Db

Server

Experimental Dispense Substrate Design

Equilibrate & Separate

Quantify

FIGURE 14.11 A high-level representation of the Symyx solubility system architecture. The work flow from experimental design in Library Studio through quantitation by LC is shown in the bottom panel.

Equilibrate & Separate

Quantify

FIGURE 14.11 A high-level representation of the Symyx solubility system architecture. The work flow from experimental design in Library Studio through quantitation by LC is shown in the bottom panel.

the high-level instrument architecture for the Symyx solubility workstation [58]. The application server acts as the hub and distributor of a coordinated informatics flow that use independent client computers to control the commercial hardware. The information is passed and received among the hardware devices through extensible markup language (XML) documents. Symyx has developed a software package, Library Studio®, which is user-friendly and powerful for experimental design. The input parameters to Library Studio are used to drive the hardware devices.

The input parameters define the compound quantities and positions, solvents, temperatures, and equilibration time. The first step of the work flow is to dispense the compound with an automated powder dispenser. The parameters from Library Studio are used to drive a powder dispenser from Autodose (Geneva, Switzerland). The next step of the work flow requires the liquid handler to take the parameters outlined in Library Studio and to dispense the solvents across the plate. Besides the routines to aspirate and dispense, the liquid-handler platform has the capability to stir and control temperature. Concurrently, while this part of the work flow is executed, the compound standards, LC methods, and calibration curves are generated for quantification purposes. After equilibration on the liquid handler, the next step in the work flow requires a separation procedure. Separation procedures can be either centrifugal or filter based. The separation procedure is used to ensure that the excess compound is separated from the solvent under saturated conditions to avoid contamination with the subsequent quantitation step. The final step in the work flow is the quantitation-based analysis with LC. The parameters from Library Studio are transferred to the LC and resultant peak areas, based on experimental conditions (e.g., reaction volumes, dilution ratios, injection volumes), and are used to calculate the solubility of the compound or compounds as a function of the solvent(s), temperature, and time.

This system architecture enables a streamlined work flow that significantly decreases the amount of time needed for an experiment. The technology enables order of magnitudes more experiments (i.e., combination of conditions) to be conducted in the same period as done manually. The power of the technology is the ease at which design, execution, and analysis experiments can be performed across a platform of hardware components. If these experiments were conducted manually, then these processes would be extremely time-consuming and laborious. Furthermore, fewer combinations would be investigated.

The Symyx solubility workstation has been integrated into the medicinal and process chemistry work flows at Amgen [60]. The technology has allowed for the investigation of numerous parameters that would otherwise not be assessed during a first-pass analysis. Experiments on lead optimization candidates to study single- and multiple-solvent effects (e.g., co-, tri-, antisolvent, etc.) as a function of temperature, time, and pH have been conducted.

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