acetilsalicilato detn

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means of a fe l lowship grant by EliLilly and Co.LITERATURE CITED

(1) Bassett, L . G., Byerly, W. Sodium,Potassium, Rubidium, and Ce-sium, in Analytical Chemistryof the Manhattan Proiect. ed-~ ~~~ ~~~~ited by C. J. Rodden; ~ p p .345-8,bfcGraw-Hill, Kerv York, 1950.(2) Boltz, D . F., Mellon, M . G., Ax . 4 ~ .CHEM.19 873-84 (1947).

3)4)

( 5 )16)

Burkser, E. S., Feldman, R. V.,Zavodskaya Lab. 7, 166-8 (1938).Burkser, E. S., Kutschment, M . S.,Mikrochemie 18 18-21 (1935).Burr, I . W. Engineerivg Statisticsand Quality Control, LIcGraw-Hill, Yew York, 1953.Duvsl. C.. Chim. anal . 34, 209-21(1952).(7 ) Geilman, W ebauhr, W. . anal .Chem. 142 241-54 (1954).8) Godeffroy, R., Ber. 9 1363-8 (1876).(9) Kahn, B., ANAL.C H E X 28 , 216-18(1956).

(10 ) Moser, L., Rietschel, E., ,l.ionalsh.(11) OLeary, W. ., Papish, J., IND.E N G .CHEM.,ANAL.ED.6 107-11

46 9-22 (1925).(1934).(12) Scroggie, A. , J . Ana. Chem. SOC.

(13 ) Snell, F. D., Snell, C. T., Colori-metric hIethods of Analysis,Vol. IV. v . 482. Van Nostrand.51 923-5 (1929).

New York, 1954.RECEIVEDor reviex September 13,1956. hccepted M arch 25, 1957.

Determination of Salicylic Acid in AspirinCLIFTON W . STRODE Jr.1 F N. STEWART H. 0 SCHOTT a n d 0 J COLEMANJohn F Queeny Plant Monsanto Chemica l Co., t . Louis, Mo.

b Spect rophotomet r i c and v isua l tech-n iques for the quant i f i ca t ion of theU.S.P. l imit test for sal icyl ic acid inacety lsa l i cy l i c ac id and asp i r in tab le tsar e descr ibed. By cont ro l l i ng thevar iab les which m ay a f fec t the fer r i csa l i cy la te co lor and the hydro lys is ofasp i r in prec is ion and accuracy w i th in0.005 are i l l us t ra ted.

ESTS LISTED I ~ Yhe U. S. Pharmaco-T eia for salicylic acid in acetylsali-cylic acid and aspirin tablets ( 7 ) d onot fulfill the needs of modern indu strybecause they are limit tests-Le.,they on ly dem ons t ra te tha t the m a-terial being examined contains moreor less tha n a n appa rent 0.10 or 0.15%free salicylic acid. hfuch of the acetyl-salicylic acid produced today containsless than 0.05% free salicylic acid, andi t is frequently necessary that themanufacturer know within 0.00570 orless the exact salicylic acid content ofhis product . Consequently, man y un-published modifications and extensionsof t he U.S.P. test ha ve evolv ed, suchas increasing sample and alcohol con-centrations, using other solvents, andtitratin g a ferric alum blank with stand-ard salicylic acid to match the colorof t he sam ple solution. As thesechanges have been developed independ-ent ly, and in some cases apparent lywithout proper consideration of t h evariables involved, conflicting data arefrequently encountered.Edwards and coworkers ( 3 ) h a v emad e a comprehensive stu dy of thesevariables, including the kinetics ofaspirin hydrolysis and the effects offactors such as pH and ionic strengthon the ferric salicylate test specified

Deceased.

