Review of
`Orga11ic Fu11ctional c;rou ps
`
`I11troductio11 to ivledicinoJ Orgunic: C:lwmistry
`
`THOMAS L. LEMKE
`University of 1-/ouston
`College of l'lwrnwcy
`Houston, Texus
`
`Second Edition
`
`LEA & FEBIC;ER
`
`Philadelphia
`
`Roxane Labs., Inc.
`Exhibit 1008
`Page 001
`
`

`
`!,ca & Fchiger
`liOO \1\!ashington Square
`l'hiladnlphia, 1'1\ lDllJG
`U.S./\.
`(215) !J22-l:l:IO
`
`1.ihrary of Congress Catalo~:ing-i11-P11lilication Data
`
`L1~n1l..1._ Thnnws !.
`Rt)\'i\:I.\' uf 01ga11ii: luncli1111;1] );l(lllllS
`
`lndu(lus i11clt~x.
`:L. C\u:rnistiv. U1g111iic.
`l, Ch1~1nislr\', Phnr1n,iu:utical.
`l. Title. iDNL~-1: 1, ClwrnL->trv. Org;inic.
`-
`2. Clwrnistry. Ph,11rnat:Putiral. civ 7·1·1 L'.1:-l·lr)
`01:1'.:i
`RS-IOJ.L:l\17
`19!1!\
`ISBN 0-81:~1-l JLH-1
`
`B'.l-~:~1110
`
`\'i I _\ ::,-
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`,·, J!l/\11 \.\· l.1•a ,\: F1~liig1:r. l'.11p~Tight t111d1·r thi: ln!cr11.di,111.1l {:up~Ti!~ht
`(:11pyrigh!
`ll11io11. :\ll l~ights l{1~S1)!\"1\tl. This h1u1~ h pr11!1•1.!pd hv \·11py1ight . .\'u )l\Jll 11! ii 11111_1· lw
`l•'J1rnilt11'1•d in onr munll1'r or b1· 1111_1· J/l('oJ11:> 11·i/h1111t 11·1if!1•11 )l!'llllJS,.iuu /Jilin Ill!'
`111dd1siw1
`
`!'1~1:-\l'l:i !.\!!I!· 1·~:!!1.il S!\'~TS ()!_. .\\l!-YH:,\
`
`Piint J\'o
`
`.l '.!
`
`Roxane Labs., Inc.
`Exhibit 1008
`Page 002
`
`

`
`16
`Predicting Water Solubility
`
`I. EMPIRIC METHOD
`\Vu havii 110\\' revie\ved the 1najor functional groups that 1night be
`nxpBc!ed in drug rnolnculos. II \Vi 11 soon btH:onH1 obvious to vnu that
`llH~ 1najority of thr~ drugs discussed nre not si1npln 1no11ofunc!ional
`n1olecult!S hut instead are polyfunc!ional 1noleculns. i\-lost drugs \viii
`be found to contain l\\'O, three, four, or 111ore of th1! organic func(cid:173)
`tional groups \Vithin a single che1nir:al unlily. l\o\v then dot~s Of\(!
`predict physical and che1nic11I properli1~s of these 111oro co1npl1:x
`111o!ecules'( i\s 111entionod throughout thf~ book. OIH~ 11111sl rocognize
`tht! individu;i\ fllllCtiO!li!J grollpS \\'ilhin thn ll10l'll LOlllplnX S\J'U!'.(cid:173)
`\Urt~S. ()net> this is donH, thl! cl1e111ical propnrlins, narntdy, in \·itro
`<>!<iliilit~· <ind
`in vivo stability. an~ t~asily pr1·dii·tt~d. TliP cl11~111ic<1l
`p1rq1r~rtiPs nl ti !unctional group ;nc usually not i!l'h:(·\cd by tln· pr1~s-
`1~11ct· td ;111nth1!r !unctioniil group \\'ilhin 1h~; n1o!ccull!. Th('n~ror('.
`Pach functional group can b1~ ln 1at1'd i11dc1 \H~1H!P11tl~· ol thP olher
`functionn! groups present.
`If \Vt~ cn11sidc~r the in1porlant physical propc~rly of \\'atcr .<-ol11bility.
