ABSTRACT
Keywords: particle size engineering, colloidal delivery systems, solubility enhancement, bioavailability, hydrophobic drugs, top-down approach, bottom-up approach, applications
constraints. Hence, development of suitable formulations for poorly water-soluble drugs is the major challenge for formulation scientists. Recent research on drug delivery for drugs with poor water solubility mainly focuses on nanotechnology-based strategies aimed at improving their therapeutic performance.Available strategies for poorly water-soluble drugs include use of aqueous mixtures with an organic solvent (e.g., water-ethanol) [2], solubilization [3], formation of complexes (e.g., using β-cyclodextrins) [4], solid dispersions [5], co-crystallization [6], exploiting the effects of pH or preparing salt forms [7]. However, these approaches have certain limitations that include safety issues associated with co-solvents, the requirement of sufficient ionizing groups for salt formation, the necessity of possessing sufficient solubility in oils or other hydrophobic media, restriction of having a suitable molecular size and shape for incorporation in the cyclodextrin ring, etc. Hence, identification of a universal formulation approach for drugs having poor water solubility is the mainstay of drug delivery research throughout the world. Nanoparticulate technology has been investigated for numerous drugs for a large number of applications. The nanoparticulate delivery systems have proven their potential toward fulfilling the need for improved health care and better patient compliance due to their versatility, flexibility and adaptability. Nanoparticulate delivery systems include polymeric nanoparticles, solid lipid nanoparticles, nanoemulsions, liposomes, nanostructured lipid carriers, nanogels, and drug nanoparticles. Pure drug nanoparticles are nowadays considered a viable formulation route for the oral administration of drugs having poor dissolution rate and/or aqueous solubility [8]. The ability to formulate poorly water-soluble compounds as nanometer-sized particles can have a dramatic effect on their performance, such as enhancing bioavailability, eliminating food effects, allowing for dose escalation; thereby improving their efficacy and safety. The potential of nanosized particles to alter tissue distribution after intravenous dosing should always be a consideration. For pure drug nanoparticles, tissue distribution by intravenous dosing depends upon the particle size and surface properties. However, solubility of a compound in blood is the primary attribute that determines its tissue distribution. If the compound is soluble in blood, the pure drug nanoparticles will show a pharmacokinetic profile similar to its solution and if
the compound has poor solubility in blood, the nanosized drug will behave similarly as other nanoparticulate formulations [9]. Nanosizing technology (nanonization) has also been applied to reduce variability in pharmacokinetic behavior of oral dosage forms [10]. Nanosizing a drug or formulating it as a nanoparticulate system results in its better dissolution and solubilization due to increase in surface area and saturation solubility. Pure drug nanoparticles have an edge over liposomes, microemulsions and polymeric nanoparticles in terms of commercialization, drug loading capacity, site-specific delivery, cost effectiveness, carrier associated side effects, local delivery and delivery of poorly water soluble and highly lipid soluble drugs [11]. Since this approach has been adapted to handle milligram quantities of drug substance, it provides an avenue for the research scientist to improve screening efforts without having to deal with solubility-related performance issues. The utility of this technology has been proven from the number of marketed/available products based on these techniques. Moreover, for marketed products that have performance issues related to poor solubility of the active, reformulation into nanosized dosage forms could offer the possibility of adding new life to old compounds while improving their efficacy and patient compliance. 10.1.1 Mechanism of Solubility Enhancement by
NanonizationNanonization of drug particles leads to an increase in the surface area, resulting in increased dissolution rate, according to Noyes-Whitney equation (Eq. 10.1). ds . ,= –dX D SXdt h C V (10.1)where, dX/dt is the dissolution rate, Xd is the amount dissolved, D is the diffusion coefficient, S is the particle surface area, V is the volume of fluid available for dissolution, Cs is the saturation solubility, and h is the effective boundary layer thickness.The equation shows that the dissolution rate of a drug is proportional to the surface area available for dissolution. This
principle has been extensively used in micronization of drugs for improving their oral bioavailability. Obviously, a decrease in particle size to nanometer range will further increase the dissolution rate due to the significant increase in effective particle surface area. As per Prandtl equation (Eq. 10.2), nanonization results in decreased diffusion layer thickness surrounding the particles and increased concentration gradient between the surface of the particle and bulk solution, which facilitates particle dissolution by increasing dissolution velocity. 1/2H 1/3 ,= Lh k V (10.2)where hH is the hydrodynamic boundary layer thickness, k is a constant, V is the relative velocity of the flowing liquid against a flat surface, and L is the length of the surface in the direction of flow.It is clear from Eqs. 10.1 and 10.2 that nanosizing is a suitable approach for increasing bioavailability of poorly soluble drugs, where dissolution is the rate-limiting step in systemic absorption [12]. Another important aspect of nanonization is an increase in saturation solubility, which can be explained by the Kelvin-Gibbs (Eq. 10.3) and the Ostwald-Freundlich (Eq. 10.4) equations. As per the Kelvin equation, the vapor pressure increases with increasing curvature of the droplet of a liquid in gas. If this is extended to a solid, it implies that the dissolution pressure increases with decrease in particle size. According to Ostwald-Freundlich equation, the increased saturation solubility is due to the creation of high-energy surfaces when disrupting the more or less ideal drug microcrystal to a nanoparticle [13]. r 2ln =P M
P rRT g r
(10.3) 2 ,= exp MS S r RT g r (10.4) where, Pr is the dissolution pressure of a particle with radius r, P∞ is the dissolution pressure of infinitely large particle, S is the
saturation solubility of the nanosized drug, S∞ is the saturation solubility of an infinitely large drug crystal, g is the crystal medium interfacial tension, M is the compound molecular weight, r is the particle radius, r is the density, R is the gas constant, and T is the temperature.The theoretical backgrounds of Kelvin, Ostwald-Freundlich, and Prandtl equations support the fact that below a size of approximately 1-2 μm, the saturation solubility is a function of the particle size.Nanosized particles also possess increased adhesiveness due to increased contact area of these particles as compared to microparticles. Moreover, they have stronger curvature leading to enhanced dissolution pressure, and reduction in diffusional distance as compared to microparticles, which in turn causes increase in dissolution velocity and consequent improvement in saturation solubility of the drug [14]. 10.2 Current Nanonization StrategiesThe two main approaches used for nanosizing drugs or formulating drug nanoparticles are top-down and bottom-up approaches. The top-down approach is widely used and generally referred to as nanosizing. This approach is based on use of mechanical force to convert large crystalline particles to nanosized drug particles. The bottom-up approach involves controlled precipitation (i.e., the drug is dissolved in one solvent and it is then precipitated by addition of an antisolvent in a controlled manner). Some of the widely employed technologies are briefly described here. 10.2.1 Media MillingThis is a widely used top-down approach for nanonization of drugs. Among all methods reported for nanosizing drug particles in pharmaceutical industry, the media milling technique is considered the leader with highest commercial applicability. In this technique, the drug particles are subjected to media milling wherein the high-energy shear forces generated because of impaction of the milling media with the drug provide energy to
disintegrate the drug microparticles to nanosized drug particles. In this method, the milling chamber is charged with milling pearls, dispersion medium (e.g., water), drug powder and a stabilizer. The pearls are rotated at a very high speed to generate strong shear forces that disintegrate the drug powder into nanoparticles [15]. The schematic diagram of the nanosizing process using media milling technology is shown in Fig. 10.1.