in the Bri t ish Pharmacopoeia . Theyrecommend conduct ing the tes t at25 C. in a solut ion buffered a t pH2.9. Colorimetric measurements arem ade a t t im ed in te rval s to p rov ide anextrapolated correction for the hydroly-sis of asp irin t o salicylic acid . A sim-plified procedure is suggested involvinga single measurement corrected for thepreviously determined hydrolysis ratea t a fixed temperature and weight ofsample.Paral le l work in this laboratory in-volving modification of the U.S.P.test, which specifies a more dilutesolution of aspirin th an does the B.P.test, has essentially verified the con-clusions of EdJvards. Th e hydrolysis ofaspirin must be controlled by definitionof pro ced ural detai ls involving concen-t ra t ion , t em pera tu re , pH. and the t im eduring Jvhich hydrolysis is significant.Calibration or comparison standardsshould be a t the same p H an d essen-tially of the same composition as thesample solutions. il pract ical tes tshould provide a depth of solutioncommensurate with adequate sensi-t ivi ty.Incorporating these considerations,the following spectrophotometricmethod has been in rout ine use inthis laboratory for the pas t 12 years.The accompanying visual comparisonmethod has been used in routine proc-ess control for the past 2 years.

SPECTROPHOTOMETRIC METHODThis method is somewhat analogousto the simplified procedure suggestedby Edwards in that a previously es t i -mated hydrolysis correction is eni-ployed, It is applicable for the de-termination of up to about 0.25%free salicylic acid in crystalline a cetyl-

salicylic acid or in granular or table teds tarch-aspir in formulat ions nhich maybe white or tinte d w ith pink or greendyes.

A p p a r a t u s a n d R e a g e n t s . AP hotovol t Mode l 102-E L u m e t r o ncolorimeter n-i th monochromaticfi l ters and 100-mm. cyl indrical cel lsis used for t r a n s m i t t a n c e m e a s u r e -m ents . Othe r ins t ru m en ts wi th s im i -l a r l i g h t p a t h s t h a t t r a n s m i t r e la t iv e l yn a r ro w b a n d s a t a b o u t 5 1 5 a n d 5 7 5mM would proba bly be sui table .Acetylsalicylic acid is purified byrecrystallization from isopropyl alcoholto an apparent free salicylic acid con-ten t of less th an 0.005%.Ferric a lum solut ion is prepared bydissolving 4.0 grams of ferric ammoniumsulfate in 40 ml. of w ater and dilu tingto 50 ml. X 10-ml. aliquot of thissolution an d 10 ml. of 0.5S hydrochloricacid are di luted to 500 ni l . with xater .The di lute solut ion is s tored in a re-fr igerator and freshly prepared eachweek.Standard salicylic acid is preparedby dissolving an accurately weighed0.1-gram portion of sublimed salicylicacid in 10 ml. of specially dena tur edFormula 30 alcohol (SD 30, 1 volume ofmethanol in 10 volumes of 190 proofethyl alcohol), adding 0 1ml. of glacialacetic acid, and diluting t o 1 liter with

water .Ca l ibra t ion . I n o ide i t o minimizethe t im e dur ing which hydro lys i st akes p lace , the co lor im e te r , a f t e r a10-minute warm-up period, is bal-a n c e d t o 100% t r a n s m i t t a n c e a t515 mp with a blank. Th e blank is1.9 ml. of SD 30 alcohol, 0.5 ml. ofglacial acetic acid, and 2.0 ml. of diluteferric alum solution, diluted to 100 ml.with Ivater. It should be freshlyprepared.From 0.2- to 2.0-ml. aliquots of t h estand ard salicylic acid solution, equiva-len t to O . O l ~ o o O.lyOalicylic acidin 0.2-gram samp les of aspirin, a re1 184 ANALYTICAL CHEMISTRY


