1074 Timolol _..

Mdt-,p ofllC Tobku: calci11111 bJdfOICII phosphate; ~ cicric acid.

anhydro us: llclOIC; mpaiu m llearatc; Dllia IWda; lllic:ro-
T1,_1To.d1~ crystals mdt It 2JS• to "6". with decomposition. crystalinc odhllote; poacau 4R (El24); soc&. Ddi at,co1..
pH late; sunset ydlow FCf (El 10): lak.
Oraltlr ops:dl uol;.,,o p,-at,c ol.
A saturated aqueous solution of 1li.1TO:cbw sodiutrt hu a pH of
about 1.9. /lljfflio, u: - - IIJdnwdc.

Diaoda dN CNSWl ts
Bioell•......
It ·ns poscalaled "7 0., ct o1s.11aa, dae ~~
• ..,.__
PK.-2.2. 6.7. 10.l . al ._....... 'wllidl
.
caaod
sodium CNlall -
betwen ..,... • tbc same labelled coa1C1K. .._ • pen
SoWllcJ due to inadcqua lc ... , procedun;s; ....... _. • • more
77r,.madw so,/i,,,,, is wry slip1ly soluble in W11Ct; sliptly solu- :aa:uracc HPLC- -,mdho cf coald.raulliaJlallr..rcnakJ.
ble ~ ethanol ; practica lly insoluble in acetooc. ia ddorororm. DUiooq-.:
111 CCJfVClftdioa willl a diDicaJ stucly.dlal ladicat fut two
aad IQ cdler. ,, is soluble io sol•tio u or albi ltydn,Kidcs, in leoce ia •ypodayn,id paticaU. 0anJ d af ~ l : I
hor solucioas or alkali carbonaca. and in mineral acids. brand$ or tlayrosiae rodium tabiiU ~ lliocqch I 1 lecure
£1«1of,H lhcy were chcmicallJ equmle at. bec:a• iiibomad diJnue
sodium powder had bcca U9Cd 10 pn,cl:,c,c die lllllecs. aacl
The solubility or thyroxine sodium dectcuc s as pH ra11s. The
solubility is incnased whaa the pH is incrased allow pH 7.4. because of striap l qaali&y coauol pu,~• --t'ill ~ I'!°"
ductioa proocss. nae factors CIOlllribaled ·CO 111t pn;dacuoa
Oilul■doa of tablets wida dayroxine sodiwn ~ ~ "' o( lbc
labdd..i m. . · - · ·
The USP spccifia that for Lcvothynwne Sodimn Tahlcts USP
Two lhyn,xinelOdium tablets (l.cYoCJlioidads,.dlraW)wm
not less than 5S% or the labelled amount oCCuHttJ.NNa04 is dccmcd lhcrapcucicallJ int.ercb aa,eabl nfter.., wa daaapy
clissomld ia IO minutes. Distolutioa medium: SOOmLot'Ci.OSM
phosphate buff'cr. pH 7.4: Apparatus 211 IOOrpm. aldlough che area lialdcr ~ ~ - ~tio ;a
~"fl'SIIS time cane wassipificaady pacer followilll......,_
A--
tion or Levoduoid • aftcr"S711lbroid (m 11 ~ ) . '
STABIUTY
'!11,roxiae-soclium is stable ia dry air. but ic·may tuna piat oa ·. WERE NCES
exposu~ tc, 5&ht. . .
I. Taca J. Oin Chim AcU 1959;4:427-37.
&posu~ or thyroxin m dilute aqueous solution. to bigh
e.
and traosf'onna- 1. Brower JF. Toler DY. RCCP,OJ..---,a- JC. J Plaann Sci .
energy gamma rad"aation causes de-iodination 1 198-4;73:IJIS-17.
1ion into other i4,dinated o,pnic rnoltcu ~ ·
J. Das Gupta v. Odom C. -~ ~ PlallalllmJ J. 1 Oin
Bl'OIIIIU' n oJ1 round that when bulk samples of thyroxine · rnarm ancr jyw,jj-_ jjj-o, .
~-:."ii ...t;~ iiibje.:t W Ul.7i11g •i W- iu • Y.:uwa cncr pbol-
4. Cafmeya- NR. Wolrsoo 88. Am J Hosp Plwm H91;'48:7J.S-
~ pentoxidc. dcciom;,ositioa in the order or 10% 10 15% ' . . . . .
9.
in 4 hours occurre d ;r the vacuum was not mainrained below 9,in .
10mm or mcn:wy . Ho~ . thyroxine sodiu~ S':>lucions in S. Dong.Ill. Young VR. Rapapoa B (lc:aaJ. Dni, Jaldl
Phann 1986-.20:77-t . . .
0.0IM ~ i c sodium h)'dtoxi de "WCte stable oYCr a 6- W-dliams LL. Olny RW. WoU'soa BB.
moach period wnen stored at S-. 6. Curr,y SH. Gusns JG,
Drug lnlell Oin Phann 1988;22:Sl9-9l. .
TaWds .7. Blouin RA, Oiftoa GD. Adams MA, F • TS. FluccfJ.
Followiq extraction of' dayroJdae rrom lhyroxiae sodium Oin Phann 1989-,1-.581-92.
lableu ( d ~ a stability-iadicatiq ff PLC analysis) . mules
iadica~ daac the 200 micn,pam pink tablets rrom oac 111111u-
ract11Rt •&:hie d an cxdpiea& or cxcipieacs that accelcrarcd Timolol (BAN~ USAN. rlNN)°
This cdfect SUFltd . . . &14 ~ ~
depualioft of diyroaio c.J eatalyti WU
.. .. •_(Sl-l-u rt-Bu1 yl1.mi no-3-(4 -morph olitac,. 1~3-yt .
IO roqube 111¢ prc:$4:Hoe or&pt.
pan-2-ol ; (S)-l-( (l,l:-d ilaech ~)f4-( 4-mor -
FUnHE a ~ T I O f f . S.,.bilitJ-iDdica1it11 assay. disroludoQ;,. 'o~y)pro
l..J.Jl)oxy}-2-pnip.ol f .:· · .·
~ coatcat llllil'otmit)t o f ( ~ sodium vi tablec.-Rich--
pboliayt)-1.2.S-tbiadiazo
: c.,H?AN 4o,s - 316.4 •. . .
bdmcr st. Amer TM. J Pba,.a Sci 1913;72:1349-SI. -

