Dissolution Testing: How the FDA Ensures Generic Drug Quality

Dissolution Testing: How the FDA Ensures Generic Drug Quality
Date: 29 Jan 2026 Medications

Why dissolution testing matters more than you think

If you take a generic pill, you expect it to work just like the brand-name version. But how does the FDA make sure it actually does? The answer isn’t in clinical trials on thousands of people. It’s in a lab, with a machine spinning a basket in a beaker of liquid. That’s dissolution testing - a quiet, critical process that keeps generic drugs safe and effective without needing to test them on humans every time.

What dissolution testing actually is

Dissolution testing measures how quickly a drug releases its active ingredient into a liquid that mimics the human digestive system. Think of it like watching a sugar cube dissolve in tea. But instead of sugar, it’s the medicine - and instead of tea, it’s a pH-controlled buffer at 37°C, the same temperature as your body.

The FDA requires this test for nearly all oral solid pills, capsules, and suspensions. It doesn’t apply to liquids you swallow or creams you rub on your skin - those are already dissolved or absorbed differently. For tablets and capsules, though, this test is non-negotiable. If the drug doesn’t dissolve properly, it won’t be absorbed. And if it’s not absorbed, it won’t work.

The five pillars of FDA dissolution requirements

When a company applies to sell a generic drug, they must submit five types of dissolution data:

  1. Solubility of the active ingredient - Is it water-soluble? Does it need special conditions to break down?
  2. Test method validation - What machine? What speed? What liquid? How much? The FDA specifies USP Apparatus 1 or 2, rotation speeds between 50-100 rpm, and volumes of 500-900 mL. The pH must match stomach or intestine conditions.
  3. Method robustness - What happens if the temperature changes by 1°C? Or the rotation speed drops by 5 rpm? The method must still give consistent results.
  4. Accuracy of measurement - Can the lab accurately measure how much drug is in the liquid? This is often done with UV spectrophotometry or HPLC.
  5. Discriminatory power - Can the test tell the difference between a good formulation and a bad one? This is especially important for low-solubility drugs or slow-release pills.
A scientist watches a tablet dissolve into glowing threads with pH timelines and f2 meter glowing in the background.

How the FDA sets the bar: 80% in 45 minutes

For most immediate-release pills, the standard is simple: at least 80% of the drug must dissolve within 45 minutes. But that’s not a one-size-fits-all rule.

For highly soluble, highly absorbable drugs (BCS Class I), the FDA allows a simpler test: one point at 30 minutes using 900 mL of 0.1N HCl. If the generic matches the brand-name drug’s release at that single point, it can skip human bioequivalence studies entirely. That’s a big deal - it saves time, money, and avoids putting patients through unnecessary trials.

For slow-release pills, things get complex. The test runs at three different pH levels: 1.2 (stomach), 4.5 (upper intestine), and 6.8 (lower intestine). There’s also alcohol challenge testing - what happens if someone takes the pill with a beer? Some pills can release all their drug at once if alcohol is present, causing dangerous spikes in blood levels. The FDA requires manufacturers to test for this risk.

The f2 factor: How similarity is measured

It’s not enough for a generic drug to dissolve 80% in 45 minutes. It has to dissolve at the same rate as the brand-name drug. That’s where the f2 similarity factor comes in.

The FDA calculates f2 by comparing the dissolution profiles of the generic and the brand-name drug over time - usually at 10, 20, 30, 45, and 60 minutes. If the f2 value is 50 or higher, the profiles are considered statistically similar. An f2 of 100 means they’re identical. Anything below 50? The application gets rejected.

This isn’t just math. It’s the difference between a drug that works and one that doesn’t. A study of 200 approved generics showed that those with f2 scores above 60 had near-identical blood levels in patients. Those below 50? Even if they met the 80% rule, their performance varied too much.

Why this matters more for generics than new drugs

New drug companies spend years and billions on clinical trials to prove their product works. Generic companies don’t. They rely on the FDA’s trust in dissolution testing as a stand-in for human data.

This is the core of the Abbreviated New Drug Application (ANDA) process. No need to repeat the clinical trials. Just prove your pill dissolves like the original. That’s why the FDA treats dissolution data as the most important part of an ANDA submission. A single flawed dissolution method can delay approval for years.

