Climbazole, Klimbazol, Climbazol, 38083-17-9

Climbazole, Klimbazol, Climbazol, 38083-17-9

CLIMBAZOLE (C₁₅H₁₇ClN₂O₂)

1. Chemical Identity and Material Classification

• Chemical Name: Climbazole, 1-(4-Chlorophenoxy)-1-(1H-imidazol-1-yl)-3,3-dimethylbutan-2-one

• Synonyms: Climbazol, 1-(4-Chlorophenoxy)-1-(1H-imidazol-1-yl)-3,3-dimethylbutane-2-one

• CAS Number: 38083-17-9

• EC Number (EINECS): 253-775-4

• Molecular Formula: C₁₅H₁₇ClN₂O₂

• Molecular Weight: 292.76 g/mol

• Chemical Class: Azole antifungal, imidazole derivative, ketone

• HS Code: 2933.29

• UN Number: Not applicable (not classified as hazardous material for transport under normal conditions)

2. Physical Properties

2.1 General Physical Properties

2.2 Solubility Properties

2.3 Particle Characterization

2.4 Hygroscopicity and Stability

3. Chemical Properties

3.1 Molecular Structure

• Structure: 1-(4-chlorophenoxy)-1-(1H-imidazol-1-yl)-3,3-dimethylbutan-2-one

• Functional groups: Imidazole ring (azole antifungal pharmacophore), chlorophenyl ether, ketone, tert-butyl group

• Key structural features:

  • Imidazole ring: Binds to fungal cytochrome P450 (CYP51) – lanosterol 14α-demethylase

  • Chlorophenyl group: Enhances antifungal activity and lipophilicity

  • tert-Butyl ketone group: Contributes to stability and lipophilicity

  • Ether linkage: Connects chlorophenyl to the main chain

• Ionization: Weakly basic (imidazole nitrogen pKa ~6.5–7.0)

• Chirality: Contains one chiral center (the carbon bearing both the imidazole and chlorophenoxy groups). Commercial climbazole is typically supplied as a racemic mixture (50:50 R/S enantiomers).

3.2 Thermal Properties

3.3 Chemical Reactivity

3.4 Antifungal Mechanism of Action (Ergosterol Biosynthesis Inhibition)

4. Commercial Grades and Specifications

5. Quality Specifications (Cosmetic/Pharmaceutical Grade)

6. Production Methods

6.1 Chemical Synthesis (Multi-step Synthesis – Industrial Method)

• Synthetic route: Multi-step synthesis starting from 4-chlorophenol and imidazole

• Simplified reaction scheme:

  1. Step 1: 4-Chlorophenol is reacted with a suitable reagent to form a chlorophenoxy intermediate.

  2. Step 2: The intermediate is reacted with imidazole to form the imidazole derivative.

  3. Step 3: Introduction of the tert-butyl ketone group via alkylation or condensation.

  4. Step 4: Purification by recrystallization (typically from ethanol or isopropanol).

• Yield: 40–60% (overall)

• Purity: ≥99.0%

• Note: The exact synthetic route is proprietary to manufacturers.

6.2 Green Synthesis (Research Scale – Not Commercial)

• Alternative methods: Enzymatic or catalytic routes have been reported but are not commercially used.

7. Mechanism of Action (Functional Mechanisms)

7.1 Antifungal Mechanism (Primary Mechanism – Anti-dandruff Activity)

• Target: Malassezia species (formerly known as Pityrosporum – M. globosa, M. restricta, M. furfur)

• Mechanism: Ergosterol biosynthesis inhibition (see section 3.4)

• Minimum Inhibitory Concentration (MIC) against Malassezia:

  • M. globosa: 0.5–4 µg/mL

  • M. restricta: 0.5–4 µg/mL

  • M. furfur: 1–8 µg/mL

• Fungistatic vs. Fungicidal: Fungistatic at low concentrations (growth inhibition), fungicidal at higher concentrations (cell death)

• Result: Reduction of Malassezia population on the scalp → reduction of dandruff, scaling, and itching

7.2 Anti-inflammatory Mechanism (Secondary – Reduction of Scalp Irritation)

• Reduction of inflammatory mediators: Climbazole reduces the production of pro-inflammatory cytokines (IL-1α, IL-1β, IL-6, TNF-α) in keratinocytes exposed to Malassezia metabolites.

• Reduction of oxidative stress: May have mild antioxidant properties.

• Result: Reduced scalp redness, itching, and irritation associated with dandruff and seborrheic dermatitis.

7.3 Keratolytic/Desquamating Mechanism (Mild – Scalp Flake Reduction)

• Normalization of keratinocyte turnover: By reducing fungal load and inflammation, climbazole helps normalize the accelerated keratinocyte turnover caused by Malassezia.

• Reduction of hyperproliferation: Decreased proliferation of epidermal keratinocytes → reduced formation of visible flakes.

• Result: Less visible dandruff flakes on scalp and hair.

