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Chapter 15
Engineering of Composite Particles for Drug Delivery Using Supercritical Fluid Technology *
B. Y . Shekunov , P. Chattopadhyay, and J. Seitzinger Pharmaceutical Technologies, Ferro Corporation, 7500 East Pleasant Valley Road, Independence, O H 44131 Corresponding author:
[email protected] *
Challenges associated with the production of micro- and nanoparticles for drug delivery can be addressed using supercritical fluids (SCFs) or liquefied gases. These fluids offer the benefits of low processing temperatures, efficient organic solvent extraction, environmentally benign processing and cost effectiveness. In this chapter, we discuss the different technological approaches which employ SCFs, in relation to potential applications such as manufacturing of particulate systems for controlled or sustained release, coating and tastemasking, respiratory formulations and nanoparticles for in creased solubilization.
Introduction The incorporation of a drug in polymer particles for sustained or controlled release has numerous advantages for drug delivery, including increased drug efficacy, reduced dosing frequency, enhanced patient compliance and reduced costs. Such products typically employ artificial or natural polymers and/or other excipients that are biocompatible and biodegradable. From yet another per234
© 2006 American Chemical Society
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235 spective, the absorption of some poorly water-soluble drugs can be significantly improved by producing formulations of the drug with water-soluble or certain biodegradable polymers or lipids. The efficient size control of micron-size particles, and particle modifications such as production of drug-encapsulated biodegradable porous or hollow structures, are essential in providing controlled release respiratory formulations with enhanced aerosolization performance. Several techniques such as emulsion solvent evaporation or extraction, coacervation and spray-drying have been suggested for the preparation of these materials. Although predominantly used now and on a relatively small scale, these methods are not free from limitations such as use of elevated temperatures and limited size control during spray-drying, and the manufacturing complexities of emulsion-based techniques. The major disadvantage associated with all the above techniques is the removal of organic solvents, which are used to dissolve polymers and active compounds. These residual solvent impurities can lead to reduction in the efficacy of the pharmaceutical product, increased toxicity, undesirable side effects and other serious complications which can create signi ficant regulatory hurdles in product development (1). Supercritical fluids (SCFs) have the following fundamental properties, which can be utilized for process engineering: 1. Efficient extraction of small organic molecules, which are miscible or at least partially soluble in SCFs, can provide an effective and environmentally benign process for cleaning of biodegradable polymers and pharmaceutical compounds at low temperature. This extraction process can be controlled by tuning the SCF density, pressure and temperature. Multiple impurities (e.g. residual solvents and monomers) can be removed by changing the SCF density. The most commonly used SCF in these applications is supercritical C 0 due to its low critical temperature, non-toxic inert nature and low cost. 2. Increased diffusivity and reduced viscosity contributing to increased masstransfer and penetration ability of SCFs are important for enhanced extraction and cleaning, especially when intensive agitation or mixing is required but difficult. Drying of porous matrixes and extraction in powder beds are exam ples of such applications. 3. Most pharmaceutical drug substances, reagents, and excipients have very low solubility in low-temperature SCFs, including C 0 . This is a major limi tation as far as the extraction process is concerned, however, it also makes possible employing SCFs as non-solvents (antisolvents) in precipitation and crystallization processes, greatly reducing use of organic solvents, increasing product purity and providing benefits of a more controlled precipitation mechanism. 4. SCFs are very efficient piasticizers of polymers, leading to a significant reduction of the glass transition temperature, T , and increased molecular diffusivity in polymers. The T depression of most biodegradable and 2
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236 pharmaceutically acceptable polymers in the presence of C 0 is a function of pressure and temperature, and typically varies between 20-100K. This property of SCFs enables applications such as low-temperature impregnation of polymers with bioactive materials, preparation of porous polymer matrixes and particles. 5. Finally, an important property of the supercritical state is its high compressi bility. Solvents, both miscible and partially miscible, when expanded together with SCFs, can be rapidly atomized into small droplets. In this role, SCF can be more efficient than compressed gases for nebulization. In certain cases, it can also be used for nebulization followed by freezing of solutions due to the Joule Thomson effect. The frozen droplets formed can be sub sequently lyophilized in order to yield the dry product with interesting mor phology. Together with these advantages, there are also several challenges associated with large-scale applications of SCFs in the pharmaceutical industry. The low solubility of most pharmaceutical ingredients in supercritical C 0 means that more complex processes than spraying by expansion have to be developed to produce particles. Another technical challenge is the immiscibility between water and C 0 , preventing efficient drying or precipitation of many biological and water-soluble substances using pure SCFs. The most important barrier however is the very nature o f pharmaceutical product development, which is cautious to any new and unproven technology. A new technology must clearly show some formulation advantages compared to more traditional techniques, and/or lead to significant improvement of the product quality and process economics. The following chapter introduces different technological approaches with SCFs, with emphasis on those which can be utilized for production of polymerdrug composite materials. We also introduce a new technique of supercritical fluid extraction from emulsions (PSFEE), which can be used to produce fine particles for various drug delivery applications.
