P .HARMACEUTICAL
`AND
`CLINICAL
`CALCULATIONS
`
`PLAINTIFFS'
`TRIAL EXHIBIT
`
`PTX0194
`
`MEDA APTX03505633
`
`PTX0194-00001
`
`1
`
`CIP2038
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
`
`

`

`PHARMACEUTICAL
`AND
`CLINICAL
`CALCULATIONS
`2nd EDmON
`
`Mansoor A. Khan, Ph.D.
`lndra K. Reddy, Ph.D.
`
`0
`
`CRC PRESS
`
`MEDA APTX03505634
`
`PTX0194-00002
`
`2
`
`

`

`CFCrtu<
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`6000 B.rokm SIKJOO P'ukW.Jo}'S"'i);",Suit'l'JOO
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`CIIC l"~,,.n.#n• •u pri"fl[(lfT.-~.J.:i r ~ j;f111•3(••Grii!Oijl,..,.lllll;(I}:IIIL.II~nil~..,...,
`
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`
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`m~lc~l hl!i.Lor ~ ri"l~~nl m•oo!wturtr's. lm.truct1oru. OLnd lhL! .1pprupn.l~ bffi pr.KlM:'It" ~tdrllnr:~-. ll«w~ of
`rh"l"'pid ..uot~·.1on m ftloC'dle.tt ou;ltnr;", ,.ar ltl~rnu.uun ~ Mlvk:, n d'»4f.V p~4urn4.1c-4u nVl< ~~~IA ic.l
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`r Wll!b\lt ·.llh'!ro.JY adm lni .. tenns. •or or lM d.r~.~p rcorommntdcd
`drog ott~mp;anlt''l' pnntOO.tnJolrudlrnl ... aDd II:
`u11 ~~ l"bt..ok. Th,, ~~ 6o'"' n~~ 1ildic;.A~..,.tlt;l~r !II p~n"-.sl.llt Lrtl~tnL'II• P.lpprnrar•~w--ur·u••t.a.bJt-~r ..a p;U-,~!Jilt
`1n.dn-.dwL Ulumiltd;y It •~ ~he 1o0le fflpmutbllltyofthc m>l'dlc~>l pto:fl:i.W:!n•l to m~ke hi Of' ba DWII'I prod'c:tifotonal
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`prTmlnloti oo P'£1blub in 1:hki f.JITID hn nol bftn. obtit.lftC'td. If ally copyn,:lu llllilh!tU.l hu mHiiM1:B ~clmo.,..lcdg.oJ
`f'I\".Ji\li!Wrll.ttiiDd l!!:!tU~~D{IW.,.I v.-rrnll)"~'i.(yln.anr(uLYTYil:p~HII.
`
`l'fli!i~ hr N-fJf•ntfti, f!·pf~!ii:!(".:l.lr:l!'lit'J'I~l!cd,.
`E ct-pt ;i:t jk"H'ft~1!t'd Llflii¢r L,.·_t;. C~j'i f•l;h ~ L:iw, tii'l- p.ut flf lhli.l!auit
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`h:li JK"rllli"'"'ILID ff"ll.llh 1lttt- puW!~h..
`
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`(hllp.ti~·.oop..,-nJ~..ooml) Qr <:OOlCiK\ lhi!! Coprr'IJ:h• Cku~n~ Cmtft~ tn.c, lCCC:). :21:2 :J!~TXIJ:I Dr-•\~~ Oiiin•
`;so.$fi)O.CCC
`v.r-..MAOl~Zl. qt
`..J,I'ttJC·f~r-~i.it u-rp:n~t-~tlttn ~lw~ prt.rl'.Jtln.l~""'~~.;.nd.l't"".,.,,,t--'HWl (c-ro~
`\'Uif' L~ of LUtrt. ror flrpnll.l lloM thu h>l\'c beft1 gr~r.kd il ph~Mo:>p~ lken'lolt by dw: CC'C".a M!p;Jr.uc :1 'l.tcm «f
`,pl'y~Dl h.._., bn:.n •rr.li"ISC'CJ,
`
`Tr..A~Pllil'tll ~~~ i('C": PI~J•t.......: l Yr .,.Otpuf'2~r A•ll~ !n'!lllv b(' 'f.)~r-'llllrlt"'o U.J rt~'W"!vd 14:.iiJr•11Aij,l', ~ild: tr"t~WI,I"-"fltV
`far kld\tlfb:ulu& 11nd !:!.~;pbnaliHI MJthll'.lt •numA LO ln.rrln5t'-
`'
`
`\'h;lit 11 1...- ·ra.:plur& f!'nadlii \li"ct. ~tc ••
`h.UjMJiwww,tl [(lra.n.dfn•d .com
`
`111M! mt;£" C::RC l 1.rcu \l>'tl-~11'"' ••
`h44i
`(WW'tf,CHf'J't.SS(Ofa
`
`MEDA APTX03505635
`
`PTX0194-00003
`
`3
`
`

`

`Calculations Involving Topical
`Ophthalmic, Nasal, and Otic Preparations
`
`CHAPTEA 8
`
`A vmiely of p~mmmceutical dosage forms are aprLied 1opic.1lly ro lll.e eye.
`nOst: f anti car '"th.ich indudjj :sulul i on.'i~ su spen:sion · ~ ilnd oin1T'L1.t!nls. ln .g,cncrat,
`drug;; lll'c· BjljlHcd to the eye tor die loe;,l eff<-ct or the li1.cdic-at1on, either t~n
`the surface o( tl:lc eye or its illtcrior. Among 1 the various lypes of dosage
`fonn s for the eye. aqueous solution are the most frequcmly used. In tile
`c;x.lcm p<>r,mcous prcl>~raticm ()f oplllhabnic f()ntllllation;, tme ~hould C(lnsi(icr
`shlrility, preservalion. isotonicity, pH and bulfering, and vi cosily. as~ I prepa(cid:173)
`ratlOJl arc !),~ntrall)• used for lltdr decong.cswnt acthil>• on tlte r1asal mucosa.
`lmportBlll con ide.ration ' in tl'te ptepat;,1tlon of na-al solution include isotonic(cid:173)
`it)'. pH" and bttffcring, ;m(l •dSC()Sity. E~r preJmr;tlions (Ire 1ll~o rcf"!Tctlto a.
`mi<' or artral preparntions. Most of th.e official ear preparmioM are aqueous
`so lution~ of 1'11cdkat io ns. Tiley ar~ used for !h-ating mild infcc!LOM, . ofteni ng
`w;tx. cleansing aflcr iukctions. dl')ing wet ·urr:.ccs. and as Mli~crtk$. he
`imponant con· idorntions in a he rormula1ion of oaic prod~1c1 inc L~tdc pH and
`buffering. Fo.r example. an otic product wi.th a pH value of les
`than 4 may
`c~usc burning ami sti11ging ·ensBtion ln the <~tr c:ma l.
`ih.e pre"enl c hapter deals with calculations involving iso!onicily. pH, and
`bu ffcring of topical prt:jmrarjon • The di cus ion pr em.ed here is at so rele•ant
`to the d(>sagc fom>s for otncr mutes of adn1i n ist l':ltit~n includ·in.\; pf1rcntcml
`ro~tcs.
`
`ISOTONICITY
`
`Wl't~ne\• er a !llllurion is separated from a solvent by a membrane p~nncablc
`only 10 ·olvcnt molcclll(;S b11t imp(;nll~~b lc to sOh!tes (refcmQ 10 as a .. ~cmi-
`
`149
`
`MEDA APTX03505636
`
`PTX0194-00004
`
`4
`
`

`

`150
`
`TOPICAL OPiilHALMIC , NASAL, AND OTIC PREPARATIONS
`
`p.:nneo1ble melllbmn\1"). 111e oi¥ent pa:;scs across tb.e membrnne into lhe
`solution. Tltis is the phenomeoor~ of o mosi . \ ltich may be defint>ll a the
`p;o;;sa~c or •OI\•cnt lllok..:ulcs fL<OI'OSS a ·elll i pcrOit~IDic lllcmbnmc 3jpiinsl l.hc
`concentmtion gmdient. O$mosi~ <:an ato oc<:ltr \ .!len a C'Jncenlml~d soluHon
`is. cpamwd from a lc . conccrunncd so lution by a cmipenncable m,;mbrarle.
`The pressure d~ffcrenlial tllal de,clops a ero. s the mcmbr.tnc is calk-d ""(J!<fi'IOiic
`[>fl.'~ll"'
`O. rnotic prc.s 11rc b a colligativc property imd i~ d.cpcndcnl on the number
`of !mrticl~ of olule(5 in a olution. The tom! 11umber of p;1rticle · of a ohne
`in a ohnlon is ll1e s11 m of lite undi ocla t~d molecul
`:md the number of
`i<m~ intQ which I he 11\olcculc diSS<Jd~lcs. The numbcrqf i o n~. in lnm. del'cnds
`on.tfle degreOt of ionizm ion. Thu •• a chemicnl th~l is high ly io11i zed contrib1M
`a greater number of particles to 11he so lution than the same amounl of a p-oorly
`ionized chemical. Wnon a c'hcmit-;;11 is a nonclcctralytc such as sucro~ Of
`11 rc~. lhc OOQcc n~ruli<J'll qf thc sol~ttio n dcp<:rnh on ly Q ll the number or m~.>lcc~ lc~
`presetlt. Ti1e 1•alues of the o:>molic pres trre and other coll.i galil•c properties
`:uc apprux.lmatcl)• the :am c Cot ~-.1 ual conc"'mmion of diffcrcnl nonllk-etrolytc
`solutions.
`Bo,JC.ly fluid:.,, i11eludin.g bloo<l and •'~'"· h•vc 1hc ~dille osmotic t>rcs~m" :us
`thai of a 0. 9% w/v sodium chloridOt solution. Solutions lm ''i ng lhe rune osmotic
`pre~sure a tllm of 0.9% wtv NaCi soiUiiOJl a~e , aid l·O be ,il·ormsic with blood.
`So lution' wi1h ;~ hi11hcr o~moric Jl"'-'surc thun J,ociy rluids arc calk-d lryperto11ir
`:.ond tllo:;c with " lower <l!>ll10iic prc.osurc !Lrc ~·l;l llcd lupot<mir.
`0 rnolic l'ffccls arc very im]'or1ant from u physiol<Jgical st\'llldroinl. TilL
`is because biological membmnes in ludi ng tile mcmbmne of red blood cells
`oohav" like semipermeab-le membmnes. Conse<jucntly, 1 i'len red blood cells
`are im m.,n;ed in It h)'f>Crlonk solution (c.g., D5 ',) S " ' D, S), they ·~uinl; '"
`water letw~ llle blood ce I I~ in a11 ~11 tempt lo d~lllle and C5tablish ;1 concentraliun
`equi li brium acros 1l1c blood cell mcmbrn1lc-. l'h•s. whenllypcnonic solurio,;s
`rl! atlmini. !crcd iniQ the blocJci $1rctll11, lhe nuid 1110\'CS fmm ontcl"Siiti>r l
`and cellular space ~tlto the intrnva, cu lar spac<:. Corw.:rsely. when c~ll s are
`tJlacoo i11 hypotonic environment (e.g •• V, NS). t'hey swell oocau e of the
`enll)' of fluid from the lnlm~-ase u lar compartmen t, and ma evemu~,1 1 y
`UJtdcrgQ lysi .
`In th" eye. l1}'f!atonic • olution~ 1'119)' ~~luse dn1wing of water tuwar<ls 1he
`site of 3pplication; wflereas hypotonic ~o l11 tions rna)' C11Use water to move
`from 1he topical npplicmion ile through 1he ti sues of ti'le eye. When l<\Stil'led
`into the eye, i:><)lunk solutionS ~·IU SC 110 lX>nlnielion or swelli ng o( the
`ti sue~ with which tho}' come in contact. :md cause nodi comfort. Therefore.
`il ls very im~rtnm 10 adjU$t the iromnic ity of topical ophthalmic proouc1 •
`ndj u. 1m ent · arc al ·o imponant for •lru;al and aurnl prcpamtions,
`t<oto11l
`Jl'U<:ntcml ~roducts. ~111d img;•ting ~ol11tion~. ~~~ 11 given prochLct, Rll the
`
`MEDA APTX03505637
`
`PTX0194-00005
`
`5
`
`

`

`Cnlrrllatio.IJ tJf l)j.utJcinfirm (i' Fartm•
`
`151
`
`:.ddihves including th.e aclh•e and inactive ingredient~. contribtlte to ltte
`o.smotic pressure of rhe sol u lion.
`
`CALCULATION OF DISSOCIATION W FACTOR
`
`Si nee osmotic pre sure dep-ends upon tt1c numbc.r of partie l.es of so I u tc( )
`in soiUiion. dtc osmotic pre sure of an eloctrolyre i diroctly proponional to
`the degree (Or cxtolll of dis ·oci,.tion. The di5sock tion f~ctor. S)1IIbo1i1.cd by
`the I etter i. can be calcu lated by dividing !he toml number of panicles which
`ions) ir1 a oiUIIon by the number of
`inclwdc undissocl:moo molecules :-u1d
`panicles bofor · dissociation. i.e.,
`
`Tm~J number of particle of so lute
`in a so lution aftcr dis:sociutio n
`i = ---------------
`Ull'l t>cr nr j)llrliclc~ hcforc dis!I(>Ci(ltion
`
`Exmnp lc L:
`
`Wh!al i the dissodarion fac tor of NaCI, ha ing i!O~ dissocimion in wmer·~
`
`Assum<; lh~l we hii\'C 100 p1U1 ick~ of Na I (lrl<Jr to dis'l'<.>ciitlion. Upon
`~ di sociation, LOO molecule or odium clllolide
`ield:
`
`S.0
`odium ion.
`80 chloride iQ n ~
`20 undissocim~d soditlm chloride panicl "
`18.0
`total particles in sol ution
`
`answer: i "' I SO/ I 00 • 1.8
`
`Nul<': Abotl l 8~ of NaCI is dissociated in wmer. Thus, tile di soci3Hon
`factor, i. or NaCI is assumed to be 1.8.
`
`E lllll]JlC 2:
`
`Wh!at i
`water'?
`
`the di soci, tion factor o f zinc ulfme, ha1•ing <10% disso i::uloa in
`
`As. umc 1hut we ha1•e I 00 ran ides of z.i nc s• lfme prior to dissoci~tion.
`pon 40 dissocinlion. 100 mo lecule.:; of ~i nc sulliuc l'icld:
`
`MEDA APTX03505638
`
`PTX0194-00006
`
`6
`
`

`

`152
`
`TOPICAL OPHTHALMIC, NASAl., AND OTIC PREPARATIONS
`
`40 zi nc ions
`<10
`sulfate ions
`60
`undi~sodu.uotl zinc sulf>He ptmiclc~
`total particles in solution
`140
`
`~nsw~r: ,· "' 140/100 = 1.4
`
`Example:>:
`
`Wnm is lhe dissociation fncwr of zinc chloride. ha,·i.ng SO% diswcinHon
`on ,.mer?
`
`/\s;;•nle 1 hm we h;lve I 00 p-articles of zinc chloride prior 10 dissodat ion.
`- pon 80% dis;socitll io n. 100 mo lecules of 1.inc chlorid~ yi.Jd:
`
`80
`zin~: ions
`(2 x 80) cl1 l01ide ion
`lt'iO
`20 undiswci:noo zinc chloride particles
`260
`lOUd pan klcs in solulion
`
`answer: ,· " 260/100 "' 2.6
`
`SODIUM CHLORIDE EQUIVALENTS OF DRUG SUBSTANCES
`'l"l:tc sodi um chloride cquiv 1ent or" ch.cmic.ai l$ de fi ned"~ the mnonnt of
`sodium chloride (in gram or groins) that has (he same osmotic pre sure as
`that of 1 g or llle c hcmic-.JI. TI1e odium ch lorid~ ·equivalents are symboliz~d
`by 1llc lcner E. The qu~nt il ies or two ~ubstance~ that ""' bownic cq u.ivalent~
`me proJ)Qrtional to the mole~:ular weigh! 11f each muHip!ied t>y 111e i value of
`the mller. Ttlu s. i r the molecular wel$ht and i val.ue of a :,\iVe.l chemical are
`known. one Ciln croleuliltc the sodium chloride eqt~h•ak:nt. E. of thi.u chemic"l
`as fo l lows~
`
`e: MW' of N~CI X i 'l;lluc of the <;hcmtca.l
`a I MW of the chemic;!l
`i value ~:~f
`
`Example 1:
`
`Calcu late the sodium. ch loride ~'<luivalerH of a I"' olutioll of pi loc::tf!l illtl
`ni!nttc.
`Pilocarpine nitrntc h~. a mo lecular weight or 27 I ~m<l i or l .l!.
`
`MEDA APTX03505639
`
`PTX0194-00007
`
`7
`
`

`

`E = .'v1 W o- NaCI Xi value o pil'lC2 rpiJle ni!TTltc
`i value of KaCl
`l\·1W of piloc:upin~ n.ilrate
`
`!.8
`5~ .5
`h"= - - x -
`1.8
`l'll
`
`= 105. J/4B7 .8
`
`= 0 .~.2 .. j .e .. J g o! piloc·m·pjn< nimtle is ~qu il'alotL[ to 0.22 _g of N~Cl
`
`" nswcr: f..'= 0. 2
`
`1-:x,unp lc 2:
`
`Ca lculate U1-o -""lium ch londc cgui\•lll cnl "I' a I'.:!- zinc ch l<mdc.
`
`f. _ MW t'f NaC'l X 1' \'Jhl~ t>f Zi<IC clllorj<l~
`i ''d ue of :-.laCI MW uf zinc chl,>r>J~
`
`f; =
`
`X
`
`5H.5
`2.6
`1.8
`136
`= 152. 11244J\
`
`::lllswer: E = 0.62
`
`Example 3:
`
`C • lcu la tc th.c ""lium c hloride. cc,ui\'al cnl of a I 'It horic ocid.
`
`Borlc ~cid Lms a mol oc~ lat wd _gJl[ ol 62 :md l of J .
`
`1'.=
`
`MW of KnCI
`i value 11 I' NuC I
`
`I ''alue of bork add
`x :....:..:=:....::.::....::.::.:..:::...::.:::.::
`.\·1"W " f boric •cid
`
`= 58.511 11-D
`
`an. wcr: 1:' = S2
`
`MEDA APTX03505640
`
`PTX0194-00008
`
`8
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`

`

`154.
`
`TOPICAL OPHTHALMIC, NASAl, ANOOTIC PREPARATIONS
`
`TABLE 8. 1. Numtn.r of l011s, Dlssocia tit:m Factor (1}, and Mc>l!wular Wsight
`(M W) o-1 Selected CompQunds..
`tons
`
`MW
`
`Uorit Jcid
`hl <>n)b<l~·"'~
`""''l'Aw. ''"l.y<ln;•o"'
`Do~ll\lS<>. 11,0
`Ma~nitol
`D<nl<:llkonium elll<>ri<k
`Coco In< I TCI
`CromolyB >Odium
`DiphdrlB HCI
`llpbedrillC IICJ
`llpiocpluii>C bil>rtmtc
`F.u
`tropine I! · I
`llom!Liroplll<' UBr
`Q,p,l••ob:>ltno II I
`U')'lclr.u;y<linc IICI
`l'h~n~l<¢'rlr>< HCI
`l'rucolllll! HCI
`Scopolamine: IIH<-311,0
`Sliver n itmtc
`S<><llum <blol'ide
`Sooium piW>splwl•. mcm.ohl~<ic, o11hydrn"'
`Sooium piW>Sphllle, mon<IOOsic-11,0
`Tclrnc-Jinc HCI
`Zioo sulfUlc·71"1',0
`Atropine .... 1ro1o. 11,0
`llpbedrlBC '"'-1 Fnlo
`S<lltinm pt>osph•>!o. clitx>~k. "''l>y'l""'•
`$(1<lill"' piM"pilillO, <li~sl<; -i ll;()
`
`LO
`1.0
`L.(l
`U)
`L.O
`1.11
`L.ll
`L.ll
`1.11
`1.11
`1.11
`Lll
`1.11
`t.&
`Lll
`1.&
`i.&
`L.S
`L.&
`L.&
`1.&
`1.&
`1.&
`1.&
`l.6
`~.6
`2.6
`2.6
`
`6.~
`171
`1~0
`19&
`1~2
`360
`3-10
`512
`311&
`102
`3JJ
`3211
`3:56
`297
`~'11
`2(1.1
`27l
`43&
`170
`511
`120
`13&
`301
`211&
`6')5
`429
`14'l
`26ll
`
`t able &.1 lists numoor of ion produced upon dissociation. di sociaHon
`fact.or (i), and molccul~r weight of sdccK..:l compound .
`
`ISOTONICITY ADJ·USTMENITS BY SODIUM CHLORIDE
`EQUIVALENT METHOD
`
`Ttle MJ<.ll~ m chloride ·~quh•ar~m me1hod is 1he most frequeruly used method
`iP !he cak lll!ll io n of 1 he 11mnnn1 of ~iu m cl!1oridc necc;k..:l1o prepare b<>l<mk
`drug &o hllions. file sod ium ch!oride equiva lent of :my drug . ub&tance, a
`diS(;U ed enrlier. is ll1c amount (in grams) of sodium chloride thnt i o moll·
`cnJi y cqul alent m I g of 1hc drug. The sodi um chloride •"<J ulvaknu for
`selected compounds me listed in n~t>re 8.2.
`
`MEDA APTX03505641
`
`PTX0194-00009
`
`9
`
`

`

`l .wrrmicity Adjw•nJterll> by S•>di!tm Cfrl01itll!! £quimlem M et/roll
`
`155
`
`ny tlyp<Jiontc so lution containing on¢ or more drug cnn be rendered
`Isotonic by addi11g appropria1e quantity of sod.lum chloride. f"Oilowing is a
`srm~pl<! prescription lhnl ti!quird i ·otonic adjustm.:nls:
`
`R
`Atropine Sulfute
`Sooiu.m Chloride
`Purified Water ad
`Make isoton. :sol.
`Sig. Gtt . Lo.u.
`
`l $
`q.s.
`100
`
`TABLE 8.2. Sodium Chfori~ Eqr.rivaienl~> (E)• M4 Freezing Point Oepre~>$ion
`(il T/") Values of Se/e.:ted Compor.tntM.
`Subslanc:e·
`E
`
`tH I"'
`
`Anunoniun~ ehloride
`rwm1~h lllC hydro,hl()ridt
`Alropiru: sodfol<
`JJ.orio .adil
`Cblorobulnool
`COC'3illC llydnx:-hlmidc
`Dexlro"" DIODOb)'drnle
`Ep~odrine h)'droohlorido
`!lfl'tco.!rille sul rL~te
`fivinep~rine bil.~llr.llc
`Eplt,e1>hri "~ h)'d""'hlmldo
`E;Jco,lrophle hycl«H;;ilati•~
`Floo•c:socln <Odlu111
`Gl\lttti111
`N;ph,olinc hydnx:-hlor>dc
`Nromy.-in >11lf~te
`Oxymell1201 ine
`l'hcnol
`I'IJcnylcplnioc hy<lrwhloridc
`J'lloonrpio"' nilrnl<:
`l'n:>-.oio~ ~y<Jro.;hlQri~c
`S<:<>p;.l•>~nio¢ ~ydJUb"'nlido
`Si l,·er 11 i1mt~
`S4..c.Jhan\ ~'i!h1ti'~
`$uii';J<li:IOII>i'-"' :;(l(lj~Jil
`Teom • lne b)•drochlarldc
`?.lmc dtlurf<k
`Zl~c stllfa1<· 7 H,O
`
`E =- 5001wn ~-t;.k,R ik· ~~i1lr:rit
`~n oQf l'.f. ii6IUbOfl.
`~ . • Fu~<:1i'!\J 1'01~ dtpfc.:
`
`1.08
`O. i'l
`0. 13
`0.52
`0. 18
`0. 16
`0. 16
`0.30
`0.23
`0. 1 ~
`0.1'9
`0. 1 ~
`0.31
`U.j-4.
`0.21
`0. 11
`0.20
`0.35
`0..3~
`0.22
`O.ll
`0. 1 ~
`0.:\'1
`).()()
`0. 2~
`O. IR
`0.62
`O. lj
`
`0..6.1
`0.08
`0.07
`0.19
`(), 14
`0.09
`0.09
`O. IS
`0. 14
`o. tl
`0. 17
`(l.l l
`0. 18
`0.20
`0. (6
`0.06
`0. 11
`0.2
`0. 1~
`[1. 1-1
`O. ll
`om
`0. 1?
`[l,j~
`0.14
`0.11
`0.31
`0.09
`
`MEDA APTX03505642
`
`PTX0194-0001 0
`
`10
`
`

`

`156
`
`TOPICAL OPHTHALMIC, NASAl, AND OTtC PREPARATIONS
`
`h1 tile prescription atxwe. 1% arropi11c ult"me i ordered. 'file sodium
`chloride equivalem o f atropine ulfate is 0.13 (refer 10 Table 8.2). Thi s means
`that ] % SOI ~ria n or llln)pi nc ~ul fatc ha~ ""'"'" USm(}tic presc•ure liS thHI Of
`0.13% solu tion of sodium chloride. This o lution is hypotonic. Addition of
`0. n g (i.e., 0.9 - 0.13 "' Cl.71) of sodium chloridt> per 100 mL of the 1%
`sn l~tion of mrol)inc ~nifm~ resu lts in a n i!>Otonic sol11tion. To d~ronn inc the
`amo11n1 (>f ~dium chloride rcqulr.:d to r.:ndcr :• given s"'luth.>n l$,Wilk. ~he
`folio\ ing step may be u ed:
`
`• Step I: Find !low much sodium chloride i n~eded ! () render tile
`formulation isomnic willl body fluids. !Remember i oto nicity
`rcfc~ ro 0.9% or 0 .9 g/100 .nt).
`• Step 2: F'ind tlile <lmount o.f odium c:hloridc represented by the
`ingredients i 11 the prcscrlption by mllhitll)•i•lll d1c q uantil o.f
`c~tth ingredicnrt b-y it ' E V"',duc. Add ~• p :dl tile v~lucs. obluincd.
`ThL is the toml amou nt of sodium c:bloride repre:;ented by all
`the ingredh;m in tlle pre~crip1jon.
`SubtraCI the tOirtl value ob't1line.:l ir1 S1cp 2 from dtu amo unt or
`~odium .;hl.,ridc rcq11 ired to render the formula tion i~olonk
`(i.e .. the ~aluc. ob1ained in u:p 1). The value. oblaincd in {fl is
`step rcpre l!nls 1bc amour~l of s.otliu m chloride required to
`render lllc :olul [Qn isoto nit.
`
`• S1c1>
`
`Example 1:
`
`Flnd 1hequ.an1lly of s.odi um c htoride required in COinf)Ounding the following
`p..._,, ri ption . 1"hc Sildi um, chloride oq1•iva lcrH o( coc;oine HCI is 0.1 6.
`
`R
`Coc.aine Hydrochloride
`Sodium Ch loride
`Purified W111cr ad
`Make i~oton. so l.
`Sig. One drop in eacl:l ~"))e.
`
`0.2
`q.s.
`30.0
`
`Slcp I: (0.91100) X • 0 = 0.27 !!
`
`Step 2: 0.20 x O. lo ;;; O.IJJ2 g
`Slcp 3: answer: 0.21 - Oc032 = 0.2 8 or 0.24 g
`
`MEDA APTX03505643
`
`PTX0194-00011
`
`11
`
`

`

`!Jotonic:i~· Atljflstm~ms by S&Jium ClrloriJie £qJ<im lenl Mi!lhod
`
`15·7
`
`Ex~mple 2;
`
`F'i nd tt>e quantily ot mdlum clllo rl!Le to be used in comprmnding the
`folio' ing prescr~pfion. The sodium ch lorid~ oqui•atenl of "phedrine
`is 0.23.
`• ul fa t
`
`Ephedrine Sulfate
`Sodium Ch loride
`Purifi·ed Wuter ad
`Make isolon. sol.
`Sig. Use \IS directed.
`
`0.5
`q,'
`50
`
`Step I : Sod iu m chloride needed m render the prescribed \'0 I ume i monic
`
`(0.9f!Ofl) X 50 = 0.45 g
`
`Sl<t() 2: 0.50 X 0.23 = 0. II g
`
`Step 3: <111 wcr: gram~ o f sodium clilloridc n~X>ded to make the • olulion
`isotonic = 0.45 - 0. 115 = 0.335 or 0.34 t
`
`Ex~mp l e 3:
`
`Find 1he quaruh, of wdium chloride to be mcd ir1 comp-ounding 'tnc folio\ •
`~' lues of odium chloride ~'<jUi\'lllcnl or e pinCjlllri ne
`i'lt; pre~cript i o n. The
`HCI ;md scopolamine HBr tlr~ 0.29 nml O. l2. re ()eclively.
`
`R
`Epinephrine Hydrochloride
`ScopeJamine Hydrobromitlc
`Sodium Chloride
`Pu rified Water ad
`Make isoton. sol.
`Sig. Usc in the eye.
`
`1%
`0.5 %
`q.s.
`60.0
`
`S1cp I : Sodium chloride needed to render 1 he prcscrib4'd ' '0 I ume i ·o10nic
`
`(0.9fl00) X 60:0.54 j;
`
`MEDA APTX03505644
`
`PTX0194-00012
`
`12
`
`

`

`158
`
`TOI>ICAL OI>HTHALMIC, NASAl, AND OTtO !>REPARATIONS
`
`SleJ) 2: (:1) lipineJ)hritw HCI:
`
`llfl00) X 6()"' Q.(l0
`
`0 .60 X 0.29 ;;;; 0, 174 lJ
`
`(t>) Scopolamine HCl:
`
`(0.5/100) )< 60 "'0.30
`
`0.30 X 0.12 ;;;; 0.036 Jl
`
`Ttu: total of sum of the weights (in grams) of epinephrine HCI md
`scopolamiGe HCI multiplied b· 1heir E ~·alues , i.e •. the m.al of (a) + (b)
`
`= 0. 174 + 0.036 g = 0.21 g
`
`Sh:p J.: answer: S<J(.!ium chloride n."lui~~d lo make lbc •olulion oSQtonit
`
`o.s4- 0.21 "'o.:n 8
`
`TONICITY AGENTS OTHER THAN SODIUM CHLORIDE
`
`lr one de · ire~ to u.·c a chemical <>I her 1hun ·<>diulll c11]Qritk su~h as dc~<.tto»C
`or boric ;~id. the q1mntily of Hmt chem icrrl c:m b<: (;lllct!lt~led by dividing lhe
`1•alue obtaitlcd In Step 3 i.e., the ~mount of dium chloride n~-eded to render
`tile ·oluli(>n i'lt)tonic with body nui(ls} will1 !he £ valu~ of l hnt ~lH!mkal. A
`proponicm can be et up whtch can b~ 1rem~d a · Step 4 in addilion lO !he
`three u:ps de cribed earlier.
`
`Fl.11d the q uatUlt)' of borlc add (in grrmts) to be us~..a ln compounding I he
`following pr.;~ripliotl.
`
`R
`Atropine Sulfate
`Boric Acid
`Puri lied \"\'\.Iter ad
`Make isoton. sol.
`Sig. One drop in each eye.
`
`]%
`q .. .
`30.0
`
`MEDA APTX03505645
`
`PTX0194-00013
`
`13
`
`

`

`Tmri4ity Ag.mu Otlli!r ltl<lll SQdiunr Cltloride
`
`159
`
`S•ep I: (0,9'/100) x 30 = 0.27 Jl
`S•ep 2: ( 11100) x. 30 = 0.3 g
`
`0.3 x CLI3 "'0.039 ll
`
`S1ep 3: 0.27 - O.Q39 "'0.231 g
`
`S1ep 4: From S1ep 3, 0.'231 g of sodium chloride i required io make Ute
`prt,paratio n isotonic. Dutthcprdlcription calls forbotic acid as the tonicity
`llgent. Bo-ric :mid h~s " " £value of OSZ. This mean< that I% boric add
`i ~ osmolically c<juivalem to 0.52% NaCI or l g of boric ttcid i C(jUivaient
`to 0 .52 g of NaCI.
`
`_ l_&_ = _ x_
`0.52 g
`0.231 g
`
`where Xi. gnnm of burlc itcid cquivnkntiQ 0.231 g or -'Odium chl~;~dd ....
`
`answer: olving for X. we g.,t: (0.23 1 x I) + 0.~2"' 0.444 !!r:ma
`
`Examp le 2:
`
`l"i nd the q"•nli ty nf b<>rit :tdd (in 1;r,u11 ~) tQ be u~ed in <::<>IIIJJ<}unding the
`following presaiplion.
`
`R
`'fem u:ain j!- Hydrochloride
`Zinc ulfate
`Boric Add
`Pu ri lied w .ucr ~d
`Make isoton. sol.
`Sig . Drop in eye.
`
`O. l
`0.0:5
`q ..
`30.0
`
`Sodium chloride ~'<! u ivaJems are as follo'
`
`Terrncaine HCI ::; 0.18
`Z inc su lfute "' O. l5
`Boric fie id = 0.:52
`
`s-.~p 1: (0.91100> " 30 "'o.27
`
`MEDA APTX03505646
`
`PTX0194-00014
`
`14
`
`

`

`160
`
`TOPICAL OPHTHALMIC . NASAL, AND OTIC· PREPARATIONS
`
`SI"P 2: (;1) Te lmcain .. li ' I;
`0.1 x 0.18 =oms g
`
`(1:1) Zinc S11lfate:
`
`Q,Q) X 0.15 "'0.0075 ~
`
`(a) + (b)= 0.018 + (1.0075 Jlc"" 0.0255 g
`
`Slcp • : 0.27 - 0.0255 = 0.2445 Or 0.2.45 );
`'lep 4: Frvm 1ep 3. 0.24.~ f; of ·odium chlurlcle i~ ro(Juired to 1nake !he
`prep;1mlio n isotonic. B~t the presc.:ri.ption COllis for boric acidm;: the tonicity
`agenL Boric ~cid has ~·~ E value of 0.52. To find the quanti I)' of boric
`:tcid <:quh>alcnt to 0.-45 l!r.uns ()f «>o:lium chlorltk a I>Hiportia" cnn he
`set up as fo llows:
`
`__I__L = _x_. -
`0.52 g 0.245 g
`
`answer: so lving for X. we get: (0.245 x I) + 05:2 '"0.471 gram
`
`Example 3:
`
`How many grams of d~x1ro.e hould be used in compoundillg llle pre·
`sc ription?
`
`R
`Ephedrine Hydrochloride
`Chiorobutano.l
`Dextrose
`Rose Water ad
`1 ake i oton. ~ol.
`Sjg. Nose drops.
`
`0.5
`0.2.5
`q.s ..
`50.0
`
`Sodium chloride eq~ i valenls are as folio\ s:
`
`Ephedrine HCI "' 0.30
`lllorol!umnol = 0.18
`D~XITIJSC "' 0 .1 6
`
`MEDA APTX03505647
`
`PTX0194-00015
`
`15
`
`

`

`Slep I' (0.9/100) x 50 = 0.45 g
`
`S1ep 2: (a) Ephedrine HCl:
`
`0.5{1 )( 0.30 "' 0.1 5 g
`
`(b)
`
`hlorobUianol:
`
`0.2.5" 0. t8 = 0.045 g
`
`(a) + (b)"' 0.15 + 0.045 g.= 0. 195 g
`
`S1ep 3: 0.45- O. l\15: 0 . .2-5 g
`
`S1ep 4:
`
`X
`____!__!__
`0.16 g 0.255 g
`
`Practice Problems
`
`When solving lhoso prublom~. re cr to Tab les R.l 11nd ~ ·- 'L' n o~...:lctL
`
`(I) Calculate the dissociation factor of pilocarpine hydrochloride dLsociating
`8(}% (2 loll ) in a certahl oonccnuatiOil.
`{2) Calculme theE Yalues of 1he follow ing aqueous solution m 1% concen·
`tr:ulon:
`
`(a) ChloroiJutanol
`(b ) Telrac:Ji1le hydrochloride
`(C) Epbcdrine sul (ttc
`
`{J) lio\ man}' grams of sodium chloride should be used in compounding
`the preseriplilln?
`
`1%
`Pmcain.c l~ydmch lori de
`q..s..
`Sodium Chloride
`Sul'rile Wmcr for Injection ad 100
`MaJ.:c, isotil fl , sol.
`Sig.
`r injc~:tion.
`
`MEDA APTX03505648
`
`PTX0194-00016
`
`16
`
`

`

`'162
`
`TOF'ICAL OF'I-fTHALMIC, NASAL, AND OTEC F'REPARATIONS
`
`{4) How m;my gmms of odium chlOride " ho~ ld be u ~ed in compo1mding
`the prescription?
`
`1):
`
`0.6
`Cocaine Hydrochloride
`ucalropi nc HydrOchloride 0.6
`Chlorobulanol
`0.1
`q.s.
`Sodium Chlori<kl
`Pt•ri 1cd W~•cr "d
`JQ,O
`M ko isolo n. snt
`Sig, for tho eye.
`
`{5) How many gram of boric acfd stlould be used in compounding 1hc
`prescription?
`
`0.06
`q.~ ,
`30.0
`
`Zinc Sulfate
`Boric Add
`Purifie<l W mer m!
`Make isown. ol.
`ig, Dro1) in eye~,
`{6) How many millili!l!rs of a 0.9% solullon or sodium chloride sll<Juld bl!
`used in c:ompou nding the prescription .
`
`Phcnyleplrrlne H ydrochloride
`Ch lorubumr>OI
`Sndiun! Ch lorid.,
`Purifil!d Wa1er ad
`Make isoton. ol.
`'" ;I' direcu .. -tl.
`'ig,
`
`I .0
`0,:5
`l.p,
`I 00.0
`
`(7) How mrul)' gram. of ~od i um ch loride hould be used in preparing the
`olutlon']
`
`De !ro e. Monohydrate
`Sodium Chloride
`Sreri le Water for lnjecrion ad
`L"l~l: I ·ownic Dextrose unci Saline Solu!lon.
`
`2.0%
`q.s.
`100(1 mL
`
`MEDA APTX03505649
`
`PTX0194-00017
`
`17
`
`

`

`l.wfrmiei~· AdjJHfrJr~nt~ by CI;> os.copic Melhnd
`
`163
`
`{8) How m ~ny milli lih!J"s of a 5%
`oompou ncling th" prescri ptiont
`
`tdut ion of boric acitl sl10uld be ~~ ~. in
`
`2%
`q ...
`15.0
`
`Oxymetazo'line HydrochLoride
`norlc Acid Solution
`Purifil"<l ~ awr ad
`lll.
`M ~ke i solOn.
`Sig. For the nose, as dt>Congesmnt.
`(9) How many grJnls Qf dcxtto!l:c Iii<'lno:>hydtiUo should be used in preparing
`a liter of :1 '11% isotonic ephednne suli'hte mu;al ·prny?
`(10) flow rnany gmms of boric: ad(! should be u~"<.l in \.vn1p01rntli11g the
`prescription'!
`
`Tctr(LL>ainc Hydrochloride
`Bone Acid
`Purifioo Wmer ad
`f!,'h!J;.c isol\m . ~ol.
`Sig. Eye drops.
`
`LO
`q .•
`30.0
`
`ISOTONICITY ADJ'USTMENTS BY CRYOSCOPIC METHOD
`
`Since osmotic pressure of a solution i not n readi ly mensurable quantity.
`l rable col i igml vc ptoll tnl~s such g · thc[Ft:e::d tJg pohrl de:prtt.<·
`oth~r t.-asily mea l
`ioJJ h u:;..:d in lhr; isol(nlicily ~k~~t i ons .. l11c n<)nnt•l freezing (or mchi11g)
`poim or a pure compound is t11.e wmpcrnw rc at 1 hicb tile "olid and tile liquid
`p hase~ ate In cqullibriuli'l m a pr". sure of I at.m, Pure wmer has a frce:ltlnll,
`p<>inl or O"C. When S<:>I\Jic;; :uc :i!dclcd 10 water, its freezing poinl is low~rcd.
`Th~ treczing ]JOint deJ:>re · ioll (<Yr lowering) of ll solvcnl i dependenl only on
`the number of particles in the olution. Blood plasma has a freezing point of
`-0.52 lor frr"Czi ng 1min1 <;lcj)rcs..~iun ofO.:>l, i.e .• (-I-Q.52})l. If frce;;:in!l, pql,tlt
`depre sion ••aluc of a chem i ~ l in cenain concentration. i~ know11. one can
`calcul:nc I he conc .. ntralio n o f th:u ch~mical r~quired for isoto,~ici ty by scn ing
`:1 proporti<l!l a. follow~:
`
`Known percentage cone.
`o f a given chemical
`reezing poim depression
`of 1he ch("Mical at that
`<:oTwcntralion
`
`X
`Freezing point dcpr·ossiOI1
`of blood plasma
`
`MEDA APTX03505650
`
`PTX0194-00018
`
`18
`
`

`

`164
`
`TOPICAL OPHTHALMIC, NASAl, ANO OHC PREPARATIONS
`
`wh..:w X~ p~icentng..: ronc..:ntrntion of ln~ l'lwmi~JI ro.'qtoirod to be iwtonic
`will! blood plasma.
`
`Since froeziflg poim depression of a eerie of compo11nd at I% conc~nLrnHon
`is rcadil y avai l'llblc frottl swndard references. lltc abov~ e.~ pres i011 ca" be
`rcp<c"'-'nlcd "''
`
`I% chemitill
`t.l) of the chemical
`
`X
`.0.1i of t:>lood plmmm or te.:us
`
`\llh(ll'c X"' p('rx:cmag..: rootccmrntion of the cllCmical required to be lsotol'lic
`wltll bloc.d plasma or t~.ars.
`
`Ex•mp lc I :
`
`1% NaCI su lution llr.l a r~'CZin::; poinl depression of 0.576°C. What Is lltc
`pcrccntlll!,C concentnillion of a I r.,quirod lo make isol\lnic ~uline solulit>n?
`
`One c-.Jn cakuhote the percenl;~j:c COrtt.'t!nlmti<ln of NaCl hy setting up the
`following prop<Jrtii:ln and wl ing for X:
`
`1%
`0.576
`
`X
`0.52
`
`X "' (0.52 x ll/0.$76
`
`= 0.903 or 0.9% w/v
`
`Ti'lus., 0.9% odium cl:lloride ha. the ame os.mmic prcssum and the :une
`rcc~ing JlCJi nt dcprc~sion of ().52 us t:hut {>f bl()('>(l pl01sma. red l>lood cells,
`1!1d IL-nr~. DruA; -~Ohllit>PS which lntve a rre~z in~ po;>inl {kprc. ~ iQ!1 t>f 0.52
`are, ther~fore. i$o!on ic witlrl blood. A J isL of freezing poin! depre sion values
`ofseleCI«<Ioompoun.<Ls ~t 1% conccntr-;nion isp"' emcd inTab l.e S.2. Tl1esc
`flT, '';tlu~s "'l'Y b~ ~$CQ tn Cll lculate !he ~oncen!ration gf lnnic-ity n.gent~.
`such a odium chloride or boric acid, needed to render a hypo1onic drug
`solution isotonic witll b l(}od plasma. The fotlo\ ing s1eps may be. u ed to
`find 1hc percentage c<uttcntrmion M Na I rcquir't.'<l 10 rend~r hypo1011ic
`drug soh•t1ons isotonic with t:>lood plasma:
`
`S1ep 1: Find ttlc \<lllue of frcc,J ng point deprcs ion of the dtug m I %
`~"'Qnccntrnti<.m. ~1}" fr0111 T;~blc 8.2.
`Step 2: Sublmcl :l'r,~ or 111" dru_g trom the v~lue of rce~ing poin,t
`
`MEDA APTX03505651
`
`PTX0194-00019
`
`19
`
`

`

`l.rotmridty Adju<frnentl b • Cl)"lJSCoopic Methot/
`
`165
`
`depression of 0.9'1 sodium chloride solu.tion, i.e .• 0.52. Tnis diffcre•1ce
`111ay be symboll:a•d as 6.1•1- ·~ hich is lhe freeocing poinr lowering neooed
`for i~oloni cily.
`
`S~t~p 3: Since 0.9% wd i~ m cl1loricle has a freezing poim depression of
`OS.2. t•ne c;m ealeulmc the pcrrclllt<tge cun<'<lnlnttion ....r sodl11m chloride
`mtuiro:d to lower ttl~ diff<:rem:e in fr~zjng point~. i.e .. tile value Qbmi ned
`in Slep 2. 6.1~1' by lh~ method of proportion. The calcu larions invo lved
`in thi. method are explained best by following e~amplcs.
`
`Examp le 2:
`
`<.:ompo~nd tlw following pr~scription •
`
`. R
`Atropine Sulf.ue
`Sodium Ch loride
`Puri:lied Waler <tdl
`Make ismon. ~ol.
`Sig . One drop in each eye.
`
`l%
`q.~.
`
`100
`
`Slep 1: Frcc~ing poinl r.lcpwssion <A7i) of I% atropine wlutiun (rrom
`Table 8.2) is 0.07.
`Slep 2: Find ilTJ by Sllblracting llle !J.1j l'alue or 1% ntrCipinc ulfahl
`from 1be !l. 7i of bloGd pla;nna. i.e .• 0.:52 - 0.01 ,. 0.45 . This mc.ans,
`uffki~nl :;odimn chloride mus1 be <Hided to lower the mezing PQinl by
`:m 11dditiomll 0.45°.
`
`Step 3: Fincl the percentage conccnlr.llion of sodium chloride tC<juirc.cl
`by citing up the pruportil:m ;~s follo ws:
`
`X
`0 .. 9%
`0.45
`0.52
`In T:1hle 8 .2, il i~ ob~rved 1hm l % solmiun ur ~[)(li11m chloride lu1 · "
`frt.-.:zi ng j)()inl lowctillj! or 0.58. T hcrcfnrc, (11:\C
`n also CXj)T<"5.
`ihe
`pruporliCin as:
`
`X
`1%
`--;;;;--
`0.58
`0.45
`
`llll~wcr: ~oh•inJ; for X. we get; (0.4510.58) x I "' 0.7&%
`
`MEDA APTX03505652
`
`PTX0194-00020
`
`20
`
`

`

`166
`
`TOPICAL OPHTHALMIC, NASAL, ANO OTIC PREPARATIONS
`
`0 .78% odium <:illoride will render the above. rr<~parntion i otonic. 'flms.
`Hte i monic solution will be prcp~rtd by dissolving 1.0 g of :.uropitte
`sulfme ancl 0 .78 g ()f .<odium chloride i11 .<uffident water m m~ke 100
`ml of so lution.
`
`Example 3:
`
`R
`Apamorphtne H}"(!rochloride
`Sodium Chloride
`Purified \¥.iter ad
`Fl isoton. wl.
`Sig. gus ii on T.LD.
`
`i%
`q .. s.
`tOO
`
`Step I: Freezing poim depression ~.il7j) of 1\t npomorphine HCI olution
`(rrom Table R.2) i 0.08.
`
`t<.-p 2: f'ind il1j by i ub ltaCtlng lhe t..T1 \'3luc of 1% atropine ulfalc
`from the A7j or blood plasma, i.e .. 0.:52 - 0.08 = 0.44. Thi~ m<!:!n •
`uffic ient sod~um <:hloride mu t be added to reduce ti:Le freezing poi nt
`by an a-ddltlo nal 0.44•.
`
`'tep 3: Find the pcre.cnlage conccnlrntion <.>f "')(iium chloride required
`by selling up the proportion as fol lows:
`0.9% -- =--
`0.52
`0.44
`
`or
`
`-- =--
`
`I%
`0.58
`
`X
`0.44
`
`wl ing for X, we gel: (0.4410.58) x I = 0.76%
`
`answer: X "' 0.76%
`
`0.76% sodium <:illorid.; will render the above jlreparation Lolonk. Thus.
`the ismonic solution will be prepared by diswlving 1.0 g of apomorphine
`hydroch lo rlde and 0.76l:) of ~d.i u l'l\ ch loride in sufficient water to make
`100 ml of ·olution.
`
`MEDA APTX03505653
`
`PTX0194-00021
`
`21
`
`

`

`Vr>lum .. ..r oJ 1.<t>-<1SfJrt>ric $llfutimu
`
`167
`
`VOLUMES OF ISO·OSMOTfC SOLUTIONS
`
`While-Vincent Method
`
`" l:lile and Vinccru' pro\·id.c:'lda mcchod forr.,-adily firtding the correc t volume
`of wmcr in which I(> dls!>(li v~ f\ dnug tO fll"{lduc-c f