Automated Sample Dissolution for Compound Libraries

Sample dissolution is a critical front-end process for compound libraries that are stored in a solid state. The solid library compounds need to be dissolved in liquid so that they can be used for further downstream processes such as primary or secondary screening assays. For pharmaceutical compound libraries, typical DMSO is used as a solvent for solid compounds, due to its unique characteristics and suitability for the task. The first dissolution step typically involves diluting a pre-weighed amount of solid sample to a consistent target concentration in DMSO, such as 100 millimolar.

Difficulties do arise with this process due to the inherent variability of the physical characteristics of the solid compounds. These samples can range from free-flowing to sticky, from hydrophobic to hydrophilic, from neutral to ionically charged. Even though DMSO has good ability to dissolve a wide range of solid compounds, it is not always a guarantee that simply adding DMSO and doing a standard mixing process with the liquid probe will perform a complete dissolution of the sample. Even if a solid dissolve entirely, the resultant solution may exhibit undesirable characteristics that may impact assays, such as opaqueness or color.

Using advanced liquid handling automation platforms from Zinsser Analytic combined with a variety of unique tools that can be added to the deck, it is now possible to more efficiently automate the compound dissolution process, even using visual feedback and branching decision-making to achieve optimum results.

A typical liquid handler will approach this task by dispensing the proper amount of DMSO into the tube or vial to achieve the desired concentration, then possibly do some mixing using the liquid handler probe. The Zinsser platform can do this PLUS use a variety of other tools to further enhance the dissolution process.

	Spray probes can be used to wash down the sides of vials – this will improve dissolution of solids that have crept up the side walls.
	Dual channel probes allow gas (nitrogen or argon) to be delivered simultaneously with liquid. This maintains an oxygen/water-free environment within the tube or vial.
	DMSO is delivered as a system directly from its original container or any desired container, allowing environmental control for the solvent and reducing exposure to other items on the system.
	Zinsser’s long experience with high-efficiency vortexing used in automated parallel synthesis is used to produce efficient vortexers for compound dissolution. Vortexing is software-controlled and can be done for any user-programmed length of time Vortexing can be done under heated or cooled conditions, or at room temp. The vortexer can even be automatically sealed with a cover plate and flooded with inert gas, providing a constantly-controlled environment for reduction of exposure to water (especially when used with dual-channel liquid/gas probe)
	Sonication can be used instead of vortexing or as a supplemental step with vortexing. A sonication probe can be placed directly in the sample liquid OR the vial can be moved by the robot gripper into a software-controlled sonication bath.
	Camera tools can be used to take images after mixing / vortexing / sonication to confirm sample dissolution. Individual vials can be imaged or even microplates or tube racks. Images can be stored on the computer with each sample’s data OR optional pattern recognition software can be used to flag non-dissolved compounds, and if desired, perform additional mixing steps
	If desired, all vials with bar codes can be scanned by the robot and the information stored along with the location of the vial in the rack. Also information associated with that vial including volumes of liquid added, camera images, etc. are stored by the software and can be easily exported for database access.
	Compound vials can be automatically capped and decapped. This preserves sample and reduces exposure to air and water.

You can determine how much automation and decision-making you would like in your automated dissolution liquid handling system. Shown below are three different possible processes in increasing complexity. Different methods can also be written so that different processes can be performed, utilizing whatever tools are installed on the deck of the liquid handler.