Chemistry:Benzoyl peroxide

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Short description: Chemical compound with uses in industry and acne treatment
Benzoyl peroxide
Benzoyl-peroxide.svg
Benzoyl-peroxide-from-xtal-3D-bs-17.png
Skeletal formula (top) Ball-and-stick model (bottom)
Clinical data
Trade namesBenzac, Panoxyl, others
Other namesbenzoperoxide, dibenzoyl peroxide (DBPO), BPO
AHFS/Drugs.comProfessional Drug Facts
MedlinePlusa601026
License data
Routes of
administration		Topical
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC14H10O4
Molar mass242.230 g·mol−1
3D model (JSmol)
Density1.334 g/cm3
Melting point103 to 105 °C (217 to 221 °F) decomposes
Solubility in waterpoor mg/mL (20 °C)

Benzoyl peroxide is a chemical compound (specifically, an organic peroxide) with structural formula (C
6H
5–C(=O)O–)
2, often abbreviated as (BzO)2. In terms of its structure, the molecule can be described as two benzoyl (C
6H
5–C(=O)–, Bz) groups connected by a peroxide (–O–O–). It is a white granular solid with a faint odour of benzaldehyde, poorly soluble in water but soluble in acetone, ethanol, and many other organic solvents. Benzoyl peroxide is an oxidizer, which is principally used as in the production of polymers.[4]

Benzoyl peroxide is mainly used in production of plastics[5] and for bleaching flour, hair, plastics and textiles.[6][7]

As a bleach, it has been used as a medication and a water disinfectant.[5][7]

As a medication, benzoyl peroxide is mostly used to treat acne, either alone or in combination with other treatments.[8] Some versions are sold mixed with antibiotics such as clindamycin.[9][10] It is on the World Health Organization's List of Essential Medicines.[11] It is available as an over-the-counter and generic medication.[12][9] It is also used in dentistry for teeth whitening. In 2021, it was the 284th most commonly prescribed medication in the United States, with more than 700,000 prescriptions.[13][14]

History

Benzoyl peroxide was first prepared and described by Liebig in 1858.[15]

Structure and reactivity

Structure of dibenzoyl peroxide from X-ray crystallography. The O=C-O-O dihedral angle is 90°. The O-O distance is 1.434 Å.[16]

The original 1858 synthesis by Liebig reacted benzoyl chloride with barium peroxide,[15] a reaction that probably follows this equation:

2 C6H5C(O)Cl + BaO2 → (C6H5CO)2O2 + BaCl2

Benzoyl peroxide is usually prepared by treating hydrogen peroxide with benzoyl chloride under alkaline conditions.

2 C6H5COCl + H2O2 + 2 NaOH → (C6H5CO)2O2 + 2 NaCl + 2 H2O

The oxygen–oxygen bond in peroxides is weak. Thus, benzoyl peroxide readily undergoes homolysis (symmetrical fission), forming free radicals:

(C6H5CO)2O2 → 2 C6H5CO•2

The symbol • indicates that the products are radicals; i.e., they contain at least one unpaired electron. Such species are highly reactive. The homolysis is usually induced by heating. The half-life of benzoyl peroxide is one hour at 92 °C. At 131 °C, the half-life is one minute.[17]

In 1901, J. H. Kastle and his graduate student A. S. Loevenhart observed that the compound made the tincture of guaiacum tincture turn blue, a sign of oxygen being released.[18] Around 1905, Loevenhart reported on the successful use of benzoyl peroxide to treat various skin conditions, including burns, chronic varicose leg tumors, and tinea sycosis. He also reported animal experiments that showed the relatively low toxicity of the compound.[19][6][20]

Treatment with benzoyl peroxide was proposed for wounds by Lyon and Reynolds in 1929, and for sycosis vulgaris and acne varioliformis by Peck and Chagrin in 1934.[20] However, preparations were often of questionable quality.[6] It was officially approved for the treatment of acne in the US in 1960.[6]

Polymerization

Benzoyl peroxide is mainly used as a radical initiator to induce chain-growth polymerization reactions,[4] such as for polyester and poly(methyl methacrylate) (PMMA) resins and dental cements and restoratives.[21] It is the most important among the various organic peroxides used for this purpose, a relatively safe alternative to the much more hazardous methyl ethyl ketone peroxide.[22][23] It is also used in rubber curing and as a finishing agent for some acetate yarns.[21]

