International Journal of Chemistry Research

ISSN- 0976-5689 Vol 2, Issue 2, 2011

ResearchArticle

VALIDATIONOFAGASCHROMATOGRAPHICMETHODFORDETERMINATIONOFETHANOL INLIQUIDPREPARATIONSINTENDEDFORCHILDREN

KASHIKARV.S.
ModernCollegeofPharmacy(Ladies),MoshiPune,(M.H.)IndiaEmail:vrushalipharma@indiatimes.com Received:09Jan2011,RevisedandAccepted:12Feb2011 ABSTRACT In1984,theAmericanAcademyofPediatricsrecommendedlimiting alcohol contenttonomorethan5%andrestrictingthevolume ofproducts containing alcohol to nonlethal quantities. In 1993, a committee representing the Food and Drug Administration and the Nonprescription Drug ManufacturersAssociationagreedtodevelopvoluntarylimitsforthealcoholcontentofliquiddosagepreparations.Thecommitteeconcludedthat alloverthecounterproductsdesignedforchildrenlessthansixyearsofageshouldbealcoholfree.Productslabeledforchildren612yearsofage should contain no more than 5% alcohol. Products for children over 12 years and adults should be limited to 10% alcohol content. In certain productsrequiringhigheralcoholcontentstoachievesolubility,warninglabelswouldinstructparentstocontactaphysicianpriortogivingthese productstochildren.Todate,limiteddocumentationofsuchinteractionexistsbecauseofalackofscientificstudiesonthissubject.Henceattempt wasmadetoevaluatequantityaswellasqualityaspectsintermsofcontaminationfrommenthol,camphorandpropyleneglycol. Keywords:GasChromatography,Validation,Alcohol,PediatricFormulations INTRODUCTION Ethanoliscommonlyusedasasolventinthemanufacturingoforal liquid dosage formulations. Two concerns exist with the use of ethanol in products designed for the pediatric market, acute intoxication with accidental overdose and chronic toxicity associated with routine use for chronic medical conditions. It is desirable that no ethanol be included in medicinal products intendedforuseinchildren. However, if ethanol is required to solubilize the active ingredients, the Committee on Drugs has made the following specific recommendations to the FDA: (1) Overthecounter (OTC) liquid preparationsshouldbelimitedtoamaximumof5%v/vethanol.(2) Physiciansupervisionissuggestedforchildrenlessthanage6years using OTC preparations containing alcohol. (3) The amount of ethanol contained in any medicinal preparation should not be able toproduceabloodconcentrationgreaterthan25mg/100mlaftera single recommended dose. (4) Appropriate intervals between medicationdosesshouldbeprescribedtopreventtheaccumulation of blood alcohol. (5) The packaged volume of ethanolcontaining products should be kept to a reasonable minimum to prevent potential lethal ingestions. (6) Safety closures should be recommended for medications with greater than 5% ethanol content. These levels represent only guidelines, however, and are not enforced by the FDA. To date, limited documentation of such interaction exists because of a lack of scientific studies on this subject. Though it is desirable that no ethanol be included in medicinal products intended for use in children, the preparations selectedcontainsupto10%ofalcoholasperlabelclaim.Reviewof literature revels that some pharmaceutical manufacturers replace ethanol as a solvent by propylene glycol, thus problem of intoxication remains same. Hence attempt was made to evaluate quantity as well as quality aspects in terms of contamination from menthol,camphorandpropyleneglycol14. MATERIALANDMETHODS AlltheworkdescribedinthispaperwascarriedoutonaChemitoGC 7610 withaflameionizationdetector861.The columnusedwas 8 feetx1/8inchcarbowax20M(HP),80100mesh. Operatingconditions 1. 2. 3. FIDH2/air:30/300ml/min. Column:Carbowax20M(HP) Columntemperature:~800c 4. 5. 6. N2carrier:~30ml/min. Injectortemperature:1800c Detectortemperature:1800c

Solvents Ethanol,HPLCgrade(99.98%),E.Merck Water,HPLCgrade,E.Merck Methods Standardethanolsolution Solutions were prepared with HPLC grade ethanol (99.98%) and HPLCgradewatertocontain1,2,3,4,5,and6percent.V/vofethanol. Samplepreparation 50 ml of sample was pipette out and transferred to 250ml round bottom flask and was attached to distillation assembly. The assembly was heated and approximately 4045ml of distillate was collectedin100mlvolumetricflask. Internalstandardmethod Highestprecisionobtainedwithinternalstandardmethod.3mlofn propanolwasaddedasaninternalstandardtothe samplesolution andtothestandardsolution.Thenvolumewasmadeupto100ml. Qualitativeanalysis Two microliters portion of sample solution and the standard solutionwasinjectedandchromatogramswereobtained.Retention time(Rt)wasrecordedastheanalyticalparameter. Quantitativeanalysis Quantitation was performed by constructing calibration graphs, which are prepared by plotting the peak area ratio ethanol to internalstandardagainstethanolcontent(Figure1). Analysisofstandardethanol A range of standard was prepared containing six different concentrationofethanol.2microliterportionofeachwasinjected and chromatograms were obtained. The graph of concentration versesareawasfoundtobelinearwith,Y=0.2563&R 2=0.9969. AnalysisofsamplebyGasChromatography2microliterportionof each sample solution was injected and chromatograms were obtained.Theconcentrationwasdeterminedfromstandardworking curve.Thevaluesobtainedweremultipliedby2toget%v/v.

