Why Does the Same Percentage of an Active Deliver a Different Dose Into Skin?
Research Team
Because the percentage on a label describes how much active sits in the container, not how much of it is free to move. Permeation into skin is driven by thermodynamic activity — the fraction of a vehicle's dissolving capacity that is already used — rather than by absolute concentration. Published comparisons of an identical labelled percentage in two different bases differ by as much as tenfold.
Published 3 November 2026. Last reviewed 3 November 2026.
The term, defined on its own
Thermodynamic activity, in a topical formulation, is the concentration of dissolved active expressed as a fraction of the maximum that the same vehicle can dissolve. Iliopoulos, Sil and Evans state it directly: “The thermodynamic activity of a solute is defined by its degree of saturation i.e., the concentration of the solute in the vehicle as a fraction of the maximum solubility in that same vehicle.” They add that “maximum thermodynamic activity, equal to one, will be reached when the drug saturates the formulation” (Front. Drug Deliv. 2022;2:1049848).
Four further terms are used below in their technical sense. Vehicle: the non-active part of a formulation — solvents, polymers, emulsifiers — in which the active is dissolved or dispersed. Saturation solubility: the largest amount of an active that will stay dissolved in a given vehicle at a given temperature. Flux: the amount of a substance crossing a unit area of skin per unit time, conventionally reported in µg/cm²/h. Stratum corneum: the outermost, non-living layer of the epidermis, and the principal barrier to percutaneous transport.
The arithmetic that follows from the definition is unforgiving. An active at 1% in a base that can dissolve 10% of it is at a degree of saturation of 0.1. The same active at 1% in a base that can dissolve only 1% is at 1.0. The two containers carry the same number on the label and a tenfold difference in the driving force for diffusion.
What the measured comparisons show
The table below collects comparisons in which the labelled concentration was held constant, or in which the lower-concentration product performed better, and the vehicle was varied.
| Active and labelled concentration | Vehicles compared | Reported difference | Endpoint and model | Source |
|---|---|---|---|---|
| Tazarotene 0.1% | Polyamide-3 film-forming solution vs. marketed cream | Film-forming system promoted ten times greater amounts of active in the upper dermis; amounts reaching the epidermis were not reported | Ex vivo pig ear skin, 50 µL over 0.5 cm² for 24 h, 10 µm horizontal sections | Kapoor et al. 2022, as reported in Iliopoulos et al. 2022 |
| Terbinafine hydrochloride 1% | Ethanol/acrylate film-forming solution vs. cream | Greater residence time and greater penetration into the stratum corneum from the film; no numeric ratio reported | In vivo human dermatopharmacokinetics, single dose | Kienzler et al. 2007, as reported in Iliopoulos et al. 2022 |
| Mometasone furoate 0.1% | Propylene glycol solution vs. cream | Greater penetration from the solution; reported qualitatively, without a figure | Vasoconstrictor assay, human skin | Zvidzayi et al. and Rath et al., as reported in Tapfumaneyi et al. 2025 |
| Clobetasol propionate 0.05% vs. 0.1% | 0.05% cream vs. 0.1% propylene glycol solution | The lower-concentration cream showed the greater degree of penetration | Vasoconstrictor assay, human skin | Zvidzayi et al. and Rath et al., as reported in Tapfumaneyi et al. 2025 |
| Methylphenidate, saturation varied | Eudragit RS vs. Eudragit E film-forming systems | Delivery “linearly proportional to the degree of drug saturation”, and additionally dependent on the polymer's anti-nucleant action | Silicone membrane in vitro | Edwards et al. 2017 |
The fourth row is the one that settles the argument. A vasoconstrictor assay — also called the human skin blanching assay, an FDA-recognised method that reads the transient whitening of skin as an index of how much corticosteroid has entered it — ranked a 0.05% cream above a 0.1% solution of the same molecule. Tapfumaneyi and colleagues attribute the result to the vehicle: the differences “were attributed to the differences in formulation vehicles and associated vehicle properties, which either enhanced or impeded drug permeation and drug release from vehicles” (Pharmaceutics 2025;17(6):764). Doubling the number on the label did not double, or even match, the delivered amount.