Other uses

Tube of a water-based 5% benzoyl peroxide preparation for the treatment of acne

Benzoyl peroxide is effective for treating acne lesions. It does not induce antibiotic resistance.[24][25] It may be combined with salicylic acid, sulfur, erythromycin or clindamycin (antibiotics), or adapalene (a synthetic retinoid). Two common combination drugs include benzoyl peroxide/clindamycin and adapalene/benzoyl peroxide, adapalene being a chemically stable retinoid that can be combined with benzoyl peroxide[26] unlike tezarotene and tretinoin. Combination products such as benzoyl peroxide/clindamycin and benzoyl peroxide/salicylic acid appear to be slightly more effective than benzoyl peroxide alone for the treatment of acne lesions.[25] The combination tretinoin/benzoyl peroxide was approved for medical use in the United States in 2021.

Benzoyl peroxide for acne treatment is typically applied to the affected areas in gel, cream, or liquid, in concentrations of 2.5% increasing through 5.0%, and up to 10%.[24] No strong evidence supports the idea that higher concentrations of benzoyl peroxide are more effective than lower concentrations.[24]

Mechanism of action

Classically, benzoyl peroxide is thought to have a three-fold activity in treating acne. It is sebostatic, comedolytic, and inhibits growth of Cutibacterium acnes, the main bacterium associated with acne.[24][27] In general, acne vulgaris is a hormone-mediated inflammation of sebaceous glands and hair follicles. Hormone changes cause an increase in keratin and sebum production, leading to blocked drainage. C. acnes has many lytic enzymes that break down the proteins and lipids in the sebum, leading to an inflammatory response. The free-radical reaction of benzoyl peroxide can break down the keratin, therefore unblocking the drainage of sebum (comedolytic). It can cause nonspecific peroxidation of C. acnes, making it bactericidal,[6] and it was thought to decrease sebum production, but disagreement exists within the literature on this.[27][28]

Some evidence suggests that benzoyl peroxide has an anti-inflammatory effect as well. In micromolar concentrations it prevents neutrophils from releasing reactive oxygen species, part of the inflammatory response in acne.[28]

Side effects

Skin irritation due to benzoyl peroxide

Application of benzoyl peroxide to the skin may result in redness, burning, and irritation. This side effect is dose-dependent.[8][12]

Because of these possible side effects, it is recommended to start with a low concentration and build up as appropriate, as the skin gradually develops tolerance to the medication. Skin sensitivity typically resolves after a few weeks of continuous use.[28][29] Irritation can also be reduced by avoiding harsh facial cleansers and wearing sunscreen prior to sun exposure.[29]

One in 500 people experience hypersensitivity to benzoyl peroxide and are liable to experience burning, itching, crusting, and possibly swelling.[30][31] About one-third of people experience phototoxicity under exposure to ultraviolet (UVB) light.[32]

Dosage

In the U.S., the typical concentration for benzoyl peroxide is 2.5% to 10% for both prescription and over-the-counter drug preparations that are used in treatment for acne.

Other medical uses

Benzoyl peroxide is used in dentistry as a tooth whitening product.

Safety

Explosion hazard

Benzoyl peroxide is potentially explosive[33] like other organic peroxides, and can cause fires without external ignition. The hazard is acute for the pure material, so the compound is generally used as a solution or a paste. For example, cosmetics contain only a small percentage of benzoyl peroxide and pose no explosion risk.

Toxicity

Benzoyl peroxide breaks down in contact with skin, producing benzoic acid and oxygen, neither of which is very toxic.[34]

The carcinogenic potential of benzoyl peroxide has been investigated. A 1981 study published in the journal Science found that although benzoyl peroxide is not a carcinogen, it does promote cell growth when applied to an initiated tumor. The study concluded, "caution should be recommended in the use of this and other free radical-generating compounds".[35]

A 1999 IARC review of carcinogenicity studies found no convincing evidence linking benzoyl peroxide acne medication to skin cancers in humans. However, some animal studies found that the compound could act as a carcinogen and enhance the effect of known carcinogens.[21]

Skin irritation

In a 1977, study using a human maximization test, 76% of subjects acquired a contact sensitization to benzoyl peroxide. Formulations of 5% and 10% were used.[36]

