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Handbook of

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IHandbook olf'

Pharma:c::euti'call 'Sailils IPlnJlperties\t Seledicniill ,1111[1 Use'

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I n~AIi\"n a.t.i'I\n -n i~ II IU n "1'0 I'll .. III.'~III .' ar lu'l a ..... I I !i~

- f IP- - -- - - -- 11- A- -- r - ,A C' h - --- Ii, -.- ·(ru-,"·'"'" 01 .. ~·ure.· laln~' ~ ·.(PP_I'l:u ," :_'Je~m~15'lry :,- .... J nLI

IHalndllboolk of Plharimace'urtiii'l 1IIISa-l'ts Pro •. Ip· .. '~rti·-·'-!·ie~-s·:~· Selection sn ··d.··· U.·:s-~,

. .. '-, ., ,.\1 . ,",_'\.;,'~I._U. I ~-.. .. '-

Dr, P., H'ei,llnch. S.t;~,h~ Leil"1:'be~s,tras~e :2 8

:0, •. "'91 ~ Of :Fre]bllrg' ~Illl B:lleisglu,

:P1\O r., (~m~ne G. We[f,m,u~h

lou,is PU'~eiur Un.ivers:jtY'1 S.'tlasbo~:rg' 'P,irucu1ty of [Plb ~rDa"cy

1-41, route Id,ll IlbJn.

F -61'j\'U)O ~U'kJr,dl

l1ris Ihu)ok W~'5 iI:',[]TII1J1IJIU:y pro~u~rn, 1Ni!l\l'~,rth~I~5, '(l!d1Il1Di' HliIll ~ 'pullililli~Jtlllil1li:5, dD 'Dot: 'W,I:H'mjlli[ rnti:!ll' iltti~(nnu[nlDi] co~tilillfi;(!d, ~]n.!.l!~iD te be fll:e!2' of '~nDllffi. :I!tJ~(I;de'f;S ,aI~' mj,yi5eG liD ki!N:Ill' :~Iil. mii'rild thDt 5tajl)ll;m)ll;rnJ1l'ii~ G!lli1n, iUllli5tmtlo:ns. ~\~;Da;:dll.illml iI1I!!l1'itnj ~5. !lli{JJ l!lJtlilll:r items m(lljf hU]jd¥l!nen'~b 'be i:nm:cU~!lle.

PU~MlSlh!2:d, johnly b:y

VHCA~, Verlag ~~~ehli:lh:a C~d~~,~~a Aela. Zth'ic:h '~Sw,U~efla~dJ WI LEV ·.vOW. W'el:nli1'''"I:m ~[lFede~~i Rf:l!l'IUJbi~i.c: of' i(j~_~Il,Y)

~i~(!Irii!l~ [[)~,FeCl)!lrn: Thaimll!5 itDI'i1l'ZllI -", Dr. M. VtUlllku:iI1 t::~~nkDre:~, frcuiIIU(I:iQ(n Ml~ nag .r: N"'Dtr.\b~1I'it 'W'!a~Z

AU liights ~~~~d, i:~ncl~nU,nl thO'S" of ~:u,i,nsla[~lOrn, 1'11[0' iM~ill~iIT 18.BI'~~*"o, 'pm1 IDr '[ili~, 'bonk may ~~ ro"f(lillIDu.l'\~d, la :aJ!I.y 'rof!ll] - 'by [f,!IhO'i.O:prirn'~:~rn;Ql. rii:~~[Omlii" or ,nny other m~f1Ill's, - InCl'li" 1~'mJnsmittm IDr 'lrnlJljj_!ilnlilll-d thruw ,81 :ma!rt1dne ~:ilin;gu_:a.' wid~D'Urn: Wrill:~f,!1 lJ)ii:lI:'m~.s5ion, from til!: (Jl\l!'hU:;hers. ~e.~.i~~tRd iTI;afiiCi~ trndC'milJru. ~t~. 'usm ln 'tni:;, bl!!a~~ ~~1iII wlw~~ ~ai!:t ~@i~dt1Ci!lU.:y :mi!Jrke~ as :S!!.l!J~:~~ 31!f!e' HO'l tn be e~ulsid!i!red 'u:np~~otleel~d 'b,y law.

'liilill:i~S': I,o\lilrnd l:n~'IE(',h. Print '1lI'lll'd Digut::llIe MooieQ~, D .. g~"~'9gl O~~~~fua14Io~hi!Stadi~ PlI1ilil ID2d i'D 'Ge-:lI'mall'l1j1'

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Forewn ird

, . - ._. "_' - ',' .~.~'

The surprise 'w,~th I[hl., v,ery 'fli'rs~ book on PhaID']nlceuNc3~, Salts is that it ha '.' appeared so late. Problems concerning the physical form of dmg '. ub,., stances have been whb us For 'n-early 1 0. years at th.,e interfaee between the

d;l· einlines ;i"l'!1~' en tial to the ....ala've'~I.n.p,···m·iIJi;n,iii. of new d' 1l"1,1![J'C"'· ehem 1:""'<:1111 ero .... a'f'l ~ID [I."' c 'F .Ill ll~~1 essen 1II: '. Ui. 1il.:· ' Uw·· ... ·.· ',Wu,:' . ~lIHIJI~l' IU .. i~·.~~~ ·I~.IJ ~'IS.j'i er 11iw! . .Jl\.?-g: ,f·,w,[:".,,-,~I.'., [lJ.~~

v'iei.op:metllt, aJna]:Ylw,c'81, chemistry, pharmaceutical s C,ieJI'C"6S pharmaeokinetie '. toxi oolo'i}'", and IC'~ i ni-ca~i s~'udie,s", These problems have ':or many :Y',ears tlgured prominently i nl the nig~~m;ares, o:f' mdustrlal chemi sl and 'pbaJrm:, ,c,L:h, not to nlenwion those of ~he:i:r qualwty' as mrers, regulasory writers j. and p.roj ect manB![IP'I~rs

1- .~~. __ ~"~

: .. he answer eo the question 'i'Why ~3', 'thi. ' book appeared so. late?'!' mLa,)'

:perhaJps have something to do 'w.ruth ~he fact th.a~ phar,ma,c:,euti,ca.l cry;s:~a~, Md.

d '" . L '~...lI II!.. iif.' d d "~I;al "!II '" B

pow er engmeenng SUO'MJllli. ee :wuun" .eJ···· 0.0 eryl'ul~. anu powder sc .eIIDe, .. "ut

such a science does. not yet exist IS a ingle concept since know ledge ~'n. this 'held is scattered am.oDl,g different disciplines such ,i'l " ,crys[al~o,genes] .• ' 'i' ICry .. taUoglfaJphy" mhe physical chen .. ~'stry alfIDd. 111ermodYlrruanlic.s. of mlll]l~iph,a':e sys'be:nis" :powder :fl(),\~ ch,a~i,ac~,efi:5tic,$, ,~uld mech~:rdcs. ipiez~,o-elec __ ,t~o$uwdc:$, the physics of complex micellar systems e te,

Academic whose vocation :11[ is to, edit this ~pe olf book, therefere, :h.e~lrd about 'nh~ spec ,j fie p- ,1,ro·'b.'~le·-1ii-lIi:g related 11'0. p harm 'a c jJi;n;",~·l· c "ii'iIi]' crysta I~ and nowder

, , 'I;;!'" , ~ __ ~ '" __ , ~ "'" I u~ ~II! _!B !II.!¥ ~I~U. 'I, " ,li!!iYi ,~""",,,,'~I!I. .. g ..,. WJ,W UJj,I, , U , ~ y,.., .

~. ~ '~' -".

engineering :ral,dly lare from lRdustTij,a'~ coUea,!ue.: who are often reticent to air

their' diffljcUl~,ti"e. ill pijJb~:iic'., Thus, h :1 .. ' only now that effort , am 'l1Ilid.lfh:aUnrn. have

'a..;;!i'O'i]l "I U!b-I~IUll~.~ •

This book is perhaps ,a~ attempt to found suc~ a :: eience, but ill the '. ense 01' a, market-driven effort bringing together C\(~~ltrri.bu!tium·, trom academic and industry. Tile book deals not o:n~:y '"~~dl1 'fjl;e problems raised ~)~' sau selec'{won s~rale gies and proces 'S, scale-up, but also 'w:ith. the ,~ndus~dmJ p'rolj)Czmty and :1~e,~tlJa~o:ry 3J$P~c~'·,··, at the heart of ths high~y regu'~,ated pharmaceutical indus .. try,

I . ..:11 "1;... h .' ,. Iii.. 'I,,;. ]'.. ,I, .iil"

cannot eno W~'hiOU,~ emp ~·,as,ruz.~n,~· '~I~~~la!t . :urtiie'ii' lex'p'~ .Of:a~u),:m. :~I~, l'e~'IJlJrn\eOl In

l. ~ " -'1

areas where ~heoret~C',al and practical knowledge m" sti~'~ :lac'ld:n,g~ for in: ranee,

the mechanisms i:rul\fO;~'v'ed '~:1Tl crystallogenes Is need ~o be elu,cj.da~ed. since we still ,cannot predict ~he so,lub~'~ "'~Y of ,9 given .~ a]t 'Wi 11 it. be o,My or' :$IOU.d? WiU it show several poruy morphs 11 Tihe ,crY'.' ta] chemj,tfY of ,crysta]Un'~ surtaces '~ regulased by specific i rn1i~eriattmom,s between fit:J,ncti.ona,'~ groups <f', posed on . he

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VI,

surfaces and v,ery small amounts, of lmpurirles ,_ lmp,a,c~s w lth (Y~her '[actors on the p,~~efer,e:rnti,'"jl~l de'Ve:~o:pm,tn~ of oae face r~,ther than Ui(itthef. but L' still in

'~l i ~ ~ 'j;.. .. - 'i'I.!, ""." ii]' 'itr. '\I" ".Iii.. '; - u - ... ~', ,. ;i.....,. ,','j;.. • ,~"l' ,'"'" 10' ! ~ ~ .~. W' th ...~. . " ....

!ILi,m!iJO .¥Ve sun ,!'r..n-o,:'W nO~w,~lln~. prectse !~.IJ-O~U tne ractcrs ,~O\ erm (jl'e tne e~,lec~fO'"

" . '.~ . f d .. . L""l' , .. W"" . 'I"" ~I I' ']b.'II' ,It ., ~ ',.,:P' , iii, the "11 ~ 'to '" ' .. ' I, ... "lw' ,

stanc 0 nrug UI!lJS anee I,.:"e are sun unm,D)',I€;:' ~O p;reu.!,ic~. ne fe~~.~o.IllS ne "_~ een

