Development Capabilities

Bioavailability Enhancement

Covar specializes in bioavailability and solubility enhancement screening programs custom designed for your molecule. Our deep experience in developing BSC II – IV drugs has led us to conclude that people remain by far the most crucial element in development success. Systematic screening of bioavailability enhancement technologies is highly recommended (versus single focus on one technology) and reduces expense while improving results.

Taking advantage of our purpose-built miniaturization laboratories (g & mg scale equipment) to encourage lean development and API conservation, our clients have access to the full range of bioavailability enhancement technologies, including:

Lipid-Based Formulations

Lipid-Based Formulations are often strong candidates when screening and selecting suitable bioavailability enhancement technologies. Individual technologies are best viewed as one tool in the toolkit. Best results are typically obtained by customized applications of multiple technologies in combination.

Together with other technologies and specialized excipients, Lipid-Based Formulations can often achieve remarkable results:

Polar and non-polar structural groups present in specialized lipid excipients can help dissolve the drug substance and then carry it to the site of action.
Lipid excipients can enhance the amount of drug substance a dosage form can carry due to increased solubility.
Specialized lipids, solvents, and/or surfactants can solubilize, disperse and transport drug substances across the gastrointestinal wall and improve absorption.
Lipids can protect drug substances from hydrolysis.

The challenges of Lipid-Based Formulations include poor stability and disagreeable taste. The risk of precipitation (crashing out) upon dilution with biological fluids or food effect must also be assessed.

Lipid-Based Formulation capabilities:

Co-solvent-solvent / Co-solvent-Co-solvent Systems
Solubility Enhancers
Permeability Enhancers
SEDDS & SMEDDS

Nanosuspensions

Nanosuspensions are often strong candidates when screening and selecting suitable bioavailability enhancement technologies. Individual technologies are best viewed as one tool in the toolkit. Best results are often obtained by customized applications of multiple technologies in combination.

Decreasing particle size increases surface area and may improve solubility and thereby bioavailability. Due to their small size, nanoparticles may even penetrate the gastrointestinal wall (or blood brain barrier) without dissolving.

Nanosuspensions present a number of common challenges:

Liquid nanosuspensions are often unstable due to phase separation and particle size increase caused by Ostwald ripening.
High concentrations of fine particles can tend to agglomerate, leading to drug loading challenges.
SEDDs require high quantities of excipients such as surfactants which can lead to toxicity challenges. Lipid excipients also tend to have disagreeable taste.

Nanosuspension technology capabilities:

High energy milling (e.g. microfluidizer)
Liquid anti-solvent precipitation
Self emulsifying methods (SEDDs or SMEDDs)

Amorphous Solid Dispersions

When screening and selecting suitable bioavailability enhancement technologies, Amorphous Solid Dispersions, can provide a powerful and elegant solution to resolve bioavailability issues. However, due to the high cost and inherent problems in later scale up, other less expensive technologies should be trialled as part of the toolkit in parallel. Drug substance suitability should also be screened prior to proceeding.

Amorphous Solid Dispersions are thermodynamically unstable dispersions of a drug in solid state with the chosen excipients. In an amorphous state, drug substance solubility can be significantly enhanced (by as much as 1000 times). Drug absorption can therefore be improved remarkably due to the high concentration gradient between biological fluids and excipients.

However, Amorphous Solid Dispersions also provide substantial challenges:

Unpredictable Stability

Formulations containing drug substances in an amorphous state are challenging to stabilize over the entire product shelf life and prone to sudden or unexpected physical changes.

Specialized Equipment

Amorphous Solid Dispersions are typically produced by either spray drying or twin screw extrusion

Spray dried formulations are easier to produce and require less drug substance. However, spray drying is comparatively costly and scale up is often problematic due to poor particle size control in large batch size spray dryers.
Twin screw extrusion is more cost-effective, easier to scale, and does not require organic solvents. However, twin-screw extrusion typically consumes larger quantities of drug substance, presenting challenges in early development.

Note: Alternative lower-cost options compared to both spray drying or twin screw extrusion may be worth consideration where process control and long-term stability are less stringent (e.g. animal studies).

Clients considering an Amorphous Solid Dispersion are strongly advised to first perform a drug substance suitability screening. This screening includes a paper assessment (e.g. glass transition temperature, solubility parameters, excipient & drug substance thermodynamics, organic solvent solubility studies) and laboratory studies (solubility & microscopy studies on a miniaturized scale).