Developing and Validating Dissolution Procedures

Feb 01, 2008

Michael E. Swartz
The dissolution performance test is a required test for all solid oral dosage forms for product release testing. It also is used commonly as a predictor of a drug product's in-vivo performance. To help satisfy dissolution requirements, the USP provides information in the way of a general chapter on dissolution, as well as related chapters on disintegration and drug release (1–3). The USP and the FDA also provide guidelines on development and validation of dissolution procedures (4–9), and while this month's column will draw from this information and will discuss the available guidance in some detail, we encourage readers to consult the references for additional details.

Ira S. Krull
In-vitro dissolution data, together with bioavailability, and chemistry, manufacturing, and control (CMC) data, is a critical component of any new drug application (NDA) submitted to the FDA. A dissolution test is really a simple concept; a tablet or capsule is placed into a known volume of media, and as it dissolves the resulting solution is sampled over time, and assayed (often by high performance liquid chromatography [HPLC], but also by spectrophotometry) for the level of active pharmaceutical ingredient (API) present. However, the design, development, and validation of the procedure can be quite involved, especially when one considers that not only must the dissolution procedure be developed and validated, but also any analytical technique used for the assay.

Qualification and Calibration

Before undertaking the task of dissolution procedure development and validation, it is necessary to invest some time and energy up front to ensure that the dissolution system itself is validated, or qualified. Qualification is a subset of the overall validation process that verifies proper module and system performance before the instrument is placed on-line in a regulated environment (10–13). Analysts for years have used prednisone and salicylic acid tablets to qualify and "chemically" calibrate dissolution instruments. Figure 1 illustrates example HPLC methods commonly used for this purpose.

Figure 1
Recent FDA guidelines suggest that alternative mechanical calibrations also can be used and, when properly executed, satisfy cGMP requirements (14,15).

Dissolution Procedure Development

The dissolution procedure has several distinct components. These components include a dissolution medium, an apparatus, the study design (including acceptance criteria), and the mode of assay. All of these components must be properly chosen and developed to provide a method that is reproducible for within-laboratory day-to-day operation and robust enough to enable transfer to another laboratory.