cW'ys~:~inil1e forms and the ,compress.~'Ib~1 ity of po'\,~d~'rs.. 'I: :ho,pe th,Dt '~'he pr :,j'ftll~nmr:v basls of OJn answer '[:1 so 'me ~tf these one .. 'i'i~l:n .will be ,iWnllJl1ld'. iilil1, !I!li" '''''''''hiH'~

~~~~_ ~ __ v. __ ~~ __ ~~ . _ ~ ~~~ _ "!JI~ ,~~._ ~ ,'~.~ I,.~ru __ ~. . ~ w.~ __ . ~_~~ ~ .w.Yl~~.I~

version of thi s bonk ..

Prof, Bertrand Castro :D',ru:llleoc~or oif the IChemictmd Deve:~orpment Sanofi .. Sy:nthelalbol

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Preface

L1ihe odgrn:t1. of ~lli1:is book ,~{)~S Ibmck to ,OJ propos;ition tnade '~y [one 0:[ us

(C' G'" ,\-11)' u,~· .~ '01' ~'P't' .~ '1' ~ 'f' the ", .. iI· ~'[" 'I· '1 '[I' t· .. , ~t D' "I" I'· ,. 1:/'1'1 1f'ij,,1: /' U~· '~C", ,jo.--

,I,~ '.'., J¥." ","I~ d ,,:;e~.lmg o.~ Jl~ ~~~e'u,f;cu~a.; ,.),eC~~$O'~ [~ . ,~V,~;~,~OJ1v,~,~ !y.~, ,-,~-:-n ,,01

wri 1Ii',o;; '1'1 ,_ ;:lI,J;,,] ~ handb 00' 'k~~' fo C' ~m ed ~"-"~'m ;]!,~ ch emist '. A~ 'm.;f'!;,n p' ~,ILI .,0;; 't"if'illnr~'"" il:!'1Ii II<O"OCiiii:l'Ii'eA

!Io~ III. Ill'",", U ,·11".,,1, t. _~. 111I~.I!.;!II.c [ .;:, ',~_. ,I"",,~ .I~'II"o 1II,m!J,n~ ,.1", " .. ~ a _'.~: \ I. I .'IUI'." 'G Illli ~I... L!lWI'e.III.'Ij"o'. a'llllao.~'l. !Jli~,

the prepararion of pharmaceutically aceeptable saln was ,rapi.dl.y considered a "I important and timely. As a, matter o~" fact, an estimated half of all drug mole,cl~lles used. hi]. medicine are ad ministered a ' salts. The s al '. formation O'f drug

.r"'~:l'iliil~I'·l·~f3l['i':e·~ h ,~I'~ been recoani ':';l"~\.rJ ,.;l~, y IIIiI '~iI:"if-',,g,IIIiI'~;l' !GI] "~fi'''''''lm'''- iiI'~I- ~'~l' onl iiI;'''II'lL·~.''' ,0 ~[ 'i~'IJ..~~ ~,~-, ~1:111~~.~U. UU,IL ..:l .l U!J. 'U .. , " ,1'~~'U,b' .llt~UJ Q_Q UJIJ.11 ~Q~"l~WIJ~~_ ~ , r'~,'~' ,VlIJ,l __ " I~. al~ _ lI!~. fIJ.-~II;I! •• ~ U.£l ~1J.l~ I.;ti~

1 . f . ilk 'I ~I" h ,. .u ,. '" 'Ii! d s: . ..lI '~I L

ecnon 0 ... · a snitaete :S fht pnor to tt e mmanon ot ..... ,00 age 'loon development ,ILI.as

b deci ., "...J '~I f . rh -p. 'I '. '. 1 Ph I" d

'.'.', . " ,'., .',,",.', '--, ,.,' .. --." -" "c,', -., "",' .. ,' ," "Ij ". "·1 ''', '--', • ..,. '" ,," ",' ,~ .. .' ',' , -.--'

ecome a eerston pcnn~ I.n tne ne~p .. llIl· 0, l.. e .. rec Ul.I.lCd.. ,. nase 0" mo . em,

dhiliJ'fI' develo '''11 me nt, S" ~I'I iII'n~i~'I· H,,f.f] y~ ho "'w,', ever, or!il c hem '''"l(!oIii' ~]. H 'Dfliiil!'\'l"'iIJ.. [0, "f" g, bo '0. ~I!,,· [d,;DJ(Ji,:1 =

_.1!! ". e:; U ' ,I . ~, ~ .,.~. ,. !!i.!!.~ p'!!: 1R.lla~. 'l' ~ W .. '" '." .!' n, " . bl!;,;o .I .. 0JI1(l, .w.~1 1!;,,!C_IIillI.'!;';-U. ;1." 1lJ, .lIi'ii. - ..... i;]J ..

= - - ~

j m1I:g with 'the prep3!rn~ion, sh~nii ficance, and selection of pharmaceutically ac-

rive ":idt" 'W ru'~ ~ fail to :f1nd one, and. ;a~'.· 0 the scientific li~[e[a:mur.e on '~h ls '~o:p:~c [S ra~her I i ~wli red and scattered acres s f~any joam als and pmJtent . 011 the other

rn,., .A iU... • + r, d ,_ + :I 1...," ...Iii .. ,_ ,. 'h'L 1~ 3' '~I"

IU w3Jno,!, ~w we 'm,aJ(Ynt,~r o:i; 'm.'~~h::urla~, chenusts W'O~ ~ln~ lfli me pharmaceuncat I n-

d ,', · 'h .. h .. · . desi d . ,-, h'

" 'I"': I." ".'1' .. . ····L' I,' I ~ I," .~, .. ' ,'1 _". _. .' ,'-'1-"-",- . 'I' 1.... ," ','-Q;-'I . "-.,. [ .w- 'Il ·1

, [~s~ry (flre orgalUIJ1C C. em.~·I·, \\'" .'o .. ;t mal m, ,concernl .1,. ~l)[ .... e.~bj1l. [an,·, tIO·,~ n,~ . ,t=

. 'I Al f" d . " .. ' Wb.""~·h e. 'II!..,' II!.. 1

SIze never [C'Oll1po~nY, as . tll~U'e '. rug en:uu.!es,,,>. ru ~.le t ,.ey :~:OCU', on uus lena. ,=

len'n:in'n" IIrn.fh~1JJ~IIn;f :0"0311 ~5a'~t formation is often restricted to [I mareinal acti vitv

~ - ~ -~ ~ '" -e r: -- ~ - -.,._;; !!:'i ~ ~~ - ~ - L.~. - . - - - -.... - -- ... -~ "';0 - -.- .~ - ,J

~d.tth the short ~,em1 atm IOC' olb~mining :l1ice'~y' crystal ~iFue ma!~eri3JJ, 'Moreo;v~r~, chemists [are no~ [expi~cidy [raJned. in dle various aspeets ot pblmlao_ud,cal salts and their' inherent OPPOI1LUi!ities. 'By bringing ~o,gedler the neces slry ~'heore~ical ~ou ndations and a. '~o:t o,:rr :practi,lcal, experience, thee objective lor iIDe :p~esenn

iL'-.. .. ' .. ik i itt" ,(-'11'11 ,[':1..". Ions ,iIf.' '~It- 0'" . r, 'i':"-' .ib;,.-- ... 'L-"~ ""~II b"·~b'~l.~'··-oFi' t •. ,

I!JJOo'. es I~O .,h~ ."1,11S ong .~.e,lIJ. ,c;3J.P .111. ~LIJ,I.e pnarmaceu .lca.w,w . .og~a'p.ILl,y"

A COl"iiC ;i-;Q; ;i iIi'II ~illi"O·~' ~'C' I'-~' 1f'iIoiii'i revi ewin Q1' the . 'Ji:,..:~ O~I'I'" obiecti ,,~';a;. '1Ii'Ii~"[ri"Q11 ted ,. '~n ,'~-:.ii!'Iii'i

n. .. ,' ',II ".!!I ":~ 1II!11,I,IIi.W . UUI! .. ruIUWL ,1111,: l: .. : ',111,[ 6 l- .' .... '. 0111 J·u . "11j1 '!i.rL~.~I"" ,~I~.I!II,oi:i!U -u l , .. ,Vl~llIIll-

:i,[ng salts ~.s fb,Uow'ied by contributions presenting the ~heol-etmcai baekg round of salt fonnl.t.ioilll,: d.i.ssoc,hlltruon and, :~oni!t ,equim'rubl'ii,a~ :Shlbility and di ri!olilut~on

(I'e";" ,I:' 1 ~~ -~ ",I ")'1 'bC',~,., ,', .,. :-,~ ",II '.':1 (, ~".,' 'II' ,~II"', ~ ,. of "C ;11,' A ,,'~ . '~.,' ,',' ',." " " ·'1 ", {['C,·t .. ' '. I ~

. ',lapl. ,c' anu,.;;, ,~, ,as, C· , 8111y, 1,.~1~ eVI.~U~ihlon 0, . OJJlu,-SI~ .U~ ,p,Ii'o:,&rnu~·· '~.:. flt1.pl., .._:i h

'. ,C'iL' i.. ..l ii!..~ . ihan .' ~ri" Iii . -'~l'~I' " 'Ii.. ,".', ... ,' "i·~" ' - ,]~ !if .. L,~·. '~I ·'~ ..... ,1 -

satety aitThlll, UIOP:: armaceuncat a we, ',~, as .puaoo·l!oo~aceu~.~C;!L.-!~,eCnll ·!.w,O,f':J'Cm~ as-

pect', I CJ;!'apt., ,4' and 5)1~ 'Cll-~Pti 6], 7" and 8' reflect the praetiee of sidt forma-

_ ~ l!II! 1

". . d '. 1 ] ~I d 'l ., Tl...ul '·'b

~10n Ul ,an. nl':ustrla :1T1e;semrc 1 anu, I~ 'ev'e, opmen'~ tUl\-'JIT10nlne:rnt, . l.e:y ue'·cnue

sal~' S~'lffi,.,.t'il!lfllt'li iI·'J~"lIi'i··.,q;'!Q!!'; a;t[L ]' [[1i;·..iI'Lil ~,t·lII"~ g,] '~laJ!I]I,m;, QC,I!;!(j'~IB' "'1"~p.aC't"iI:" n'r' "'al~' nrnd' U' pitl' n·m. a·lIfIi,d: ~:._ I I~ ~!~l ~~[,.~yl~;J! · .. ·.11.. gl~b~,1w~~, II ~U _~1'=1 lI:'_~", ,w'·. b,~ a .. ·. ~,W~ ~a ... ~~ .. I)jl ~I(~ ,~. I~J' lLJ,:,: IV.· . "\r.tll- yl,IlJlj! l: _ .W.I'·.· .

'nhe ~~,~pll.l~ficance of salt. ·rorma·'ion 'm'm indlu[ triail p.:m1JCe<.,hlj,17. 'The wnvolliorewen'n

~" ,,-- - -~,~ ~ - ~ -- -~ -.-- ~...,. = . ~." . " , , .. ~... ",i;:~ " . . " "..,., .. .

[ot' luth,ofi.~Ie~, rn So de~~h: wi~h '~n IChap[t~ 9 and. l' 0, 'yihlch are devoted 'tto pat:enj~

... ·~"il 'Iiil~n'~ ~'l-"]I"~;In,""'ijJ ;',0[',',' " ~~ ,_ ~<, ':o1"i' --,~.;'~,~'.I".' A"·"'''''[d'· ~ ",~,~,,~, :. the,;, ~', ,.~., "1\ijj .... '[·',t ... [O·~,F>. ~,:-~ 0,111' 'f'JiI..." ma'~b"

,~lllll.u ,I: ~,~M ~u.v.l. ,J ru,;,),:stle.,~ 1~ 5'PIQCd ve,~y., ·::iJU ,res:; UII,g, .. ",e, pI iW;;;. ".m I ·iD1!i!i;Ors ~J!J,. 1IJ.W1~ ~" .

'b h h ~ h f h b k ffi .'~ 1 f' .,

. .- ~ . ~ ,.-. ~ . - -

.. 'en,c . ,~, t ;:e I ,a'~ Ie "apter.s, 01 ~ t, ,e ·.~);O,.:' :'eaclJJ:re pracuc,a . e,}t,am.,p es 0:. :1P,repMatOml:

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0'[ S;~.lLS, presented in. the 8Ity:!le of model procedures (C/~apl'" ll) I;j nd .3J .. , omprehensive annotated. CO~]J1JpHaJHon O[ the ~Jldivid'IJa~. ".,[1 t .. forming acids .and bases, 'W wth tth.eir relevant properties I( Cli.o.~,t" ,12), fo-I1owed 'b,Y ·an .ApfJ'ft',tdix eon'Lahni.rn1'o ~a.b~e' .. , \vj.~h [he acids .and bases :;ud,€d a]pbab_:~'b:~3!lly.. and by p~~ vailues and.lIJPplje.nl'e~l~ed ·w.~.'th other useful facts and. (lata ..

A,Hog·er[Jher~ the "e 'e·halP~·e[, reflect ~Jhe ~~~Il~idic "p'U'nary i haraeter of ior= mation and selection of Sui~9bte salt forms 10" dml.g . ~ ubstances, .A.n mUe:11l11pt is

made t,.n· ~ ~ "~'b'!I;I' .1J a~111iI1 "U'1i'iiI to AI.rnJI~';;:i!. sui .,;ilm and ,,;n'ili'IN""' , 'o,jIt ;, .... 't';.,. ';iD' '~i~":,n:m; not onlv

~.lJllU.'U~ ,-,I,;, i".;-"!ji. _~, l,~~[:"lll .. ~ -IIJIJ 'IJ,-~ ·',~U-al~!\r.I ,~I~ u.~ ['_'_W.t'l :··!I!J.!''-'ILL.PIir· '" "-"l~ JIj.~JJLlu, .lI.l. g}IUJ.Y~.I lI.WY .• 'UllUl "

s~rvi~'Thg n~edic~!n:id t(!:h.'em:ists.~, bu~ also a]i'l the other' :se~em:·ti>·ls who N~ 'irnvo1ved. ~11l. the research and development of drugs and their :Illllaon~tceuti.ltal dos ',:.ge ·.OFmDS .•

A. book dealing wi.~h. such. ;&~. tflldy it1l'teF.d~sciplinm7 '~,Mbi~ c~ relies om. con-

"t·1:.._ .r ; . ·,t .... "I.' ']"1 ·_..iP:_·' .AIl" _ .. f"·· ~:k· .. fron ~·.A ,', -~ . .J - rod'" ,.

tneunons o~: a we 1., ... coonl.J.U1.a~eu team 0, I.Ulbll.or~, . rom :Ul~.UL&ry. ~jih;)I, acaeemsa

r epre £!!;'nl['- in 0' the vario ~.~ .Ail" ,. C' ~ipl~i ;11IfIi es ~i nvo 'lv: ed :]' iI'N, the process of d iI1"11'l,!lJ -,t".,. ~I.t· for-

,J IIJir- .. ~ I~ ~ .• C. l~ 1II~ .~.~, l .' .I~~, U .",. '~l W.lJj IJ.II~· ~. 'F r·o"· • '!. ... ' 'l~_mJ '=~. r~ I'" U~~~.-J! IUl I .' W Ilk :,~ =~t~LW ~ ,~,~l,: ,_,

marion and. : .1e~.I~ction :for pharmaceutical :l~.ll"lod net ;. :in I¢Ul i odD :tr.il,a~ environ~lilenjt The editors wish to thank ,aU. the ,aumon for th.eir- engaged coo,pe,roci1tl':n. and their patience du ring the oo:'vrn .~. i,on lllOcedufe' . lha~. were necessary to arrive .a~: this cloml:pfehen',l'e: and wen·a·balanced. .hlrwdb·L~~ Thanks ar-e .aJ~il): dLU~; ro ,F. O. Ajt:i.yi ~ H;. ,i\s,c.n ; ~ .and C;, ,Hq~. w.ho- accepted te C ..m:r]],bute. to ~he b .... ok in the y,ery las~ mo'ooe.nt.. Tile ~d~:~or·. 'wish to ,3,iC'blo'w]edgle 'the smooth ,and ·exce'Ue:flt (;ooperado'f'l. 'wi'~'h 'Ve-,~'la" J' H:eh etica ,Cld':I",C{J A,ct:a in tile :prepm"~' ,at:won of me '\jo~lJme:: Tht)~:~\CiS' ."QUtZM,~~ ... A.ssi>~atnt Editor~ for hi p3Jjti~f1t mild attentive harnd.·~·rnn,g of all the practical detaJ~s of the editorial precess, and

D·.·!~·:. M'·~ '~()' i·'~k·t-j·J;1: K! If:",nlr·~:;'·I:nk. M. < .~·':'Iia:i!lJ'l··ln,O' Director .~iIFliiAI. '".-iI~·t·'~iI!':"'··'1fi ... C .••. ib.'i,~:~~ ''''~Q: :'1" h··,.;; ':1

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wnspirdJtion and for h~· uOJtiring~'cl[1UJt~ny jn btID~g~m1.g hi" IC\OO siderable comprehensive knowledge mto ·tIDS project, Thank Me also expressed to .l.tIl'FY Lesko of the U .. S, Food and Drw"g ,AdllHni s~rll[:io\lll. fot' es tabl ~ sh'iug. he'Epfu[

... ~. ~i' ~, o· ~. ,f>" 'i"Il..~:'" '[' '. ,D H~:" ,'" ';; !IT'. II, ,r' ~ ~ - 11_ .. ~ -..,]~ . ...:I 11·:6 ~ , ~ ,- ,- '-It

comacts. ·._,ne 0.1 rne e~,d JO.m'· I. r: C,' '" '~'. i ~r,m ... eruuy acsnow "J3uge"" me support

granted b NC·.n'O,ttis ,A.,G~ Basel, and, ~J.he permisslon to use ·their ScientU1.,.)

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:MicbaeJ J'., 'Bowk,er

:M:;; J",owker COD'U ting "' ~l1j't,ed., 3'6~ Burses 'Way.~,

,H:u;M:on,~, Brentwood,

Essex C,M: 13 2PS~ UK,

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:Da.-vid _J~ W~ 'Gr·a.mI.

Uni 'teFs:i.~y of Minnesota 'COI~ lege 0" Pharmacy Dept. of .. harmaceatic ' .

. . ~ •. inneapolis, :M.N· !j:'4!5,5 =034.J!. 'U.S .A.~

(Tel.:: + I. I( 6, :~. 2) 624,., 3'9i.S 6':, fax: + l 16, :~. 2 '.1 625-0609:;,

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2-5-8 ~ [H.wfo:mach'i l-Chome. S-hina.g;H'\v,a-,ku. 'Tokyo 140.,. Japan

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Stal!i~e!' Lee

4 Manor C f:ie'o';C'e~l~ Macclesfield SK 1,0 2BN· UK

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r.vf,asabir-o N',akano

Department o,f Pharrrna.cy, Kumamoto 'U niver ._,wty :H'os:pi'nal Faculty of :Phal1'm11lCY

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Kumamot ._. 860=08 I, 11 '~' Japan

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,FFled~~eb Pfann'k,ucll, Roche Vitamin" Ltd,

H:lI mtDJaJD ' ..•... u~l[iliorn (JJIUd. Health

N'utridom So'felY (VFKS) Building 1'?' l,4f9b

p~ ,0," :0,0,1\

C[H -4f070 Basel, Switzerland

(Tet: ,~~ l (61) 687 017 99" fax: 'f.4U (61) 168'~ 6,8 19; e-mail: Iriedlie b.pfannkuch I@n)che.loom)

'.ladhIMl Pud.i'poo_;d,i;

Novartis Pili1Il·.Illac_ietl:~ical:_, Corp. B uHding, ,4101

:1 :He~a.~tb Plaza

Eas~ Hanover, ,N] 07;9'36~10:80, U',,,S.A,.

(Te~ .: +:~ (973) 781-13,85; Iax: "*":~ (973) 78 ~ =45561:; e-mail: mladlhu .,p~dl:ipeddi, @])hwtm;[t,ru);vmt~s,.cO~1fl)

p r-e'~t[io,~ts address: B'iri:sto~,-"M:y,e~," :S[q~J::i.ibb ICO'. ~ P~!u_~r.rn13Cel!lti.lcs R&,D~ Brunswick, ~.",.", J 081903..10 m 91" us .,A.,

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B,'~'i~dru~lg 40'

.~, :Hea:Uh, Plaza,

EaS'~: Hanover, '_ J 07936 ... :~, 080~ 'U',.S .s:

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:Pt, , emrleh Stahl Lerchem trasse 2:8

01.7'9104 Freiburg '~'m Bre~ls',f:iall, - Germany

I(Tet:' ,+.t9 (761) 548 2,3~ fax:' +49 (7'6l) ,5$62 91:~,0::, e-maikheinrich "',>~Ihl~:fr'@ ~,=ord'~:r:H~;,"de)1

Ca.~~~e '-_-iJ'~, WCf'M.,I-h

Loui Pasteur '._ niversity, Strasbourg Fac~~l'ty of Pharmacy

1-~,-, route d~ R'hin

F'-6 7 400 Illkirch, France

(VeL:: "*"33 38:8 '0" .37 22: fax: +33 3.88, fiJI? 41' 94;,

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o ]-

• . ,". r '.-

.l.aprn,er .

.of I:ordc :Equi l:ibri,a

M'ichoxtl B'~ ". 'ln~rln:~, D{1 vid ,J.. 'w. Grant." aJ[]d P;Hein:,riel" Staid

0. '7

Chapter 2

'119'

·S.3

1. :~.1

m35

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,~ ._"

Chl:p,.t~r 7 A, Pmcedure ·~or' S,a'~ .. t Se'~)~c~Ion ,and, IOpdrnl~za:t~,on M'lchae'l J. Bowker

'~I t:. "I ,W,I~,.

S' l L d- C' I~ ., '" H' (f· t;an _,:cy ,'·ee an· '.'. ,~~,.r$ st:,~an, ,:,: 0(,-

H e,I'uy;i'ng Asche'" J~'n,-.ichi l{,a,1;do1j' and ,F~uuni layo O. ,A.jay~i

Ch apter 1.:~ Selected Procedures for 'the 'Pr,e,pan!tion of

·Ii1L"I'lIl'r· FMi o:'Ii ,r..e~I'il~']· n ~1:~I'~,'iIJ' A'" .... f'IDIimfi'FI;~· • .'lle· 'S' "',1- t'l .r.1~:I~« -,IJ,I,:I,~.t''';;' ,,,,,I,,,. ,!""~,III,lII'i ,I \,,;'I!.i""'.rti~j!J.}'l' ";'''1, 'Ii.',

ICan~i.ite IG" 'Wen1U~',tJ~ and p. ,H:e',iIU~'Clt St(1)l~1

,;,An! l~~'~

'"'lI1,iiC~ ~U\~

P: H' ; 'h' ~ ... ~~' '0 C'" 'l"I' G'" - I!M: ' . h'

'"il _;." ., ," I. 1 ' •..•. • .1 r"' I '.- , • " _"]' - I'" ,"

,', e,~n nc.: .,;,.ttl J, ;3.n., 'I. ·aJ.,HL ,e,. ..:e n:lult I ,

S ub] oct-Index

361

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. 'n trod u:' . etio .. :·:;n.·

I. "'-'" . L. I .. •

l..,v .. ' ':~-I=J'-I~ G.,~ . W. ". rerm -U' .',- L, an d P. H' IB;:n.,:;~'b - .,- ahl

IUJ .. ~lIIl'!J.llI ._~ . ~ __ ~~._,_,_. __ Ill] I~~.~ ,~i!!!1 ·_,~lJl __ "'lI~_~~, _ ~_g~. '_'

I.provhl,g: So,l'ubi' it,'

B·' - t':" -. . - .. ..\1 - .. '-~' - . b. .' '- -. 1 D'· '.- '~I' ,~., .- '.. . . . A ..-,'L... ,. -. - '1'· . ". . '~l

e _ ore onuergoln,g .Pw,~~!BLrm.aC\(h.O~U'::<HLI. evamanon alfruu, otner prec lDlC~b

. tud II jJi;it" ,. 'unto: iL eti c a-"r iIi'Ii "'l,iihnlr-:Jj'~1 "11;1'"'1 ;:V'g;, prin ciol ii:!iI' 'm- -11i'~llt'l ~I'I,(!I~·~,~'~'m.'IjJ' be AI·' , Om vQd: In

. I..: UJlII}~.;;)r~ -:'j'" W.I· IlL P." .... _. lIJ.I.~!-IJ)IJI( D.m R~ ~W".>~!ii.r :: I, J ,1l,1}~lI'r J~:'. I, ,1"~ 1~J.-.;Ji'Ua,W~W.j.' . ',~, U_ .: . ·.·W.<·l~. ,'Ii ,·Jl~

the majority of cases the' objective is to render the ,cortlpound wmt:_t-somu'ble ..

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more water-soluble a compound i s the 'more diffusible ~"t ~,S," Th ls causes it to be less speciflc in i,ns acti vity, and more Uable to :rap,jd elimin ~ltwon and ~hefiefore, shorter acting,

U may al so 'be pointed otnJ~, here that nrue:i:mll,haneo'Us presence ~)f ,an ionized hydrophilic group on ,~ne Ifind of ;0. iOollpol,ar U:pophlUc ,chain. confers tto the ITJO;~!~~~le ,~U1, amph~:p'hUi.cI' 'soap-like' character. Such compounds can ShO'\iV' a detergent behavior towards naruerous membranes, and, "n particalsr, ~hey c2IJ.n Induce: hemelysis of erythrocytes.

Some 'Of ~!he bie-active bases are oily or low-melting solids and are liable

't", ',' oxidation A"'" c c '-:,"'-"':+'-IIi' .. ''1',~,,'~I,t> forrr tio , "', ",,:,;', ']d' ',' c'""d' ,eli, ... ·t'I:·~'IIi' '-'~ ... ·_"c:~Ii',.__.~I,_,

. .0 oxioa won" .ppropnare san ormanon can yte ,', ,P,lro.· .UC'I.a,~]al~ &J'I!..' l~ry8!,jl~

. ' .

m;', .',' A,'-"· !b1i ,',- i!i'·"~'.":--' m"·'- ,- '. ~ Ai" " ',ii' 't'l· :,": ,--..III,. ,.', ," ":1:.- iii-" ,',' e ,~" .. A hence ![]I'I;fiiiii'iBri"!!li,'!I'~llI

~ W ru.e~ ~ a~y ~.\.!i ,PIli,J,[1,1! y.!, ore resisram dlWaJlJ, us. oxieaaon, ~nu'l' :!~!"';'" .,';j,.;)~~ ,~. ~~LIr.""'!I, ;i:)~.~,~,}

h a ve a 'I. oi1l.,ge f' shelf :~'ru'~e",

Po. (,'-[,'l.rmi·lo·. ·'It'P· 'hi~'m-'"_""

" . l.1" ~ = . ~ ~-~

,- ,

Selecting a, salt s~li~l!ble 150r ,I ,ceRmin route ol:f ad:mln.ls~J.r2l!tilo,rn or :3, paniculam- dosage form 0:[ a drug, substance requires, that all the relevant olid-state properties of the :~, a~,'t candidates be ~hotoiJ.,ghly i [live" 'ti,~;a;~,ed. Polymerph W •. ' ,m and. pseudopolymcrphism are freq uendy c:rUlcll points in determining pref-

". .'.. ,. r'. . '.' '. . '11ri- It anot 'b . . 'D . ~"IO ::: oh + ~'m' _- :', ;g, wid I .... -- .. ' ',.' 'd' 1 ""lL. I " ',-,', " .',' ,.

erences I,or one .' ~h'l., 11e0 anomer, cOitym rp ss L ,Qj, wiaesprea ,_- pnenomenon

observed in more than half of all drug substances 1[2],. 'The: ChO(W,Cle of the most

,"', ,', .. _.,,' te , _',,],·...iII, 'L"'" ,jI'" '.' ": of consid "'-'b-·t· r., .. - j,', ,-.,,'. '[J'i' ,..:1,-', nost

appropna . SOlUM,""" ate lIi.orml IS o ..,;' nsiaeraoie ~,mporl,;aft;ce,. ,",ere" me most

prominent aspect to be COI[1H;'~.dered is s~3;biUty., First of all, this means tbe;m1ody FI amic stilbHitty at the solid-state fo m, but also chemical stabil'~litty aJrui re-

cti '~"" {'-']I' ,,",,' ",.,·,,"'L,:"]"iIt': t , Iii'i.,,·, ,,,iII" b·::-"'''m~,,,_...,. ": .. the '-""", ""'" "f "", .. :",_.:'. us)

,ac.~vl~y '!i.e.S,. I' companmnty, r.e., 1!i,IU~ s"aID~hY Ul !- ne presence 0" exeipiems)

. .

1"t'II a'!jJ' v ~'rv fro fIf1i ;l'i"!i.ne eolvm .',nmL, ~o·, ~I:41e'" .... ,'t· her In 'm' ,IAIoCl~' , .... ':']i, ..... ;C!I!""' '1·111'11'""" mod ;;,~,Ii"'>Iti,~'1 n'n

,~"IJI. J '- ~"" j ,~., 'IU!, IIIJ.I,V "'" r'V"',J' J~v,. lIi""n I~h. IlUL '!<;,!I _' !!..oW,,, "" ,., '!! .. J',;:)I~, ",ua!!;,;oliJl'~ !i.h"" ~:!!'!!J. I!! it !l!i",i~I~ ~V,p,

- -

thermody n.amic~i~Wy s~a:b~e ,am room ternperamre ,w" [[be ~1ll05~ ap'pilop,ri~'l'e one.

T .... :·" \. 11'111>.,·· ,,,·~~";il ~~'"'b:;,, forn "~"", ,.t .. "',.L ," .. , . .".,',-. '11~c+,-,':' ·11, "i,,'h·· '~'~.",=-.. ,'''~liil

rns ,~S' IIlW,lLe soua- stare ,01 m nll~O W,~!,I.'Cw w,~, soon,G,1 'Or ,~al.Je;,r,~, a 01" I elf .. 'I'm,s W ~ ~ ~

ev,em1~uam~:y ~r;m;rls'fbrTim,., However, bru,gh..,energy mechanieal processe :uth as

"':"1]" ,.' .,,' ,""" ,'-,,' '·""·d··'· ,"""", ,t,', __ ., ""~" ,'" f", -. not table -, ~1l11l rng 01 compression can .u1.', uce tmn' "w:o,nmatloll [.0 I, • OU11, JIDO_ ~ .. _:aVI,le at