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Results and Discussion SCF Methods Supercritical Antisolvent (SAS) Precipitation Antisolvent methods constitute the majority of the current SCF particle formation techniques (1-3). They are based on a simple principle, whereby a
237 drug and excipient (e.g. polymer or lipid) are co-precipitated together, using the antisolvent (non-solvent) properties of supercritical carbon dioxide, since most polymers and drugs are not soluble in C 0 . This method is likely to succeed when polymer and drug molecules are compatible with each other, forming ordered solid solutions, molecular dispersions or amorphous mixtures by strong hydrogen bonding or complex formation (3,4). In the event of solid phase separation or re-crystallization, a non-homogeneous drug dispersion or partial coating could occur, leading to a characteristic "burst" drug release in disso lution studies. A n example of successful co-precipitation is microencapsulation of budesonide into poly(L-lactic acid) (PLLA) in an amorphous form (5). Another example includes production of a solid solution of theophylline in ethyl cellulose at drug loadings up to 35% (6). In certain cases some of the drugs can be precipitated with polymers using a hydrophobic ion pairing (HIP) approach (7), by which ionic species can be directly solubilized in non-aqueous solutions using pairing of charged molecules with oppositely charged surfactants. Such complexes may prevent drug re-crystallization and promote uniform release profiles. A significant problem with the antisolvent process is that SCFs, including most commonly used C 0 , are excellent plasticizers of many polymers and lipids, in particular those with a significant amorphous phase and high molecular weight, causing swelling and agglomeration in particles. Amorphous highmolecular weight polymers are often preferable for drug formulation, allowing for more uniform release and more efficient drug loading than polymers of semicrystalline structure or low-molecular weight. Thus a compromise has to be found by optimizing processing conditions to prevent agglomeration in C 0 whilst retaining sufficient drug-release properties of such polymers (8). The antisolvent techniques are difficult to use for water-soluble compounds because they have to be dissolved in the same solvent as the polymer. However, an example in Figure 1 illustrates that suspensions of such compounds in a polymer solution can be used for particle coating, with potential applications for taste-masking or sustained release formulations. Coated particles of an ex tremely bitter and highly water-soluble drug were prepared in our laboratory for use in fast disintegrating tablets. Crystals of the drug, with particle sizes ran ging between 50 and 150 |im in size, where coated with ethyl cellulose with drug loading between 40-60% to obtain a defined release profile, allowing for 90% drug dissolved within 40 minutes (Figure 1). The bitter taste of the original water-soluble drug was significantly reduced by this formulation. The particles also exhibited sufficient mechanical strength for the tablet compression.
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238
Figure I. (a) Particles of a bitter drug coated with ethyl cellulose using antisolvent precipitation with CO2 and (h) correspondent release profile.
Rapid Expansion of Supercritical Solutions (RESS) The RESS technique involves precipitation of particulate material by expan sion of a solution in SCFs (9). Its applications are limited to compounds which have an appreciable solubility in the SCFs. As a rule, when a compound is soluble in supercritical C 0 at concentrations above 10 mole fraction, RESS is preferred as it provides a simple, direct, solvent-free and continuous process to particle production, it can be optimized to achieve a relatively narrow particle size distribution, and can also be used for the coating of micron particles with C0 -soluble polymers such as low-molecular weight ( M