INCOMPATIBIUTY/COMPATIIIDTV
APJ)fflf tl lcac:hiag ordiethyl ;hthalaCC. ;ICdcnt u a plasticiser in
the cicsicxa~ mtc, one wand of diyrotiae sodium tabletscon-
was
detected ia boules coataiaiaa 100 lab.lees. but not in bo&tles
taining 1000 tablets; IIO leaching was'clclcctecl in thn=c· othet-
·
brands.4
Tamolol Maleate (BANM . USAN. rfNNM)
FORMU LATION C:, H:JNJO_,S.CJH•OJ =432.S
C fS-:?68J9-7S-8 (timolol); 26921-17-S (timolol maka1c)
. Excipitn ls . .
Pkannacopoelal s«alus
Excipicnts that have been used in presentations.of lhyroxine
sodium include: BP. USP (timolol maleatc)
 'Timolol 107S
Prepuadoas
(CuH~N.OJS.C.H.O,.) is diaohot in 20 minutes. Dwolatioa
~ mediam: 500 mL of O.IN laydroclaloric acid; Appuatus I at
T.-lol Tablces BP (Tunolol Malca&c Tablets) Coa • • IOOrpm.
inalcate. Tableucontaiain.. i1I acb. l0
'Omolol,
•
IO uuoa
~~!!.~~lol
u.·-:-- ~-=:;=:).·~~~
• taiD tinwlol

