Particle design of poorly water-soluble drug substances using supercritical fluid technologies

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Advanced Drug Delivery Reviews 60 (2008) 388 – 398 www.elsevier.com/locate/addr

Particle design of poorly water-soluble drug substances using supercritical fluid technologies ☆ Takehiko Yasuji a , Hirofumi Takeuchi b,⁎, Yoshiaki Kawashima c a

b

Pharmaceutical Research and Technology Labs, Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan Pharmaceutical Engineering, Department of Manufacturing Pharmacy, Gifu Pharmaceutical University, 5-6-1, Mitahora-higashi, Gifu, Gifu 502-8585, Japan c Pharmaceutical Engineering, School of Pharmaceutical science, Aichi Gukuin University, 1-100 Kusumoto, Chikusaku, Nagoya, Aichi 464-8650, Japan Received 4 December 2006; accepted 23 March 2007 Available online 11 October 2007

Abstract In order to improve the dissolution properties of poorly water-soluble drugs, some drugs were subjected to micronization or prepared as composite particles using supercritical fluid (SCF) technology with carbon dioxide (CO2). Solubility in CO2 is the key when using this method. Solubility affects the supersaturation of the materials in the solvent as well as the mass transfer of that solvent, which are both critical to the micronization of the materials and the formation of the composite particles. Some useful techniques that can be used to avoid the problems posed by the characteristics of the drug itself are combining SC-CO2 with other technologies, such as the formation of coacervates or emulsions, and other equipment types, such as milling or ultrasound fields. Another advantage of SCF technology is that it is considered to be green chemistry. SC-CO2 can improve the solubility of poorly water-soluble drug substances using few or no organic solvents and with little or no heating. © 2007 Elsevier B.V. All rights reserved. Keywords: Solubilization; Supercritical fluid carbon dioxide; Micronization; Composite particles; Solid dispersion; Complex formation; Coacervate

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . Fundamental properties of SC-CO2 technology 2.1. Solubility of materials in SC-CO2 . . . 2.2. Measurement of solubility in SC-CO2 . 3. SC-CO2 drug solubilization technology . . . . 3.1. Micronization . . . . . . . . . . . . . 3.2. Composite particles . . . . . . . . . . 4. Conclusion. . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .

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1. Introduction ☆

This review is part of the Advanced Drug Delivery Reviews theme issue on “Drug Delivery Applications of Supercritical Fluid Technology”. ⁎ Corresponding author. Tel.: +81 58 237 8574; fax: +81 58 237 6524. E-mail address: [email protected] (H. Takeuchi). 0169-409X/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2007.03.025

In the drug discovery field, there are a seemingly infinite number of cutting-edge materials to be synthesized and screened using combinatorial chemistry and systematic high throughput screening technology, respectively. To aid the drug production

T. Yasuji et al. / Advanced Drug Delivery Reviews 60 (2008) 388–398

process, Amidon et al. suggested using the biopharmaceutical classification system (BCS), which categorizes active pharmaceutical ingredients for oral administration into four groups, class I (high solubility and high permeability), class II (low solubility and high permeability), class III (high solubility and low permeability), and class IV (low solubility and low permeability), and correlates in-vitro drug dissolution with in-vivo bioavailability [1,2]. It has been reported that 40% or more of the drug candidates are either biopharmaceutical class II (low solubility and high permeability) or class IV (low solubility and low permeability); that is, they have a big problem with solubility in water. The oral bioavailability of drug products made with these candidates may be limited due to slow drug dissolution in the gastrointestinal tract [3]. One reason why the number of poorly soluble drug candidates has increased is because of the “drug-like” structures resulting from the optimization of specific binding to target receptors or enzymes. Because of this, a large percentage of the recent drug candidates have had huge molecular weights and lots of substitutions. According to the “Rule of Five” suggested by Lipinski et al., appropriate “drug-like” compounds do not have a molecular weight of more than 500 Da, do not have a calculated log scale of n-octanol/water partition coefficient of greater than 5, have no more than 10 hydrogen bond acceptors, and no more than 5 hydrogen bond donors [4]. Although these rules of thumb used for drug discovery and screening have long been established, lots of substances with low water solubility still become candidates for development. This development has led to issues such as non-linear pharmacokinetics, intra- and inter-individual absorption variability for some drug substances, and the increased cost of both the final drug product as well as the drug development process itself. Therefore, it is desirable to improve the solubility of the drug candidates through the use of various pharmaceutical technologies.

