HYDROCHLOROTHIAZIDE 1. Exposure Data 1.1.2 Structural and molecular formulae and relative molecular mass 1.1 Identification of the agent O O OO 1.1.1 Nomenclature S S N H Chem. Abstr. Serv. Reg. No.: 58-93-5 (SciFinder, H2N 2013) Cl N Chem. Abstr. Serv. Name: 2H-1,2,4-Benzo- H thiadiazine-7-sulfonamide, 6-chloro-3,4-di- hydro-1,1-dioxide (SciFinder, 2013) IUPAC systematic name: 6-Chloro-1,1-dioxo- C7H8ClN3O4S2 3,4-dihydro-2H-1,2,4-benzothiadiazine-7- Relative molecular mass: 297.74 (O’Neil, 2001) sulfonamide Synonyms: Dihydrochlorothiazid; Dihydro- 1.1.3 Chemical and physical properties of the chloro thiazide; Dihydrochlorothiazidum; pure substance Di hy dro chlorurit; Dihydrochlorurite; Di hy dro xychlorothiazidum; HCTZ; HCZ; Description: A white or almost white, crys- Hydrochlorothiazid; Hydrochlorthiazide talline powder; odourless or almost odourless (DrugBank, 2013); Hidroclorotiazida; (WHO, 2006) Hydrochlorothiazidum; Chlorsulfonamido- Density: 1.693 g/cm3 (calculated) (Lookchem, dihydrobenzothiadiazine dioxide; Chloro- 2013) sulthiadil; 3,4-dihydrochloro thiazide (IPCS, 2013) Melting point: 273–275 °C (O’Neil, 2001) WHO International Nonproprietary Name Spectroscopy data: Infrared, Raman, ultra- (INN): Hydrochlorothiazidum (WHO, 2006) violet, proton nuclear magnetic resonance (1H-NMR) and 13C-NMR spectral data have been reported. Solubility: Very slightly soluble in water (722 mg/L at 25 °C; Deppeler, 1981); soluble in ethanol at ~750 g/L and in acetone (WHO, 2006); soluble in dilute ammonia; freely soluble in sodium hydroxide solution, in 285 IARC MONOGRAPHS – 108 n-butylamine and in dimethylformamide; • 6-Chloro-N-[(6-chloro-7-sulfamoyl-2,3- sparingly soluble in alcohol; insoluble in dihy dro-4H-1,2,4-benzothiadiazin-4-yl ether, chloroform and in dilute mineral acids 1,1-dioxide)methyl]-3,4-dihydro-2H- (HSDB, 2013). 1,2,4-benzothiadiazine-7-sulfonamide Octanol/water partition coefficient (log P): 1,1-dioxide. −0.07 (Chemspider, 2013) Dissociation constant: pK = 7.9 ; pK = 9.2 a a2 1.2 Analysis (O’Neil, 2001) An overview of selected analytical methods is 1.1.4 Technical products and impurities presented in Table 1.1. (a) Trade names 1.3 Production and use Acuren; Adelphan; Apo-Hydro; Aqua- zide; Clorana; Colidur; Colonraitai; Cotrazid; 1.3.1 Production process Decazon; Dehydratin; Dehydrazid; Depress; Hydrochlorothiazide is synthesized by Dichlotride; Dichlozid; Di-Eudrin; Dihydrochl either the reaction of para-formaldehyde with Ozide; Dihydrochlorothiazide; Dihydrodiazid; 5-chloro-2,4-disulfamoylaniline in nonaqueous Disalunil; Disothiazide; Dithiazide; Dithiazide; media, or the reaction of formaldehyde with Diunorm; Diunorm; Diurace; Diural; Diuren; 6-chloro-7-sulfamoyl-2H-1,2,4-benzothiadi- Diurex; Diurezin; Diuzid; Do-Hydro; Drenol; azine-1,1-dioxide in aqueous alkaline solution Duberzide; Edepress; Esidrex; Esidrix; H.C.T.; (Deppeler, 1981). HCT [manufacturer]; Hexazide; Hidro- clorotiazida; Hidrochlorotiazid Alkaloid; 1.3.2 Use Hidro med; Hidroronol; Hidrosaluretil; Hidro- tiadol; HTZ; Hybozide; Hychlozide; Hydrex; (a) Indications Hydride; Hydrochlorothiazide; Hydrochloro- Hydrochlorothiazide is a thiazide-type thiazidum