Acetyl Cysteine Literature Corrections Made

DRUG INFORMATION

NAME OF THE DRUG: N-acetyl –L- cysteine

STRUCTURE:

IUPAC NAME: (2R)-2-acetamido-3-sulfanylpropanoic acid

SYNONYMS :acetein, acetylcysteine, N-acetylcysteine, N-acetyl-N-cysteine, N- acetyl-3-mercaptoalanine, airbron, broncholysin, fluimucetin, fluimucil, flumicil, inspir, mercapturic acid, mucolyticum, mucolyticum lappe, mucolytikum lappe, mucomyst, mucosolvin, NAC, NAC-TB, NSC 111180, parvolex, respaire.

MOLECULAR FORMULA: C5H9NO3S

MOLECULAR WEIGHT: 163.2 (anhydrous)

PHYSICAL PROPERTIES –

1) Appearance:

EUROPEAN PHARMACOPOEIA

UNITED STATES PHARMACOPOEIA

SIGMA ALDRICH

A white crystalline powder or colourless crystals

- White to white with light yellow cast powder

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2) Melting Point:



SIGMA ALDRICH

104OC - 1100C - 109°C -110°C

3)Specific optical rotation



SIGMA ALDRICH

+21.0 to +27 .0 +21 to +27 Optical rotation: +5°(c = 3% in water)

4)pH :



SIGMA ALDRICH

2.0 to 2.8(0.125g/ml) 2.0 to 2.8(1in 100) -

5) Odour : slight acetic odour

6) Taste: characteristic sour taste

7) pKa - 3.24 (carboxylic acid moiety), 9.52 (SH group)

8) logP - -0.66

9) Solubility



SIGMA ALDRICH

Soluble in water and alcohol

insoluble in methylene chloride

- soluble 1 in 8 of water and 1 in 2 of ethanol

insoluble in chloroform and ether

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Soluble in hot isopropyl alcohol, methyl acetate, and ethyl acetate

RELATED SUBSTANCES –

A) L-cystine (EP impurity A,USP impurity A)

B) L-cysteine ( EP Impurity B)

L-cysteine hydrochloride (USP impurity B)

C) N,N’-diacetyl –L-cystine(EP impurity C,USP impurity C)

D) N,S-diacetyl –L-cysteine(EP impurity D,USP impurity D)

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JOURNAL ARTICLES AND MONOGRAPHS

Journal name Author Article name Comments

Analytical methods

Aline Ferreira ourique et al

A LC UV method to assay N- acetyl cysteine without derrivitization :analysis of pharmaceutical products

Column :phenomenex luna C18 (250x 4.60 mm,5 microns,100A0 )

Mobile phase :KH2PO4(0.05M):ACN (95:5)(pH adjusted with 0.095% phosphoric acid )

Injection volume -100µl

Flow rate :1.3ml/min

Wavelength :214 nm

Run time -10 mins

Retention time :6 mins

Temperature :25±1°C

Journal of chromatography

B.toussaint et al Quantitative analysis of N –acetyl cysteine and its pharmacopoeial impurities in a pharmaceutical formulation by liquid chromatography –UV detection mass spectrometry.

Column :platinum EPS C18 (150x2.1mm,5 microns )

Mobile phase :ACN :NH3-formic acid (7/12mM)(2:98v/v)at pH3

Flow rate -0.3ml/min

Wavelength :210 nm

Injection volume -10 µl

Temperature -25°C

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- it includes all the four pharmaceutical impurities as per EP

Journal of pharmaceutical and biomedical analysis

J Farquhar et al A reversed phase high performance liquid chromatographic assay for the determination of N-acetyl cysteine in aqueous formulations

Column : C18spherisorb(200mm×5mm,10µm)

Mobile phase :0.5%m/v aqueous solution of sodium perchlorate at pH2

Flow rate -2ml/min

Wavelength -215nm

Temperature -60°C

Using internal standard solutions -0.4mg/ml l-tyrosine in dil ortho phosphoric acid (pH2)

The method is capable for the simultaneous determination of acetyl cysteine and N,N diacetyl cysteine (impurity C)

from the degradation studies carried out by exposing the aqueous formulation (pH6) to atmospheric oxygen for 4,20,30,37 for 12 months reports the formation of N,N diacetyl cystine (impurity C) N,S diacetyl cystiene(imp D) ,L-cysteine(imp B) and an impurity 4 (structure given in the article )

The retention time of the impurity 4 has been provided but its formation nor its structure elucidation has been discussed .