....__te puri6cd W&lcl'. pH 6.S to 7.S. Eye

III STtWUTY /
. .CODlaiaiq the equnoalcnt of0.2S% wfv and 0~% w'- of
limolol aie aaally available. •· TanololmaieauiltepCNICd" IObeulftmdylUblcat room._.
Tinaolol M~le Tablets USP. peratlft both ia dacsolid ICale u4•aqueous tolutiom (the lat-
ter pnM,ciCled from lipt). lloftwr, la sdlutioa. dec1n11110lidota
TeatOlol·M·te-Ophthalmic.Solutioa USP. pH 6.S'Jo 1.S
1i111o1o1 Ma&,11: and Hydrochlorothiazide Tablets USP. • CUOCQll'OQ~10cln... s~araot...,._wcn-
N ~ q l .. .. violec imdiation: 1111c pH.or.,··.... •bility a abcMat P.1(4.
Sacral dqradatioll pn;dilclr (mdadiq isoumolol. 4-bydroxy-
Bcdsil ~
- -., ·r.k timolol
.,{,_:-_. .~ • .;i,',J~~-ff.t . .. mabte I0nt• .HDOrpbalioo-1,2,S,chiidime, aad ~3-morpboliDo-.
a ~·,.-,u1- 7 ' ~ ~ ·..;klOmg. 1.2.,_,lriediuole l~),-W ~ llolated. ID die eolid «a1e.
T ~ ~ ) . .£~ ..,,._ tiaaolol (u maleate) Cl.2S% w/v a 5% ._ olliliaaW:~ ~ ..,._ wlaca k was .....
anclo.5%•/Y. at ts" for 3 wecb (loo,4 rclatne laamidity). wbaaa ao doooat-
£.w tlroi,,_~ preservative flft. timolol (u maleaae) 0.2S% w'v and poticioa was DOlcld oa ap,an.&o iDtAmc altraflOlct. ~
O.S% wfv. ' was
tion, although surf'ace.dilCOloatioll oblenecl. ·
Eye drop IOlulioas of timolol malcatc f.r/4 w/Y al pH 2.6. 6.1.
c.c~IMl's•-•once 9.7. and II.I wcre.saailised ei1ber by autodavins al 110" for
Sollditot~ 30 minaaa or by tlaile filuatioa;S acalen1Cd -.ability tat1 at
r~:~1eaae BP should be kept in a well-dosed cooaainer ~. w. aad IO" wae dacD IIDdcrtakea. Optimum stability of
uil~from fipL timolol auatc was inc&:aso1 at pHU . .
:.::::!' -~ USP should be pttSelWd in wdl-c:losed con•
iNCOMPATIBIU'.fY/COMPATIBILITY
~[OIJ!I# .
Tuao~.Maleate Tabicas USP should be praemed io well-dosed AdlorpcioDO,limalolOGIO~a dsoct,catswusbowDIO .
COD&amers. decRUe ill die order: dwQIII > mapesiuaa crisl~tc > rcp-
Tuaolol Maleatc Ophahalrnic Solution USP should be PftSCl'Ved la.r at&apalcife-cialoidal allapwpc > tao&a.6 ID amcn1. die
ia light. lipt«siswn cootaiDCtS. · cxteotofadsocpcioaiDcn:aedudlepH(raagcO.S IOLS,at3r)
The coatainer for 6locadraa tablets should be kept wdJ closed WU i.ncRucd wbcrcuncglipble~ in ahedqrecof adwp-
Storage should be in a cool place. protcded fr.:,m lighL · tioo occumd with inaase in tcmpcratuic (ranee n- sen.
to
limoptol eye drops should be protected rrom light. Tbty a.re
stable at room temperature. . ·

of~~--
FORMULATION

PHYSICAL PROPERTIES Exdplellts

Excipicnas that.ha"!C been used :o·pccsco.taaions
Tunolol ~ ~•~alt exists ,as a white or almost white crystalline eate iodudc:: · . ·
· powder or as colourless crystals.
To6ku: iodigo carmine (El32); magnesium IICU&te; microcrJs-
Mtltiacpolat ~lline ce!lulosc:; '1ardL . .
E~ ..-ops: ~ u m cbloride; sodium -add p~ec;·
Tunolol ~ melts al about 199•. with decomposiliocL . sodi~ hydro~ sodium pbospbate. . • . . .
pH
BloaTa11aWlty
pH of a 2% wfv solution-: or 1imalol maltatt. 3.8 to 4.3.
miiociat1oa -.at . The onl bioavailability .of:timolol ~ to lbc
· rou~ bas 1ieca cabda\ed as 7S.1% and 61% :I: 6% ·i n ~
aura~
pK., ... - iQVOlviag he' aad I.ca' bcaiqay wlll!llcffl. sapccliwly.
PK. w.lucso(9.031 and 9.212 ha~ been dcaennined ~ • i o - t
T~as•etaalMl1fflJ . l
~ ~ , ~• M;~nd lS~. rapcetivdy. _
p ~ cocik:ictit Skin permeation k ritro or~ malcate from.a IOm,/mL ·
• . sollltion in buft'cr (pH 7.4) through human cadaver skin waa.sis-
·a.o, 11 <wa1er1ocianon:, , :91 ~ .. · nificantly enhanc,ec: by the addition of.Jauryl chloride.• An
An-octanol-water partition coeffic:icnt or 82.0 (log P. Ul) was increase ia ~ C'OCICClltration OC: lauryl chloride froni 6% vJv
calcub~l at pH 7.4 al 3~. . ''? .10%. vJ,, • ~ the ""-' t•molol maleate pi:t_mcatioa, as
Soiatimty; d~ an mcrease.111·t~ d_urat~ llf' appliC.ation..Dimcthyl ~ -·
~xidc 10% '1/v and oleic acid 10% v/v also enbaind pemaea. ·
T"""1ol ma(tatt is soluble I in IS of·water. I in 21 of Clhanol, uon. although to a lesser extent~ . . . .-.. · :·.. . .
and in methanol; it is sparingly soluble in chloroform (I in;40)". Permeatioo of'ti~ through hairlcss11IOCI# skin in wiro was ·
and in P..ropyJeac.glyc:ol; it is prac:tically insoluble or ia:soluble studied from scvcrarr:cscrvoiis with or without a rat~trol- • •
in ether and in cy~loheitane. ling membrane '(Silutic, polyethylene vinyl acetate. or
porous polyp"?py~).1 _The reservoirs were hydrophilic .(4¾
micro-
Dissolution
?'rmellosc ~n•m en punfied water or I Y. Carbopol 934 in pur-
The USP specific$ th.u for T imolol Malcate Tablets USP cot less ified wa.tCf, adJustcd to pH 7) or hydrophobic (4Ve Acrosil 200 in
than 801/. or the labelled amount of timolol calcate silicone ftuid or Plas1ibasc).
 1076 Tolbutamidc

