Elsevier

Advanced Drug Delivery Reviews

Volume 60, Issue 3, 14 February 2008, Pages 388-398
Advanced Drug Delivery Reviews

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

https://doi.org/10.1016/j.addr.2007.03.025Get rights and content

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.

Introduction

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 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.

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], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [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], [20], [21], [22], [23], [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], [26], [27], [28], [29], [30], [31], [32], [33]. The liquid 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], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [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], [47], [48], [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], [51], [52], [53], [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], [56], [57], [58], [59], [60], [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 SC-CO2 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], [64], [65], [66], [67], [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], [70], [71], [72], the aerosol solvent extraction system (ASES) technique [73], [74], [75], [76], and the solution enhanced dispersion with supercritical fluid (SEDS) technique [37], [77], [78], [79], [80], [81], [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.

Section snippets

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

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

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

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 from Higuchi Biosciences Center for Drug Delivery Research, the University of Kansas, for their supervision and assistance in learning SCF technology and performing the SCF with the coacervate method.

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