International journal of drug development and research

Sheikh sana et al Development and validation of RP-HPLC method for the estimation of N-acetyl cysteine in wet cough syrup

Column :waters symmetry C18 (150x4.6mm i.d.,3.5microns )

Mobile phase :KH2PO4(pH3):ACN

Time A B0 95 55 95 510 20 80

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15 95 520 95 5

Flow rate -0.8ml/min Run time -20 mins

forced degradation studies were carried under acid,base,peroxide ,sulfite ,heat and light .

The four pharmacopoeial impurities had been identified in the degraded sample .

Other unknown impurity peaks in addition to the pharmacopoeial impurities were also observed .

American journal of health systems –pharmacy

Alexander L.Fohl et al Stability of extemporaneously prepared acetyl cysteine 1% and 10 %solutions for treatment of meconium ileus

Column -150×3.9mm,4µm

Mobile phase –0.05M KH2PO4(pH3)

Wavelength -210 nm

Flow rate -1ml /min

Degradation samples were prepared in acidic ,alkaline ,oxidative conditions .The retention time for the degradation products have been provided but whether these match to pharmaceutical impurities is unclear .

Stability samples (1% aqnd 10 %) were prepared and stored at room temperature and samples were withdrawn at 7,14,30,60 and 90 days .A significant decrease in percentage of NAC has been reported at 90 days but no information regarding the degradtion products has been provided .

Hence it is unclear if the degradation products match with the pharmacopoeial impurities and whether new impurities are formed .

Journal of pharmacy practice and research

The –phung To et al Stability of a formulated N-acetyl cysteine capsule for prevention of contrast induced nephropathy

Column –AllsphereODS2(250mm×4.6mm,5µ)

Mobile phase -

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0.05MKH2PO4(pH3):ACN(98:2)

Wavelength -214nm

Flow rate -1.5ml/min Run time -9 minutes

Capsules were stored at 2-8°C, 18-25°C,and 40°C with and without desiccant at ambient and high humidity .

The article reports that in the high temperature high humidity conditions there was significant loss in percentage of NAC but it could not be accounted for in terms of mass balance production of NAC impurities .It assumes that the imbalance can be due to the inaccurate recovery of acetyl cysteine from the degraded capsules or NAC degraded into other break down products that were undetectable by the HPLC method used in the study .

American journal of health systems –pharmacy

Rivka Siden et al Stability of a flavoured formulation of acetyl cysteine for oral administration

Column-250mm×4.6mm,5µ

Mobile phase -0.05MKH2PO4 (pH3)

Wavelength -210 nm

Flow rate 1ml/min

Retention time -9.48 mins

Strawberry flavoured acetyl cysteine solution was prepared and stored at room temperature and in refrigerated conditions .samples were withdrawn at 0,7,14,21,28 and 35 days . There is a decrease in percentage of acetyl cysteine but there is no mention whether or not degradation products have been formed .

The forced degradation samples were prepared under

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oxidative,acidic and alkaline conditions .The article reports the retention time of N,N diacetyl cysteine(acetyl cysteine impurity C) which is the oxidative degradation product.

It reports the presence of other degradation peaks but it is unclear as to whether the degradation peaks correspond to the pharmacopoeial impurities or not .

Peritoneal dialysis international

Eun-Young Seo et al Stability of N-acetyl cysteine in peritoneal dialysis solution

Column –phenomenex C18

Mobile phase -0.05MKH2PO4 (pH3)

Flow rate -1.5ml/min

Wavelength -214 nm

Retention time -5.4 mins

The solutions of NAC in peritoneal dialysis solution were kept at 4°C and at room temperature .Samples were withdrawn at 0,1,3,7,15,30,60,90,120,150,180 days .A decrease in percentage of NAC has been reported but no information whether or not degradation products are formed has been provided .

