DIAZEPAM
`
`This substance was considered by previous working groups in October 1976 (lARC,
`1977) and March 1987 (IARC, 1987). Since that time, new data have become available,
`and these have been incorporated into the monograph and taken into consideration in the
`evaluation.
`
`1. Exposure Data
`
`1.1 Chemical and physical data
`
`1. 1 . 1 Nomel1clature
`
`Chem. Abstr. Serv. Reg. No.: 439-14-5
`Deleted CAS Reg. No.: 11100-37-1; 53320-84-6
`Chem. Abstr. Name: 7-Chloro- 1 ,3-dihydro- 1 -methyl-5-phenyl-2H- 1 ,4-benzodiazepin-
`2-one
`IUPAC Systematic Name: 7-Chloro- 1 ,3-dihydro- 1 -methyl-S-phenyl-2H-l ,4-benzo-
`diazepin-2-one
`SYl1ol1ym: Methyldiazepinone
`
`1.1.2 Structural al1d molecular fonnulae and relative molecular mass
`
`CH,
`
`~)o-N
`
`CI
`
`Ci6H1,ClN20
`
`Relative molecular mass: 284.75
`
`1.1.3
`
`(a)
`(b)
`(c)
`
`Chemical al1d physical properties of the pure substal1ce
`DescriptiOI1: Off-white to yellow, odourless, crystalline powder (Gennaro, 1995)
`Meltil1g-poil1t: i 25- 126°C (Budavari, 1995)
`Spectroscopy data: Infrared, ultraviolet, nuclear magnetic resonance and mass
`spectral data have been reported (MacDonald et al., 1972).
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`38
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`lARe MONOGRAPHS VOLUME 66
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`(d) So!uhility: Slightly soluble in water (1 g/333 mL); soluble in acetone, benzene,
`chloroform (1 g/2 mL), diethyl ether (1 g/39 mL), dimethylformamide and etha-
`nol (1 g/16 mL) (Gennaro, 1995)
`(e) Stahility: Stable in air (Gennaro, 1995)
`(f Dissociatiol1 COl1stal1t: pK" = 3.4 (American Hospital Formulary Service, 1995)
`
`1.1.4 Techl1ical products and impurities
`
`Diazepam is available as 2-, 5- and 10-mg tablets, IS-mg extended release capsules,
`2- and 5-mg/5 mL oral solutions, 5-mg/mL concentrated oral solution, 5-mg/mL paren-
`teral injection, 5-mg/mL emulsion injection, 2- and 4-mg/mL rectal tube solutions and
`10-mg suppositories. Preparations may also contain acetylated monoglycerides, anhy-
`drous glucose, benzoic acid, benzyl alcohol, corn starch, ethanol, flavouring, fractionated
`egg phospholipids, fractionated soya bean oil, glycerol, lactose, magnesium stearate,
`methyl hydroxypropylcellulose, polyethylene glycol, propylene glycol, saccharin,
`sodium benzoate, sodium hydroxide, talc, D&C Yellow 10 (Quinoline Yellow), FD&C
`Blue 1 (Brilliant Blue FCF) or FD&C Yellow 6 (Sunset Yellow FCF). Sodium benzoate,
`benzoic acid and sodium hydroxide are added to the commercially available injection
`products to adjust pH (Thomas, 1991; Farmindustria, 1993; British Medical Asso-
`ciation/Royal Pharmaceutical Society of Great Britain, 1994; American Hospital For-
`mulary Service, 1995; Medical Economics, 1996).
`Trade names and designations of the chemical and its pharmaceutical preparations
`include: Aliseum; Alupram; Amiprol; An-Ding; Anksiyolin; Ansiolin; Ansiolisina;
`Antenex; Apaurin; Apozepam; Armonil; Assival; Atensine; Atilen; Avex; Bensedin;
`Betapam; Bialzepam; Calmocitene; Calmpose; Canazepam; Cercine; Ceregulart; Con-
`dition; Deprestop; Diacepan; Diaceplex; Dialag; Dialar; Diapam; Diatran; Diaz; Diazem;
`Diazemuls; Diazepam-Lipuro; Diazidem; Dienpax; Dipam; Dizac; Dizam; Domalium;
`Doval; Drenian; Ducene; Duksen; Duxen; E-Pam; Eridan; Erital; Eurosan; Euphorin;
`Evacalm; Faustan; Gewacalm; Hexalid; Horizon; Kiatrium; LA 11 1; Lamra; Lembrol;
`Levium; Liberetas; Lizan; Lorinon; Mandrozep; Metil Gobanal; Méval; Morosan; Néo-
`Calme; Neosorex; Nervium; Neurolytril; Noan; Notense; Novazam; Novodipam;
`Paceum; Pacipam; Pacitran; Pax; Paxate; Paxel; Pro-Pam; Psychopax; Q-Pam; Quétinil;
`Quievita; Relaminal; Relanium; Relivan; Remedium; Renborin; Rival; Ro 5-2807; Saro-
`met; Scriptopam; Sedapam; Sedipam; Seduxen; Serenak; Serenamin; Serenzin; Servi-
`zepam; Setonil; Sibazon; Sibazone; Sico Relax; Solis; Somasedan; Sonacon; Stesolid;
`Stesolin; Stress-Pam; Tensium; Tensopam; Tiromne; Tranimul; Tranquase; Tranquirit;
`Tranquo-Puren; Tranquo-Tablinen; Umbrium; Unisedil; Valaxona; ValCaps; Valclair;
`Valeo; Valibrin; Valiquid; Valitran; Valium; Valrelease; Vatran; Vival; Vivol; Wy 3467;
`Zepam; Zetran.
`
`1.1.5 Analysis
`
`Several international pharmacopoeias specify potentiometric titration with perchloric
`acid as the assay for purity of diazepam, and thin-layer chromatography for determining
`impurities and decomposition products. Assay methods for diazepam in capsules, tablets
`
`Fresenius Ex. 2025
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254