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Although salt formulation is routinely employed and some prodrug technologies address drug structure design in the pursuit of drug discovery [5], it might actually be too difficult to change the chemical structure of the drug substance after development of the product formulation has already begun. Numerous approaches that manipulate particle design in an effort to improve the solubility of poorly water-soluble drug substances are successful and result in marketable technology and products (Table 1). The use of current technology to enhance the solubility of drug substances can be approached in three ways. First is the micronization of drug substances, especially nanoparticulate materials [6–18]. This uses the Noyes–Whitney equation, which demonstrates that the dissolution rate is directly proportional to the surface area of the drug, to increase the effective surface area for dissolution. Micronization also improves the solubility of drug substances with a particle size of less than 1 μm. This is supported by the Ostwald– Freundlich equation, which demonstrates that solubility increases exponentially as a function of particle size. This approach could be used for pharmaceutical products with a high drug load, although it might be an expensive process. The second approach deals with composite particle formation, such as those resulting from solid solution and dispersion technologies for drug substances [19–24]. These technologies modify the physical structure of the crystal to obtain substances with higher entropy and enthalpy than the steady crystalline form, such as the amorphous or polymorphic forms. Improved wettability is also achieved through the use of wetting compounds for composite particles. This approach has been used in the past, and time has shown that there are some disadvantages. Specially, the chemical and physical stability of products made using this approach becomes a little problematic during the development and marketing phases. The third approach involves the creation of liquid formulations, which broadly includes delivery forms such as complexes, soft gelatin, liquid emulsions, and micelles [25–33]. The liquid

Table 1 Marketed approaches for solubility enhancement of poorly water-soluble drug substances Categories Micronization (nanoparticle)

Down-sizing

Build-up

Composite particles (solid dispersion, solid solution, etc.)

Descriptions

Representative

Owners

Marketed products

Ref.

Milling Homogenization

NanoCrystal® IDD™ Nanopure® Nanoedge SCF milling SFEE SAS-EM™ BioAqueousSM Meltrex™ Lipid base Microtrol® BioAqueousSM Expansion Infuse-X® Captisol® RPScherersol® TOCOSOL™ SolEmuls® SMEDDS™ NanoCap™ Nanosomes

Elan SkyePharma PharmaSol Baxter DuPont Ferro Corp. Thar Tech. Dow SOLIQS Camurus AB Supernus Pharm. Dow Ferro Corp. Lavipharma Cydex Cardinal Health SONUS PharmaSol Gattefosse NanoCarrier Aphios Corporation

Rapamune®, Emend® Triglide™ Under development Under development Under development Under development Under development Under development Verapamil SR Elyzol® Carbatrol® Under development Under development Under development Geodon®, Vfend® Lots of OTC Under development Under development Under development Under development Under development

[6,7] [8] [9,10] [11] [12] [13,14] [15,16] [17,18] [19,20] [21]

SCF SCF Precipitation HMT Modeling Spray freezing SCF

Liquid-like formulation

Complexation Soft gelatin Lipid emulsion Self-emulsions Micelles SCF

[22,23] [24] [25,26] [27] [28] [29,30] [31] [32] [33]

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Table 2 Classification of SCF technologies in pharmaceutical fields Rule of SCF

Available process candidate

Critical factors of SCF for particle production

Typical types of produced particles

Solvent

RESS Impregnation RESS-coating Anti-solvent processes Expansion (PGSS) Milling

Solubility of materials, pre-expansion conditions, spray device Solubility of materials, plasticization, diffusion property Solubility of materials, pre-expansion conditions, spray device Solubility of materials, solvent extraction, mass transfer Pre-expansion, diffusion property, mass transfer Solubility of materials, diffusion property, viscosity

Micronized particles, composite particles Composite particles Microcapsules Micronized particles, composite particles Porous materials, composite particle Micronized particles

