..

Acyclovir 711
lo• and Pcd::2· oxidation, catal) sed by metal io ·
t,y~:i. cc,tlttollcd' during nebulisation into oxygen. " · l:iamlow EE. Blankenship DR, 8ryan HD; Bull Parent Drug
Ass 1961;22:122-6. · · .
'CIIII'-"-timing acctylc:ystel~ (u sodium salt), disodium
dOO sodium hydroddc. and punficd. water has been com- S. · Van Locuen AC. De Jong A, Van dcr Meer YO, Schwl~ten
HR (German). Pharm Weekbl 198S;l20:313-l7. . . .
available In the ~SA for admi~rati_on by inhalation
acbalilcr• or by direct tracheal lnstdlauon. When paclc-
alftPOulcs under nitrogen such a solution was staled to
111
»- ..i. 1ndefinlte11'•4 . Acyclovir (BAN, USAN) A , i ,
t,c Ill- nc Injection (neutralised with sodium bicarbonate ill ' r~
~ i n g 0.0S% disodium cdctatc) ir. ampoules in the • Ac:iclovir (rlNN); acydogua:nosine .
• ~ of oxygen scored at clcvat~ tcmJ>«:raturc;s (too• and 9~2-Hydroxyethoxymcthyl)guanin~; 2-amino;l,9-dihydro-9-
a20') sbCJWCd very slow decompos1t1on which followed . first- ((2-hydroxyethoxy)methyl}-6H-punn-6-one :
!n1erklnctics.s · · . CaH11NsO3 ,;:: 225.2 ·

aNCOMPATIBllJTY/COMPATI.BIUTY •
TbcrC is a possi"bl1i!f of physicai or ~hemical incompatibility
t,el1ICCII ~cd)'lcyslesne and followtng:. •i:ttpho!eridn, ampi-
..,,l___N>
cinin sod!U!1'• chlo"!etracycbne hydrochl?nde., chymotrypsin,
cryt1iromyan lac:tobionate.. '!'4?5! metals (1n particular copper, HzN~t,J-NI • .
iron. nickel), oxygen and ox1d1S1ng substances, oxytetracycline · CH2 0CH2CH20H
hydrodiloride. rubber, letAcydlnC' hydrochloride., trypsin.
Some aau'biotics may be ina~vatcd ir nebulised .with ac:etylc:ys-
td11C. . Acyclovir Sodium (BANM, USAN)
i=u,.t11ElllHrollMA110H. Ccimpatibility study between acetylcys- Adclovir Sodium (rlNNM) .
tcinc and some commonly used tablet cxcipients-Kerc J, Srcic C.H 10 N 5NaO> • 247.2
S, Urleb U, Kanalcc A. Kofler B, Smid-Korbai J. J Pharm Phar- CA~S9277-89-3 (acyclovir): 696S7-Sl-8 (acyclovir sodium)
..
macol 1992;44:SIS-18.
. .
·
Phannacopoelal status ·
BP, USP (acyclovir)
FORMULATION
· Prcparatioas
Exdplents
Excipiertts that have bo,:n used in prcsc~tatioris or acctylcystcinc Non-com~dial
include: . Zovirax (Wellcome).. Tablets; acyclovir 200mg. 400mg, and
T..bk:r..:.p.......;.n:; co!lc!d.::.! =!!:=; !.?!:t~e; ?n:!.g!?~s!~rn. !!~-~!~: 800 mg (Shingles Treatment Paclc). · .
microcrystallinc cellulose. SusPfflSion. sugar free. acyclovir 200 ingjs mL Dllumt: cquai
Grllllllltt and potrdn- (for oral solution): acacia; Jk:arotcnc volume of synsp or sorbitol 101ution.'(70Y,.). non-crptallisi"i
(El~): colloidal silica; dcxtrin: glycine; maltodcxtrin; sac- gt'adc. Ure of diluttd suspension 28 days at·2S•. butit ls rccom•
charin; sodium ascorbatc; sodium citrate; sodium methyl mended that dilutions arc freshly prepared.
h)'droxybcnzoate; sucrose; sunset yellow FCF (EllO): DL:.U-· Cream, ac:ydovir 5% wfw In an aqueous cream basis. Should not
toc:opherot; xylitoL '. · be c!iiutcd or used as a basis for the inC'orporatlon or other med-
Sol1111o,u (for Mbullsation or focai inst/I/at/on): disodium cde- icaments. . . .•.
tate; sodium hydroxide. . · " · Oplithalmk olntmmt, acyclovir 3% wfw lo a white soft paraffin
basis. . . . • . .. ··. ·.
f!:__drop,: baizalkoaium chlorid,;.disodicm cdclatc; hypromct-
,v.c; sodium hydroxide. ' /ntrawnOIIS infllSlon (Zovlru J.V.). powder for recoasdtutlon. ·
1n/tctions: disodium cdctatc:; llodium hydroxide. Vials containing the cqutvalent or 250mg and 500 mg _o r sterile ·
acyclovir (u sodium salt), for "ffl:Onstitution with water :for.
Pac1tat1ac injections or sodium chloride 0.9% injection to provide a solu- ··
A • . . tion or acydo'Vir 25 mg/mL · When reconstituted. pH Is aboul
pacbgc dcYdopcd by Hamlow ~, al 4 for an acctyl- 11. For further dilution. Zmimc 1.V. is compab"blc with:
:_anc S?'ution (that contained aoetylcyslcine. disodium. cdc- sodium chloride 0.9% injection; sodium chloride 0.45% injec,- · •·
pol sodn1111 hydroxide to pH 7, and water) comprised . a lion; sodium chloride 0.18% and glucose 4% il\)ection; sodium
11~)'1cnc plug dosure with a rubber diaphragm below an chloride 0.45% and glucose 2.5% injection; or compound
Plcbn~um seal fitted to a glass vial ancf was suii.ble for aseptic sodium lad.ate inj«tion. Reconstitution and dilution should
lhci ling or a sterile solution. Solutions lost less than w•. or be performed immcdiatdy before use and under run ucptic QOn• ·
r acety1cystc1ne content afrer 2 'years at r~m temperature. ditions (product containc no &ntimicrcbial prc:)Cfftti-ve}. The
. infu,ion is stable for PP to 12 houn at 20• when reconstituted
R.Ei:tR.ENCES and diluted is ~mmended; solutions should not be refriger-