Solutions of NAC were forcefully degraded under acidic and alkaline conditions .But no information is provided regarding the degradation products .

So it is unclear whether the impurities generated match with the pharmacopoeial impurities .

Annals of emerging medicine

William H.Dribben et al Stability and microbiology of inhalant N-acetyl cysteine used as an intravenous solution for the treatment of acetaminophen poisoning

USP method for the assay of acetyl cysteine

Solutions of inhalent NAC were compounded and stored at 25°C/60%RH,40°C/75%RH and at ambient conditions .the samples were withdrawn at 0,4,8,12,24,36,48,60 and 72 hrs . A decrease in percentage of NAC has been reported .No information whether or not impurities has been

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generated has been provided . The article reports that the

solution which was kept at accelerated conditions did not degrade at those conditions hence it is limited to drawing conclusions on the effects of these accelerated conditions on stability

hence it is unclear whether the impurities if generated will match with the pharmacopoeial impurities or not .

Journal of the Chilean Chemical Society

Siddiquiet al Iodate oxidation of N-acetyl L-cysteine :application in drug determination and characterization of its oxidation and degradation products by mass spectrometry

A kinetic spectrophotometric method based on initial rate measurement of the oxidation of of N-acetyl cysteine with iodate has been developed for the determination of N-acetyl cysteine .The reaction product was characterized using mass spectrometry .The m/z ratio was 326 which indicated the formation of disulphide acetyl cysteine

The degradation products of acetyl cysteine was also prepared and characterized

1.53×10-4 M NAC in presence of 1.25×10-2 M sodium hydroxide was heated at 100°Cat 30 minutes .In this condition the acetamide group breaks away from the parent compound leaving behind a compound with m/z ratio 103 .Since acetamide is highly unstable it gets converted to acetic acid having m/z ratio of 59

1.53×10-4 M NAC was heated with 5.0×10-4M hydrochloric acid for 30 minutes at 100°C.The acid degradation product has a mass no of 121 and from the mass spectra formation of cysteine was predicted

100mg of acetyl cysteine was heated at 100°C for 30 minutes and from the heated sample 1.53×10-4 M NAC was prepared .The mass spectrometric

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analysis revealed a compound with mass no 119.04

1.53×10-4 M NAC was subjected to peroxide degradation by subjecting heating the parent compound in presence of 5ml of 3% hydrogen peroxide for 30 mins at 100°C.The mass spectra had revealed a major compound is formed at m/z 160.

The degradation products prepared under iodate/iodide conditions is N,S diacetyl cysteine which is acetyl cysteine impurity D and has been reported by few articles as an impurity formed during degradation studies .

The degradation product under acidic condition -cysteine correspond to impurity B as per EP and has been reported by a few articles as a manufacturing impurity as well as a degrdation product .

The degrdation products under alkaline ,peroxide and heat conditions does not match with the pharacopoeial impurities and have not yet been reported in the stability related articles .

Analytica Chimica Acta

Xinyi Wang Ruoyun et al N-acetylcysteine induced quenching of red fluorescent oligonucleotide-stabilized silver nanoclusters and the application in pharmaceutical detection

A new, simple and sensitive method for determination of N-acetylcysteine (NAC) based on quenching of the red fluorescence of oligonuleotide-protected silver nanoculsters (Ag NCs) was described This method was further used for the assay of N-acetyl cysteine in granules.

Journal of chromatography and biomedicalapplications

Nuran Ercal et al High-performance liquid chromatography assay for N-acetylcysteine in biological samples following derivatization with N-( 1-pyrenyl)maleimide

Column –C18 (100x 4.6 mm ,3µ)( (Astec, Whippany, NJ, USA)

Mobile phase – water: acetonitrile (50:50, v/v) (pH 3.75)

Flow rate - 0.45 ml/min.

Excitation wavelength - 330 nm Emission wavelength of 380 nm.

