Cetrimide
`
`C
`
`Nonproprietary Names
`1
`BP: Cetrimide
`PhEur: Cetrimide
`
`Synonyms
`2
`Bromat; Cetab; Cetavlon; Cetraol; cetrimidum; Lissolamine V;
`Micol; Morpan CHSA; Morphans; Quammonium; Sucticide.
`
`Chemical Name and CAS Registry Number
`3
`Cetrimide [8044-71-1]
`Note that the above name, CAS Registry Number, and synonyms
`refer to the PhEur 6.0 material which, although it consists
`predominantly of
`trimethyltetradecylammonium bromide, may
`also contain smaller amounts of other bromides; see Section 4.
`There is
`some confusion in the literature regarding the
`synonyms, CAS Registry Number, and molecular weight applied
`to cetrimide. Chemical Abstracts has assigned [8044-71-1] to
`cetrimide and describes that material as a mixture of alkyltrimethy-
`lammonium bromides of different alkyl chain lengths. Different
`CAS Registry Numbers have been assigned to the individual pure
`components. While these numbers should not be interchanged, it is
`common to find the molecular weight and CAS Registry Number of
`trimethyltetradecylammonium bromide
`[1119-97-7] used for
`cetrimide, as this is the principal component, defined in both the
`BP 2009 and PhEur 6.0. It should be noted however, that the
`original BP 1953 described the principal component of cetrimide as
`hexadecyltrimethylammonium bromide.
`The CAS Registry Number for hexadecyltrimethylammonium
`hydroxide [505-86-2] has also been widely applied to cetrimide.
`Therefore, careful inspection of experimental details and suppliers’
`specifications in the literature is encouraged to determine the
`specific nature of the ‘cetrimide’ material used in individual studies.
`See Section 17 for further information.
`
`Empirical Formula and Molecular Weight
`4
`Cetrimide consists mainly of trimethyltetradecylammonium bro-
`mide (C17H38BrN), and may contain smaller amounts of dodecyl-
`trimethylammonium
`bromide
`(C15H34BrN)
`and
`hexadecyltrimethylammonium bromide (C19H42BrN).
`C17H38BrN
`336.40
`See also Section 17.
`
`5
`
`Structural Formula
`
`where
`n = 11 for dodecyltrimethylammonium bromide
`n = 13 for trimethyltetradecylammonium bromide
`n = 15 for hexadecyltrimethylammonium bromide
`
`Functional Category
`6
`Antimicrobial preservative; antiseptic; cationic surfactant; disin-
`fectant.
`
`152
`
`7
`
`Applications in Pharmaceutical Formulation or
`Technology
`Cetrimide is a quaternary ammonium compound that is used in
`cosmetics and pharmaceutical formulations as an antimicrobial
`preservative; see Section 10. It may also be used as a cationic
`surfactant.
`In eye-drops,
`it
`is used as a preservative at a
`concentration of 0.005% w/v.
`Therapeutically, cetrimide is used in relatively high concentra-
`tions, generally as 0.1–1.0% w/v aqueous solutions, cream or spray
`as a topical antiseptic for skin, burns, and wounds.(1) Solutions
`containing up to 10% w/v cetrimide are used as shampoos to
`remove the scales in seborrheic dermatitis.
`Cetrimide is also used as a cleanser and disinfectant for hard
`contact lenses, although it should not be used on soft lenses; as an
`ingredient of cetrimide emulsifying wax, and in o/w creams (e.g.
`cetrimide cream).
`
`Description
`8
`Cetrimide is a white to creamy white, free-flowing powder, with a
`faint but characteristic odor and a bitter, soapy taste.
`
`Pharmacopeial Specifications
`9
`See Table I.
`
`Table I: Pharmacopeial specifications for cetrimide.
