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IODOMETRIC DETERMINATION OF CYSTAMINE DIHYDROCHLORIDE IN TABLETS USING POTASSIUM HYDROGENPEROXOMONOSULPHATE

IODOMETRIC DETERMINATION OF CYSTAMINE DIHYDROCHLORIDE IN TABLETS USING POTASSIUM HYDROGENPEROXOMONOSULPHATEIODOMETRIC DETERMINATION OF CYSTAMINE DIHYDROCHLORIDE IN TABLETS USING POTASSIUM HYDROGENPEROXOMONOSULPHATE
Vladislav Kovalenko, студент

Николай Блажеевский, доктор медицинских наук, профессор

Харьковский национальный фармацевтический университет, Украина

Участник конференции

Kinetic of Cystamine dihydrochloride S2(CH2CH2NH2)2·2HCl oxidation by Potassium hydrogenperoxomonosulphate(KHSO5) was studied in aqueous buffer solutions of pH 3.3; 3.9; 4.9; 5.8 and 6.8 under second-order conditions at the temperature 293 K. The possibility of application of KHSO5 as reagent for oxidimetric determination of  Cystamine dihydrochloride in tabtets 0.2 g was investigated. Cystamine dihydrochloride was determined by indirect titration with KHSO5. With this proposed method, 2,0-10 mg of Cystamine dihydrochloride can be accurately and precisely analyzed (RSD<1.6%, δ< RSD).

Keywords: Kinetics, S-oxidation, Cystamine dihydrochloride, Determination, Potassium hydrogenperoxomonosulphate(KHSO5)

 

Introduction

Cystamine dihydrochloride (cystamine hydrochloride RS-1) is an emergency radioprotection from the group of sulfur-containing drugs [1]. It was determinated coulonometrically with electrogenerated bromine [2-4]. Potentiometric titration of this compound after its reduction using silver nitrate as titrant and sulfide-selective indicator electrode was also elaborated [5].

Cуstamine dihydrochloride in pure form, tablets and biological media have been determined by thin-layer chromatography [6]. The analytical methods used for it determination in substance included alkalimetric titration in non-aqueous medium [7], direct spectrophotometry in the range (5.3-16.0)×10-4 mol/ L [6] оr based on the reaction of cystamine with p-nitrophenyl-diazonium to form a red-colored diazoamino compound and subsequent photometric analysis at the wavelength of 510 nm [8], and also using HPLC method with coulometric detection [9]. Like all other disulfides, Cystamine is interesting substrate for oxidation reactions as it may undergo either electrophilic or nucleophilic oxidation [10]. The mode of oxidation is controlled largely by the by the pH of the reaction mixture [10], whereas solvent effects are minimal. So, stepwise oxidation of Cystamine dihydrochloride with m-Chlorperbenzoic acid first gives 2-amonoethyl 2-amonoethanethiolsulfinate dihydrochloride and then the corresponding thiolsulfonate [11]. In basic solution a nucleophilic attack of the peroxy anion takes place at the sulfur atom [12].

The present communication reports the use of potassium hydrogen peroxomonosulfate(КHSO5) for the indirect titrimetric determination of Cystamine. The proposed method is based on the oxidation of Cystamine with the oxidant in buffer solution at the pH 5.8 to the Cystamine disulfone NH2(CH2)2S(=O)2S(=O)2(CH2)2NH2. The excess КHSO5 was iodometry titrated applying either visual end-point detection.

Experimental section

Reagents and Materials

As oxidant was used potassium hydrogenperoxomonosulphate, KHSO5, commonly known as potassium monopersulfate, which is present as a component of a triple salt with the formula 2KHSO5·KHSO4·K2SO4 potassium hydrogen peroxymonosulfate sulfate (5:3:2:2).

Cystamine dihydrochloride (2,2′-Diaminodiethyl disulfide dihydrochloride; C4H14Cl2N2S2,Mw = 225.2 g/mol). Standard solution with a concentration of 2 mg/ml Cystamine dihydrochloride prepared by dissolving 0.2030 g of the 98.5% substance in double-distilled water in a volumetric flask with a capacity of 100 ml. Hydrochloricacid diluted: was prepared with 0.1 mol/L Normadose® (standard titre).