`it is follnd lh<ll polyf11nctiona! 111ol1~cu]Ps lH'lnn·1~ sonH~\vhal differ·
`i·ntly !h1tn n1onofu11ctional n1olec11lns. 1\ si1nple sun111101tion of thP
`\\'illl!r-snlubilizing properties of each functional group \Viii usually
`not lnild tn" succPsslul prediction of \Valt~r solubility fur lhe 111orLo
`coinplt~x syst1:1ns. \Vhen one looks at tlu: \V<i\l~r-solubilizing propnity
`of d single functiooal group, there~ is no possibility of intra1nolt~t:ul.:1r
`bonding. that is, bonding \\'ithin th1? n1oh~cule. bf!causn no second
`func:tion;il group is p1esont. Cln the other hand, \Vith polylunction<d
`inoleculos, inlrJ1nolcculnr bonding 1nay beconH~ a significant in(cid:173)
`teraction. \'\'ith the individual functio1101l groups. the solubilizing
`potential of the groups tuuk in lo cunsiduralion inter111olecnlar bond(cid:173)
`ing. As an exan1ple 1 an Hlcohol functional group in a 1nolecule such
`as hexanol binds to a second 1nolecule of hexanol through dipole.
`
`I I :l
`
`Roxane Labs., Inc.
`Exhibit 1008
`Page 003
`
`

`
`IH
`
`dipo\1: bonding. This bonding rnust ht! broken in ordnr to disso\\'P
`11H~ hf:\all()l 111 \\'nti~r. \\'ht'!I 01H' stat(';, that ;in ;1]c{)ltol fHnl:tio11al
`grotql solubiliz1~s 11pprn.\i111cdn[\- si\ 1:;1rlion atorn!-'., this sl<1lH1111~lll
`!ook into co11sid(~l'il1inn inh~rnuih·culi!r h11nding of this t~'pt!. Hut
`\\·hat about lht~ pol~·h111clio11a! 1nolr:c:ul()s·: Tin~ i11ltffn11il1:c:ular bond.
`ing bn\\\'n1n1 likl~ lunctional grrHtps t:an still occur, bul no\\' a llP\\'
`typu of bonding is possib!P, thu i11lrtirHolt-~c11!ar bond. Bonding inav
`11ccur lu.'l\\'OHll dissi111il<lr lunctional groups, and thes!~ !ypPs (Jf
`intnrrnulucular and i11\ra1nu!ecular bonding 1nuy bl'. quilt~ strong. In
`order !or ;i n1olnct1h! In dissolve in \\'alr~r. thB intrarnol(:cular and
`i11lt~rn1u!ecular bnnding 111usl first bt! hrokc~n so that the \\'dtor ino!i?·
`culus c1111 bond to the functional group.'>.
`
`Phenol
`
`Tyrosine
`
`Solubility irl wate1·
`
`0. '15 ~/ 1000 11il
`
`(_' 2s 0 c
`
`:\11 1:xc1:lli~nt i'X<1111p!t~ ol th1' in1portilnt:f' of i1ilr<Hnolt!t:lllilr hond(cid:173)
`i11g is sc1:n \\·ith !lit! ;1111i11n ;icid tvrosint~. 'J'liis 1nnlt:culc• lias thn~i:
`functional groups pn!snnl. ;1 pln:nol. an <1111inc_~. <1nd a c;1rln)x.vlic ;1cicL
`By a sin1pln sun1111ntio11 ol thu \\'at1~r-sulublli1,ing potential of each
`functional group, one \\'tiuld predict thnt the phenol \\·ould sol(cid:173)
`ubilizr: n to 7 carbon atu1n~:. th1) an1i1u~ O lo 7 carbon aton1s, and thu
`c:arhoxyl 5 to ti cnrhon ato111s, giving a tot;1I su\uhiliz.ing potentinl of
`17 to 20 c<Jrbon aton1s. T~'rosine contains n cnrbons, yet tlie 1nolecul1:
`is sol11bl(~ lo the extent nf O,;i(}; •. ·rhe u:xplnnation for this lack of \vatHr
`solubility CHI\ Jin und1:rslood if Oil!~ f{)COgllii'.l~S t111: possibility nr
`intra1noh~culnr bonding. ·rhe n1ninn acid c;111 nxi."I ns a Z\vitluriun
`(Fig. Ill·- J ). The charged 1nolr~cult~ 1~xhihits inlran1olt~cu!ar ion-ion
`bonding. As a result. this destroys thi~ nhilit~: of th use t\vo funclioll<1l
`groups lo bond to \Vnter. ·rho phnnol is not capable by ilsL~lf of dis(cid:173)
`solving the 111olccule. If the intra1nolr:culnr bonding is dPstro~·od by
`either adding sodiu1n hydroxith~ or hydrochloric acid lo ll11: arninu
`ncid, the resulting c:o1npound l1t~con1es quite \Valer solubln.