pha:: ·,
I. Unt CJ ·
In: Cooper MS, editor. Quality _control an the
l97J:l:~uticat industry: vol 2; London: Academic Press.
.• ated.

Conta_lnen aod storage

2. Harnlow EE . : Solid stau . ·
l. T•llcy JR MPee~ GE. Anesthesiology 1967:28:934-5. 1 . ·
Acyclovir BP should be _kepl in a we_ll-c!osccS con~iner.
1973:30:Si6-;J,anan RA. Sommers EB. Am J HOSt> Phann Acyclovir USP should be preserved 1n ttghl containers.
 712 Acyclovir

Dosait: forms
Zovlrax tablets, suspension, cream. ophth.ilmic ointment. and
Acyclovir exhibited greater stabiiity in an alkaline
in an acidic solution during the development of a :~~.or.
1
.•
~h
Zovirax I.V. should be stored below is•: the cream. and the
m:onstltuted and diluted infoslon should not be refrigera11:d.
minutes in IN sulphuric acid and in IN sodium
bo'i:~
~ting HPLC m~t~od- for quantitation of acyclovir in llY-tlldj.
ointments, and tnJCCllons.4 When acyclovir was
bYcfrf~ 10
The 200mg tablets and Shingles Treatment Pack should be
kept dry; loss of 'potency' was about 12o/a and S¼, o~
larly, Du Guptaeta!S measured a 271/a and 13%1.>ssJ'
PHYSICAL PROPERTIES vir when i~ was boiled for 30 minutes .in supburic add~
sodium hydroxide, respectively. '., 811d 1q
Acyclo,ir is a white or almost white, ~rystallinc ·p owder. Negligible decomposition of acyclovir sodium was~
HPlC) when solutions of acyclovir sodium (Burroughs 'W(h,;
Mclrlllc polat come) S mg/ml in sodium chloride 0.91/o in,icc:tion or la al tll-
. Acyclorir is stated to melt at about .230°, with do;1:amposition S¾ injection were stcred in Vial!cx plastic bags at s- and .,;;o;e
(BP) or at tcmpcratures higher than 2so•. with. decomposition
(USP). · ·
37 days.s However. at s•.
pl'C(!ipi~tion of ac:ydovir wu nxi:
althouch the precipitate rcdissc:ilwd when the lerapcra!U,e
increased to 2s•. ·
Dbsodalloa constuts .
pK. 2.27. 9.251 · . · INCOMPATIBILITY/COMPATIBILITY
or
From determinations p:lnition coefficients Kristi t:I a/ 2 calcu•
lated the ionisation constants for acyclovir (by two linear regres- Acyclovir so:iium sterile powder (Zovirax, Burrou&bs Wdl-
sion methods) to be: pK_ 1 2.41 :I: 0.27 or 2.39 and pKa1 ~me, USA) is incompatible with hydroxybcnzbatts; prccipita.
9.06 :I: 0.88 or _9.JI. at room temperature. tio'1 may occur if it is reconstituted with baclcriostatlc water
ror injection which contuns hydroxybcnzo:ttcs. Further dilu,
Partition codtkieat · tion or reconsti'tutcd acyclovir solution with blood prodllClS or
Kristi t:t a/1 calculated values for apparent partition coefficients colloidal proteins is not recommended. ·.
or acyclovir between water and n-o<:tanol over ·a range of pH On admixture (in glucose S% iajcdion) of acyclovir sod.um
valllr$ at room temperature. Values for the 'real partition c:oef• Smg/mL (Burroughs Wellcome) with dopamine hydrocbloridc
ficient· (P) calculated. using two sets or results. by !WO linear 1.6 mg/ml (Abbott) or dobutaminc hydrochloride I mg/ml ·
regression methods were 0.024 and 0.022. . (Lilly). brown discoloration was apparent after l 'bours 811d I
hour, respectively.' Das Gupta et ars attril:::tcd such discolora•
. SolubDity . lion to oxidation of dopamine or dobutaminc; no 1oss·.orlC)'Clo:
Acyclorlr is slightly soluble in water; insoluble in ethanol: prac- vir was detected afler 2 hours at 25" in !admixtures of acyclovir
