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Agilent autosamplers and iChemExplorer combine to automate and miniaturize small molecule pharma apps

By Graham Farrell
Agilent Science Writer

and Smriti Khera
Agilent Global Pharmaceutical Segment Marketing Manager

Pharmaceutical chemistry comes in several forms. Specialized chemists perform some very specific tasks and have distinctive considerations. Medicinal chemists in the discovery stage are tasked with finding the right molecule to bring about a desired medical outcome, whereas process chemists in development must find the right way to synthesize a drug candidate.

Chemistry across pharmaceutical R&D

In practice, medicinal chemists typically generate many analogs of a given lead series to optimize and test. Analytical and pre-formulation functions that support the discovery stage also look at a vast number of compounds from chemical series that the chemists produce. The aim is to evaluate their physicochemical, biological, and drug metabolism-pharmacokinetics (DMPK) profiles, and help make critical decisions on discovery projects.

On the other hand, process chemists develop and optimize a synthetic scheme and pilot plant procedure to manufacture compounds for the drug development phase and beyond. They must identify a chemical process that is safe and cost- and labor-efficient for large-scale manufacturing, with a “green” and reproducible synthetic route. To do this, process chemists optimize each step in the synthesis by running several series of similar experiments with potentially several independent variables, such as specific reagents, reagent amounts, catalysts, other reaction conditions, and solvents.

Divergent experiments, convergent goals

Despite the divergent synthetic goals of the two groups of pharmaceutical chemists, there are many commonalities. Both groups usually run very similar synthetic reactions for generating analogs or trying to optimize a synthesis.

Both groups also want to vary reaction conditions systematically, such as screening various catalysts for a desired synthesis or varying substrates and functional groups. Therefore, both medicinal and process chemists benefit from automation and miniaturization to help with some of the labor-intensive repetitive steps. Analytical and formulation teams also stand to benefit from automation of laborious tasks. This is exactly the role of iChemExplorer, together with online sampling to monitor experiments taking place inside the autosampler.

Figure 1. The iChemExplorer platform sits handily beneath the autosampler.

The birth of iChemExplorer

Once upon a time, a chemist cut a hole in the bottom of the autosampler and the iChemExplorer was born (Figure 1). This platform is now used by many top-tier pharmaceutical innovators in the evaluation of early stage candidates and optimizing scale up. In essence, chemists use milligrams of starting material in an autosampler vial that acts as the reaction vessel. This minimizes waste and speeds results.

iChemExplorer is a unique platform that delivers automation and miniaturization to many pharmaceutical applications, including chemical synthesis. With the added functionality of iChemExplorer, chemists can perform chemical reactions with fine temperature control, up to very high temperatures – all inside an Agilent HPLC autosampler.

The ICEtray is a drop-in replacement for the Agilent 100-position vial tray. The ICEtray holds 57, 2 mL vials all in a single temperature zone. The recommended operating range is 5 to 80 °C, but heating up to 150 °C is possible. The separate flow tray facilitates circulation of a heat transfer fluid from a programmable circulator to control the tray temperature. With the flow tray installed, you can run samples at sub-ambient temperatures and automatically operate controlled cooling ramps managed by the software. A magnetic drive powers the stirrer bars in the vials to 1,000 rpm.

iChemExplorer – a perfect match for Agilent HPLC and LC solutions

The iChemExplorer platform was originally developed for Agilent HPLC and is compatible with the standard and high-performance Agilent 1260 and 1290 Infinity LC autosamplers. The 1260 and 1290 Infinity LCs are well-established product lines, ubiquitous in the pharmaceutical industry – most labs have at least one. However, iChemExplorer is not yet available with the newly introduced Agilent 1290 Infinity II Multisampler.

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Figure 2. The comprehensive and easy-to-use interface of iChemExplorer.

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Figure 3. Example peak area data from iChemExplorer on an Agilent HPLC, showing product (blue), reagent (brown) and byproduct (red).

Easily acquire data and report results with iChemExplorer

The iChemExplorer user interface includes iSample, which allows users to fill in the blanks to create a sampling sequence, and iHeat, for manual and automatic temperature control (Figure 2). With iGraph, one click lets users create and customize peak profiles, paste to other applications, and export in MS Excel®. The user interface seamlessly integrates with Agilent ChemStation and also has useful tools for helping automate several routine workflows, such as solubility studies (using the iSample solubility tool).

Key iChemExplorer applications

A typical analysis performed by iChemExplorer when used with an Agilent autosampler is shown in Figure 3. Key applications include:

• Analoging/targeted libraries
• Exploratory chemistry
• Process optimization (catalyst screening, design of experiments, reaction monitoring)
• Solubility studies
• Stability and forced degradation
• Genotoxic impurities

Agilent has a wide array of solutions for small molecule pharma

Agilent offers a broad spectrum of solutions for separation and detection, including the Agilent 1290 Infinity II LC, which maximizes analytical, instrument, and lab efficiencies. The Agilent analytical HPLC and UHPLC columns deliver the fast, reproducible results you need, offering the lowest detection levels of any high resolution LC/MS instrument. The 6495 Triple Quadrupole LC/MS system which provides superior sensitivity, renowned reliability, and overall system robustness.

All Agilent solutions for small molecule pharmaceutical applications deliver enhanced sensitivity and data quality for profiling, identifying, characterizing, and quantifying compounds of interest with confidence. Meet the family and see how Agilent can help you move from insight to outcome.

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