Solent™ Parenteral Dilution Studies

For the development and manufacture of stable parenteral formulations, not only does the active ingredient have to be physically and chemically stable in the formulation matrix upon manufacture and storage, it also has to be stable upon injection and dilution in biological fluid media.

Various techniques have been used for improving the solubility of poorly soluble drugs; pH control and co-solvent systems are important examples of such techniques. However, for parenteral solubilising formulations, not only does the solubility of the drug in the formulation matrix need to be assessed, the likelihood of drug precipitation upon administration also needs to be considered. Dilution of such formulations in biological fluids may create a supersaturated system with the potential for drug precipitation. In parallel, the rapid pH switch may also affect formulations which required specific control of pH to maintain drug solubility (i.e. salts of weakly basic compounds).

Precipitation may not only affect the efficacy and pharmacokinetics of the drug, but may also cause pain at the site of injection as well as inflammatory reactions. In parallel, other factors also need to be considered, such as injection volume (direct injection versus infusion), injection rate and frequency of dosing, which cannot be accurately assessed using static dilution methods. Thus, development of a dynamic method to predict the possibility and the extent of drug precipitation upon administration may rapidly expedite the development of such drugs.

At Kuecept, we have extended the capabilities of the Solent™ parenteral screen to include monitoring drug precipitation upon injection and dilution in human blood serum. Using our specially designed dynamic continuous flow system, we can mimic more closely the injection process, monitoring drug precipitation directly upon and after injection whilst controlling specific parameters such as blood temperature, volume and flow rate, injection volume, speed and frequency of dosing. Precipitation is directly monitored using in-situ microscopic analysis, as well as at-line turbidometric / particle size measurements for sub visible particles.

The above video shows the precipitation of drug particles in human blood serum 5 minutes after direct injection of a beta-cyclodextrin formulation into the continuous flow system.

With the ability to screen up to 5 formulations per day, the data generated can help to rapidly identify stable parenteral formulations for poorly soluble compounds that can be progressed safely and confidently into in vivo models.

For more information on this service please contact us directly.