UConn researchers have patented a novel instrument that will help assess early in the drug development process how potential new drugs will dissolve in fluids.
Major drug manufacturers invest millions of dollars in research and development in order to make sure their products are safe, effective, and of the highest quality.
Despite showing potential in a Petri dish or research lab, a great many pharmaceutical products never make it to the commercial market because they are too toxic, too unstable, don’t dissolve properly in the body, or have some other critical flaw that can’t be overcome.
Catching a problem early in development saves manufacturers both time and money and, ultimately, reduces the costs for medicines that get transferred to consumers.
Now, pharmaceutical sciences associate professor Robin Bogner and mechanical engineering professor Theodore Bergman – along with a pharmacy graduate student and two engineering undergrads – have created a novel instrument that they say will help pharmaceutical companies develop new medicines more efficiently.
Testing potential new drugs
When companies test potential new drug candidates to see how they dissolve in different solutions, researchers rely on a steady wave of analytics coming out of a monitor while the chemical reaction takes place. If the results are skewed, the developer may repeat the process until – through trial and error – the drug either dissolves properly or they write the product off. This process not only takes time and money, it uses up the relatively limited bits of a new medicine that are made available to testers in the lab.
Bogner and Bergman’s instrument – called a dissolution flow cell – is a palm-sized apparatus that allows researchers to view in real time the transition taking place when a small sample of a drug in a solid state dissolves in fluid. Being able to clearly see (using stereomicroscopy, Raman microscopy, or similar methods) what is happening in the conversion process and compare those results to the computer analytics helps drug developers identify and address problems quickly, the researchers say.
“Having an early understanding as to how a drug will behave is important,” says Bogner, an expert in drug dissolution technology. “It removes some of the risks and allows manufacturers to focus money and resources into areas that potentially bring more medicines to more people more quickly.”
Academic research assisting private industry
Leaders in the School of Pharmacy say the patented flow cell invention is a prime example of how UConn’s academic research can assist private industry in addressing issues and improving manufacturing techniques similar to what is being proposed at the University’s new Technology Park. It is also an example of UConn’s leadership in the area of pharmaceutical technology and manufacturing science. UConn is a major contributor to the non-profit National Institute for Pharmaceutical Technology and Education (NIPTE), which recently entered into a long-term agreement with the U.S. Food and Drug Administration to improve drug manufacturing standards in the U.S.
“The development of this flow cell illustrates the great value of cross-disciplinary team work,” says Debra Kendall, head of the Department of Pharmaceutical Sciences and Board of Trustees Distinguished Professor of Medicinal Chemistry. Here, professors and students in pharmacy and in engineering merged their expertise to invent an instrument addressing a critical need in the development of novel therapeutics to improve human healthcare.”
The flow cell is made up of two carefully engineered steel plates that are sandwiched together. The bottom plate has a narrow channel running through it in which a very small amount (5-10 mg) of a drug sample can be inserted. The top plate, which is removable, has a glass window that allows researchers to observe the drug sample dissolving (or not) as it sits in the channel. Small holes at either end of the instrument allow tubes to be attached so that any mix of fluids mimicking what is in the human body can flow through the channel and interact with the drug.
Bogner and Bergman began working on the device in 2005. UConn alumna Kristyn Greco ’10 Ph.D., helped design the flow cell while she was a doctoral student in pharmaceutical science at the University. Two mechanical engineering alums, Derek Michaels ’06 (ENG) and Szymon Chawarski ’06 (ENG), who were undergraduates at the time, helped build the instrument as part of their senior design project in 2006. With the help of UConn’s Office of Technology Commercialization, the research group successfully patented the instrument in February 2011 and is currently marketing it for commercial use.
“Working in a team to develop this device was a great learning experience,” says Greco, now a scientist at Bristol Meyers Squibb in Syracuse, N.Y. “You have to learn to adapt to different working styles, as well as try to integrate each person’s ideas into the design. Innovation is an iterative process; it takes small steps to get to the end result.”
The UConn device was actually Greco’s second patent.
“Before attending graduate school, I worked for a small drug development company in Cambridge, Mass. where I received my first patent for controlled release salt forms of drugs used for schizophrenia,” Greco says. “It has always been a goal of mine to earn a patent. … I feel it is an exciting experience to be part of the invention process and to be recognized for that by earning a patent.”
Building a reliable device
While the group knew what it wanted to create, building a reliable device was a challenge.
“From an engineering perspective there were some stumbling blocks,” says Bergman, an expert in heat and mass transfer. “For instance, we needed to find a way to insert the dosage into the device, secure it, and then clamp down on it without crushing it. The students used their understanding of fundamental engineering principles to figure out how to minimize the stresses and yet, at the same time, keep the device from leaking when fluid went through it. There were a lot of practical issues that the students addressed very well.”
The ability of researchers to control and record the fluid dynamics – what flows into the device and conversely, what flows out of it – is also a boost, Bogner and Bergman say.
“In a usual powder dissolution test, you might get numbers in your results saying something went wrong or something is happening, but you don’t know what exactly is happening,” Bogner says. “You might speculate as to what is happening, but with this device we don’t have to. We can see what is going on.”
Finding the appropriate dissolution rate is important. According to an article last year in Chemical & Engineering News, about 40 percent of marketed drugs are thought to be poorly water soluble. It is believed that anywhere from 70 percent to 90 percent of drug candidates currently in the commercial pipeline have an even more serious problem – low solubility – which is considered to be a leading challenge in drug development.
As drug developers focus more and more of their research on creating complex, advanced pharmaceutics that target specific biological molecules, they are encountering these problems with low solubility and low permeability, according to the Chemical & Engineering News article.
In the article, Bogner described the situation this way: “It’s extraordinarily exciting to find a drug that binds very well with what you think absolutely is the target site that will affect disease, and it’s awfully tough when someone says, ‘It’s a nice molecule, but we are never going to be able to make a product out of it.’”
The new instrument will help identify more readily those that will pass the test.