Sink conditions in release testing
Under the Noyes-Whitney model, a closed medium at three times the saturation volume loses a third of its dissolution driving force at full release, and at ten times a tenth, by this page’s calculation. The usual multiple comes from a general dissolution text. The sources checked here give no depot-specific criterion, so report the ratio and the solubility behind it.
What are sink conditions?
Sink conditions are a margin between the drug in the medium and the most the medium can dissolve. The European Pharmacopoeia’s dissolution text, read in its British Pharmacopoeia copy, says the material already in solution then “does not exert a significant modifying effect” on the rate. FDA’s veterinary compilation for immediate-release oral forms defines them as the volume of fluid needed to fully dissolve three times the targeted amount of drug substance, so the profile is influenced primarily by the formulation rather than by solubility.
Both wordings limit solubility’s influence without removing it. Without the margin, a curve that flattens has at least two readings: the depot slowed down, or the medium filled up.
How do you calculate the sink ratio?
Divide the medium volume by the saturation volume.
- Solubility: measure it in the release medium, at test temperature. A surfactant changes it.
- Saturation volume: divide the targeted amount of drug by that solubility.
- Sink ratio: divide the medium volume by the saturation volume.
One published example is an aqueous suspension of medroxyprogesterone acetate, in a dialysis method its authors set aside for poor discrimination. It isn’t a PLGA depot. The inputs are 16 mg of drug, 300 mL of medium, and a solubility of 545.98 µg/mL in pH 7.4 buffer with 1% sodium dodecyl sulfate. This page’s calculation from them: 16 mg divided by 0.546 mg/mL gives 29.3 mL, and 300 divided by 29.3 gives about 10.
Driving force at each ratio. The Noyes-Whitney equation scales dissolution rate with solubility minus bulk concentration. If all the drug dissolves and nothing is replaced, concentration peaks at solubility divided by the ratio. By that calculation the driving force falls 33% at a ratio of 3 and 10% at a ratio of 10. The equation describes a dissolving solid. A depot limited by its carrier may feel less of this.
Each interval when medium is replaced. Compare the drug released in that interval, plus any drug left in carried-over medium, with solubility times the fill volume. The burst interval is the one to check first, and initial burst release has its own page. This check follows from the definition, and the sources checked here don’t state it as a rule.
What ratio counts as sink conditions?
At least three times the saturation volume is the lowest multiple in the sources checked here, and none of them gives a criterion written for depots.
| Source | What it says | Written for |
|---|---|---|
| Ph. Eur. 5.17.1, British Pharmacopoeia copy | Normally at least 3 to 10 times the saturation volume | Dissolution testing, non-mandatory. Names oral forms, patches and gums, and no parenteral product |
| 2026 review | At least three- to ten-fold, citing Ph. Eur. 5.17.1 | A restatement in a review of PLGA long-acting injectables |
| FDA veterinary compilation | Volume that fully dissolves three times the targeted amount of drug substance | Immediate-release oral forms |
| Dissolution Technologies, 2008 | At least three times the volume of a saturated solution, at the highest dose | Dissolution methods, in the authors’ own opinion |
| Dissolution Technologies, 2013 | At least three times, and some companies use five or ten | Dissolution methods, in the authors’ own opinion |
These rows share a lineage, so five rows aren’t five confirmations. The FDA section refers readers to USP <1092>, one author of both Q&As is with USP, and the review cites the pharmacopoeia. The 2013 Q&A also gives the counter-case: some dissolution tests discriminate better when sink isn’t followed.
USP <1092> is the chapter on developing dissolution procedures. USP <1001> covers release methods for parenteral preparations.
Why do sink conditions matter in a depot study?
Sink conditions make a release result more likely to reflect the dosage form, the 2026 review says, citing USP <1092>. They may also affect comparisons between methods. Bao and colleagues list media volume, 150 mL against 500 mL and so different folds of sink, among four differences between two apparatus 2 methods that gave different release rates. Hydrodynamics, membrane area and compartment design changed too, so the study doesn’t separate sink’s share.
The review treats the injection site differently from the vessel. Fluid volume at a subcutaneous or intramuscular site is small, yet fluid keeps moving and drug diffuses away, so the surrounding tissue may act as a sink, it says, citing Wang and colleagues. It also says sink can’t be assumed in vivo when a test simulates the physiological environment.
How do you hold sink conditions over a long depot study?