Anti-solvent Others

formulation is often used to launch drug products with low solubility, especially those to be marketed as parenterals. While ease of processing is a distinct advantage when using this type of technology, difficulties, such as cost and a large applied dose, are often encountered when formulating high-dose drug products. The use of supercritical fluid (SCF) technology to improve solubility can improve the marketability of many types of products, as shown in Table 1. Recently, increased attention has been given to the application of SCF technology to various processes, including those for nutraceutical manufacturing, the petroleum industry, chromatography, and pigment production as well as pharmaceutical development [34]. In fact, the pharmaceutical applications of SCF technology have been summarized in several excellent review articles [34–45]. Since SCF technology can be used to produce particles with suitable aerodynamic diameters within a narrow particle size range, it is easy to see that the use of SCF technology for pharmaceuticals is advantageous. For this reason, commercial application is gradually gaining popularity, but, although SCF technology has been used to manufacture dry powders for pulmonary delivery [46–49], practical application in the pharmaceutical field has been slow to diversify. Two of the main advantages of SCF technology are that it requires few or no organic solvents and little or no heating to produce the fundamental particles. Manufacturers have made the most of this and other advantages offered by SCF technology with CO2 (SC-CO2). In pharmaceutical applications, carbon dioxide (CO2) is the most widely used SCF because it has a low critical point and is non-toxic. Biopharmaceutical materials such as vaccines, proteins, peptides, and DNA are also processed using this approach [50–54]. SC-CO2 technology itself can be classified into three broad categories (Table 2). SC-CO2 can be used (1) as a solvent for a drug substance and its excipients, (2) as an anti-solvent for the precipitation of materials dissolved in organic solvents, and (3) as a medium for other fluids techniques [40]. The first method is generally known as the rapid expansion of supercritical fluid (RESS) [35,55–61]. However, most pharmaceutical substances frequently used for the development of particle design are not sufficiently soluble in SC-CO2 to affect an efficient production process. Thus, it is often necessary to use an organic co-solvent [62]. The second method, i.e. the anti-solvent method, is gradually becoming more diversified, but currently it is applied using two general techniques. The first technique involves pumping SCCO2 into an organic solution of the materials to expand and extract the solvent, which results in the precipitation of the materials. This technique has been called gas anti-solvent (GAS) [63–68]. The second technique involves spraying the organic solution into SC-

CO2 to precipitate the solute. This technique can be further divided into the supercritical anti-solvent (SAS) technique [69–72], the aerosol solvent extraction system (ASES) technique [73–76], and the solution enhanced dispersion with supercritical fluid (SEDS) technique [37,77–82], among others. Recently developed solubilization technologies that utilize SC-CO2 technology will be summarized in this paper. The micronization and morphology controls for some model drugs were tested using SC-CO2 technology. Composite particles, which included solid dispersion, and complex formulation, were also recently manufactured using SC-CO2 technology. This paper focuses mainly on the latest micronization techniques for drug substances, and the preparation of composite particles for drugs and various additives to enhance the solubility of the drug substance. The conclusion will contain a brief discussion of SC-CO2 technology as it applies to drug solubilization. 2. Fundamental properties of SC-CO2 technology for solubilization For all substances, there is a specific phase where critical pressure (Pc) and critical temperature (Tc) exist at the same time. In this phase, the pressure is sufficient to prevent the substance from becoming vapor, but the temperature causes molecular mobility to increase. This temperature is also high enough to prevent the substance from becoming liquid, but at the same time the pressure puts a limit on the degree of molecular mobility [37,38,55]. This phase in which both critical pressure and temperature have either been reached or exceeded, possesses unique characteristics. Substances in this phase are generally called supercritical fluids. In other words, a supercritical fluid can behave as either a liquid or a gas, but is actually neither. Table 3 shows the physicochemical properties of a SCF compared with those of liquid and gas. The density, viscosity, diffusion coefficient, and heat conductivity values are between those for liquid and gas. The density of a SCF is either the same or close to that of liquid, which allow SCFs to enhance solubility more than gas could. In contrast, because its diffusion coefficient is close to that of gas, the viscosity of a SCF is much lower than that of a Table 3 Characteristics of supercritical fluid compared with those of liquid and gas

3

Density (kg/m ) Viscosity (μPa s) Diffusion coefficient (m2/s) Heat conductivity (W/mK)