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added to 100-ml. glass-stoppered cylin-ders.One gram of purified acetylsalicylicacid is now dissolved in 9.3 ml. of SD 30alcohol and d iluted to 100ml. with waterpreviously adjusted to 25 C. A timeris s ta r ted as the water i s added.A 20-ml. aliquot of the acetylsalicylicacid solution is added to one of thecylinders containing standard salicylicacid, followed by 2.0 ml. of ferric alumsolution . The volume is made up to100 ml. with water a t 25 C .Th e t ransmit tan ce is measured wi th ina maximum of 5 minutes, noting theexact t ime following the reading. Th enumbe r of 15-second intervals requiredfor the m anipula t ion is mul tip lied by ahydrolysis constant of 0 .001, and theproduct is added t o the equivalentpercentage of salicylic acid in 0.2 gra mof aspirin represented by the appropri-ate aliquot of standard solution taken.A fresh portion of t,he purified acetyl-salicylic acid is dissolved and aliquotedfor treatment with each increment ofsalicylic acid. Th e corrected percent '-ages are plotted against tra nsm ittancesin the usua l manner .Th i s c u rve a t 515 nip is used in theanalysis of crystalline acetylsalicylicacid, and in the analysis of white- orgreen-tinted starch-aspirin forniula-tions. For pink-tinted starch-aspirinformulations, a separate curve based onmeasurements a t 575 nip is constructed.D e te rmina t ion . I s in the ca l ibra -t i on procedure t he i n s t rume n t i spre l iminar i ly w armed up a nd ba l -a nc e d a t t he a pp rop r i a t e w a ve l e ng thwith the reagent b lank . One gra m ofthe ace ty lsa l icyl ic ac id sample , or aweight of s ta rch- aspir in formula t ionc a l c u l a te d to c o n ta in 1 .0 g ra m ofacetylsalicylic acid, is dissolved orslurried in 9.3 ml. of S D 30 alcoholin a d ~ y , 100-nil . glass-stopperedcylinder. Th e mixture is diluted to100 ml. with water at 25 C., and t 'het imer i s s ta r ted concurrent ly . If starchis present t he m ixture is fi l tered inimedi-ately by suction through a small circleof W h a t m a n S o . 50 fil ter paper.A 20-ml. aliquot of the clear solutionis treat ed JTith 2.0 ml. of d ilute ferricalum solution and diluted to 100 ml.with water. Th e transmit,tance is meas-ured and the t ime noted . ,4hydrolysiscorrection, calculated as in the cali-bration procedure, is deducted from theapparent per cent salicylic acid corre-sponding t o t h e t ransmit tance found.

VISUAL METHODThis method is l imited to the estima-tion of free salicylic acid in essentiallycolorless samples.A p p a r at u s a n d S t a n d a r d s. h l a t c h e d100-ml . ta l l -form Nessler tub es a reused wi th a su i t a b l e r a c k . A series ofs t a n da rd s i s p re pa re d by d i lu t ingf rom 0.2- o 2 .0-ml . a l iquots of t h esta nd ard sa l icylic ac id so lu t ion , inincrements of 0.2 ni l . , to about 50ml . i n se pa ra t e X ess le r t ube s . Ea c hso lu t ion is t he n t r e a t e d w i th 1 .9 ml.

T a b l e I9cPresent0.0020.0020.0020 0020 0020 0270 0270 0270 0520 0520 0520 0520 0750 0770 1020 1020 SO2

Dete rm ina t ion of Sabcy l ic Ac id in Acety lsa l icy l ic Ac id b yS p e ct r o p h o t o m et r ic M e t h o d7 ound

0 0040 0040 0030 0040 os00 0250 0310 0270 0520 0430 0560 0480 0770 076

0.0020,0020.0030.0080.0020.0270.0270,0280,0540.0490.0600,0510.0760.0740 102 0 1020 104 0 1020 SO2 0 098

Std. dev. of precision, 0.0024Std. dev. of accuracy, 0.0023

Dev from Known0 0000 002$0 002 0 0000 001 o 001

O 006o 002t 008 0 000-0 002 0 000O 004 0 0000 000 o 0010 000 o 002-0 009 -0 003- to 004 0 008-0 004 -0 0010 002 o 001-0 001 -0 0030 000 0 000J-0 002 0 0000 000 -0 004

of SD 30 alcohol, 0.5 nil. of glacialacetic acid, and 2.0 ml. of dilute ferrica lum solu t ion , then d i lu ted to 100 ml.wi th water . These stan dards a refreshly prepared every two weeks andare kept covered when no t in use.D e te rmina t ion . The sa mp le ist r e a t e d as i n t he i n s t rume n ta l me thodexcept th a t , if no sta rch is present , a2 .0-ml. a l iquo t of t he i n i t i a l und i lu t e da lcohol so lu t ion is taken for colorde ve lopme n t : w a te r , p re v ious lycooled to 10 C . , i s used for the f ina ld i lu t ion . By c onve n ie n t p re a r ra nge -me n t of a pp a ra tu s a nd r e a ge n t s , t hetime required for subsequent manipula-tions is held n thin 30 seconds. With inthis interval the developed samplesolution is compared longitudinally n-iththe s tandards above a whi te back-g round . F rom the s t a nda rds mos tclosely matching the sample, the sali-cyc l ic ac id content i s est imated to thenearest 0.0057,.