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1.8 1.6 1.4

RESPONSEA/I.S

1.2 1 0.8 0.6 0.4 0.2 0 1 2 3 4 CONCENTRATION%v/v 5 6

Fig.1:Standardcurveofethanolbygaschromatography

Table1:Analysesofsamples Sample S1,[A,B,C] S2,[A,B,C] S3,[A,B,C] S4,[A,B,C] S5,[A,B,C] Labelclaim 4%V/V 5%V/V 5%V/V 9%V/V 9.5%V/V Percentcontent 4.564.72 5.05.72 5.15.38 9.5210.5 10.8811.86 Variation 12.5%17.5%V/V 14.0%V/V 2.08.0%V/V 5.514.4%V/V 5.2614.73%V/V

S1toS5Samplecode.[A,B,C]Threedifferentbatchesofeachsample Studyofvalidationparameters Validationisdocumentedevidence,whichprovidesahighdegreeof assurance for specific method. It is completed to insure that an analytical method is accurate, reproducible and rugged over the . specific range that analyst is analyzed to provide an assurance of reliabilityandforFDAcompliance.Methodvalidationistheprocess ofprovidingassurancethatananalyticalmethodisacceptableforits intendedpurpose.

Table2:Studyofvalidationparameter5 ValidationParameters SystemSuitability Linearity RecoveryStudy Precisionforsystem RuggednessbyAnalyst RuggednessonDays Results Mean=3.03% S.D.=0.0407 R.S.D.=1.34% Y=0.2563X R2=0.9969 %recovery=103.5% Mean=3.03% S.D.=0.0407 R.S.D.=1.34% Mean=2.67% S.D.=0.035 R.S.D.=1.31% Mean=2.05% S.D.=0.026 R.S.D.=1.13%

RESULTSANDDISCUSSION During qualitative evaluation, retention time, the analytical parameterrecordedfoundtobesameforboth,standardethanoland the alcohol in the various formulations. This indicates that the alcohol present is ethanol. The results obtained by quantitative evaluation do not comply with label claim for alcohol contents. Considerablevariationwasfound, Preparation S1 having label claim of 4% v/v shows batch to batch variation upto 12.5%17.5% Preparation S2 having label claim of 5%v/v shows batch to batch variation upto 14%. Preparation S3 having label claim of 5% shows batch to batch variation upto 2% 8%. Preparation S4 having label claim of 9% shows batch to batch variationupto5.55%14.44%.PreparationS5havinglabelclaimof 9.5%showsbatchtobatchvariationupto5.26%14.73%.

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CONCLUSION Pediatriciansandotherhealthcareprovidersshouldbeawareofthe widespread presence of alcohol in liquid medications and its potential to toxicity. Alcoholcontaining medicines may affect the disposition of other drugs, cause undesirable drug interactions, or induce disulfiram (Antabuse)like reactions. Since CNS toxicity occurswhentheconcentrationofethanolinthebloodis25mg/100 mL,asingledoseofalcoholcontainingmedicationmustnotbeable to produce this level of ethanol. Although fatal blood ethanol concentrations are widely quoted, such information does not take into consideration the effects of chronic administration, effects of simultaneous treatment with other medications, possible development of hypoglycemia, and reported fatalities with lower blood concentrations. Finally, continued efforts should be made to havealcoholremovedfromliquidpreparationsforchildren.Inthose

instances in which alcohol is a necessary solvent, preparations shouldbepackagedinsmallvolumeswithsafetyclosures. REFERENCES 1. 2. 3. 4. 5. CommitteeonDrugs,AmericanAcademyofPediatrics,Ethanol in liquid preparations intended for children, Pediatrics 1984; 734057. Anon, Panel recommends limits on alcohol content of nonprescriptionproducts.AmJHospPharm1993;50400. McCoy HG, Cipolle RI, Ehiers SM, et al: Severe methanol poisoning.Applicationofapharmacokineticmodelforethanol therapyandhemodialysis.Am,JMed1979;67804807 Golightly LK, Smolinske SS, Bennett ML et al. Pharmaceutical excipients.Adverseeffectsassociatedwithinactiveingredients indrugproducts.PartI.MedToxicol1988;312865. Engineer M, analytical Method Validation. Express Pharma Pulse,Oct.1998,13

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