Eco-Friendly HBL: Cheaper, Cleaner, And Ready For Pharma
By Katie Anderson, Chief Editor, Pharmaceutical Online
The U.S. pharmaceutical industry has recently been tasked with not only onshoring more manufacturing but also reducing drug prices and stockpiling crucial medicines. Researchers at the University of Maine may have found a way to do two out of three by developing a new method of producing (S)-3-hydroxy-γ-butyrolactone (HBL) for statins, HIV inhibitors and antibiotics that can lower their production cost with an added benefit of reducing their carbon footprint. Thomas Schwartz, associate professor in the Maine College of Engineering and Computing as well as associate director of the UMaine Forest Bioproducts Research Institute (FBRI), was lead author of the paper where the team describes the process by which they converted glucose to a chiral HBL suitable for pharmaceuticals.
Initial Research In Polymers
Schwartz went on to join the University of Maine, where he has continued collaborating with Kersten to research biomass feedstock conversion into petrochemical alternative intermediates, which then can be turned into final products though a combination of chemical processing. “So, you combine chemical and biological processing. And this sort of opens the doors to products that you might not be able to get any other way,” explained Schwartz.
And open the door it did, when Kersten was studying production of cortalcerone via domain knockout modifications. It was then that the team discovered what they call trione, a key component in their current research.
“There are three domains in the enzyme, and Phil and his team were trying to identify the functions of each of them. And when they knocked out one of the domains, he accumulated this very reactive intermediate with three carbonyl groups that we called trione,” added Schwartz. After that the team asked themselves what else they could make with trione.
Stumbling Into Pharma
So, how did the team get from glucose to HBL you may wonder? The answer lies in experimenting with trione.
“We look at, if you break this bond or that bond, and discovered that there's a bond that should be pretty easy to cleave, and that if you follow the rest of the pathway, you would get to HBL,” explained Schwartz. The team was interested in the HBL final product and then ran with that.2
At the time, Schwartz had just arrived at Maine, so the team set up a joint venture between the University of Wisconsin, the University of Maine and the Forest Products Lab, which provided funding from the USDA Forest Service to continue their research.
Just like their prior work, the team started with glucose. For the purposes of their research, they purchased standard glucose, but Schwartz highlighted that there are numerous biomass sources to obtain glucose, including woody biomasses or in the case of pure glucose, sources like sugarcane, sugar beets, or cornstarch.
The glucose is oxidized to form glucosone and then reacted with the enzyme aldose-2-ulose dehydratase to produce trione. “Aldose-2-ulose dehydratase is the enzyme that would normally make cortalcerone, but Phil knocked out one of the domains, so it now makes trione,” added Schwartz.
From there, two reactions occur: the retro aldol reaction to break the carbon-carbon bond and and acid/base catalysis. “We evaluated a couple [bases] in the paper. One of them is sodium bicarbonate, which is effective. There's another homogeneous base, called piperrazine, that also works. The reaction's a little bit faster, but both of those give you good yields and reasonable reaction times.”
The last step is to hydrolyze the ester, which makes glycolic acid as a byproduct and HBL. It is then separated from water through solvent extraction.
Benefits of a Bio HBL
Although Schwartz’s team does have some interest in exploring the glycolic acid byproduct produced by the process, they are currently focused on HBL’s benefit for pharmaceuticals. Not only do they estimate that this HBL could be produced more cost-effectively compared to petrochemical processes, but it also would have a lower carbon footprint, is inherently chiral and produces a high yield.
Schwarz’s colleague, Sampath Gunukula, with a background in process design and economic analysis, put together a process flow sheet to help estimate the cost of the process compared to the traditional petrochemical route and found it to about 60% less.
The current process to produce HBL is fossil-fuel based, and the reactions are done in a petrochemical facility. The reactions are done at a high temperature, with energy provided by burning fossil fuels. Conversely, the bio-based process is done at an ambient temperature without fossil fuels and requiring less energy, reducing the overall carbon footprint significantly.
The titers used are also high, at 100 grams per liter. Schwartz explained, “This is one of the reasons that we think the cost is low. It simplifies the downstream purification.
“You know, our yields are very high, which is usually good from the perspective of working with biomass feedstocks. One of the challenges in a lot of biomass bioproducts processes is that if your yield is low, your feedstock costs are higher than they would be in petroleum. That would add to process expense. Our yields are high, so that's not that concerning.”
Pharmaceutical applications of HBL must be chiral, and this bio-based HBL is already chiral, unlike its petrochemically-produced counterparts. “We natively start with the right stereoisomer--the glucose itself is chiral. We never do any chemistry on that carbon through this whole process, and so the final product is actually enantiopure,” noted Schwartz.
Scale Up and The Future
Now that the first part of their research is completed, Schwartz and his team are looking into what lies ahead, including: scale-up, partnerships and additional end materials.
The group does some scale-up work, but further partnerships are necessary to bring them into fruition. Their first round of research was possible with funding, and future pilot-level trials will require additional monetary resources.
The team is also looking into the commercial viability of the byproduct glycolic acid, which is produced at one mole for every mole of HBL. “In our economic analysis in the paper, we didn't consider [glycolic acid] as a valuable product, although it actually is. Glycolic acid is a valuable product in its own right, and there are not a lot of bio-based processes to get to glycolic acid,” added Schwartz,
The team is excited to unveil this research at a time when there is more of a push for domestic biotech production. In the meantime, they are working at ways to improve the process and make it more efficient. “We are using simple base catalysts like baking soda, but maybe that is not the most efficient way to do it. So, we are looking at catalysts that are easier to recover while maintaining the same temperature and pressure advantages we have.
Another area of interest is making different materials by changing the starting sugar. “If you start from xylose, you should be able to make 3-hydroxypropionic acid, which is a monomer for some important polymers. And there might be others as well,” added Schwartz.
At a time when the pharmaceutical industry is laser focused on reducing pharmaceutical costs and stockpiling critical drugs, an alternative that does just that seems more than fortuitous, and the added eco-benefit is just icing on the cake…or pill.
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