Liquid

SCF

Gas

1000 10− 3 b10− 9 b10− 1

200–900 10− 5–10 −4 10− 7–10− 8 10− 3–10− 1

0.6–1 10− 5 10− 5 10− 3

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liquid, which allows for the rapid mass transfer or penetration of the SCF into materials, as well as jet precipitation, which cannot be achieved with a liquid. In addition, these physical properties of a SCF, such as density, viscosity, diffusion coefficient, and heat conductivity values, can varied by changing slightly the temperature and pressure around critical point [39,83–85]. Carbon dioxide (CO2) is the most common and useful medium for pharmaceutical applications. Its relatively low critical point (31.0 °C and 73.8 bar) allows easy processing and manufacturing for pharmaceutical products. Other advantages of CO2 are that it is non-toxic, non-flammable, easy to recycle, cost-effective, relatively safe, and environmentally acceptable [35,37,39,86]. Carbon dioxide is a relatively non-polar solvent, therefore, if a compound dissolves in hexane, then it should also dissolve in SC-CO2 [36]. This attribute, along with other unique properties of SC-CO2, makes it useful for various purposes, such as drying processes, analytical separation processes, and the manufacturing of particles, as well as use as an extraction medium [39–41,87–90]. The physicochemical properties of SC-CO2 are key factors in particle design for pharmaceutical compounds. In particular, solubility in SC-CO2 is the major prerequisite for designing particles using SC-CO2, that is, the applicability of the technology is dependent on this solubility. When SC-CO2 is used as a solvent, the size distribution and morphology of the particles produced are a function of the concentration of the materials in SC-CO2 and the subsequent expansion conditions [35]. In contrast, the SC-CO2 anti-solvent process is based on the change in the solubilization power of a solvent that results from adding SC-CO2 to it, as well as the miscibility of that solvent in SC-CO2. In the following section, the solubility of materials in SC-CO2 will be briefly described from the viewpoint of particle design for drug solubilization. 2.1. Solubility of materials in SC-CO2 Since particle design using SC-CO2 technology employs rapid changes in solubility as the chief means of substance manipulation, solubility in SC-CO2 is very important for the success of processes, such as rapid expansion of supercritical fluid (RESS), gas anti-solvent (GAS), supercritical anti-solvent (SAS), and particle from a gas-saturated solution (PGSS), etc. When SC-CO2 is used as a solvent for materials (e.g. RESS), checking the solubility of the materials under various conditions (pressure and temperature) is absolutely necessary for particle production, as SC-CO2 should dissolve the materials to be micronized. The mixture of materials with SC-CO2 is usually expanded in a reactor and precipitated as a solid formulation. When SC-CO2 is used as an anti-solvent, the key to producing the particles is generally considered to be the supersaturation of the solution of materials via the counter-diffusion of SC-CO2 and the solvent. The solubility of the materials in SC-CO2 influences the degree of this supersaturation. Also, the re-extraction of precipitated materials in SC-CO2 or SC-CO2 modified with solvent should be avoided during the particle formulation process. In the case of PGSS, SC-CO2 should be soluble in melted material, but this material is not required to be soluble in SC-CO2. As stated above,

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the degree of solubility is critical for controlling the properties during SC-CO2 processing both with and without the solvent. The solubility data from representative active pharmaceutical ingredients are shown in Table 4. Ibuprofen [61,91–93], griseofulvin [15,69,94–96], and nifedipine [97,98] are sometimes used as model drugs with poor water solubility for experiments using SC-CO2 solubilization technology. The solubility of these materials in pure SC-CO2 increases with the density of the fluid, which then leads to increased pressure. However, the use of SC-CO2 as a solvent for pharmaceutical compounds is limited because of the low polarity of CO2 and the associated lack of capacity for specific solvent–solute interactions. For a solute with very opposite polarity, SC-CO2 might even be considered as an anti-solvent rather than a solvent. One approach to solving this problem is changing the fluid, to nitrogen, N2, or water, although each is associated with other problems that must be dealt with. Another way that the solvent power of SC-CO2 could be enhanced is by adding small amounts of a highly polar co-solvent to help increase SC-CO2's solvent power [62,99–101]. Mishima et al. reported the successful formation of polymeric micro-particles using RESS with a non-solvent [102–104]. A cosolvent with increased solubility should be chosen; however, a non-solvent can be used to avoid particle agglomeration. Micronized particles containing active pharmaceutical ingredients have been produced using this technology. The solubility of materials in pure CO2 or CO2 with solvent is the most important factor to consider when choosing the appropriate process to enhance the drug solubilization during SC-CO2 processing. 2.2. Measurement of solubility in SC-CO2 When assessing the solubility of pharmaceutical ingredients in SC-CO2, choice of method is critical. The methods available are roughly divided into three categories: The first is the gravimetric method, in which materials are collected by a trap after being saturated in a reactor. Schmitt and Reid suggested Table 4 Solubility of representative active pharmaceutical ingredients (ibuprofen, nifedipine, and griseofulvin) in SC-CO2 Drug substance

Supercritical conditions Temperature (K)

Pressure (bar)

Ibprofen (R)

308

Ibprofen (S)