:n)01U temperature, Such trans form atio III processes may lead 'no either' an 0 ther

... .', ~I m ~ . . ,iii', . , .'. - '1' Iii, ~" '," .-. .. " - 'a;.. '. " ,,;;-' 'II" 'd' .AI.-· ,', -, ~ ".- -, .-, ... ~ .. '. "1' " - ,"

,t,rysta.w,~,I,ne rorm or l~·SU I~, in an amerpnous m,3!lJenl,1J, an I oo no~ necessamy run

to comeleteness Several teehnieues have been propos ed ,Md are applied '[0

f!'" , .~. 1 '.'

,AI iii"'" ,,'" ',' the Ili'III...,p "'m-' """ .. lvcc 'ilri,"m'" ieallv 't"a'bil' , ,~", . "T':he': ,.:0. • .'--'11" "':1.,. 'm" "C'!:ii' unement of

u'~hernll'Une ,I"", I~~ 1II~r. " " ,!.,.!1U,j' rrn!llillo ,,' ~,Ir;;.. t_ , .1' ,'. _ ,I.e .l!J.o.rm" = f!:S!"", n~C,~.l!lllU}~ ,', ~J," W, "'"' . , • "til" V.

'[" "b""'1 ,0 '" ~ ,. iIl..' f a mi f" t:. ~.AI iii-.. "'

SO'JJ _:w.j~y,! equ'~,!I.~,liVratIOn. or' a mixture o rorms J,n su~p;e:nsi"on amllllJ, observing

any change of their' mass ratio over' time, 'therm.o3'na'ly~ic:a'~ data such. as, '~:he

J

,

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4

melting points 'of the PU[''C po~)(~norphs, or the behavior of eutectic mixtu ,es at reduc d temperatures, and ,ell1Jth:aJ''y-~,entp~E,a'[lUre diagr~ ms [3]., ,A 'v,ar~elY

f' 'i,.., ,;, ,', h d- fij.., '. , d-I ;',04 ,; y-:-' • 1 1Ii..,' '"

o ~ec,{iI:1.~!ques ~!i, a~, nanr tor 'C~iuatact-.enzlng, ,iiiJL :1,iII.!I,ent[ -Ylug: po ym,o,qh~':: :,-:m.y

PO\! der d!1,:~fr,acU(:H'!L! JR, ,andl ,R,'''ftl.a'~~ spectra, ·,oUd,-,;.,£aL ,,','--, MR~ and '~la_don~

fi'u;m' tperat -ll'llii'P "'" ii"".;cll'iiI'II iii'IIl']~ 'i'ri, 0 techni (;1'1 ~ ;iJI,~ lIJi~:.: :: ,~, ,[Y. 'I}.W'~ ~.i~.(J.W,11W,IL. ,il.W;C ~I~ ," ,~=W~I ~I J~~ ues,

·S,.':_' , , It- 'F'~-" ~ ,'-""'t~''- I' '," " i-: 'M'" '- j' I" "I' '1 ,',d" I It- _'"','Ii 'po' ,- "'J-!-'~"-

13 ,- . o,rm,8 ,-1011, ,as a,:, ,ea,ns 1~'ILl' . g,",_,uI_:r, a.1J I, lrOOlSi,~n,g

Sa'U: . ormation '~" an ,es~iIbJ~'shed means for. tbe :i'o:~!al\1i,'oo and 'puri:6cat~,on of abstances, This applies not only for the final step j n the :syrn:l'he:"ru S o'f I, drug. Also, along a, synthetic route, sul-n. formation can afford an economic means to 5!epanrultc' an ru n;t,enuedi,ate -[rom side products,

As Ylidllcry.s:tamnzadon In general, also c,i~J{,sta]l]ilation of sahs is associated "f),tth the ~'ta]m ,0" polymorp'hism~ ICmy~:taUwzatioi['~.·, in the :p'h3Jm1ao~lln[,cal itlJdiJ~~mjt are m,usdy carried Otw~, batch-wise, The techniqlues UJ'. ed ,8'fe cooi:~'inl'~, evaporation drowning .. out, and reaction cry~3J]u.zatru.o'1i1", ',omlu)]JUy, me process wiU be (;a_"~ied out as llUll'Seeded crys~w]jz;afo,lJ1~ fi=-I:yi~ OJI1 spontaneous nucleation and the m'oolf1lca,t1:o-m '~t: entails, In :1 I.a'rg;e :numoo;'l]" of cases, tht wHI be; ,a.n UI[1jstable mjo{lrn'ficatio-:rl~, as i· .. prledi,cted b,' ,Oll"n1tCl,'ld' s rule (;If ~ tlg.e •. ,. However, an unstable 'form ~>" prone to a phase transfermanon either while the '~!lJoducn is s~U1. in suspension, durlng workup, or even du ri n,i S~o.U,a.~IS., The ll~~,er case is not ae "eptlble" since 'chm\: \I' ould ,question reproduci'blie produc~ properties,

The growing number 0:( chiral drugs requires e ftl!c lie nt, :m!ethiod:s, ~or pro _' d~c-i:llg 'these compounds in I'll eililafl~jo,m,eF~!cany liligb~,y pure form, Despite 'nhe ~,v:a,"'~,able alternative techniques, optical resolution 'v,ill diastereoisomerie

if' '~I'I '1- '~~n -m- - ,.;a;iiI';I.;iI!1Tii IFrn'll1- : :ifIi ;;'r'Ii ) ~.'b'a m- - n.c,,~" wi ":i]a'i'v III iI;1',Q_;;a1 m- r' ,tl/lltib'O·-AI for p~"'I~ll1g,it"l" !1'rIij]i' 'iI!l~l'llre ,~ifi-'NI~~ifl,=,

~~. 1 ~,v gl~j"~U ~ .. , lfj, \r"[ i 1 JH.IILIHI. . 1~1.~~ . v~I!i., -e- ~ U_'_'~J.' ~,~~U, .. ~I~_~_W, ,.U .. lly, . . ~.r·U!_l. 11lle1 .rlU ,'. 'Ii.i';M.IIl~lIU11,

riomers, Enantlomers can be: ~H~:,pa!fated. :rl~om racemic drug ,~u bstances or intermediates along '.)'.Ill'theUc routes by fr~cti(Hl}'9Jl erystall i ·a,djo:rn. of :~Ufl i,fable dil,:~t:e~Fei()ii,·· omerie ": alts,

""'" do, a-'--Ip-~'.a- ,j]i!I';flin-- '.'..". ,·.'t..'e~- Th A"'Q'P-Ou-'-4f~c~: Use 0-'---0- de' Pharmaeeu 'iI1;,Pa~ II .,. •. ,II, ,Ill" u ,IV !I,,JII·., ,,",'.1, 11;1" ,.,.... ,lllli.-_~1!Ii.r ,I , ,'. U_q.1I. ,1_IIII_iQ,!!I!..I!!J!!;o._ ,1.\',1,,",,_11,

Drn.~a,r~: • ?r=ml

~~ ~. ~ l~ = U --~

'F- '0' 'f n 'FiI'eij;,'j,i' chem ical ,enlfi'~~v considered e "ii' develooment .. ~Iif" .g;, dru -![!J!' ro~'I11-~"'-'1:::-

" -" U ,11.1,. - '~~, !!;.oJ 11_ ,I. " iii, "~~~ : 11j.J,11!-,J' ~,III,I,"'~, ,1j;,.o~,IV_ !I/~~ U!J;i'- "". ~ 'Vr'!~~-.R!!!!, ~_;;); ,g), '_ . "0 ..... I!R ,1!.I!)Ii

date; i~ ls im:po-rtanlt to achieve ,opdmlJ :1"Ill_ysllcal and ehemicel s~a'bili~y" The

f-, b 1 Ill.. Ib, "1]1 d 'L " '~'I '"L'I," h ,.

orm to - e e lOS6m, mnst ne cnemrca y ane :p',~J,:y,s~,iC'n~ ~,:y l~omlPat1,IDj.le w:ru.t;, , eX!CI,-

'pj!trns and adj U'VOO~8 in a, 'pha1imaocuticmJ fotlifll,ldaliorn~, h 'mill· I 'be able to resist

'-h'" '. 1- d' '" 1 r-' d '" '"

J • ,--' -. '_'-'~ "._. l-:-\ .. ~! ~~.,-.~ -.~.~ .~', -'-.-:' ~~' .. ~.-.' - '1"-.,' - r ·~I·· -. ~., -.:: , ": '," '1" "., " I ',':, i .. ', ,.

n ae nl~CFOenVJfOnmen~a ,an macro ,envu~orunenl~a actors ur ng proees mg

,and storage, and. must have :p.~o_peni:es to,DfI,:,f*-ti,blle w,itih. the toohn,ol"o,IY ,ap,pl~ed in the mf~nufac~Jdre 0'( '~~e corresponding dosage fonn,

Copy rig hted m ateri al

uEl t"\r];~R' "1if'1ii ~';f! 'S.'cLiii':',CT- iiilOif;;.t "'Pl.Tn 'Urf!!'''-' 11= .[\V :- ,G .', lIJ lILICr.;)!". ".: ,C -"C.",· ,lij ... ,~ ~'rti ,MJJ'I It;. ,_",' .;:ji,~

i:' oJi

S>'11J(~~,'~11' "~,'-"lIt'1i'i~~iji'.:'l, g-u-'I'dc I 'M,l 1?~tl~'i6~1I~,g,t)i:n'm ,o':':f'-' ' ':";;O-'IIAp:~~!1!i;'1 p-''-~r''~-p-'.~rt:'-';I~~'

aI.IJ.~~~· ,ii::Jr~jl~ _1. _ I uti J.j~-:a ... U .. 1& . .1 .. llv"Il'l..r.u.1 1 U, ," ~ . ~l~

'Ni! nocere' is one of the oldest and, the lop,ml1,o,:~ requirements for a 'ther= ape'IJtruc treatmem. ' -or ~hi, reason, 'the step next to the, detection 0:'; a, die sired biological 3Jct~'v'rnty of a new chemical entity is to initiate toxicological and, pharmacological W n v'e~ tigat["ln: on the s a'rety of ,8 pot,erw~~ia.'~ drug candidate, Because the salt form of an active compound :DULY m,o(Ui:~~r ~.l: b~lo,hJ,li,c~d performance b;!: 1Ji'~ -,O"i' toxicological ,and se&ety consideratiens al .. o :pl.ay a, role in salt selection.

Pharmaccktnetic properties may be modified by [choo,. ;hl,g salts '~dd]j. dJfferent solubllitles. Or~d a!bsolilDUon may ,,_ 0 be aceeleeated or retarded us compared ~O' a r--e"e~ence form. Se~,lecdoll of ,8 sp!ari-n,lly ;'_iolulb:le (alt. lean be Ill. 11-

eematlve te F"o'-m: p" ]-'~"'~-'lhA.,.,:I _'-I.f.i~': p, -~'t'-'iI'\"'-I""'~!o'-n' bv ;U;Q; .... Ii..'Hj·'i;'~I-C1Ji:~P.""I'-I' 'm'" ,a;,~c, ures

!!l.,,,,,,~,,_[_,g;L~\ I"", ~IV!' 11;;0' I~~~,~'~'[""'~.'!I,,\,#Y. li,'~, ¥~~;"'" If"",~,;;h y,~d' '-"-'J !!!,II;,.III;,.<~rn'~I!IVI,~"".l!',~~,'i;.o~lL ' ,,,,",,~.~ ~ ,!!i,,;-'~"

Wrnt'1ll pro'per' choice of ,a ph;mr.macod.ynam!i.caUy active ta.don or r :-If'lo,n as m:he ,co1Jnter;..'~o'n 'fro:r' an h~)nwza;ble dmg molecule it I.S somenmes llCKU:d ~-' ~O' ach:ie/v'e ,3d, ~y:mell ru-s:ti,!c ,eff@c~. 10 iOoUinten\ct ~ide' effects lor to faci II,tta~e' the de-

toxi ,;tI:jI,C- arion of the maln !!iii .... ,t~ V,,::Ii; pri iIi'Ii C]~ if1'!I;ioli, ~' .: [~ .. W ,~'. ~." ~I: .: l. IU! '·;I}II.r,:.· r __ ~IUILlJ a/w·LlJj.···_· ["- '.: ·,IJ"lI.lU .l"o". lll~/'~~ii'

tc:""1 'm m; ~ml,\i!' salt ,t.'lI'1i.lII'11IlI8i'~lt~i,O-' 'n ~ o-"m- - etimes offers on'i''! iilt'~i nn c' !Ii"O-' bi iIFIi'nil"i; ~1i ~"fflII""~'i it ~ ;F!;'IJII]Jl-~,~ .. ~rp~~Ij.:!Il! ~@.I.~~. ~,t~~ ~~~~,,~,,: ,~~~, ~1.' .. __ ~ ~.~.t,~~0! I". 1II!1;11~,d! ~~I~~,..:~.i~~·t~ l~:"} u,_:~lr·'~'tQ~,l~.~~~w--~,I~~~

problems such as suppres slon o:f pat n on. ].njiecd,on~ Q,\~Ml);,~d ance of ~looal :b"lfita,tion, tasse-masklng (bi~te:rn.!ess lete,,) or a:voidi.ng 'raJU,tici'~y (i-~"';8\.~ corrosion of

m- - 'l':u1Il'i iiI' ~ g 1'I-;.lItiil'i1n- "'m i(jI' 8f111'i iii ;I'nm- - ent) ~.:J.~~ .. 1"1~~l~lU " I. lie] ~"I~"~ll~'" ~1II.~IL·:·i'

E' -"1-' ,~ '-'r· ,jj+L, P ',ii;.,.,.. "'1-' P'~'-' 't- 't-_iI!,,-"x,~·ens..on or, ~1:II,e ,c..:-a.n;IiI,~: ,I :,['iO'Al~:C[_-lo.m

A.- alrel.dy mentioned above, file salt :fo.llm~ 3S, \"e:IJ'11 IS- a. panicular solid-

st ate form of a d' ifi'nl'I'iIJ sub !:",tg lIi'Ii .... iiJII ean :1" nfl U[oi!lIi!FIi 11"';0 '3' vaei a~"'V '01' 'il'IFf;II"pn"";'lhriillll'lllit' IIiIlll"np-Qf. ·iJIi. ,,_~l~; ,". 1 !.' .. ~ "I~,I;IIJ 'lUI! I. . ~ 11Y1C .;i. ", .: .. f~~l~('.tJltl~~,~, ~ ~'_lILI . llU , IU~',lillf~l~ I", ·~',ualj. ~lL,J" .' ',. ,I] IJ.IJ . i -Y.W! ~~.lll.l ll~11J Y, : ~ . ~

'tW_,CS .. , e.g. '" the Slolubil:ity ,and] :[a:~e 0,:[ dissoletion ~ 'the chemical stalbHity 0]" com:padIOU ity 'ww th exc! p:ie~n:t8,~ etc. A. 'new 8,a]1 of a drn"g substance alr-eady ~ fa! use

mo:;y fo 'Iii'" exam ple allo w'" 'ei, [ ,ii·ii'if'inl-;a;;r- manufacmrlns orocedure of the dosase

_ ,~:", lD.~ ,_. ,,~- [~~,~~ ~ ~,_:' ~,1~~ ,(_~lI,1 _ .... '.'/.. ~J ",~.aJ.II.I.,f.-·~[~~: _.:. ,In I' ,!I!oJl' QL .. _.1~1~: -,~.IJJ.[~ ,~w,v.., ' ... U1L ~l' ,J I.",. IWIl •. " UJUll"liit~,~ .. ·

f,onn Of. mla.y 'be more st:ab~.Ie than the sah :hh:herto in use ~ it ~lla,y ,ba:Ye: a, :Pf.o" ~l ~.Ie or properties ~haJt. make it :$.0 haible fOF' a, new :rol!l~:e 0'" ,3d.m:ilrni'st~ido,:rn~, or

Copy rig hted m ateri al

II!}'H' A" 'm"M' , ,Ii; 'C""'E'U'TIC' ..... 'm' 0' A III' ':r" _,

~~. I . l'·~ '.~. 1'-\, . ." : I.' r.o til .: ~ ~~ ,.Jii~l

-h ~ . fj '~d f' -]h .. . ] , .. ' ..

","., , I . , •. ". "'!jJ'"'' ""W .. " .... : ··C .. ·· ... , ..•.•. ".,. ",-··.',· .. C,· •... '.- ... '-.

~, e new sa t m-may even open ,I, new ne .. ;, 0 [J terapeunc lal~p ,1(:a!nO'n~, .,ny

'0' ne of ~In ell ad VO:I'T1iI~'~"i" ses '1"~!!1II\,r therefore 1.rIO-· 'lIi'ii'i!:"'(l' tute IIfi ~w ('o,~1 a ; :m;ifl' "O-I~' ~,riil, ~. t'~I11"--

' .. ,I,iII. 'lUI ''''!lII,.. . ,_ iIiJIIJIII'l0'b- ~ ,I III W!lIII,.1 ,~, IIJ,JJ.h •• ". 11'. '.1,1",,.,,,", ... In"", 1 .. _. /!I;;r U!!;,;_. """~" .IIJ1!JILW";' . ". ,Ii, ~!I.~ ...... '1Il.1"" .

sion of prop"f,etary- rhQ:hts, The same ,C', n aeelv :fo,l1" ~he. d.en,~c~iof1l, of a :~,ew

81. :m.. , . ~ .., . ,~ _.. ~"'- -- -... - ~-,t:",~.J ~ - -~ ~ ~ ~ _ .. - - - ~ .. ~ .. - -"'-

po'~,mo~h s

. Along the route of a new' drug product to the marke i1, the final step is to

btai .,.."",~".' ~ f: .,'L ~I 'iii;;. '.. 'N" . h ~ II;,.

(} tam miiliill, llteh:rng approvai :' rom tne re.guwla'tto.r.,y autnonues, . evertnetess, ~lI'lg

regulaeory aspects need, '~O be taken into accoum ~ight i!t ·the n'rui'~ia,tion of a development pro] ect iIIVo~,''Ving a, new' salt, ,A, new salt of an approved drug, ' ub-

'iran' .... e i ~]. iI\~, erinc ;I'nm a ".iIi '11' a:w "",,'I:;;; emi r» <!iIi'~1 e'ifii't'~'ii'-Y' Wlk.,,: .... ]. -'ll wn ul d' ~j;1!otll'i iil';i'~ - a- ·4?~I'i 'n .A .. ~ :·I~.· lJj-IIJ~~ : ,I· ... ~I J~-~ F'., '[I.lI ··:·~[I~·lIJ.~~1i ~J IJ; ~',_'.< eneuucsn Y~~I)ldlrJl_::.· ·.>._·~:U~ ," . .'_. ::Iu '_' I.," ~1~~'~JIj.lI:::-·': .• : .tIYlIJ U:" .·~f-

sier to be su,bnf~ined 'for' marketing ;ap,p,fovat. However, the :~e,gulato:uy treatmen~ of new salts of' approved drugs rn:lIW:y :F.ely 1.0 some de aiJ'~'<, 0.:1:1 the facts alreo dy known ,albotwt ~he acf vie ,endt, of the :il!ew salt within its :1'r1.0r therapeudc use,

Both, drnf1)e.rlen~ polymorphs and. d'ifieret[rt sa:~'1-, .alld ~ai~:l ;any polymorphs of those, may alter the peri()rmDanc:e: of a, drug, For mh'i'~, reason ,the regulato-

fv '~IMIII~I""nr~'l~; .... ,iI:' .,.;.t:ii.qu·' ire ,,;;a,iI'iI, exhau Ii::':"; 'i,;!""," search for p' . '1IIu-ml il"!l;m~'~''''' '''I nrlrll1' 'o'i' o'!i; ,.,iI·ifjl'i ,g J.i g!~I~J.~'i ~ ~ ~ ~I~~ ~ I~ ••.. ..:_ .t V. gl.J.~ [~A' :__~,".J. ~,t~ .: ~,[~ ~~Q~~ ~ e- ,~~\~ . '. : !JJ.!'.- - ._!'U'~'r·I.~~~ 1) ~ "._!~ _~. 'j .'. b I~ ~=~. ~,~

sub.···taru;oe,. The manufacturer W$ requlred to maJke ,3. ~~b~ta'Ot~a'~ed, choice 'For one Q;" the forms, or a. defined mixture 0:[ forms, Changes hll the 'POlYllliU)rph~ic form of 'the batches produced Me seen. as :~'mdj,tati ve of ehaoges in the produclion proce '~'~ also requiring ~he reproducible crys allizasion ()if a, cenaiu solid"t~ru!te -fO,f[f1JJ1+

S·c -'t' [S·c .' '.' H·I . ., -

,8 " : ,e ec LOll,

Copy rig hted m ateri al

7

pr[iepar~ti'y'!e w'O~k. and numerous COi'Uy investigations, This fact, in Idd:~tion!, underlines ~he :~'m,:pona.n,ce of I !care:fu'~ selection of the most 8ui~ab~e drug: saU.

[2] [J.~

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Cha:.p1t1e .. · "~r'

==. . ... 1

1. '~'filItroducliom

2.. Jentzauon or 'lofiopru!trwc 'E~ectro~ytef}

3. Po~lypriJt i,t.; : . tect ... !)lY~les

4. AnJlJpho~e~!ic·.· ~ec~rolytes ,fWDld ,Z,;vrnUlernloIls

'I"iJ; 'E"II':'ifi":"rn.Ie''Ji!;,'~''''''''' f"J Ii F.,IICm::n c~ Lr.;:)

IiI

A.n u n.d~:r.s'[',an[U [Dl1g; of rnord l.I.'tWO·lfi ~g L1 i I ibdm. t'orms, ~he fOUiJiJdati.on 'for !i),llib e-

.l"i - '],iC>nl'"' ,AI ~ ;Co·c I r- e .':~ Oi'fMCO ..,.,.,iIt- (io.t],'DI,t', ,{o"F'lir-:-ma,1Ii ~ '0' .n·:· and ·p .. ·.f"fi·ijl,t.:Oi'"1 ~ ,o;,jl!o p'··hV;f'·i:;i'Ioij"iiJl"';l\. emica m ~ '\II' seeakl!i;-ll.li,;.olillllj; !JI!l~'!L. !l;.-b,~U .. c·.I~~ v.~ .:;I!$L ~,vf_~_~d·c·._._. ;g;U~,c' '.:' _·'\,lI'.ItIi,;.oW.d~"h~ .. J.;;J!.I~"!;,lf\o;".lll ...... 1 ,t_ ¢' .. I~'~'J.iH""""~ ·c·

.'.--. . t - - 'i"lJ.. ·~.A ,(; ... ill- . - .~ rIi"~ - (lI'''''~lII' -,t;~,., ~. ..... j - Ur iii' . j;.·iilh '. .' -]. '" ,ll"" ...... :1 ...

~n.g ca~J.vo ~n]rY~s 001·nII eXI.$'!j"I,n,_ ofU.g enunes Oeilon~ I~O me !CJL..: O.~ w,e~.

electrolytes, i .. e. ~ substances -rham.!, in 21q e ueous sOllu:t:~on, af-t: pte· eO'n as ···Ionized

- .

'..... '. ',;:'om'" - . ..! c', '~I':" . _. . "I!: .' - .. ]' :. Co -·IiI.'. . ffeets both .:-IiJ....:-., J . ".'iil...,-".! .•. ~ ·...:il b.' ... :~11 ·'IfJ':~ "'; - '11'

species, romzauon o.w moiec lID ~e.· ·fiL reets . om p~wy seocnermcm .. anl;;.W lulO,w.O,1 -l.C~' i

= ~ . '-

propertie '. ~ 'Moreo've; ':" electrolytes are capable of' ':unnJng \vlm other e ,0';WO~

'~ytles :solid '~,aJ~s as new entities. A. salt formation ls a means of mo(lw'fyifig: '~I mportant properties of dlru,~ su bstances, I. basic un,de;lfs~aJlldln.g of tbe .won i 2:21'HOrnl ,equi~~blE'ja. of electrolytes is necessary 'for" uecessfully a[l'll·~.:yiDg ltibil', toot

S'··i!"1i;-·- - .~,., ential ·-1,;[-'····"··~·1Ib.·'· ",'. '-"1"1-"':- -'.',' .-·11',-"..,'1,",·· ,th·:c-.'i'., ·-:h·'··- .c·t··-·,· CI·"ffj,-, .. ·,,·,-.·-,tt,~o···'·'·c.·- .. ·

,.i'Vme 'es",t!l1Jw [i'C :m._ruon8~upfs. I:Je pll'\e8ernd~·u. ~n _ _j IS c~ aplLer. ····0 IIc~en~ i!/·' r pnc,-

tic .... 'I lOi no] l' .... ~'·L~lnrn. q IIfiI d' wi ~1M..·ii'-l'I j·t "..'RI ~ ~m- '-1'1' TIIi'P to be In-v 1Il--1'1jlJ1·1·~I' ~·t·;;·"'·~le and 0\fi~ lll'iil'{f ~ l~jjl~l·n, 'iii,~,;Eliiifl

~ ~~ ~~~, 1~,V·[t-_..·'~ ,~,~~~, ~ ~ yr~ ~ I~~.~:... '\'r~-. tl1J ~~I~, w' ~Jljl"~ ~~' ~ ~~ ~'.' I ... ~ !gtd ~~.~ '. wr~ ',r- ~ 1!i;~~J_}... . ~'V~ ~.~,~ ~·~!J~~l'IIJ ~!~ ~~vr-

~ l d ... ~ F homuah 'h 1.1-' ~ d' h

- '. '-J':" . ',1 -I _",: I' . - . ~ ",."' - I - I _ • .' " 1- _. '-', ~ ". ", ·1 - ,''"'..", •••. • ,- ,= - . t'.-: ._ _. .-_ '-.",

rencai '. etai . '., .. or 'a, mort! L.,orOUI. treatment, L e reifH C.1l" ts re .. errec to t~e

te ··xtnro··:"·o,k.·· 0,.' 'p~ly: sical C" .'b· ,;Q'm" i ·t"-l): J.

~11lJ ,. '!U . U. .l~flj;pi.'.~ .. r ..... 1.. .. . . .,

. -. ,-

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2" Ionization 0:' M:on.o:proti.c Ele:ctr:ol,yrtes

The ope;ll',a'~ing, principle of ],CHilWlado,n .of solutes i.ll1l ,3Qu:e01llS sys~em'~, h~ tba~ the '~rn:l;ns.'fer' of protons from one molecule to the other er e- len from one functiona.! sire in .' , molecule to another ~~;:,I~e within 'the same nl'ol,lecul'~e~ is mediated. [h:~l th~' omnipresent pfi~~)on: ~Jrnd, O'H- ions, 'W~bU_ 'being: m,w,a'~_ '~~h3in,~ in a,q_u"eorUJIS s.ys~,e:ms,~ free protons do not exist 'bult rather ,P_l0 P'f:_'SLOt. 'w'n dlc_·i;rdrated '''~il'm as, H 301+ Ions, aU '~'he :~oUoiw:iile con ,w.deratl'lis wn~, deaJ w,ith POOI-, tons for the ease of bandling- expressions. \Vi:dlout compro:mi ~ing tJtr-' validity eif ~he resu h: _ .'

According '~:O ~ffile B'rif}~~'!u€cI:~Lolvry theO,f)'ii .. :~}eJc~n·)lIJeS are C: assifled as ac"ds 1'I1,d, bases.Acids II"C: defined as co'mpouild.s 'bal, i:n. aqueous O:~:IJ;hOnj,

can release a ('!.'n]V'!;III;t~-d:' proton while bases are 'DO~ 'l~l'no'il~n,,,,~I.~, Iii,ill:~'fi' ca 1IfI''?I>f''~'Ini:'' a

~u "I!;:~ !L;li ~ Q OJV "1!l!!jIL ..... _ 'V'I!J, ~~~, "n~ ...... ~ _ ",-,_!JII.!!;;r _ n __ l""""'~!!tJr!J!l U "",,L "1;". _U i!l;'!'W""'.II""ij: g:

proton, ThUS't acids are :p~o~,o-n don,o,rs Md bases are p1'O'~on ,n'~yeptors"

The dissociation of a mcnoprotic acid HA, can 'be d escrl be d by the '01-, 'toiw"i filS leJqiUlili br ~ um:

J)

T"h ·'-~+'b·· "K"' f' "'h" ".. -'h .' .., -. d d-

o lIi ,~ .~ ,- -' _-, I I" I ,.. -. ,-." II I _ J...-. ,- , ti I: .. "_ ,-' - pr;jI~ -. , .• ,".. ",[ I ~ - . . •

:: e equ ~ I, ,_ nu m constant " ',OJ 0., ~ . lIS react Ul)',1il 1- _ ~_ e ,~o.l!l:1 :taJtl0.n c ~.n~~ nant ,ilJn : _, I, z-

fined b~y

(2)

As :i,oJd:z~;JjI:j,on'orm stant~, are sma'n ,and in(L,nVenie:n,t ftgur-e th_ y ar -,' expres: :ed ,3- their negative :I:o'g;~ur~,'~h,m,:

(3-)

Thus as ,an example, the K; 0" acetic ac ~d (,A,c;OH) com errs ,~f.m l ~ 7.38, '. 10-5 110 p,Ka;:= -4,.76. The ,K'{1Olr the :pKQ, is the lirey :parlmet~,[' i.rndi"ca~:in._-~' ~he .,tre:n.gth ~)f an 8Jc:I!(I, .

.s'~ mfll:~lr~:y'; for a monobasic cornpoand 'd:l:e dlh~s!l)cw,afti_lon eqo:i l~b.riom, is expre ssed as follows:

(,AI,)"

-m ..

(5)

Copy rig hted m ateri al

A fter dissol ving an acidic dnlg" substance 'HA in H~O', the tetal mass con-

, • I • _ IIi . _ . I. ", . ' __ .l, • _ ,. • • ••• • . _ . .. _ l . = , I l"'l _ ~ 'I __ _ _ _ _._ _ _ _ _ _ _ _ _

, ' ,Iii" • ,-_;, " ,-: '. A" "'-'1-" 'i·'i,.. - - ,', ,.--,';'_ d- '( - [A: -~]'Ii - 'iii ('= [HA"" ] " ,n, m, "~".,, '" ,. 1----"', ,.,:,

centratron 01, ~ Lc'~' w leUL r ,~O,I!l~le:= ,,:, j or not I.... "':', I; m sonmon remains

..... ;f'!;;- - :" ~"!!ri<T'i;'i' irr '~"'n~""~"~ 'ue' '-0' ¥" ,;.'I!..oa. exte "",,iii' '0'£ dl ssoei 'Jilt"j,o' 'n Ire' 'i]lI r» t' '".r1i.1Ifii ''!'iI.1'iii",1 l~ ,~_ 'f;Ii:",~ '~i''im-' - 'Ji; m m

