indo concentrations. The morphology and size of the precipitate were considerably improved when using CO2 compared to ethanol. The replacement of ethanol with dense CO2 dramatically decreased the volumetric requirements of antisolvent and aided antisolvent recovery from the organic solution. Most significantly, the processing time was decreased by 80% with CO2 while significant reductions in residual solvent levels were also achieved. The combination of a single-stage, continuous reaction with product purification and (micronized) formulation is desirable from a processing view. The synthesis process was combined with the aerosol solvent extraction system (ASES) technique to simultaneously synthesize and precipitate Cu-Indo.57 Purity was maintained at 100% provided that the CO2 was at a pressure greater than 100 bar. Owen et al. also developed a combined ASES synthesis technique for the photopolymerization and precipitation of cross-linked polymers suitable for medicinal drug delivery.58 The monomer [poly(ethylene glycol) (PEG1000) diacrylate] and photoinitiator (dimethoxy2-phenylacetophenone) were dissolved in methylene chloride. The solution was then sprayed cocurrently with supercritical CO2 at 85 bar and 35 °C, whereupon the CO2 dissolved the organic solvent. The solution with rapidly increasing concentration of monomer/initiator was illuminated with light, yielding the simultaneous photopolymerization and precipitation of polymer mi-
crospheres. The size and morphology of the polymer microspheres were found to be strong functions of the initiator concentration and the light intensity. Conversions of almost 80% of the monomer were obtained. The technique requires only a single vessel for the product synthesis and separation and also generates two other factors (light intensity and initiator concentration) that can be utilized to tune the precipitate characteristics. Polymer Impregnation A notable property of DGs is the ability to diffuse into the amorphous glassy region of polymers and swell polymeric matrixes. A DG, saturated with a component, can pass through polymeric matrixes, and the solute can thus be impregnated in the matrix. The DG impregnation technology can be adopted to form drug/polymer, polymer/polymer, and metal/polymer composites for the formation of long-term drug-delivery devices and prostheses and the improvement of therapeutic dosing and stability.59,60 In the pharmaceutical industry, DG polymer impregnation processes have already been used to produce patches and catheters.59 The conventional production of a drug entrapped in a polymer involves the solubilization of the active molecule in a solvent, the partitioning of the solute between solvent and polymeric substrate, and a final solvent removal step. Using a DG as the solvent to entrap the drug has the advantage that a separate purification stage is not required because it is performed as part of the impregnation. The DG solvent is transformed into a gas through depressurization and easily separated from the extract. Carli et al. studied the feasibility of utilizing DGs as solvents to impregnate various drugs, such as acyclovir (an antiviral), in polymeric matrixes.61 A drug loading in cross-linked poly(methyl methacrylate) of 20% was obtained.61 Generally, all compounds exhibiting a reasonable solubility in dense CO2 alone or combined with small quantities of other solvents such as ethanol are suitable for processing with DG impregnation to produce polymeric formulations for controlled release. The anticancer drug fluorouracil and the estrogen β-estradiol belong to this category.62 The antiinflammatory drugs ibuprofen,63 ketoprofen, and nimesulide64 are examples of active compounds that have been embedded in polymeric matrixes by DG techniques. Compounds with low solubilities in DGs can also be embedded in polymers using DGs as impregnating media. It has been observed that, because of favorable partition coefficients between the polymer and the DG, reasonable concentrations of the guest molecules in the substrates can be easily attained.65 Active compounds with low solubilities in DGs can also be dissolved in a conventional solvent, after which the polymeric substrate is placed in the solvent and the DG is added. The DG will diffuse through the conventional solvent and into the polymeric substrate, causing the polymer to swell. The active compounds diffuse into the swollen polymeric matrix. Subsequently, the pressure can be released, causing the polymer to change to a nonswollen condition in which the solute is trapped.66 Alternatively, it is possible to dissolve the active component and the polymer in different solvents and then emulsify the mixture of the two solutions. The emulsion is placed in a pressure vessel and exposed to high-pressure CO2, which then diffuses into the polymer and facilitates the permeation of the active compound. Under rapid de-
Ind. Eng. Chem. Res., Vol. 42, No. 25, 2003 6481 Table 1. Conventional Methods of Micronization141 method
size distribution (µm)
disadvantages
fluid energy mill spray drying lyophilization solution preparation freeze-drying
1-5 ∼5