308

Nifedipene

333

100 150 200 100 150 200 135 210 296 135 210 283 130 130 130

353

Griseofulvin

303 308 318

Solubility (mole fraction ⁎ 103) 2.34 5.57 11.23 2.83 7.36 10.96 50.8 150.6 305.9 13.5 181.1 380.3 700 700 400

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that the solubility of materials was dependent on which supercritical solvent was used to dissolve the compound. They found that carbon dioxide was an effective solvent for many materials, especially polar compounds, when using the gravimetric method [105,106]. The second method is cloud point measurement via a view cell, which consists of a pressureresistant vessel and a window [107–109]. O'Neill et al. measured the cloud points of various homopolymers and calculated the solubility of various materials. It was concluded that the increased solubility of amorphous polymers corresponded with decreases in the cohesive energy density or surface tension of the polymers. The third method is spectrophotometry on a UV/VIS or Raman spectrophotometer. The results in the literature from Rehman et al. are very interesting in that the solubility of nicotinic acid in SC-CO2 was used to optimize particle formulation via SEDS process [110]. It is important to take the solubility level of the materials into consideration when determining which measurement and evaluation methods are most appropriate. 3. SC-CO2 drug solubilization technology The first application of SCF technology to drug solubilization was by Krukonis et al. in the 1980s, after which time many researchers improved the solubility of drug substances using simple equipment for RESS, SAS, and so on. However, the success of the functional particles, in particular, the submicronized particles or solid dispersion for enhancing drug solubility, depended mostly on the characteristics of the material. From the viewpoint of drug solubilization, control of the physicochemical properties of the materials produced by SC-CO2 was not as accomplished as that of other solubilization technology methods, like spray drying and wet milling. In addition, it was not easy to produce material on a large scale because of the low solubility of the materials in SC-CO2 for RESS and the low feeding rate of the solution into SC-CO2 for SAS. Currently, SC-CO2 technologies are combined with other technologies, such as the use of a characteristic nozzle (e.g. CANBD, by Sievers et al. [111,112]), sonication for mass transfer enhancement (e.g. SAS-EM, ultrasonic nozzle) [15,16,113,114], and conventional powder technologies (fluidized bed granulation, freeze drying, and so on) [115,116] to improve manufacturability and produce particles with the desired characteristics. SC-CO2 has also begun to be used as an expansion or milling medium or as a drying agent for solvent [117,118]. Although the technologies and their applications are becoming more diversified, micronization and the preparation of composite particles are the only two reasons to use general SC-CO2 techniques during pharmaceutical product manufacturing. In the next section, micronization and the formulation of functional composite particles for drug solubilization will be discussed. 3.1. Micronization Poorly water-soluble drug substances are usually micronized in two ways, either the original materials are decreased (sized-down) or increased (built-up) (Table 1). Traditional milling technology,

i.e. dry milling, is still important, and is used to ensure the quality of the drug products (content uniformity testing). However, when dry milling, it is difficult to reduce the particle size below 1 μm (the critical particle size for organic compounds), since the cohesiveness of the particles is determined during the manufacturing process. Some wet milling and homogenization technologies are used to submicronize materials without concern for particle cohesiveness [6–11]. Unfortunately, the physicochemical stability of the materials treated in this way is threatened by the high temperature and pressure, and contamination by the milling media is also a possibility. Although technologies that build-up materials, such as precipitation methods [13–18], are very useful for producing nanoparticulate materials, the use of these materials to accomplish processes like concentrating a nano-sized suspension, offers no advantage over any other technology. Numerous investigations into the micronization of drug substances have been conducted using conventional SC-CO2 technologies. Jung and Perrut reviewed the SCF particle design theory in an attempt to enhance the basic dissolution methods used with supercritical fluid (RESS, SAS, PGSS, and impregnation) [40]. When using the RESS process, success is dependent on the specific structure and capability of the equipment, i.e. spraying distance, pre-expansion pressure, and nozzle length, as well as the characteristics of the starting materials. Charoenchaitrakool et al. showed that the powder dissolution rate of micronized ibuprofen in phosphate buffer was 5-fold greater than that of the original materials. This was due to the reduction of both particle size (2.5 μm) and the degree of crystallinity, even though the particles obtained were aggregated. Nifedipine particles were successfully micronized to the uniform size of 15 to 30 μm using particles created from the gas-saturated solution (PGSS) process [91]. The mean particle size was reduced by increasing the pre-expansion pressure, which resulted in a higher dissolution rate than that of the original nifedipine powder [98]. However, the dissolution rate did not improve as much as expected, which was probably because of the agglomeration and poor wettability of the micronized particles. Griseofulvin particles were successfully micronized using the supercritical assisted atomization (SAA) technique. Spherical particles with mean diameters ranging from 0.5 to 3 μm were produced. The dissolution rate of SAA-processed griseofulvin formulated with starch in a gelatin capsule is faster than that of jet-milled and original griseofulvin. However, the initial dissolution rate of the drug is almost the same for both particle types, again probably because of the agglomeration of the particles during and after micronization and the poor wettability of the particles produced [119]. Several new technologies, in combination with other established ones, have been used in attempt to overcome the major issues, which include production efficiency, drug-specific particle design (such as particle size distribution and polymorphism), and limited dissolution improvement due to particle agglomeration. RESS-AS, a method that includes the rapid expansion of a supercritical solution into an aqueous solution, was performed in an attempt to impede any increase in particles size, and agglomeration of the submicronized particles [120–122]. It was shown that using polymeric or oligomeric stabilization together

