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Clotrimazole, Clotrimazolum, 23593-75-1

Clotrimazole, Clotrimazolum, 23593-75-1

CLOTRIMAZOLE

SECTION 1: PRODUCT IDENTITY AND CHEMICAL IDENTIFICATION

Parameter Information
Product Name Clotrimazole
Chemical Name (IUPAC) 1-[(2-Chlorophenyl)(diphenyl)methyl]-1H-imidazole
Common Names Clotrimazole, Clotrimazolum, BAY 5097
CAS Number 23593-75-1
EC Number (EINECS) 245-764-4
Molecular Formula C₂₂H₁₇ClN₂
Molecular Weight 344.84 g/mol
Chemical Class Azole antifungal; Imidazole derivative
Pharmacological Class Antifungal agent (broad-spectrum)
Pharmacopoeia Grade USP, EP, JP, BP

SECTION 2: CHEMICAL STRUCTURE

                  Cl
                   |
              C₆H₄
                \
                 C
                / \
               /   \
              /     \
        C₆H₅         C₆H₅
              \     /
               \   /
                \ /
                 C
                 ‖
                 N
                / \
               /   \
              /     \
             CH      CH
              \     /
               \   /
                \ /
                 N

    Clotrimazole
    1-[(2-Chlorophenyl)(diphenyl)methyl]-1H-imidazole
    C₂₂H₁₇ClN₂

Simplified Structure:

            Cl
             |
    (C₆H₅)₂—C—(C₆H₄)—N
             |
             C
            / \
           /   \
          /     \
         CH     CH
          \     /
           \   /
            \ /
             N

    Clotrimazole
    Triphenylmethyl imidazole derivative
Parameter Description
Molecular Formula C₂₂H₁₇ClN₂
Molecular Weight 344.84 g/mol
Chemical Class Imidazole derivative; Azole antifungal
Functional Groups Imidazole ring, chlorophenyl, diphenylmethyl
SMILES C1=CC=C(C=C1)C(C2=CC=CC=C2)(C3=CC=CC=C3Cl)N4C=CN=C4
InChI InChI=1S/C22H17ClN2/c23-20-13-7-6-12-19(20)22(21-14-8-4-9-15-21,16-10-2-1-3-11-16)25-17-18-24-22/h1-15,17-18,22H
InChI Key VNFPBHJOKIVQEB-UHFFFAOYSA-N
Hydrogen Bond Donors 0
Hydrogen Bond Acceptors 2
Rotatable Bond Count 4
Polar Surface Area (PSA) 17.8 Ų
Optical Activity Not optically active (achiral)
Steric Structure Bond between triphenylmethyl group and imidazole ring

SECTION 3: PHYSICAL AND CHEMICAL PROPERTIES

Property Value Test Method / Note
Appearance White to off-white crystalline powder Visual
Odor Odorless Olfactometric
Molecular Weight 344.84 g/mol Calculated
Melting Point 147 – 149°C DSC / Capillary
Density (20°C) ~1.25 g/cm³ (estimated) -
Solubility in Water (25°C) Very slightly soluble (~0.0001 mg/mL) General Method
Solubility in Ethanol Soluble (~20-30 mg/mL) General Method
Solubility in Methanol Soluble General Method
Solubility in Propylene Glycol Soluble (~5-10 mg/mL) General Method
Solubility in DMSO Soluble (~50-80 mg/mL) General Method
Solubility in Chloroform Soluble General Method
Solubility in Acetone Soluble General Method
Solubility in PEG Soluble General Method
Log P (Octanol/Water) ~5.5-6.0 (highly lipophilic) Calculated / Experimental
pKa ~4.7 (imidazole nitrogen protonation) -
pH (Saturated aqueous solution) ~6.5-7.0 (neutral) pH Meter
Vapor Pressure (25°C) Very low (<0.001 mmHg) -
Flash Point >150°C -
Thermal Stability Stable up to 200°C -
Hygroscopicity Not hygroscopic -
Polymorphism Known polymorphic forms (Form I, II, III) XRD / DSC
Refractive Index ~1.65 (estimated) -
UV Maximum (λmax) ~260-265 nm (methanol) UV-VIS Spectrophotometer