Add volume, replace medium or change the medium’s solubility, and expect each move to cost something. The review names these moves, and the depot release methods comparison covers method choice.
| Method | Move | Cost or check |
|---|---|---|
| Sample and separate | Replace medium after sampling, or use a larger container for a poorly soluble drug | The review prefers small volumes when analytical sensitivity is limited, so added volume can push the drug below detection |
| Flow-through cell | Raise the medium volume for a poorly soluble drug | The review says volume can come down when sensitivity is limited. A closed loop recirculates a fixed volume, so drug should accumulate there, which is this page’s inference |
Dialysis adds a second comparison: the review asks for an outer volume at least 6 to 10 times the volume inside the bag, which keeps a gradient across the membrane and says nothing about solubility.
Changes to the medium carry their own checks:
- Solubilizers: the review says some media need surfactants or organic solvents, and they change the medium the depot sits in. It reports one accelerated study, separate from any sink goal, in which 0.1% Triton X-100 at 40 °C sped water uptake and altered PLGA phase separation, and the kinetics stopped matching real-time release.
- Low-level surfactant: polysorbate at 0.02% to 0.05% is frequent in PLGA microparticle testing, where the review ties it to aggregation and floating. Measure solubility in that medium before counting it toward sink.
- Evaporation: the review says to consider whether medium lost over a long run affects sink.
Where can a depot saturate anyway?
A dialysis device can saturate while the vessel stays at sink, because the sink ratio covers only the outer medium.
In the medroxyprogesterone method, the authors report sink in the 300 mL vessel, while the 1 mL device held all 16 mg. If solubility inside matched the outer medium, only about 0.5 mg stays in solution there (1 mL times 0.546 mg/mL, this page’s calculation). The authors say the method’s low sensitivity may be due to a sink violation in the sac. The review gives the condition: small volume and limited membrane area can violate sink inside when release from the carrier outpaces diffusion through the membrane.
A sink ratio can’t show that a method tells formulations apart or that a curve matches in vivo release. The release testing guide covers that evidence.
What a GelTech study measures on sink conditions
A GelTech study measures the drug and the depot on one timeline, in the medium agreed with you. Carousel runs six chambers per unit, each a 24 mL sample chamber inside a 50 mL incubation chamber, in media from pH 1.5 to 12 that can include surfactants, closed loop or open loop. It weighs each sample’s wet mass at every timepoint, and integrated instruments such as UV-Vis, HPLC and LC-MS read the drug in sampled medium. For PLGA, molecular weight falls before mass is lost, so GelTech measures molecular weight separately, in its own lab.
This page’s example wouldn’t fit one fill: 24 mL against its 29.3 mL saturation volume gives a ratio of about 0.8. Replacing medium or running flow-through changes that sum, so the check is per interval.
Because Carousel tests samples immersed in fluid at controlled conditions over weeks to months, its data sits closer to in vivo conditions than conventional bench methods, which gives a stronger basis for IVIVC. It doesn’t predict in vivo results.
GelTech doesn’t run animal or clinical studies, or accredited biocompatibility or sterility testing. See drug delivery and how a pilot study works.
Sources
- British Pharmacopoeia 2013, Appendix XII B annex, Recommendations on dissolution testing (Ph. Eur. general text 5.17.1)
- Lusina Kregar M, Krtalić I, Šagud I. An overview of in vitro release methods for long-acting injectable products based on PLGA. Methods Protoc. 2026;9(3):87
- FDA, Animal & Veterinary. Compilation of FDA guidance and resources for in vitro dissolution testing of immediate release solid oral dosage forms, 2025
- Bao Q, Wang X, Zou Y, Wang Y, Burgess DJ. In vitro release testing method development for long-acting injectable suspensions. Int J Pharm. 2022;622:121840
- Brown W, Marques M. May 2008 questions and answers. Dissolution Technologies. 2008
- Brown W, Marques M. May 2013 questions and answers. Dissolution Technologies. 2013
- StatPearls. Biochemistry, dissolution and solubility
- USP. General chapter <1092> The dissolution procedure: development and validation
- USP. General chapter <1001> In vitro release test methods for parenteral drug preparations
Related reading
Questions
Which dose goes into a sink conditions calculation?
Sink conditions are calculated against the full targeted amount of drug in the sample, since all of it can end up in the medium. FDA's veterinary compilation asks for solubility data covering the entire range of strengths when a product has several.
Can a surfactant be used to reach sink conditions?
A surfactant can be used to reach sink conditions, and FDA's veterinary compilation says its selection should follow the drug's characteristics. Its example is that an anionic surfactant such as sodium lauryl sulfate isn't appropriate with a cationic drug.
Are sink conditions always required in a release study?
Sink conditions aren't mandatory in the sources checked here, and the European Pharmacopoeia text describes itself as non-mandatory. A 2026 review says quality control release testing of PLGA products generally runs under sink, while non-sink testing may be warranted for some products. It adds that sink can't be assumed in vivo when a test simulates the physiological environment.