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with RESS in a liquid solvent could keep the drug nanoparticles from agglomerating. On another front, a method that included the rapid expansion of supercritical solution with solid cosolvent (RESS-SC) not only inhibited the agglomeration of nanoparticles during the process, but improved the solubility of the materials in SC-CO2 [95,123,124]. With the use of menthol as a solid co-solvent, the nanoparticle formulation of griseofulvin successfully achieved a particle size range of 50 to 250 nm with no agglomeration. In addition, the solubility was enhanced approximately 28-fold compared to that of the conventional RESS process without co-solvent. In the case of phenytoin nanoparticles, solubility enhancement increased the production rate 400-fold over the RESS process. The solid co-solvent, menthol, was easily removed from the drug nanoparticles by sublimation and lyophilization, which also allowed the drypowdered nanoparticles to be recovered, all in one step. The SAS-EM technique, conceived by Chattopadhyay and Gupta [15,16], can successfully produce griseofulvin nanoparticles as small as 200 nm. This technology uses ultrasonic frequency with supercritical anti-solvent precipitation to enhance mass transfer. The ultrasound power transducer alters the particle size and morphology of the particles produced. This was confirmed by the increase in the yield of the griseofulvin nanoparticles that resulted from corresponding increases in the power supply. Snavely et al. produced micronized insulin particles by using PCA (precipitation with compressed antisolvent) with an ultrasound nozzle. The resulting precipitated powder was composed of physical aggregates (1–5 μm) of 50nm spheres. This method was originally developed to create particles for pulmonary delivery. The supercritical fluid extraction of emulsions (SFEE) process, which produces a suspension of griseofulvin nanoparticles, was conducted by Shekunov et al. [13,14]. The nano-suspension was produced by using SC-CO2 to extract the internal phase of an oilin-water emulsion. This oil-in-water emulsion may act as a kind of “micro-reactor” that allows supersaturation and crystal nucleation to occur during nanoparticle formulation. This process produces particles with diameters ranging from 100 to 1000 nm and dissolution rates 5- to 10-fold higher than that of drug particles micronized by jet milling. This technology combines the advantages of using of an emulsion, which control particle size and surface properties, with the continuous SCF extraction process. Since the primary controlling parameters are the physical properties of the emulsion, rather than of the characteristics of the active pharmaceutical ingredients, care must be taken to create a formulation that will sustain a stable emulsion and particle suspension. SC-CO2 technology, especially when combined with other technologies, is the favored method for micronizing poorly water-soluble drug particles. It may also be possible to control particle formulation by manipulating the physicochemical properties specific to the drug being manufactured. Scale-up studies from laboratory to pilot or commercial size batches have been performed in recent years. However, pharmaceutical formulators and manufacturers must pay careful attention to achieve the proper degree of dissolution enhancement for each drug substance.