SECTION 4: PHARMACOLOGICAL PROPERTIES AND MECHANISM OF ACTION

Property Description
Pharmacological Class Antifungal agent (Azole, Imidazole derivative)
Mechanism of Action Inhibits the 14α-demethylase enzyme (CYP51) in the fungal cell membrane. Blocks ergosterol synthesis; Disrupts cell membrane integrity; Leads to fungal cell death.
Spectrum Broad-spectrum antifungal; Dermatophytes, yeasts, molds, dimorphic fungi
Susceptible Organisms • Candida albicans
• Trichophyton rubrum
• Trichophyton mentagrophytes
• Epidermophyton floccosum
• Microsporum canis
• Malassezia furfur (Pityriasis versicolor)
• Aspergillus species (limited)
Antibacterial Activity Limited antibacterial activity (against Gram-positive bacteria)
Topical Bioavailability Low; poorly absorbed through skin; Accumulates in stratum corneum and epidermis
Systemic Absorption Very low in topical application (<0.5%); Well absorbed orally (systemic use limited)
Metabolism Hepatic metabolism (CYP3A4)
Elimination Mainly excreted in feces (~90%); Urine (~10%)
Plasma Half-Life ~2-4 hours (oral administration)
Protein Binding ~90-95% (albumin)
In Vitro MIC Values • C. albicans: 0.5-2 µg/mL
• T. rubrum: 1-4 µg/mL
• M. furfur: 0.5-2 µg/mL

SECTION 5: CLINICAL USE AND INDICATIONS

Indication Formulation Concentration Frequency Duration
Tinea Pedis (Athlete's Foot) Cream / Topical Solution 1% Twice daily 2-4 weeks
Tinea Cruris (Jock Itch) Cream / Powder 1% Twice daily 2-4 weeks
Tinea Corporis (Body Ringworm) Cream / Lotion 1% Twice daily 2-4 weeks
Tinea Versicolor (Pityriasis Versicolor) Cream / Topical Solution 1% 1-2 times daily 2-4 weeks
Candidiasis (Cutaneous / Mucosal) Cream / Vaginal Tablet 1% / 100-500 mg 1-2 times daily 1-2 weeks
Vaginal Candidiasis Vaginal Tablet / Cream 100 mg / 500 mg / 1% Once daily 1-6 days
Oral Candidiasis (Thrush) Lozenge / Oral Suspension 10 mg 4-5 times daily 7-14 days
Dermatophytosis (Tinea Unguium - Off-label) Topical Solution 1% 1-2 times daily 6-12 months

SECTION 6: COMMERCIAL GRADES AND VARIANTS

Grade / Type Purity Particle Size Primary Application
Pharmaceutical Grade (USP/EP) ≥99.0% Standard Topical creams, ointments, lotions, vaginal tablets
Micronized Grade ≥99.0% D90 <10 μm (micronized) High solubility formulations, better penetration
Research Grade (R&D) ≥99.5% Standard Analytical standards, formulation development
GMP Grade ≥99.0% Standard / Micronized Pharmaceutical manufacturing
Analytical Standard ≥99.8% Standard HPLC reference standards

SECTION 7: COMMERCIAL PRODUCT COMPARISON

Brand Name Strength / Concentration Formulation Indication Manufacturer
Canesten® 1% Cream / Solution / Powder Tinea, Candidiasis Bayer
Lotrimin® 1% Cream / Lotion / Solution Tinea, Candidiasis Bayer / Generic
Clotrimaderm® 1% Cream Tinea, Candidiasis Generic
Gyne-Lotrimin® 100 mg / 500 mg / 1% Vaginal tablet / Cream Vaginal candidiasis Bayer
Canesten® 500 500 mg Vaginal tablet Vaginal candidiasis Bayer
Clotrimazole (Generic) 1% / 100 mg / 500 mg Various Tinea, Candidiasis Multi-source