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Injection volume - 20µlScientia Pharmaceutica

Rim Haggag et al Derivatization with 4-Chloro-7-nitro-2,1,3-benzoxadiazole for the spectrophotometric and differential Pulse polarographic determination of acetylcysteine and captopri

Acetylcysteine and captopril were determined based on their reaction with 4-chloro-7-nitro-2, 1, 3-benzoxadiazole (NBD-Cl) in the presence of sodium tetraborate in absolute methanol. The yellow coloured products obtained were measured spectrophotometrically at 417 and 420 nm for acetyl cysteine and captopril respectively and by differential pulse polarography at -872 and -1007 mV for acetyl cysteine and captopril respectively .The methods were validated and used for the determination of drugs in pharmaceutical preparations.

Chromatographia V. Cavrini et al HPLC Determination of Thiol Drugs in Pharmaceutical Formulations Using Ethacrynic Acid as a Precolumn Ultraviolet Derivatization Reagent

HPLC method has been developed for the determination of aliphatic thiol drugs, such as N-acetyI-L-cysteine, captopril and mer- captopropionylglycine in pharmaceutical formulations. The procedure involves a precolumn derivatization of the thiol drug with ethacrynic acid followed by reversed- phase HPLC separation and UV detection. The method is reliable for the quality control of commercial dosage forms of the examined thiol drugs.

Analytical Letters W. Baeyens et al Hplc Determination of N-Acetylcysteine in Pharmaceutical Preparations After Pre-Column Derivatization With ThiolyteR MB Using Fluorescence Detection

Column- Lichrosorb C18 ( 250 x 4.6 mm ,10µ)

Temperature - 22° C

Flow rate -2ml/min

Mobile phase -acetic acid 1 % (v/v) 95 ml : acetone 5 ml.

Excitation wavelength - 380 nm Emission wavelengths-470 nm

Acta chromatographica

Y. Vander Heyden et al Development and validation of an HPLC method with post-column derivatization for assay of N-acetylcysteine in plasma

Column-LiChrosorb C-18 ( 250 mm × 4.6 mm , 5 µm)

Mobile phase - 1% acetonitrile (ACN) in phosphate buffer (pH 3.0)

flow rate- 1.0 mL min−1.

Excitation wavelength - 365 nmEmission wavelength -442 nm

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Science Asia Elham Anwer Tahaa et al Kinetic Spectrophotometic Determination of Acetylcysteine and Carbocisteine in Bulk Powder and in Drug Formulations

Kinetic spectrophotometric method for the determination of acetylcysteine and carbocisteine is described.The method is based on the reaction between the drugs and 4-chloro-7-nitrobenzo-2-oxa 1, 3 -diazole (NBD-Cl) in an alkaline medium.the absorbance was measured at 424 nm at ambient temperature (250C ±5) for a fixed time of 30 minutes for acetyl cysteine , and at 468 nm for a fixed time of 15 minutes at 70 0C for Carbocisteine.the method was successfully applied for the determination of the two drugs in bulk powder, in pharmaceutical formulations as well as in the presence of their related substances .

International Journal of Pharmaceutical and Phytopharmacological Research

Nitin S et al Development and validation of spectroscopic method for simultaneous estimation of acebrophylline and acetylcysteine in capsule dosage form

A simple, economic, sensitive, accurate and reproducible spectroscopic method has been developed and validated for the simultaneous estimation of Acebrophylline and Acetylcysteine in capsule dosage form by Simultaneous equation method.

International Journal of Analytical Chemistry

Lea Kukoc-Modun et al Spectrophotometric Determination of N-Acetyl-L-Cysteine and N-(2-Mercaptopropionyl)-Glycine in Pharmaceutical Preparations

The proposed equilibrium method for the determination of N-acetyl-L-cysteine (NAC) and N-(2-mercaptopropionyl)glycine (MPG) is based on a coupled two-step redox and complexation reaction. In the first step, Fe(III) is reduced to Fe(II) by NAC or MPG. Subsequently, Fe(II) is complexed with 2,4,6-tripyridyl-s- triazine (TPTZ).The method was successfully applied to quantify NAC and MPG in pharmaceutical preparations.

