title: Purification and identification of an impurity in bulk hydrochlorothiazide.
abstract: Hydrochlorothiazide (6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide) (HCTZ) 1 is a widely used diuretic and anti-hypertensive. Recently, the Pharmeuropa recognized a new impurity initially thought to be an HCTZ dimer 6, which consists of the active drug (HCTZ) linked via the former beta-ring methylene to a known degradate, 5-chloro-2,4-disulfamylaniline 2. In an effort to meet a new requirement, an analytical high-pressure liquid chromatography method was developed that was selective and sensitive to the subject impurity. The impurity was concentrated and purified using a combination of solid phase extraction and reverse-phase high-pressure liquid chromatography. Subsequently, the impurity has been identified as a specific HCTZ-CH2-HCTZ isomer utilizing a variety of analytical techniques, including hydrolysis, ultraviolet spectroscopy, liquid chromatography/mass spectrometry, and 1H and 13C nuclear magnetic resonance (NMR) spectroscopy. The data resulting from the application of these analytical techniques confirm the identity of the impurity as a methylene bridged pair of HCTZ molecules; however, a total of six possible isomers 7a-f exist because of the presence of three reactive amines/sulfonamides on each HCTZ molecule. One unique molecular structure (4-[[6-chloro-3,4,-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide]-methyl]-chloro-3-hydro-H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide) 7f was identified using two-dimensional COSY, NOESY, and TOCSY 1H NMR experiments.
authors.affiliation: Regulatory & Analytical Sciences, Merck & Co., Inc., WP38-3, West Point, PA 19486, USA. xueguang_fang@merck.com
authors.forename: X
authors.initials: X
authors.lastname: Fang
authors.forename: R T
authors.initials: RT
authors.lastname: Bibart
authors.forename: S
authors.initials: S
authors.lastname: Mayr
authors.forename: W
authors.initials: W
authors.lastname: Yin
authors.forename: P A
authors.initials: PA
authors.lastname: Harmon
authors.forename: J F
authors.initials: JF
authors.lastname: McCafferty
authors.forename: R J
authors.initials: RJ
authors.lastname: Tyrrell
authors.forename: R A
authors.initials: RA
authors.lastname: Reed
mesh_terms: D000959:Antihypertensive Agents / Q000737:chemistry / Q000302:isolation & purification*; D004340:Drug Contamination; D006852:Hydrochlorothiazide / Q000737:chemistry / Q000302:isolation & purification*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods
chemical_list: D000959:Antihypertensive Agents; D006852:Hydrochlorothiazide