Seeking a Dissolution-Test Solution for Inhaled Drugs

For decades, pharmaceutical companies have accepted dissolution testing as a valuable method for controlling the quality of tablets and capsules. Dissolution testing helps manufacturers measure the batch-to-batch consistency of their products and also can confirm that dosage forms release various formulations at the correct rate over the intended period. The US Pharmacopeia describes a standard method for conducting dissolution testing of tablets and capsules, and regulators expect companies to adhere to this technique.

The drive to extend patents by reformulating products as new dosage forms has contributed to the pharmaceutical industry’s increasing interest in inhaled drugs, but USP does not describe a method to perform dissolution testing on these products. Until recently, most manufacturers considered dissolution testing unnecessary for inhaled drugs and preferred to rely on other tests that they considered adequate. Yet a standard dissolution test for inhaled products could be at least as useful a quality-control tool as it has been for tablets and capsules. It also could allow innovators to set dissolution standards for their products that makers of generic drugs would have to meet. These considerations have prompted several researchers to propose standard dissolution-testing methods for inhaled drugs.

In 2003, Neal Davies, associate professor of pharmaceutical sciences at Washington State University, and graduate student Majid Feddah proposed a technique based on a USP type 4 flow-through cell, a device commonly used to test the dissolution of tablets and capsules. Their method used an in-line high-performance liquid chromatography pump to control the drug’s flow rate. Because no USP-certified lung fluid was available for dissolution testing, Davies and Feddah developed one that contained a lung surfactant after reviewing the literature.

Unlike previous dissolution-testing methods, the Davies technique linked the flow-through system to a cascade impactor, which separates emitted doses into fractions according to particle size and measures particle-size distribution. Particle size is critical to a drug’s disposition and action in the lung, and particle-size distribution is “an absolutely essential part of dissolution testing of inhaled products,” says Davies. Davies’s intent was to concentrate on the dissolution of the respirable fraction of the active ingredient because the behavior of larger, ingested particles is of little importance to drug action.

Although they agree that Davies had the right focus, some observers say that his method opened up an opportunity for further improvement. Because the technique gathered the dose in the cascade impactor’s induction port before dissolution testing, it measured data for the total emitted dose, rather than for the portion that would be deposited in the lung. “The size-fractionating capabilities of the cascade impactor were not really exploited to the full,” says Mark Copley, sales director of Copley Scientific (Nottingham, UK).

Davies’s method has not been proven appropriate as a dissolution test for air-classified particles and does not provide a clear picture of inhaled drugs’ overall dissolution profiles, according to Jason T. McConville, assistant professor of pharmaceutics at the University of Texas at Austin. On the other hand, it potentially could overcome the problems associated with dispersing powders using a standard dissolution. These problems often can result in poor homogeneity, particles that stick to the dissolution apparatus, or sampling undissolved particles, says McConville.

In May 2010, Yoen-Ju Son, McConville’s graduate student, proposed a new technique based on a modified dissolution tester. The tester incorporated a membrane-containing holder, which was designed to enclose air-classified formulations for uniform testing in the dissolution apparatus. Son’s technique used a Next-Generation Impactor (NGI) (MSP, Shoreview, MN) to separate and classify inhalation powders. An NGI is a high-throughput cascade impactor with a design that lends itself to this type of modification. The method tested each particle-size fraction for its own dissolution rate.

Son’s technique seems to have several advantages. Its dissolution procedure, apparatus, dose-collection method, medium, and test conditions were based on those listed in USP General Chapter . The USP method is straightforward and well established in most pharmaceutical laboratories, says Copley, a coauthor of Son’s paper. In comparison with previous dissolution-testing methods, Son’s technique limits the amount of solvent used, thus posing less risk of influencing the drug’s observed rate of dissolution. The reduction of solvent also allows the technique to simulate conditions in the lung more closely.

But the Son method also creates conditions that may be different from those in the lung. The technique is a stirring-paddle method, but the “overall respiratory tract is a stagnant system and is not well stirred,” says Davies. The respiratory tract contains a small amount of aqueous fluid, and its flow rate would favor stagnant conditions, he adds.

Other characteristics of the Son technique could potentially bias test results. As a result of drug-wetting issues, drug loading on the holder influences the drug-release rate. “This characteristic may limit its utility and reproducibility compared with other methods,” says Davies. In addition, Son has not yet attempted in vitro–in vivo correlations, which must be examined and have been explored by other groups.

“Dissolution studies for inhaled products are still in their infancy,” says Davies. Further experiments could bring greater understanding, help refine testing techniques for these drugs, and advance toward in vitro–in vivo correlations. The growing interest in inhaled products, the emergence of new modified-release formulations, and the development of advanced drug-delivery systems will likely underscore the importance of dissolution testing in the future. The pharmaceutical industry now understands the need and potential benefits of this procedure more clearly, and the development of a standard dissolution-testing method for inhalable products may not be far off.