Molecules Josipa Giljanović et al Flow Injection Spectrophotometric Determination of N-Acetyl-L-cysteine as a Complex with Palladium(II)

A flow-injection analysis with spectrophotometric detection, suitable for the determination of N-acetyl-L-cysteine (NAC) is described . NAC and Pd2+ form complexes of Pd2+:NAC molar ratios of 1:1 and 1:2.The proposed method was compared with the classic spectrophotometric determination of NAC, using the same reagent, PdCl2.

Journal of . Brazillian Chemical . Society

Willian T. Suarez et al Flow Injection Turbidimetric Determination of Acetylcysteine in Pharmaceutical

A simple, accurate and precise flow-injection turbidimetric procedure is reported for the determination of acetylcysteine in pharmaceutical formulations. The procedure is based on

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Formulations Using Silver Nitrate as Precipitant Reagent

the precipitation of acetylcysteine with silver nitrate solution in acid medium and the insoluble salt produced was monitored at 410 nm.

Instrumentation Science & Technology

Paraskevas D et al A Green Hplc Method For The Determination Of N-Acetylcysteine Using Post-Column Derivatization With Methyl-Propiolate

Column - C18( 150 × 4.6 mm i.d.,5 μm )( Prevail )

Mobile phase - 0.05 % v/v CH3COOH + 1 mmol L–1 EDTA in water

Wavelength - 285 nm

Flow rate -1ml/min

Journal of Chemistry

Shaesta quyoom et al Potentiometric and UV Spectral Studies of Binary and Ternary Complexes of Some Metal Ions with N-Acetylcysteine and Amino Acids

The formation constants of the binary 1:1 and 1:2 and 1:1:1 ternary complexes complexes of Cu(II), Zn(II), Cd(II), Hg(II), and Pb(II) with N-acetylcysteine and some biologically important amino acids as secondary ligands have been determined potentiometrically in aqueous mediumat 25°C. The formation constants of the 1:1 complexes were found to be higher than 1:2 complexes and the metal ions follow the order Hg(II) >Cu(II) >Cd(II) >Zn(II).

International journal of electrochemical science

Acelino Cardoso de Sá et al

Determination of N-Acetylcysteine by Cyclic Voltammetry Using Modified Carbon Paste Electrode with Copper Nitroprusside Adsorbed on the 3–Aminopropylsilica.

Copper nitroprusside was formed on aminopropylsilica silica gel surface .The cyclic voltammogram of CuNPSD were found to exhibit two redox couples with (Eθ’)1 = 0.34 V; (Eθ’)2 = 0.76 V.The second redox process ((Eθ’)2 presented by the graphite paste electrode with SiCuNP shows electrocatalytic activity for the oxidation of N-acetylcysteine. The linear range for the determination of N-acetylcysteine was found between 9.9 × 10-5 and 8.9 × 10-4 mol L-1 showing a detection limit of 4.18 × 10-5 mol L-1

Biopharmaceutics & drug disposition

Bernard Gabard Endogenous plasma N-acetylcysteine and single dose oral bioavailability from two different formulations as determined by a new analytical method.

Column -Nucleosil 120 C18 3 µm (80 x 4 mm)

Excitation wavelength- 325 nm,Emission wavelength - 415 nm

Mobile phase : Ethano l:H3P04 (0.1 M) (4:96)

In this method N-acetylcysteine in plasma is reduced using tributyl-

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phosphine followed by post-HPLC column derivatisation with o-phthalaldehyde

A crossover study was done to compare the bioavailability of two different formulations of N-acetylcysteine.

The drug was detected in plasma for up to 12 h after administration of a single oral dose

Acta Chimica Slovenica

Ana Luiza de Toledo Fornazari et al

Flow Injection Spectrophotometric System for N-Acetyl-L- Cysteine Determination in Pharmaceuticals

The oxidation of N-acetyl-L-cysteine by iron(III) is performed and the iron(II) produced was determined spectrophotometrically as a stable tris(1,10-phenantroline)iron(II) complex at 510 nm

Journal of Chemical research

Waseem Amir Flow-injection Determination of Cysteine, N-Acetyl Cysteine and Glutathione in Pharmaceuticals via Potassium Ferricyanide-Fe(III) Spectrophotometric System