`
`Test
`
`Identification
`Characters
`Acidity or alkalinity
`Appearance of solution
`Amines and amine salts
`Loss on drying
`Sulfated ash
`Assay (as C17H38BrN, dried basis)
`
`PhEur 6.0
`þ
`þ
`þ
`þ
`þ
`42.0%
`40.5%
`96.0–101.0%
`
`10 Typical Properties
`Acidity/alkalinity pH = 5.0–7.5 (1% w/v aqueous solution)
`Antimicrobial activity Cetrimide has good bactericidal activity
`against Gram-positive species but is less active against Gram-
`negative species. Pseudomonas species, particularly Pseudomo-
`nas aeruginosa, may exhibit resistance. Cetrimide is most
`effective at neutral or slightly alkaline pH values, with activity
`appreciably reduced in acidic media and in the presence of
`organic matter. The activity of cetrimide is enhanced in the
`presence of alcohols. The activity of cetrimide against resistant
`strains of Pseudomonas aeruginosa, Aspergillus niger, and
`Candida albicans is significantly increased by the addition of
`edetic acid.(2) Cetrimide has variable antifungal activity,(3,4) is
`effective against some viruses, and is inactive against bacterial
`spores. Typical minimum inhibitory concentrations (MICs) are
`shown in Table II.
`Critical micelle concentration 3.08 mmol/kg(10) (in water)
`Melting point 232–2478C
`Moisture content At 40–50% relative humidity and 208C,
`cetrimide absorbs sufficient moisture to cause caking and retard
`flow properties.
`NIR spectra see Figure 1.
`Partition coefficients
`Liquid paraffin : water = <1;
`Vegetable oil : water = <1.
`
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`

`

` 0.5
`
`2258
`
`2298
`2324
`2363
`
`1750
`
`2232
`
`Adverse effects that have been reported following irrigation of
`hydatid cysts with cetrimide solution include chemical peritoni-
`tis,(14) methemoglobinemia with cyanosis,(15) and metabolic dis-
`orders.(16)
`
`Cetrimide
`
`153
`
`log(1/R)
`
`2351
`
`1215 1392
`
`1672
`
`1765
`
`3.5
`
`0.0
`
`000 × [2nd deriv. log(1/R)]
`
`1730
`
`2246
`2271
`
`2312
`
`−5.01
`−0.2
`1100 1300 1500 1700 1900 2100 2300 2500
`Wavelength/nm
`
`Figure 1: Near-infrared spectrum of cetrimide measured by reflectance.
`
`Table II: Minimum inhibitory concentrations (MIC) of cetrimide.
`
`Microorganism
`
`Escherichia coli
`Pseudomonas aeruginosa
`Staphylococcus aureus
`Camphylobacter jejuni
`Staphylococcus aureus (NCTC-8325-4)
`Staphylococcus aureus (SH1000)
`Pseudomonas aeruginosa (PAO1 (ATCC 15692))
`Streptococcus pneumoniae R919
`
`MIC (mg/mL)
`
`30
`300
`10
`8(5)
`0.25(6)
`0.63(7)
`36(8)
`1.0(9)
`
`Solubility Freely soluble in chloroform, ethanol
`(95%), and
`water; practically insoluble in ether. A 2% w/v aqueous solution
`foams strongly on shaking.
`
`11 Stability and Storage Conditions
`Cetrimide is chemically stable in the dry state, and also in aqueous
`solution at ambient
`temperatures. Aqueous solutions may be
`sterilized by autoclaving. Water containing metal ions and organic
`matter may reduce the antimicrobial activity of cetrimide.
`The bulk material should be stored in a well-closed container in a
`cool, dry place.
`
`12 Incompatibilities
`Incompatible with soaps, anionic surfactants, high concentrations
`of nonionic surfactants, bentonite, iodine, phenylmercuric nitrate,
`alkali hydroxides, and acid dyes. Aqueous solutions react with
`metals.
`
`13 Method of Manufacture
`Cetrimide is prepared by the condensation of suitable alkyl
`bromides and trimethylamine.
`
`14 Safety
`Most adverse effects reported relate to the therapeutic use of
`cetrimide.
`If
`ingested orally, cetrimide and other quaternary
`ammonium compounds can cause nausea, vomiting, muscle
`paralysis, CNS depression, and hypotension; concentrated solutions
`may cause esophageal damage and necrosis. The fatal oral human
`dose is estimated to be 1.0–3.0 g.(11)
`At the concentrations used topically, solutions do not generally
`cause irritation, although concentrated solutions have occasionally
`been reported to cause burns. Cases of hypersensitivity have been
`reported following repeated application.(12,13)
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances and
`quantity of material handled. Cetrimide powder and concentrated
`cetrimide solutions are irritant; avoid inhalation, ingestion, and skin
`and eye contact. Eye protection, gloves, and a respirator are
`recommended.(17)
`
`C
`
`16 Regulatory Status
`Included in nonparenteral medicines licensed in the UK. Included in
`the Canadian List of Acceptable Non-medicinal Ingredients.