Ocular ddl, ery . 7. Else OF. Sorenson H. Edwards IR. Eur

The release rate of timolol In •itro rrom J Oia Pbannacot
a Oclritc (a polysaa:har• 1971:14:431--1.
idc. low-aoetyl gcllan gum) 0.6% sol 1. Wilson TW. FltOC' WB. Johnson GE. Holm ·
u~ WU
rrom. hydroityclhykcllulose O.S% solulion: bolhsimila! CO lbat MC. Huber PB,ral. Oin PhannacolTbcr 1912es 01., Tlianc:o
tained limolol malcatc 0.34% and maa solUUOC\SCOf!• ;32(6):676--ls
nltot (IQ ldu!M ~ 9. Soni S. Jaia SK. Jain NK. Dn1
city).•• However, in rabhlt.r, grcacer ocul 1 Oct hid ,.._ ;
ar c:or.cien~doni ol 1992;11(10):1127-35.
timolol were measured rrom lhc Oclrice
tolutlout ~~ II• au ;o. Rozier A. Mamet C. Grow J. Plaioanet B. Ill J Pham
inc the study period: • . . . .· . • ' ceutics 1989-.57:163-1. ia-
·
,n ~ -~ " the ocular bioavalla~tt -c i!-..-,. . . •t. Thenncs F. Rozier A. PluoaDe& 8, OnM
unde collQefttration
aca. raque vcnus time~-°"~~~•~
ous humour. and lrit/dllai'y bday.' la_
~~ ·: ceulics 19 9ia t~.
l Finne U. Kyyr6nca K. Urui A. J
latJ Plauma.
J.
·
· solutions with 0.6% ~i c:;·~ ~ -~ CoalrOIW ldcase
~• er r~
SIW ~) an d With pol . ... ~ 7·.'"_. ,'-
yYI . .. . ·,\,'.., ··-r:,r;--~
polymer.) than rrom the rcf'ereac~
'~
,,,- OJ%~;.,
e IO I~ ·. ,, .. , . ;.. /,.
•
1919:10: 189-94. ,