",,",Jvns.Ui~,LU, 1 " ,,,,,,~,,tr"ro.,;""'lll.1 '" ,"_ 'I!, ,JI hi.,' ,,i"!i,,[iro..,,W,1!11l ,Ill U _' 'lU!'!i;r- wJ!l.JI ",IJ,I, ",', ~, ,'!!;.!!'n ~u. " Ul'!.;; ""'~ ,p.__-!Ii ~

of the :speci, es Clontairlhrlg ,A,;:

[A,~d _; HA.]] + [A.-~

(6)

To describe the extent of' an ionization equjlibrium, ,Elj"~~ 5' is substiteted into E(lU'. 2 for I HA ' which y~emds

K~ ~ I(~AT~ - [.1\-]]);;;; rH'+~]·' [.A,-] (7)

,amd the solution for [A l

()

.... [A - ~l~ /(fJ

fA- = A· ~(~WJ+ s,

(9)

and - as mass balance is maintained the '[racdon of the unionized snecies is

. _. . !!! - ,., _. . • . _. . . ... . . . ~. ~J ~.. ~ l!.J •• - ~ - ~ ~ - - - - _" - - - - - JI:" -

.-, , . - I[.H'A] [H'+ ]

~ ~,] f - - ~'--JftA, ,_, _' '-_A ~ - I A"" - ] - [H': ';'] .... L v'

'1' ' '. . --r A,~;

(10)

'TJT,8J1sf{H'med into an e)tpre:5s~lon: with convenienr :~o,gari,d:ullj,e terms, 'w'hereby [~~·r"]] is replaced by the fam'iiU,ar' definition of p'H,~

P'H-'~' -, '10,01 ifH"': +] (l ru ),1

, ,_' , ".;:; l :" ; ~ - J

we obtain

and '~I 0'11" .,'1"';(.]1, Iii md iii it" soc j. '!:II ted ~li""~ 'd' '[;1, ,,11jJ, ~J.i l 'Il._ ,1110,.. U i ,U,III,o:!I<':), ",li'l., ~""" , o{;l/v,1I.1 - ,

f 3)

'For bases, the corresponding lequl.dons mary be derl ved from EqJu. 4 and

5 · C Iii'ii.,,- ,~.E 'riiIo--.~loi!1,':'- ·C.o-:' th 4'i' fractions of the 'n-Ii"""h'~'O_"'i'NI'i!!Ii't"1Jhd:' base cj'., - otalln.4 of '["he In 1!!~JIie Sru,u,I!C \-",,"~y •. !I.--·v,1[ ~_ ,iJi,.,O nJi'..,r;.."~_l.,I,IIl.:l!' ..... L I. .. ,t'I,UI!I; . .tllIIllI,"",,·· . ,. """'-'!ji ,,J'OH*''Ii '~!!I!tU. .. .Ii .~~-

unionized base ~.,-,-:; '-~' ", ,rf~ ,:- __ .' obtair

LUUOrWlZe __ ' ase species, s H, we 0 1·,~_alL1.

~

fDH+ ;;;; 1 '+, lO:pM - ,K;iI

(]-.i\11)"

J '91+ . .'

Copy rig hted m ateri al

'Th~' ~' .. It!> .<!in·I,' !ll,rtI,'~ Fl;1i'rii, describe i'n !D, m· n(!,i condensed '~Af"~m' .;O,L,C ';'o'i;:!i;rre:m a'it~,oiffi""";'1i1 be-

'_ ,_.J~ '.~ ~'~l~,OJIJJ.U'J.lI_ J I:: 'b--i).~ ,w·· -~ III . , 10 .... IUi.1jl!~ '-' . ,IUI"- ~iI,~a!VU J1U1l1 [I. U.W."_. JI. 1 ~~ l -,_ W}_ Il.:ll·"-·_·ll.lIL· ,[lll',r ll)., .-

tWleer.m plKllIJ ,and sohnien pIH .. [:i" also app.,en~. d1a't 'the pKl1 ." :,: ·the k~y :pltlllDeter of' I:n drug SJUIb- !!taID;O~:~', ~(.dl iO'niza'ble fUl'lc;ti,onal g~ou.p:,~ ·pooi'!/',i.d1rmg: the measure of strength o:f acids and bases (,lab'ie).,

.I[i" .. --, I' ')II l"~ , . beu '--d'llt·-, ,.' . 'I'I~ ,.dI0',.,.,,'.'lI!... t.°'.I. ~',., -,'- , ,I:: . th .... ' ~ .. .--.

·~lI,nif,., ... ~ - .. J ,cau. ,'. e IJlie c l:O gonelf,aiNJe ~!I.~tSI,l-IDI.II!)(U,lJ.o.n 'lW,111gi[,lm~, .linr _J~ 1011.-'

,~.ZJed and unionized species as I, 'fi!Jl(1}cUolll. ,o.f p,H:~ ,As .n, lexam"lle~, 'the· d:ru'sb-i'bu=· 'U!on dj,aagfam. '~or AcOiH:, a monopllJue acid w]'tn ,ilJ!. 'llK~ 'of ,4· ... '·6\, Is ':lilow[W '~1!l

\C"~. , I'~' S':':'--:'':::''j''O'',J!!jf'' d'~,~, 'j'''''·''b' i''iiii;~AT'Ijj ,d'!offiilljl1' 2~'m~ offii,1',i'§.;"i;; i'!<!i!!i,]11a.-4I '-',01I-";I!!i- :-";!l,j;~i'iIi'i'riJ 'd:~I?i!!iI,emr-;jil'iii'iii'ii'~' ,fj/ijj_j\;!i;

.!I'~ ~g. .~ .. "·"~""!!;.o.I~"~-" '" 1 -!;.I.ru. _' !I!.II d """,I. II. llJ.l~f Q .. ~'l!' pl~u 1I!;.>!!1ll!- JlI!!if~' r.;;Ii!pIIi"l.'- ~ja"!!YI1!.II. I. - l~~ 'QjU.~i3 ,~J 'N!'!!IiOi'

.. . J - ". -··tt H 'n' - .. '" .. - m- .-__ " ~ ~. d

.... . ~. I ' I" ,I, I I" 1.··.,", - ,. .-" I '.' f.', ,'.1 I :,'"' . ','. ',' . - I '.'J '! 1 -,.", - i .' °I I I ( -

~,nslg' 1[, mto [, e .P, ra!rng~1 W" ere .Lon ~zaluJ;n ts e rectrve ") comp ete, ,m·,

where ru·~ 1, not, The' area o'f the diagram, may be d]-v'~ded. into 'We.e F,egio/llls,: two ,o:f ~he:m. are those w:hcre ,on:~.y' O\fIJ_~ Oir the 5,:p,ec[lM, L :p,me:n:t,. Tbey' mne sep-

1iI'li,=·4·ii::;

u [j,~

.Ii i!¥i=.n,.;

~ll!.J 7.~

o

I~ pH'

., . .,

l~'

if:ig .. 1 •. pH'·D'f!pl!~~fkNir ,(liSI;,ib~ti(m: of icmi"Z.~eo. ,gi'id ,~'j!~'i~~:i,le<l. species 0/ A,cOII' j;,W ,a,,~\ ,mu~ s.o~.r.~~'iw~ '("'p~~nlillofl dm~,sm.)1

Copy rig hted m ateri al

'pll!l1'lifliIP,~IIJ]!!TliIg'S·· $., I~~' 'Re" " -T'10"~" "N':" A'~", il\;.1I"1Ii"'II1 U~ iIC'

" R,V., ~~ 1. .~ 'P [I- I I~_~ _ . ,~.~., "_", '_ , J ._~-, lILJ! .' ~~lD:i

13

arated by a region of transition where one species is decreasing \vh'~i'~e '~he

"~iL'-I'C'i-':' "'" '·"·ci ... ·'-"-,-:,~',·,-·('J T·h~'-:-.;fi, '.~-~.~,iI1'~" where more than "9'01: of one E'ii(f .. t:L·e (,'P-J!Ji,,",,']";:Ii;",

o __ lelD' IS ru n"",reasma,~,. ' __ ,I"", ,f':iln~,~~, ~ W~""'~.I: ,_.~ _ ., ,._IIJ. ''7 ,'"'If) ", " lII.iIl., 1IiJ!,.n 1i.o'!i;r .'-'

predominates are demarcated 'by '~W() p'H-u,ni~s above and below, respective't, the t . 'H . 'I' . '~.AI ' t·'·· 1 !f'G'!; iii"h . K'" ". 'm, . 'f~"11 '7:'6' • , ~"k.,t.:!; ,'- H" "~'a'-- 'iff -;f'; ~ "1, 7~"6 ,y~, u e P',: ' vame icenuea 'W' I~, e P'::,H vame 0 ,~, "',.'" '"e?,.,!, I~U"": p~~ ranges ';';';',~",,'i"

and > 6.7'6. Thus the mtermediate region spans, about four p,:H: units,,, ,Over ~~e

P,H' ranee from "7,"6", iIt,o •. ··· '6~.7,,;;_. the ~'~"t1II';I.n.ili1·:I1"BAI fo um beeins to decrease '\lihUe ~he

, '~";c"-' "iii,! .,,,,1, ,_. .!l, .. ~ liJI,IIJ,iU. 'Y!J.U'!U!, , u;.vU .1.1,1, ...... ~!Ii.10!!0 V _'i;;o,_!!!'''''' __ .... -I' . _

au won increases, '1ft thi pmlwlcular range a :sh~,f~ ] n :p:H l:m'lm,'edi,a~e:~y causes a, shift 'Of tthe proportions o'{ the ~,Qnized. and unionized species. The 'point

= '"

where the distribution line s for the two species intersect ,alid ea.ch species :ru S,

~ '. 'I f ~ . · '0 5 5:0~ "%"" 'k' [. h K' .'

1:-1 "',' -, .~,'. [ .~ .~·I ~ '-.-:- ... ---;- •• ~",:;'.-"."--:-'. J.' .. :. -.,_._ : L " , .. _.,-_, .' I • "J I:

'p.n~senl Ul !~qUI, racrU)I!lS~ ""e"" " '"c" .or ,-', ':'. 'l! m,II1',. ,8 _,:e p .. ; ';3J'''

P' '~I' ...ll '. a '. b u, • .' d .'L... d' . th .

, -or potyprouc ,cOmpOU[h.w$" ]:O:rlJi:iz.au.,orru .-e;I!ia;Vl0r :rnS I escn ue .. .' \~:It;" ,a senes,

. ,"r·· "-:-'H'" ,.;:it. '~'-:-I' (1'-' ,~,,;j, ". ~ ,·"m~'i;.;., . .'~", . "',,' ,-,,- ',' .:~ .,'-"'.' i[,l...-:,~!,- •.. ,,-,.;11' '-,' ''''" .. ·...:I·"- .. I": .. ·~'··~· acid utth ~.

O~, P ,_,-uepen:_ en,!!', equw~~,l!Inl, expressions, ¥',{.lI;;SQ" ,1:Q,n ,~.S a u. ,prOIl.LC acio wn .. ' a

.iI'!'~' 'N,...~, c '''~', ,n" ~:U"C: " .c .. K:" ~ '1 100")' and W'" esker ~::;c ~ .A,lIC" tetrazole- '." H· ' ;{ i("II,K:' _, 4: 1': 3~1 \,..arluoxy efi).::."p Ip,~,,;,,~,~: = J',.-;J._ .'. ,alll.L,_I""'QlK!I;".-" !i1t.luw, 11U ... '1. ,uLluil,,-,~ '''''' \ll..!' 't'I!.2~' . ,. '

l leasi f-- . '. [[ ]'~] Tw b . di ., .'. . 'to 'b .,

- " ~ .~. -~ - ~ '. ,-, ,-- ~ ~ '-'-~·cr I L ~ _ .... Ill- ~.~ II _ .. " '.'-. ',',.,' .!!' .... ~ ',' :"'" ·····1 ,',.' I 1'[ I _ ...

as the prot.on-fir; e2tS,rnn,~ , Ufi'C'tlO:m~ I ' • ,.'0 ,u,'Sieqw.enL '. JSsoc,ruJatl:on ieqUl. 'I",na

~ b id (1-.' "~h"

-~- ~,~ .• I; -, .. 'I - -~. '-, . ';-~ 1. ' ,-,-. 1 "-l- , . '[l"ii." l'l!"

!f1:1,1IlJ,S [, ee C onsic ere ., m ~.~, W 5:, case:

K~I «, .. l·

H,lA.... ._ ,H.A'-':.... -, ,A?'- +- :H+

4-

H'T

=D' .. :". ,·t·'·· :-..... :~.", 'i"~' .'.... ,..', "f" ~,1.." 'f" '. ,iIi-'.' ".' ';'f ',"" iJl,.. .' ;,f~ th ~.' '~'1Ib. . ::_::_ .c: ~;. ~c ,jl"'-"~ ~',iifi;1 i~,t'!IIA i;',;QI

' .... ' e .,e,rm:lnl.~.~on 0, IIj.,Ue, .. r.a.Cd,on, 0., reac~ w 0.. . ne IJl"w,wree g,,t' ..... ...,,lll;.;.· ..,1iI TV:!'" "",I;;!!I~, ~.,'!;.-,. I'

',Ii!.. . ~.' .'~, ,,;il ~,d U A~" the . .. . ·i . H' 'A" - . I' d ,tt~,~ d " ~ ni -n A 2~ 're

Cut nO]]J:lo:nWltu aero ,1~1l1"j; t e mono-emon ,; , a1rn:I_, l~iDJIj~ '. r-amen ,M., .. '~-

-~I}'C:' ~ ":-h ., ~ ilih 'c' - .... ,'iI!... """k ' .. ' , .. "-"'1 """""'1 _,~, "Th·"·',·l· ,,- . ...:1,. ~'·i~'1 ""I ~,~' oft .... ,~

t[1,UIT-eS, notn equuinna ro oe ta .. en. IDID accoum. ". 1S, emu, 11,,0 m, set CL III ee

E .". }" 7-:-: t ilfrll' . qns", :' .... -.,;7.

(1,7)

(18)

(19)

Based ,0' iii'Ii. these ~'ill..e.··:r' 'p .• ee ~;,a'~'1· 0' ...• ]'11; diagr a ,1m, sho wn c' ]"'n'- Fie. 2 was. c onstmc red . dis-

~1 .• _Ii..iU , I~,W ILU ~. ~ Ill~ W , .;]I..' III.II:_ Ilk , ,III U.IIQ ' .!II III i!j ,;J!W W . , _ ~ _ i:JJ" _ _ _ _ _ .. _. ... .,

PblUru ne: the :p. :H' distribation of tbe three sp ecies, Since tbe two 'oK. values of

,"'_1'; '1!!.rI'· [ .••..... _. I,. . ... ~ ~.-- - - ~ - ~~ ~ . It:· ILl

Copy rig hted m ateri al

14f

lSI

~K~.,~ ~I(;[~l pH

Vt11$'{IJ~1,iIQl;~;r are close to each other ~be mone-asion !can l~xi:slIO'oi.'Y I'nl a nmO'w 'pH raage w:i~b, ,I, :maxiwu:m 'ffICt~on 0"10",5'6 ,IlU piN 4".3,,.

In e£hylemedi,amln~te;tr,aaoedc acid, (HDTA.)~ 't.h~ dlssociatien ,o,f '~ourtruc'wrl~~'~:Y ideJJ1:ri[c~d iCai'boxy ,gr-ou.ps. produces five dIffefieQ~ S]J~c~eJ~;:

.10)

.. ', K1 K'lK),

fHA.l- :;;;; [H+]3 + Ki 1"*]2 + Ki K2 [H'"] + .Kj K2 K3 + KI .1(z.K3 K4/[H+ ('24)

Copy rig hted m ateri al

1Jil'D ·O-IIi'}'d'R.T~ -ire,1f'! S- Ei '~'~ '0' "N A- 'k_'I'!FI. U' sa

F".[\.>_ .. ·.IU"',I::i:;·:·,.,ILE~~,~ · ll4LC'b,W · .:_~: ···_.L~U ,".~ .

15

Fig'" J~ the d:~stri'budon. diagram o:fi~,e: five species invo:~V'ed in ~he dissoelation of EDIT A ~, is 'based om. the Eans. ,21' - ,25 and, the 'p,K ". values, 2J) 2.1'-

~i '_ 1i!.II,

e: 2~-' - ~ "d~ 'iIO'" 3i: "]b"'" . "n' . 0' '~'" 1 0 . ',' '2-' I 9-' ," r ,- - _! ,'iii.,' ~',- .. - .. , ,,-, '[" " 'I it .

'UI.~,~, 1.0,_ ,Ill" .,,:., " , e :p ... :F.,an~e 1['0111 ",.0' to z .. ' lSI 01 plmCu.dlr nlVerest,,, ,:,n .1;:8, \1II~le"",

,- .. thre ," '~-.,., HI A" H'" A" - " 'd~ 'H: A·-·,1-.-~~,.-· ... , " l ,~-'~ . ",1.-; >- ~qJ:- 'T .... ,·' ", l'e t_n~e :f!i',p-ecle".s~, '~' 4-: : II ,,,'3;' 'j; ali1.'·: " ',}-; "coe,;:u st :at .!Jeve~.s o~ ~ .)'1-'0. '" n~,S ~, ,

due to the close pro:x:~m)ly of the pK ~" ~I ,and. :pKa;,2; values f2 . .o and 2" 1'~ resp.),

-crvr - . 1 h ,.4, - " 1 b 'iIb..' f' 'h .' '. ;,

,GU', .1\ is au exampie ,t : at cemonstrases ,3. 't)'pl,lca, ,.eul,Vlo:r 0' t r' e ,~owzat]Oll

of muhivalent acids, At ,I first ,glance it, :m'~"gtru~, appear surprising 'llhalt 'title identical caeboxvlie-acid srouns shoal d h a ve different aci d. streneths, However .

. , .. ~ _., .i"11' , ... ' -'~=' '-',~ -'-~ .. ~l,,_ "'_ ._., .-.. •.....•.... ~ - - - - --J.

'this can be und.ers:m,ood, I'S, 'the ,e1fFect 0:[ 'the stepwise increa . ,in 2 ne,g,a'dve char-

- -

ge :in, the. molecule, as the protons - one a:fterr the other, dissociate from '~he; 'C3Jf-

'boxy groups" A 'flier' dissociation of the :fi:[s~~ one, the most distant protlon 'will be the second lone leaving. The tlhird proton leaving bas. lev-en ,S C'8'rib(ll.ylate a;udnn in close proximity, 'tb;is, be,in,g '~he reason for the much larger difference between the 'nK . step' ,IS, "2 ,3lrnd 3. Because o'r the [aft~,e distance, the elecrrosrat-

_ .~ ~ _., ,~""'a, . ',' .-.~' .. ".' ' .. '._' = -=.- ~- I~'- -------'~ '_ - t- • , • _ •••. -_.. ' .. 1

ic- 'Erffect 0,' the first carboxv late ,ooiolm is n~]]eF' '~O\V in ho;~drnng 'back the sec."

_' _,I'!!! . __ ~ ~" '_' _ ,.. ~ ,., ',J'l .. [ .• . _. . l 1 l • , .. ~ j. ,_.. '~_ ~,.~ ' __ 1 ~. r.. - _. ..

OI1l.d PF()'[orn. Therefore, the second, p,K:~ is, ~~d:milar to the first 'To 'be, re,:lleas!ed~ the: thl rd ,and, fourth P.lll"~-OI1iS. need :nuu:b :rugheF' pH 'v,alue5,~, since tffile 'body of the 'illol.eCitde now' carries charges ,=-2 and -3~, respectively,

,AU the relationships above bold, likewise :fQrf base " because their proto'm a~,ed 'forms, must be reg zarded as the corresnondln n- acids

. ,{! . 1 •• 1 .I ~. ,I ••. _.1. ._., .. _'. . . .'. . . =.. _ = _~. ~.~ _I I~ • __ . _ ., ~ ~ •• !!I

w Iili]i

"u

.. '" - ~

"'" 1IiI, iii;!

Q, !iJ!.'!.OI'

'iLQ

'11~.... I

-....,.'~

'c . ~ EIJ'TA

'lJ;_

I,

'I

.. !~ .. I I,

I, il I,

~I

I,

~,



e,

I, I

• !

'.

~ "

III" '

~

0- "']'

~iii::;J

li

I I

1 . I

I I

./ I

I t l-~~I

\

'\

\ \

o

,0,

i[Ji

t2,

1,4,

Copy rig hted m ateri al

'* A-· h - ,. '1 - I _ d Z ·'tt· I;'

. - - -- _. - - _ - - - -.'. -- - = - . . . . ~ _. -' .. =-- , - r- - n'

li', ...•• ,p • otertc , '., ectro ,ytes ,8Il .• _ .. ' ..... Will ,!e~, ,t._ •.....

An]p:hO'te:r~c' substances ar-e rhos e that ,contain 'both. acidic am,d basic fane-

t,:~ Q"ftI;.-; ~i O'l;"ii"iIilllll'P'" For ;Qi',,",',;rr)j m nle m' '1IltFIIl"V' o· "f~ ~·b.m, ""'rrr;' Oc']'.AI g'ln,it,oq ~n'n,;" . ,t,t' '~'IIfIi":~ FiIfiII,j '~r.m;,d'· o,"i; ~,n

~lci~,"l~ ~I! '01"'11, :'" . '., "".h.a, .. lit'. !!;.;o jl .. 'gllJII,$ .•. '., U~,~ ,y,1,l:"f I .. '. ,Y, '~~.!IIIIIL~!OIUIIIII":·~' '"_IJ,II~ I.III.u..!'!;.'W'··. '!O,!\C;v'"

n ~ ~t··'-::·I·:'a·.·n~['!!Ii D'IO ..... ni sts are '~JjIr1,'!i1l.';f'i't'{'"ric .~~£I:l'ii'r~,'x"'~,He', 11"k. e narcotic antaeo ry ~,5,~. C~ti1l,-

. l~. . . It~ lllll.~.,;]l g g ~~W"'~W'l!..l'I,J!i;<- ll"~_ i:_ !!l;. __ I!.o!'.. " ... U~ ~L .. _ ~"'~ ~~~ ~!L _I!l.~ _ 'V'~I

taim a tertiary a~,ru,phat"lc amine and. a :p,heno'~, 'with .pJ(a, values IOf' 8,.'1' ,Wd. '9.,'9S;'!1

iii" ~. '-TI " ~ '. - _ ..4.'" - _. _ - fo - :rt1 J"i1i .' ~ - iPn i, Ii"'la..4 .' IAi ~.' 'iii·

r.,e·pI3CI~l'Vell,y,. '" le •. pec,ru,3!fl,OD, i~,d,a,gr,a~m ~I'r ,~'¥a~~'I;ex'O,tle m'..; p.ltui\r.WIIY~liI, ~'~.i r ~,I'.' "~ ,ilL"

'(1-" Ii" . Ib, . ..iI" . • ,. 116. -. d .' ., 1Il;,.

aCl, tc ~. otnnoa, 'ml~,I~e preaommani species IS, tue, :p,r.o~:o(rnJa~e" ,aU1JliU! W:ru,bi neu-

~ra~~ phenol (/.;,.0)' A.·.··. the pH approaches :nentra.'lUy. (be amine is, depr-O'£lonat~:d 8irnd :rrorm~ the ,com,:pJ.le~,eb~ neutral am,:p'hoteri.!c molecule ((00)" Tbbj; species reaches l~' maxi mum fraction mit pH, ~l33., A" the :p,H inereas es further, 'the

h ]. O"H "'r '. .",1 h ~l ,. ,.., I

pnenouc .:,. -, group mssocrates, ano u e p:lileu0Ill11n,i)iI1t species IS, tl1,e neutral

amine with the phenolate anionic group" l([o,..J. Conversely, ~11, amphoterlc molecule can ccntain both acidic ,and basic funetionalities and not pass through the unionized neutral state a.'~oim\g Ute ,H~c;fd.'e bun: :F.iJfJj'[J,e;F.' '~U1J!u.gh, 18 net nelll~fa] state tha~, contalns 'both a [lo~ i.dve I:Bd 11' . ,gad'y' " c-:harg\e, termed a, l,WW tterion,

Z'winerilo:ns are the special ease among ~unp'ho~er,ic co(tnpou~dl-, ill 'wb",c::h ~he; ne~ uncharged species results 'when b-oth an acid am,d a. basic function ,a]"16

• .. .AI T-Iib, '~I "] ",11 h '~I '~I ,Ii:" ~ ., ,.

iomzeo. ne ctassscal ano per, taps :OliOS" re:.~e:'v',amjt crass or zwnb'~r~O:fU_lC com-

pounds are the amino acids, A mina acids Ire o.rg,3'1ll1,IC acids Icont~thli ng, bonh amino and c3Jrlbo:x,y groups and. provide the btll'~ldin,g bl ~.' ~-'k~ :fo." proteins. The simple ami no c C ids contai rn: on'~y these two Ienizable moledes, Consider ,glyif'>'I11JJ~ the simel ~ ~'t '!!I1I'1I1iI1':nn i(';f"!i1A ,wo;;'t'lii-. the 1M v Vgl)·'nli!flilr' pK '3",c: '''li'l*~'i..~'!liI'''''..li iIi'iII"Ii

[~1~~·~~. " I~ ~'.I!!!~!I!~' ,~ .. ··I. ,g{!'~U!;':~Vi Q~IIJU~ '~'>,i, .~.~ ... ~ FIA~ -":"0· IU~~ .: I. :1"'3Jlil =~ ~l.[" '[j ... ~,'~~IJ:I,U'~I"~J 1~.UI

~I

0.8

.- _ •• -."I'~'I.l • __ •• ~ .....

\

\

\

,

~ _iill "{)

Ii» ii"Ii &i' fi 'Y.Q

00

+

"--

o

. j' ," I

J

I

I

I'

.#

Iil' ...... ~~~~~~~""""'iiiiiiiiiiiiioo ~'WIiI'_' _~

10

.. ~ ,~,

'I

",

\

'~,

'\

\

\,

"

- ....

'~I ... -

:2

1.2

Copy rig hted m ateri al

,tb,~ ,,7 - -lo...-.,,-" , ijJ' -, ','-' ')' -..I~, K' ~!n 18, I ""--IH' '-',--',', ,-)"

tne 'ClliuvX_Y JOU[) 3J!I1y, ,P"3J,l-' 7+._,-' ',,-. r: :2 gJOIll,(j'.,

+- _·HJ + -H~

:H3,N'~CH2~ICOOIH: Sg -'~ H:3N'~CH,--- ,COO- .:... 'Ii', :H:,N-"CH"2-C'OO=

~ '_ -li-Hi' _, - U4 ,_

A Z B

A~, dl(~-- :pH moves 'f~om low to ~@;b values w:ll1,eo ,an :ac:idii,c ::'olut~on is ti .. 'tF,a~,ed, wi .• alkali ~he' COO,H: group of' species .A, is deprotonased, and the'

--~,-,-,,' "'~"~" e- -~ Z'" ,'c: ,it--:--_-_~,-A A'-' -:t- -, ','--" ,...:i:'" ". '"~-''' ,~, - " .. , "', "Ib, ,..(I iiI,t.. '-' '-'

.lWl~lte:n,on ,',', ,IS rormeo.. s t ae secono somzanon step I,S appreacaea, [IJ,!IC pro-

ton :':- - ~JI.::. .-::: -- Al ,if: ~ .. ,-~ ~ ,,,'ii-., ~ '8" 'N::- "4-' 17-- ~'I~' ,-, C,' ,~, ,~" -, ·,-~"m·d-; 'ii,b,.~ . I - ,;' 7' C 'iU 'Th- " ''Ij,,\f ·~'--w '" -~ - ',' ,. ,;

on 1. retea eo ,~ro.nl me ,,]. group ~.O yte,W,! • me aJUOlll1 .D!~ ,.lJ.1 e ,z. nuenon IS

t'"'b- - :' ,-;1"",'-1,- '." ,- -"Iii- ", "" :", ,'- ,.', ' ~'il- "jOilli, 4: 3'il:.#", "'H' ~ "i '''':11'0' 'I _. I ,~,~-, -, '~' .. -,~ .... ,

. _He p.reu.onunamll~ :speCIes Ul I,", ~,e ,1l]1LI]j~e . ,.,_ .,J ...... ,P, " , ...... s, I o,~, alCCOlJl Dd!llg ~Of ,more

th~n !Og..'iI71o of t-'Ill t!!; '["0'1"'11' ~] vcine 'in, sohnion,

_____ QL_ -;J' 7'~ . = __ ...... __ ru b~J,_I.u.~ = ~ QV_,-", I, ~~ __

A,-- ,-,e_.-jI,~,--",II+'~I'C-~"" ~',:,: of ''',~" ~t--:~'t",--:",~, ,~"~ -, ,·:~I'·'b~_"'~ c'---'i\r"'d: -- '~h~'" 'tj" :(1' ,-,,-- -, ntals of

n unu,eFsl~aJn'!"dII"g 0 tomza ~on ,"",qUId .f1a, pm. ,~.es I~, e tun amentars or

] , · 'F-~~' b '~- l' f ' .' 'b I· ~. '" '0

, .. :-., "-:J~_-_~ :~j, ;.r_:. 'j-':" I '~."[~ ~'i;"'1 ' .. ~"~ ", '-1-:- -'~'-I-I-I-'" _-. "':-'1 j'-"r-' ; 1'-:"'-1 .~ ~ [," j'" _,1,-'" _'; IlL' '--I'!.':.:" ,"-.

S8 1 ,uJmabo.n.. , OJ s~a. e S~- t .orman on [,0 e CO.nl.,p ete, ion Il.'amlo.m, must oe

effec~i ve~y co'm:pl"e~,e 'such that a :s,~ ngle 'rn,oniz;ati(~n state is, formed, ,\Vhen ion-

.' ~ . '. '. 1 - -- h '11- ~ .' - f-' d' 6- - - a. T'm~ '.

,- .... 1 .. ··'.- -'(I' -. -··,·'-~1-"" ,"., '. I I. ," I '1"·" II' '- .. ··1······" . .l(·:r- "', "!ll '1 l n ",- {-I'["j :-.", " .. II!!" I.. -.' 1-1- '. _ ,'J'" _

,~""" ·aJtJo,n, ~"" U1C om/p, ete, l~, e resu t ~,S I, mrxmre 0':, ,,,-.1.,, erent species, " ie incom-

'pl"e~e':~y ionised mixed state is, :wnher--el1:dy less stable and lac-k- the UHfI'm molecular Co.~l1lpositrn.on necessary to form a stable so:mi.d,. ,A~ best, ~be yield of

'1'1' " 't'I·' ., 1--·'~ i ."~ - h ,. -, 'bI -~ 'f.]' - -"fi ' I

. . '. " , .. _ . l ' .. . .. , I', '" ,. . I' . ~, '.' '.' . .. .,.",",..". , _..' • .",. , l' I. I,' r ~ •. , • ", - . I' 'i' .

a wei -crysta ,JZU:l,g S3 t~ ,II S, "i(~W \'11 U e iO[, er species not a 1_ e to ,,,ru t t lie crysta ~

,~ ,~ ~."~ ,-, '. H '. .' ,-, ~] ]1-

, ", . _ I ',' . _ . -, ," .. _. .. ,-- .' ','., _.", .' 1 . I' ,", ,- ", [ 1 ",._ ", .. , ", ." .. 'r J' ... _ '. . 1 J'

,panem, remai n ,mil so, unon. ,;-. ,!Oli -ever In worse cases ,W m,pure crysta ,S resu ~ t~

h· h ., - f: . ~ 'r ". T -, h f' ," , -, . h

' 1· ': ' .. ' . L '. J" '. '.' : '.' .. " ••••• '. • •• '" ~ ".- ••••• ,..'.' , •• ' •• r "., ~'.',' .. 'J :' ~,. '. " .'. • • r. I :.. . I'" -'. .', .... ..' -, :."j'