tically insoluble in most organic solvents: soluble in dilute aqu- .s odium (Smg/mL) in a 1:1 · ratio with dopami~ (Solopak.
eous solutions of alkali hydroxides and mineral acids. . USA}° 1.6.m g/mL or dobutamine (U!ly, USA.) I mg/ml. Solu-
· .«qclorlr sodium is soluble I in 10 ofw~ter. _tions were prepared in glu<:osc S% injection. · " •·
The manuractUrcrs or Zovirax . {Ru.,...,~~:-'°?s W~U~=~. US.A.) .A.~--:!o..-::- ~!wrn ;.·a• ~'f\~iitli11CU i.u UC visuaiiy compatibiewidl
state that the inaximua. solubility or free acytjc,vir in water at SOcommonlt used intnverious drugs (undcrcoadiiionssimalat~
Jr is 2.S mg/inL Kealey er al' report an intriasic solubility of ing Y-sitc injection) during a .4-hour study pcrioch.t 2S"·undc!'
lmg/mL · . '~- · · . ftuo~nt lighL6 •• · •
,,:\: · ·~:'.•;•.
The same workers' attempted to enhance t&e water s:;'.::6ility of
acyclovir at neutral pH by the Conna•!on of.!=Omplcxcs with FORMULATION .
ligands such as aic:ocinamide and raff'eine. Fonuation constants ·
(K1) were detcnniaed from a series of phase-solubility cxpcri~ · Exclplents
. mcnts and correlation was clcmoastratcd between· the forma- Excipients that have been· used in prcscntadons'ot a~oxir
lion constant and hydrophobicity or alic ligand. The low K1 include: , .• ··
values obtained for acydovir complcltcs dictate that.a high con- . Capsultr. ·11.c:tose; magnesium stcuatc; maizt. starch;_ sodium
=itration oflipnd is DCCCSSUY lo achieve solubilities at thcra~ lauryl sulphate. · · ·. • · . ·'
pcu(igUy active lcYCls (acydovir-<alfcinc K1 ..,'j 2.4 M- 1, Tab/etr. lactose; magnesium stcanate: microcrystaDine cdlulo5C:
1
acyclovir-nicotinamidc - 3.34 M- ). To ac!lievc solubility povidone: sodium starch glyc9llate. . •
eahanccmcnt. lhc caJcuJated .amount of caffeine and oicotina- Crt:amr. aqueous cream: cetostcuy1 alcoilol; liquid pua!iia:
midc required to-be··tolentcd pct' dose (SOO mg acyc:lovir) .is ~loxamcr 407; propylcnc st,col; IOdiani lauryl salpba!C: . : ,
•Uc .uid 9.4c. rapcc:lM:ly. 1bc authocs concluded chat c:af. Ourtmortr.macrogots. • -· '
fciuc and aicotinamidc were oflimircd value u solubility cnhan- Opl,tl,a/,nic olntmmts: white sol\
C1Ct1 ~D parenteral Cormulatiom of acyclovir. . . Topical prcpuatlons :· .
Dissolution Pcnetra~ion or acydovir through hwnan skin was~
from a macrogol oinl{IIC;'lt; I-fold and 8).fold inc:rc&JCS ~jjccl
Automated dissoliition &csting with ftow-in,icction analysis, dis-·
sot.,ticn profiles fo1 the antiviral drugs. DHPG and acyclovir. ftux of acyclovir were shown, rcspcc:tively, from a modi.
ir: capsule formulations - Kenley RA. Jackson SE. Visor GC. aqueous cream vehicle and ,i ·dimethyl sulpbo.udc
Winterle JS. Drug Dev Ind Pharm 1987:13:39-56. · ·c-ompared to the macrogol vehicle.· Formulations contal

STABILITY
acycl~vir S:-,' .. .. ·. .·
ucous
In cmn~a P_•cs and "!'c~. acyclovir So/o presented 1n .•n aq the
RcfrigcnHion of rec~ns1ituted sol~1i~n• of-acyclovir ~odium can . ~am (which ~?nla1ncd 40% propylene glycol 10 an<:re&SC aive
•queous ·soh,1b1hty or acyc:lovir)-was found 10 more ell'eC t•
result in the formauon of a prcc1p11atc. The prcc1p11ate redis-
lhan acyclovit S¼ in a macrogol ointment basis in thc uca
solves. at room temperature. mcnt of cxperin1cn1al herpes simplex infections.•