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3.2. Composite particles Historically, solid dispersion and solution technologies have been investigated in an attempt to enhance the bioavailability of drug products. One of the hurdles that must be overcome when using any type of dispersion technology is the assurance of physicochemical stability during the manufacturing process (including scale-up to commercial size batches) and the shelflife of the drug products. Therefore, the use of additives and organic solvents is necessary to enhance drug dissolution and maintain the stability of amorphous or polymorphic drug substances. Sometimes this makes the formulation for solid dispersion complicated. However, problems with physicochemical stability can be resolved by adding several stabilizers and antiseptic agents to the formulation. These conventional technologies used to improve the solubility of poorly water-soluble drugs are numerous and are often developed as needed on a case-by-case basis (product-by-product formulation). Recently, SCF technology has been used with anti-solvent methods for solid dispersion. Sethia et al. conducted a comparison of the physicochemical properties of carbamazepine solid dispersion in polyvinylpyrrolidone (PVP) prepared using either a conventional solvent evaporation or a SC-CO2 process [125]. The intrinsic dissolution rate obtained for the supercritical-based processed solid dispersion was 4-fold higher than that for the pure drug. Other techniques using solvent-free supercritical fluid processing include simply mixing together apparatus indomethacin and PVP to co-precipitate them as porous composite particles [126]. The drug dissolution rate of composite particles is higher than that of the crystalline form alone because of the porous and amorphous structure of the composite particles formed during SC-CO2 processing. Juppo et al. reported that solid dispersions of the hydrophobic drug and its carriers, such as mannitol and Eudragit E100, could be prepared using SEDS [77]. The SEDS process has been shown to be effective for forming complexes with mannitol or the basic carbonyl group on the Eudragit E100 molecule, as well as for making intimate blends and solid solutions for the model drug and its carriers. The dissolution rate of the drug in particles manufactured by the SEDS method was higher than that of drug substance itself. In these studies, the model drug, which was hydrophobic, was minimally soluble in SC-CO2, and the drug content in the particles produced was lower than the theoretical value. It is also difficult to form polymeric particles with Eudragit E100 because of its low glass transition temperature (Tg, about 50 °C), which may be further reduced by SC-CO2 [127]. In general, the preparation of fine particles of polymeric materials with low Tg, low crystallinity, and high viscosity dissolved in solution would be difficult using conventional SCF methods. Bleich et al. also pointed out that when the aerosol solvent extraction system (ASES) is used with polymers and low polarity drugs like piroxicam, the drugs are extracted into the SC-CO2 modified with solvent. This results in lower drug loading than nominal one in the composite particles [74]. SC-CO2 technology combined with the coacervate method has been used to produce a micronized solid dispersion by

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Fig. 1. Comparison of the viscosity of PVP coacervate in 25/75 (v/v) ethanol/ hexanes with that of PVP ethanol solution.

spraying PVP-based coacervate containing phenytoin through an ultrasonic converging–diverging nozzle [115]. Compared to conventional SCF solution spraying techniques, composite particles with smaller and narrower particle distribution can be produced easily and with a better yield. The detailed mechanism of this method will be delineated in the future, but the stages of particle formulation that have been theorized so far are described as follows: (1) coacervate formation leads to a decrease in both the viscosity of spray solution (Fig. 1) and the interaction between the materials and the solvent, (2) the ultrasonic converging– diverging nozzle uses ultrasonic waves to atomize the solution

droplet, (3) the increase in the mixing speed gained through (1) and (2) increases the rate of mass transfer between the droplets and scheme SC-CO2 technology combined with coacervate method was illustrated in Fig. 2. Even though extraction of the drug into SC-CO2 modified with solvent is limited, use of the coacervate method increases the amount of drug in the composite particles. This is probably because the coacervate mixture consists of a homogenous solution of polymer and drug as well as small droplets of polymer-rich second liquid phase that contain the drug. The drug release rate of the solid dispersion produced by the coacervate method is higher than that of particles produced by the conventional SC-CO2 method or the physical mixture of phenytoin and PVP (Fig. 3). It has been shown that the coacervate method is an effective process for preparing micronized solid dispersions of water-insoluble drugs. The advantage of this system is in the preparation of tiny drug/polymer particles with large surface areas and high potential energies, which then yields an enhanced dissolution rate. In addition, this method may offer advantages over conventional methods when high drug and/or polymer concentrations are employed to increase production throughput. Making a complex with cyclodextrin is a technique used to improve drug solubility in many composite particle methods. SCCO2 technology was applied to formulate the complexes between the drug (such as indomethacin) and cyclodextrin derivatives (such as hydroxypropyl-β-cyclodextrin (HP-β-CD)) to improve the solubility of poorly water-soluble drugs [93,128,129]. Exposure of SC-CO2 to indomethacin and HP-β-CD mixtures

Fig. 2. Scheme of the proposed mechanism for the SC-CO2 technology with coacervate method.

