I. What Is 4-Hydroxyethylpiperazine Ethane Sulfonic Acid (HEPES)
HEPES is a zwitterionic organic sulfonate salt. Its molecule carries both an acidic sulfonic acid group and a basic piperazine group, giving it excellent pH buffering capacity, with a pKa of approximately 7.55 (25°C) and a buffering range of 6.8–8.2.
Basic Physicochemical Parameters
Parameter | Description |
|---|---|
Common Name | 4-Hydroxyethylpiperazine Ethane Sulfonic Acid |
INCI Name | Hydroxyethylpiperazine Ethane Sulfonic Acid |
Abbreviation | HEPES |
CAS Number | 7365-45-9 |
Appearance | White crystalline powder at high purity |
Solubility | Readily soluble in water; insoluble in oil systems |
Core Functions | Buffering agent, pH adjuster, skin conditioning aid |
Storage Conditions | Sealed, cool, dry, protected from light; 24-month shelf life |
II. Mechanism of Action
1. pH Buffering and Stabilization Mechanism
HEPES relies on its zwitterionic structure. When the formulation experiences pH fluctuations caused by ingredient dissolution, electrolyte addition, temperature changes, long-term storage, or repeated contamination from opening, the molecule can bind or release hydrogen ions to suppress significant pH drift, maintaining a stable acid-base environment—functioning as a "pH shock absorber" for the formulation. Many actives (peptides, vitamin C derivatives, fruit acids, plant fermentation extracts) are highly pH-sensitive; pH shifts can cause active degradation, discoloration, odor deterioration, and viscosity changes. HEPES reduces pH drift during the storage period, protecting active integrity and extending formulation shelf life.
2. Auxiliary Keratolytic Effect (Synergistic)
In suitable formulation environments, HEPES can mildly weaken the connections between corneocytes, achieving gentle softening of dead skin cells and helping improve roughness and dullness. This effect is weaker than AHAs and salicylic acid, is auxiliary in nature, and is highly dependent on concentration and overall formulation pH. It should not be equated with chemical exfoliating ingredients.
3. Auxiliary Enhancement of Active Bioavailability
After gentle stratum corneum conditioning, co-formulated brightening and soothing actives can more readily act on the stratum corneum, providing formulation synergy. However, this does not constitute strong transdermal penetration enhancement and does not compromise the skin barrier.
III. Suitable Cosmetic Product Applications
HEPES has excellent water solubility and is compatible with the vast majority of water-phase and oil-in-water emulsion systems. Mainstream application formats include:
Active serums: Peptide serums, vitamin derivative serums, gentle exfoliating treatment serums—stabilizing actives and reducing irritation risk from pH fluctuations.
Sheet masks and ampoules: Sheet mask solutions and single-dose ampoules—maintaining solution pH stability and reducing storage-related discoloration.
Lotions and creams: Repair lotions and conditioning creams—compatible with emulsion systems, mitigating long-term storage pH drift.
Eye care products: Eye creams and eye mask serums—the delicate eye area benefits from stable buffering to reduce irritation risk.
Gentle acid exfoliating products: Formulations with low-irritation acids such as lactobionic acid and gluconolactone—buffering to stabilize the system and balancing exfoliating efficacy with skin tolerance.
Gels and sprays: Water-based gels and hydrating mists.
Not recommended scenarios: Pure oil systems (HEPES is insoluble); formulations with high concentrations of strong oxidizers require careful evaluation; infant cosmetics require strict safety assessment before use.
IV. Recommended Usage Levels and Formulation Compatibility Considerations
1. Industry Reference Usage Range
There is no mandatory national limit. The following are references from mature market formulations; final levels should be determined by the company's safety assessment report:
Product Type | Reference Concentration (w/w) | Application Purpose |
|---|---|---|
Serums, ampoules | 0.2–2.5% | Stabilize pH, protect actives |
Mask solutions | 0.1–1.5% | Maintain solution stability |
Lotions/creams | 0.2–2.0% | Stabilize emulsion system, delay pH drift |
Eye care products | 0.1–1.0% | Gentle buffering, control irritation risk |
Gentle exfoliating/treatment formulas | 0.5–3.0% | Buffering + auxiliary keratolytic synergy |
Higher concentration does not mean better results. Excessive concentrations can increase eye irritation risk; eye formulations should use the lower end of the range.
2. Formulation Compatibility Points
✅ Recommended combination directions:
HEPES + Panthenol + Sodium Hyaluronate: Buffering with enhanced moisturizing and repair benefits, reducing discomfort from keratolytic effects.
HEPES + Peptides + Plant Extracts: Stabilizing the system and protecting heat-sensitive, pH-sensitive actives.
HEPES + Mild acids such as lactobionic acid: Stabilizing the acid system's pH and optimizing sensory experience.
⚠️ Caution required:
Strong oxidizer systems: Coexistence of HEPES with strong oxidizers carries a risk of free radical generation; light exposure and accelerated stability testing are mandatory.
Complex formulations should employ a composite buffering system rather than relying solely on HEPES for all pH control.
HEPES buffers optimally in the 6.8–8.2 range. If the target formulation pH deviates significantly from this range, buffering capacity diminishes—do not force its use.
Manufacturing process: Dissolve in the water phase with low-temperature stirring; add other active ingredients only after complete dissolution.
Finished products must undergo: freeze-thaw cycling, light exposure, and long-term storage stability testing, monitoring pH, color, and odor changes.
V. Cosmetic Regulations and Claim Requirements
1. Ingredient Status: HEPES is listed as an ingredient already in use in Chinese cosmetics and is not classified as a new ingredient. It can be filed and used normally. Functional categories for filing: buffering agent, pH adjuster, skin conditioning agent.
2. Compliant Claim Descriptions:
Stabilizes formulation pH and reduces pH drift during storage.
Creates a gentle, stable formulation environment that protects actives.
Auxiliary softening of dead skin cells, improving skin roughness.
Suitable for gentle conditioning skincare formulations.
3. Prohibited Exaggerated Claims:
❌ Prohibited from claiming whitening, acne treatment, anti-wrinkle, or anti-inflammatory effects as standalone HEPES functions.
❌ Medical claims are prohibited; must not claim treatment of skin diseases.
❌ Auxiliary keratolytic effects must not be presented as intensive exfoliation comparable to high-concentration AHAs.
Conclusion
HEPES is a high-performance zwitterionic buffering ingredient that, through its excellent pH stabilization capacity, is widely used in active-containing formulations. Its core value lies in safeguarding formulation system stability and synergistically supporting other functional ingredients—it is not a standalone high-efficacy active. R&D teams should observe the applicable pH buffering window, control usage levels, avoid strong oxidizer compatibility risks, and strictly adhere to claim boundaries, combining stability and safety assessments to develop compliant, stable skincare products.
Our company supplies high-purity cosmetic-grade HEPES raw material with consistent purity. Samples and formulation technical support are available. We support both small and bulk orders, helping brands complete the development of active-based skincare products.
References
[1] PubChem. 4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid[EB/OL]. https://pubchem.ncbi.nlm.nih.gov/compound/7365 45 9
[2] 中国专利数据库。一种含生物缓冲剂的护肤品 CN102793657B [P]. 2015
[3] Cosmetics-Info. HEPES-Hydroxyethylpiperazine Ethane Sulfonic Acid [EB/OL]. https://www.cosmeticsinfo.org