A simple, rapid and economical flow injection spectrophotometric method for the determination of cysteine, N-acetyl cysteine and glutathione in pharmaceutical formulations was established with Fe(III)/ ferricyanide reduction and soluble Prussian blue detection system. The calibration graphs are linear in the concentration ranges of (1―100)×10–6 mol/L for cysteine and N-acetyl cysteine, and (1―50)×10–6 mol/L for glutathione

Journal of Chromatography

C. Celma et al Determination of N-

acetylcysteine in human plasma by liquid chromatography coupled to tandem mass spectrometry

Column -. Kromasil C18 column (5034.6 mm ,5 microns )

Mobile phase - acetonitrile : water (70:30)

Flow rate - 1 ml/min.

The analytical method consists of plasma digestion with dithiothreitol in order to reduce all the oxidized forms of N-acetylcysteine, and extraction with ethyl acetate followed by determination of levels by an LC–MS–MS method

Journal of Chromatography B:Biomedical applications

Longo A.,Toro M. Determination of N-acetylcysteine in human plasma by gas chromatography—mass spectrometry

NAC was extracted from plasma with ethyl acetate and derivatized in two steps with 2-praponol and pentafluoropropionic anhydride. The volatile derivative obtained was ideal for gas chromatographic—mass spectrometric

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analysis.International Journal of Electrochemical Science

Ante Prkić et al Direct Potentiometric Determination of N-acetyl-L-cysteine (NAC) in Real Samples by Using “home made” Iodide ISE

Iodide ion selective electrode membrane was made of AgI:Ag2S:PTFE( Polytetrafluoroethylene )= 1:1:2. The Proposed method was used the for determination of NAC in acetic buffer, pH 5 without pre-treatment of pharmaceuticals. The determination is based on the reaction between NAC and Ag+ from electrode membrane. The method has a linear response range for NAC from 2×10−5 to 1×10−2 mol L−1 with limit of detection of 7.8×10−6 mol L−1.

Il Farmaco

Ghannam S.,Brashy A.et al

Fluorimetric determination of some thiol compounds in their dosage forms

Three pharmaceutical compounds containing thiol groups namely, captopril, d-penicillamine and N-acetylcysteine were detrmined. The drugs are reacted with 1,2-naphthoquinone-4-sulfonic acid. The latter is reduced to 1,2-dihydroxynaphthalene-4-sulfonic acid which has a maximum fluorescence intensity at 480/318 nm (λEm/Ex).the method has a range of 0.5–4.5 μg ml−1 with minimum detectability 0.05 μg ml−1

MONOGRAPHSEuropean pharmacopeia

Note –the related substance LC method undergoing improvement

Test for related substances

Column –C18 (0.25Mx 4mm .)

Mobile phase –water R :ACN (97:3) (mix and adjust to pH3)

Wavelength -220nm Injection volume-20µl

Retention time for acetyl cysteine -6.4 minutes L cysteine-2.2 mins L-cysteine-2.4mins Acetyl cysteine impurity C-12 mins Acetyl cysteine impurity D-14 mins

The sample and standard solutions are prepared in 0.01Mhydrochloric acid

United states pharmacopoeia

Assay of acetyl cysteine

15

Note : Monograph being revised

Column :C18 (30cmx3.9 mmi.d.)

Mobile phase –0.05M potassium dihydrogen phosphate buffer (pH3)

Flow rate -1.5 ml/min Injection volume -10µlWavelength -214nm

Internal standard –DL-phenyl alanine

Relative retention time -6.4 minutes Internal standard –DL-phenylalanine Sample ,standard and internal standard

solutions are prepared in sodium metabisulfite solution (1in 2000)

United states pharmacopoeia Assay of acetyl cysteine solution

Column :C18 (30cmx3.9 mmi.d.)