I990:65: 19-27.
•
ll. Finne U. Vlisinca V. Urtti A.
Int J Pllanaaciealic:
The suitabt1ity of alkyl !"OllOelten o(~ _
14. Finac U. R6nlct6 KM, Urtu• •
malcic anhydride) as bioeroclil,le add Yit iy(,~ ~ A. J Phana Sci
te
con1rollcd-rclcase delivery or thnolol malepolysaers for . . ..
1991:I0(7):670-l.
ate has bcei imati- IS. Finne U. Hannus M. Urtti A.
1ated i,e "''° and ut riw>. 11• 16 Ma nis ms
dalCd and "'ethods to improve the ocu of'ldcue ~~ 1992:78:237-11.
Int J Phanucc1atics
la~ ic: • ~ 16. Finne U. Salivirta J. Urtti A.
ralio were studied in rabbits. Int J •Plwruccutics
. · ·· 1991;7S:RI-R4.
. .
FUlTlfEll IHFOUCATKIH.. lnta pRt& • and . • •. .of(be
IIOD .-~ - -. .,
kinccics or lranSdcnnal dr ug ~
timoiol-Guy RH. Had paft J. ocatndiol. b,- iae _ Tolbutamide (BAN. rlN N)
lot J l " b au~ d
1986-J2:IS9-63. Finite dose pcrc:utaaeoas
ory and its application to in rllro
·4nla alisorptioa:-ffio.
1imolol pcn nea ~llb _oc a Butamidum: IOl&IYbutamide
K.. Yamada T. J Phann Sci l990;.'J9(l'l~l~ Mk1tyl-3-tosylura: · · .
. pret. n:atmeot tS.:.t9:·~ ~q li-· benanesulfonaniidc. N-{(butyla-
aephnnc • pff oil
and solutioa tic:ulu iiad ..........:.. mino)carbonyl)-4-mcthyl-; l-butyl-3-p-eo
.
absorption ofOCtdarly ap pli ed~ • I . . ,_,..•. ,....~~ lylsulpl:ocaylwa
n~~ CuH1aN1O,S • 270.lS
Urui A. J Phann Sci 1990:79(8):681-91. Prod . •
improved ocular delivery: synthesis. ~ rup ofdaiolol fqr
philicity or various timolol _esie n (O-a -~ •a d lpo-
and pivalcyl}-Buildgaard H. Buur A. l. propeoayt. batyryl
cety
<;:ba
Int J Pharmaceutics 1986;33:I.S-26. Tam n_g S-C. Lee VHL
rctc. ctst.f liry snA li~~ t.m, -.~;'
olol pcodrugs: syntl-.-
~ nri~ J! ! ~.. ~~! !t,! !!!'!
aromatic esters or timolol-Bundgaar
d H. Buur A. Cballg S-
C. lee VH L Int J Plwmaccutic:s !988;46:7
lation or timolol by suspension and micc 7-U. NanocDcipsu-
Ue polymerisalio.-{suo-
CCSlful preparatioa by micdlc polymer TolbuQ\r,lide Sodium {BANM. rlNN M)
SO% or timolol) using nonionic surfacta isatioa (cncal?"11'~ of
nts and. vanou_s ~ CuHnN1NaOJS =292.J
rcrs}-Harmia•Pulkkincn T. lbantola CAS--64-77-7 (tolbuwnidc); 473-41-6
son E. Acta Phann Fenn 1986;95(2 TUOIIII A. ~ m -
A. (sodiUlll salt)
)'.89--96. ~~ ~ Plianaacopoelal stah.ls
biodegradable poly(lactic-co-glycofte)
acid ~ and
thei r;,,"''° reka se o[ timotol m a l e a ~
J, Edsrun K. A ~ M. In~ J ~ C. Cadfoa
BP. USP
l~~ ~~S :- Pftpandons ·
~- ~~ ~d na gd eli ;C ry ~f or
~~ ~- - C-,,,.dial
die s~t im ~. l.l nv itr o~ • .
~ v. Repta Int J ~ u c s~~
!'J· ,A ;_Pi~ijin>. To!batanaide Tablets
BP. Tablets containing, ia ach. 500m
l99 0;6 l.:2 3~. ; Ocv- g
lat anc! S)'SICIIIIC ahsorpt1on IC r«H1
Rork G. Scad~ T, Finne U. Rcpt&
lt#--Urtti , .. r~ IOlb utamidc.Jre usua availabli •· ·
JO....,_T ~ Tablets--lly USP . .· . . ' •~
. . ..
AJ. lat J ~ . ~ Tolbutamidc Sodium USP prep. · ·
1990;61:241-9.
__ . · ..-ich the aid or sodium hJdroxi~ it
a,w dot . colbtdlmJ dc
is suitabic for pueaceral
REFERENCES ft. pH between a.o and u.
in a solution cont&M SOm&/aaL
I. O'Neill CT, Deasy PB. lntJ Pbannacc X011-COm~nd1al
utic:s 198&;<8:U7-S4. Rastinon (Hoc scht). Tobltts. tolbutamidc 500mg.
2. Schocnwald RO, Huang .
1983;72(11):1266-72. · · ·. H•S. J . Ptiarnt Sci !~lbt.'1ar.'lidc:
lab~ s
3. Burgot Q, Sem nd P. Bu~ ot J-L •. · . CP. Evans. Kerfoot. (~ mg) a!"e also available fn,m APS, Cox.
Int J: ~ i c s
1990:l'il:7~. ·
4. Mazzo OJ. Loper AE. ln: FloreyK.cdit. · · '· · -· ·· ·· · C..aalaers and ston ce
or. !-~ ~p ro. . S,,lidstatt
files or:drug substanc.-cs: vol •6• to ndon:
Academic Press. To31butamidc BP 1hould
1987:641-92. · be kept in well-closed containers. .
S. Guvcncr B. Ccvhcr E. Acta Phar·m Turc·· ·
ica 19&9:11(4):169 · T.>lbutamidc ·usP should be preserved in
76. -: well-dosed containers.
· · ·· · · ' · · l>JIIJft /ornis
6. AI-Oohary O. Lyal J. Murray JB.
1988:63(1 ): 13- 18. Pharm Ma ·Helv ~le Tolbutamide
Sodium USP should be kept in containe
Sl:!tablc for sterile solids. n