Measuring dissolution profiles of single controlled-release drug pellets

Abstract

Many solid-dose oral drug products are engineered to release their active ingredients into the body at a certain rate. Techniques for measuring the dissolution or degradation of a drug product in vitro play a crucial role in predicting how a drug product will perform in vivo. However, 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. In this work, we demonstrate a simple and fully-automated technique for obtaining dissolution profiles from single controlled-release pellets. We accomplished this by inverting the drug dissolution problem: instead of measuring the increase in the concentration of drug compounds in the solution during dissolution (as is commonly done), we monitor the decrease in the buoyant mass of the solid controlled-release pellet as it dissolves. We weigh 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. An electronic circuit keeps the glass tube vibrating at its resonance frequency, which is inversely proportional to the mass of the tube and its contents. When a pellet flows through the tube, the resonance frequency briefly changes by an amount that is inversely proportional to the buoyant mass of the pellet. 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, we 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 our method also revealed differences between different pellets from the same drug product. 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.

Figure 1

Using a vibrating tube sensor to obtain the dissolution profile of a single controlled-release pellet, bead, or granule obtained from a multi-particle drug product. The sensor (A) consists of a hollow glass tube bent in three places to form a tuning-fork shape and mounted so that the two “tines” of the fork (labeled 2 and 4) are free to move. The tube is filled with fluid, and an electronic feedback circuit (not shown) keeps the tube vibrating at its resonance frequency (474.25 Hz); this frequency is inversely proportional to the mass of the tube and its contents. When a pellet (in this case, a pellet from inside a capsule of the proton pump inhibitor lansoprazole) passes through the tube, the pellet causes the tube’s resonance frequency to change momentarily by an amount that is proportional to the buoyant mass of the pellet. This change is recorded as two peaks in the plot of resonance frequency vs. time (B); the labels 1–5 on this plot correspond to the pellet’s position at points 1–5 in (A), and the height of the peaks in (B) (about 100 mHz or 0.1 Hz) are proportional to the buoyant mass of the pellet (about 180 $\mathrm{\mu }$g). By repeatedly passing the pellet back and forth through the tube as the pellet dissolves and plotting the resonance frequency vs. time (C), the shrinking peak heights record the dissolution of the pellet over the 40-minute experiment. The inset plots (a) through (d) provide closeup views of the peaks at 2, 6, 15, and 19 minutes. Finally, by plotting peak height vs. time and applying the tube’s calibration factor (D), we can observe different pellet dissolution rates and other meaningful events throughout the dissolution process.

Figure 2

Using vibrating tube sensors to obtain single-pellet dissolution profiles (B) for three different over-the-counter proton pump inhibitor drugs, omeprazole, lansoprazole, and esomeprazole, in gastric fluids simulating the contents of the stomach (pH 2.0; red points) and the intestines (pH 7.0; blue points). For each drug, three separate controlled-release pellets (like the ones circled in red in A) were removed from capsules and tested at each pH value. In the simulated stomach contents at pH 2.0, the enteric coatings on the pellets protected the pellets from dissolution, and the measured pellet masses remain largely unchanged for at least 40 min. In contrast, in the simulated intestinal contents at pH 7.0, all three types of pellets dissolve within a few minutes, though they do so in very different ways. The omeprazole-containing pellets (generic; Walgreens Pharmacy) begin dissolving immediately, slowly losing mass at a rate of –0.18 $\mathrm{\mu }$g/min for about 30 min, then abruptly losing the remaining mass at a rate of –1.5 $\mathrm{\mu }$g/min and dissolving completely by the 35 min mark. In contrast, the lansoprazole-containing pellets (generic; CVS Pharmacy) remained unchanged for the first 10 min, then suddenly dissolved away in less than 2 min. Finally, the esomeprazole-containing pellets (brand name Nexium; Pfizer) initially dissolved slowly at a rate of –0.20 $\mathrm{\mu }$g/min for the first 15 min, then abruptly switched to a faster dissolution rate of –4.4 $\mathrm{\mu }$g/min and dissolved completely by the 20 min mark. The similarities between the different pellets from the same drug product suggest good pellet-to-pellet consistency in the manufacture of these controlled release formulations, and the differences between the different drugs indicate that the different products have different controlled release mechanisms (and consequently may have different dosing behavior) despite all having the same intended function in the body.

Figure 3

Using vibrating tube sensors to measure single-pellet dissolution profiles for two different controlled-release drug products containing the same dose of the same active ingredient, lansoprazole. For each drug product, three pellets were tested in simulated intestinal fluid at pH 7.0. The generic lansoprazole-containing pellets had the largest starting masses (150 to 200 $\mathrm{\mu }$g) and the fastest dissolution (disappearing completely in only 10 min). In contrast, the name-brand lansoprazole-containing pellets had the smallest starting masses (only around 7 $\mathrm{\mu }$g) and the slowest dissolution (dissolving at –100 ng/min for the first 20 min, then accelerating to a dissolution rate of –400 ng/min until the pellets fully dissolved at the 30 min mark. These results show that different formulations of the same active ingredient can have dramatically different single-pellet dissolution profiles, and may help explain any clinically-observed differences in the behaviors of these products.

Figure 4

Measurements of the buoyant mass of a single controlled-release esomeprazole-containing pellet in simulated stomach contents (pH 2.0; red points) and simulated intestinal contents (pH 7.0; blue points) obtained every few seconds for 24 h. These results confirm that vibrating tube sensors can measure extremely slow dissolution rates (nanograms per hour) over extended periods of time.