New analytical methods being developed help researchers better understand the link between microstructures and how a drug disintegrates.
By David Pittman
Pharmaceutical researchers today are working to better understand how the microstructure of drug products influences how it disintegrates, which leads to different absorption rates in the body and different clinical results.
Scientists are developing assays to determine a drug’s pore structure, which is a better representation of how a solid drug will break down after ingestion, as explained in an April 4 American Association of Pharmaceutical Scientists webinar, entitled Right, First Time for Tablet Disintegration and Dissolution – Interplay between Formulation and Dosage Form Microstructure.
“So far, industrial practice and R&D assays typically focus heavily on dissolution,” said Axel Zeitler, Ph.D., professor of microstructure engineering at the Department of Chemical Engineering and Biotechnology at the University of Cambridge in England.
But how drug products break down is underappreciated, despite how critical it is to performance. “It may be due to the fact that the test in the pharmacopeia for disintegration – which is a great test for measuring compliance but doesn’t really tell you much about how disintegration happens – has led to this situation where we somewhat overlook the disintegration process itself.”
Zeitler and Daniel Markl, Ph.D., chancellor’s fellow and lecturer at the University of Strathclyde in Glasgow, Scotland, have been working to develop tests to better understand how disintegration takes place.
“We would argue that porosity is the key step here,” Zeitler said. “We would argue it’s a much more critical attribute compared to other metrics that we currently use such as hardness of the tablet."
Porosity is the measure of the size of the open space between material, excipients, and active ingredients in a drug product. It is directly related to how much force is applied while compressing the ingredients into a dosage form. But how all the particles fit together determines how liquid is absorbed and how quickly the interparticle bonds breakdown.
Zeitler calls porosity a critical quality attribute, effecting both the disintegration and dissolution of drug products. His work to measure porosity before and during manufacturing can complement more traditional chemical assays, like Raman and near-infrared spectroscopy, to measure physical microstructure properties that can be linked to dissolution.
“Our strategy in the medium term from an academic point-of-view is to establish a method for and find out how it can help with development problems,” Zeitler said. “Really understanding the impact of what happens in the process influences the performance of the tablet later on.”
As they explained during the webinar, Zeitler and Markl are working to develop real-time release assays that can help identify issues and troubleshoot problems so products can arrive right the first time. Because there’s no chemometric calibration required, the measurement is relatively straightforward and takes less than a second to complete.
They’ve found that terahertz time-domain spectroscopy is a superior method to other ways that commonly characterize pore structure like X-ray computed tomography or mercury porosimetry. Terahertz time-domain spectroscopy is faster and has potential at-line or in-line use. Markl said it can be used on tablets as large as 5.6 mm thick and still maintain accuracy. Simple mathematical modeling can yield the porosity based on the spectroscopy reading and refractive indexes.
Drug developers, however, need to measure more than just the porosity. They determine other characteristics such as pore shape, which influences how liquid penetrates tablets and how the disintegration process mechanically works. “In the end, we will need to combine several different methods to capture different stages of these complex processes occurring during disintegration and dissolution,” Markl said.
Markl explained during the webinar that terahertz time-domain spectroscopy, when used in combination with other techniques, can reveal an array of characteristics, including how fast liquid is absorbed and how it relates to pore structure and tortuosity. All are important in knowing how fast a tablet will dissolve and be taken up in the body. Importantly, the grade of excipient used will influence results because they will have different properties, which is important to keep in mind.
“It’s one thing to understand the formulation, but as pharmaceutical scientists, in development, we need to think about what happens later on in the process. What does the process do to a dosage form that will then impact its performance later on,” Zeitler said. “That’s something we can start to study for the first time because before there weren’t really these methods around to explore this properly.”
For example, researchers can start to look at how the shape of product or how its formulation can be altered to adjust clinical outcomes.
Zeitler and Markl worked with a pharmaceutical company in the U.K. to test their methods on a real-world product that never made it to market and found it works on more complex dosage forms. Although, they are still working to reduce the margin of error when correlating with dissolution, which is needed to fully understand the breakdown process.
Zeitler and Markl are currently working with technology and instrument companies to develop a test that quickly measures the porosity of tablets. The assay can measure pores down to about 1 to 5 microns wide. Their goal is to develop an assay that can be used in real-time release processes during manufacturing or inserted directly into the line-in continuous manufacturing. They hope to have more to share in the coming year.
“It’s really a great challenge scientifically, but if we tackle it, we can maybe integrate the disintegration process directly into dissolution models,” Zeitler said. “That should make them more successful.”
Listen to the webinar in full, and learn about upcoming webinars or submit a proposal for a new webinar.
David Pittman is a science and medical writer based in Washington, D.C.