SECTION 8: FORMULATION GUIDELINES

Parameter Recommendation
Concentration 1% in topical formulations (standard); 100-500 mg in vaginal tablets
Vehicle • Creams: O/W (oil-water) or W/O (water-oil) emulsions
• Ointments: Hydrocarbon base (petrolatum, mineral oil)
• Lotions: Alcohol-water or PEG-based
• Solutions: Propylene glycol, ethanol, PEG
Melting Temperature Melt at 60-70°C; avoid high temperatures (>80°C) causing degradation
pH Range Optimum pH 4.0-7.0; More stable in acidic medium
Solvents • Propylene glycol (5-20%)
• Ethanol (5-20%)
• Polyethylene glycol (PEG 400)
• Dimethyl sulfoxide (DMSO, limited)
Surfactants Nonionic (Tween 80, Span 80) and anionic (sodium lauryl sulfate) compatible; Incompatible with cationic at high concentrations
Emollients Cetyl alcohol, stearic acid, stearyl alcohol, isopropyl myristate, squalane
Preservatives Methyl paraben, propyl paraben, benzalkonium chloride, phenoxyethanol
Antioxidants BHT, BHA, Vitamin E (to prevent oxidation)
Penetration Enhancers Propylene glycol (5-20%), DMSO, ethanol, azone, Transcutol®
Thickeners Carbomer, cetostearyl alcohol, xanthan gum, hydroxyethyl cellulose
Vaginal Tablet Formulation Lactose, MCC, sodium starch glycolate, magnesium stearate, povidone
Compatibility Compatible with most excipients; Avoid strong acids and bases; Incompatible with oxidizing agents
Sterilization Autoclaving not recommended (degradation); Ionizing radiation (gamma) sterilization; Aseptic filtration (0.2 µm)
Topical Shelf Life 24-36 months (proper storage)

SECTION 9: QUALITY SPECIFICATIONS (USP/EP)

Parameter USP / EP Specification Test Method
Appearance White to off-white crystalline powder Visual
Assay (on dried basis) ≥99.0% - ≤101.0% HPLC
Melting Point 147 – 149°C Capillary
Water Content ≤0.5% Karl Fischer
Residue on Ignition ≤0.1% Gravimetric
Heavy Metals ≤20 ppm USP <231>
Single Impurity ≤0.3% HPLC
Total Impurities ≤0.7% HPLC
Chloride ≤0.02% Titrimetric
Sulfate ≤0.05% Turbidimetric
Particle Size Customer specific Laser Diffraction
Microbiological Purity TAMC ≤10² CFU/g; TYMC ≤10¹ CFU/g USP <61>
E. coli Negative USP <62>
Salmonella Negative USP <62>
S. aureus Negative USP <62>
P. aeruginosa Negative USP <62>

SECTION 10: ANALYTICAL METHODS AND QUALITY CONTROL

Parameter Test Method Description
Assay HPLC (USP) C18 column, UV detector 254 nm, mobile phase: acetonitrile / pH 6.0 buffer (60:40)
Melting Point Capillary (USP) 147 – 149°C range
Water Content Karl Fischer (USP) ≤0.5%
Residue on Ignition Gravimetric (USP) ≤0.1%
Heavy Metals ICP-MS / USP <231> ≤20 ppm
Related Substances HPLC (USP) Single impurity ≤0.3%; Total ≤0.7%
Polymorphic Form XRD / DSC Form I or Form II (specified)
Solubility Test USP / EP Soluble in specified solvents
Particle Size Laser Diffraction D90 <10 μm (micronized grade)
UV Spectroscopy UV-VIS λmax ~260-265 nm (methanol)
IR Spectroscopy KBr pellet Characteristic peaks
Microbiological Test USP <61> / <62> Negative for pathogens

