Trends in drug discovery: improving productivity with increased confidence

Like many companies in today’s environment, pharmaceutical companies must improve their bottom line results in increasingly difficult circumstances.  Among the challenges uniquely faced in the pharmaceuticals industry are:
  •  Companies continue to increase investment in research and development, although the returns are lower as the number of new approvals is declining
  •  Pipelines for promising new therapies are in decline, with many companies seeing a larger portion of revenues coming from older products that will soon lose patent protection
  •  Costs to develop new drugs continue to increase, with some estimates placing the total cost of bringing a new therapy to market at USD 1.6 billion and take greater than 10 years

Advancing technologies in separations are assisting pharmaceutical companies in responding to these challenges.  One exciting development is in the medicinal chemistry laboratory, where innovations in flash chromatography are making it possible to generate more potential hits faster and with less rework.

Flash chromatography: advantages in drug discovery
It is well understood that the drug discovery process is slow and iterative involving various stages of synthesis and selection of “target molecules”. Bottlenecks, especially in purification, waste time and money which stalls compound submission and progression in research and development. A target compound’s successful progression through hit to lead status not only depends upon the structure-based biological activity; but also hinges on compound purity. By submitting high purity compounds, chemists have more certainty in bioassay results and can “pass” or “fail” compounds faster because false “hits” from reaction by-products and skewed bioassay concentrations can be avoided. The purity and stability of entire compound collections has worried the pharmaceuticals industry for years and has been the focus of discussion and debate among analytical chemists for many years. Ever since the early 1990s, pharmaceutical companies have been plagued by compound purity concerns following the industry’s failed attempt to turbo-boost their pipelines with major investments in high-throughput synthesis efforts. This lead generation strategy, formerly known as “combinatorial” chemistry (a term that is now taboo), was criticized for producing highly impure targets and false hits.

Accessing purity and removing contaminants sounds easy enough, but most chemists agree that it completely depends on the ability to detect both “target” compounds and all contaminants present in a sample at submission. Truly “universal” detection is nonexistent, but new detection advancements allow reliable and familiar techniques like flash chromatography to overcome this common challenge. Most importantly, chemists prefer flash over reversed phase HPLC or SPE techniques since easily removed organic solvents can be used in an automated fashion to reduce purity concerns in drug discovery.

Flash, fundamentally a liquid chromatography technique, involves loading a sample into a cartridge containing a silica adsorbent, using pressure to push the sample with a solvent through the cartridge, and collecting the purified fractions.  A flash system including a pump, detector, and fraction collector automates the process of purifying, identifying, and collecting the individual compounds.

Medicinal chemistry labs have increased their adoption of flash chromatography, as it is a fast, simple, and inexpensive means of purifying reaction mixtures into potential hits and impurities.  Prior to using flash chromatography, medicinal chemists used lengthy manual column chromatography or relied on preparative chromatography labs to purify their mixtures, forcing them to give up custody of their reaction materials and lengthening the time to find potential hits.  The ease of use of flash systems, along with robust designs that allow for a wide variety of materials to be purified, allowed the medicinal chemists to take control of their purifications themselves and reduce the amount of time to submit potential hits.

The technology for flash systems has continued to evolve, creating more opportunities to improve productivity in drug discovery.  Innovations in detection and collection, operating pressure, and separations media are the newest advances that continue to help the medicinal chemists more quickly and effectively submit the next revolutionary medications.

Advances in detection and collection
Flash systems traditionally use an ultraviolet (UV) detector, which works based on a compound’s absorption of various wavelengths of UV light.  Compounds with UV active properties show a response to these detectors and are known as “chromophores”. 

However, the UV detection method is not effective when mixtures include compounds without these chromophoric properties (“non-chromophores”).  If a non-chromophoric impurity is present in the reaction mixture, it can co-elute with the compound of interest, potentially causing an interaction with the hit and reduce its concentration and purity.  In the worst case, a promising new therapy can be lost due to contamination with an impurity that the flash system missed.  At best, it creates days or weeks of rework for the medicinal chemist when an analytical lab with more sophisticated equipment detects the impurity.  Similarly, the potential hit itself may be a non-chromophore and would be completely missed by traditional flash systems.

Grace Davison Discovery Sciences, a company that provides a full range of chromatography and separations tools to pharmaceutical and life sciences companies, has introduced the new Reveleris™ Flash Chromatography System.  This new system solves the non-chromophoric compound problem with its patent-pending RevealX™ detection technology.  This detection and collection system integrates three separate signals, including dual-UV and evaporative light scattering (ELSD), allowing the medicinal chemist to see both chromophores and non-chromophores.  This innovative system saves the medicinal chemist time, reduces rework, and increases the possibility of generating a hit that eventually will become a lead.

Advances in pressure and media
In addition to detection and collection technology, flash cartridge design and operating pressure have an impact on the effectiveness and efficiency of a flash separation.  The flash cartridge, where the reaction mixture is resolved into its components, performs based on the properties of the silica media it contains.   The silica media determines how much material can be loaded into the cartridge and separated, and how efficiently and quickly the mixture can be resolved into its components.

A trend in the development of flash systems has been an increase in operating pressure, allowing faster flow rates to be used.  In order to accommodate this increase in pressure, the flash cartridge must also be upgraded and able to safely withstand the higher system pressure.  The silica media in the cartridge, which determines how easily compounds can be resolved, must also be changed for the higher system pressures.  Typically, higher-pressure cartridges are packed with silica having a smaller particle size and tighter size distribution, allowing for efficient separations and maximum resolution.

Grace Davison Discovery Sciences, a division of W.R. Grace and Co., was an early developer of silica gel and was the first company to sell silica gel commercially in 1921.  In 1981, Grace also launched its industry-leading DAVISIL® Chromatographic Silica Gel, which has been used extensively in flash chromatography.  The new Reveleris™ SRC Cartridges, part of the newly launched system, were developed with a new grade of DAVISIL® Silica that allow for double the loading capacity of similar cartridges, whilst increasing resolution.  This increase in loading enables the medicinal chemist to use smaller, less expensive cartridges or to shorten runtimes and improve productivity.

Conclusion
The new detection and collection technology, along with developments in silica and cartridge technology, combine to improve productivity in the medicinal chemistry lab.  Medicinal chemists can detect and collect more compounds and impurities, perform their work faster, and reduce their need for rework.  As this advanced technology is adopted, pharmaceutical companies can benefit from this productivity gain and increase their chances of finding the next innovative therapy.

The information presented herein is derived from our testing and experience. It is offered for your consideration and verification. Since operating conditions vary significantly, and are not under our control, we disclaim all warranties on the results that may be obtained from the use of our products. Grace reserves the right to change prices and/or specifications without prior notification. W. R. Grace & Co.-Conn. and its subsidiaries can not be held responsible for any damage or injury occurring as a result of improper installation or use of its products.
REVELERIS™, REVEALX™, and SRC™ are trademarks of Alltech Associates, Inc.  GRACE®, GRACE DAVISON® and DAVILSIL® are trademarks, registered in the United States and/or other countries, of W. R. Grace & Co.-Conn.  GRACE DAVISON DISCOVERY SCIENCES™ is a trademark of W. R. Grace & Co.-Conn.

Alltech Associates, Inc. is a wholly owned subsidiary of W. R. Grace & Co.-Conn. Grace Davison Discovery Sciences is a product group of W. R. Grace & Co.-Conn., which now includes all product lines formerly sold under the Alltech brand. © Copyright 2009 Alltech Associates, Inc. All rights reserved.