`/\ltho11gh less dra1natic, 1nos1 functional groups arc~ capabl1_1 of
`sho\vi11g sonH~ intra- and inlern1olecular hydrngun bonding. \\'hich
`di~crc;is(~S the polentinl for pron1oting \\'Hll~r so!ubilit~·· !lo\\' n111cli
`
`Roxane Labs., Inc.
`Exhibit 1008
`Page 004
`
`

`
`Pn~dicting \Votvr Solu/Jilily
`
`115
`
`Z11itteri(inic fo1~1
`
`O CH
`
`110
`
`1
`
`-u1.(
`'
`"'0
`l\ll ,·
`-
`
`.
`
`\Vcigh! should he giv1nl In t!ach such interaction for individual func(cid:173)
`lional grnups'! '!'his is a difficult qUl~stion lo ans\ver. but as a gunend
`ruli~, if onn is conservative in tl11; a1nount of soiubilizing potential
`that is givi>n to nach functional group. one \viii find that faidy accu(cid:173)
`rate prodictions con be n1ade for polyfunction:il 1nolecules.
`In ·rabln IH--1, the various functional groups that ha\'(~ been dis(cid:173)
`cussed are listed \\'ilh the solubilizing poln11lial of uach group \Vhen
`prnsenl in a 1nonofunctional 1noloculc and the so!ubilizing potential
`\Vhnn present in a polyfunctional 1nolecule. 'J'his lallor valun \Viti be
`thn n1orn u:-;eful value, since n1osl of the 111olcculos thnl \Ve discuss
`\viii he polyh1nclionnl.
`Scvurnl exa1nplus \Vil! help do111onstralo this 1ntdhod of predicting
`\\'<lier solubility. Jn the first 1nolncule (Fig. IG--:n. one should recog·
`nize the pri!sence of fn'o tertinr~' a111ines. If the n1nrn liberal soluhiliz(cid:173)
`ing pute11tial for <lll a111i11e is usnd. ii rnight be t~XJH~ct1)d thnt f!<H:h
`il!HilH~ \\'ouJt\ !Ja\'H the Capability uf S(]!U\ii[izi11g l!jl tu 7 Carbon
`;itn1ns. lt!i!ding !11 n tot;il pntnnti;il of dis'..;nl\·ing l·I t:11rllon <1\0111s in
`th1• 111o!!'cul<'. :--ii net~ thD ninl(:cul(• contains l :i c;irh\lll ;ihnns. 1J!l!'
`11·011ld pn~dicl th;!t the 1nol(~cule 11·nu!d lu~ sol11hl1~. l_~.si11g th(~ lll!lri_'
`c:o11sPr1·<1ti\'(~ t)slirnate and illln1vi11g :l c:arhons 11·<.1rth ol S(llubilil~' lo
`1~;1cli an1i11t), a prediction ol in:;oluhl1~ \\·ould r1~stt!! I! turns out that
`the 111o!t~cuh! is \Vl!lnr .soluble. '/'ht~ use of tlii~ n1ore lib(!rill t~stin1afi~ in
`order to obtain tht! correct results is nr:ccptable in this cast~ since !hn
`111ult?culo r:onl<Jins only a1nin1~s that acl alike. not cn!ating nny lit!\\'
`i11tcr- and inlr<unolecular horHLs.
`\\'ith porn-di1nethyl<1111i11obcnzaldeliyd1? (Fig.
`lli-.. ~), a nint~­
`c.irhon 1nuh!cult~. the lihf-~ral nstiinati~ \\101ild prt!dict solubility, since
`
`Roxane Labs., Inc.