7.4 Deposition Mechanism on Scalp and Hair

• Lipophilic nature: Due to its lipophilic character (log P ~3.8–4.2), climbazole partitions into the lipid-rich layers of the scalp (stratum corneum) and hair cuticle.

• Surfactant interactions: In shampoo formulations, climbazole is solubilized in surfactant micelles. Upon dilution with water during rinsing, the micelles break down, and climbazole precipitates onto the scalp and hair (deposition).

• Substantivity: Climbazole has good substantivity (binding) to the scalp and hair, providing residual antifungal activity between washes.

• Result: Prolonged antifungal effect (continues between shampoo uses).

8. Applications

8.1 Anti-dandruff Shampoos – Largest Application (~80–90%)

Formulation note for shampoos:

• Solubilization method: Pre-dissolve climbazole in propylene glycol (USP) at a 1:2 to 1:4 ratio (climbazole:propylene glycol) with heating (40–50°C).

• Alternative solubilization: Pre-dissolve in a surfactant-rich premix (e.g., with sodium laureth sulfate or cocamidopropyl betaine) with heating.

• Incorporation temperature: Add to the formulation at 40–50°C.

• pH range for stability: 4–8 (optimal pH 5–6 – typical shampoo pH).

8.2 Hair Conditioners and Scalp Treatments

8.3 Topical Antifungal Creams, Lotions, and Ointments (Pharmaceutical)

8.4 Other Cosmetic Products

8.5 Veterinary Applications

9. Climbazole vs. Other Anti-dandruff Active Ingredients – Comparison

10. Toxicology and Safety

10.1 Acute Toxicity

10.2 Subchronic and Chronic Toxicity

10.3 Special Concerns and Considerations

10.4 GHS Classification

Signal word: WARNING

10.5 NFPA Rating

11. Safety Precautions and Personal Protective Equipment (PPE)

Hazards:

• Harmful if swallowed (H302).

• Causes eye irritation (H319).

• Very toxic to aquatic life with long-lasting effects (H410).

• Combustible dust – may form explosive dust-air mixtures at high concentrations (though low hazard).

• Dust may cause mechanical irritation to eyes and respiratory tract.

PPE (recommended – for powder handling):

• Respiratory protection: P1 or P2 dust mask (when handling large quantities of powder).

• Eye protection: Safety glasses with side shields (dust protection). Chemical splash goggles recommended for large-scale handling.

• Gloves: Nitrile or latex gloves (for handling concentrated powder).

• Protective clothing: Laboratory coat or standard work clothing.

• Footwear: Closed-toe shoes.

Engineering controls:

• Local exhaust ventilation (LEV) for dust control during weighing and mixing.

• General room ventilation.

• Dust collection system for large-scale handling.

Storage conditions:

Environmental precautions (very important):

• Do not discharge into water bodies, sewers, or the environment. Climbazole is very toxic to aquatic organisms (algae, fish, invertebrates).

• Disposal: Dispose of as hazardous waste (environmentally hazardous substance). Incineration (with flue gas treatment) is preferred.

• Spill cleanup: Collect spilled material using a dust-rated vacuum or wet-sweeping (avoid dust generation). Do not wash into drains. Dispose of as hazardous waste.

First aid:

• Inhalation: Move to fresh air. No specific treatment required. Seek medical attention if respiratory irritation persists.

• Skin contact: Wash with water and soap. No specific treatment required.

• Eye contact: Rinse with water for several minutes, lifting eyelids. Remove contact lenses. Seek medical attention if irritation persists.

• Ingestion: Rinse mouth. Drink water. Do NOT induce vomiting. Seek medical attention if large amounts ingested.

Firefighting:

• Fire class: Combustible dust (Class A) – low fire hazard.

• Extinguishing media: Water spray, dry chemical powder (ABC), CO₂, foam.

• Firefighting instructions: Firefighters should wear SCBA and full protective gear. Toxic decomposition products (HCl, CO, NOx) may be released.

12. Environmental Fate

13. Storage and Shelf Life

13.1 Storage Conditions

13.2 Shelf Life and Degradation

14. Transport Information

Transport note: Climbazole is not classified as a hazardous material for transport under UN Model Regulations. However, due to its aquatic toxicity, some countries may require environmental hazard labeling for bulk shipments.

15. Synonyms and Common Names

• English: Climbazole, Climbazol, 1-(4-Chlorophenoxy)-1-(1H-imidazol-1-yl)-3,3-dimethylbutan-2-one, 1-(4-Chlorophenoxy)-1-(1H-imidazol-1-yl)-3,3-dimethylbutane-2-one

• German: Climbazol

• French: Climbazole

• Spanish: Climbazol

• Trade names: Climbazole (generic), Climbazol (various), Crinipan® AD (BASF/Lonza – climbazole-based anti-dandruff active), Ketoconazole alternative (non-prescription), generic climbazole

Note: Crinipan® AD is a registered trademark of BASF/Lonza for a climbazole-based anti-dandruff active ingredient (often supplied as a 20% solution in propylene glycol).