SECTION 11: SAFETY PROFILE AND TOXICOLOGICAL ASSESSMENT

Parameter Value / Description
GHS Classification Irritant; Skin irritation, eye irritation; Low acute toxicity
Signal Word Warning
Hazard Pictograms GHS07 (Exclamation mark)
Hazard Statements (H-Codes) H315 (Causes skin irritation), H319 (Causes serious eye irritation), H335 (May cause respiratory irritation)
Precautionary Statements (P-Codes) P261, P264, P271, P280, P302+P352, P305+P351+P338, P312, P332+P313, P337+P313, P362+P364, P403+P233, P405, P501
Acute Oral Toxicity (LD50, Rat) >1000 mg/kg (low toxicity)
Acute Dermal Toxicity (LD50, Rabbit) >2000 mg/kg (low toxicity)
Skin Irritation Mild irritant (Category 2)
Eye Irritation Mild-moderate irritant (Category 2A)
Skin Sensitization May cause sensitization (rare)
Carcinogenicity Not classified as carcinogenic
Mutagenicity Not mutagenic (AMES test negative)
Reproductive Toxicity No reproductive toxicity (rat)
Target Organs Skin, eyes, respiratory tract (dust)
Drug Interactions CYP3A4 inhibitor; Potential interaction with other azoles
Pregnancy Category FDA Category B; No risk in animal studies; Use only if clearly necessary
Lactation Unknown; Use with caution
Pediatric Use Caution in children under 2 years of age
Local Tolerability Well tolerated in topical application; Rare local irritation
Ecotoxicity Moderate toxicity to aquatic organisms; Avoid release to environment

SECTION 12: FIRST AID MEASURES

Route of Exposure Action
Inhalation If inhaled as powder, move to fresh air. Seek medical attention if respiratory irritation or symptoms persist.
Skin Contact Remove contaminated clothing. Wash with plenty of soap and water. Seek medical attention if irritation develops.
Eye Contact Rinse thoroughly with plenty of water for at least 15 minutes. Keep eyelids open. Remove contact lenses if present. Seek medical attention if irritation persists.
Ingestion Rinse mouth with water. Do NOT induce vomiting. Drink 1-2 glasses of water. Seek medical attention.
Note Symptomatic treatment is administered. No specific antidote available.

SECTION 13: ADVERSE EFFECTS AND MANAGEMENT

Adverse Effect Frequency Severity Management
Local Skin Irritation Common (5-10%) Mild Temporary; treatment can be continued
Pruritus / Itching Common (5-10%) Mild Temporary; antihistamines
Erythema / Redness Common (5-10%) Mild Usually transient; reduced application
Burning / Stinging Common (5-10%) Mild At application site; transient
Dryness / Scaling Less common (2-5%) Mild Moisturizers; dose reduction
Rash / Urticaria Rare (<1%) Moderate Discontinue treatment; antihistamines
Allergic Contact Dermatitis Very rare (<0.1%) Moderate-Severe Discontinue treatment; corticosteroids
Nausea (Oral form) Less common Mild Take with food

SECTION 14: STORAGE AND SHELF LIFE

Parameter Information
Storage Conditions Store in a cool (<25°C), dry, well-ventilated area; protect from light and moisture.
Temperature Limits 15-25°C (ideal); do not exceed 30°C
Humidity Low humidity environment (not hygroscopic)
Light Light sensitive; Light-proof containers (amber glass, aluminum, HDPE)
Oxygen Protect against oxidation; keep containers tightly closed
Incompatible Materials Strong oxidizing agents, strong acids, strong bases
Container Requirements Light-proof, moisture-proof containers: Amber glass bottles, aluminum foil bags, HDPE
Shelf Life 36 months (unopened original packaging, under proper storage conditions)
Shelf Life (After Opening) 12-18 months (under proper storage conditions)
Signs of Degradation Color change (yellowing), caking, decreased solubility, HPLC impurity increase
Stability Warning May degrade under light and moisture; Oxidized product may form impurities

SECTION 15: PACKAGING OPTIONS

Packaging Type Quantity / Capacity Material Application Area
Fiber Drum 25 kg Fiber / PE liner Pharmaceutical manufacturing, industrial supply
HDPE Drum 25 kg, 50 kg HDPE (opaque, moisture barrier) Pharmaceutical, industrial supply
Aluminum Foil Bag 1 kg, 5 kg, 10 kg Aluminum / PE (light and moisture proof) High purity, pharmaceutical
Amber Glass Bottle 100 g, 500 g, 1 kg Amber glass (UV protected) Laboratory, analytical standards
Kraft Bag (PE Lined) 10 kg, 25 kg Kraft paper / PE liner Economical packaging
IBC Container 500 kg, 1000 kg UV-protected HDPE Large-scale industrial supply