Mobile phase –0.05M potassium dihydrogen phosphate buffer (pH3)

Flow rate -1.5 ml/min Injection volume -10µlWavelength -214nm

Internal standard –DL-phenyl alanine

• Relative retention time -6.4 minutes • Internal standard –DL-phenylalanine• Sample ,standard and internal standard solutions are prepared in sodium metabisulfite solution (1in 2000)

USP Medicines Compendium

Note –Monographs proposed for development

Acetyl cysteine capsulesAcetyl cysteine for injection Acetyl cysteine for oral solution Acetyl cysteine inhalation solution Acetyl cysteine injection Acetyl cysteine oral solution Acetyl cysteine tablets Acetyl cysteine and Cefexime tablets Acetyl cysteine and Isoproterenol inhalation solution

British pharmacopoeia (test for related substances of acetyl cysteine) Column -0.25Mx4mm i.d.Stationary phase –octadecyl silyl silica gel ,5 microns

Mobile phase –water :ACN (97:3)

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Flow rate -1ml /min

Wavelength -220nm Run time -30 minutes Retention time -6.4 minutes

BIOCHEMISTRY AND PHARMACOKINETICS

NAC is a sulfhydryl-containing compound rapidly absorbed into various tissues following an oral dose, deacetylated and metabolized in the intestines and liver, and its metabolites incorporated into proteins and peptides. Peak plasma levels of NAC occur approximately one hour after an oral dose; at 12 hours post-dose it is undetectable in plasma. Despite a relatively low bioavailability of only 4-10 per cent, oral administration of NAC appears to be clinically effective. The biological activity of NAC is attributed to its sulfhydryl group; while its acetylsubstituted amino group affords it protection against oxidative and metabolic processes.NAC administration is an effective method of increasing plasma glutathione (GSH) levels, as incorporation of cysteine into GSH appears to be the rate-limiting step in GSH synthesis.

MECHANISMS OF ACTION

NAC’s effectiveness is primarily attributed to its ability to reduce extracellular cystine to cysteine, and as a source of sulfhydryl groups. NAC stimulates glutathione synthesis, enhances glutathione-S-transferase activity, promotes liver detoxification by inhibiting xenobiotic biotransformation, and is a powerful nucleophile capable of scavenging free radicals. NAC’s effectiveness as a mucolytic agent results from its sulfhydryl group interacting with disulphide bonds in mucoproteins, with mucus subsequently being broken into smaller, less viscous units.

REFRENCES

1. Cavrini V , Gatti R. HPLC Determination Of Thiol Drugs In Pharmaceutical Formulations Using Ethacrynic Acid As A Precolumn Ultraviolet Derivatization Reagent . Chromatographia 1987; 23(9): 680.

2. Paraskevas D. Tzanavaras. A Green Hplc Method For The Determination Of N-Acetylcysteine Using Post-Column Derivatization With Methyl-Propiolate. Instrumentation Science & Technology 2012.; 40 (2): 150-160

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3. Quyoom S, Khan B.. Potentiometric And Uv Spectral Studies Of Binary And Ternary Complexes Of Some Metal Ions With N-Acetylcysteine And Amino Acids . Journal Of Chemistry 2009; 6(S1): S117-S122

4. Cardoso A., Paim L,. Determination Of N-Acetylcysteine By Cyclic Voltammetry Using Modified Carbon Paste Electrode With Copper Nitroprusside Adsorbed On The 3–Aminopropylsilica. International Journal Of Electrochemical Science 2011; 6(): 3754 - 3767.

5. Fornazari A,Suarez W. Flow Injection Spectrophotometric System For N-Acetyl-L- Cysteine Determination In Pharmaceuticals. Acta Chimica Slovenica 2005; 52(): 164–167.

6. Prkić A, Giljanović J. Direct Potentiometric Determination Of N-Acetyl-L-Cysteine (NAC) In Real Samples By Using “Home Made” Iodide ISE . International Journal Of Electrochemical Science 2011; 6: 5388 – 5395

7. Giljanović J Brkljača M,. Flow Injection Spectrophotometric Determination Of N-Acetyl-L-Cysteine As A Complex With Palladium(II) . Molecules 2011; 16: 7224-7236

8. Celma C ,Allue A. Determination Of N-Acetylcysteine In Human Plasma By Liquid Chromatography Coupled To Tandem Mass Spectrometry . Journal Of Chromatography 2000; 870 : 13–22

9. Wang X, Lin R. N-Acetylcysteine Induced Quenching Of Red Fluorescent Oligonucleotide-Stabilized Silver Nanoclusters And The Application In Pharmaceutical Detection. Analytica Chimica Acta 2013: 1-23.

