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LeadershipWith synthesizing new molecular entities (NMEs) our mission in life as chemists, we are innovators, creators even. In drug discovery research, these NMEs stand a good chance of becoming a cure for a major illness or disease. Few roles in life provide such opportunity for making a positive impact on society as does being a medicinal chemist. It is no wonder that we are so emotionally attached and protective of the targets we create, almost in a parental way. This is why we need to carefully manage every step of the NME synthetic process. The question is, how can we ensure that we have full control over one of the most important, yet least enjoyable steps in the process – purification?
The need to control every step of the synthetic process
The chemistry of drug discovery starts with careful and deliberate molecular design as part of the design-make-test-analyze (or DMTA) cycle. Medicinal chemists work through a retrosynthon methodology to map out the multi-step pathway for building the target NME from simpler building blocks. The make stage of the cycle involves a mastery of organic synthesis, including choosing the right reagents and controlling organic reactions to maximize the yield of the target as well as each intermediate defined in the synthesis pathway and minimize amounts of undesired side products. Reaction conditions are also selected to quickly drive the reaction to completion without compromising the integrity of the target compound.
Purification – a means to an end
Despite the care taken to control the inputs for NME synthesis, chemists often lose control when advancing the outputs, or intermediates, to the next step or when submitting an NME ready for biological testing. Why? Well, the one important (and chemists report to be the most critical) step in the make stage is compound purification. Limited chemistry education and practical training may mean using inefficient ‘flash’ separations involving glass columns packed with silica, loading the sample on the top of the silica bed, eluting with an organic solvent mixture, and laboriously hand-collecting the eluent into numerous test tubes. Not being masters of chromatographic separations, the chemists see a real risk of losing control of the target and the synthesis process at the purification step. And it is not a good use of their time.
With purification regarded as the largest bottleneck in the make stage of the DMTA cycle, medicinal chemists have adopted automated flash column chromatography to get the job done quickly. Despite this, they are seldom in complete control of the separation, with success in purification relying on luck versus know-how. The result is less-than-pure compounds, poor target yields, and frustration as the drug discovery project is slowed down. Many therefore view flash separation on automated systems as both a ‘dark art’ and a necessary evil.
Having control saves time in drug discovery
Medicinal chemists working in pharma and biotech cannot afford to waste time with purification. Synthesizing NMEs is slow, iterative and laborious, without even considering the time spent conducting chromatographic purifications. Solving these workflow problems has involved significant investments in automated flash chromatography systems.
Automated flash chromatography systems should be like an ATM (automated teller machine) that quickly and faultlessly dispenses the cash (or purified target compound in this case). After all, no one wants to wait a long time and would never consider walking away from an ATM without their cash, right? The same logic applies to an automated flash system. The need to boost productivity in drug discovery research means that medicinal chemists must work smarter, not harder. Automated flash chromatography will remain as the go-to choice for chemists who want to get pure target compounds in-hand fast and advance their discovery projects quickly. This means chemists now depend on state-of-the-art, intelligent flash systems to simplify and speed up the process.
Putting the chemist back in control of purification
Automated flash systems that just pump solvents and collect fractions are outdated and do not really enable the chemist to be in full control of their separations. Although such systems work to free the chemist’s time (time spent being their own fraction collector, etc,), they leave compound purity and recovery to chance. However, contemporary automated flash chromatography systems, such as the Biotage® Selekt flash system equipped with high-performance Biotage® Sfär columns, put the chemist back in control. Selekt flash system, with its intuitive interface design, provides straightforward access to instrument control and method guidance to ensure the separation works well the first time.
With the Selekt system, chemists enjoy more predictable purification outcomes, delivering purified targets in record time.