SECTION 16: TRANSPORTATION INFORMATION

Parameter Information
UN Number Not applicable (not classified as dangerous substance)
Hazard Class Not applicable
Packing Group Not applicable
ADR/RID Not classified as dangerous goods
IMDG Code Not marine pollutant
IATA (Air) Not classified as dangerous goods; can be transported by air
Transport Temperature Ambient temperature; protect from heat, moisture, and light
Transport Precautions Light-proof packaging; keep away from strong oxidizing agents
Spill Cleanup Collect mechanically; clean with absorbent material; avoid dust generation
Marine Pollutant No

SECTION 17: OTHER NAMES AND SYNONYMS

Type Name
Chemical Name (IUPAC) 1-[(2-Chlorophenyl)(diphenyl)methyl]-1H-imidazole
Common Names Clotrimazole, Clotrimazolum, BAY 5097
Trade Marks Canesten®, Lotrimin®, Clotrimaderm®, Gyne-Lotrimin®, Mycelex®
USP Name Clotrimazole
EP Name Clotrimazole
CAS Number 23593-75-1
EC Number 245-764-4
PubChem CID 2812
DrugBank ID DB00257
FDA UNII G07GZ97H65
ATC Code D01AC01 (topical), G01AF02 (vaginal)

SECTION 18: GHS CLASSIFICATION AND LABELING

Parameter Information
GHS Classification Skin Irritant Category 2; Eye Irritant Category 2A; STOT SE3
Signal Word Warning
Hazard Pictograms GHS07 (Exclamation mark)
Hazard Statements (H-Codes) H315 (Causes skin irritation), H319 (Causes serious eye irritation), H335 (May cause respiratory irritation)
Precautionary Statements (P-Codes) P261, P264, P271, P280, P302+P352, P305+P351+P338, P312, P332+P313, P337+P313, P362+P364, P403+P233, P405, P501
NFPA 704 Classification Health: 1, Flammability: 1, Reactivity: 0

SECTION 19: ENVIRONMENTAL IMPACT AND DISPOSAL

Parameter Information
Biodegradability Limited; slowly biodegradable
Aquatic Toxicity (EC50) >10 mg/L (Daphnia magna) - moderate toxicity
Aquatic Toxicity (LC50) >10 mg/L (fish) - moderate toxicity
Soil Mobility Low-Moderate (lipophilic)
Bioaccumulation Potential Moderate-High (log P ~5.5-6.0)
Persistence Moderate; may persist in the environment
Disposal Method Dispose of in accordance with local, regional, and national regulations
Incineration Controlled incineration facilities; energy recovery possible
Sewer Discharge Do not discharge into sewers or water resources
Environmental Precautions Prevent environmental spread during spills; collect with absorbent material
Ecotoxicity Note May pose potential risk to aquatic ecosystems; should be used with care

SECTION 20: FREQUENTLY ASKED QUESTIONS

Question Answer
Q1: What is Clotrimazole and what does it do? Clotrimazole is a broad-spectrum antifungal agent. It is effective against dermatophytes, yeasts (Candida), and molds. It is used to treat athlete's foot, jock itch, vaginal yeast infections, and pityriasis versicolor.
Q2: How does Clotrimazole work? It inhibits the 14α-demethylase enzyme in the fungal cell membrane, blocking ergosterol synthesis. This disrupts cell membrane integrity and leads to fungal cell death.
Q3: Is Clotrimazole safe? It has a good safety profile for topical use. Local side effects such as skin irritation, burning, or itching are rare. Systemic absorption is very low.
Q4: How long does Clotrimazole take to work? Symptom improvement usually begins within a few days. However, full treatment requires 2-4 weeks (tinea infections) or 1-2 weeks (vaginal candidiasis).
Q5: Can Clotrimazole be used during pregnancy? FDA Pregnancy Category B. No risk has been shown in animal studies. Use during pregnancy only if clearly necessary.
Q6: What are the side effects of Clotrimazole? Local skin irritation, redness, itching, burning sensation. Rarely allergic reactions. Nausea may occur with oral forms.
Q7: What is the difference between Clotrimazole and other antifungals? Clotrimazole belongs to the imidazole class (azoles). Terbinafine (allylamine) and nystatin (polyene) have different mechanisms of action. Clotrimazole is broad-spectrum.
Q8: Why is micronized Clotrimazole preferred? Micronized clotrimazole has a smaller particle size (D90 <10 μm). This provides better solubility and skin penetration in formulations.
Q9: What is the shelf life of Clotrimazole? 36 months under proper storage conditions (cool, dry, light-protected).
Q10: Is Clotrimazole soluble in water? No, it is very slightly soluble (~0.0001 mg/mL). It is lipophilic and soluble in organic solvents such as ethanol, propylene glycol, and DMSO.