Even small changes - switching a supplier, changing a tablet coating, moving production to a new factory - require new dissolution testing. The FDA’s SUPAC-IR guidelines demand that manufacturers prove no change in dissolution profile after any manufacturing tweak. If the drug releases faster or slower after the change, the product can’t be sold without re-approval.

A brand-name pill dissolves perfectly beside a generic one transformed by an FDA seal, with a glowing f2=87 symbol between them.

Real-world challenges: The 6-month grind

Developing a dissolution method isn’t quick. For complex drugs - especially those with poor solubility or modified-release coatings - it can take 6 to 12 months. Labs run hundreds of tests, adjusting pH, surfactants, agitation speed, and temperature to find the right conditions.

The FDA maintains a public Dissolution Methods Database with over 2,800 recommended methods. Manufacturers use this as a starting point. But even then, they often need to customize. One company spent 14 months trying to find a method that could distinguish between two nearly identical extended-release formulations. Only after adding a surfactant to the medium did the test show a clear difference.

And the paperwork? A single ANDA submission can include 50 to 100 pages of dissolution development data. That’s just one part of the application - but it’s often the part that triggers the most questions from FDA reviewers.

What’s changing in 2026

The FDA is pushing toward more physiologically relevant testing. That means using fluids that better mimic real stomach and gut conditions - not just buffer solutions. There’s also growing interest in expanding biowaivers to BCS Class III drugs (high solubility, low permeability), which could cut approval times for hundreds of generics.

By 2025, an estimated 35% of generic approvals will use standardized dissolution methods to skip human trials - up from 25% in 2020. But the FDA’s message is clear: dissolution testing must be product-specific. No shortcuts. No blanket rules. Every drug gets its own test, tailored to how it behaves in the body.

Bottom line: Trust, but verify

You don’t need to know how dissolution testing works to take your generic pill. But you should know this: the FDA doesn’t rely on luck or trust. They use science - precise, repeatable, measurable science - to make sure every generic drug you take performs like the brand-name version. It’s not glamorous. It’s not flashy. But without it, the entire system of affordable medicines would collapse.

What is dissolution testing in generic drugs?

Dissolution testing is a lab procedure that measures how quickly a drug releases its active ingredient in a liquid that simulates the human digestive system. It’s used by the FDA to prove that a generic drug releases its medicine at the same rate and amount as the brand-name version, ensuring it will work the same way in the body.

Why doesn’t the FDA require human trials for every generic drug?

The FDA allows biowaivers for certain generics - especially those with high solubility and permeability (BCS Class I) - if their dissolution profile matches the brand-name drug exactly. Since dissolution rate strongly predicts how the drug behaves in the body, human trials become unnecessary. This saves time, money, and avoids exposing patients to experimental conditions.

What is the f2 similarity factor?

The f2 factor is a statistical tool the FDA uses to compare the dissolution profiles of a generic drug and its brand-name counterpart. It measures how closely the two release their active ingredients over time. An f2 value of 50 or higher means the profiles are similar enough to be considered bioequivalent. Below 50, the generic is rejected.

How does the FDA handle slow-release or extended-release generics?

For extended-release products, the FDA requires dissolution testing under multiple pH conditions (1.2, 4.5, and 6.8) to simulate different parts of the digestive tract. They also test for "dose dumping" - when alcohol or food causes the drug to release all at once. Manufacturers must prove their formulation remains stable under these conditions to get approval.

Can a generic drug be approved even if its dissolution profile differs from the brand?

Yes - but only in rare cases. If a generic shows a different dissolution profile but still proves bioequivalence in human studies, the FDA may set unique dissolution specifications for that product. This usually happens with low-solubility drugs where standard methods don’t capture real-world performance. The FDA still requires strong scientific justification.

What happens if a generic drug manufacturer changes its formula?

Any change - even switching suppliers of an inactive ingredient - triggers new dissolution testing under FDA’s SUPAC-IR guidelines. The manufacturer must prove the new version releases the drug at the same rate as the original. If the profile changes, the FDA may require re-approval or even pull the product from the market.

by Salvadore Dulaney
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Dissolution Testing: How the FDA Ensures Generic Drug Quality