Broadening the Toolbox in Drug Development and Analysis

January 2, 2012
Patricia Van Arnum

Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Pharmaceutical Technology, Pharmaceutical Technology-01-02-2012, Volume 36, Issue 1

Some recent advances involve strategies for accelerating reaction discovery, approaches for inducing chirality and stereochemical analysis, and applications in nanotechnology for protein elucidation.

Producing pharmaceutical compounds in a cost-effective and operationally efficient way is an ongoing challenge for process R&D chemists. Improving product yield, purity, and enantioselectivity requires a myriad of approaches and tools to enhance process understanding and analysis. Some recent advances involve strategies for accelerating reaction discovery, approaches for inducing chirality and stereochemical analysis, and applications in nanotechnology for protein elucidation.

Accelerated serendipity

Researchers at Princeton University recently reported on the use of "accelerated serendipity," a process involving robotics and high-throughput and automated workflow as a tool in process R&D. The researchers wanted to see whether serendipity could be forced or simulated to occur on a predictable basis in the realm of reaction discovery to provide a reliable platform to access valuable transformations or unexpected reaction pathways (1). The researchers used a high-throughput, automated workflow and evaluated a large number of random reactions and discovered a photoredox-catalyzed carbon–hydrogen arylation reaction for constructing benzylic amines, an important structural component within pharmaceutical compounds that is not readily accessed by means of simple substrates. The mechanism directly coupled tertiary amines with cyanoaromatics by using mild and operationally manageable reaction conditions. The researchers asserted that this carbon–carbon bond-forming protocol can be widely used in the synthesis of benzylic and heterobenzylic amines (1).

Patricia Van Arnum

"This is a very different way of approaching how we come up with valuable chemical reactions," said David MacMillan, professor of chemistry at Princeton University and co-author of the recent study, in a Nov. 28, 2011, Princeton University release. "Our process is designed specifically for serendipity to occur. The molecules that should be combined are those for which the result is unknown," he said. "In our lab, we used this technique to make new findings in a much more routine and rapid fashion, and we show that if you have enough events involved, serendipity won't be rare. In fact, you can enable it to happen on almost a daily basis."

MacMillan conceived of accelerated serendipity following his doctoral work at the University of California–Irvine during the 1990s, according to the Princeton University release. When envisioning his team's recently reported project, MacMillan calculated that if, in a single day, he ran the equivalent of one reaction per day for three years—nearly 1100 reactions—the odds favored a new discovery, according to the release. The Princeton University researchers began running reactions once a day using a high-throughput, automated reaction accelerator in Princeton's Merck Center for Catalysis.

A key part of the process was applying photoredox catalysis, an approach to synthesize chemical reactions using a low-power light source, according to the university release. MacMillan had earlier reported on the use of photoredox catalysis with organocatalysis in the direct asymmetric alkylation of aldehydes (2). The use of photoredox catalysts in organic-compound synthesis is relatively new comparative to other chemocatalytic approaches and broadened the compounds and reactions under study. For their latest work, MacMillan and his team carried out this process on the molecules before each reaction cycle. In the case of the researchers' recent work, the focus was on benzylic amines, important in many pharmaceutical compounds.

"We quickly realized that any pharmaceutical research chemist could immediately take these very simple components and, via a reaction no one had known about, start assembling molecules with an adjacent aromatic ring rapidly," MacMillan said in the university release. "Instead of having to construct these important molecules circuitously using lots of different chemistry over a period of days if not weeks, we can now do it immediately in the space of one chemical reaction in one day," he said.

Chiral chemistry

Inducing chirality. Researchers at Case Western Reserve University developed a "top-down" approach to introduce chirality into a nonchiral molecule by using a macroscopic blunt force to impose and induce chirality. "The key is that we used a macroscopic force to create chirality down to the molecular level," said Charles Rosenblatt, professor of physics at Case Western Reserve University in Cleveland, Ohio, in a December 2011, press release and senior author of a recent paper on the research (3).

Specifically, the researchers imposed a macroscopic helical twist on an achiral nematic liquid crystal by controlling the azimuthal alignment directions at the two substrates (3). On application of an electric field, the director rotates in the substrate plane. This electroclinic effect, which requires the presence of chirality, is strongest at the two substrates and increases with increasing imposed twist distortion (3).

Formulation development forum: nanosized dendrimers

The researchers treated two glass slides so that cigar-shaped liquid crystal molecules would align along a particular direction. They then created a thin cell with the slides, but rotated the two alignment directions by approximately a 20-degree angle, according to the university release. The 20-degree difference caused the molecules' orientation to undergo a right-handed helical rotation, or a so-called imposed "chiral twist." Because of the higher energy needed to maintain the naturally left-handed molecules in the crystal, some of the left-handed molecules in the crystal became right-handed, with this shift being the induced chirality. To test for chirality, the researchers applied an electrical field perpendicular to the molecules. If there were no chirality, there would be nothing to see. If there were chirality, the helical twist would rotate in proportion to the amount of right-handed excess. The result was a model involving a trade-off among bulk elastic energy, surface anchoring energy, and deracemization entropy that suggested the large equilibrium director rotation induced a deracemization of chiral conformations in the molecules or "top-down" chiral induction (3).