The preparation a diluted sodium hydroxide solutions: Add topreviously aged for two weeksprepared saturated (50% w/v) solution of sodium hydroxide calculated volume of freshly boiledand cooled distilled water. Other concentrations were prepared by dilution. Potassium iodide 5% solution:  5.0 g of potassium iodide was dissolved in 50 ml of freshly boiled and cooled water. It is then filled with the same solvent to 100 ml.  The solution should be colourless. Sodium thiosulphate standard solution: c(Na2S2O3∙5H2O) = 0,1 mol/L), was prepared with 0.1 mol/L Normadose® (standard titre) in freshly boiled and cooled distilled water with addition of 0.5 g sodium carbonate in a 1L volumetric flask. Microburette 10 ml, 0.01 ml graduation.The preparation of pH buffer solutions.

For pH= 3.3: Dissolve 12.0 g of anhydrous sodium dihydrogen phosphate in distilled water, adjust the pH with dilute phosphoric acid (100 g/L) and dilute to 1000 ml with distilled water. For pH= 3.9: Dissolve 12.0 g of anhydrous sodium dihydrogen phosphate in distilled water, adjust the pH with dilute phosphoric acid (100 g/L) and dilute to 1000 ml with distilled water. For pH= 4.9: To 100 ml 0.1 M potassium hydrogen phthalate add 38.8 ml of 0.1 mol/L   solution NaOH, and made up to 200 ml with distilled water. For pH= 5.8:  To 100.0 ml 0.1 mol/L solution of potassium dihydrogen phosphate add 7.2 ml of 0.1 mol/L solution NaOH, and made up to 200 ml with distilled water. For pH = 6.8: To 100.0 ml 0.1 mol/L solution of potassium dihydrogen phosphate add 44.8 ml of 0.1 mol/L solution NaOH, and made up to 200 ml with distilled water.

Kinetic studies were carried out in water medium under second-order conditions with potassium hydrogenperoxomonosulphate (KHSO5) in the temperature 293 K. The reaction was followed by estimating the unreacted potassium hydrogenperoxomonosulphate as a function of time by using the iodometric method. The liberated iodine was titrated against standard sodium thiosulphate solution by using starch as indicator. From the titre values, plots of 1/c vs time were made and from the slope of such plots, the second order rate constants, kobs (L mol−1 min−1) were obtained. с - current molar concentration of potassium hydrogenperoxomonosulphate (for time t, min), mol/L. It was checked that the results were reproducible within ±5% error. To determine the stoichiometry of the reaction, potassium hydrogenperoxomonosulphate titration of standard solutions was carried out.

Procedure of determination Cystamine dihydrochloride: Transfer using a pipette an accurately measured volumes (1-5 ml) of prepared of sample solution or standard solution (2.0 mg/ml) to 100-ml measuring flask, add 20 ml of 0.025 mol/L previously prepared solution of the potassium hydrogenperoxomonosulphate, pH buffer solution (60 ml) (start stopclock) andwater to bring the final volume of solution to 100 mL. Mix to homogeneity (start stopclock). Using a pipette, over a determined period of time (2 min), transfer 10.00 ml to the reaction mixture in 100 ml Erlenmeyer flask. Add 5 ml of diluted hydrochloric acid and 5 ml of 5% solution of potassium iodide while shaking.  The formed iodine is titrated with 0.02 mol/L sodium thiosulphate using microburette till the mixture turns colourless (V1).  Repeat the titration without Cystamine dihydrochloride (control titration) (V0).

Calculate the amount of the Cystamine from the equation Cystamine dihydrochloride (mg)=[(V0V1) х M х Rх 10]  / 2 N , where V0 is the volume of sodium thiosulphate consumed in the blank titration (ml); V1 is the volume of sodium thiosulphate consumed in the experiment (ml); M is the relative molecular mass of the Cyctamine dihydrochloride; R is the molarity of the sodium thiosulphate solution; N is the number of moles of oxidizing agent per mole of sample.