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Fig. 3. Dissolution profiles of phenytoin from SCF composite particles with phenytoin and PVP at a ratio of 1:2 in SGF with 1% SLS. SCF12c, SCF12s, and PM12 stand for SCF particles from the coacervate method, the solution method, and the physical mixture of the drug and PVP, respectively.

enhances the drug solution rate compared with untreated physical mixtures. One possible reason for this improvement is that solidstate inclusion complexes are formed upon treatment with SCCO2. These then expose physical mixtures of the drug and HP-βCD to SC-CO2. This SCF process has an advantage over the conventional cyclodextrin complex formulation, because it consists of only a single-step, and is organic solvent-free. 4. Conclusion The micronization and morphology controls for some model drugs conducted using SC-CO2 technology have been summarized in this paper. It is clear that SC-CO2 is a useful way to improve the solubility of drug particles in water. The micronization of pharmaceutical materials is slowly becoming more popular, and the use of SCF technology to produce composite particles is increasing little by little. Combining SCF with other technologies (coacervate and emulsion), as well as special equipment methods (spray drying, specialized nozzles, and freeze drying) is useful for the production of functional particles, including drug substances. These combinations increase versatility, and thereby, also increase the chances of developing methods that will improve drug solubility for some drug substances. Although conventional SC-CO2 technology might be able to produce single or submicron particles for most drugs, drug-specific characteristics, such as polymorphism, have a significant impact on the quality of the final drug products. These characteristics must be taken into consideration when choosing a formulation method. The combination of SC-CO2 technology with other technologies could potentially resolve these issues by taking a control of the physicochemical variables involved. An example of this is the combination of SC-CO2 technology with the coacervate method as well as the supercritical fluid extraction of emulsions (SFEE) process. The composite particles, consisting of polymeric materials and drug substance, were prepared by using SC-CO2 desolvation of the coacervate. SC-CO2 precipitation of coacervate has been shown to be an effective process for manufacturing micronized solid dispersions of poorly

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soluble drugs. Since coacervate preparation decreases the viscosity of a liquid spray, this method might have an advantage over conventional SC-CO2 processing during scale-up studies when high drug and polymer loading is required. SC-CO2 technology has also been the focus of much attention because it is considered to be a “green” process. Since environmental concerns have become increasingly more important in the eyes of the regulatory authorities, manufacturers have been searching for ways to reduce the use of large amounts of toxic organic solvents, such as halogenated solvents. Therefore, since few or no organic solvents are used during the SC-CO2 process, and little or no heating is required, its use for the production of functional particles for active pharmaceutical ingredients is very attractive, especially for biopharmaceutical materials. SC-CO2 is also very useful for drug solubilization because it is possible that CO2 could be used in place of a large portion or even all of the conventional organic solvents required. For these reasons, practical application of this technology in the drug solubilization field is highly desirable. From a technical view, SCF particle design technology, as it applies to production of pharmaceutical active ingredients, is in its infancy. Although large-scale commercial use of SCF technology has been used successfully to decaffeinate coffee and tea, as well as extract spices, hops, and flavoring, it has not yet become the first choice technology for particle design in the pharmaceutical industry. The reason behind this may be the cost of installing GMP-compliant equipment, and the relatively limited experience most manufacturers have with commercial production scale-up for this type of technology. Although CO2 is inexpensive and can be recycled, the capital investment and running cost for SC-CO2 technology processes are at least as much as those for other multipurpose processes, such as fluidized bed granulation, spray drying, and freeze drying. However, a recently published study on scale-up for particle formulation has cast a positive light on the idea [130–132]. The study offers evidence that commercial-scale supercritical fluid facilities can be successful not only for the food and dry cleaning industries, but also for pharmaceutical particle design. Therefore, industry may slowly be realizing that GMPcompliance is not a true obstacle to SCF processing. In fact, industry may soon come to realize that, for product commercialization, the unique properties of SC-CO2 technology make it the outstanding choice, a cut above the ready-made technologies. However, formal comparisons of the cost-effectiveness of commercial-scale SC-CO2 processes compared with readymade technologies, such as spray drying and freeze drying still need to be made. Use of cutting-edge technologies such as SC-CO2 can lead to great improvements in the commercialized production methods for particle formulation. The end result will be enhanced drug solubility, which will improve the overall performance of the drug, and manufacturing methods that are more environmentally friendly. Acknowledgment Part of this work was supported by the Kansas Technology Enterprise Cooperation through the Centers of Excellence Program. The authors thank Dr. Roger Rajewski and the associates

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