Drug dissolution solution

Researchers develop method of assessing time-release drugs

January 26, 2021
Ilene Schneider
Drug dissolution solution

RIVERSIDE, Calif.—How do pharmaceutical companies determine how a drug dissolves in the body, so that a time-release drug is releasing slowly into the bloodstream to provide benefits over the specified period of time? Drug dissolution must be measured under laboratory conditions that closely simulate what happens in the body. 

Otherwise, if a drug dissolves too slowly or too quickly, the results can be disastrous. For instance, OxyContin, which contains the opiate oxycodone, was supposed to offer 12-hour pain relief—but it dissolved much faster in some patients, causing them to take it more frequently and become addicted.

Researchers at the University of California, Riverside have developed a simple, inexpensive way to measure drug dissolution that should help pharmaceutical companies to create better and more consistent time-release drug products. As corresponding author William Grover, an associate professor of bioengineering at the Marlan and Rosemary Bourns College of Engineering at UC Riverside, explained, “We directly measured dissolution profiles of single drug granules, which are the little spheres you see when you open up a capsule. We accomplished this using a vibrating tube sensor, which is just a piece of glass tubing bent in the shape of a tuning fork.”

In an article in Scientific Reports, Grover, doctoral student Heran Bhakta, and undergraduate student Jessica Lin explained how they took a radically different approach. Instead of measuring the increasing concentration of the drug in the fluid, they decided to measure the decreasing mass of a solid pellet as it dissolved. 

As they reported, “Existing techniques are often labor-intensive, time-consuming, irreproducible, require specialized analytical equipment, and provide only ‘snapshots’ of drug dissolution every few minutes. These limitations make it difficult for pharmaceutical companies to obtain full dissolution profiles for drug products in a variety of different conditions, as recommended by the US Food and Drug Administration. Additionally, for drug dosage forms containing multiple controlled-release pellets, particles, beads, granules, etc. in a single capsule or tablet, measurements of the dissolution of the entire multi-particle capsule or tablet are incapable of detecting pellet-to-pellet variations in controlled release behavior.”

They added, “Developing controlled-release oral drug products is difficult in part because many factors can influence drug dissolution in the body. These factors include the pH and chemical composition of the gastrointestinal fluid, the hydrodynamics of the fluid caused by gastrointestinal motility, the patient’s metabolism and sex, and many other factors. Indeed, something as simple as taking OxyContin with a high-fat meal can increase the amount of oxycodone in the patient’s blood by 25 percent.”

In what the researchers described as “a simple and fully automated technique for obtaining dissolution profiles from single controlled-release pellets,” they monitored the decrease in the buoyant mass of the solid controlled-release pellet as it dissolved. The researchers weighed “single controlled-release pellets in fluid using a vibrating tube sensor, a piece of glass tubing bent into a tuning-fork shape and filled with any desired fluid.” They used an electronic circuit to keep the glass tube vibrating at its resonance frequency, “which is inversely proportional to the mass of the tube and its contents.”

As a pellet flows through the tube, the resonance frequency changes briefly “by an amount that is inversely proportional to the buoyant mass of the pellet,” the researchers said. They added, “By passing the pellet back-and-forth through the vibrating tube sensor, we can monitor its mass as it degrades or dissolves, with high temporal resolution (measurements every few seconds) and mass resolution (700 nanogram resolution).” 

As a proof of concept, the researchers used this technique to measure the single-pellet dissolution profiles of several commercial controlled-release proton pump inhibitors in simulated stomach and intestinal contents, as well as comparing name-brand and generic formulations of the same drug. In each case, vibrating tube sensor data revealed significantly different dissolution profiles for the different drugs, and, in some cases, this method also revealed differences between different pellets from the same drug product. 

The researchers said that the technique addresses many of the shortcomings of existing testing methods, requires no additional analytical instruments, and is suitable for both fast-dissolving and slow-dissolving formulations. They claimed that by providing dissolution profiles for individual pellets, the method can capture variations in pellet dissolution behavior that other methods cannot. 

“By measuring any controlled-release pellets, particles, beads or granules in any physiologically-relevant environment in a fully-automated fashion, this method can augment and potentially replace current dissolution tests and support product development and quality assurance in the pharmaceutical industry,” the research team concluded.

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