RESULTSTypical calibration curves for thespectrophotometric method show con-formance to Beer's law.Hydrolysis curves were constructedfrom transmittance ineasurenients madea t t imed in te rva ls on thermosta tedsolutions of asp irin an d ferric alum.These curves indicated that, under the

conditions of the spectrophotometricmethod, salicylic acid increased at arate of 0.0036% per minute for thefirst 5 to 7 minutes a t 25' C. The ra t ewas 0.0054% per minute a t 30 C.a nd 0.0028% per minute a t 20 C.This emDhasizes the need for reason-

cylic acid by a procedure analogous tothat followed in calibration for thespectrophotometric meth od. Results ofthe analysis of these mixtures (TableI) indicate that, in the range of con-centrations measured, the precisionand accuracy of the spectrophotometricmethod are within 0.005% salicylica c id a t t he 95% confidence level.Comparisons of results obtained bythe spectrophotometric and visualmethods (Table 11) indicate reproduci-bility of comparable m agn itud e be-tween the methods.

Tab le II Com par i s on of Spec t ro-pho tom et r i c and V is ual M e thodsSample Spectro-Salicylic Acid, 7cSo photometric Visual

1 0 028 0 0252 n n i x 0 0203 0.032 0.0304 0.054 0 0505 0.036 0.0356 0.045 0.040? 0 043 0 0400 030 0 025Std. dev. ofreproduci-bility 0 0024

Results of the analysis of typicalwhite, pink, and green aspirin granula-tions containing from 10 to 2070 starchare given in Table 111. Although theover-all precision was maintained, in-dividual determinations on some of thepink granulations varied the most.

ably close temperature control in theing out the visual procedure within 30to 40 seconds a t 10 C., the hydrolysis In a t t e mp t s t o circumvent hydrolysiserror appea rs to be within the experi- complications, some experimentationmenta l e rror . was conducted toxvard developing theK now n a moun t s of salicylic acid were ferric salicylate coIor in nonaqueo usadded to specially purified acetylsali- media. Th is work was analogous to

spectrophotometric meth od. By carry- DISCUSSION

VOL. 29 NO. 8 AUGUST 1957 1185


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t h a t of Wisp and Brode 8)and Solowayand Wilen 6) , who described methodsfor carrying out qualitative ferricchloride test s for phenols in organicsolvents using pyridine as an alkaliniz-ing agent. Khi le this approa ch ap-peared to have some promise as thebasis of a spec t rophotometr ic method,sufficiently stalile solutions of aspirinfor permanent standards for visualcomparison could no t bc prepared.Standards containing only s:ilicylic aciddiffered in hue from solutions of aspirin,making visual comparisons subjective.In aqueous media the ferric salicylatecolor is sensitive to pH and to changesin ionic s t rength a t the same pH (1-4).Glass electrode measurements made onsolutions prepared according to theU.S.P. monograph directions Y) howedt h a t t h e pH of the aspirin solution isabout 2.8, whereas the pH of thesalicylic acid comparison standard isabove 3.5. Figure 1 i l lustrates thevariation in ferric salicylate transmit-tance when the pH of salicylic acid solu-tions is adjusted from 3.5 through 2.8with acetic acid. This tend s to indi-c a t e t ha t t he U S P omparison stand-ar d is dark er tha n the color producedby an equiv alent amo un t of salicylicac id in the aspi r in so lu t ion and tha tresults based thereon may be too low.In the spec t rophotometr ic methoddescribed, pH discrepancies and pos-

T a b le 111 Determina t ion of Sal icy l icAc id in S tarch-Asp i r in Formula t ions byS p e c tr o Dh o t o m e t r ic M e t h o dSampleNO.