SECTION 21: QUICK REFERENCE TABLE

Property Value
CAS Number 23593-75-1
Molecular Formula C₂₂H₁₇ClN₂
Molecular Weight 344.84 g/mol
Appearance White to off-white crystalline powder
Melting Point 147 – 149°C
Water Solubility Very slightly soluble (~0.0001 mg/mL)
Log P ~5.5-6.0 (lipophilic)
Primary Function Antifungal (azole)
Clinical Indications Tinea pedis, Tinea cruris, Candidiasis, Pityriasis versicolor
Typical Topical Concentration 1%
Pharmacopoeia Grade USP, EP, JP, BP
Shelf Life 36 months
Storage Cool (<25°C), dry, light-protected
GHS Classification Irritant (GHS07)
FDA Pregnancy Category B
Main Applications Topical antifungal, vaginal antifungal

SECTION 22: CRITICAL WARNINGS AND BEST PRACTICES

CRITICAL WARNINGS:

  1. Light sensitivity: Clotrimazole is light sensitive. Store in light-proof containers (amber glass, aluminum, HDPE).

  2. Skin/eye irritation: Avoid skin and eye contact. Wash with plenty of water if contact occurs.

  3. Pregnancy: FDA Category B. Use during pregnancy only if clearly necessary.

  4. Drug interactions: CYP3A4 inhibitor. Potential interactions with other drugs.

  5. Micronization: Micronized form provides better penetration but dust control is mandatory.

  6. High temperature: Do not keep above melting point (~147°C) for extended periods (degradation).

  7. Sterilization: Autoclaving not recommended. Use gamma radiation or aseptic filtration.

BEST PRACTICE RECOMMENDATIONS:

  1. Formulation: 1% clotrimazole is the standard concentration for topical formulations. Melt in the oil phase at 60-70°C (oil-water emulsion).

  2. Solubilization: Use propylene glycol, ethanol, or PEG 400 for dissolution. Do not add directly to the water phase.

  3. Penetration enhancement: Use propylene glycol (5-20%) or Transcutol® to improve skin penetration.

  4. pH control: Optimum pH 4.0-7.0. More stable in acidic medium.

  5. Preservative addition: Add methyl paraben/propyl paraben or phenoxyethanol to topical formulations.

  6. Stability studies: Degradation profile under light, moisture, and temperature; shelf life determination.

  7. Quality control: Assay (HPLC), melting point, water content, heavy metals, microbiological purity.

  8. Micronized use: Micronized clotrimazole (D90 <10 μm) is preferred for formulations requiring high solubility and penetration.

  9. GMP compliance: Manufacture in accordance with pharmacopoeia (USP/EP) standards.

  10. Patient education: Inform patients and physicians about treatment duration, application frequency, and possible side effects.

LEGAL DISCLAIMER:

The information provided in this document is based on our current knowledge and experience and is presented in good faith. However, as all conditions of use are beyond our control, it does not constitute a binding specification or guarantee. This Technical Data Sheet is for informational purposes only. Users are responsible for testing suitability for their own applications and for complying with all local, regional, and national regulations. For complete safety, storage, use, handling, waste, and regulatory compliance information, please refer to the official Safety Data Sheet (SDS/MSDS) provided by the manufacturer/supplier. Clotrimazole is a pharmaceutical active ingredient; its use must be under the supervision of a healthcare professional.

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