16. Climbazole in Anti-dandruff Shampoos – Formulation Guide

16.1 Typical Concentration by Product Type

16.2 Solubilization and Incorporation Guide for Formulators

16.3 Recommended Minimum Inhibitory Concentration (MIC) against Malassezia species

17. Frequently Asked Questions (FAQs)

Q1: What is climbazole and what is it used for?
A1: Climbazole is an imidazole antifungal agent used primarily as an anti-dandruff active ingredient in shampoos and scalp treatments. It is effective against Malassezia species (formerly Pityrosporum), the fungi responsible for dandruff, seborrheic dermatitis, and tinea versicolor. Approximately 80–90% of climbazole production is used in anti-dandruff shampoos.

Q2: How does climbazole work against dandruff?
A2: Climbazole inhibits ergosterol biosynthesis in fungal cell membranes by blocking the enzyme lanosterol 14α-demethylase (CYP51). This leads to depletion of ergosterol (an essential membrane component) and accumulation of toxic sterols, disrupting membrane integrity and killing or inhibiting the growth of Malassezia fungi on the scalp.

Q3: Is climbazole safe for daily use in shampoos?
A3: Yes, climbazole is considered safe for daily or frequent use in shampoos at concentrations up to 0.5% (EU maximum). Systemic absorption through the scalp is very low (<0.1%). It is non-irritating to the skin (at recommended concentrations) and has a very low incidence of allergic reactions. It is also considered safe for use during pregnancy and lactation.

Q4: What is the difference between climbazole and ketoconazole?
A4: Both are imidazole antifungals with the same mechanism of action (ergosterol synthesis inhibition). Key differences:

• Ketoconazole is a stronger antifungal (lower MIC values) but requires a prescription in many countries for oral and some topical forms. It has a higher risk of systemic side effects.

• Climbazole is slightly weaker but can be used OTC in cosmetics (no prescription). It has an excellent safety profile and is less likely to cause resistance. Climbazole is also more lipophilic, providing better deposition on the scalp.

• For anti-dandruff shampoos, both are effective. Climbazole is often preferred for OTC cosmetic products.

Q5: Is climbazole a prescription drug?
A5: It depends on the concentration and application:

• Shampoos (≤0.5%): Non-prescription (cosmetic/OTC) in most countries (EU, Japan, Korea, many others). In the USA, climbazole is not yet included in the FDA OTC monograph but is used in some products.

• Topical creams (>0.5%): May require a prescription depending on the country and concentration (0.5–1.0%).

• Oral formulations: Prescription only (climbazole is not typically used orally due to safety concerns).

Q6: Can climbazole be used for seborrheic dermatitis on the face?
A6: Yes, climbazole is effective for facial seborrheic dermatitis (redness, scaling, itching). It is available in some creams, lotions, and face washes at concentrations of 0.3–1.0%. It is less irritating than some other antifungal agents (e.g., ketoconazole cream may cause stinging). Always follow the product instructions.

Q7: Is climbazole effective against tinea versicolor (pityriasis versicolor)?
A7: Yes, climbazole is effective against Malassezia furfur, the causative agent of tinea versicolor (a superficial fungal infection causing discolored patches on the chest, back, and arms). Climbazole-containing body washes, shampoos (used as body wash), or creams can be used for treatment and prevention.

Q8: What are the potential side effects of climbazole?
A8: At recommended concentrations (<0.5% in shampoos), side effects are very rare:

• Mild eye irritation if product enters eyes (rinse thoroughly).

• Allergic contact dermatitis (extremely rare – <0.01% of users).

• Skin dryness or scaling with overuse (reduced by using a moisturizer or conditioner).

• No significant systemic side effects due to very low absorption.

Q9: How should climbazole be formulated in anti-dandruff shampoos?
A9: Climbazole is lipophilic (poorly water-soluble). It is typically pre-dissolved in propylene glycol (USP) at a 1:2 to 1:4 ratio (climbazole:PG) with heating to 40–50°C. This solution is then added to the shampoo base at 40–50°C. The final shampoo pH should be 5–6 for stability. Maximum EU concentration is 0.5%.

Q10: Is climbazole environmentally safe?
A10: Climbazole has high aquatic toxicity (very toxic to algae, daphnia, and fish). It is not readily biodegradable. Therefore, climbazole-containing products should not be discharged into water bodies, and manufacturing waste should be properly treated or incinerated. Environmental risk assessments are required for regulatory approval.

18. Summary Table – Key Specifications at a Glance

*This TDS is prepared in compliance with ISO 11014-1 format and is intended for cosmetic formulators, pharmaceutical scientists, dermatologists, anti-dandruff product developers, haircare product manufacturers, and procurement personnel. Certificates of Analysis (CoA), Safety Data Sheets (SDS), and sample validation reports are available upon request.*