The U.S. National Institute for Occupational Safety and Health has developed criteria for a recommended standard for occupational exposure to benzoyl peroxide.[37]

Cloth staining

A bleached fabric stain caused by contact with benzoyl peroxide

Contact with fabrics or hair, such as from still-moist acne medication, can cause permanent color dampening almost immediately. Even secondary contact can cause bleaching, for example, contact with a towel that has been used to wash off benzoyl peroxide-containing hygiene products.[38]

References

  1. ↑ "Epsolay- benzoyl peroxide cream". 25 April 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=507e2cd7-6bcf-4606-bc62-694d64537701. 
  2. ↑ "Epsolay- benzoyl peroxide cream". 5 May 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2bb9bab5-770e-4e91-8d51-b9750454daf8. 
  3. ↑ IUPAC Chemical Nomenclature and Structure Representation Division (2013). "P-65.7.5". in Favre, Henri A.; Powell, Warren H.. Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013. IUPAC–RSC. ISBN 978-0-85404-182-4. https://pubs.rsc.org/en/Content/eBook/978-0-85404-182-4. 
  4. ↑ 4.0 4.1 "Ullmann's Encyclopedia of Industrial Chemistry". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a19_199. 
  5. ↑ 5.0 5.1 (in en) Encyclopaedia of Occupational Health and Safety: Guides, indexes, directory. International Labour Organization. 1998. p. 104. ISBN 9789221098171. https://books.google.com/books?id=e4_S46UcI2AC&pg=PT404. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 (in en) ACNE and ROSACEA (3 ed.). Springer Science & Business Media. 2012. p. 613. ISBN 9783642597152. https://books.google.com/books?id=0cD-CAAAQBAJ&pg=PA613. 
  7. ↑ 7.0 7.1 (in en) Alcamo's Fundamentals of Microbiology: Body Systems. Jones & Bartlett Publishers. 2012. p. 214. ISBN 9781449605957. https://books.google.com/books?id=cRaMAQAAQBAJ&pg=PA214. 
  8. ↑ 8.0 8.1 WHO Model Formulary 2008. World Health Organization. 2009. pp. 307–308. ISBN 9789241547659. 
  9. ↑ 9.0 9.1 British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 820. ISBN 9780857111562. 
  10. ↑ (in en) Dermatology (2 ed.). Springer Science & Business Media. 2012. p. 1039. ISBN 9783642979316. https://books.google.com/books?id=kK_rCAAAQBAJ&pg=PA1039. 
  11. ↑ The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. 2023. WHO/MHP/HPS/EML/2023.02. 
  12. ↑ 12.0 12.1 Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. 2015. p. 173. ISBN 9781284057560. 
  13. ↑ "The Top 300 of 2021". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  14. ↑ "Benzoyl Peroxide - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/BenzoylPeroxide. 
  15. ↑ 15.0 15.1 "Ueber die Bildung der Hyperoxyde organischer Säureradicale". Justus Liebigs Ann. Chem. 108: 79–83. 1858. doi:10.1002/jlac.18581080117. https://zenodo.org/record/1427113. Retrieved 2 July 2019. 
  16. ↑ "Radical pair in crystalline dibenzoyl peroxide evidence for triplet ground states". Tetrahedron 38 (6): 765–775. 1982. doi:10.1016/0040-4020(82)80157-9. 
  17. ↑ Li III H (1998). "Chapter 2" (PDF). Synthesis, Characterization and Properties of Vinyl Ester Matrix Resins (Ph.D.). University of Vermont. hdl:10919/30521. Archived from the original on 20 September 2006. Retrieved 17 February 2007.
  18. ↑ "On the Nature of Certain Oxidizing Ferments". American Chemical Journal 2: 539–566. 1901. 
  19. ↑ "Benzoylsuperoxyds, ein neues therapeutisches Agens" (in German). Therap Monatscheftel 12: 426–428. 1905. 
  20. ↑ 20.0 20.1 "Benzoyl peroxide: a history of early research and researchers". International Journal of Dermatology 41 (3): 185–8. March 2002. doi:10.1046/j.1365-4362.2002.01371.x. PMID 12010349. 