Pushing past saturation, and why it does not hold
Supersaturation is the state in which a vehicle holds more dissolved active than its saturation solubility allows, giving a degree of saturation above one. The classic route to it, described by Coldman, Poulsen and Higuchi in 1969, is a mixture of a volatile and a non-volatile solvent: the volatile fraction evaporates after application, concentrating the active in what remains. Those authors found maximum permeation from formulations with a high volatile-solvent content, and attributed it to the high thermodynamic potential of the supersaturated residue (J. Pharm. Sci. 1969;58:1098–1102).
The limitation is intrinsic, not technical. Iliopoulos and colleagues put it plainly: “supersaturated solutions are inherently thermodynamically unstable due to eventual recrystallization.” An active that has recrystallised is no longer dissolved, and only dissolved material diffuses. Edwards and colleagues showed that the polymer chosen to delay that recrystallisation is itself a determinant of delivery, alongside the degree of saturation (Eur. J. Pharm. Biopharm. 2017;114:164–174). A supersaturated claim without an anti-nucleant strategy describes a state that does not survive the shelf.
What these figures do not license
Every quantified comparison in the table comes from a pharmaceutical product: a corticosteroid, an antifungal, a prescription retinoid, a stimulant. They were measured ex vivo, in vitro, or by a blanching assay, and they establish a principle about vehicles — not a magnitude that transfers to any other molecule, vehicle or product class. Cosmetic products are not medicines, and none of these numbers may be read as describing one.
Two further constraints bound the whole discussion. Tapfumaneyi and colleagues put the fraction of applied material that successfully crosses the stratum corneum at “approximately 30%”, and note that molecules below 500 Da permeate more readily; Iliopoulos and colleagues give an “optimal range of logP (o/w) between 1 and 3” for passive transport. These are physicochemical windows, not guarantees: a molecule inside them may still fail to reach a target, and a favourable degree of saturation cannot rescue one that falls far outside them.
The same reasoning governs ascorbic acid and its esters, where the delivered amount depends on protonation state and on the oxidative stability of the molecule rather than on the labelled percentage. TTS Clinical sets out that case, with its pH and stability constraints, in an open-access technical report (doi:10.5281/zenodo.22491021).
What this changes in a formulation brief
A percentage alone is an incomplete specification. A specification that can be evaluated states the active's saturation solubility in the finished vehicle, the resulting degree of saturation, and — where the formulation relies on a supersaturated residue — the mechanism that prevents recrystallisation and the period over which it holds. Formulating to the criteria of compounding pharmacy means committing to those three numbers, because they are the ones that determine how much of a declared percentage is available to move at all.
References
- Iliopoulos F., Sil B. C., Evans C. L. (2022). The role of excipients in promoting topical and transdermal delivery: current limitations and future perspectives. Frontiers in Drug Delivery 2:1049848. doi:10.3389/fddev.2022.1049848
- Tapfumaneyi P., Phan K., Huang Y., Sodsri K., Namjoshi S., Maibach H., Mohammed Y. (2025). Solute–vehicle–skin interactions and their contribution to pharmacokinetics of skin delivery. Pharmaceutics 17(6):764. doi:10.3390/pharmaceutics17060764
- Edwards A., Qi S., Liu F., Brown M., McAuley W. (2017). Rationalising polymer selection for supersaturated film forming systems produced by an aerosol spray for the transdermal delivery of methylphenidate. European Journal of Pharmaceutics and Biopharmaceutics 114:164–174. doi:10.1016/j.ejpb.2017.01.013
- Coldman M., Poulsen B., Higuchi T. (1969). Enhancement of percutaneous absorption by the use of volatile: nonvolatile systems as vehicles. Journal of Pharmaceutical Sciences 58:1098–1102. doi:10.1002/jps.2600580912
- TTS Clinical Scientific Team (2026). Topical vitamin C: the pH constraint on L-ascorbic acid and the oxidative stability of tetrahexyldecyl ascorbate, v1.0. doi:10.5281/zenodo.22491021
Scope note. This article describes findings published in the cited scientific literature and the physicochemical principles those findings support. It is not a product claim, and nothing in it should be read as a statement about the effects of any TTS Clinical or Truth Treatment Systems product, or as medical advice. Figures obtained with pharmaceutical actives are reported as such and do not transfer to cosmetic products.