Assay of Cystamine dihydrochloride in tablets «Cystamine 0.2 g»: Dissolve about 0.25 g, accurately weighed, of powder tablets of Cystamine dihydrochloride in 15-20 ml of distilled water. The slurry was filtered through a paper filter into a 100 ml volumetric flask, washed several times andwater to bring the final volume of solution to 100 mL. Transfer using a pipette an accurately measured volumes (5 ml) of prepared solution to 100-ml measuring flask, add 20 ml of 0.025 mol/L previously prepared solution of the potassium hydrogenperoxomonosulphate, pH buffer solution (70 ml) andwater to bring the final volume of solution to 100 mL. Mix to homogeneity (start stopclock). Using a pipette, over a determined period of time (2 min), transfer 10.00 ml to the reaction mixture in 100 ml Erlenmeyer flask. Add 5 ml of diluted hydrochloric acid and 5 ml of 5% solution of potassium iodide while shaking.  The formed iodine is titrated with 0.02 mol / L sodium thiosulphate using microburette till the mixture turns colourless.  Repeat the titration without Cystamine dihydrochloride (control titration).

Add using a pipette an accurately measured analiquotvolumes (5 ml) of Standard solution (2.00 mg/ml) of Cystamine dihydrochloride to a known volume (20 ml) of 0.025 mol/L previously prepared solution of the potassium hydrogenperoxomonosulphate in 100 ml measuring flask, add pH buffer solution (70 ml) andwater to bring the final volume of solution to 100 mL. Mix to homogeneity (start stopclock). Using a pipette, over a determined period of time, transfer 10.00 ml to the reaction mixture in 100 ml Erlenmeyer flask. Add 5 ml of diluted hydrochloric acid and 5 ml of 5% solution of potassium iodide while shaking.  The formed iodine is titrated with 0.02 mol/L sodium thiosulphate using microburette till the mixture turns colourless. Repeat the titration without Cystamine dihydrochloride (control titration).

Calculate the amount of the Cystamine dihydrochloride from the equation: Х(g)=[(V0V1) × m(St.) × m ]/ [(V0 (St.) – V1 (St.)] × m1, where V0 is the volume of sodium thiosulphate consumed in the control  titration (ml); V1 is the volume of sodium thiosulphate consumed in the work experiment with sample of Cystamine dihydrochloride tablets (ml); V0(St.) is the volume of sodium thiosulphate consumed in the control titration in the experiment without of the Standard  solution (ml); V1(St.) is the volume of sodium thiosulphate consumed in the experiment with Standard  solution of Cystamine dihydrochloride (ml); m1, m  and m(St.) - weight of powder tablets of Cystamine dihydrochloride, average weight of a one tablet and weight of the standard «Cystamine dihydrochloride» sample respectively in g.

Results and discussion

Investigation of the kinetic dependence on pH of the Cystamine-potassium hydrogenperoxomonosulphatereaction at 293 K and over pH range 3.3 to 6.8 yields bimolecular rate constants (L mol-1 min -1). Figure 1 shows a typical Cystamine oxidation kinetic curves. The optimum for the Cystamine dihydrochloride determination was pH 5,8. Semilogarithmic anamorphose of kinetic curves of Cystamine dihydrochloride oxidation kinetics versus pH indicate a second order of reaction (Fig. 2). The observed rate constant kobs is reasonably constant over the first half of oxidation of Cystamine to the disulfoxide Cystamine NH2(CH2)2S(=O)S(=O)(CH2)2NH2, but later the reaction slows down, implying that the later stages of formation of the corresponding of disulfone (or tetraoxo) Cystamine NH2(CH2)2S(=O)2S(=O)2(CH2)2NH2).

Scheme. The reaction mechanism of oxidation Cystamine dihydrochloride with potassium hydrogenperoxomonosulphate

To determine Cystamine dihydrochloride, iodometric back titration method was proposed. The method is based on the oxidation of Cystamine dihydrochloride by an excess of potassium hydrogenperoxomonosulphate. Table 1 shows the results obtained by the recommended procedure for five replicate titrations of mixtures containing the four species at various concentrations.

 

Fig. 1. Concenrtation versus time plot of potassium hydrogenperoxomonosulfate during the oxidation of Cystamine. с(KHSO5) = (3.4-3.54)·10-3 М; с(Cystamine) = 4.4·10-4 М. рН: 1-3,3; 2-3,9; 3-4,9; 4-5,8; 5-6,8.

