Bioavailability Enhancement

Aqueous solubility of a given molecule is the interplay of multiple factors, including solid state properties, ionization (pH, pKa), and solute/solvate interactions. The most thermodynamically stable form of an API has the lowest energy state and the lowest solubility.

Higher solubility is typically observed from solids with a higher energy state (metastable or amorphous solids). If you have poor water solubility and cannot make any salts or co-crystals with your API, then you need to consider making amorphous material by spray drying or hot melt extrusion (HME).

Nanomilling, referred to as high energy media milling or wet ball milling, is the process by which the particle size of an API is reduced in a liquid vehicle (typically aqueous) via grinding using polymeric or ceramic media.

The critical aspect of nanomilling is the tremendous increase in surface area achieved resulting in faster API dissolution and increase in solubility. The liquid vehicle usually contains a surface-active agent which allows the slurry to become a colloidal suspension. These surface-active agents also tend to stabilize the particle size of the drug during the milling process.

Nanomilling is a closed system process so the milling environment is controlled and the operators are protected, which is important if the API is highly potent. It’s an efficient, robust, reproducible, and scalable operation.

Micronization is a process for reducing the diameter of a solid material’s particles to enable its solubility. Traditional techniques for micronization have been based on friction to reduce particle size, which can be accomplished by milling or grinding particles.

Sieving equipment and mills are used to mill solids to reduce their size. It enlarges the particle surface, which increases the speed of dissolution, and it evens out differences between particle sizes to ensure homogeneous mixing.

Lipid-based formulations including SEDDS/SMEDDS and liposomes are drug delivery systems that use an emulsion achieved by chemical rather than mechanical means; it is driven by the intrinsic property of the drug formulation, rather than by special mixing or handling.

These formulations allow API solubility to be maintained during gastrointestinal dilution and transit. A typical formulation might be composed of an oily vehicle (lipid), a surfactant, and a co-surfactant, or else a single excipient with self-emulsifying properties and is filled into capsules (softgels or hard capsules) or compressed into tablets.