Major Pharma Companies Use Direct Dilution to Get Better Results

Written by Allison @ Labcyte on May 07, 2018

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To analyze a compound or potential drug of interest, researchers devise dose-response experiments to better understand the drug-interaction relationship. This dose-response relationship describes how the individual responds to differing concentrations. It also helps to determine the required dose and frequency as well as the therapeutic index for a drug in a cohort population.

To test the dose-response relationship, Labcyte's acoustic liquid handling utilizes a novel "direct dilution" technique that transfers samples directly to the assay well. Using the acoustic droplet ejection technology, Echo® Liquid Handlers are able to transfer volumes that are directly proportional to the amount of compound required to give the desired concentration. Direct dilution is a highly precise method for generating different drug concentrations for dose-response experiments at a microliter level.

Direct Dilution Using Acoustic Droplet Ejection

Why Do Drug Discovery Scientists Prefer Direct Dilution?

Just like any tool, accuracy and precision are key. With traditional serial dilution methods there is a high potential for inaccuracies due to propagation errors and use of pipette tips. Serial dilutions are also tedious and manually time-consuming. These flaws in the dilution steps lead to results that are sub-par for modern-day drug development standards. Using traditional tip-based liquid handling for serial dilutions may compound errors made during each successive serial dilution, mix, and transfer.

The inadequacies of serial dilution are not limited to concentration errors. Hydrophobic compounds are lost from solution during aqueous serial dilutions. These hydrophobic compounds adhere to the plastic tips and surfaces that come in contact with samples processed on traditional liquid handling systems.

Comparing the Accuracy of Serial vs. Direct Dilution Techniques

The real issue for the medicinal chemist is finding the exact molecular structure that will provide the most potent relief to the patient. Researchers from Bristol-Myers Squibb compared the activity of over 1,000 compounds using both serial dilution and direct dilution. They found that the loss of hydrophobic compounds during serial dilution resulted in many false negatives. Very potent compounds were falsely identified as inactive using the serial dilution technique (circled in red). Mass spectrometric analyses support this finding and show significant compound loss during serial dilution.

Echo Liquid Handlers are designed to perform precise and accurate direct dilutions. The advantage of the Echo instrument over others is that solutions never come into contact with a pipette tip, pin tool, or spray nozzle. Direct dilution is not possible with pipet tips, as it requires the ability to transfer extremely small volumes of stock solution. Utilizing acoustic droplet ejection technology, the Echo Liquid Handler is able to dispense highly-controlled droplets with exquisite precision and accuracy. This non-contact method eliminates the potential for leachates, cross-contamination, and sample loss.

Accelerating Drug Discovery

Acoustic liquid dispensing and the benefits of direct dilution have led to better dose-response experiments and faster drug development around the world. Pharmaceutical companies like AstraZeneca, GSK, Merck, and Novartis have adopted the Echo direct dilution technology to grow and scale their research and development efforts that span a wide range of applications. We believe the benefits of this technique are significant and see a growing shift in both large-scale pharmaceutical companies and smaller research laboratories to adopt non-contact liquid handling as their method of choice.

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