`Exhibit 1008
`Page 005
`
`

`
`l lfi
`
`He\'ieH' of CJrgonic FunclionnJ C;roups
`·ra hie
`lli-· L
`\Vat1~r-Soluhilizing Pntuntia! of C)rgllnic l·'ttnctional C~roup;;
`\\'hen Jlrnst~lll in H \1ono- or Polyfunction;d \lul1~cule.
`\Vat1:r Solubility !s l)nfi1H:d :\s .--· l'\, SolulJi!ity.
`
`i'lJlyfu11ctinn:1l l·:olerule
`
`r, l cohc1 l
`
`Phenol
`
`r tltr:i·
`r, l dehydc
`
`l'.etone
`
`f\111 i ne
`
`Carhoxylic Acid
`
`lster
`
`f11ni de
`
`Urea, C.1 rbona le,
`(.arbJmate
`
`to (, cr.rbon<,
`
`c1rhons
`
`" to
`4 ID " C<ldlO!lS
`,, to
`cilrbons
`s to 6 ca rt.ions
`
`6 lo
`
`carbons
`
`s lo " (,)ftJOllS
`
`(, c,1 rbons
`
`6 c,H·hons
`
`C(HC
`' )
`
`)
`
`---·-o
`---·- /ti"
`
`CH 3
`
`Cll 3
`
`Cl J11 20N2
`
`7 + 7 " 14
`3 + 3
`6
`
`Cii rbons
`
`'"
`
`to 4 carbons
`
`cilrt.ons
`
`carbons
`
`c<1 rhon".
`
`cc1rhons
`
`cudions
`
`J cod)ons
`
`2 to J c,11·tions
`
`? c,irllons
`
`~-~ .110
`
`f:
`
`----~/N\
`
`Cll
`3
`
`l,113
`
`c9H11 MO
`J + s
`3 + 2
`
`12
`
`5
`
`Slightly Soluble
`\·later Soluble
`l1n!diciion of w;Jtpr s11luhility o! 01gani1 mo!t•ctdf•s using n111no· and
`Fig. 111·-L.
`1H1lyfu11cti(1nal f•slim,iti~s 1nr tlw h11ic.tio11a! grt111r1s
`
`Roxane Labs., Inc.
`Exhibit 1008
`Page 006
`
`

`
`Predicting \\'ult~r Soltdiilily
`
`117
`
`11u~ r11nini! is cap11blc 1d solnhilizing tip tn s1~v~~11 carho11 ;·itnn1s <1nd i!!l
`.ild1:h.\·di· cotdd so!uhilizt' tip lrl li\'t~ i:ilrl>otl Hlrir11s_
`( )11 t!i1~ (lllH'r
`h;uid. thi: r:n11s1:r\'t1li\'t' i>->ti111;llr' \\'1nild pr1~rlict i11so!11bilit_v \\'ilh th<'
`H!llin1~ \\'Orth lhP~f~ and tlu~ ;dd1d1vd1~ \\'tirlh l'.\'O f:drbon ;llu1n~;. '!'his
`tnol1~c1ilt: is listt~d <1.-. slightly .->iJliihl(~. ,1 n'.sult lh.1t fa]J:,, htd\\'f!r!n the
`l\\'n t~sli1natus. '!'his sin1ply sho\\·s that !lJt~st~ .11·1~ only pn~dictions
`and, \Yilh bordi~rline cotnpo11nds.1nay lead to inar;curatu results. 'l'he
`next t~xan1pli!s (Fig. l!i-:q lnad to a 1noro accurate prl'diclion. In lhP
`first CO!lljJOUIHI (Fig. lH-3). one should rnc:ognizu tJH! !lf!)Sl!IJCO uf
`
`0
`
`':::
`CH{-011
`/._o;l~
`"\o
`
`CH
`
`C-O
`3
`
`7 t
`
`?
`
`t 3 t 4
`
`29
`
`13
`
`c2l11l'3trn~
`
`(, • ' 5 • 7 "
`• ) • ' ) "
`
`}:.Jter ln~o 1 oli lf'
`
`"
`
`II
`
`Pn~didion of w,ih:r solnliilit.\· of 01go111ic rnol1'(.t1IP.-; lhill)~ 1nrn10· .111d
`ll>- .l
`1-'ig.
`pu!\'lt11n:lion,1I P~l11lld!(•S fur th1· tu!lt".tl<lllil) g1rn1Jl.~
`
`l1!rliary a111iru~. [)sing the: 111onn(cid:173)
`thruu !~thnrs. a phenol. and <l
`fu11ctional solubilizi[lg potential. our~ \votdd HXp1~ct t~nough sol(cid:173)
`uhilit~· fron1 these groups to disso!vt! this l!l-carhon co1npound,
`sincu i~nch ether \votdd h1! assignnd :) carbons, the phenol 7 carbnns,
`a11tl the a in inn 7 carbons \\'Orth of solubilizing potonlial. If ont) usl~s
`tht> 1nnn~ cnnsorvative estin1ate. \Vhich takes into consideration the
`ln!ra- and inter1nolecular bonding, ho\Vt~vin, 1~ach t!lhi~r contributes
`\\vo c11rbons \\'Orth of solubilil~1 • \\'hilt~ thr~ phenol and n1nin1~ con(cid:173)
`lriliute thrtH! and four c:arhnns \\'Orth of solubilizing polnntiill. rn(cid:173)
`spectivel)'. ·rhe proclictinn no\\' is th;1I tin~ 1nolecule is insoluble in
`\Valer, and this turns nut to b1~ the C<1Se.
`'rhe noxt l\Vo cxu1nplcs use the s11111e appronch. ·rhe first con1-
`pound (Fig. 11)--4) has \\\'O ethers, l\vo alcohols. and an ustor. lJsing
`the libernl 1nonofunctional estinHlles for \Valer solubilily \Vould pre(cid:173)
`dict a soluble cornpound, \Vhile the conservalivu Gstirnate \vould
`predict only 15 carbons \vorth of solubility. Siner- the con1pound
`possnssi~s 15 carbons, one \\'Oti!d pred i1·t sol 11 hi Ii t y by ci I her approach
`and the co1npound is soluble. In the last cu1npnund \\'C should rec-
`
`Roxane Labs., Inc.
`Exhibit 1008
`Page 007
`
`

`
`I Ill
`
`Ht:vien· of (Jrgonic Funclionul (;roups
`
`"'"---/ --
`
`3
`
`Cll
`
`HO L_
`--
`
`n
`
`OH-----
`-1;-r:111
`C!L
`'
`
`(J
`
`1
`!(' I.
`
`"
`
`(,
`
`(
`
`(,
`
`1 '
`H~ tee So lt1b 1 e
`
`?i
`
`F
`
`:, X '.i
`
`2S
`
`11'
`
`r,
`
`7 = JC
`
`6
`
`IB
`
`l'H'diction ot WHlt·1· soluliility 1Jf organic 1Jl\)l1'Ct!l•~S using 1no110- ,1111!
`!ti- ·L
`l'ig
`JH)l~·!1111di11n.1l 1•slir11atc.s ltJr !ht: lurn.lio11;1l gr;1111>s
`
`ognizc tJH~ preSetlCH ol' five elhnrs, a kctOllt:, i!tld a phenol. ·rhe liberal
`C~Stilllille \\'CHiJd l'l!Slllt in ii prediclioll Of \Valer snfubi!ity for this
`2J-carbon co1npound. hut using th!~ consDrvativu nsti1nate !ht) n1or£~
`uccurale prediction of \\'atcw insolubility \Vould n~sult.
`
`2. ANALYTIC METHOD
`'l'hroughout this presentation, e1npha::;is has buen placed on the
`\\'alnr~solubilizing properties of the r:on11non organic functional
`groups. '!'his \Vas recapitulated in ·rable 1n-·1 \Vilh carbon(cid:173)
`soluhilizing potentials for each functional group, and the use of
`thesn values \Vas de111u11stratod by the exarnples shcnvn in Figures
`l!i-2 through lti-4. \Vhiln !his appro;ich is e1npiric, others have
`altu111ptcd tu derive nn analytic 1nethod for calculation of \Vatur sol(cid:173)
`uhilit~·. ()ne such n1athn111atical approach recently n~ported by L. 1\.
`Catt~s (1\in. J. Phann. Ed.