Vi ten 'COl1S,~,st 0" mixtures 01, species. "n, t . e case 0, Z w,rn,Uenol1s e. g,. '~; w,JJ~~n

,an ,amm,onWll,m salt is being prepared, the ~~tdt-,forming acid 'mUl be of sufflcll~n~ ~[mnpth to nrevent '~'he 'Cl!l'ibOiX,iNj:~ rnC:-18ICid function fro'nil diss;Qciadng··' since

_.~._.~~., .• ~_~,._::;;,o .~ ._. _._ _.-_. __ .= ._~. __ ... ~ .. ,._ .. . _ :.I~. III.;.! _ .t . ..:I .. ..:. '. !Ii;:! .••

dle carboxy gro up! is the moiety dlar~, must remain full y un~onized, when a species with a net ,pos,iti'Ve c:hargle is required,

The; relati ve sb'en,ptlh s of the. dmg~' entity and, tthe salt-formin p seecies 'm ay>

~._ ._ ••• ~ __ •• ~_ ~._::":J. .~ _ • ~ '- • .:...1 .::":J ~ ,_ .•• M. _.__ .~ ~ , )~ ~. __ ~. ~ __ .~_:

'Ii..,a; ~1iI'i~~'~'f:r,_.l .... ~Jfillifili' ,"ifi ."Iii"Ii,---~.c. ""<!];;fi'--C!' '1'0 JfiI-C,c"~ ~"~ ':-;i+"'b-~'~I.;fI, T·~ ·,IIr.n'-~ ~e z, ~:>; '-t_"-o-~ r., rhe sol IJ)", hl,QU_,~, 1I;;r,~II!;;."~.t~ ~u .;iI"'-!'!,m'~ 1!io;..;p,."Ci,j ~' .. ~n8JU]1r~ jf;w, ;:,~a. IW~, !l1nl!J.~.ml ~OnlZaJ'n wn u Ie ,i:_} ,-

id ~ tate 'The 'triuol:~e: ,antifungal ageni~s o!1 the a-stt.yry:~(~alfi-'b,:lnol class are chafBc~ed zed bv the~~t verv WEald v basic triazole ring , whose 'p-K.- value '~na,v :ran-

~--~.- .. - rJ .. --.~ .. _..;J .. _. - J' ~.. .. ~ , -: ~~r~ - .~.- ~ _._J' -----

D" 'f: ',,, '- 1 a rio 2'" 'C' -- 'r 'Ii' -'II' ~ .' .'11.- . ~ . ---- d -~.-;:I!.., 'H'C· '-'1 C' fIi" . ,£ l' )-, , ,-

be ,,,[011.1, ,.0, 11,.;0 / •• ~,.-·IJ,s;~,a _ Ule sa~ t.s, welit prepare, .. , w H~ ~, ,I •... _: pn'iil = '~~I., ,I. or

IC/"'H' S""O--:'I H' '(' ~ K:' '''')'' W~-'·· 'iltil.· Hie' "1 .' I'it . . ~" . ..:I ... ~'~I- V ~ ted iii- ~, --" -- ~ - ~

, .,' 3 '.' ..... J .. p" ta :-,~ .,,~ "":'-- U.em I~d,e: , " :s.ah w;as s,~oreu a)~, e,W.iel·~·aJj~' , !.l'el1.Ipe a,-

nUlres ~ :H,ICI 'w'·a( parthtlill y f1CI,tISOO which. was inferr-ed :rr-om a 12'% 10k', o:f

l.,.,.iL:I'F'i;;~id,;a, o:f-iii',JI:!i;:r-- '6, 'h oiit ,6"."'-'0"'1 'O'I'C: '- 'II'n ; ...... 0' ml-p.~'~'o . .-rrii ,j;.'~~ " . .t'!ii 'l"i"IIa!ii,iI!..i!!!i,;ffi~~~.L1U:::o-' .-rri;'!!lit-"~ "Q,'[ri' 'W' :,.g, ;[,:'ia,_

1I;,.o~-~,'V'''lI!,c "'" Q_~,I!!-V= .~ ,_-, ,Qi!!., ..... " . '. Ji!l!!! 11".1 =L,,--'l:l.J!~, .' '.I!I!~, !!!.~~II;..< ,~~,I,"""!r~~g;!~,",~~ U;! ',!!I'P~~' .~~_-,I~ .. 'Q~ ~~'-'!!,

'I!..] ·,&1,-, '1 ' .' 'k iii .', ir '£0-'--:' o'c· f'2" 1]--1 T'iI)..,'r."" .'-" "i'~'" - ~ --,,' 'i;' '1:.."-" ,'" -- f _...!I,' ,'m:,.,i'li;' "

IJ), ,e 21~ I.:e~ .;1' wee,; S S'lllor2lige ,iII." 'u_1 '~. 11./- • "IIHJtiIS, CI,Uh,,~.oral inn ',;1.. ue eX,e,IiiCleu, Wnen

- ~ ·'d - - . - 'h ", . - ", 'f' 11 K d ,0 1] . ,~ '111 ' ,

· r •. !,' " .. - - q(]l '_1" it", ._. '.r .: •..... _ ' . f.' ': I' : .", _ 1 ' ',.' ,":., ':·.1' . ',:" '. r .•........ J r" ':II~

eon~\~,Ie.rn~Gi' 1,le ~,onlza.uornl!o ,OW P'_-:',:Jj co,mlpO-Ulllc,S,j 'espe(l3.:y W1JL, ,ccn~n.~el,=

ions, '~;b~t corresp(n:~d. '~O 'Vo:l:mli~,ie ac.mds o.F' bases.

Copy rig hted m ateri al

Copy rig hted m ateri al

Cha ·p .• ter ~:,

.. ""',,' ""'~

S<I- "1' , bilit ::' " ·d,··1 D"-'~':" ";'1' rt ,i!!!I<,"-"i ,c' : -";'r--- 'W:', :__~:' k"·' A·'·" ",<I!!l:d· I'.

-·_·,0: U . ,I, ,I --y" a··I,n, . ,:,-I,S-:,.S-· 0-, r- n, 111,0", D; 0" ~a- ','-. '." ",I"I,,_'~,,_·

... ,. __ - , ... _',.~.,: ._-_-~'. _~ . .. _ ,_. __ -"I. _' ... _ '_ . __ ~_.~. _~ " ~ __ " __ @/.

8,:' , ..... ,.- ,_"~I , ' i-'d'" 'S'~l __ ,··,t·--'-··:"

, ,B,ses" 8.0 __ , ~,,:··:,a_Js,

by '~J,ad,.u. ,ru.€U.pedld.i *' , ,A,bu, T~ Mi!' _'eF,aj'udcUn~ Da,yj,d, ,l~ W~, •• ··,ra:nt and :p~ :H:e,inrlicb S:ta~h~

C- - -'1- -ts-

, 10D', :flU! ""

~, ~ hl:~rodll[1cUo,n

2,. So1uJb::i.U'[y Behavior 0'_- Acids, Bases, and. 'nelr Sa~l~s, 2., ~. :rvJ.,easure!1ne~rru~ ,(rf A.queoU's S(l~ubnity

2.2. Ge neral Features of pH = So~ubi H~,y Profiles 2.3. PI~~J rn~~,

2.4,. :D:iftl.c'lihi"e~, ir:n. De~~m-url1-ru:naJ~~!o.nl of Salt So:I,lbul'l~ty

3 Dissolution Behavior or Acids Bases, :~~ud Their g,aillts ,'., ~, :l,ea ~:ue'm.en~ ,of Dim' ~o~ru.ti.'on R~te

.3.2. Disselution inito R,eac~hfi~ : ," edia

4,,, Reh:vauce of p:H Relations of Sol~j]IbWlicty and ,Dil' ssolntien ro g,[aJ;1t Se~ee~jio~ and ' -!orriflu~,~tion

4. ~. :,o~l!lJti.on. ::,,'o[~njll~ liion. ' 4.2. So~id Fermnlations

5;, Non-Ideal So!~,ubrnlity Beh:~vio;r' 'r:fIi'E:-' - 'E'I)'e" ." C'· 'j'l('!

li\· "_. 1'=& "_". ~JI

~'mpoolv!ement of dissolution rate o-f '\veaik'~y ae ~dj,c or weaJdy basic drugs th at are pOOF!i.y solu ble I,S one oif the pri mar,Y' reasons :fjl)o:r' :p,fepa.rati,on of phannaceudc!a~ s.alt forms I[ 1 - 1]" .s,a1~ forms .ha,ve ~d "10 'been u~H~d '~O control

d- --- ~. .;.I" H'" '~II- Co,t-" - [~"o@'l' [-'i[l] ''IT''Jil...'. - Ii!... 'I" -- -- -- - • -- -:- 111'1.,· - U .J _. . -- d -! ,If!' ii'ii!."

_ rug uI8S0~Utl,on ~!d.~ _~' _ '. ,It ms ,cw~ap,,,eF' e,x,aml[~es. I~J~e prt-oepenaencies -O"~ '~~~e

so~ !!1,bU:!rty ,and dlssolutlon rate of pharmaceutical acids, bases, and salt -C'." ,and

tl ., "~IJV" 'i'iC ~I-I ."" 'd~ " ,,-,-,.d r - - ;. '. 'it,-- ,t·1!.. . "j' ;'l' , "'L-'" - . ,- "r- itt,. , ,If":', .' iI ,1Ili, I'~ .

u.~ re~ e .~ a.rn.c e 10 ~ li._ ~.e, Ie .' e,penue,nCle ' !lO ud:; .' e, ec ~o.ll1 0 'L_lle drUb. ,Ilnt m,.

Copy rig hted m ateri al

20

DiU' 1;, n·ll.ill A 'C' ... !I"iF'rCAll. >t" J.j, III"'· 'il""iii:" r-'"""I~~~~':' - U ltil}·.:··· ,;.~ ~~~l~~':

S':::: I HAl·+ [A~]

Copy rig hted m ateri al

(3)

The ~,otaj ·.o:~u:bilit.y in R,e,i,l:On; 11" is described by:

s=(m+[::I}JK,p

K· ::::fN's' ~] .. rA "l

'I~J ~= _r. __ , tl~ ~

(4)

(5)

Wllili6ll:~ .. K· .. ,. _ li~ the 'Sl!ry'I~I'I'b: ril'IL;I,t~'!j;J' n,-","",...:II~I·II~t· 'o:··,r· .~.II6.,a. salt

' __ . ~.lI'I!r.,i ~~. '~.p illliJi . JJIL~ '!.I;.!.Ull~~ - 11J:lli LJJ' l~ll \JJUj~~'L. ~j.l~ ~R JII!!·

FO,f a ·weall{J.:y acidic ,coimpound a'm :pH« p'K~ i(e' •. g .. ~ 'by 2: units)~ the s()~ubi~ity is practically :hu:lependient: lor :pH and remains conS"nan-~. at S11. At. :pH :> p~~~

1Ii'~. . ···1I~b~·C' .. ···~I'··'i- ..•.. ~ .. "1 ,.~ .' -u .. , .' ..•.. ~ ...• ~ ttallv ., ··:~iIi;·rt... ····H- t·, ~ '~L -"C, S'" .~'. '. 1· ... 1 " 11.~ -' ..• --_11, r'

I~.~e ~().~.u~ ,.~~~: .. :y mereases exponenuauy Wl.!!.l~~ .P'·~··~ \E.e~, .. IIJ.O,~ _\, meeeases ,1:10eru',lIJl

, · ~k'H') A~" " .. -"" f.. H'" '11 .. ,..;Il.,. ] .. - 'm"'· .-. .., ,'~.". 'I!...'~ . 'f" ··m, b"'I'·'· . ,"-'Il..

wun :p , ... '. .:~, t .9 certam Pi.,.. vatue, tne . og:'-'.dm.,car re ,o,UO.nSnl.p' 01. SO.w.lJ.;_ .h.Uy W ~,tILII

nH·: a'L.·iil'i'1lniii'lv ends and '~;h;Q; ;i.C'iIFii: '11Ii'b;'I'~'iiV plot 'elll'iii',;i:iiii'1t'1"Il'Lii'!I!l!!i>t1l,oi'Ii 1·/': The nN': 'II.!',r}·1'11'10 w' here ,rl, _,._ [.: _,IljI!,IJ, ~l,r'~- ,J' .. _ .1.IU:~I- 0-: ~l ~ . ~ .:,u!. ,lol, :_ ,1I,~,lII'~J' ": 1-.' .. L;] .'~., < ~,"""lI,';:' ,H.~O l~,U"'jI; , "I: I. ." J'.' ,r"" "" 'Ol_I,u'~ .". J:I,. ',1 ..

jriil_,i\O···.O,1···' , U .. V __ .

,

10 .. '11 '

/ .... pi:: / i

'II I II

,~ .

I I

I ~

I

_/ I

o I

.. / I

sr' I

~~,OO¢AT i

I

Reg'fon iJ Solid' Phase:

Sal,'"

2:

,4·

61 pH

Gi -0

'oiiII2··' l!~,

·f:ig. ~ •. ,II-S;fJi~fbitir!l p'I"Oflie of ,€t u'i'ea k I)' acidic dn~'g~I' .1F1~_rblpfin.fei:l, 1J£,ii~i".g' ,N,(J',OH 1~lred:~a"ilj,fn, f~um [2n

Copy rig hted m ateri al

..,.." ~:L

PH] A In! 'l_iIl A ;""!~UTII'C' ,&L If'! ,,it, 'f 'Tlf'i. ~ ,_ft_lli'JfIir-I~£-l;~~ .. · " J._. n 'ilIr"il..;l !!lil;

file hyo K:,gion; 'tllU.mr;:ecl i. the :pH of .maximJUDl ,.-Oblbili~y,- refetted w! 11;$ :pHma)l;,"

Tlh,IU~" ~\tVO equations 1.'Eq,,:~S'. 2' and 4)1 are :F:ieqt.ar~Fed '~n describe 'the entire

'pH =' o'm'U.b'''~jty pm!:6:le o(f :1 .mllll1!lJ~pmtic aeid, The a,c~.iv.i'ly Icoeaic.~e11lt~ me:IDC assumed to, equaJI u:ldty in I~he ilbove eq,'lidl~jbrlitt .A:p.pU.cm;t:!toIilIO'f ,acd.v.hy IClan_J:m. _.I;, has been discu sed ,i:m. 'lhe ]i~e:r'l'tture [1'1' - :n'9, " 'Ilume 16qjuiU,briJ:1 for poIY,pmti,c Ina mMp\h;O~-6ri.IC compounds hmlve: been des !Ctm~, by ,Pec,1e and 11 ~~"'1. [[ 18] ~

F,~lfJ'" ,2 s:h.lOW~ th _' more !~I.~If]j~f';a,1 ,ite'I:t'iIi'Ii'i~C n( - '0'8= -:'~1!IJ--_~i~11;ii~J.' 'b-~:·~'Il,;.g"v~o.'i'" ·iiJ!IlIi'~,·L ~ lia ~ tlJ _ _ _ tJ __ _ _ _ 11 _ [~. __ 'A ~~ Jlt_ ~_I_,,~.~,I~ ~ trot' ~ iYL _jUtlIJjI~:J ~-Ilg _ I;UlL '"·lIltWI~~l

reference '(10 a. w,eak~.y baslc cOim:poumd, 4-'~ 4- [_ -c~hlor-O(l;aphdtat _D-2,~-yl)cDr-· bony np'iperidi.n~ m -yl },~ 1-(,4-:f11llI1looopl:bltDy~)bll1l,'&ajl .. :~. -on~ [[]. 9 [., The ~o,l u.bi[i~.y as a. function of :p.H,-, in the presence Oi,F' absence o.f ,a,dd.e--d r-_il'CL ts ~:'b(l~D ~:ft FIg'., ,21~ '_' rom left to right, the :inlthlll increase In :oluib!~lhlf is due Ito iii decrease i.n the eoromon-ion ,(dfect ~i):f (Cll~ The toRIll ichlorid,e ion co.oeDbi~.i.lo[Dj is :m:pprex W mal[t:dy equm,'~ to '[h.- 'COIl'iiC1eoK-a.thlD o:f the .ru.ooi~ed :s,peci,~'<, plus, the ,hydro .. ge:n. iOl.tl. conloen'[l~ad.oml. At h.w,,~:hef :p,H: '(~ues (-.8""'] ,« [[B8'* [)., thM-e is a miniml,'~ Ich~e irn ~olubni'l,y wru'th pIH" :H,o*evm: a s]'i;gll'~ ~nc1~e3!: e in sol .. ubiU~y lel.dru,n,g up '~:O the maxll11ll;um, is due to an increase In 'the I!Inc:l\B!Jled "ipe ~,~ ,', ' eoneen fllfon f ee ~20] for dg~' j'~s),. A:, 'nbe: :p,H. increases, a l"'D:pid decrease in somlll,bil:i~.y lbeyofIDd. the [l,:H:im'iM :i l dUJe '~O ,I decrease ,bll 'dle. e: :relll'~ 'of :i.OJll'(2)JU}(Hij,.,

" "t. higlitelt pH' '~!:DJtu~s (pH» p' ,.~)~ the :'o,lub~ :i.'ty .i s, [l([",mu:;l;iica], .y i:fiI,de:~:u:~~ndent of plH and remains ClOn:iil~un lit the intrinsic ,:~olubi'~:~.;~ of the 'b~ll' e, The 'p;rec~c e

10

2:

[Fig. 2, ,p(I'-S()l~fhili~)i' P,~JUIi of '" ~!~et",kt, Msir:: ltim,'g;, 4~'4~1 (16~c/~$,otmnilpk'l.l~~'Ii:~2-}~IJ~(jrb,(jfl:plJ'~ pi"fi:,ridl:rJ.-,I·y'iJ .. I··(4~fl~,oropk(ti,~:)4Jb,fIi~m'~ =. l'-(}J'JJ!n, wrJi,I: Nel. k~,y: (G) n~ :N:aC~ ladd_f~~l; f') O.O'lM ,_ a;CI,~ (OJ 0.Q25';~ "i]CI; ( _ ~I O\,!I}S;M ::, '~C~ ~'~_m'\l_ ~ 'rb m U"]I).,

Copy rig hted m ateri al

23

(:!,I

S:::::::: S",:,·' (. 'II - [H~·] J'"

, ·0 1 + ".

"" Ka,:

,v' J

,n"a. ' '«

H+ )l.."j •.. p

lJoR,ardl.,tf let ,(,I;. [2 [ ] reponed ·1:lli111t. 'i;he excess solid :1.0 equfUbri.u:m wUh '~he ",.a~lJIJa~[ed. [," O~.UdOTii. of doxycycline [at :pHWinax conralned bonh the: free base and the hydrochloride salt phases, By setting .s equal ~n EqltJ.. 7 and 8.~, and sO~'vimll the resuhing quadratic lequ:athln,! these authors derived mm express ion 'for pHn~ax 0" a. base.

S' pH: maN. ~ :pK a + lO,g .~[I

. . ._.. _.. \/ Ksp

The above equasion provides I, 'qu:all"rtj,~arHve means to understand the effect of

('9)

0;) [~n increase 'hl1. 't'he p'K~, by one uni~. (i'.,[(!,.,~ ~he strength of drue base hlcreases) n~suU" :rn'D an inerease of ~he :pH:~~:~ b,Y one unit:

b) alll order of 'm.a,~n.itude increase in the :hllrln~,:iC' LolubiUty ofthe 'fF,:ee base increases the :pHi1iln~. by one un it;

'I ,an order of Ilnlglf1~lude inereese in. th,eo:~llI,'bi:ljly 0'( the salt '. \,_ ·.K -,p) results

in ,3 decrease in the :pHH:n~, by one unit,

T!II.., -"r.. effe ·'ii,· .- -,-, '·]'1' ,"t- "it -,~ :" - Ft ~'

IIIlie~'!;.,; ["",I, .. eC'Lg, lire II .. , UI, ~J',a~,f'JUi II,n , - ~8. ~.'.,

Copy rig hted m ateri al

c)

o

0 :2' ,4- 6 8,
pi&-! ,;2

4.;pHI

. 0'.1 "K$p, ': '.' .

. _ ~~~~ =--=~~- __ ="~'r=~~. .

T

!!:

4 pH

A d 'b·D ..... 1 ..;11 B'~ .~,;.;;,., ,:I I' 'II . L. '~A 'iI-. it': f~'

, So noted by tsoearaus ;a~H.1J .""i"~C,~,,j~'O£}t~: ;;;,; ,I. ,~, ~ue '~:a~.'~ aJnu. bte ~re,e " 'Orftl

simultaneous ly exist :i'tl the solid state in e-Quil:ib:Fii~Jm, uritb the SIUJ'F,ated solu .. , lion as a. thermodynamieally ~ m.valian.~~ system ,at pH ,= ·p,:Hl,fimax. as ·bown in the Scheme.

Copy rig hted m ateri al

ittlj,DO-' 'rn::iIED·T·iiiCi e ,e;E"rEC' , "'11!'mo" "CoN" A'" 'Jii.!rrn 'U'!I:"'!E' lr ,1:'Pi,' . _.' . t.'", . lj~'" 1 ,~J.l:JJlI~, .;:) .~'. . . . ,~j .W,. . .. -.: ~l" _J. ~ L' " r: .;l! l~

25

B, +, H,';Io' ;to C.' ,I-

" I ", ,I

11

'W·hem. a small amount of [.H,+] is added to ~he, sy~~en1. at p:H:ma·x, tm:e equi ... ~ibrium. shifts to the :rru.g:hm.~ and conversion of tbe "f~~~e base 'no the salt OCCU:F' along the ,equH~b:r~.um pa~h shown. The reverse process occur", when ·8 small amount of alkali is added a. Both nhe :p:H alia solub:iUty remain inv~fuan( until one of ~he solid phases i51, completely con verted to ~he other, The term 'i',G.ib,bs j bfll1rfti~r'~' has been, used. to describe ~lhl':·. phenomenon ._ ~ 5]1,

Stl:e.~:!:,g et al. ,[ 19' I reported ,3, study where ~ffi1e :J,.H ...... ·.·o;~uibili~y profiles -of terfenadtne were determined using different acids. The maximem solubilisy (Sllumlil) and p,U~JlruHl'~ depended on the acid. used. for piH: adjustment aJS shown in Fig. 4.=he dependence of Sw..l~X. on the counter ... ion aris es from ihe differences in the solubility of different salts, i.e., U1J~) ion pairs forming ,9, salt, 'The solubi~ ~ty of a sah is affected by I, number 0'( factors including its :nle~.t~n~ poInt and counter-ion :h.ydrophob.ruc:wty [I 4]., S ometi mes, a. higher Slm<DO ·wi~h. a partlcular cou nter-ion ~11 ay be due t.1C) formation (]if 3J supersaturated 50~'IJ:ti,on 3:$, discussed below.

Formetion of metastable, supersaturated solutions near p·H~nax ha~, IbeeJi observed in pH:-Slol'ubiU~y profiles [:22-26]., Fig., 5 shows a piH,-scd,ubili.'I:_Y" profile 'where supersaturation nell pHn~~~. :I . seen ~21]. Metastable 'pseudoequilibrium' solutions were formed ()Ef~.:y when the starting ~lThI,te:rwII~. used 'for' the phase sollubiIity st:ud,y wars, ~he free base. Such an inconsi steney in the sol-

hili b iJi,., • 1 f: 'ki ~ 'I.., "~;'I formati

Dol It]I,.e~~a.v:~or may result : rom ,. onenc earners to pnase ~ra118: orruanon

where nucleasion o,:f one phase ()CCUfS, more readily than that of the other; n

'1Ii-;, 'ild k ,,;i· t'b . h" , I" b"' ~I' ,~, '1 in thi '" lid 111...

Sw~ouw. !iJJe noteo tnat ~ "e . so ~rt~w:ruty V~~LUes in ttus region WOUJ;' not nave a

~,rue thermodynamic meaning. F.i8·~ 6 shows the peculiar pH =·L)~~.'lJbnily :1'['0= file of' papa verine 1[2:5]. Self-associatton eii:; sol ute molecules OIl" ~he metastable n~ltu:re of ~he system due to incon 81 stent nucleation of the f[lee base or the salt ma,y ha:ve resulted in such a profi le, If supersarurstion is. SUsp~('~ed w'nl o}enerminatlon of p':H:~sohJ;bi~orut:y profiles, it may 'be p:rlJld,en~ to 'seed' ~he" system with the expected sa'~t form (or the free acid or base, as appropriare) to facilirate [Wuc'~eado~'D! ..

for practical purposes, P'H.D~UlX must be; considered as I. 'range ~ of p,:H. over which a change in ~h,e equilibrium solid phase OCJcnfS •. AJthou,g~ the nlaM~e-

Copy rig hted m ateri al

E

'~

'Oli' e-

li<;;

,ii......ii

3

.., L

1

2'

-

4 5":1

, ,

IpiH

>0' o

6'

,

-

--0-'1

..... ".

o

pH

: ~:ig. 5. pli-Solub-iUt}f jJ'ro/il.(! of ,I]: ~lr,e'Cll")f b(1s,i-c con,p(]~m(lt., eEL $,0. u-Slin(I1' ,f&' -, I~e,e b{}j'~~ (drr~ cles) (.lJtttl ,p-lt.(f,ph(.t~e sed'r: (squares) a'~: tire starting m ,j't ',!'rl(t~' . .su;p~r;SfI_(q!l.9 futl[n.;1fiIJ was observed, only

when tile free base wa ruffil:e: 5 tarti [1 0' :In-iI'!Iil-'~rl',O'Ii'1 (,' ~,!"'Iii\"'lil!:V~ 'iI:"iI~ 2, 7'1'),-

_ _ _ _ _ --,c; -!!!! .... ~ -,,-,-, _ ~' ..... U__~ lJI ~ _.u il.~,'!LIJlI I ,.

Copy rig hted m ateri al

];)m!' 'O'Iiil'E""'R' 'filiCiC' ,('I elLice'- 'T~'O"''' A" N'" 'D" 'U'!r"'!C

; "lIJ'l' ," .IIJ~· . -:" , ,lIJ.Il.J..::J!",!ijL.:i lL:i ,.~. J."'~, ''''. r ..... ,," J.'.~

27

I~'O:::' ~I .. :. ...

-

1,

" '1 l

'\

\

\ \

','"

,'. ' ....

:3 ,4-

pH

'7

Fig. 6,< /jtl-SoluhiJ#y fJrofUe tif' ~pa~:;!?r,ine u.fiin':J' tIel'. De bflij A~n ~wilme' 8ho\l. s I~h~ Ilh~- retrnc"llI, sol • .fbilily :prol~,~e (Iru~h"'a.wn from [25 j).

'. ~ f' '~" f" A" E 9" '.... . '. ml- 1-·d ~. '~I

~iDla.ttc,~_ ,'ormo _,;;Ui.Oil1 outuned in " .qn. . .,.... W S '[ iJJ~or-emU:;,I~ Y v,a i· _; e:~·· pmm , .. ' n'~aw

re,aliz:atio:n 0"( precise 'p:H,mn~_N may not be possible due: to kinetic effects. Ca rs tens 'n I[ 2:8] discussed the general features of '{he. :pH~, olubility profile 'Of a d~ivm~~lernlii~ acid (H:2~A) and the poorly reproducible nature of 'the p'!Hlmll~ reaion

,0' "11" •

. ln a. ~y:p'rncal salt ·.o~ ubility experiment an amonm 0:[ ·aJt thought to be in

,-. ,. . '" ." "f'~ iii' . ~ - r. bi 'Ii""i'- I'~ -- .. e 't" ,~' . _' ~,~ '~I'~"-b' > ~,. "'oA .~, H 0" oN ,- ...;11 ~L, . I .. ,'. . 'Iii' -~, • ,.

excess 0 II!!,,, SOI~U I.l~ruty unu . ,W',;;, eiqll!lld ··n.l!l~e!J. wn . '-'2.'" any !~~we ,;;upemiD~)~l!Ink 1:, as-

saved fo r ,d"'m" -g-' content __ The ~ltln,i'i!!", so :il·j1d:' however mav not be the ~:~'~'It ,~~'i~I~'

I:'IjJ' 'l!.;-1iU It', '..' '\.r l! ~ 1,.\.tIILll~ Il , W ~\rI ~Ilil~~ !L!.IJ~ _. tIll . _ 'I!r . ~ t ~lL~~,J ~~ 'lUI ~ _ 1.1;'__ '!}~~ ~ y~~

'("I ..... ~J"IiI;P; ootenrla ~I fo "f-- i ~,~, ":1 ~"!'i!i";F1IC:-';; u, .;; ;:"10,'" to the free ,Iit;:"lo,r>m- - 'II'~iI" ueh ;1I'fIi ,;!"!oo'jJlI:;d;, ,~L....." m-' ·';[1!.r!Iii'~{_.

V 'L "1,1i;,,.' la~'I!..!! ~!IIIII !l..~ y.1II. ,~I " 11.11<,,;]1 IIU,~ oJI..... ~ U I,Y,I,I, ~. 1.I,.....~.!I.i.....,~ U.II .. L. .11.11 ~ ",lid,.... .iloIo 1!..";!;lII~ """ !Um.WI!;.< _' ...... ~.o:!i

ured l·o~ub:iJli~y does not :(jiepre,Slef~~ ~hat oif the salt [2 'I[] '~HI., ,n is sil11.:p~.:y lhe . o!m~

ubihtv o'r'iril!..'f· free ferm '",,"'i' ,(·;.iI!..l']ilil' parti "'-"1'110". p'H~ The InH' of the li:!'~lIil 'I;'!IiD;iHl' '''1'10' . iii"IIl . ..-c~!I:i\

"'JILJ.'·~·"·IJ· -.::}j IL~iJ .;~~ ,~~!,.- UIJ ~~ .. ··_W,~~}~. '·~_lJ(l~ ~LI.~r~_'- : .. : I~ ,.~.[~ IF',,,- [,_:,-,1; ;~"::I.'_ ~'~._·I • .r.-~LIl_W':, ·_.~J.I 1Ji~:;;"

, . .,- ·..;1, .,- . I~']- ,'., '. C' t , .. ~, '. "f~' . ." - - '--:: .:~ .. ' .-'. . ,iii ,j,;ii!." ". . or, 1111' 'ii" th ' 'f' 1 . ,Ii - Th" . , ~, . . I I' . . ' .. ' 'ir

penes on me extens 0 conversion 0.1 me sa ~. 1,\0 tne .. F0, rorm, !._ apparent

'I 'b"]·~ . .-] ~ ies with th ~. f.' lh' ' '. l .' 'f' . '~·d' '-JI '

. . -', I I f 'I, : ! . ,'f I' ", ~ ~ . ',' J I', '. '. .:,.: ' • I J. 'J - • ' • r . ., . ,. ~, I ", ' [ ,[ .' i . "I'" -,....' ~ ',' .' , . i" 'j'l .. ", • - ': I"

5,0. JJ.~ 1. Y , t aere ore, vanes WU, - re r.a 10 0 e LOla, amount ;0, SQ, ,IJ' UJ mat

of tile S~)· VI' nt. III ed for dIe exp .rjl:lllfu~n~ UJuH 18 critical ratio i: , reached, To ens,rulre reliable measurement of ' ,aU : .. ' ohJJ[bi~ity the solid 'p'h~se lilllJl s~ c'on~~im e':x,-,