  21. ↑ 21.0 21.1 21.2 International Agency for Research on Cancer (1999): "Benzoyl peroxide". in Re-evaluation of Some Organic Chemicals, Hydrazine and Hydrogen Peroxide . Monographs on the Evaluation of Carcinogenic Risks to Humans, number 71, pages 345–358. ISBN 92-832-1271-1
  22. ↑ "Initiation By Diacyl Peroxides". https://polymerdatabase.com/polymer%20chemistry/Diaroyl%20Peroxides.html. 
  23. ↑ "Error - Evonik Industries AG". http://www.degaroute.com/sites/dc/Downloadcenter/Evonik/Product/DEGAROUTE/en/Degaroute%20Brosch%C3%BCre.pdf. 
  24. ↑ 24.0 24.1 24.2 24.3 "Newer approaches to the treatment of acne vulgaris". American Journal of Clinical Dermatology 13 (6): 357–64. December 2012. doi:10.2165/11632500-000000000-00000. PMID 22920095. 
  25. ↑ 25.0 25.1 "Meta-analysis comparing efficacy of benzoyl peroxide, clindamycin, benzoyl peroxide with salicylic acid, and combination benzoyl peroxide/clindamycin in acne". Journal of the American Academy of Dermatology 63 (1): 52–62. July 2010. doi:10.1016/j.jaad.2009.07.052. PMID 20488582. 
  26. ↑ "Adapalene". StatPearls. Treasure Island (FL): StatPearls Publishing. 2022. http://www.ncbi.nlm.nih.gov/books/NBK482509/. Retrieved 24 July 2022. 
  27. ↑ 27.0 27.1 "Benzoyl peroxide". Acta Dermato-Venereologica. Supplementum 89: 57–63. 1 January 1980. doi:10.2340/00015555895763. PMID 6162349. 
  28. ↑ 28.0 28.1 28.2 "[Acne therapy with topical benzoyl peroxide, antibiotics and azelaic acid]" (in German). Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology 4 (4): 293–300. April 2006. doi:10.1111/j.1610-0387.2006.05931.x. PMID 16638058. 
  29. ↑ 29.0 29.1 Applied Therapeutics: The Clinical Use of Drugs (10th ed.). Baltimore: Wolters Kluwer Health/Lippincott Williams & Wilkins. 2013. p. 949. ISBN 978-1609137137. 
  30. ↑ "Benzoyl peroxide: lack of sensitization". Acta Dermato-Venereologica 62 (5): 458–9. 1982. doi:10.2340/0001555562458459. PMID 6183909. 
  31. ↑ "Benzoyl peroxide". Mayo Clinic. 1 January 2016. http://www.mayoclinic.org/drugs-supplements/benzoyl-peroxide-topical-route/side-effects/drg-20062425. 
  32. ↑ "[Phototoxic activity of 5% benzoyl peroxide in man. Use of a new methodology]". Dermatologica 167 (1): 19–23. 1 January 1983. doi:10.1159/000249739. PMID 6628794. 
  33. ↑ "Chemical Safety Data: Benzoyl peroxide". Oxford University. 17 March 2005. http://cartwright.chem.ox.ac.uk/hsci/chemicals/benzoyl_peroxide.html. 
  34. ↑ Benzoyl peroxide, SIDS Initial Assessment Report, Geneva: United Nations Environment Programme, April 2004, http://www.inchem.org/documents/sids/sids/BENZOYLPER.pdf 
  35. ↑ "Skin tumor-promoting activity of benzoyl peroxide, a widely used free radical-generating compound". Science 213 (4511): 1023–5. August 1981. doi:10.1126/science.6791284. PMID 6791284. Bibcode: 1981Sci...213.1023S. 
  36. ↑ "Contact sensitization to benzoyl peroxide". Contact Dermatitis 3 (5): 273–5. October 1977. doi:10.1111/j.1600-0536.1977.tb03674.x. PMID 145346. 
  37. ↑ Criteria for a Recommended Standard: Occupational Exposure to Benzoyl Peroxide (77-166). 6 June 2014. doi:10.26616/NIOSHPUB76128. https://www.cdc.gov/niosh/docs/77-166/default.html. Retrieved 15 July 2016. 
  38. ↑ "The short-term treatment of acne vulgaris with benzoyl peroxide: effects on the surface and follicular cutaneous microflora". The British Journal of Dermatology 132 (2): 204–8. February 1995. doi:10.1111/j.1365-2133.1995.tb05014.x. PMID 7888356. 

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