 

 

Fig. 2. pH effects on the kinetics of the Cystamine - KHSO5 reaction. pH : 1- 3,3;  2 – 3,9; 3 – 4,9; 4 – 5,8; 5 – 6,8. с(KHSO5)=(3.4-3.5)·10-3 М; с(Cystamine) = 4.4·10-4 М. 293 K

 

 

 

Tabl. 1

Determination of Cystamine dihydrochloride acid by iodometric method with use potassium hydrogenperoxomonosulphateas oxidizing agent

mg taken

% recovered,*

RSD,%

δ, %

2.0

5.0

10.0

2.02±0.04

5.02±0.05

10.03±0.06

1.59

0.80

0.71

+1.0

+0.4

+0.3

 

* Average of 5 determinations (P = 0.95).

The advantages of the applied analytical techniques in the determination of Cystamine dihydrochloride acid in tablets «Cystamine 0.2 g» has been presented. A paired t-test showed that all results obtained for Cystamine dihydrochlorideacid in pharmaceutical product using the proposed procedure and the official procedure agreed at the 95% confidence level (Tabl. 2).

 

Tabl. 2

Determination of Cystamine dihydrochloride in tablets «Cystamine 0.2 g» by iodometric method using potassium hydrogenperoxomonosulphate

Content of Cystamine dihydrochloride, g

Recovered, 

(%)

Metrological characteristics

(n=5; P=0.95)

0.2065*

(103.3%)

0.2052±0.004 g

(102.45±1.50%)

RSD=1.57%

(δ=-0.63%)

 

*Spectrophotometric method data, µ.

 

Conclusions. The kinetic studies of oxidation of Cystamine dihydrochloride by potassium hydrogenperoxomonosulphate (KHSO5) have been carried out in buffer solutions under second-order conditions in the temperature 293 K. The second order rate constants, kobs (L mol−1 min−1) have been calculated from kinetic values. A suitable mechanism scheme based on these observations was proposed. The possibility of application of KHSO5 as reagent in the oxidimetric determination of Cystamine dihydrochloride was investigated. The proposed method is based on the quantitative and stoichiometry oxidation of Cystamine dihydrochloride with the oxidant in aqueous media to the corresponding disulfone Cystamine NH2(CH2)2S(=O)2S(=O)2(CH2)2NH2). The excess KHSO5 was iodometry titrated applying either visual end-point detection. With this proposed method, 2,0-10 mg of Cystamine dihydrochloride can be accurately and precisely analyzed (RSD<1.6%, δ< RSD).

 

     References:

  1. Mashkovskiy M.D. Lekarstvennyie sredstva. – 16-e izd. pererab., ispravl. i dop. Moskwa., Novaya volna, 2012. – 1216 s. (Russian)
  2. Sakharov A.A. Quantitative coulomtric determination of cystamine. Khimiko-Farmatsevticheskii Zhurnal, 1978. Vol. 12, No. 8, pp. 136-140.
  3. Ciesielski W., Skowron M. Coulometric Titration of Disulfides with Electrogenerated Chlorine. Chem. Anal. (Warsaw). 2005. Vol. 50. P. 47-53.
  4. Okislitelno-vosstanovitelnoe titrovanie/ Sost. V.I. Danevich, M.I. Bureneva. – SPb. : SPHFA, 2001. – 44 s. (Russian)
  5. Karandi I.V. Potentsiometricheskoe opredelenie organicheskih disulfidov s ispolzovaniem formamidinsulfinovoy kislotyi v kachestve vosstanovitelnogo agenta. Zhurnal analiticheskoy himii 1999. T.54, № 8. S.848-850 (Russian)
  6. Trohimchuk V.V., Chakchir B.A., Hveschuk P.F., Alekseev V.V. Kontrol kachestva tsistamina digidrohlorida v protsesse hraneniya. Farmatsiya. 1985. №1. S. 33-35. (Russian)
  7. ФС 42-237-72
  8. Metodicheskie ukazaniya po spektrofotometricheskomu izmereniyu kontsentratsii bis-(beta-aminoetil)-disulfida digidrohlorida (Tsistamina) v vozduhe rabochey zonyi. MUK 4.1.814-99 (Russian)
  9. Pinto J. T., Khomenko T., Szabo S., Mc Laren G. D., Denton T. T., Krasnikov B. F., Jeitner T. M., Cooper J.L. Measurement of sulfur-containing compounds involved in the metabolism and transport of cysteamine and cystamine. Regional differences in cerebral metabolism. J. Chromatog. B, 2009, Vol. 877, No 28, P. 3434-3441.
  10.  Drug Design: Medicinal Chemistry: A Series of Monographs, Volume 6, Ed. E. J. Ariëns, Elsevier, 2017. – 382 p.
  11.  Daniel L. KlaymanGeorge W. A. Milne2-Amino-Δ2-thiazolines from Aminoethyl Thiosulfates. The Mass Spectra of 2-Amino-Δ2-thiazolines and Related Compounds J. Org. Chem., 1966, 31 (7), pp 2349–2355. DOI: 10.1021/jo01345a064
  12.  Smith, M. B., March, J. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Sixth Edition WILEY-INTERSCIENCE A JOHN WILEY & SONS, INC., PUBLICATION. 2007. 2357 p.
  13.  Price J.S., Tasker I.R., Appelman E.H., O’Hare P.A.G. Thermochemistry of inorganic sulfur compounds IX. Molar heat capacity of KHSO5(cr) from 5 to 300 K, and the partial molar entropy of HSO5-(aq). J. Chem. Thermodynam.1986. Vol. 18, No. 10.P. 923-930.
Комментарии: 7

