3/7/2020 NF Monographs: Benzalkonium Chloride

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Benzalkonium Chloride

Ammonium, alkyldimethyl(phenylmethyl)-, chloride.

Alkylbenzyldimethylammonium chloride [8001-54-5].

» Benzalkonium Chloride is a mixture of alkylbenzyldimethylammonium chlorides of the general formula:

[C6H5CH2N(CH3)2R]Cl

in which R represents a mixture of alkyls, including all or some of the group beginning with n-C8H17 and extending through higher
homologs, with n-C12H25, n-C14H29, and n-C16H33 comprising the major portion. On the anhydrous basis, the content of the n-
C12H25 homolog is not less than 40.0 percent, and the content of the n-C14H29 homolog is not less than 20.0 percent, of the total
alkylbenzyldimethylammonium chloride content. The amounts of the n-C12H25 and n-C14H29 homolog components comprise
together not less than 70.0 percent of the total alkylbenzyldimethylammonium chloride content. The total
alkylbenzyldimethylammonium chloride content, calculated on the anhydrous basis, allowance being made for the amount of
residue on ignition, is not less than 97.0 percent and not more than 103.0 percent of [C6H5CH2N(CH3)2R]Cl.

Packaging and storage— Preserve in tight containers.

USP Reference standards 11 — USP Benzalkonium Chloride RS.

Identification—

A: To a solution (1 in 100) add 2 N nitric acid or mercuric chloride TS: a white precipitate is formed, and it is soluble in alcohol.

B: Dissolve about 200 mg in 1 mL of sulfuric acid, add 100 mg of sodium nitrate, and heat on a steam bath for 5 minutes. Cool, dilute with water to 10 mL,
add 500 mg of zinc dust, and warm for 5 minutes on a steam bath. To 2 mL of the clear supernatant add 1 mL of sodium nitrite solution (1 in 20), cool in ice
water, then add 3 mL of a solution of 500 mg of 2-naphthol in 10 mL of 6 N ammonium hydroxide: an orange-red color is produced.

C: A solution of it in a mixture of equal volumes of water and alcohol responds to the tests for Chloride 191 .

Water, Method I 921 : not more than 15.0%.

Residue on ignition 281 : not more than 2.0%.

Water-insoluble matter— A solution (1 in 10) is free from turbidity and insoluble matter.

Limit of foreign amines— To 5 mL of a solution (1 in 50) add 3 mL of 1 N sodium hydroxide: no precipitate is formed. Heat to boiling: the odor of amines is
not perceptible.

Ratio of alkyl components—

Mobile phase— Adjust a 0.1 M solution of sodium acetate with glacial acetic acid to a pH of 5.0. Mix 55 parts of this solution with 45 parts of acetonitrile, filter,
and degas. The acetonitrile concentration may be varied from 40 parts to 60 parts to meet system suitability requirements.

Standard solution— Dilute USP Benzalkonium Chloride RS with water to obtain a solution having a known concentration of about 4 mg per mL.

Test solution— Dissolve about 1 g of Benzalkonium Chloride, accurately weighed, in water in a 50-mL volumetric flask, dilute with water to volume, and mix.
Pipet 5.0 mL of this solution into a 25-mL volumetric flask, dilute with water to volume, and mix.

Chromatographic system (see Chromatography 621 )— The liquid chromatograph is equipped with a 254-nm detector and a 3.9-mm × 30-cm column that
contains packing L10. The flow rate is about 2 mL per minute. Chromatograph the Standard solution, and record the peak areas as directed for Procedure:
the resolution, R, between the C12 and C14 peaks is not less than 1.5; the column efficiency, determined from the C12 peak, is not less than 1000 theoretical
plates; and the relative standard deviation for replicate injections is not more than 2.0% determined from the C12 peak.

Procedure— Inject about 20 µL of the Test solution into the chromatograph, record the chromatogram, and measure the peak areas. Identify the homolog
peaks by comparison of the retention times with those from the Standard solution, similarly chromatographed. Calculate the percentage of each quaternary
ammonium homolog taken by the formula:
100(A/B),
in which A is the product of the area obtained from the homolog multiplied by its molecular weight; and B is the sum of all of these products. The molecular
weights of the C10, C12, C14, and C16 homologs are 312, 340, 368, and 396, respectively.

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3/7/2020 NF Monographs: Benzalkonium Chloride

Residual solvents 467 : meets the requirements.

(Official January 1, 2007)

Assay for total alkylbenzyldimethylammonium chlorides— Weigh accurately a quantity of Benzalkonium Chloride equivalent to about 500 mg of
anhydrous benzalkonium chloride, and transfer, with the aid of 35 mL of water, to a glass-stoppered, 250-mL conical separator containing 25 mL of
chloroform. Add 10.0 mL of freshly prepared potassium iodide solution (1 in 20), insert the stopper in the separator, shake, allow the layers to separate, and
discard the chloroform layer. Wash the aqueous layer with three 10-mL portions of chloroform, and discard the washings. Transfer the aqueous layer to a
glass-stoppered, 250-mL conical flask, and rinse the separator with three 5-mL portions of water, adding the washings to the flask. Add 40 mL of cold
hydrochloric acid to the flask, mix, and titrate with 0.05 M potassium iodate VS until the solution becomes light brown in color. Add 5 mL of chloroform, insert
the stopper into the flask, and shake vigorously. Continue the titration, dropwise, with shaking after each addition, until the chloroform layer becomes
colorless and the aqueous layer is clear yellow. Perform a blank determination, using 20 mL of water as the sample. The difference between the two titrations
represents the amount of potassium iodate equivalent to the weight of benzalkonium chloride in the sample. Each mL of 0.05 M potassium iodate is
equivalent to x/10 mg of benzalkonium chloride, where x represents the average molecular weight of the sample, derived by summing, for all homologs, the
products
W(A/B),
where W is the molecular weight of a given homolog, A is the area of the peak produced by that homolog in the chromatogram from the Ratio of alkyl
components test, and B is the total peak area for all homologs in that chromatogram.

Auxiliary Information— Staff Liaison : Hong Wang, Ph.D. , Senior Scientific Associate
Expert Committee : (EM205) Excipient Monographs 2
USP29–NF24 Page 3281
Pharmacopeial Forum : Volume No. 27(4) Page 2789
Phone Number : 1-301-816-8351

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