. ~

cess salt ,\f~ier ea uilibil,a'~ioim,., A'f~ler :i'Solmdon and aj'i:r~d~ ~'n:" of !he exces s. ·~~ol~d

"'!Il ~ll· ,~

phase, :thefma~ ana~~ysi,:s Piflovides, a p:r'e~i miIuu'Y i:lld;,cati,oilll of phase ~1['!an~:rfOl"-'

Copy rig hted m ateri al

madlon,. ,llU·~her ,confhrmnmtwon Qf 'IDle :1rt[rtJUJre; 1(,"'; 'd1e ei cess s lid. 'phale may 'be

,iLt',·'· 'dlbl' ' .. ,' , rill, ·X.".',·· 'd"·"·' .;fi-, ""',ff,', -,·,"JI·.·,- .-tt.,...'IiI- .. ,," ]"'i!i:'" If the excess

OiU arnne;. .y POW,gCf " ,~[a.y ai m ,aCI~om· ~.ry or el!!J~m"nl,g 8_01 ,..;.~S~ .iL. ne excess

som:id :p.ha·,t is e:ll1:n~,re.:lly' in 'the 'free' :rUir.m~, the iexper':me;m,t must 'be, repel :~ed. 'wid) a h:igller solid to solvenr (H20) ratio uno] 'ttw excess solid ,,;o(Fl'~aiin'·, IIiw ,:alt. ]f,.". some cases comnlete i[!'l'li;rtill,\~mlF;l1'iO"ll of '~'~'e salt tOI 'i"~J~ free fo :fl11 ma.v oecer ;3;~.

1t.ll~1 ~U[ J I ¥ rw=~~ ~ __ U ~l~tty' ~ll-v _ V~ ~ _ ~ .~~ ~ _ u ~w.~ - - --= - - - y~ - = = - - 1I1 ~ - ~ - -J _ _ _ _ _

~I ~ j)o - ~ d- iii' 'I . Iii' ~ - -. ,t, ~ fte . 'm . ..;al" iii' . "~ .. 'l~i'" . . ,1If' "'~ 'I' .

au :SOi_ll_ -1~,O""'SjOlllldCilll 1 2h.,ru .. OS" 0, .~D ,~,ea,!JLnlg: Ilt)! J]or,llllldo;rn. '(h: a, le,l .

A· '!'lil _i ',~1'111:ii' .r\!'f'- ,.:Il,; 0;; :m.-.lb· """;'II,jI'O;; n'I'llo'e'd'fllllnim';0i1lfli10ft1li '·1 '11" ,.nm· ;Co, "".i'lIi it'lIDo' "'IiI HI 'i'lIoii".'IO;Winit· 'tin nJ' :~'I!"'JO;

, ~-'. "-!~. [I. ¥ 111.1 ]11. U, L~,II~ U,·. U '~.~. r~ ,[I,.: . .JIJ, Ul I ~W.IJU[llI;- I lll.Jll. . u. ~~. ~![;;.I~Lii· -1- !U.:!UIl. !mJLi~1Ii.ii 1 _ lit" Iu ~u J 1 ~1Ii.ii

'I _. r 1- '~I ~ ,. U L 'il . !il;", 'L ·'11'" f II... ,

9."01 ,WI~]ODl 00', a, :: .w. ';~h.'n a'~ I, eoneentraaon '\~I'eu rn;,eJJ.ow tne :so!.JlllII).'~,d.'ly 0- .' tne ~,au;t

, .. ',. ,Ii" d if ,. th rt" ,'II, 'hi ' ,:. ']"11 'Il.. . I' .' ,t;,,~ ~I . ..(1 ,'.. . ..' "'iiI' it,"

1'i"IS e snmate .. : rom me ,1\ SI!> \1_ uue 1 WI. ,J! ee I'ns UC1CC'-,1L !LIlli u,ljle ~o pl}eC:~.'ldrh.I'on.

of the free unionized form, To :fu;nlha' d!evdop 'ltbj iji: polnt A~~cI.'· )rso~ And. Piora [2] defined the term ~,~~,omcibhJlme~d.c: SO:lllf~i~ilt){ ,E 'The stoi}cbi@me'tric

. .'III"N;'lm!llbl;i~'I"llil·'V '0"";[' ;oj; '~I., ~ 1,,"!.lJj~'~ ,ji,f! t':I;;.;;;;. ,··nin·~III"!i""'Tfij't'Ii'~'III',il"'iifliii:'ii' lif'litf~' ~'Mi'iIi!ii< ~'iiiilr-'~Ir-'II.. l;F!;,illiIlTli; 'b'l~ e· i..:iIJ'" ssol 'iji~I..11 in

. Yl!~ . W ~ IIJ"Jll .'. u JI.l~, II -iJ!~l~'~ ,~ • .:Jl 1~1~~ _ u' ~~.~~,t..w.'U1UU',~~ u'~ I;]IgJll,~ '¥![r tll~l~t~ ~~~~ .~ y ~IU V vU

.C(· ',::" 'H"" 10 ... W·', .. :lk, '.--! ,t:~. ~"".-'!t:·-I·- ofa ":;-,=::. ·',·::·~\-'t·,;p;! I-::,I:·t·,'b.~. -"--·'~I,-,i,~...:al .Iit-,~~ ,~ ,-- _ ·T·IiJ,.·

pure .1·. . . . ,~'j~,~ 1110 ~.O[IlUlJdUIl1l, 0 a, ,prec, .,Pb,I,~ OJ. . JJJJ!~ UliUllOlll ~jlieu, ,w.Jiiee ,w.onn ~ .ue

authors pointed ou~. '~hmt dite diffi,cu~U:C"s; of Ulow' ~aJPparelld: c·ol,UJbni;~.y'~' of ,I, salt due to free fOlrm p.:r-ecd.p'C::iit:aj~i!l)n m-a~ '[be lencottll'n~,er-ed, in 'th~ 'lmooclh:dc'ol ''-:I'n9('il',e;s

~,[J" ,r~ ~

_,r.''':1 o:i.'i..i'o::ii'~1 oemen iii 1iI.'iJ1- -h' 'em ifIi' ..... iii'liICBIii"i';piii"'!lliIIi",;;:o"d' 'n'IIU"["'II' niH!' :jlil;'li; H' '0···1 ~'ii"A 'il''Q;fIIIU' ,ii'il''iCiid ·ifnl"" II',,,,,, v '1" U'~. UI~¥lli ... W.lUV',··: ,~w.lII~ 'lilY, ,. ,: !!i;.ilUIII.IIt .. """'11:"~III,·~jW. ::V.~ .. '.' .'Vtl:w: :1I,li~" '1' ru'1!1;,0 ,lil!li.ri,_ ,u1 .... !J, .I~,IJ· LiIW!'/!i;.,,=

cology 't:les1tim,g,. However, app(lio.prblj~le piN ;mdj U' ·'tmen.1t ~]lc.n,dd overcome 'nhi':, p.robm,em.

J Do!! - - - J t"'~ - -- "8' 11- - 'i!I' - -- ,- r'~ A"· -'''''d "8" -, nd ' - - '!i __ 'S-I- )~. -

. I·' -,- ",' .. ", - . ,'-j' -" ,", •• ", •..• ," '.", '. '" ,.J' i . ',' _' . '[ ",

. • (;SilO ,0 ~,IOII. ,.Ie; !aVIOIJr UJCI 1 51: , .. ISes, '. ., e!l[f 13~,

The b:rml d'jss.(J~~~'t.i,o'''t refers ~,o! the OI'ltmU process hy ,.~'.hlc,:h ;3 solid compound di solves i.n a Hq.urn.d, medhgrm .. 'w'hile di's:J(JI,~t.~'i'o1i. rt(;i.t(;' i. 'i1llt kj,petlfc descript r ,gi:v:ing t~he nruJLe at \\1fh,licb the di' "·ol,u 11l(U 'tae:, place i The concept of siollUb~l.i:~y" 0111. the other hand .. j,n],p~.i,es 'ttb~:t the process Oo:f dissolution h~s ,ealcliie.d equ:iUbrium ,and. '~lh~ '··ol'Ooom is :~a!turaJted~ D\is~o:~lI1IdJ!)D rilLe of' '~cdids rns (t :paralrt1.0unt wm,poftance :~:n ,the~ dleve~o,ment of PIli:lwll1:lCI0'PbC;al p:roduc't!. and quaUty IC011itIlOt S.~dt. '~ilfn1tltj.ion i" OVJ]C 'of the mos t ,COllliHi11l00]Y ,emp'~)lJyed '~eclhm!·.q ues to i.Rljp[(Di\' e dh~sol:~,:u:M.'olrn (),f 'wleak~.y' acid~~· Of basic dlool!c.i"

A numb~r of 'theories, o:r the dis' .... ·l'U!dOtl. of~,ond,.-:· b-a;\.·'_ been ',.fopo~ed, I[ l1] ]1 ~30t Howe'\u!~I"~. Ihe ,~:bnpl:~e dlfl.lrt:.;,:I()U :mode] m,l~' 't) .. ;ad~q.iila'~~ to describe the dis:~oludojm 'behavwor of mos'[ :phumac~UI.t~!cal soUds in ,a.q,lU~jOU8 a:md rn10(1;~ ,aque01l1,· media The diffusi,o(ll la:y'u model (F:~g'," n assumes 'lba~: a thin JJ1lm of' sm:tUJ,a ed ' .. o[uUOJll, of' oomooiM:r.atrnon ,C s exists ;9,t ,the inrerface of' the d;rn.ssol:hf= w,ng saUd I'nd '[be d'~:SI5,olutjjJ(J!in :medilum" The disl O;~,lJllio(ll r.miW is ,coo,tt.roned by the di:ffus:ion rase of solnte m,OI:~ec~:des, from thi tbin ,'-Itlllfltl$d, film Into the bulk solution, The i()oinlcenitrntion ()if '~h,e Slo:lute in. 'the. bulk is denoted by' 'Ch. A. the di stance x increases :fm!11lJl1 ,x =: 0 (m.'t the. Sl[[H3;Ce o(f 'lt~e 'oUd) tD x ~ ,11; (a;t( '~he be,gi:mmi ng of' tJ]~ bliftk '~'oml1l:tiion), ,the cODoe;n.tlta'~io\rn. decf'eaJs~, 'fw':m, ,c =: C . '~IO' C =: Cb.. Bey'ood x =, h'r!! dl!l~ btdk COOC~~I,tmmiJOii remaius 1[[[li1i~nr.1 am Cb.' In. the simp;~e~~ IOlrm o:f th~ 'ntrueotl~Y~ fOI:now:i:l1g Fick s :Fir,s't La:w, 'tklie rate 0" d:Wss()~u:·,

Copy rig hted m ateri al

,,~, -~

,ffo-p.

~ ---- """', """, 'rv~ . ,~

~

I I

""'", I

I

,e ,=: C'b ~---~:~" ~~~~~

I I I

:K::-' hi

, ,dn'~ ,D!

J=:_ =:-'1,,(;,-'(.;-)

A "dr' II s ~

where, J I,S flux, 'which. is de:lflncd as rU~le amount ,~11 0(1 materlal die> OIl: led , and, ~h,e~~e:for-e~, 't~an5pon,ed. across ~he diffu'-;;;nIDD W,s:y,er, hfl unit time :per' 'llJ1oj~ -:-ulrffimve area ,', of the dissol V:hl"g solid .. , ,DI is the diffu'slo;n, (Joe.,ffieiiemJt (diffw,si'\ri.'n:y) of' the so.hll:tt,e. ,Eq,lt., JOI is, 'the Nerr1,s,t"',fj'rEfH'I!Jlrr d:i:H\w( j,lon :blrye;r- :fOml of 'tbe :-'-O'1eS~' Wlti,t,,;j;e)~ iequati.(')n [.31].. Under "~;hlik'~ ,collldidoil~ (C"b< Ul% olf c,~)- the equaJJtJO(1f:i

]'~ If' 'iii"p",gj .. Ii ..... Jo,d- 'fiO" ,I!ii! W"~-~,!YI~I~:;_ ~I.::~,

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_n, 1!:L.-:,", other ·h'~;iRl..:m1 ,;" r.a<!':lii ..... ~''''4i~ ril'( nm tt"f'ioIFllI 1Ii!!o"!.''',ii',,:II6.,grll'iIifr.I9< 'P;~I!iIiif''';;\O- TiiI ,~, occer :t"1Il'i1 cn~'lrlflf-;,;n;.-iflIdi1!', 'YlJt.] ~Il;m; LlJlI W-Jl ~IHI ~U~ ,~. lI/~g~~~J _ ~ ,W, J r )UU'liJIl ~'A~W.W_g:lll'I\~'~ Jj,~~~L.-_l._ .'Jlll U~~ . ,W,1l ~ull~ ~lI,U\IJ.IJ~1Il

f;o,IT' d:ws' olruJ ion of 'weak, acids, bases, I~md rbeir Salil:Ul- tile pH, of 'llie dl~I'li,o:n, ~,ayer' :i " 'especI,3JUy im,pcd:', ~n~," A, [lumJber 'of mrJdeb~ :l1ae been pmpo ed to le,'~a~,=,

mif. b .' ., "Ijl:'"d b ..;II "",'I ,. no' "':L. dl'~"' .,

~J(lile serr- ·.Uw,:I:Ie:nng (;apac:~ty O(~, acms, ea a", aou saats, ulloo:nb-o.w.dnl Ln0 .', b':"'Il;l'WOlil

ml!l'ilJl\P!i'" p" H· 1'(·iii'ii'Ii'~'i""rA. Aiffi .. 'l"~iif'Ii'm;:li"",jj;iI.;,m nH')' ~""'"' ":"";i!50Iii"i;~~~,""""'~ 'L.,l'CII'il:",ii, . .ff'j;)" ,i,iko!!i, iI'Ii'i';;'50,~ ..... ,-~~iii'\l ;i!'1i;,1i( ~,a,J';""" _. '_ " .. ,1!I,1I,ll~!!i"f . '!I;,JI'""II;.,fJ.II' . III:VU .~.~JI;."u~WIi. cW"" >.' .II. It:~ lyt~,\,!u":"",,I!l4!1;,i;mI. t)r,~~ _, !!YI',~. llU...... .1IJ1J. •. ~nlll"J' yl,~.

"L.. AI II 111... IIJ.. d" ... ,..:1 1).., G d D"· :t.., []' I

tnese ~W"IDOue~'s w,~31S !U~en .' l·CUS ... ~ 1lJ'y .... ··r'''f;j;t' Ill: . r:d,,'It'C-rd "~'.

A'· -'.' . ,-' '11"" . ;f;', ""~,,,-II'"' '~-I' ,~:~" 'd'-'II'~ ii>L" 'ii ill}... d"~'~ . ,~' .

, CO',lnmon a~' 'lu,mp"JO,m, 011. ,lmOS", ul _'O,II.lJ]a!!it@lI. m.O.::__ e,,I) .. , 1-', !~!Uii~ lu~e . .::.ll il,U~ l10n

~,H.yelB ~h,OOFY 'ru s sd'~ ~ mppU"c~b~e 't~l' reactive '. Iy.s~'entl ,amd ,.1 acid-base :Pf'otOI

h . ," .' .-.- '~I ~ "'I'·'1b • .. d' . m

'_', _', _. " ," t. 'j'_"'-, ,',-,", I" ,.- •. ".'._" ','- .. 1 .' .'," I,' .. ',,'_' I ',_ , '." '. ' ", _ ri ", . ",' U I ,,". ", 'l'- 1\'"'

excr ange reaction , occur ,.lrlst~U:1l,tall1eou .. ; .,'1,. omc ,eq,1IJI l.·na are set up, ,an., t, e

second order jA; fferent ;i,all. ' .nnIU. ,~,.,' ~lIfIilip 'iW:olr'" ,~ri, .... ,i'.,~" S·.~"·iifli\ll'"\~nIA. L'i!lIili)J]I' li'1iI"«' ,A,j'·"IJ,ji!·ii,""i;!1'iIo :!'n!'l~

0l!J"""1!;;,, ~J . iI,!UIi~ lU.i!I' 1t11!;"oo1l!.",",1,~ .. !II "'"",.. w,L VIIUI~ .III. ,f:"" ,I! ~,I!'II;, ... . !W-'I/;;i'!U'u!Jli ,. Mi' u,~. !i,.III.dJJ.I .. , ~ItUitll,~. """

so~v~d 'w['~h derfii'm,'ed. bOU'l1ldary ,co\l1di:~iOlEH:I,~ 'BqljUlj~i,o~'~·, are d -rived. for' d.i:ff~l .. ,ioD laver p"H : nd :111Ul'.~ 'tm'aIilJ'·:fer· rates 'm.1n term , o,.f i[(]jd~p-·;~r:lJd.allittL: '-'-.-e'-,e:llmb'·; na-

.... J.. '_:" ....... . ... - ...... - -- - - ~ ~ - - ~ ~=- - -- ~- - - ~~,y - . ~ pa

ram,e~e .~,~ " uch as dlifful~ :io.o Cloc:ffic;ienL" p.K.~, \f~JUes. uJd :inmu': :i!c ;'ol~u.biUt)~· of '~he d:ls:solving spec~.le~,. The; ,colm:p'b.~xity a_fliJi ICclJlfIcy' 01:[ 'lb,e models depe"tiid 0111 the ,Illumb .. - F' of lequU:Ullrim. ,conslder-ed,. Th_e :~aUen,t: . Imr~:, l(Jf' .,lome IOf these models ,3)I01nl 'wi mh :heir' a:pplicatrnons, 11~; ptresented below, 'hI 'tile: :roUow'i'm,g dlscussion, tthe: m;athiema:Ulcal leqrllati,lo\m"\~ '.'hie)} De o:f~e:m, un:wield.y~ Me p\F,e .. senrted 'mo an ,eKt:en~ lo;n~~y liteoo. "iUl' to de.vei~,op' Mw,e pif',a,·U,c~d '~'mlP'~:iC'ad,o(n,' of'

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3 '1

, I,.

theoretical concepts Reference is made ~u '~he: ,B:pproip,riate -;our-cer; fir, 'm wl1.~,ch ~twe e,)UliC~ lequm:ti.of]( can be o'b~aio'ed~ :,: :O\¥fr\f£F" if iO(llf' Za!bOiD i': [ ft·' .. ~ ,i,ns~a,tl'~aneou" I', 'for carbon acids s1lIch as ph&nyU)utftZlOne I~Jr' 7-acle~)dttu~o1Ph:ylline, rate equations ' :or '~e relevant 1ie3!ct~ofDj enter ilru~()1 il11J6 dJiNerel'rj,a1 equations repre. en.'ted by ,Fi'ck 's Second La w (:t,~ di:ftu' :i.on,. These coml:f~elUe![ are not considered here; ~h~y have 'been, fe.v~,lewed :in [I 7]~

H'i'gI;I.'chi et al. -~,2,~ reporte d me >i,lfiIlJlIJ,m'taoel1t. ,cheml,cad :r _ aetiOI!lM,d, di,f~u'w,lon (SCRD) model '~O:f' dls8ol:~U.'tl,,);rn. of benzoic ,aJd, lotDI_ ~ 'bl:icol:~.'IllI,tio([iL The ,au~holfs :prov.wded predi,cd''lllc_' '~quat~oWl~ rCif' the :w,nmrin:s:I.lc d[··~ollUfuon ril~e or :1f1I'IJI.x,,~ J., o:f mbe acid in terms O1f fU:~1danl,eml'tmJ :p.~lUltetet8 S !lei) as di:f.JJ.iu' . lion 100- c'ffi(;'w.len'l" .. , of 'femc'tan~8 IJ11d produets, the 'i'nbllii:_ 11~' .. (J;~,IMdbUitl" of 'drue :IDcld,- 'the strength of the base, :~Ullid. the I,p~paren.t io,:niz3Jit]o(n COill~/~an.'[;S!~ Hl,,!~tcA~,)' et ,a:l" ~413']1 also reported In, equation for 'the :ru.rui~ia]l Idi":' ~ohJlio(n; rate of sodium salt of a weak acid. dissolving bil, I.crn,dll,c medium.

a '.'. considerlng ,~dd:itjonml lequ:ru ~ibriJa'j MO'(JiIU(',' let' a~',. [44] e,xlellded, 't- e SiCRDI model, to di o;'''O'[Udorllll kinetics of carboxvllc ,acids, in~(al unbw:ffemd. me-

I~"

dia whose pH 'w;a~ cOI1'rroU ." d b~t ,I. plH=·~a.t~ 'T11!e aJu.tho ,'-, p\rese~Fir~ed, :[0 e:x",res~

I,ruon 'for the IClOnCenjtr~!t",on of llydrog)eo ~,Ion ,aim, 'tbe' ,.ufflCe .. ·f '·.Ud, (0: ~O):

(12)

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p,Ho 6; I

:2 L:_»-' __ ----il[- ..... [ __ .................................................. ~ ................... iiiiiiiiiiiIIIoiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii ............ iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii .........

:2:

8 plHbu1k

110

'''II'') ~.l~

R= * _{~iA[HA)o-~HW]o~;~~DoJ~HOH"""']Il-[OH-li.1)] (U) Fig. 9 shows good agreement between the experimental 'flux, and, ~h,~l'n predicted by the extended SC':R.D rnodel, The :flat regions :i:lJil [he plot ,~, are the result of self-buffermg C'ap~,cruly of the acids, Benzoic acid, with 'higbesrn~ acid dis, ociation ICO]1'<, tan", and intrinsic so:~,u'bit'ity~ ShOiWS '~,aJg,est: 'b'lllHf;lmg:-capac~;.y. These models were '~,a,'~er. extended to dissolutien oif cal'boA.yI~,c acids into 'bu':,=, fered systems [4.5] [46] '. In ,3 buffered :mledi'u'm, the buffer ,ca;pla,ci'ly of the medi urn influences the p,:H or 'nhe: micro-envi [tnnlleu~, ifff the solid. 'The h rn,gher the bu:ft~er strength the closer w:iU. be ~h.e surface ",:H, to the, bulk 'p'I~1t The: H'Ill~h.o.lrs'i' therefore, recommended that H[I,e exact 'buffer >co(mdi.'tio(fJI s be L pecUiied 'whe:l!l, reporti ng di, olution rates,

"'" ,W J' b' [4"1] ,- d 'b, - - - ,...iI.' ,. if" co, ". .. dO' 'II -,'. ,- f n.!~'- " iaua ,,' ,', " [1;::pOl[i[e ,." on 'l~~e, predscncn {h, :nl1iU·tl;l~.'C ., ~ ,~,SSO',u.ulUIn nues Oil ~

eoh ad' Ii'~ III'Ii e !lUn "':I~ ....,11 iproteveri :~lI,e hvd 00- - .... ,'11-;',10- '.';'d'D F1'i '1'1''''' J.l. 'i'!Io'li'Iid'~,JI;;i']"U'!i']iLi"J:Ii'" [ ..1..110' ' dQ1I/'e' !!!Jf: '~~:~'~ tne (u~~I!'U U,~ ,-',Jj[ :~·lJ1;';;··._.·~JIll.i~~' 11~11IJ··I·. . .~~]Lf:-: J.tJj :: e, .'.~ ~" iln~~L.:"If; ~!.Illtl·.·. Jg'~~~O~'I~'- ~-~O.·" .~,,""._·l, ,~.

oped equation I for the diffusion ~m,yeJr pH and ,~Dltritrn~,i.'c diss 1ution raile, of mesatamlne in a, tr~.proti,c buffer systems, The 3llurth.o ..... discussed, 'tbe relevance of 'F~H -d'i'S,Siolu'l~oW1 'nr,ofi'~es t@ development 0:" at controlled release fonwocd:n."

,F ,r ,

'[lorn. The concept of micm-;env,~r!Olnllttenr ['m) [l'H: bas been utiU zed in a number'

of' additional reports to u'lldersllll.d d:~ ssolution of 'phlr~na.celJ.ticam salts and their behavior in formulatiens £9] [216] [49 - 51 ],.

Copy rig hted m ateri al

" " ,

,~' ~:

u et:

o I -~

2' -4.

e

IU'

8,'

1·-;.:

10

12

pH',II'

, bu~k

f:ig.9. ,il;e.ltuive ,dJ~s(jbi:l'io~ rtilt?;, 'R~ "IS, p'H:~~'k jOf se~~'r<~d ,CQr,fwxytic ,~'(:id:s at 25 ~C, ,11 = O~5M (K.Cl) u,d,~~g (I p"J~s,~nl' to ',WJ€I~J;U'al'~l c,(J'Uslant l':Hm~lJii' The :'o~id lines M,e' ~mt@ se lp:fiedi~tecl by ~h ~ '~u~mjiof! and ~!ro.e d,~m pO-Inh:; ,~ those 1e:~pe~iMe:!1IltaHy d:ere~iWIDli ned; 10 ~~rnen '~O tJl\'e: di ~ohJ'liro~m, r:~u~ ,at pH' 2JJO~ p::= 0,;.5.;. {'0):: 'ind~M~~h~j~; (,.,; 2~n~p~Lhoi~' ~,c id" ~nd f ,); benzoic acid

O:,emi~'W:UllJ from, [44]}.

The SC,RD :01.'odel ,and, 'rhe Nerns,t·,Brunru!r total ,,:Jo]ulbHi:irty :m,odel ,assume

that 'm~~('i transfer ACP;,'~r r j;'!('i 1"ili~m·"liJril'm'!lL1 ·b!IL~' . diffusi A'ffi M· ~'i,ifI" iii':i"!i'lil't"i; ,,f,'~'iii'" ·d' 'I"~ql.:!i; i';F;; linuid 1~.J.I~~'J_;l .r ;tl~iO _~;[QW.IJi.j!,ll~_- \j::_ ~~=Ij-ii) ~',iJ-l, I. ~'_-,IIJWlj' '-·'·I1.; U,lIj ... ,!IkIl~' ~1;ltl'.J ,.;,"" .~.~"'l!-" U'~EI;II-'··jl.I~~'- I .. ~~ ~IUI .: ~u~ -J

movement or convection, is, ,1,eneraU,:y ignowred, MooJeJ,s 'w~:th increa ed cornple.xhy tlrHU ,hl(;lude 'both, conveetive and d'iffUsiv,e tr,anlsport have been :~epo-rt,·, ed 1[5;2] £.53]"

Bo:g;ardN's and Blacbvootl' -[21.1 [54] I'm;vesd,g;aled, the d.issoludon. Df doxycy. 1," . , ,jb ... base ~ d . iii' 'L,.A . L,] .~..:I .. ·liii' A~·· ii, . H AI .(.i'Iil]~ " . ·iii"t [L .. ,". _ ._ ·d· ," .c 1m-C JJ me .• 'ase .all: , hiS nyumCn ,Or1l'UJe :~, I~,. . ... ·.I~~ p" .: , ,~, 1 .. !Il;1 •. ,J~, ilce~a~e IIlU ~ 1,Ie;I"'.1 3111: .

n. :~ :MI phos~:)h!ajl:e bu;Her, me disso'~:Liltilo':rn mite of 'the hydroc:tdo:ride solt was :s'ilg.'·' nifiiC81lUy' higher than tlhlill. of the free base, The dissolu~'i.o,n rate of the :hyd~ll];'"

,~,]' ~. '"...:. .~ h' 'W~' he W' ~ v' ,'. , ,",&'::' "~L'II' '~I, ,., ,,.L.. , the ,f,: . 'L.. . "', In 'II 'iii; oil 'H'Cm

'Cw'W ;onue sau w as, I~O~" ever, signmean ,~y .~ower':-J:I_.a:n,:: e tree ease mil Ud,,~l'll ,~,.w

m~diu;m" This reduced di ssolution rate was autibu:bed. no tbe co:mnl0n, .. ion effect

in chlorid ,~_~_n'i',r!ii,i,n1;i'jj"!fi media In t,iU.,'e m . icro -environ ~m~-'to.ii'ii't, of ~,IiJ..",", .A']i'~IIl1'~;t'~··O'·1ifiI l ;:·'V~Iif-' " .. ,U. Uill,J!)''''-'''''''U,U,U1c~,lIUUifl! ,I '''''''',hIQ •.. 1Il0l1 I~U~ "LI··~,,··c V-!llILY!.'V~~,~·_·,""!II!I!!- > I~n~ li,IC,U'c ~"!I!:'!'.:!I!!I ~:l''''''~'

'nhe free base did not :Fead.U.y convert to 'E'm.e Hel s~dt, d.uring, the eX,:pefl'mentm]

t;l" m~ ,~o "" ..... "'11'],0 '1liI11I'1ii..:a1 Wi .... "" not it"DiIfli il:";'t~il1iJ'e .. ..".., the common-io m OU:a"i'"it' 0' ·f-' , .... IJ..,I,O, ·flI"'·..:IA

!!J, __ !!;,;< "'''''''-III ,,,",, ~)lIIIU!i ~ .,. i!O!Id ,u'U'. ,iJ!· ...... ,IJ.li:l!\~. Ii "'" .' LU .1,1,., II!;"oJUIIJ,IIIJllll.l. ,VU-II, . I '"",,U,I!, ... -,! ... I., ... ""'W W~" .1 ,iIl,J'II;""

Hig~,c:hl et at. 1[,S,.5] reported experimental dissol,ut~om, profiles 0-':' I, l-hexameth.yI,lene-,p'-'lol,yls:u'~·fonyl·~',e;'mi.'caIDb\a'l~de and, its sodium salt, and those pre-

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no ADM" aC---'ell 'frT1I';F!I'AL 1if'l . .Ii..'II' "II!'IC'., ~~: .. R·." C!IUjJJJt~··~~~I~

dieted bY' S,C:R~D model, 'When the 'bil,.d:k 'buffer IODnClemr~:raJt;.'rnD. '.,IS h:rn:sb. imd, tl!u~ 'p:H 'was ,~~)'w~ the dissolution fro,m, the s~llt 'was, e' ,enbiaUy equ~d to 'tba;n (]If the free acid dUJe to :rC(FmaJtion 'Q'_:' ,I, COI.-, of 'the 'free' acid (,2L id.-C08Jt:) Ion 'the -:I'urface of' 'the dlssol vlng'oUd.,- t ilittenne-~:r ate pH condidons I, -\~tepwi"e'- di 1- ,oilluti,on occurred due to 'time, '~omna'rio(l] of' an iomti:ai[ ,ac:ilJl,,!col!t 'fbl:io!wed, by ~1t!1 di·:'olut~on~ and ~lhf~n ttID~ di:~'-S!olutruon ()if the ,sodiu:m sa]t before ,8 second IDcid:coat 'was "omu~d" ,An, hi,,~be:F':pIH, ,C()lodi'l1Joft.; nOII(Jonrv:_fSIOI1, to the free acldl ' .. 1M ob served and the dis' O;htlnOn. of Ule laU wm;.i faster, HO:~¥ieVeF.: "';Ijl,cb.:tep',:]',jf; profiles are unCOmR~O(Il,.

S:eFtajlJf'd'dl.'l:i, ,IIJo' Ja'm'~1'sl'~' '24, 1 reported the effect, !O'f.' ,di'ftu ~.io.ml blJ:yel p!:H on the dissolution rate of theOrpm,ynijtile~ ·a]:i,icylilC: acid, amtd, 'bclrnm,ic acid. The (Us= -o!~1J:~i,Oilii, :J3Me c!f ,odlUl,m a'~:~,!c.Yllt:e \1_I,S, 'Sign'ii'fi.lcQDdy' :ltJig!hM ~l1a.n '~I't Icr sall'Cy:~~IC 1C:~d all. all plH:s in:vie~dgtl'ved '(pH l,,:n .. 2,,,m a_Did 7)" The aotmD -., '----ea'llf~ed, ~be plH: o the dlffu"i"o[lJJ laJ,ym' a.ad showed Itha,~ wide ,Clmerel1l!e~, ,eJd:,~;~ed, be-