`Cetrimide is on the list of ‘Existing Active Substances’ on the
`market in the Europe, and is registered according to REACH
`regulation. Cetrimide is not present in any approved product in the
`USA.
`
`17 Related Substances
`Benzalkonium chloride; benzethonium chloride; dodecyltrimethy-
`lammonium bromide; hexadecyltrimethylammonium bromide;
`trimethyltetradecylammonium bromide.
`Dodecyltrimethylammonium bromide
`Empirical formula C15H34BrN
`Molecular weight 308.35
`CAS number
`[1119-94-4]
`Synonyms DTAB; N-lauryl-N,N,N-trimethylammonium bro-
`mide; N,N,N-trimethyldodecylammonium bromide.
`Safety
`LD50 (mouse, IV): 5.2 mg/kg(18)
`LD50 (rat, IV): 6.8 mg/kg
`Hexadecyltrimethylammonium bromide
`Empirical formula C19H42BrN
`Molecular weight 364.48
`CAS number
`[57-09-0]
`Synonyms Cetrimide BP 1953; cetrimonium bromide; cetyltri-
`methylammonium bromide; CTAB; N,N,N-trimethylhexadecy-
`lammonium bromide.
`Appearance A white to creamy-white, voluminous, free-flowing
`powder, with a characteristic faint odor and bitter, soapy taste.
`Melting point 237–2438C
`Safety
`LD50 (guinea pig, SC): 100 mg/kg(19)
`LD50 (mouse, IP): 106 mg/kg
`LD50 (mouse, IV): 32 mg/kg
`LD50 (rabbit, IP): 125 mg/kg
`LD50 (rabbit, SC): 125 mg/kg
`LD50 (rat, IV): 44 mg/kg
`LD50 (rat, oral): 410 mg/kg
`Solubility Freely soluble in ethanol (95%); soluble 1 in 10 parts of
`water.
`Comments The original cetrimide BP 1953 consisted largely of
`hexadecyltrimethylammonium bromide, with smaller amounts
`of analogous alkyltrimethylammonium bromides. It contained a
`considerable proportion of
`inorganic salts, chiefly sodium
`bromide, and was less soluble than the present product.
`Trimethyltetradecylammonium bromide
`Empirical formula C17H38BrN
`Molecular weight 336.40
`CAS number
`[1119-97-7]
`
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`

`C
`
`154
`
`Cetrimide
`
`Synonyms Myristyltrimethylammonium bromide;
`tetradecyltri-
`methylammonium bromide; N,N,N-trimethyl-1-tetradecanami-
`nium bromide.
`Safety
`LD50 (mouse, IV): 12 mg/kg(20)
`LD50 (rat, IV): 15 mg/kg
`
`18 Comments
`As a precaution against contamination with Pseudomonas species
`resistant to cetrimide, stock solutions may be further protected by
`adding at least 7% v/v ethanol or 4% v/v propan-2-ol.
`The EINECS number for cetrimide is 214-291-9. The PubChem
`Compound ID (CID) for cetrimide includes 68166 (trimethylhex-
`adecylammonium hydroxide) and 14250 (trimethyltetradecylam-
`monium bromide).
`
`19 Specific References
`1 Langford JH et al. Topical antimicrobial prophylaxis in minor wounds.
`Ann Pharmacother 1997; 31(5): 559–563.
`2 Esimone CO et al. The effect of ethylenediamine tetraacetic acid on the
`antimicrobial properties of benzoic acid and cetrimide. J Pharm Res
`Devel 1999; 4(1): 1–8.
`3 Mahmoud YA-G. In vitro and in vivo antifungal activity of cetrimide
`(cetyltrimethyl ammonium bromide) against fungal keratitis caused by
`Fusarium solani. Mycoses 2007; 50(1): 64–70.
`4 Gupta AK et al. Fungicidal activities of commonly used disinfectants
`and antifungal pharmaceutical spray preparations against clinical
`strains of Aspergillus and Candida species. Med Mycol 2002; 40:
`201–208.