Коваленко Владислав Сергеевич

Шановні колеги! Висловлюємо подяку за ознайомлення з нашою роботою і за таку високу оцінку! З повагою автори.

Василенко Елена Ивановна

Шановні автори! Уважно прочитала вашу доповідь. Щиро вдячна за обґрунтовано поданий, багатий матеріал. З повагою і побажаннями наснаги, успіхів в науковій діяльності. Олена

Блажеевский Николай Евстафьевич

Щиро дякую!

Кацан Валентина Андреевна

Шановний Владиславе, Ви розробили простий і надійний метод кількісного визначення цистаміну. Дуже важливо, що він не потребує дороговартісних реактивів і обладнання, а обраний Вами для визначення за надлишком реагенту йодометричний метод є досить точним. Ретельно і професійно підібрані оптимальні умови для реакції з принципово новим реагентом, пероксимоносульфатом калію, досліджено кінетику реакції за різних рН. Успіхів та нових оригінальних ідей Вам у подальших дослідженнях і велике спасибі за активну участь у нашому форумі! З повагою та найкращими побажаннями, Валентина Кацан

Коваленко Владислав Сергеевич

Шановна Валентина Андріївна! Дуже вдячні Вам за високу оцінку. Продовжуємо шукати нові горизонти з досліджень.

Блажеевский Николай Евстафьевич

Владик! Молодець! Ціква Твоя доповідь і заслуговує на високу оцінку!

Блажеевский Николай Евстафьевич

Щиро дякую Вам за коментар та оцінку роботи мого учня.
Комментарии: 7

Коваленко Владислав Сергеевич

Шановні колеги! Висловлюємо подяку за ознайомлення з нашою роботою і за таку високу оцінку! З повагою автори.

Василенко Елена Ивановна

Шановні автори! Уважно прочитала вашу доповідь. Щиро вдячна за обґрунтовано поданий, багатий матеріал. З повагою і побажаннями наснаги, успіхів в науковій діяльності. Олена

Блажеевский Николай Евстафьевич

Щиро дякую!

Кацан Валентина Андреевна

Шановний Владиславе, Ви розробили простий і надійний метод кількісного визначення цистаміну. Дуже важливо, що він не потребує дороговартісних реактивів і обладнання, а обраний Вами для визначення за надлишком реагенту йодометричний метод є досить точним. Ретельно і професійно підібрані оптимальні умови для реакції з принципово новим реагентом, пероксимоносульфатом калію, досліджено кінетику реакції за різних рН. Успіхів та нових оригінальних ідей Вам у подальших дослідженнях і велике спасибі за активну участь у нашому форумі! З повагою та найкращими побажаннями, Валентина Кацан

Коваленко Владислав Сергеевич

Шановна Валентина Андріївна! Дуже вдячні Вам за високу оцінку. Продовжуємо шукати нові горизонти з досліджень.

Блажеевский Николай Евстафьевич

Владик! Молодець! Ціква Твоя доповідь і заслуговує на високу оцінку!

Блажеевский Николай Евстафьевич

Щиро дякую Вам за коментар та оцінку роботи мого учня.
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