By Neil Canavan
A collaborative effort between the University of Leeds and Durham University in England and U.S.-based GlaxoSmithKline (GSK) may soon change the way certain drugs are manufactured by “printing” the active pharmaceutical ingredient (API) on the surface of an otherwise inert tablet. It’s hoped this new process will assure quality control, enhance safety, and, at the same time, reduce cost.
We first focused on drops in solution, which is fairly straightforward. Now we’re looking at droplets with the drug in suspension.
—Nik Kapur, PhD, University of Leeds
Allan Clarke, director of innovative manufacturing at GSK, initiated the project. Clarke wanted to revolutionize the processes for making GSK’s most potent orally administered drugs. These compounds, which have therapeutic activity ranging from a few micrograms to a few milligrams, present demanding quality control challenges. Hormonal agents represent one example of this type of compound. “We have a number of such compounds in our portfolio, which require the controlled, consistent application of micrograms of API as part of a tablet that weighs over 200 milligrams.”
Highly potent drugs also demand cumbersome and expensive safety and containment procedures. “This is necessary because if you inhaled even a small quantity of API, you would get a pharmaceutical dose.” At first blush, the solution to both of these problems was just that: Put the API in solution. This method would allow for a so-called “shirtsleeves” working environment without onerous respirators and would facilitate the measurement of small doses by creating a liquid of known API concentration, which could then be aliquoted—printed with an inkjet-like nozzle—onto the surface of a tablet. Simple enough.
Multiple Images Needed
It was up to GSK to invent the rest: drug formulations that result in manageable drops and imaging technologies that verify the drop volume or drug dose as it is being applied. “We’re talking about multiple images for every single tablet, at a rate of six tablets per second, per nozzle, on a system of multiple nozzles. That’s very different than conventional manufacture where you blend a 600-kilogram batch of API and excipients and feed it into tablet press, and then statistically sample for quality assurance,” Clarke said.
After developing the process and building industrial-scale equipment for low-dose products, GSK reached out to Nik Kapur, PhD, an expert in the fluid mechanics of droplets at the University of Leeds. GSK asked him to create dynamic models that would allow for expansion of the program to higher dose products.
“We first focused on drops in solution,” said Dr. Kapur, “which is fairly straightforward. Now we’re looking at droplets with the drug in suspension.” The idea is to enable the application of compounds that are not readily solubilized, as well as to increase the loading capacity per drop for drugs that require higher doses than those previously used.
In accomplishing this expansion, imaging was again key: “Droplets are incredibly complicated things. When you start to look at them using high-speed photography, you see how very small changes in the suspension have a dramatic impact on the way droplets form,” Dr Kapur said.
He is also interested in scale. The typical inkjet nozzle might be 20 to 30 microns across, whereas GSK is looking to dispense droplet volumes that might be millimeters in diameter. “My goal is to try to understand the influence of all the interrelated variables,” said Dr. Kapur. Ideally, at the end of what is slated to be a two-year collaboration (funded in part by England’s Technology Strategy Board) Dr. Kapur hopes to supply GSK with a recipe card, “a guide for the formulation of drugs that result in a workable droplet and the mechanical parameters that they can play with to achieve the desired deposition.”
This technology will only apply to immediate release therapeutics, however. Just as with a printer cartridge, the creation of printed combination drugs may be possible.