USP Principal Scientific Liaison Margareth Marques, Ph.D., provides answers to questions regarding dissolution, disintegration and drug release tests.
Dissolution, disintegration and drug release tests, also called performance tests, are important tools that can be used during the entire lifecycle of a drug product, from early development throughout its shelf life. Dissolution and drug release measure the amount of active ingredient(s) released from the dosage form over time under standardized conditions. Depending on the physical-chemical characteristics of the active ingredient and on the release mechanism of the drug product, dissolution testing may be replaced with disintegration with appropriate justification.
Q: What information do the performance tests provide?
A: At the early stages of product development, the performance tests can help in the development and optimization of formulations; identify key drug characteristics; and measure the impact of manufacturing parameters on the release mechanism. Later, they are can help optimize the process scale-up, process transfers, evaluation of process reproducibility, and assess product stability. Also, they can be used to establish an in vivo/in vitro correlation (IVIVC) that can be very useful in post-approval changes.
Performance tests are mandatory for almost all dosage forms. In general, the exceptions are solutions and powders or granulates that when reconstituted according to the patient instructions result in a solution. USP recommends verifying the dosage forms that are exempted from performance tests with the regulatory authorities from the region where the drug product is going to be registered.
Q: What standards does USP offer to support dosage form performance testing?
A: USP offers both documentary and physical reference standards to support dosage form performance testing.
USP’s compendia of official documentary drug standards—the United States Pharmacopeia–National Formulary (USP–NF)—contains more than 900 monographs with dissolution, disintegration or drug release requirements. The apparatuses and general procedures to carry out these performance tests are detailed in the following General Chapters:
- <701> Disintegration,
- <711> Dissolution, and
- <724> Drug Release and <1724> Semisolid Drug Products—Performance Tests.
Other related USP General Chapters are <1087> Intrinsic Dissolution—Dissolution Testing Procedures for Rotating Disk and Stationary Disk, <1088> In Vitro and In Vivo Evaluation of Dosage Forms, <1090> Assessment of Drug Product Performance—Bioavailability, Bioequivalence, and Dissolution, <1092> The Dissolution Procedure: Development and Validation, and <1094> Capsules—Dissolution Testing and Related Quality Attributes.
USP also offers physical reference standards (e.g., USP Prednisone Tablets RS) to support Dissolution Performance Verification Testing (PVT).
Q: Are there tools and resources to help with the application of USP’s dissolution standards/methods?
A: Yes, USP recently introduced the USP Dissolution Methods Database. This free searchable database contains the test conditions (except Tolerance and Acceptance Criteria) as stated in the sections referring to dissolution, disintegration or drug Release tests in the respective USP drug product monograph. Users can easily find out what monographs specify use of a specific apparatus, which methods require mediums with a certain pH value, where the preparation of a particular dissolution medium can be found, and more. The database is updated with the release of each new USP¬NF, including supplements, and can be downloaded at www.usp.org/dissolutionDB.
USP also offers other Dissolution-specific compendial tools, including the Calculation Tool for the PVT of Dissolution Assemblies and a Dissolution Toolkit which can help with the correct set-up, operation and performance of the basket and paddle apparatuses and test assembly when performing PVT.
In addition, for detailed classroom and laboratory instruction on interpreting and applying USP’s dissolution standards, USP has developed education courses and webinars on a variety of related dissolution-related topics.