Polpharma; Hydroklortiazid diuretic chiefly used as an antihypertension Evo lan; Hydromed; Hydrozide; Hypodehydra; agent for the control of elevated blood pres- Hypothiazid; Hytaz; Hyzide; Keshiau; Klorzide; sure (Table 1.2). It is often combined with other Koliside; Locoid; Lonpra; Microzide; Monozid; agents in the treatment of hypertension, either Nefrix; Newtolide; Nisidrex; Nor-Tiazida; Oretic; through separate prescriptions for hydrochloro- Ridaq; Rofucal; Tandiur; Tiazid; Urilzid; Xenia thiazide and the other agents, or through the use (MicroMedex, 2013). of combination products in which a single tablet (b) Impurities contains hydrochlorothiazide plus one other antihypertensive medication (more rarely, two Some impurities are described in the other agents). European Pharmacopoeia (2005): In the USA, hydrochlorothiazide is indicated • Chlorothiazide (active drug rarely used as an for “the management of hypertension either as alternative to hydrochlorothiazide) the sole therapeutic agent or in combination • 4-Amino-6-chlorobenzene-1,3-disulfona- with other antihypertensives” and is recom- mide (salamide) mended as first-line medication Chobanian( et al., 2003). The Food and Drug Administration 286 Table 1.1 Analytical methods for hydrochlorothiazide Sample matrix Sample preparation Analytical method Detection limit Reference Compendial methods Assay – Potentiometry – Indian Titrant: 0.1 M TBAH Pharmacopoeia Reference electrode: calomel or silver–silver chloride (2010) Indicator electrode: glass electrode 1 mL of 0.1 M TBAH is equivalent to 0.01488 g of HCTZ Assay for – UV-visible spectroscopy wavelength: 273 nm – Indian HCTZ tablets Pharmacopoeia (2010) Assay for – HPLC column: C18 – US HCTZ tablets Mobile phase: monobasic sodium phosphate and acetonitrile Pharmacopeia (9 : 1) (2007) pH 3.0 ± 0.1 Flow rate: 2 mL/min Non-compendial methods Human plasma Addition of internal standard (clortalidone) HPLC–tandem mass spectrometry 5 ng/mL (LLOQ) Sousa et al. and MTBE, centrifugation, addition of Column: C18 Linearity: (2009) solvent to organic phase, evaporation and Mobile phase: acetonitrile and water (80 : 20, v/v) SRM 5–400 ng/mL reconstitution in acetonitrile and water transition: 296.10 m/z, 204.85 m/z (1 : 1, v/v) Human urine Mix urine samples with deionized water, HPLC–narrow bore chromatography 1 µg/mL (LOD) Farthing et al. centrifuge Column: C18 Linearity: (1998) Mobile phase: acetic acid and acetonitrile (93 : 7) pH 3 2–50 µg/mL Wavelength: 272 nm Flow rate: 0.30 mL/min Human serum Gel filtration of the sera on Sephadex G-15, HPLC 50 ng/mL (LOD) Christophersen extraction of the protein-free fraction of the Column: C18 (Spherisorb ODS) et al. (1977) effluent with ethyl acetate Mobile phase: 15% methanol in water Rat plasma To plasma add internal standard (HFTZ), LC–ESI–MS Linearity: Takubo et al. Hydrochlorothiazide extraction with MTBE Column: C8 4–1000 ng/mL (2004) Mobile phase: distilled water and acetonitrile (85 : 15) Accuracy: Negative ionization mode 100.8–113.1% Precision: 0.28–16.4% 287 288 IARC MONOGRAPHSIARC 108 – Table 1.1 (continued) Sample matrix Sample preparation Analytical method Detection limit Reference Human plasma, Derivatization