12345678910

123456

123456

Salicylic Acid Found, oKhite Granulations

0 .032 0 .0320 .030 0 .0290 .026 0 .0230 .022 0 .0230.029 0 .0260 .036 0.0360.033 0 ,0320 .024 0 .0280 .022 0 .0180.020 0 .023Green Granulations

0 057 0 0600 053 0 0510 073 0 0690 057 0 0570 045 0 0460 041 0 038

Pink Granulations0 043 0 038

bP H

3.5 2 8 2.3l l l l i l l i l l

c

45-0.26 MG SAL ICYL IC ACID -0 0 0.5 4.0ML.GLACIAL ACETIC ACID

F igure 1. Effect of acet ic ac id on t ransmi t tance offerr ic a lum -treated solutionsMeasurements made at 5 15 mg; 100-ml . volume

sible errors arising from small hgdrolg-sis constant variations are minimizedby incorporating equal amounts ofacetylsalicylic acid in the calibrationstandar ds. In the visual metho d, ace-tic acid is used to adjust the pH of thecomparison standards approximatelyto the nomina l va lue of the samplesolution. The acetic acid has the fur-the r effect of pre ven ting fading of th ecolor and precipitation, presumably ofan iron compound, which was observedt o occur in stored color standards whichhad not been acidified. Th e mean ah-sorptivity of a typical series of stand-ard s conta ining acetic acid was 10.7,while that of standards containingaspirin was 10.8. A similar seriesacidified to the same pH with hydro-chloric acid had an absorptivity of11.9 indic ating th at t he effect of aceticacid is more similar to that of aspirin.Evidence has been presented tha tthe ferric salicylate color is influencedby th e concentration of organic solventin aqueous mixtures 1, 6, 8). Visualobservations substa ntiated by tristim-ulus measurements 5) on ferric sali-cylate solutions c ontain ing respectively2 a n d 20 alcohol or acetone ind icatedth at th e color intenaity increased and th ehue varied with t he concentration oforganic solvent, and th at acetone hada greater intensifying effect than alco-hol. Because the difference in inten-

t o 100 ml. with water, represents asupersa tura ted so lu t ion a t 25 C. mightjustify an increase in the alcohol con-centration. In the authors experience,however, crystallization during manipu-lation has never been a problem if t healiquoting and second dilution are per-formed with the rapidity specified inthe procedural details. Were thealcohol concentration in the samplesolution increased, i t would have tobe ad justed in like manner in the stand-ards for the v isua l method.

LITERATURE CITED(1) Beck, P. F., Dansk . T idsskr . Farm .(2) Broumand, H., Smith, J. H., J . Am.Chem. SOC 4,1013-16 (1952).(3) E dwards, L . J., Gore, D. S . Rapson,H. D. C., Taylor, 11 P., J . Pharni.and Pharniacol. 7, 892-902 (1955).4) Illari, G., -Inn.ch im. applicata 29,490-500 (1938).( 5 ) XIellon, 31. G., Analytical -1hsorp-tion Spectroscopy, pp. 535-7,

IYiley) Sew T o r k , 1950.( 6 ) Soloxay, S . Kilen, S. H., Ar.4~.C H E M . 4, 979-83 (1952).( 7 ) U. S. Pharmacopeia, XI, pp. 19-21,Mack Writing Co., Easton, Pa.,

1055.(8) Wisp, E. F., Brode, IT R., J . Am .

9, 289-302 (1936).

0 014 0 042 sifying effect was not large. alcohol Chein. SOC 6 1037 (1934).0 054 0 0590 050 0 0560 059 0 0530 061 0 062 U S P est.has been retained as a solvent in theproposed methods in harm ony with the REC EIVE Dor reviely October 8, 1956.Accepted ,April 10, 1957. Division ofT h e fact th at th e initial solutio n in th e AknalYtical Chpm istry, Sym posiu m onAnalysis of Fine Chemicals and Pharma-precision 0 0023 proposed methods, contain ing gram ceuticals, 130th Aleeting, AkCS, .itlanticCity, K . J.,September 1956.

Std . dev: ofof aspirin in 9.3 ml. of alcohol diluted

1186 ANALYTICAL CHEMISTRY

acetilsalicilato detn

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