The Value of In Vitro Dissolution in Drug Development

A Position Paper from the AAPS In Vitro Release and Dissolution Focus Group

Dissolution is a common characterization test used by the pharmaceutical industry to guide formulation design and to control product quality. It is often a required performance test for solid dosage forms, transdermal patches, and suspensions. Dissolution is also the only test that measures in vitro drug release as a function of time, which may reflect the reproducibility of the manufacturing process and, in some cases, the drug's in vivo performance.

Despite its wide use in pharmaceutical development and registration, there is still a lack of thorough understanding of what dissolution testing means, what it should measure, and the value it adds at various stages of drug development. There are inconsistencies, therefore, in industry practices and regulatory expectations with regard to dissolution testing. These inconsistences present even greater challenges when trying to implement quality by design (QbD), which defines the future state of dissolution, its value, method design, and links to the design space. The International Conference on Harmonization Quality Guidelines, Q8 Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System manifest the global efforts from industry and regulators to establish a consistent quality system from a QbD perspective.

This article provides a science-based analysis of the values of dissolution testing in the drug-development continuum for common solid dosage forms. The authors focus on immediate release, modified release, extended release, and QbD systems.

Value of dissolution testing: candidate selection–Phase I

Phase I clinical studies are designed to determine the metabolic and pharmacologic actions of a particular drug in humans, the side effects associated with increasing dosage, and, if possible, early evidence of efficacy. To achieve these goals, the dosage form should have adequate bioavailability to ensure that the drug is delivered to the site of preferred action. At this stage, dissolution testing can be used to:

  • Characterize the active pharmaceutical ingredient (API)
  • Select toxicology formulations
  • Develop a Phase I formulation
  • Control quality.

One intended use for the dissolution test is to reflect the in vivo behavior of the pharmaceutical product. Thus, dissolution testing can be used to guide the selection of API properties as well as the toxicology and Phase I formulations for evaluation in animals and humans. Dissolution methods that use a medium that mimics human GI fluid should be investigated and used to probe in vivo–in vitro correlations and relationships (IVIVC and IVIVR). In cases where IVIVC can be difficult (e.g., when the in vivo behavior is controlled by several other factors), dissolution or disintegration testing can still add value as a quality-control tool for batch release, batch-to-batch consistency, and stability monitoring.

Drug substance characterization

Defining an appropriate drug substance form with suitable physicochemical properties is important for formulation development. Drug-substance properties are chosen to balance formulation stability, processibility, and bioavailability. Drug-substance properties (e.g., particle size, intrinsic dissolution, crystal properties) can have an impact on dosage-form bioavailability. Dissolution testing is a useful tool for screening drug-substance salt forms with different crystal forms and particle sizes. Biorelevant gastrointestinal (GI) media such as simulated gastric fluid (SGF) and fasted-state simulated small-intestinal fluid (FaSSIF), should be considered at this stage to elucidate where the drug will be solubilized and the potential for supersaturation or precipitation of drug substance in the GI tract (1). These methods provide the basis for toxicology formulation and Phase I formulation design.

The availability of drug substance is limited at this early stage. Small-volume dissolution using a very small quantity of the drug, therefore, can provide helpful information. Commercial availability of fiberoptics-integrated small-volume dissolution (microdissolution) apparatus has made quick drug-release assessment possible (2). Dissolution of the free form and different salts in various pH media can help in salt selection. The salt or free base that gives the optimum dissolution rate, amount dissolved, and a favorable or minimum precipitation rate is generally chosen. Observations of the dissolution behavior of the drug substance provide important clues that can facilitate formulation selection and development. If the drug particles aggregate or float, for example, and do not dissolve, the use of surfactants or a wet granulation process may be used to overcome the problem.