with Reverse phase HPLC 3.3 ng/mL Huang et al. simultaneous 2,4-dibromoacetophenone (pBPB) to form Column: C18 (LOQ) (2006) determination captopril-pBPB adduct. Extraction of Mobile phase: acetonitrile, trifluoroacetic acid and water of HCTZ and HCTZ and derivatized captopril with ether (gradient elution) captopril and dichloromethane Flow rate:1.2 mL/min Human plasma, Liquid–liquid extraction with diethyl ether LC–MS Linearity: Yan et al. simultaneous and dichloromethane (60 : 40) Column: C8 1.00–600 ng/mL (2008) quantitation Mobile phase: acetonitrile, 10 mM ammonium acetate and of HCTZ and formic acid (gradient elution) telmisartan Flow rate: 1.2 mL/min SRM transition: 295.9 m/z → 268.9 m/z Negative ionization mode Human blood Addition of the internal standard, benzene GLC 0.05 µg/mL Vandenheuvel and plasma extraction, extraction with ethyl acetate, Column: glass U-tube (sensitivity) et al. (1975) back-extraction into NH4OH, adjustment Carrier gas: argon : methane (95 : 5) to pH 3.7 and extraction with ethyl acetate, Flow rate: 60 mL/min evaporation, dissolution of the residue in Detector: electron capture detector trimethylanilinium hydroxide in methanol In tablets Dissolve drug in 0.02 M NaOH, dilute with Electrochemical study 5.0 ng/mL Abdel Razak Britton–Robinson buffer pH 3.3 Electrode: glass carbon electrode (LOD) (2004) pH 3.3 Oxidation potential: + 1040 mV In urine Centrifugation at 4000 g/mL spiked with Electrochemical study 14 ng/mL Abdel Razak HCTZ and diluted with Britton–Robinson Electrode: glass carbon electrode (2004) buffer pH 3.3 pH 3.3 Oxidation potential: + 1040 mV In Solution of HCTZ in acetone Diffuse reflectance spectroscopy: Whatman 42 filter paper as 1.32 × 10−2 mol/L Gotardo et al. pharmaceutical the solid support (LOD) (2005) formulations Solvents: acetone and methanol (HPLC grade); PDAC used Linearity: for spot reaction with HCTZ 3.36 × 10−2 to 1.01 × 10−1 mol/L GLC, gas-liquid chromatography; HCTZ, hydrochlorothiazide; HFTZ, hydrofluorothiazide; HPLC, high-performance liquid chromatography; LC-MS, liquid chromatography mass spectroscopy; LC–ESI–MS, liquid chromatography–electrospray ionization–mass spectrometry; LOD, limit of detection; LLOQ, lower limit of quantification; LOQ, limit of quantification; MTBE, methyl tert-butyl ether; PDAC, para-dimethylamino cinnamaldehyde; SRM, single reaction monitoring; TBAH, tetrabutylammoniumhydroxide; UV, ultraviolet; v/v, volume per volume Hydrochlorothiazide Table 1.2 Most commonly reported clinical indications for hydrochlorothiazide in the USA, 2012 Diagnosisa ICD-9 code Drug uses (in thousands) Percentage of total Essential hypertension, NOS 401.90 21 194 86.9 Hypertensive heart disease, other 402.90 713 2.9 Chronic ischaemic disease, unspecified, with hypertension 414.50 324 1.3 Hypertension, benign 401.10 187 0.8 Surgery after heart disease V67.03 153 0.6 Hypertensive renal disease 403.90 136 0.6 Oedema, NOS 782.30 122 0.5 Cerebrovascular accident 436.00 86 0.4 Metabolic/insulin resistance syndrome 277.70 82 0.3 All other diagnoses – 1 332 5.5 Total with reported diagnoses – 24 383 100 a No diagnosis was stated for 0.2% of drug uses. NOS, not otherwise specified