10. Haggag R,Belal S.,Shaalan R. Derivatization With 4-Chloro-7-Nitro-2,1,3-Benzoxadiazole For The Spectrophotometric And Differential Pulse Polarographic Determination Of Acetylcysteine And Captopril . Scientia Pharmaceutica 2008; 76: 33–48 .

11. Jadhav N,Lalitha K. DEVELOPMENT AND VALIDATION OF SPECTROSCOPIC METHOD FOR SIMULTANEOUS ESTIMATION OF ACEBROPHYLLINE AND ACETYLCYSTEINE IN CAPSULE DOSAGE FORM . International Journal Of Pharmaceutical And Phytopharmacological Research (Eijppr) : 1-9.

12. Heyden Y.,Mangelings D. Development And Validation Of An Hplc Method With Post-Column Derivatisation For Assay Of N-Acetylcysteine In Plasma. Acta Chromatographica 2004 ; 14: 149-164.

13. Suarez W.,Vieira H.,Fatibello-Filho O.. Flow Injection Turbidimetric Determination Of Acetylcysteine In Pharmaceutical Formulations Using Silver Nitrate As Precipitant Reagent. Journal Of . Brazillian Chemical . Society 2007; 18(5): 1028-1033

14. Amir W,Mohammad Y, Abdul N. Flow-Injection Determination Of Cysteine, N-Acetyl Cysteine And Glutathione In Pharmaceuticals Via Potassium Ferricyanide-Fe(III) Spectrophotometric System . Journal Of Chemical Research 2010; 26(6): 893—898

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15. Gabard B. Endogenous Plasma N-Acetylcysteine And Single Dose Oral Bioavailability From Two Different Formulations As Determined By A New Analytical Metho. Biopharmaceutics & Drug Disposition 1991; 12: 343-353 .

16. Ercal n.,oztezcan s.,matthews r.. High-performance liquid chromatography assay for n-acetylcysteine in biological samples following derivatization with n-( 1-pyrenyl)maleimide . Journal of chromatography b: biomedicala pplications 1996; 685: 329-334 .

17. Baeyens W., Van Der Weken G., Lin Ling B.. Hplc Determination Of N-Acetylcysteine In Pharmaceutical Preparations After Pre-Column Derivatization With Thiolyter MB Using Fluorescence Detection . Analytical Letters 2006; 21(5): 741-757

18. Taha E.,Hassan N., Abdel Aal F., Fattah L.. Kinetic Spectrophotometic Determination of Acetylcysteine and Carbocisteine in Bulk Powder and in Drug Formulations. ScienceAsia 3 2008; 34: 107-113.

19. Sana S., Rajani A., Sumedha N.. Development and Validation of RP-HPLC Method for the Estimation of N- Acetylcysteine in Wet Cough Syrup. International Journal of Drug Development & Research 2012; 4(2): 285-293.

20. Toussaint B.,Pitti C.,Ceccato A.. Quantitative analysis of N-acetylcysteine and its pharmacopeial impurities in a pharmaceutical formulation by liquid chromatography–UV detection–mass spectrometry. Journal of Chromatography A 2000; 896: 191–199.

21. Siddiqui M., Wabaidur S.,Alothman Z.. Iodate Oxidation Of N-Acetyl L-Cysteine: Application In Drug Determination And Char- Acterization Of Its Oxidation And Degradation Product By Mass Spectrometry . Journal Of The Chilean Chemical Society 2014; 59(N1): 2303-2307.

22. Kukoc-Modun L., Radić N.. Spectrophotometric Determination of N-Acetyl-L-Cysteine and N-(2-Mercaptopropionyl)-Glycine in Pharmaceutical Preparations. International Journal of Analytical Chemistry 2011; 2011: 1-6.

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30. Ourique A.,Coradini K.. A LC UV method to assay N- acetyl cysteine without derrivitization :analysis of pharmaceutical products . Analytical methods 2013; 5: 3321-3327.

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Acetyl Cysteine Literature Corrections Made