i1i''Ii:U;iEliQil;ii lilb.,~, 'b.u] II", 'nH' ''!!Ii'I;iiA ;i1be, .411·'ff~'~'I'it!';lnn--- '~I~,'\JIiDr- 'p-'H" Tka disso '~IIIJI- 11i";,nn, . .4~'Ii·g, .... nln:t'nm- --n;;;iD-A I~ '¥v YW. Jlll [lJJl~,.¥ ~!JJ. _ ~~ ,~. 1 I~J}U lU~,~ IU 1 y·i.1ti~u. WrAij!'~... .' !ll IL I~~ 'U_:IjIilU· .,W.· ·~~JU,W.c1J U~g~U, '~·VllJJ]~lIU,. 1 LlIrwUl

we~ ~ '~O the H" ',n',;st'-Bj,"~I~jt~le'J~' form of the .', 10_ " e 1'- U"/~i't'",- J~' 'eq,ltrUIJ'tli,o(l, {Eqm,. ,10' and 1'J')1 when s ai~urm.t~on soluJbru,Uitt,y in 'llh,e; d:~:ffu slon la,ye1l was used (fur. IC~, in ECJ~~',. J J) ,r.IJtl1U~~i!' 'than 'ttL 51o~ubU,il} ,lit. 'the :p,H' olf 'tb _" 'buU.:; I~ 11l]t1:(ft" Tbj,., r-e~'I~~, fO;n(1iWi~, from the fact 'thM: 'the scn::n m,idel lind the 'vrJiaJ '/II!:d)jm~ty mOOe~ would Y'wleld comparable results .when 'the OII,'flu· ioa I:, oeffici DlL, 'f a11 dis~l)!-\f~,ng: Of reacft[ng: speeie . iWreet eq'I'all :4'>]1. 10 m,Dst eases, tb_ ItU,fiii'os:~ion ICOe'ffJJc'wlen~ of '[tIDe free, form and its salt do D,ot d:il'ffe:f' w,~,dlel,.... [4.2~. i,

S' r.Qj~~lddl'':I. and Ja.1iDl,,~ki [24] poi'OJ -100, out 'rnhm,t the ,a'b -:Vie pri,nc.:',ples, of dif=, :frlJ'si()~ la.ye~r e'ff~ct ~lla.y be used fO(Il' fr :tim_IuoD of '[D- dissOI:~,'IJ:li,lo:m, rate of a drug or. i "I·,aJr. under various :piH eonditions. The flJux,- J'ru'-, hl a 'pwti,cubtr 'bUJ:~k medium under sink conditions is given by:

V=i- .... ,

J'- =,' ,. 'bs.O-I,

:1-' hi

(l4)

'I, D ....alil\,. 116., 111;,., ,. m ~ ... 11 ., !ill,. - •

wnere I> ,anu, ~'~' n~,ve 'I~-we ilClOllive~I!lI;~j[iiJ;rn;a~ meanmg, m1l!u C's. O=~ ts me ·altl.ll:rn~~OI1,

··o~[lib,i~i~y I~ the ~rffusioD :~,a:,er plH for 'the' chosen di,~sn~.'l:lIli,lo;m, :lJ1l1edill,[l,M (M~'=,

,..J'i~t~~~ J-'IIi The "t!:li~irN"" of s: "l~~;::' 'mnp-~ ~i'ii"';'m-c \'!'IIj'f~,A from If'ii-.,o. n:u',=!.-iif'II:~IJLII- .... t:I'IIJiitw 'plll'\\i'1ii,~]'~I.pi,

u,_,,~_;!!_,_, '" ,W,i!i~_IY;~~!g I!U! IJ".S~IG--] @r ,~'U~. ,R!~-'!io;iU ,1II.'!IjJ! ,Ul!!;,;; 11:"'"' ,- -'I!..!I,~_UJl,1 -s - \II,uJlU,,,,,,,"

-.~ :'~'I'h-I- k-" - I . ,- JI1A, - . if! ,.'Ii.._ .A,~, -- '-, ·"i!'I-c 'ii" c;H'" ~. '::-,- .. -.' :,-" " If;'ii.. dif ~- "", ~- ..... i '

W W ~_ m,-Flow,~e y,g'c CD I!! me 'ul U, !I'o1I) ,!J,R,)?1er p . ,OJ ,1,'0 measure me on IJI, ,[0,1:11, ~)a:yeli

(lIM, I, small volume of 'the disso ,utio(n, mediUJ.1 ]:8, Idded, '~~O a, [ar-g;e exee _~'I orf

the 's:n~~"';il mixed iniin, 'm V""(r- tAY ,gg"FiiiA .. bel nH' is m-Cla'~'Ii:'!'II~'Ii'O.Ai 'b-'v !'iii m'H' ';D:milJj,,.,. .. -_ .... -...iIo ,;1\. '~I

II, "i;,;o' .;;v~ ~U'!' ,fliJvU IV~,I I~ . _ u . """.in!., ~11lI,IINJ1, II1.U~ r) . 0, - - !!;;"-a,;J!I!I!iI'IIi,l!!;,Ol,JIi, '-,.1; i~, if-I, ' " ~~,I!l;,;iro;.llUl~!II;,o,. 1:"U"'"

b~JTDa~i~'el:y~ Iii miero-eleetrodc m m,y- 'be inserted direcn[,'·"IIi~o tile, dis~Ullll![I:Jio(m, :medilu:m _ 36]1. As' unung thail DI I:flIO hm ILniu:iball1ged under ,id-el1:ttjlc ] byldm"", d,:ynallnruc cCindidons, ~he :lftu-x,~ J,_~ in ,Q, second mOOlium (M'di'uJfl; ,2) i;-,::

D·' C' fii "'"

J- _,.!!JIi-~

-:l;;;;:;;; _

I,

(,IS)

J~

J''J" 1C:;:5 .0=2:

Copy rig hted m ateri al

35

4~ Relevance of p'H Illelio'tioDS, of' .so,lu·bin',y· la·ud. Dissu·l:nti.o·n. 'In S~~d·t Selection and :~ormuJa .. ljol:rI

4 '111 'S' '·1 I ..,.... F" ] t'"

, ,",.IIl.,.. , 0': lll~~OIl. . orlDlWlc il 'lOIlS

For formulation of a stable soludon dossge form (oral or parenteral \ 'nffile equ rn librlum solubi I.:i.~y :is more i n];portaJI'I,~ rather than the rate of dissolution. ~ In-san' salt formation wlth ~]le free form, and au a:PPOOljriaJte' counteF:"'~on to adi ust ~!H ma v orovi de the same advantaze as u·.:m'rJ 0 a salt, A '~r.le1 hIli' nanr i n-

.J " ~!I..!. .I;-;-I'! = .- ,J" ~ r.:J -- ~ -- - ~ - ~ ~ ~ _. -- ~ - ~ - -,~ ~ - - j II~ . I - _.. •• IF·' .... 1 l. ..:.IIl J -

ve s;tiga,don .of pH ~solMbiH,~ :p.ml:fw ~,e with diffen!n~. counter-ion s P~O;\{ ides .3!IJ1

indication of the counter-ion bes;~, su ited to maxi mize 'ol,ubi~ii:'y (or optimize p:H: I as illustrated in Fig. 4" Further udUzawtruon of this principle '\V'HS reported

'b'" ~A - ..•. -" r;" ... ,' ,...,!II A . ,I , '. " ['51&] 'T··t... - ···!I.'h···--.".;al '.'-' ..... 'tr '~i" ·d· th ·t,·· "r. '~l'i"" '·1 . I,Y iVJIl';u·~·a .. ,iF' eh ,aHu. ,l'lt~:erSOl$) ~c u _ ~ _ : e ·aIDII~_ ors lJIJe.m'Ornl· _ . ~a.~e. 11e".a~ mUh~ .. p e

OOlU~II~e:r .. ions j. added ~ n predetermined amounts 80 as :110t 'to exceed the solub~i~i~y product I ,K5~.) 0; any salt, provided signi:flcandy h:wg'llJer ~c().~u·biHty t~arrn

.. ,,~,. .~I ... " ., - ... -, ~'., .,. T-'h ., 'I; .. ,. , ..... 'f'~ ,c·'H' 't, -. c. -'J' ···t'· .. '- .tt _.- r-'I ~.~., . " ith

any smgre counter-son, . ~ e rerevance 0 p =~~(l[, . o 'S:QJlW_IOn rorrruuanons wu •.

acceptable :IPH '~O[, ~'n:tra,'Veno'lD],:, administranon has been Jep,):r~led 1[20]1. If pH adjustment alone does not provide s;ufTllcrn.lent~ :sn]ub:~:U,'~y enhancement, CO~l1b:i·""· nation approaches such as addition of a co-solvent IhJ!:D,1 with piH adjustment m,a.y be used .[201] [51 ~., The equilibrium solubility oif a salt and its, free form

•. '. "', - .', ,ii[ t , ..ti .[ .... , b , ... .'~_... '" .... -'d" id .' ti . ·'1 . "'-'d"""''''C''-''- .. ···f: ""H' ..... ···r-"'b~:"· .;' .. "

are expected 0, e me same unoer .rul~en tear cone mons 0' .... p ." C10II)],J]II~F-.rn.IOIlrnJ,! .

. ,cj; In·d. -, :"'0' TilI'I' ~". stren !prtli!... However, t'~~'l~' form '" 'm av (l'~'1"1 'I 1Ik;aii co "n: 1~,;i~~III'IIi::!i;;il fo ir ] :1' i1Ill~ ~1··I.d;'- Io '1',·,

~~ !._ .~. ,Ii ~~...., ,,]I .. ~~'~"~I!i.W ~.. !!,-,!!.V "" '¥ \;<. , "'~.~ I,", I 1,.l.I"I.I.S, ... _fJ . .J ,;:)I~ .... 1!lJ!!;"o '!;,o .... ,.a!.IIIU ...... III, li;;.<U! l' ,'H ''''iIi!!.!l!~ 1'.

mill ~I'I ati O'lil,'i.:' '('£1'1;" 'FPiill"'!;;.R;;I!iI;,.,_.f';; Iifi Iii')' ~"o· nvenien .... o ('I'I'i ro'h ~,' 'r~"'n~ ":11 "':I,t 0:1':5:0· .·~1'11'1'1ii':1· '0'" A" A.A ;'·;1" O"m ... 111

~ Ji~ [II ':'ll~~ .lvf.l 1:.I"'1,";fU~~~!-i_iHIl~~~ I~"'__:",I'I." ,'i~lIl~·_,~,",I,f~-~ i~±iitl~~ll~I::' U J ,Ut~ .. ,.w,lU !UlI . ..-J: ",~~.~r. : .. 1,L~,iil 'UIljJ.~,~ ,', lllk!iW

of .. ~", ~ 1 the lit . - ' .• - ':. fl' _ .... -.... th .-~'ii;.. '., ,if'~, ,I~' ,'~I fo ". '. . ·.~I de c ·t· '1'1 ,', ,,"'·t,· ~,act,(H S L ~ a,~ lfllay w n: .. uenee ne enoree O'.W. nne ,L Ulilb, .orm mem te cry' a , lm~'y

and sol ~d $:tah~ s~3Jbrn ~ ~ ny ,and, w.u~, be discussed in detail ru,mt C/~(Jpl,t 16 ..

The !eqllU,i~,~,briLW:r.n :'ohb"'~i~.y and the rate ofdissoluti .n. are lequaU.y impor-

',.- .. ,'. ,r.:. ". ..~ '~I, .€ ...... - .•.. ·t·· ... d' ..;1 .f-".. ..... m do ' .. ,t . "-', W· .::'. 'h- .,' 'ill' .' A iIi';(J' .~1. 'd' _. .ra r- - ill'

tant .. ror ~allJt. rorms mteee ea ror orar .. osage ~,Or.IlUL..: ~~e ,8 uel~~n.we~-, account .

. 1:' 1'~ '1" ., - "1 .. 'i"+" 'if" iii' "'.'~'-' " . . ,·,·ir··· d" C~i. Iii' ~ . b ." 11' ,.:I ..... , ..... , ", ,iI

o,~ sa, .11" seiec ~,~.'OfID ,,~[ai',",e,gu;~ ~, ou bU1IJe. In ". ~',n['p',i; .• 'O.j. a nnet iUU~CU'· ,$10n 0.1.

pl:H-solub:I.lhy principles related 'EO salt selection 'win 'be presented here.

Biopharmaceurical evaluation in '~he early development '~t~ge ICM'lI. idenri-

,Cr-' .~,Iif''':~-r- , .-..~-- f'~· ".", A·~""I '[ .. ' ,,', 'I"·, - ,:"iIt ..ill A···· ·c ,t"::: it' . t· '-. ,",--, ,-" '-1 . 'i,,4 .

.l Y l.~. urug aesorpuon Is l.d:' .'. 0.,D. on-rate- JIlll~eu •..... Ji ,8 ~,U1h. SI~~P' .~ III evaiuan ng

I. alt fonnadon 'no improve dissolution ra.te.· the 'pH~sollrdblU:kY behavior is in ..

Copy rig hted m ateri al

vesti .. galed using: pure, crystalline, well-characrerlzed acid base, or a salt form .. Generally speaking, pl:H·~so.~ubi~i[y ptoflile~. g,enerated using a 'free form or irs >I.h: are comparable, if not IdeIirilc~l, '\\f h en. tile same acid Olf' base .m ' .. ' used for pH. :~djulrl1jent in both cases, Examples of 'this o'bs.etv,afiol:m, and de'Vimt~(Jns ~he~eo,'r have been dii,sCltSed. 'by ,L(t"'~,'vidg,.1 and I,"o,;;;.rig,c;'i (,,;:,,7],.

~n dele'l'minrung ,~qU00US ~o:~ubiUty of ,.iOU,·, 't'he. p~),·,Itd ' ef ".'C:;~ lOt' sand to solvent ratio on 801ubUi~.y MU'Slt be tICPt. in mind, It is l~_n_'fl,;ti~J '~' .. I uodler,·tmmd the factors that effect ,a,queous so;~u'biU~y o:f '. alt 'i~orm .... ~ ;al'thoUl,gh attempu;, to predict salt sol ubl~ wty have not been 'fuBy sueee ··,ful except '~. :~' : .'~ta'bnhi,ng: general trends I[ 1 '~HII[.5,8].,

I' omparis on of the &qU60U s s,(dubi~ ~:~y IO:f' variou s salts wi.d1. ebe free 'form,

'''lJjnljf'1i;riI1I,£1; 'rt'1;.-;i'i1' TfI,;If'o'~' 'p' 00'" 'C, l..;i~ 'JI,T'ri; '~I'I"m"d"I~"""1;t"~t'iI;'n 0"£ '!Il.uil!..'1" ..... \., form ""'11'0' 1i1'1111.1 J ' iII'!11It in op,t'I-m··"",'11 @~!lI:...lI!~~~ ,IJ'~I'~'p.,,· :I,~~I~, ,~" ,'.-,}',' ~!lUI'~ ~jl,lI, . ~_,I.:.' ~I~~_~~JI,IV_ ,.'_, ,w. "·.W-~, I~II, ll.r~, ,,~. , M· ,1.11!-I"llII, .~'._ ':.;)I!o-~~ ~ ,~. .._,_;>1.)1 ~ . ~w.

d.ru ssole r tion behavior, The dissolution of' a L alt can be equal, hig'b-er or' :~O\V,el' than tha'm of the free 'form. depending on 'r'he mlcro-environmental p.H It the

"':I:II"f':~I;('!~' of It: ... ·e~·, dissolving :sJ~]',~~I" "tl'~m;" P'i"~, '1,..~1.v,;;rj;: :b~ Ifill m" . ."'3. Id: ~ bv severel \"oIfliilr~~~',;Iii!;""'1

~ ~, ~~fI!r..'I!id' U l~rlI,~, .1. Y ~ w .llHIj, 1 W!!Uf. .I.u.. . L~ . . 'La ,Iltg . ~ ~., lI.~ ~.~ # ~ ~!\r' U w • V,IJ lI\.~.t ru.!

" '" " ... 11" :1" II '" 'II K . ..,1·' ,. '~I 1

to use in tn I1lI . :IIC 'lwl:S~IO~.utMJ.lil rates at mutnpte ,P, " 100 11b:.d.'U 0 Iii I, , to leV~JJl;late re ~,""

tive performance of sahs .and free forms, :[f: buffer ~,:o.lu~jo:n, ,UI:i:' used, fhe 'buf .. , 'ter"~Jre:til"gnh and compo I",'iiolil must be, chosen w:ith due consideratien to p:hy" .,"", iological cenditions becau e the diffu,"'.on 13,yeJ' 'p,M depends 00:11. the strength of the buffer among other factors [44 ~"' U is ,adivi sable 'to' include simulated gastric and "~n,~etrnn:al fluids described in, '(,he U'"SJ?~, or in [591] a·. dissolution test media.

Although i,n~rin~i,c di5S01:~ud,orn :ni!~,e :. ,'[udie's, .ftfe 'f'equen~ly used as one of the criteria fo " SI,mt selection, [~. has 'been, :~: .. pl·lned 'b.,a:n disc dis!:'ol,udon fates ma,y tend '~O exaggerate ~Ile rea] differ!ences in ,the. di~':o'i!lJl~hliJil rates that: would

'b' btain . ..:1 €: ,.',,', l' .f,'", 'I '·.'iii';"· ,'. [€'I 'p"" ~I' r "II' it", ,,'~" be v '~"

ne o tainea rrom capsu e rormu anons ;:ti',' oW'uer 1(111 sso ,UI~Jo.lil m.ay ae varu-

able but lack of reliable pm:~c~,!e SI[Ze or surface area in the ewdy development phase may ~rnni~. exten ive powder d:i : s 01.'0 tio.o, studies.

The relati ve supe,rio,dty of a. single salt or th. -: free fOlf,ID'1lJJ may :rUJ~: ,alw',D'.y _;;;, be obvious fr0'l11 the result. I ,otf I.ntFin~dc: dt~:ohrrdo,n. rates, be_~ausl~ of the diflf~erenoe:· wn ~Jh.e se:II'f-:blru'ffering ca:pac'hy of rhe salt ;and. t'h,~ free form, 'T.hL, is rn llus,uab.,dI in Fi'g," ,1 () where ~he relative p, rformanee of '~h,' :' ree :fOlrml or the salt. depended 'On 'the pH" Jrn"ucl1. cases, a ,jtui~iciotu~, choice 0(,' the :fina.'~, form W' required based on a balance of 'phy:s,i,Qoh]',@;hJa~ (! -e g"" :pH~J the gastro-intesti n",]i tract) .and pby,,.,; icc-chemical (e';",·,.; IPI,i(a - p':H,ma~) faeton ,," ,11~''''l)l'~tJl bio ...

avai ~1"1II1b.'il~i~,;rv studi £!iI'to' ;IH g nimals !1'11C";in'g ~1b'ii!Ii' free form g,n,....lll iF"i'JII'II"Q;,jji1:u'~~v character

' . ~.~,., ~ ,,11:10'111 ~ II,I~~' 0)' ,,_l .', W' :lIill,l, ," III..L n ,,,,]I,OJ; IU;;:';:III'WII,: ': Il.ln!;.; , .. ,I,,",,~ : 0:.' ,n '(~1II110. !i.,ic;U,II;,oJlI.U"J'· ~.: I(w' u,'Ii,;. ~!'" , ....

. , 'I ] f' id Ii-. ,F:: ] f 'II '" 1[6' '0 'TL 11

~ zeo sa .' :l OfID'nS C~Ui1, guioe tne ~ ina . 'o:rm seteenen ll'c,: i, ',. ne Ico,:ml,p,lex' uatl!lJie·

of physiological vari bles may Dot always I:~'~O~.· prediction of the relative i';i:~V.i"~ 0 performa Ice. olf a salt form I:lJ1d ~,t· free form [~l:'] ['6,2]" However, a caJJre:ful phy.sico-,ch~'mi,c~d CllII!fm,C'tler,i:za~iom, of salt forms prior no ,i:lil;"'V;lJO test .. , i,ng provides ;3 rational basis for ~e~'~i~cUo:n ,flUld, 'mJm~miu .. ~ the number of

.;.I;,il ~ ,.;'~~.n ~'r-i ,;'j; ~ e l;lp.'I~,'~· ~(,iI; !IJ v' I~: ,,1l1i&J.1Il . .i) .•

3.0

:2,.5

a

''I;.

'\ \

\.

" 'iI;.

'\ '\

IQ

\.

'\'

'i!;.

i!;;.

,\, \,

"

";;; ,!;;,

b

nl ~ ~III'~

n Ul

II

2

p,Hbullk

F:iJ:~", 10. lr,lu',fJuic Ji:ssalt,~'J,~\~n r:a~'e ,f,}J' b~~pil~c,~'.iJ~e (Jud' il:!; hydm'("-ir:lo,ride saJt ,~:s a ft$U- ",'iQJ~ ,t~.Ji ,0/ t/ile: di~'iS:()"'id,i'iOli~ medi",wn" The faster dli:S~!i)l~ujiion. iQ[ I~he Stlll~11. a-~ pH valu _ s ,g;refilt~r ~an m, ID';, due'

,- -

h) grem~r' s~~rni-b~:U~,i ne C~:PiIiftl,y (roorown fj'o'~ [26])<

,1"1:1 addirlon b) general solubiUty c:'ilaracte'ri's:d,tS" ,3 pH~ 'o'-ub;'jity profile (e. 8'"", PIHliUI~~) also provides In:s,~g__ht Inro pOIlen,dol oonv'et, io:n (l!M: ,9, "W'leak '~tin to nhe fr-ee 'fQif'm upon formulamioI1l, o.~" sterage. For leX3iuitp]le- when the miCM-' ,environmental p,H o-f a, salt of a we'ak~:y acidi c drug is 1 -, '£naJl], dl- P':Hn]I1X- eonversion 0:[ the salt to the free acid ,"ilay OCic~m:r upon '<l"oli,a,~e or 'form ulation ~1631,. The i nfluenee 0'( pHm~ __ . on salt ~la!b:lllity is fUlnbe]]" discussed :h'l. Cflaplt~ 6.,

5- 'N-"" 'Id .- S:-' 'I b~'I'~" B" h ,Ii

,," "-',' , , " , -' -,' ",; '" "',' - ',-',', -' ' , ' '

,_ ~ ," _ o.n'"","_ ,eo_, ~" 0,_1lI_ :'1_1" ~;e ._8 v!I'or

Copy rig hted m ateri al

DH A. iIJI!,ijj..;iIi .1\ ~U,T Tr'li'iii'C'A:' L~ it";Ii; 'iii' !:r'~ . r nl~~,IJH~~VI Jj.W :__ _ .~ .. !I3(H,lILn, l!JI1'!l

..:11. ". z ; . 0-' ~"_ I~'" :';jj.Ib, ,·:b.,. I' Lo ." ". '.' ii'I.,.;···· ,·1, .. H ' "I'"L He'" -iii .' .. ~

I~jjj[~,re 1." ,a,~reemen ~~ WI uw [~,~eory i, . _.' . we;rml1"g Il,me su' ·lpen:~u.o.D Pl. - . :.:~ tn ; .. ,':'_ ~. 'caII,IL:lCy,

1 .... ri;n'llir.atil'.:;I, ..... iii'li1 "",;1: the 'H~'P ~'i!ri'II'i·' 'ii.n ~1Il...i!!i' free 'i!ri,f.'l;,~·;oi1 '1lr;i!:!!!1i;i"1i;I'iiU' 'ii'h;i!!i; Ii1I=HI. t- ".' .~. 9.1) •• '5i"ii'ii,..<1i :-

II;.iV~.~ '!If!!j,.'~'~.VIII.~ !Ij"lI.~ cU!bo . ,-"II:.. iJ!;g;,,~ .. ~v II!.!U:~""" _.I!.~~ iI!!,,~,lu, !!J!IiOi"'!IIJ~ ~_,_!IiOi it"= "'mwc,~C1]:,. I. I, . ~.Ly m,

~A.. ,',,~'.~ ;! - ·'~I t...~~I·'. A' ..;II"~, iii·;' _. o· ,'il... ' .. =H 'f'·'ii." . '.'_ .!'.. I '!j.i,., 'H'IO'D' 1l..,' ..

reyJUjct~on ],noW.uU~,IlUy .. ,; ,luJUSdllilJ:e;, ~1J,Le .P',;, ,10,. IwwC !UI',penS:lOD. WI,lIl,J,w, " JGi~, ,~~owe _.

er, resulted in a ;:b~lml de,.· :iiJ;U.ro;rn ofo:~,'IliI:biUt\}' fml'm .; te 'RheowfcaJ '--H-',O'hll-

-~, - . - .. - -----r -. ---~ - - - -----',} =-~'" -- -- _.l JL

b:U i'~y proflle .. ,A'-DJaly[S,w ~'. ol:f ·i.he solid ,pibL' :,_ at pH 8:",~S: I]e.·· ," than 'the p'Hmu1 ,8;~ 911 show,ed, Icoover sion of th ~ ~. ·oUd phase lO! a m__Oif1rO·~,ydEa!m.e '=O,f\lU of ,cry:· lal]jj'FJjeJ

(clI';' ~':ii~ ) 'HEP' (2-: 1 ~) U' d ~ d '" . " h . d '~ ~ d

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.; ,rue .0 e.I)ULC2 . , ,," .' .' .' ,; r satt .. . .... ni . ,en- nonum, IDOtlt .. ,~,~UJ;rl"; t: e e:N:"peCil~~ 'OJ,I.

';h'Cilli~" 1"'- mAI·JU;;. ~b. ..... ,iii: " .. ",'~~ WI,- '1iI..,,··~I~ 1 ~. '.' .C - .~'illti-,' AI"., .'.' ,.". .....,jf' , .'. ". ,·'..-!I ... ,11.·lt,·' '.'

p, ",,-,se wo U~,u 11lJf! I~H,e tree acm. .. _ .wwlwe a C!omp1.IJed! lulSCLil SSUJII, U,il ,lll!oIIl=·,~U!e~,~, ~ ~Je··

1· ft n;H' iIl1'n'll~ mLtil'II]· iil>v b Bh'ilfiI'!IIJ. ~ if'fIor ; it':!' 'I)..'B 'n'ii'ii,...:I1 ,fj'lI!..;iJii C!\pnn.p~ of" rt,'Ilr-;.~ It'O'L'~lnli'\,iiI'" 1i"1!..·0 g;L~. ,Il!i. A.

[I,ll r" '-aul,~luIU,IJ'~'ll~'J" _"-I!ir.,Wl",.~.fU,. lI.i.1IIllJP-~t ... ~I,IJIlY ~~.I~ ~~Ult':~ " :l~~~~jl}~ !W\W=~~~.:"'-~!jl ~1J,llb- I~JQ!~,.'~ ¥" .. ~-

] ·'d' d t .'~~ .~ '. '~h l .. ~" .' ~·th·,

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aJnp es !ElIJe .pm'Y.rul. ,e:, ~.O u .Ustf,Ble .' e comp, e J,.le'S, oae may_ ncollil n~ef W[ ,

ph a-'l!'lM!! ...... \03i~I'II~'·i "'" '!lI m 'mllf"'~ d ba >'a!(!l ,;mo'1ll d their . ''ffii111i1~

: .'" lit .~ U.llli1ll1~U IU~li."ru~, ;l!1!!i;,r~,I.. ',,~, .'.' ;1I;,;o1lJ'~I!IlL ,). "UII;,..; :.i!!lI!.~I' l~

['9] .[mO] U ~]

[J 2.] UJ1 ~: :~4·] [15] [il(H i: r7]

[~ 8,] [1'91] [20] [2 j,]

[22] [23]

~24] [2;5] l[l6,]

[27] ~281

j e

[l] $. Agb~J:k~r; S; Li:m:!,eJ]lb~um~ T .. Hwguclli, J: ,P.~'arm~, Sci. I,'!\tlfij 65" 7'4·1'-1·4!~i.

[2] I. O. A.n(ffie;D' on, K,. :p~ :FIDoira'ti 'Pr-ejpU'atiol!1: ,~f 'W,Me_ 'OillqjlJl~~ o~:uwn.' , W(D:w!1gh ~ , '<0' _, m~t "on'!" j,n "The Pract[oo ·of Medl~c~iilam ICIi1.ewIDsllrJ"' I' Bd. 'e'., 113. '\\?~[JIIJllAth ~ Acad~mJic IP'rn\e: S!'

:lc:uu,doll" ]"99(i. '1]i9 = 154., .

[3] G. S. B,aJlk~r, c. T., Rh~desl' "'Moo~m, :fllru ao~umlcs'! , ,Mmcool De ... ~~ ,Ne~' YOfrk~ 1,Igt7gi.

[4.] $" M. B~~~'! l .. D, B~.b;1e~:~. D. C .. M:c(Jffljk~lill~!S~t J, 'htJ'ftL~' Sid., 1,"'\, i5~ ,'-·JS-· .. !20.

[,5] :M" Oiba~di t • D,ruQ;pll!~aG~umJ~s, ~ID1d Cli'(iljc~l P~amla~oti e~t[~:,\ Lea ud [febi\8£~! 'bj'l adeIDpbi~. ru 19. '~L

[~I] C. A. H~ seh, :1. ~. M,~~~eng~rt J.. L. ]3,mIlI,Om1J. J; ,'l~"'jj~. Sci. U;n,Si, 61" 23'~ - 23'6.

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:~"8:J~, 9,~ 809 -~s: 19.

[8] 'W" A., ,R;i'tse~~I. j,fJandboo . of' l:3sw(; Plt~UilrMIJacO:k" ~ti~I!"rll1g :b~temUlelDO~ :Ptillilrn~cii!tLoll1ti$ ~nc.! l-lbtmru:!I~DID1, 1916. .

. ~., J" B~enji~rui!ll! l., H. Lin, IJr~f .. DelP" ,ind, Plt~'r:itl, 1191S.:,~ 11,.7'1'1-19101"

l Uf lIFIIo'til ... 'T' U'" - ~. I· D '" 'm' .... - - J~ iII]!f i[! .• '1iIIft~\;I"'::li! II 'll"'li·~ ~ "]:'''li'1[)i

.,,~:. 1JLI!'1:'1Iie:I'l~ .l co, ,n~guc ]1" '. o:J!,. ,IINJ;;;C ~! ~. .III~i~'n'1,i~, <i;.l!C~, JIi''""''i J.l~, !II ,.}~j _' ~ ;).~C"

K. A.. IG~.]11Ilo:r8," "'A l'eXJI)bCJ;[;,k 10((' 'h~iiOOM1t~eali ,A'IiI;IDI,ysru!lii! 1 lJliJ]_, \\nl~ey '.' .so:~,~, .N!i!!~ .. Vo:rk~

1981. ~

A. s, Ke~ll~Y; s, c, :M:e ta, IG. 'w. Ratib~ug'b j ,Plt;1.n"i~. B'es. :~,992., ~'! .t 0912- rn iOO,5.

R. D~h~l.run" C. ,M:t,Donailldl!, 'V; 'R·, Su:r:u:Wewblmld,. J. Ph~,r:1f1,. Plztzr1,n.CKYJl. 1911',~ J9,; 241J1-2S::I." B. D. Am1der. '10m, R. ,~'" COIiiJ1i"~di" 1.. ,Ph'artJj., lSa. :~.nSli' 7'4', . : 1. :5:- 81~l

