Improving drug analysis

When it comes to taking prescription drugs, dosage is important. But if drug products are not tested carefully, even the right dosage could still be wrong.

How a pharmaceutical company prepares a formulated drug product may be as important as the structure of the drug itself.

Aaron Rossini, assistant professor in the Department of Chemistry at Iowa State University, helps pharmaceutical companies test their drug products using nuclear magnetic resonance (NMR) spectroscopy.

It starts with the solid-state from of a drug. Solid forms of drugs are preferred for products because they have a longer shelf life. However, many drugs can be produced in different solid forms — known as polymorphs — where the individual drug molecules may have different orientations in the solid state depending on how the drug is crystallized and purified.

"Is the form of the drug that was put in at the start of the manufacturing process what ends up in the final product that people are going to ingest?" Rossini asks. "This is really one of the key questions."

Pharmaceutical companies perform extensive tests to identify the different polymorphs and determine which solid form will be most effective in the final formulated drug products. Some drugs are blended with polymers or crystallized with additives to improve their effectiveness.

"If the form of the drug changes during the manufacturing process and the wrong solid form ends up in the final product, you may not actually get the dose of drug that you need," Rossini said. "This is because some of the forms may have poor dissolution rates, meaning that when you ingest the pill the drug may not be released in your digestive tract properly."

To analyze the solid structure of drugs, Rossini uses solid-state NMR spectroscopy. Traditional NMR experiments use samples that have been dissolved into solutions; but solid-state NMR is needed to investigate solid materials.

"Distinct solid forms of drugs will generally give a unique or distinct solid-state NMR spectrum," he said. “Solid-state NMR can also detect interactions between the drug molecules and additives in the pills.”

However, drug products are often very challenging to study by solid-state NMR spectroscopy because the active pharmaceutical ingredient often represents a small fraction of the total tablet. Most of the tablet is usually made up of filler material, like lactose, which is often more than 90 percent of the weight of the tablet.

Consequently, solid-state NMR analysis can require several days to get a strong enough signal from the drug in a tablet. It can also be tricky to distinguish the drug’s NMR signals from the NMR signals coming from filler material. To address these challenges, Rossini’s research group uses a dynamic nuclear polarization (DNP) NMR spectrometer.

The DNP NMR spectrometer — housed in the lab of Marek Pruski, adjunct professor of chemistry and a scientist in the Department of Energy’s DOE Ames Laboratory —DNP can enhance the sensitivity of NMR experiments by orders of magnitude. The DNP spectrometer in the Ames Lab is one of only about 5 such machines in North America.

DNP enables NMR experiments on tablets with low drug loads, where the drug is a small percentage by weight of the tablet, to be performed in minutes, rather than days or weeks that are normally required. This increase in sensitivity also makes it possible to do other types of NMR experiments that can eliminate interfering signals coming from the filler materials in the pill. While NMR typically detects carbon atoms, an element also found in the fillers, the sensitivity of the DNP enhanced NMR makes it easier to perform NMR experiments with nitrogen or chlorine. The NMR signals from the drug can then be clearly observed because these elements are usually only found in the drug.

Currently, Rossini is collaborating with Karthik Nagapundi and Joseph Lubach, scientists at Genentech, Inc to demonstrate and explore how DNP enhanced NMR can be used to study drug products with low drug loads. This research will help pharmaceutical companies devise formulated drug products and ensure that their customers get the right dose of drug from every pill.

Founded 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious or life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit