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Tablets & Capsules July 2016 31 increase side effects. Some insoluble APIs cannot be deliv- ered orally at all. Consequently, poor aqueous solubility remains a major problem when formulating NCEs into oral drug products. Advantages of solubility enhancement include faster absorption, greater bioavailability, and better efficacy. Better solubility can also reduce the dosage and thus unpleasant side effects. That, in turn, can improve patient compliance. Methods to improve bioavailability There are several options for overcoming poor bioavail- ability. A pharmacokinetic approach may involve modify- ing, if possible, the chemical structure of the compound. Examples include preparing esters or various salts. A phar- maceutical approach may involve modifying the formu- lation, manufacturing process, or physicochemical properties of the API. With this approach, formulators gener- ally focus on two areas: enhancing the solubility and dissolution rate of the API and/or enhancing permeability. Solubility refers to the maximum concentration of the API dissolved in a solvent under specific temperature, pH, and pressure. Solubility modification can be chemical or physical. Physical modification includes particle size reduc- tion and/or changing the crystal habit from a crystalline form to a different polymorph or an amorphous form. The tendency of molecules to exist in different physical forms may be advantageous in some instances. For example, it may enable you to use a more soluble polymorph or amor- phous form. Adjustment of pH. Adjusting the pH is a simple and common method of increasing the aqueous solubility of an ionizable compound. It works because absorption depends largely on diffusion, which varies with the pH of the differ- ent regions of the GI tract, as well as the acid dissociation constant (pKa) and permeability of the API. The absorption process is moderated by the surface area of the region of release and its pH, which affects ionization of the API. If the pH of a drug product with low water solubility is changed, parts of the molecule that may be protonated (base) or deprotonated (acid) may acquire the potential to be dissolved in water. While parameters like salt selection and pH are considerations at the pre-formulation stage, using excipients to adjust the pH is an option during formu- lation development. Particle size reduction. When reducing particle size to enhance solubility, you can choose from several dry and wet techniques. The choice may depend on the final parti- cle size you're seeking. It's also essential to know the prop- erties of the material because almost all techniques involve creating new surface ara and this requires adding energy proportional to the bonds holding the particles together. Is the material ductile or brittle? Brittle materials are easier to fracture. Conventional dry reduction techniques use compression or impact. Compression mills work via moving jaws, rolls, or a gyratory cone. Roller mills can produce very fine parti- cles. Impact mills uses either mechanical or fluid energy. Mechanical impact equipment includes hammermills, screen mills, pin mills, and air classifying mills. Fluid-energy impact equipment includes spiral jet mills and fluid-energy mills. Wet grinding is appropriate when fine particles, e.g. nanoparticles, are required or where an explosion or dust hazard exists. The fluid can be water, oil, or a nonaqueous solvent. Surfactants. Using surfactants as solubilizing agents is another means to enhance solubility. The capacity of sur- factants to solubilize an API depends on many factors, including the surfactant's chemical structure, the API's chemical structure, tempera- ture, pH, and ionic strength. At low usage levels, surfactants may reduce surface energy of the API crystal to increase its solubilization rate. Nonionic surfactants are usually better solubilizing agents than ionic surfactants for hydrophobic APIs. With polar APIs, it's more complicated to establish a general relationship between the degree of solubilization and the chemical structure of the surfactant. Dispersions If these basic techniques cannot suitably enhance bioavailability, other technologies, such as disper- sions, may be appropriate. A solid dispersion is a mixture of one or more APIs in an inert carrier or matrix at a solid state. Because dispersions decrease particle size and/or increase surface area, they can improve the dissolution rate and bioavailability of poorly water-soluble APIs. They're prepared by melting, by using a solvent, or by a using a melt-solvent method. Methods for preparing disper- sions may include melt or melt-solvent techniques, precipi- tation, spray drying, and hot-melt extrusion. Upon expo- sure to an aqueous medium, the carrier in a solid dispersion dissolves and the API is released as very fine particles. In a melt or melt-solvent process, an API is dissolved/dis- persed in a molten carrier with or without the aid of a sol- vent. This mixture is cooled to form a solid mass that can then be further processed. A spray-dried dispersion is a single-phase, amorphous molecular dispersion of an API in a carrier matrix. That is, the compound is molecularly "dissolved" in a solid matrix. This is achieved by combining the API and a solvent and then evaporating the solvent from droplets quickly enough to prevent phase separation or crystallization. In solid amorphous dispersions, the API is adsorbed on to the surface of an insoluble material such as silicon diox- ide, which has a large surface area. The result is an increase in the dispersion's surface area relative to the normal disper- sion of the API. This allows rapid dissolution of the API, much faster than the unprocessed crystalline API. Hot-melt extrusion applies heat, pressure, and agitation to combine materials and then forces the mixture through a Enhancement strategies include adjusting pH, reducing particle size, using surfactants, creating dispersions, and molecularly encapsulating the API.