Identification and quality control of the drug diutsifon and its semiproduct using the1H NMR technique

Abstract

Diutsifon, or 4,4'-(6-methyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidinyl-5-sulfonylamido)diphenylsulfone (I), is a drug recommended for use in medical practice as a highly effective immunomodulator [ 1 ].Diutsifon synthesis is based on the reaction of its semiproduct, 6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidinyl-5-sulfoehloride (II) with 4,4'-diaminodiphenylsulfone (IU) Z2]. The semiproduct is obtained by the sulfochlorination [3] 3f 6-methyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidine (6-aaethyluraeil, IV), which accounts for the possible presence ff compound IV as an impurity in the target product. Thus, ~ae parent substance of diutsifon, synthesized using the above ~heme, may contain compounds III and IV (an admixture of 9 ompound II is hydrolyzed and decomposed to IV in the ,'tage of purification of compound I).It was important to study compound I and its semiproduct 'I in order to develop objective methods for their identifieaion and quality control that would be applicable in commer-:ial drug production. To date, no data have been published on he analysis of diutsifon and its semiproducts by physical nethods such as 1H NMR spectroscopy. This circumstance nay be explained by the absence of technology providing the ;ynthesis of sufficiently pure substances, which is confu'med ~y the scatter of the melting temperatures of compound (II) eported by different researchers [3 -5].The IH NMR technique offers high speed of analysis and s sufficiently informative to judge on both structure and :omposition (quality) of the substance analyzed.Wehave studied compounds I and II by IH NMR specroscopy and compared the obtained spectra with those of the ~ssible impurities III and IV in order to assess the ability of qMR to identify these compounds and to provide a method ~f quality control for the commercial production of diutsifon nd its semiproduct.Institute of Pharmacology and Toxicology, Academy of Medical Sciences of Ukraine, Kiev, Ukraine. 454 EXPERIMENTAL PARTThe purity of compounds I and II was confirmed by the results of elemental analyses and the quantitative determination of chloride ions. The latter analysis was performed by the titrimetric method for compound II and by the potentiometfic titration with 0.1 N sodium hydroxide for compound I. The titration with the Fischer reagent showed the presence of two water molecules in the molecule of diutsifon. The melting temperatures of compounds I and II were 260-265"C and 250-255~ respectively, both with decomposition.The purity of compounds III and IV used in the comparative analysis was confirmed by methods stipulated by the corresponding Pharmacopoeial issues [6,7].The IH NMR spectra of compounds I-IV were measured at 20~ on a Varian VXR-300 Fourier-transform pulsed NMR spectrometer operated at 300 MHz. The measurements were performed using 0.1 M sample solutions in deuterated DMSO, with tetramethylsilane as the internal standard.The IH NMR spectrum of compound II contains the proton signals in the form of a singlet at ~ = 2.36 ppm and a broad singlet at 5 = 13.41 -13.60...

Determination of organic impurities in pharmaceutical preparations

“…NMR spectrometry is finding increasing application for the identification of unknown organic impurities in pharmaceutical preparations [50,60,72,[80][81][82][83][84][85]. This method is highly informative and allows conclusions to be drawn on the structure of the components in a mixture of related compounds because the form of the NMR spectrum changes on even an insignificant change in the geometry of the molecule and bond orders.…”

“…It requires the use of several independent approaches. The problem can be partially solved by HPLC using the diode-array UV detector [58,[70][71][72][73][74][75], mass spectrometer (MS) [51,71,[76][77][78][79], and nuclear magnetic resonance (NMR) spectrometer [50,60,72,[80][81][82][83][84][85].…”

Determination of organic impurities in pharmaceutical preparations

“…The problem can be partially solved by HPLC using the diode-array UV detector [58,[70][71][72][73][74][75], mass spectrometer (MS) [51,71,[76][77][78][79], and nuclear magnetic resonance (NMR) spectrometer [50,60,72,[80][81][82][83][84][85]. It requires the use of several independent approaches.…”