Naloxone Hydrochloride
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C19H21NO4·HCl 363.84
Morphinan-6-one, 4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)-, hydrochloride, (5)-.
17-Allyl-4,5-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride [357-08-4].

Dihydrate 399.87 [51481-60-8].
» Naloxone Hydrochloride is anhydrous or contains two molecules of water of hydration. It contains not less than 98.0 percent and not more than 100.5 percent of C19H21NO4·HCl, calculated on the dried basis.
Packaging and storage— Preserve in tight, light-resistant containers. Store at 25, excursions permitted between 15 and 30.
Identification, Infrared Absorption 197K
Test specimen— Dissolve about 150 mg in 25 mL of water in a small separator, add a few drops of 6 N ammonium hydroxide slowly until no more white precipitate is formed. Extract with three 5-mL portions of chloroform, pass the extracts through a dry filter, collecting the filtrate in a small flask. Evaporate the filtrate on a steam bath to dryness, and dry the residue at 105 for one hour.
Specific rotation 781S: between 170 and 181.
Test solution: 25 mg per mL, in water.
Loss on drying 731 Dry it at 105 to constant weight: the anhydrous form loses not more than 0.5% of its weight, and the hydrous form loses not more than 11.0% of its weight.
Noroxymorphone hydrochloride [(–)-4,5-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride] and other impurities— Transfer about 40 mg, accurately weighed, to a 5-mL volumetric flask, dissolve completely in 2.0 mL of water, add methanol to volume, and mix, to obtain the test solution. Prepare a solution of USP Naloxone RS in chloroform containing about 7.6 mg per mL. Prepare a solution of USP Noroxymorphone Hydrochloride RS in dilute methanol (3 in 5) containing 0.084 mg per mL. Apply 5 µL each of the test solution and the two Standard solutions to a thin-layer chromatographic plate (see Chromatography 621) coated with a 0.25-mm layer of chromatographic silica gel that previously has been activated by heating for 15 minutes at 105. Immediately place the plate in a suitable chromatographic chamber containing a 1 in 20 solution of methanol in ammoniacal butanol previously prepared by shaking 100 mL of butyl alcohol with 60 mL of ammonium hydroxide solution (1 in 100) and discarding the lower layer. Develop the chromatogram, protected from light, until the solvent front has moved about 10 cm from the point of application. Remove the plate, dry thoroughly, and spray with ferric chloride-potassium ferricyanide reagent prepared, immediately prior to use, by dissolving 100 mg of potassium ferricyanide in 20 mL of ferric chloride solution (1 in 10). Other than the principal spot corresponding in RF value to that of USP Naloxone RS and the spot at the origin (ammonium chloride), no other spot is more intense than the spot corresponding to that of USP Noroxymorphone Hydrochloride RS (1.0%).
Chloride content— Dissolve about 300 mg, accurately weighed, in 50 mL of methanol contained in a 125-mL conical flask, add 5 mL of glacial acetic acid and 2 drops of eosin Y TS, and titrate with 0.1 N silver nitrate VS to a pink endpoint. Each mL of 0.1 N silver nitrate is equivalent to 3.545 mg of chloride. Not less than 9.54% and not more than 9.94%, calculated on the dried basis, is found.
Assay— Dissolve about 300 mg of Naloxone Hydrochloride, previously dried and accurately weighed, in a mixture of 40 mL of glacial acetic acid and 10 mL of acetic anhydride; add 10 mL of mercuric acetate TS and 1 drop of methyl violet TS; and titrate with 0.1 N perchloric acid VS. Perform a blank determination, and make any necessary correction. Each mL of 0.1 N perchloric acid is equivalent to 36.38 mg of C19H21NO4·HCl.
Auxiliary Information— Please check for your question in the FAQs before contacting USP.
Topic/Question Contact Expert Committee
Monograph Clydewyn M. Anthony, Ph.D.
(MDCCA05) Monograph Development-Cough Cold and Analgesics
Reference Standards Lili Wang, Technical Services Scientist
USP32–NF27 Page 3027
Pharmacopeial Forum: Volume No. 29(6) Page 1936