Divide and Conquer

Chiral Technologies Inc. (CTI), a supplier of chiral stationary-phase media and chromatography services to the pharmaceutical industry, expects its sales to grow by more than 25% this year. A recent decision by a customer, Cephalon, provides a glimpse into the reason why.

Cephalon is a biopharmaceutical company with a strategy of acquiring late-stage or already marketed drugs to provide sales and profits while it develops its own new product pipeline. In 1993, it licensed the wakefulness-promoting drug modafinil from France's Group Lafon. The drug, known as Provigil, was approved as a narcolepsy treatment in 1998 and today is Cephalon's biggest seller.

After launching Provigil, the company set out to expand the drug's applications. In January of this year, the Food & Drug Administration approved it for patients with excessive sleepiness due to sleep apnea and shift work. Cephalon is also studying the drug's use in treating attention deficit hyperactivity disorder.

Unlike many of the small-molecule drugs on the market today, modafinil is a racemic compound. Cephalon found in preclinical work that modafinil's R isomer works longer than the racemic mixture, and by late 2003 the firm was conducting Phase III clinical trials to verify these results. It anticipates filing a New Drug Application for R-modafinil in narcolepsy and sleep apnea treatment later this year.

When approval of the single-enantiomer drug became a possibility, Nelson Landmesser, a senior Cephalon scientist working in chemical process development, was given the task of developing a commercial route to the enantiomer to supplement the company's racemic modafinil production in Mitry-Mory, France. At a recent event at CTI's new headquarters and technical center in West Chester, Pa., Landmesser described how Cephalon came to embrace chromatographic separation.

"I'm a synthetic organic chemist by training, so I started to think about diastereomeric salts and asymmetric synthesis," Landmesser said. But his boss, Senior Vice President of Research John P. Mallamo, asked him to consider chiral chromatography--a technique Landmesser was familiar with but wasn't sure was appropriate for producing large quantities of an enantiomer.

Landmesser became a believer not long after launching a feasibility study with the help of CTI and the French firm Novasep, a leader in chiral separation equipment and a frequent collaborator with CTI. In just two months of batch chromatographic separation of racemic modafinil in Novasep equipment with CTI chiral stationary-phase media, Cephalon was able to obtain 60 kg of R-modafinil for use in Phase I trials.

For Phase II and III trials, Cephalon needed 600 kg, too large a quantity to be effectively obtained from a batch process. Instead, the company moved the job into simulated-moving-bed (SMB) chromatography equipment operated by Novasep in Pompey, France.

Ten months later, Landmesser said, Cephalon has received almost the full 600 kg and is now lining up firms to supply even larger quantities in anticipation of launching the new drug, called Nuvigil. The entire process, from feasibility study to commercial rollout, will have taken only 24 months. "As a synthetic chemist, I realize this is remarkable technology," he said.

More and more chemists seem to be coming to the same realization. Christopher J. Welch, a process researcher at Merck, said at the CTI event that chiral chromatography has "completely revolutionized" pharmaceutical research in the past 10 years. "We can get our hands on material in one day that can take a year to get by other methods," he said.

Surprisingly, CTI and its parent company, Japan's Daicel Chemical Industries, have sold their polysaccharide-based chiral stationary-phase media only since the early 1990s. In 1994, Belgium's UCB gave the separation technology a stamp of approval when it became the first drug company to choose it for commercial production of an enantiomer.

SINCE THEN, firms such as Lundbeck, Pfizer, and now Cephalon have picked chiral chromatography for large-scale enantiomer separation. A half-dozen fine chemicals companies--including Pharma-Eco, Aerojet, Honeywell, Finorga, and Bayer--have added SMB to their technology toolboxes.

Thanks to this blossoming in chromatographic chiral separation, CTI's sales have soared in recent years, hitting about $20 million annually, according to Thomas B. Lewis, president and chief executive officer. Along the way, he noted, the company outgrew its old facilities in Exton, Pa.

At the new West Chester site, Lewis said, CTI enjoys a fivefold increase in capacity to provide chiral separation services. The company offers high-performance liquid chromatography, SMB, and supercritical-fluid-based techniques and can now run separation campaigns of up to 50 kg for drug companies conducting early-phase clinical trials.

Lewis was hired in 1992, not long after Hisao Nishimura, a Daicel chemist, had been sent to the U.S. to introduce the new chiral stationary-phase media. Since then, Lewis has had the satisfaction of seeing the drug industry adopt a technology that his firm helped make possible. As he said at the event, "The journey from Japan to West Chester has been a lot of fun."