Researchers with Southwest Research Institute stumbled onto a chemical purification breakthrough that has potential to bring down drug discovery costs that keep smaller pharmaceutical companies out of the market — all thanks to a serendipitous discovery and South Texas tap water.
In 2020, SwRI organic chemist Shawn Blumberg and his lab were up against a tight deadline to purify a batch of compounds being tested as antidotes to chemical weapons and pesticides. Purification is an important part of the drug discovery process, and often an expensive bottleneck for companies.
Typically, the lab would use purified water as its solvent in the purification process, but their deionized water system was offline.
So Blumberg got creative: He used tap water with a pinch of hydrochloric acid as a substitute. They achieved unexpectedly good purification results, results that couldn’t be replicated when their deionized water system was back online.
Realizing that South Texas tap water is notoriously hard — containing elevated levels of calcium chloride and other minerals — Blumberg wondered: “Is this magic something … is it calcium?” he said.
Fellow SwRI chemist Travis Menard conducted a follow-up study to determine if the results were legit.
Five years later, the researchers believe their discovery has potential to bring down preventative costs in drug discovery.
“If you can lower that barrier for entry into the [research and development] then you can get more successful drugs in the clinic,” Blumberg said.
The importance of purification in drug discovery
Discovering and synthesizing new drugs for clinical trials and eventually approval by the U.S. Food and Drug Administration is expensive, lengthy and filled with failure.
The average cost of bringing one new drug from discovery all the way to clinical trials and federal approval is $1.3 billion, according to a 2020 JAMA paper. Additionally, 90% of clinical drug developments fail, never making it past phase I clinical trials.
“If you can lower that barrier for entry into the [research and development] then you can get more successful drugs in the clinic,” Blumberg said. “Right now, the only players that can play in the environment are big pharma, who has the money to basically throw stuff at the wall and see what sticks. If you’re a startup company that’s trying to borrow money from a rich uncle, and then also grant money, it doesn’t go very far.”
In the earliest stage of drug development, when researchers have chemical compounds they suspect could be developed into a medical treatment, chemists use a technique called chromatography to purify the active pharmaceutical ingredient (API) before it can advance to pre-clinical trials.
Purification can be an expensive and time consuming bottleneck for companies, but the SwRI researchers believe they’ve found an inexpensive improvement to the process. It’s a vital step, though, because researchers must ensure that they’ve isolated the specific chemical component they’re aiming for and not others in the drug.
“If you give a drug that’s not pure enough, and you [conduct] toxicological studies, that’s a problem,” Blumberg said. “Is it the impurities in the drug, or is it the drug itself? And so there’s a conundrum. How pure is too pure? And then how do you do reasonably pure quickly? And that’s where chromatography fits in.”
Illustrating the importance of chromatography further, Menard explained that there’s a thin line, chemically speaking, between ADHD medications like Adderall and illegal street methamphetamine.
“Methamphetamine is actually a prescription drug, you can get that prescribed by your doctor and go pick it up at a pharmacy,” he said. “The difference there is that it was made under highly controlled conditions by a chemist in a lab and is then extensively purified to become a very pure and safe product. If it gets made on the street, you have no idea what’s left over in there from the making of it. The idea is getting only the thing you want and nothing else so that it’s as safe as possible.”
How chromatography works
There’s several methods of chromatography, but essentially all of them aim to isolate chemical compounds in a mixture. Coffee companies often use chromatography to test the caffeine content of their products. And you’ve probably done chromatography yourself in the form of paper chromatography science experiments in school, separating different ink pigments in a water solvent.
“Chromatography is a means to an end,” Menard said after a short demonstration of SwRI’s chromatography machine. “And, it’s a secret, but I hate doing chromatography. It’s time consuming, it can be difficult, so we’re trying to make it a little easier, faster, more cost effective.”
Publishing research on chromatography itself is unusual, like “a mechanic publishing a paper on a wrench,” Menard later added.
The process is essentially placing a mixture into a solvent (either liquid or gas), which then gets passed through a column filled with material, called the stationary phase. Usually that material is silica gel, an inexpensive moisture absorber.
The problem is that some compounds don’t separate well with silica gel alone, requiring additional materials that might be 20 to 50 times more expensive and hard to find in bulk. With the help of calcium carbonate though, Menard and Blumberg say their process allows for the use of silica gel alone in many cases.
“It would never have occurred to me to put salts into the [liquid solvent], specifically calcium,” Blumberg said. “When Travis [tested] other salts, calcium was kind of unique in terms of the performance. Not only is calcium pretty inexpensive, but it operates in this niche window … making the purification much, much better.”
The researchers have used the improved “ion-assisted chromatography” method on several APIs in development at SwRI in recent years. They soon plan to test this new method on peptide drugs like GLP-1 medications for weight loss and diabetes.
“For peptide drugs, purification is probably one of the biggest cost drivers and bottlenecks, and so we’re extremely curious about utilizing this discovery to lower the cost for basically whole categories of drug development,” Blumberg said. “If this can be applied, you can make some pretty big impacts pretty easily.”