`5 Pumbwe L et al. Evidence for multiple-antibiotic resistance in
`Campylobacter jejuni not mediated by CmeB or CmeF. Antimicrob
`Agents Chemother 2005; 49(4): 1289–1293.
`6 Kaatz GW et al. Multidrug resistance in Staphylococcus aureus due to
`overexpression of a novel multidrug and toxin extrusion (MATE)
`transport protein. Antimicrob Agents Chemomother 2005; 49(5):
`1857–1864.
`7 Kaatz GW, Seo SM. Effect of substrate exposure and other growth
`condition manipulations on norA expression. J Antimicrob Chemother
`2004; 54(2): 364–369.
`8 Loughlin MF et al. Pseudomonas aeruginosa cells adapted to
`benzalkonium chloride show resistance to other membrane-active
`agents but not to clinically relevant antibiotics. J Antimicrob Che-
`mother 2002; 49(4): 631–639.
`9 Coyle EA et al. Activities of newer fluoroquinolones against cipro-
`floxacin-resistant Streptococcus pneumoniae. Antimicrob Agents Che-
`mother 2001; 45(6): 1654–1659.
`10 Attwood D, Patel HK. Composition of mixed micellar systems of
`cetrimide and chlorhexidine digluconate. Int J Pharm 1989; 49(2): 129–
`134.
`11 Arena JM. Poisonings and other health hazards associated with the use
`of detergents. JAMA 1964; 190: 56–58.
`
`12 Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation
`Agents: A Handbook of Excipients. New York: Marcel Dekker, 1989.
`13 Tomar J et al. Contact allergies to cosmetics: testing with 52 cosmetic
`ingredients and personal products. J Dermatol 2005; 32(12): 951–955.
`14 Gilchrist DS. Chemical peritonitis after cetrimide washout in hydatid-
`cyst surgery [letter]. Lancet 1979; 2: 1374.
`15 Baraka A et al. Cetrimide-induced methaemoglobinaemia after surgical
`excision of hydatid cyst [letter]. Lancet 1980; 2: 88–89.
`16 Momblano P et al. Metabolic acidosis induced by cetrimonium bromide
`[letter]. Lancet 1984; 2: 1045.
`17 Jacobs JY. Work hazards from drug handling. Pharm J 1984; 233: 195–
`196.
`18 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th
`edn. New York: Wiley, 2004; 1550.
`19 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th
`edn. New York: Wiley, 2004; 1925.
`20 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th
`edn. New York: Wiley, 2004; 3385–3386.
`
`20 General References
`August PJ. Cutaneous necrosis due to cetrimide application. Br Med J 1975;
`1: 70.
`Eccleston GM. Phase transitions in ternary systems and oil-in-water
`emulsions containing cetrimide and fatty alcohols. Int J Pharm 1985;
`27: 311–323.
`European Commission, REACH Regulation (EC) 1907/2006, 2006. http://
`ec.europa.eu/environment/chemicals/reach/reach_intro.html
`(accessed
`16 January 2009).
`Evans BK et al. The disinfection of silicone-foam dressings. J Clin Hosp
`Pharm 1985; 10: 289–295.
`Gilbert PM, Moore LE. Cationic antisepctics: diversity of action under a
`common epithet. J Appl Microbial 2005; 99(4): 703–715.
`Louden JD, Rowe RC. A quantitative examination of the structure of
`emulsions prepared using cetostearyl alcohol and cetrimide using Fourier
`transform infrared microscopy. Int J Pharm 1990; 63: 219–225.
`Rowe RC, Patel HK. The effect of temperature on the conductivity of gels
`and emulsions prepared from cetrimide and cetostearyl alcohol. J Pharm
`Pharmacol 1985; 37: 564–567.
`Rowe RC et al. The stability of oil-in-water emulsions containing cetrimide
`and cetostearyl alcohol. Int J Pharm 1986; 31: 281–282.
`Smith ARW et al. The differing effects of cetyltrimethylammonium bromide
`and cetrimide BP upon growing cultures of Escherichia coli NCIB 8277. J
`Appl Bacteriol 1975; 38: 143–149.
`
`21 Author
`MA Mitchell.
`
`22 Date of Revision
`16 January 2009.
`
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