Swallowing a pill is simple. Developing one the body will absorb into the bloodstream and deliver to the precise location, at the right concentration and in the optimal sequence is complex. The vast majority of pills are composed of powders, materials with properties of both solids and liquids, and they are tricky to design and manufacture because of their sometimes unpredictable behaviors.
Credit: NJIT
Swallowing a pill is simple. Developing one the body will absorb into the bloodstream and deliver to the precise location, at the right concentration and in the optimal sequence is complex. The vast majority of pills are composed of powders, materials with properties of both solids and liquids, and they are tricky to design and manufacture because of their sometimes unpredictable behaviors.
“Drugmakers face a number of fundamental problems,” says Rajesh Davé, a distinguished professor of chemical and materials engineering at NJIT who specializes in particle design. “Most drug molecules in the pipeline – about 80% – are poorly soluble, for example, making it difficult for the body to incorporate and distribute them effectively. The experimentation needed to bring them to market is lengthy and expensive. Quality, affordability and accessibility remain challenges.”
More than a dozen pharmaceutical companies and equipment manufacturers have turned to Davé and Calvin Sun, a collaborator at the University of Minnesota who specializes in particle and crystal engineering, to help them tackle shared hurdles in research and development. These include acquiring a better understanding of various powder properties and the ability to predict their behaviors, while exploiting that knowledge to develop ways to design new drugs digitally and simpler methods to manufacture them.
At an initial brainstorming session in the summer of 2019, potential industry partners spoke bluntly about the pressures they face to develop new drugs swiftly and cost-effectively.
“They said it used to take them 10 to 12 years to develop a new drug at a cost of over a $1 billion, but that they no longer have the luxury of that amount of time or expense,” said Davé. “Our goal is to help them come up with good formulations in a quarter of that time and a tenth of the material cost.”
Their Center for Integrated Material Science and Engineering for Pharmaceutical Products (CIMSEPP), a National Science Foundation-designated and funded Industry-University Cooperative Research Center, will investigate drug particles at the molecular and particulate scale to see how they behave when blended with other powders and in the various steps of manufacturing, among other settings. The companies, along with the Lawrence Livermore National Laboratory, directly fund their research and provide mentorship to each of the projects they collectively chose. They will share all of the intellectual property developed.
Different categories of drugs present distinct challenges. For example, one class of analgesics is poorly water soluble and therefore requires additives to increase absorption. On the other hand, a common diabetes drug is too soluble, thus needing additives that will slow the process down so the active ingredients are not washed out of the body before they take effect. High potency drugs, such as contraceptives, come in such tiny amounts that pills with precise amounts of the drug are difficult to manufacture. One of the goals of CIMSEPP is to come up with more efficient formulations that require less filler material, yet achieve high quality and efficacy.
“We can modify their crystal structure by finding new ways to pack their molecules,” said Sun. “Think about the differences between diamond and graphite, which are both composed of pure carbon. We design the structure of drug molecules to deliver desired properties. Acetaminophen can exist in multiple structures, but one can be compressed more easily into tablets.”
Maintaining those molecular structures can be a challenge, however.
“When drug molecules are arranged in a less orderly form, for example, they’re more soluble, but they don’t want to stay that way – they want to crystallize,” Davé noted. “We combine them with additives to keep them amorphous, but that increases the pill size, while also making them more difficult and expensive to manufacture. We’re investigating the influence of additives and manufacturing processes on various competing requirements such as improved solubility, shelf life and pill size to identify the best combinations for achieving the highest quality, smaller-sized product.”
Manufacturing powder-based tablets is itself an intricate, multi-step process and the risk of shutdown is high. The more steps there are, the higher the risk of failure. Adding to the complexity, drug powders may behave one way when assembled in a small batch and another when manufactured at scale.
“If a drug sticks to the die punches during tablet compression, you may have to stop the entire process, for example,” Sun said.
And unlike liquids out of a tank that can be precisely dispensed, powders may or may not discharge consistently out of a container or hopper due to cohesion and friction. This makes it difficult to fill a small die, while ensuring the precise amount of each of over half a dozen ingredients, each intended to provide a particular function, such as faster disintegration. The ability to compress thousands of uniformly formed tablets per minute is non-trivial. This problem can be overcome through appropriate particle design to enhance the flow and uniformity of the blend during manufacturing, the collaborators said.
The team’s goal is to reduce the amount of experimentation needed, eliminating the need to conduct trial and error for every drug developed, for example, and to decrease the number of manufacturing steps from as many as eight in some cases, to two or three.
“Drug developers need better predictability. They need to know how individual powders will behave collectively, which will work better in combinations and how they will respond to the many steps of the manufacturing process, which includes milling, grinding, feeding, mixing, coating and compaction, among others,” said Davé.
The team will develop a database of materials, properties and methodologies for designing and producing the formulations, including mixtures with more than half a dozen ingredients, into tablets.
Davé has engineered particles in a variety of ways: to increase the absorption rates of drugs with poor water solubility, to delay the release of medications that degrade in the acidic environment of the stomach, to mask the bitter tastes of drugs and to improve their flow by encasing them in a thin coating of nanoparticles.
Sun, a professor of pharmaceutics and associate head of that department in the College of Pharmacy at the University of Minnesota Medical School, takes an integrated crystal and particle engineering approach to simultaneously improve properties of drugs and their formulations to ensure desired dissolution, stability and taste, and to improve manufacturing efficiency and product quality.
By simplifying the process, drugmakers may be able to manufacture medications cost-effectively in the U.S.
“A drug may be synthesized in one country and manufactured in another. We can’t afford to do quality control checks in some of these countries. There are also storing, handling and transportation challenges,” Davé said. “Our reliance on offshore manufacturing is the cause of numerous drug product recalls due to quality issues.”