Stereochemical analysis. Researchers at Carnegie Mellon University successfully used nuclear magnetic resonance (NMR) to analyze the stereochemical structure of gold nanoparticles, a potentially important advance in drug development. Determining a nanoparticle's chirality is a key step toward developing them as chiral catalysts.

The researchers reported on the chirality in gold nanoclusters by NMR spectroscopic probing of the surface ligands. The Au38 (SR)24 and Au25 (SR)18 (where, R = CH2CH2Ph) were used as representative models for chiral and nonchiral nanoclusters, respectively (4). The researchers compared the NMR signal from the hydrogen atoms in the nonchiral gold nanoparticle with the NMR signal from the hydrogen atoms in the chiral gold nanoparticle. The NMR method overcame the limitations of circular dichoism spectroscopy in determining the chirality of gold nanoparticles in a racemic mixture. The nanoparticles' chiral core induced the methylene group's two hydrogen atoms to give off different frequencies, a phenomenon known as diastereotopicity.

The researchers compared the NMR signal from the hydrogen atoms in the nonchiral gold nanoparticle with the NMR signal from the hydrogen atoms in the chiral gold nanoparticle. The nonchiral nanoparticle's NMR spectrum did not reveal any differences, but the chiral nanoparticle's NMR spectrum revealed two different hydrogen signals, providing a simple and efficient way of telling whether the particle is chiral or not, even for a 50/50 mixture of isomers, according to a Dec. 7, 2011, Carnegie Mellon University release. The researchers concluded that NMR spectroscopy can be a useful tool for investigating chirality in gold nanoclusters. Since the diastereotopicity induced on the methylene protons by chiral nanoclusters is independent of the enantiomeric composition of the chiral particles, NMR can probe the chirality of the nanoclusters even in the case of a racemic mixture while circular dichroism spectroscopy is not useful for racemic mixtures (4).

Applications in nanotechnology

Interdisciplinary approaches in chemistry, biology, polymer science, and the new sciences, such as nanotechnology, are important in advancing drug development and drug delivery. Researchers at the University at Buffalo have synthesized tiny, molecular cages that can be used to capture and purify nanomaterials. The traps are derived from a special kind of molecule, so-called a "bottle-brush molecule," which consists of small organic tubes whose interior walls carry a negative charge. This feature enables the tubes to selectively encapsulate only positively charged particles, according to a Dec. 5, 2011, University of Buffalo press release. The researchers reported on the new method for fabricating amphiphilic organic nanotubes from multicomponent bottlebrush copolymers with triblock terpolymer side chains. The obtained nanotubes were highly selective carriers for positively charged molecules and nanometer-size macromolecules by means of liquid–liquid extractions. The researchers were able to discriminate between dendrimers with about 2 nm size differentials (5). These kinds of cages could be used, in the future, to expedite tasks, such as segregating large quantum dots from small quantum dots or separating proteins by size and charge.

"The shapes and sizes of molecules and nanomaterials dictate their utility for desired applications," said Javid Rzayev, assistant professor of chemistry at the University of Buffalo and co-author of the study, in the university release. "Our molecular cages will allow one to separate particles and molecules with predetermined dimensions, thus creating uniform building blocks for the fabrication of advanced materials."

To create the traps, Rzayev and his team first constructed a special kind of molecule called a bottle-brush molecule. These resemble a round hair brush, with molecular "bristles" protruding all the way around a molecular backbone, according to the university release. After stitching the bristles together, the researchers hollowed out the center of each bottle-brush molecule, leaving behind a tube-like structure. When building the bottlebrush molecules, the scientists constructed each molecule using molecular structures that disintegrate upon coming into contact with water and around this core, attached a layer of negatively charged carboxylic acid groups. To design the molecule, the scientists immersed it water, in effect hollowing the core. The resulting structure was the trap, a nanotube whose inner walls were negatively charged due to the presence of the newly exposed carboxylic acid groups, according to the university release.

To test the tubes' effectiveness as traps, the researchers designed a series of experiments involving a two-layered chemical cocktail, according to the university release. The bottom layers consisted of a chloroform solution containing the nanotubes, and the top layer consisted of a water-based solution containing positively charged dyes. After shaking, the nanotubes collided with and trapped the dyes, bringing the dyes into the chloroform solution. In similar experiments, the researchers used the nanotubes to extract dendrimers from an aqueous solution. The nanotubes were designed so that dendrimers with a diameter of 2.8 nm were trapped, and dendrimers that were 4.3 nm across were left in solution. To remove the captured dendrimers from the nanotubes, the researchers lowered the pH of the chloroform solution, which shut down the negative charge inside the traps and allows the captured particles to be released from their cages, according to the university release.


1. A. McNally, C.K. Prier, and D.W.C. MacMillan Science 334 (6059), 1114–1117 (2011).

2. D.A. Nicewicz and D.W.C. MacMillan, Science 322 (5898) 77–80 (2008).

3. C. Rosenblatt et al., Phys. Rev. Lett. 107 (23), 237804–7808 (2011).

4. R.R. Gil et al., ACS Nano5 (11), 8935–8942 (2011).

5. J. Rzayev and K. Huang, J. Am. Chem. Soc. 133 (42), 16726–16729 (2011).

Patricia Van Arnum is a executive editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072,