A Test That Needs to Mean Something
Dissolution testing is one of the most widely performed analyses in pharmaceutical development. It is also one of the most frequently misunderstood.
A dissolution test that cannot distinguish a good batch from a bad one is not a quality control tool. It is a formality. And a test that shows 98% release in 30 minutes in pH 6.8 phosphate buffer, but the drug is barely absorbed in patients, is actively misleading. The goal is a method that reflects what actually happens when the patient swallows the tablet.
Getting that right requires understanding the biology of oral drug absorption, the limitations of the most common test methods, and how to match the method to the molecule and the formulation.
The BCS Framework as Your Starting Point
The Biopharmaceutics Classification System (BCS) divides drugs into four classes based on solubility and permeability. The class tells you which absorption step is rate-limiting, and therefore what your dissolution method needs to capture.
| BCS Class | Solubility | Permeability | Rate-Limiting Step | Dissolution Test Priority |
| Class I | High | High | Gastric emptying | Simple: discriminate fast from slow release; biowaver often available |
| Class II | Low | High | Dissolution in GI fluid | Critical: method must reflect solubility-limited dissolution; biorelevant media often needed |
| Class III | High | Low | Permeation across intestinal wall | Less critical for formulation discrimination; API properties dominate |
| Class IV | Low | Low | Both dissolution and permeation | Most challenging: biorelevant media important; in vitro-in vivo correlation difficult |
Standard Buffer vs. Biorelevant Media: When It Matters
Standard Buffer Methods
Standard USP buffer systems at pH 1.2, 4.5, and 6.8 are the default for most regulatory dissolution work. They are simple, reproducible, and well-understood. For BCS Class I drugs and many conventional formulations, they do the job.
For BCS Class II and IV drugs, they often do not. Aqueous buffers lack the surfactant and bile salt content of real gastrointestinal fluid. A poorly soluble API may show 100% release in a standard buffer with a high concentration of solubilising excipients, then fail to achieve adequate exposure in patients because the dissolution medium in the GI tract has very different solubilising power.
Biorelevant Media
Biorelevant media such as FaSSIF (fasted-state simulated intestinal fluid) and FeSSIF (fed-state simulated intestinal fluid) contain bile salts and lecithin at physiologically relevant concentrations. They better mimic the solubilising capacity of the intestinal environment and are far more discriminating for BCS Class II molecules.
They are also more variable to prepare, more expensive, and not required by regulators for routine release testing. The practical approach is to use biorelevant media during development to understand in vivo-predictive performance, then design a simpler validated method for GMP release that is correlated to the biorelevant results.
In Vitro-In Vivo Correlation (IVIVC): The Regulatory Goal
An IVIVC links the in vitro dissolution profile to the in vivo absorption profile, creating a model that allows dissolution data to predict bioavailability. A validated Level A IVIVC, where the in vitro dissolution curve maps point-by-point to the in vivo absorption curve, is the most valuable outcome: it allows dissolution testing to serve as a surrogate for bioavailability studies when the formulation changes. The FDA’s IVIVC guidance for extended release oral dosage forms outlines the requirements for establishing and using an IVIVC in regulatory submissions.
Establishing an IVIVC is not always feasible, particularly for Class II/IV molecules with complex absorption behaviour. But even a partial correlation, or a mechanistic understanding of why in vitro and in vivo profiles differ, is more valuable than a dissolution method selected without considering the biology.
Dissolution Testing for Modified Release Products
Extended release, delayed release, and pulsatile release dosage forms require dissolution methods that capture the full release profile over the intended release duration. A method that tests at a single timepoint, or that uses conditions where the release mechanism does not function correctly, will not discriminate failing from passing formulations.
For enteric-coated products, the dissolution method must include a two-stage test: acid stage exposure at pH 1.2 (to confirm the coating resists gastric conditions) followed by buffer stage at pH 6.8 (to confirm complete release in intestinal conditions). The duration and test conditions of each stage must reflect the gastric residence time expected in the target patient population.
Ardena’s Dissolution Development Expertise
Ardena’s analytical teams at Ghent develop dissolution methods as an integrated part of formulation development programmes, not as a separate analytical exercise. Method design is informed by the molecule’s BCS classification, the intended formulation, and the clinical context, ensuring that the method reflects in vivo performance and supports the regulatory filing.
