A robotic liquid handler is the centerpiece of automation in drug-discovery laboratories and is an important component of the sample-preparation process.
To automate sample preparation, a liquid-handling robot (i.e., liquid-handler) as commonly used in high throughput screening laboratories  is essential. This device transfers aliquots of sample or solvent and should eliminate the need for manual pipetting. In practice, workstations with a multichannel pipetting arm are sufficient to achieve the throughput required for a typical MS lab. If sample collection and distribution is not standardized to the SBS microplate format (www.sbs.org), then it is necessary to use a liquid handler that can access samples individually. Commercial devices with 1 to 16 independent probes are available. Independent probes are required for applications such as the preparation of serial dilutions or cherry-picking. Robotic liquid-handling arms with fully independent tip-positioning systems that have independent y- and z-axis movement are available for applications that require flexible pipetting. Liquid handlers can also be purchased equipped with accessories such as wash stations, vacuum boxes, heat exchangers, or plate readers that are fitted on the deck of the platform application-specific tasks. New features such as real-time optical position calibration can be useful, especially when disposable tips are used with high-density plate formats.
To minimize the risks of cross-contamination many laboratories will use disposable tips instead of fixed, washable tips. The use of disposable tips is and has been an area of constant discussion within the automation community. Fixed tip operations are inherently more reliable and cost effective, and in many cases, suitable washing procedures can be identified that can reduce the levels of carryover below detection limits. Many liquid handlers provide a mechanism of liquid detection that can be used to limit the exposure of tips to liquid, and thereby help prevent cross-contamination. However, depending on the nature of the compounds to be analyzed, compliance and liability issues, the use of disposable tips may be required. A number of different approaches to liquid handling, such as positive displacement, system liquid, and air pressure, have been incorporated into liquid handlers currently on the market. With the various pipetting approaches there are various ways to perform liquid sensing to detect empty sample wells or pipetting errors. The most common approach to liquid sensing is capacitive detection between the pipette tip and the metal surface of the deck. This approach requires the use of carbonized conducting tips. Another approach is the use of pressure sensing, in which an expected pressure increase can be predicted and measured. If the actual pressure during pipetting deviates significantly, then an error is indicated.
It is necessary to adjust the hardware and the liquid-handling parameters (syringe size, pipetting speed, break-off speed, air gaps, tip touching, clot detection, calibration factors, etc.) of the pipetting robot for accurate and precise liquid transfer. Many robots can achieve a coefficient of variation (CV) below 5% in the 1- to 100^L range when properly programmed and calibrated.
It is especially important to perform calibration experiments with plasma or other high-viscosity samples. Automated procedures that include on-line gravimetric and density determinations have been reported [68,69]. Not all workstations provide the same level of tuning of liquid-class parameters. Some vendors offer multivariate analysis packages that help users set up the appropriate liquid-class experiments and then use statistical approaches such as design of experiment (DOE) to guide the determination of optimal liquid-handling parameters .
Modern systems should provide a visual interface for rapid method development that can be mastered by a properly trained staff. A more dynamic integration of the robot into a work flow usually requires some form of scripting or high-level programming skills. The programmability and user interface of a robot is a critical factor to obtain user acceptance. The reader can find more details on the robotic platforms currently on the market in recently published review articles [71,72].
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