`·lS. 11, l\JHI) is no\\' pl'!~sc:nted. '!'his ;ip(cid:173)
`pro;1t;h is bdsed upon thn partitioning of a dr11g bPl\\'t~t~n nctanol (<1
`
`l Olj P c
`
`Cone. of Druy
`
`in Octanol
`
`Cone. of Drug in Water
`
`st;ual;ird fur lipophilic r11udi<1) and \Vatur. 'l'ht~ bast)·len lngarith1n of
`llit~ p11rli liull C1lt?fficionts ls dt~fint:d as log P. \\'hilt~ tilt: 1111:.isurcd tog
`JI valuns urn n 111easuru uf thu solubility charil1Jeristics ul lht1 \\'hole
`n1oh~c11le. nnn can usu fragr11011ts of tliu \vholt~ n1ol1!cu\(! and <1ssign a
`sp1~cific hydrophilic-liptiphilic value (d1:fi1H~d ilS rr \'alur~) to t?ach of
`
`Roxane Labs., Inc.
`Exhibit 1008
`Page 008
`
`

`
`Prndicling l\'olr'r Sn/uhi/il_\'
`
`! l ~ l
`
`lht~'.;i' lrilg1111'nls. Thus. ;1 c;dcu]illPd log!' CilJl ill) oht.-Jl1u!d I>\' tlu: surn
`oJ !Iii• li\·drnphilic-lipopliilic fragr111~11ts:
`
`1 " I'
`0
`cal c.
`
`:i
`
`( frnqr11ents)
`
`T'o tlS!' tliis proccd11rH. !ht~ stud1nil l\Htst lragnll'td thP 1nol1:cult! into
`h;1sic units ;ind ;1.ssign ;111 appropriatn ;-; \'<lltu~ r;1)!T()Spondi11g to flu~
`.iltlllls t>r groups of atonis pn~sPnt. 'l'abli~ ll'i ~ lists th1! 1:01n1no11
`!i.tgnu~nts fo1111d in organic ru{Jl!~r:ulcs and t!u~ir n- \'altlt~s. Positi\·i~
`\'<Jl\H\S fur " 1t1na11 th;tl tlH~ frag1ncnt. rt~lati\'!! tn hydro,!.,:Pll. i:-. lipo(cid:173)
`philic or favors solubility in octanol. :\ ncgaliYn \'td11t~ indicntns a
`hydrophilic group and thus an aflinit~· for \Valor. \Vhil1~ llH! nnvi(cid:173)
`roninenl of !ht~ substituont can influence tl11? rr valu1~. such cliangns
`aro s111nll. and for our purposes this factor can lu~ nt!gl<~ctP.d.
`'l'hrnugh the Bxanlination of a large nun1ber of experi111entally ob(cid:173)
`tnined Jog P and solubility valtu!s. an arbitrary standard has been
`
`Table lG-2.
`l!~rdrophilir>lipophi!ic Valu1~s (rr Values) for
`()rgn11ic Frc1g1ne11ls
`
`C(•liphollc) ........... , ............. . + O.S
`
`Phenyl ...................... , , .. , , . • . .
`
`+ 2, 0
`
`Cl., .............................. , .. , + 0.5
`
`0/10 .................................. +0.2
`
`IMHB ........•...............•......... + 0.65
`s.. .. . . . . . .. . . . . . . . . . . . . . . ... . . .. . . . . .
`O•C-0. ....... ....... ... .. . ... .........
`
`0.7
`
`0.0
`
`O•C-H (other than •mine)..............
`
`O (hydroxyl, phenol, ether)...........
`
`II (amine) .............................
`o2N (aliphatic) ................. _ .... ,
`1' (aromatic).......................
`0
`
`2
`
`0.7
`
`1 .0
`
`1.0
`
`0.85
`
`0.28
`
`Roxane Labs., Inc.
`Exhibit 1008
`Page 009
`
`

`
`120
`
`(~Oii u
`
`Cale. log P will1011t
`
`JMHB
`
`Cale. lo<J r 1·iilh !MHG
`
`l'henyl ..
`
`OH ..
`
`IH-0 ..
`
`Pn:>rliction:
`
`Soluble
`
`2.0
`
`1.0
`
`(I. 7
`
`! 0.3
`
`Phenyl.,, ........... .
`
`OH ..
`
`O=C-0.
`
`IMHB ..
