ABSTRACT
Keywords: nanomedicine, nanomilling, intestinal absorption, emulsion-templated freeze-drying, spray drying, depot, solid drug nanoparticles, homogenization, pharmacokinetics, oral dose, long acting formulations 8.1 IntroductionThe formation of nanoparticles for drug delivery applications has been approached using several strategies. These are divided into two general approaches, namely, forming a nanocarrier for the drug [1, 2] or making a nanoparticle directly from the active pharmaceutical ingredient (API). Solid drug nanoparticles (SDNs) [3] are predominantly used for oral dosed therapies containing poorly soluble compounds and, recently, the production of long acting (LA) injected depot formulations. The issue of poor water-
solubility of current and future APIs is considerable within the pharmaceutical industry and estimates vary from 40-90% of potential new API candidates having poor or limited solubility. This has the impact of reducing the success rate within the development pipeline and also impeding the effectiveness of many medicines in current clinical use. The impact of solubility on drug delivery is often interpreted using the biopharmaceutical classification system (BCS) and nanocarrier and SDN strategies are being discussed to overcome such solubility issues [4, 5]. Poor water-solubility may also lead to difficulties in formulating compounds into viable dosage forms (for example tablets, capsules, syrups, gels or depots) and SDNs have been used to overcome manufacturing problems, allowing products to reach patients. The purpose of this chapter is to provide an overview of current methodologies for manufacture of SDNs and to use specific examples that highlight the pharmacokinetic benefits that they confer. 8.2 Physical Properties of Solid Drug
NanoparticlesSDNs, frequently referred to as nanosuspensions or nano-dispersions, typically consist of drug particles with an average diameter of less than 1 µm (1000 nm) that are suspended within a liquid and stabilized by soluble polymers and surfactants. A poorly water-soluble API that is within this size range will have a considerably increased surface area when compared to the same mass of API with particles in the multi-micron size range. As a comparison, a single 1 mm (1000 µm) cube of poor water-soluble API will have a surface area of 6 × 106 µm2 (6 × 1000 × 1000 µm). If this cube of API is broken into identical 10 µm (10,000 nm) cubes, each new API particle would only have a surface area of 600 µm2. However, 1 × 106 particles of this size would have been generated from the larger particle that collectively would present a surface area of 600 × 106 µm2. A reduction in particle size from 10 µm to 200 nm (0.2 µm) would create 125 × 109 cubic API nanoparticles, each with a surface area of just 0.24 µm2, but a collective surface area of 30 × 109 µm2; a 5000-fold increase in surface area over the single 1 mm API particle (Fig. 8.1). The
consideration of particle surface area is important due to the Noyes-Whitney (Eq. 8.1) and Kelvin (Eq. 8.2) equations [6].s= –dC DA C Cdt hV (8.1) app m0 2ln =S VS rRT (8.2)The Noyes-Whitney equation relates the dissolution rate (dC/dt) directly to the surface area of the material that is dissolving (A) and a significant increase in surface area, as demonstrated above, will have a considerable increase in the observed dissolution rate. The Kelvin equation demonstrates an unexpected effect of decreasing size into the nanoscale regime; the ratio of the apparent solubility (Sapp) and equilibrium solubility (S0) is inversely proportional to the particle radius (r), again leading to an improvement in the apparent solubility of a compound with decreasing particle size.