`
`o n
`
`( , ' I
`
`1.(\
`
`0. 7
`
`+ O.CiS
`
`+ 0.95
`
`( :.1luilalio11 111 n-;11\-1 -;()luhilit;· ol \,ilic\'ll< ;ic1d 1\·ithlll1! illld \\'ilh l!w
`lh :;
`l'ig
`i11lr,011nli'11d.1r hnlfog<'ll b1indi11g fl\lll/H 1.n.lo1
`
`Prr.d i cl i 0n :
`
`lnsolublt•
`
`adoptl~d \\'lu~rnby those chl~111icals \Villi a pusili\'t~ log P v<dnc o\'1:r
`I·{)' :1 a rt! consi d{!r1Hl \\'a tur i nsol u lile r i .{!.,sol II bi Ii t \'is h!SS I hi Ill :1. :1 •:;, i II
`\Valer-a dnfinition for solubility used by the i .!SI'). l.og P \'Cdut!S less
`than +0.5 are cunsid1H·Bcl to bn \\·attJr soluhhL
`
`Procaine
`
`6-CO+O.'············
`
`Phenyl ........... .
`
`2-tlfl-1.0 .............. .
`
`1.0
`
`?,(]
`
`?.O
`
`O"C-0-..... .. .. .... .. ...... O.l
`
`Prediction:
`
`Insoluble
`
`' ? . 3
`
`Roxane Labs., Inc.
`Exhibit 1008
`Page 010
`
`

`
`l l:1·; Ill• 1!111d ·d i.;il1 11Liti11~ •,\'dll'I ';ululiilit\ \i,ic; pl\1\'l'd 11111\\• t•lli•('·
`1n1il1't:11lt~c., (.(1t1Lnnin!.! l. t:I. ,'.: .
`\\'J11i .i l.11~_.,1· lllt111h1•1 11! i!l;!illlH
`li\·1 1
`.ind ( l. hut :--;e\'1~r.il add it irln<1! !<1LhH;; 111;1\· li;1\'I' (11
`ll1' LPn~id(~J (~d 1(11
`.',p1'cilii: drug.c;. 1\ 1:01nplicoti11g l;u:tor jc., llH~ i1illu1~1H;(~ id i11\ra-
`1111d1~c11ltJr h::dr(>gPn honding (l\ll!HI n11 1; \'illttP~;. ;\s disLl\ssnd in
`!lit! pn•\·in11s Prnpiric 11ppro;u:h to pn~dic:ling \\'flier solubility. !\\JIB
`\\'otild b1~ PXJH!<:\nd to dncrn;1s1~ \\'illPr sol11hi!it:," ;ind. tllf!rcfon~.
`\\'IH~rt~ l\l! IB 1~;..:isls, a~,. \'Hl11c~ of ·1·tl.H:1 is ildd1~d to thn c:<ilc:ulutions.
`:\n (~xan1plc ol using this f;1c\or is sho\\'!l for salic~1 \ic acid
`fl .. !g. lfi---:'"1].
`Thi~ log JI \'alu1~s of ;1 drug \\"ith i!Cid or bt1si~ charoctnr ;1n1 i11f111-
`E?nced by tho pl I of thB n1t~dia ln \Vhich th1~ drug is plilcnd. This is not
`surprising. sincP acid or basu groups ,,·ill bHr:onH~ ionic under ap(cid:173)
`propri<tlt? conditions. ;\/though thn ;r \'alut~s givi!ll in 'J'0h!i? !{)-~!
`\\'t~ri~ obtained 11ndor conditions in \Vhich th1! ;i111inP, phenol. or ca1··
`box.\' lie ac:id Rl'I) un-ionizud, \Vhlch \\'otdd alltH\' an accur;1!1? predic(cid:173)
`t inn uf log P. ohserv1~d log Ps at v<iriuus pJI values 1nay not be nccu(cid:173)
`rn!o fol' \Valer prediction. rrhe exp1!riliH~ntal log Ps found for procaine
`am ··ll.:l2 (pll 7) and IJ.14 (pl! B), both of which would lttad to the
`pn~dictinn that procainn is \\'ulnr solubln. 111 fact. procai11n is. sulnbln
`to tln! exh!nl of O.:i':·;) al pl I 7. '!'he c:;ilculillinl lug P
`+2.'.l (Fig. Iii·--{))
`COJTHc:tly prt!dicts that prot:<iinu is \\'ill1H· i11~o!ulilt~.
`
`Roxane Labs., Inc.
`Exhibit 1008
`Page 011