, . Alfdleef~ J3~U;tn,r~. P~(;"fl,~~Kal. Crn~~J,'~, :1'"1" 4,!, :16:5 - 1'7'"

z, T., iC~m<@rwbm~" J~, PMffl~~, cSd, 1,'7,1., Iti7., .~ 25,1- ~ '200.

D. J, 'W, Gimm~. "f: ":i;gudlwi~, ';,'.ru\!!lb:tr~:y B~~I!i!!ruor;' lijji(f O~_ic C-O:Ilii1p--;::trn~l~'", J~~rarD Y:'lle-y &, .:" ens, Ne;w ¥[PR" ru 99:(t

C. c, Peck, t, Z. Bel~,eot! J: ,f'~nn., Sci. :~,I",I~ 6"11, :~2=:~1."l.

'W, H, S'too~gi S", K. __ "~j i P. E. . 'elJms" Fcllm (J'" H. t:0;~~1 ,J. P1l.g,n,rJ.~ Sci. 1,'.4, .7 j'~ :1679= 1684-., s F; Kramer, GL. L. YUH" J~. P,'~'tJrm., .sci; :~,g'1.:J., I(jJ'rJ! :~, BOO,- 'rn,19Mo.

,it B,. ,H;O~0~ih!i1 5:! R., :1(" :81.~1C:kWiOOd!5 J;, .f,it.l,(!) Fm' e. Sci, I,,,,g,~ 6' i'i ~: I .• :,-194,~

A. 'f Ildl C, • .J.JII" , I J I ... : J' ,0,11\, ~ .• '1Iw~ "lii.1l '~II ~? ]~. ''lIi

R,. • ~it.ll" ..1i~r.aJI!JtI!.l\/!!Ul, .' '; " •. , 1if;~t1!'r~ ~hu,!. -; ,IIICR'aI"tn. ,JiCi\. \~.~\I ,~"'"tI!\I' " ,";';,-. ,~'"

.1\. l~" M., g,~r,Bj~)ddll,n~ ,p: IC., S:h~m~ :DI,. :Mllf501;1,~ D. p~ Bem 'Iie;i:m, ·M. A. ... ,'u:JllsJli-ne~ J. ,Pi~rm'. Sd. U.lI'. 75; 4,92.-4'96.,

J!i; l' M'![" ".iI..iiI' 1~ J- 'i~:: J' i!lilf ![" • 'III Dill!rI:! ~'A ~I.I· ] ·!i::~li

1'11;,. ,., ..• :J·!i:imJlI,!IDi:;n,lII~Iil,!:~. .' _,~,ws'I'i;.i, ~., ,!!!-,"I~rmk, J~, ~I;:;,i!!i~, J';"'~ 'W~";-, j~".

A,. T. M .. S'0'j""aj~dtlmii" ,., '., Roooff:;, I., ,P/~lJj"If~. S;ci. :~,IM1' 13',; 11,103·-1211,

Iii. le··.··, ~1iI..'ait:t, '1\,:"1', il'.~f11Irni·I·,aj ~~. ~~1jiil11~'i"m ... ~, 'iii ~ ~ 1! ,:II'. "'!ij~i m _."""\f1li

411 _ ~ ~U!l&l __ -'P Ji¥l'_ ~y.,~ __ .!!J~ ~_ ~ Jill ~l!l.! 1!"I:I;ir. ntt:i. ,~,:77:~~j ~.JI,!! ~~ lit -' (flU.

M. T .. Led!w.i!!dg~ 01• t CO\m,g~n", ,'i~t:' .. J. ,PJ.i~rmi. I,'nl. ,/74'1 1. 87- lOOt.

J. T. 'C.s~~~Ii!J~ tI;:Ph .. 1Jtl~ool!!ld~~l 'P.rl~roal!l~. bioD 1'" Mw:iIOOiI De:ti,ern'!. Nleiw: :;(D{r:k~ :-: ' .. ~' <, 19!19,

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..::!'IU _ ,IJI., ,., ,'~ afS'L:eIll:sen! .:JiOJlj tIIJ I:" l.rniIlil~,lCethlCiS. l"r.lli'!oo'C, _mlj .... ,~ ~ ,i ""Ii""""" ,.l'!w.o' 'ilMUJ,~' -'~~ _, _ ~~ .... ~L) ... ~ ~ ~-,~ ~ ~ _' '"

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[,3~,] S,. S. Yang: 11'. K. [u-uill}@ry" J" P~-arm~ s« 1,'72;, a. 26=40.

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[3_"8_:] M"" -l~d" ',: A 8' - dr,~ l 0 S'-'- -~d-~~ f A a.. -, PI' ,.,-,-, S'-l-- • m'8~ 19 ~09= U'S

"', • ,," ,1(;, ',.a'SSDIl ~ ",. ,I-(!I. II,n~ ". ", '", ,umn. e o.,~ ",C,rliJ ' "jQI~, .rLL"t,€I(':. " . '--. ~"" ,.. _ ~ ~ ,',

[39]' M.: ,j.ctllias on, A.. B,:[1~~~fI:. t., 0'., 'S'UI~d~~,o:f. l~~t. J; P,;IUU'"j~l" 'UU13~ 15.~ :' ~7'~1~1;[.

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[4, J ][ fL M,. AbdOi~;, "Dis&@;hlllt~Qn, D,iGa~',5tilabm,rniit!tf ,and H~,oeqllJiv~leliu::'e i, Macik Pulbffiwsl]iing CO.i Cu- ,ton - . [9:S'9'.

[~,2] \V~ ID. 'H1g~ch" '" E. l., Parrottl 'D'. lE., Wl!~rst~r~ T. :Hlig!)J,(:'ru~ J. Am. IcJ:fJ_llnli. S()~:. Sci. Ed. :~'gS81"

S7:~ .31'6,-3,83,.

~4-,3 ~ W. ~. H'igucffiThi~, E. :~, elsen, J. G. Wa,g-ne:r, • .J. ,PhlJ'rm,. Sc.l'" 1964,~ 53,. 33,3 -,33-5.,

~"1,114' ],1 'U Iii""!! 'M''- , "- -.. 'M' ,-, _o!;, '-M'· ~,~,-,- ~ 'v J 1fiJii,· ~~, ~~ .. ,~,,¥ • -~ 'V II' '("1\ ·'11 J J}j;1"' Ji,ii"~,r ,(" ~i 'Iiil,a'~ 'i-tril

["iii ~ ,1I1.'i;;.... "'_:1'.:, I OiIllllLey" ,~, ,. ,;M.", "~ ,iIIIUllinill! Ji'i;;.", .• I[1JIlmmeIliSd'~;~llll~ ..• ,ill. ;;;J~~,., a, 0'.' r~.,1£_,~,t _!Ii. ..,.. ~.. = ~Q,='i! ': v"

[L3-22.

~'.11 ~]~ U r. ~M~ - - ~ M~ ~.!i, ~M'~'· ~,~ - ~ if ~ u· -~ ~ ~ _ ~ ~,~ te ~ -_ V' J' 'S"i\ '1'1 J' ,°/" _~~~ ~ ,(" -i lfi~U '"'101

~''"I:'',j Ii:'ii. ... '0'. ' loomll;eY~1 ,~,. ,M.", ":.,,~I~iUlJ!V1II,, 1Ii'ti.", .Ii'. rtnarneis 'e~;III1,: • '. '!ie. 'a.. r~.fal"tJ';!!. ;.li.~._"" ,~;l!',_,,_,,~ r"

22=32.

~4!6l1 J1. Ct Aun~ln5" :M:. Z. S,O'!UudiD,mdl" 1:.. A. ,M:yers" K. J. :Hlimmels,:~~:in,. 'Y. J. S'l~JI'a. J. PI!'(~J~l.

se: 1915~ 7-fl,! 1. 305,-1 j[ IS;.

[47] t L A~=J ~llab]! ,Dru~' ,D,el.J: ,;'rId: ,':~p,{]rn,~'. m990~, ie; 3·47 -.J16~1

:[48] :D. L, Pireme~., J, 'w. M~lI:gI~r., Phar1i1. Re'ff.. 1[99\J;,~ 1'0" ~ 28.5 - rn 2~l~1

[4;91] :R. t. f'Qrbes~ P. 'y.~~~, J. R. :O~~:idson" I~H'. ,J:" Ph~'J"',n. :115j9,S;,! ,12'6~ 1.'99 =, 2Ci8.

[5U] ,", Ra;m1lOoLa; O. L -Co.r:rll.~n,; ,D,if~'" J,' lle~l. lfi~t, Pt~arm~ 1;8[1" 1 j 'b ~ 703 ~ 11'20.

( ~_ ; ',1-[,]- '~l. 0' '0'''' -H- -'- -- iii. -"'- 'fl' ~ "1 .. ,~ - S D..-. - ~ -- . 0' 1)---:-' [ ~' - "~, D~ - - - - '] iIIii!D"'!ll III" 4 ~cl 44'°

,J _ " "D, i., .• ,:uyn~il~" n,. ,(];ec,I'!i!~[". II:' eters, ,if',[~-8" e~'. ,in~~ ;Il-,dan"., '-70 Ii!'.. ,f ,J'JI~.',;t!' _' - ~. ,-,,0.,

(52] 'D. P; Me ,:.',am~_ta-; o . A~lflttdon.; J, .Pi:~'1rul~ Sci, :~'91'i :75,,858,-868,.

[Si3) M" z, S'[]ul:hn~rdl D'", 'v. [G~een~, v. ~. S~.eUa, :1"(,. 1, Himme[ste'ill, Pltattil." R,f's. 1",:1;" 9"

.58,~69.,

[$4.] 11'. a BO,g;;Ulid~5., R" :K;" Blac'kwood. J~ P'/mrm" S i :nt.19" 68.. 1 ~ 83- - ~I '~ &~"

[,~'~,]" 'W :1' 'H'- 'I - .. " A, MI- O!;, 'F.II '0· 'U., W-' Ie '~iii ~I'" J' ,[II ii, if' • 'iii ""'.~ :5..:~ @o ~I '~I

_"::1'.:11 _~:. ~,. ' ,,~_gu~ u ~ " . ~,. "tr" ,~ ... ,17";;, ,~,lrnp(er~ ',' ~. 0. ,n;[I'mw lllil",. ,:r_:'_'~,~'an}l;., sci. ,iII,:7U~i~, .''''', :~ - w ~ •

[.56] M. M~gy.-lfe~l. '8. D, AIade.roon. PluJI·mSci. 1998. .1'.. ,8-400.

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[.59J V. J. S~:ent'l!l' S. 'M:al1Dd_Ilti;uffmjio,~ 1<.. 'Te[\e:da~ V" M. R_410 ,J. Phan~'l" Sci. 1'9098\ 81:, 123:5--124 :ii • [60] S~ :L. Lil!.~ L, Lacffirul1Wn~ c. J. S'W~rll, C, P. Hu~b\Il~r.,.1. Ptf£~rrjj'., .sci. :1'9',2;;, 6 f, 1:418-1,422. [!'i[~] E. S," Rati~,e~, J. -0. e,ald~I~IUlSt t, ~. RfIi~:~I~, t :~. Snow:~ :M. :M. :~eg, .J. ,P~,,'ar!m~ sa. :11'1'12:, 1.1,~

,I¢06-409[,,,

['1~"'1 'M': J' n"r'b,u;'1Qi·f1 'I' '~Ii'ofi:l'., n A if'd,~'H' ' ...... [ "Tn.~'h' C'" 'M'-' ''''''IIY'i;i' In; M" -", ""'l,,",j"I'I~"""'''l 'M' : L iiI"'!'''''I~>r'"I''

"-!lie?] ',:,_, c .... ,g~~ '-~_!-'''Jl~ ,~., 'l.:11I,!!.r!1~ .PI-,., ~~~'I,g;~'i ,L}, • .t'~!'!-I!-. " , ,~,_-~,u,~,""."" ~. " .. ,,~~ ,;i"'\~I", ,,",,',~IIIlJ.,!I!IL;I'.I!I .. um~, : ',.~ , '_. UIi.JI,~ '€I_~

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Chapter ,3

bv 'D"'~"--'''-':III.~ -c---- 'i', c,--_~ and 'D-;i!01 td-· Jr ~w.-- -G--;' - ---,

l ' -DOle _Ie, '-' ~ron i~Ul' ,-,a\. " ,-_ 'i.~' - - ,ran~~

Contents

~: '. h1t~ndU:C'~:~on

2.. Tberrnodynamic Background

:," 1. Phase Diil~gr,~nl O'f a. Single Compo'fD,ent Exhib:h~iln,Q; P~'~lym,oW]lhi.. m 2,.2. Phase 'D'w,~gW',~m:S1 of 'B rnn ary MJ xtures

2",3. Amorphous State

3. PThly sicochemical Properties 3 .1., ~le]ll~g 'Po;j nt

3.2., Sj)lulDHity

3.3. Dissolution Rate 3.4,,., Heat of Solueion

3.5,,,, In;t'e!r,ac~:~!Dm 'with '\Va'tf!'f Vapor 3.(i, Den "ity

3" 7.. Mlorphol~ogy

4. :K'i netic Aspeets

5. Study of'Tra;nsl~~onJs, between Solid Plh,ase,-

6 S'i' abi ~I'·I ~"'J' B-: ehavior • lin I UL'4 - ,llUy,i' w , ~

1. Molecular ModeUirng and So~i d.~SI~;a~e Predicdon 'ip'~ ~'()'~ iro.'ii'C--- - ,.....E-.'~J

,[f\.J~lI:--'·,C.,K ~~.''''ij ._. ~

11' IR,trodu,ctjo:n

Copy rig hted m ateri al

DU' .,!;. '1!!i.1'iiLifl' ·~.CIr:'II' MI"'I\·C' '" II' 'S··· .A. 'I ''1f'\(,!',. [t="j[]bFLJl!il¥Ilft.. ~cry 11 If .. ~ " .. \M:Lll ~jlil

Copy rig hted m ateri al

Chemgl~~ II

1

II

li.iit il-..ili nlall;i!l!L

Iintemal SllJdure ,Ii

I

!~- --

"J - • - I

,',,' II)' OO,S!

I,

Single Entity "'~ph I

Mrl~!\aJir' ,Addud II

II

iO;Ii",,~;B!I:.."j"'Ii_i..:1 ... , ,~ ... j'~i5'i_ a_~~l'I~-y~II!I~glq~ Q~'~Qu:ii

I

Ic,r,ys-tal 'hardness,!, and ,oompactibiltn,y,. Of' 'maj or coneem are the iIf1JueltC'e " lof" ~all'~ form, pC!m,y:morp:bi,sm and, :pseudopo]YlillmpJ1ism, ()O 't,he[,lpe~hc effi,(',IC'J, 'toX!iJt-

'ii'Ir'!jJ and b,i,_;m'u\~'~i ~l.gb~'~I.;ltu ['C:']I [IL I [U1. '~ .,] 'i!lII'n.dl ii"'i;JflIj 'pli!..l'!iiil~'!JiIlif'II,;f:J;:I'nltl· cal 'li'1.,.np,pC!<C!'i: III'NI!iIJ' Ir 11 AI]'

lJ,L,~1"' IQ.IJ,IJ.:: ':!,~~~_~',,"'QJIJ=Wln~ ,W~WJI~,~j: .]II UI ... w,u~' 1.)1, ~_ldWI, 1~1I.l11. ,_:,W~W!i'J.l.W,-~.lI.lI_~'_'''-lY- ,.!itlIJ ~.IU~IIir.-.:J.-illiWJIIIO till ...

I ~'iIt':] ".'"fi",h"""I"""'II~~·""l""~' ,fi 11]1 ... '11." ..... ,.'b,::,,' '~d'" "'" .;.~,.4,.-, ~,",~",'."~.~I.-,.'C'Jb,':~".-" ~',---,

I, ';' 0,1, p" ar,mj}U:leU~U::aJ ,pm!JIIllC'lS,., r[hY,lllOllpuw!m 10, ' pseUUopo,Il_y,moq;JJIHILlSlll ,aIei.

'~~JruOIW.n '~IO b1]'OujenOe e,ve~ stage :rnn tbe mannfaeture lod sWF,a,ge ,of plum:na=' eeetkals '. The Inl;etJ~aJio,'®fd ICV(' renee IO,~ ,H>anwoniwdon (leN) f1liqJui:res inv)e~ti"cadon~ ,and 18J,Jl al:yti.lc aI, ploo~dl11!~ 't1oli' fttew drug ~ub~r-ID£~' and pharma-

,-:A"'If",Ii"'-i ,:c·,.....,.,.4r-'.(i!itl~ ,.- :-;-;';Ii"l ~,i"".,-,-, to ,I!!jj ,d-I~If'!;:~~'~,o'lf'iil 'i'r.~~ 1["iI6",'] [1l"'j~]1 T~,a;;, 'Miiiiii;~'y,','m·iFiiimL:l·,·m ~rFli'd'

O!l;;o'IllJ,~lb.; .. ai1 pt!!i .. I!!Ii.'UI!;;,.'~ IO",uf1.llJ!Dg ~ ... ~ . "",~lO)l '. n y, '1;;,0' ...... ~ oIL '. _ " _ '.' ,u ....... g .... ,~.,.,. u~,,~,~.rn.·, ,I ,!, ,p:u '

...-al 'II '11..'" ~ 'l'.. " l' Ik,.., 'ii.,. ",...,.4: ['iID 2H]

,P&elUUiopOt,~y:nlo.l1>,I:~~.'s'm O:~_. :M,My p\~:tmD!,aOelilJ~lICa S nave @eeo r-ev~e::w~ J! b - ,~u ~

2 T: "h" - ---,-- -'dl --- _ -'--'''~ -, '8' :,_, '-k'---'- --'od- '

I jQ'rm' 0 'VD0'lfli1Ii'II~ .. If.:li'iP .' 'pi'li'llAr ''I'll' , . ,

,it I~ l :. - ,'_ I,__,j.:' R~_Id_~~l~ . _~- "'r~~! VI~~ . .____.

Copy rig hte d m ateri al

,J.~l,jl, ~

may be arranged in one o~~ ~be; fluldl:m~ntw. c:r-y.~~,a~ Sy'<~i'~~Rl$i: biJC1if[t~.C,. m,O,ID;O""

~I " .• Iil-., 'I b ,. , '1 ,. .~.~ .~ '-b' ,. . 'I;,.-'~

c ~ w me, arb wO(I~, ],om, :-liCt '~~tFlgO!I1Uiitt tr~lonl~ ~ ,~le.:mj}O:JlI._,~ or ,All ':IJC~" ,;-, __ C'.~IJ C:ryS'~~L

S':~l'stefm ~.s chanwcteri.ztd 'by uJrd.lque :re.bl!t~.on~b~.ps exlsUmg amon,g Itlllie cry,si:a) a '-',I s and the a;~gl~, between them .. , The :mo ~t w~wd!tly ,kuOYin:w le':':amp]e 0, / polymorphism is mbe e'~emeTilt CybOID, wlld"c'b ,caD. exi '£ :rn:n 'the form of ,gmpl'l'l.'n,e. (I~exagonm~)', diamond (_'Illbic':', Of' as fullerenes (C'6~' and C,O,)I~ Among the dj.:F ... , ferent forms or :llarmce!tamn'~.~ one is ,8, mono,f~'·"nic poly:rDOqlh ,and. anoiher is

['~ h bi ~ "h' '1]-h - ~ f; ,-- - -'f -ow"·'- - - - - -, te -- on'.'h- 1f1--o---

~ itPIi iIf'PIi~ FIi'iF'iirr· ·1if'f1,;f~ I~llif!il !nn V!"~I ntli1f1i - TVJ:lD ilRirriPrF'lll!E'- In; Lif'!I~ ':' I ~JnnlB gJRB 't~' P l~lrt,' nr. ~ I 'I me '_

'~\UI ~'.I _ 1,III!It,J U,I.iI.!II,· .w"," ,F'U ',J' ,1.'I.II,V,~.Jf'" . , •... ,L....,'1;;0 U,W.U,IMd' U . 'I!;,;"'" 1 'U,IILII'!;,;;' ,lJ.I!;,;'!;,;I ~, '"" !IOII~' , ,. UiL " -' "

bic ,3.mlid. [WOI forms are mo(rn.!oc:linrn.'c,.

The :reladoro·h:ip,~, betweea dlffet1en~. phases e. g .. ' , po~y,morpllf,~, of a substance are geverned 'by ,Gibbs'!' phase :ri1Jl1_:':

fl)

whetie 'C is the nu:m'ber of components, P is 'the nu:m'ber of phases thai~ exist ~,n equIUbri,um.~ and IF is 'the f[lu,mIbel" of degrees 10:[ freedom, i.e.; the variance,

f Ii!... T.... . '1'.',~ I ., 'I).., f ii~b. • b~

o 'n~~e sy~:bem,. .u,e~ :~n.'~e,ler, ,£" tn ,c!q.I1.". rooogJrU7Jes 'tu.at '~\~Oi 0(:' iUm,e v',ana,~,leS~1

rnl,anlemy I~eln',ernumre 8!Jf1d. :pw~",;_,llIrre, ,IR no~. u-'ochled w:idl. 'tit_, :reJl.tive UIl'llonJts of '~he components, In ,com( rest to b oithr vlfllbll~;,!! ", nned to:n~.m'~mlli as, whic ~ do reflect the relative amounts

ln ~h,e case ., ,If a >~ln:ll;~it subs t~ulICJe, sruc:h I, I dtml~ c,'bibt.'Ung POI, :y~no.~'ft plllw'S.m~. Ie equals uln:ity'.,:[ O(F,I!e 'p!tU1S1t,! i. fd'.,~, lone, PO!,~.:ym,o:rptru'i is present, Pi = J ~

ih"- erefo ,~, 'P" '_' 2=:, ·lP;'nl~~' 'i1'i~'iJ'.t!ii'iJii'iIi, 1i,"tOlli'ii' ~L;I!!i, u"',iFil,;r;,'if'io"!;I!1i; F- ='C: m" 1il!ii;;'!Ij'Ji'!ii'~'if'iiI'ff t"Il..;n;,ifio b o th

" l.;;;,~L~ ',". ~~,. '=' .. '!l ~~""'I~j!!l I ~ ~'¥~~W-~': I,J.ll!~16 l~ll~/~ ·~'~4I"Il~P__l!,I.~~ j • --- .~iJ,~ ,~,_._{~~lIJ~.W,~.ll~ ~-~:~~J~. ~.: _,I!lL_.

temeerature Ina eressure ltla:w be varied tvi lb,o'd'~ 'chal1f'lltiQ p: 'I!he mumb - r ()i:f

,Ir' ~~. [J' ~ b

phases [:_- 'two phases i.e., ItWIrJ. polymorphi,-, ,Olre :m:n 'cquili.briODl,- P' - '2;" in.

wh.wlch case 'the 'v',Rrii,unc1e :P ~ 1 'I' meani.n~· that ' ;11 ,Q. chosen pressure, lJI,suaU:y OJtmospherlc pres "Illf.ie, dIe temperature of the '~\ysle'JJlJ1 is fi xed. at the so-called ~;r,~Fl,sidOiO te'~l1p~ta'rlllre', ~~., The IcorJ1cb;urion fl~m, the p1hare rule i, tlla!. on~y' one

h .'" t ,. It, lihi~ d- t ti, j" •

[P', iase can exist Ii,' ,any g~.v'eim. tempersrure an~. pressure, except a . me IIi:J,RIllI!U""

IU! 0 [I:i, temperature at a de:fi:n.,~d pressure, IUhli~]lilU.y ,aJ'~m.ospheri.IC" in ~f:hicb case two phases, e.g., :poly'mQ(['phs,. exist '~:n e()I~~:ili.'blti,u:1l1m

Tll,., f' It " ' .,.;" ~, '~ '1,1;., ,. ;I,,,,,,", ther . 'II'

.' ne preees t: 0" 'IhnruJU','~ilOJrma'd.CHl (l1:1Ii oae :po.l:y,mO(I]lu. ~DIW anomer ~S' m, [pllJl3J.e

i' 'It·' 'h·' 'w.. ~I" i'n ir'll." 'lb., 'II ii' .'

rransmon, ty .1 :ru,IC;W.W,~, acco~,u~~ng ',~, 'I,~.~e :pule ruse, :m_l,y OCCllUr' alL ,a, g ven pressure

[L 'L • t h it Ii' '1If(" ii·:L 'I.. Fili"llflii·' ft."" "IIk'11 tp'lI!.., t-

ury c~dln,g:~:n,g me liemper,lI:~!lJlre:.. ,Il." me P'Ui3l e '1iJl,~n ,;m.'d,orru :~,S rever ;(IIl1'JJe, '~ue '~WO

~ Ib, ~ '. 'f d fr'b, ' -, , f~' ii,lLh,. , ., ti "L jf.,' .,

lPo~.y:n:m.o.rp\l.~'" are e'~~a,,;mI,:'I!O,~:'ropes,!, 3:111,' tne len.eJgJ 0" me lu.,g :;[ lOll. on ueaidil1g l,

endothermic. If the phase traJ'n:sitio!ll i" i,rre;'v' ~r.sib'.e 'dru,e 'two po: .:Y~I[I.O\rpb:Sl Moe monotropes, :iu, 'which case o(rn,m:y one form is s'taib~e 'w'hailte'Vier the temperature, ~urld the· Itr.ansfortmadon of '~he: ilJuls~ab~e '~orln 'to the stable one is exothermic. For kinetic :1·eaSOIlilS'I! ,an lUJ'llll·U~b~e '[O(f,m Illlay eX.i:s;1 fOIE ,8 'tiDle o'IJI,'lsj.de 'lbe :F,e,g:io.lll ~s;si,ltii,ed by the :pha:-e (nm(gmm and the phase rule, ,911d I, 'tben. 'tlemu~d. a 'nel;a~i'ta',ble' fO:Fm, .. Fig., 2 presents 'the. I.wa ,typa. of :p'ba!u! dilgr,8m O~ a ".";ing;~.e compon nt \;vith pG::"~ymorJdlic b~hJa.vioj':!, a) relp're~ern.It~,n,g en;mul~iotFO,lPY:, and bi), repre ,cnUnl m,!oDo'WO:P'y"

Copy rig hted m ateri al

-pm nrr.n::;:'D!'1i'~~S· ,('! ~JLE~110"'N" A-' :Jrr..J'fln; U""'E' J

_' ,1:\;,Vll:--,L:dl~,lI, ll~tl:i"'_,'l~ ri]1tl:i_,. - "}'k~ ,IJ. j ~., '>" ~l " -·,lL""'!I,lL/. .... ~. ",_

4-'~

.J

-~

Solid i~

SdJid U

b)

,I'

J~F

if !

" '~

,S~ltd [I I 'II.

" ~

j.'

/I .J'

I

f

;

I

,f.-

I! 'f' i'

A,

'~ilg, 2. P:ha.J,f di:,~tJrol,~ ,(J/ pre$S,~ffl V',S,. te.rnperatlJre jo,r ,t:l :d,~g,l'e cmuJ.;jou~u;II' sh(J!I~',in8' ,il) e~,~a~,~,_ t,i,'(')~mvy;, and b) ,t,,~(lllO't,rov:y (:ult~r' S, C. WiaJruWwmik!J ,D. J[., 'W, 'G~i[mt, ~',P:ilialySijC'ld, Ctiemi:M:ry :for Stu.dents of Pt"~Mac)r and B~o~~I"!", ,3wd '~'~"! :LO\:~gm~n~ :LD~,don" U. 'K "'r. ~,!9'j'11 :P'", ,4'2)

a)

, [iLiq;ui~

Energy (tl H)

b)

[Eli _~'"'" .... """ ... -

-'~I~==:':~,~

jIj; """,

Temperature,

F.i.,g+ 3,. EI~~U8)1' (li(;18)\~ms ~d'low,i,rJ,g P,"Q,t~if of e,mJ~(.II;'p,!; IH'~ ,(JI'l,d Qi,bbs .free- ,e'Ja;e,rSJ:1; O',~ V'S., U!I:ni!J(!r .. ,atf~:re'~ T~ ff}'" ~'hft SQ#d emil ,'l'qui"l ,p$i'{l,if.e:r; of i~: S;"l;j]:'l.e- ,ci().t1JJWUT"~, s1i'owing ~'. uanJio,tw,py. (Jfi-a b)- ;1j'cmot'rolfJ:!' '[after [22.]l

T~ bi 'I" . f- - ·t - ~ t - - di' . ~ - - - - - -k - ~ d .. - ~ - - ~ d ~ -~ - - -.,. .. t - ~ . - ~

-.- '.".' .',' ." ,.,,- - - ' .... - '.'. - -" -' w'···· '- . '-' '" '_.- ! ..... , '. ~'-'." -, ,.'- . "1',

e ,81,ny 0, 3, sys ern to pe .. nrm wor _ ann to unoergo a span 1 iEWJ]t10U,

~'h~ ~ ~ ~ it ~ c ~,t-- ~iI' ~ - ~ - - - -- .. ~ ~.~ ~ ~ - -fi-"':il 'ii..-~ ~'Ik au ,r .. fr - en-' - G"'- whi h

c :ang,e SL constant pressure [5 measurea uy !~t~e .: "U'uS ' fee i=-_~er-gy:!, . :~,_,:' :_j:C __

is given by

('J')'-

~:.

tn g)enef~t~,~ me tbermodynunic rel aU:ion's:hip' between ~,wo pol,:ym,o:rphic phas-

- -' , ..

ell 1'., reeres 'n~,ed- bv m'lo~dn' (\j' the Gibb« fr-ee enerov a ' ,3. r1J:lllC~'i (lIn of temoera-

- ~~ - - r~ - - . -_. - J' r = . -_ .~ .. . . .. _- .. ~. !ll.b,J'· .~ - -_.. _:!J. - . - _. ---r'~~ ~-

ture fo lii'" 6,~ ch form « ,[j"'~ - 3~) 'lI-'f" the 'tWA curves ';;'ii;"Ii'ii'i3i;~o::!i ... t II-.e'~ .... w' ,~'ib.·e 'n'IIoe'iIi'(-iIH',O' rur 11'-. Ii eacr _ 0,uu. I!I",I, e- "R.',. ':",., ,.Il ,U;!!;,;. 1._-_'0' I~, ,II '!If ";;]I ,III. II U,'"" it ili!!i.,;-";'. IIJI' ',iI!v ... Ii!U.' III,iI, ',W ',line

Copy rig hted m ateri al

46

poi 'MI'~1 O:~ each n£'fu~ vmoreh ~;m; 'reve' 'iII'\I:1'l·Il..[~Le·' transi li'~ln~n .fiif'" il""nr , '. ~i!ri;'i· ~i.'e' iI!',ec '''~m'lf'iI;e'r~~i'j'hl'i r'~ T

~·.·v, [I ~~. '_ IIJ '!:r~ '" ll",-v~,J' V,IO ,(f-W rn'~J ~J , ... ,' -a- • I.-JI IU W· . IL·1 __ LIj I~ J !LJIJ U,. V~~Ll..~, J' • !HIll r~AI.l.Il:_. ~~'_, ,_I ,I{'" ._ ., !(:_ •• "~l_' ~ .~i I:

" f." th ',-, ~' 1iJ., ",- " " ~,~, '(. A' iii, ft, ,'. ,.',. - ",' 'Ij~"l '., '~'II' '-'1 "if'" .,1I,~· " -:::~,'I/.., " ", iI...,' 'I"-h' " ',-. ",' ./, ,[-, "': '.

0.. ~. ,e w n,l~er. 'elCI~ IOn.~ .' ~.~ I~. ~em,penwdllieiU UeJJo,,", J '~,l! .POJJ)' morp,~,11 " "nas I. ,e O\JiI't':J ree

e III'ii erg Y· "IIFiI'd' ;j C' therefo 'I'~ the ,~III-.';i!!I!r·mo~·...I''IlJ'1IfIi am '~I cal 'il'U' C' ab ·II;fIi; '~II"ioiii"m't'rii '"'!il,~'I1.·'1"lle 'fiI,ri, temeer

~ ~'!!;"Il, ~,', '(lIin ;_, :"'';''1' 'Il,: ,:I.;"";W [!!;",~ !~.: ~'iI !~lII.W ' U.h,." .U,j 1Il1;~ " : III!~., .I!~ oj 1(11, i,~.'"",,, ~.IIUI',lIdl:lI.llfjJri U",I~' Q!". !i.[~: ,~ ".~"';I!I--

atures above ~~, polymorph D, is s'nable. 1m the case of mon,Q'lJopy: the hJglleF'

'~.' f' . 'I ···'~b···h d- .' l~~- b l ~.,

--"1' 1."- 0 rq[" .~,' -r~' I"i,.!i""i" n",", ...• ".--" ..... ,-, ,-. 1-' ,", ,!I .' . I.-. . _", I ... ~I·I·-- -:-.-:-'

me, tmg rorm 15, a .W,dYS tne t ermo~,ynamru_ca yla. e term,

f3/~lu·l1'.e1" [2] ,_ 23~] proposed to 'pllof. energy d~agI'a]frf: ( . is. 3.how.rnm"g mJhe

free en~n::rv 8f1lr .. ~1 '~Il~' enttu .. mp·O'·v >tl,;to' 'fr'~U~lIr,.""~'ioc"n,. n'f: 'l'D!!NIi'no.lI;"·H'tl.1ii'C·'1 A' ". ,j[! it'.'JIJ!..'O':ftill1'r1; ';i'ffiil."",~',...., j'" h .~' _', '- [:.. I!! ~Ii;;>~',~,j~ L _ Y, ~ ,=iI;;;o' V_,~ ~ ~aJIi' ,;j uJ" . _ u ..... '!l,..~· I,~" 'VI . . /Ii;.;~~LII:,r~~": 1Ii.~'II.· .. ,'.;;]< i.CJ~.IIi.' ,'y,.II.III. ,U:l ,J]' ~golii,. , j/~1!:

and h' ,3 n,()~a'.~i,o [d. 'i'~4!!f~:'lloif"~' between [~nl"'ilI,IIiI,lI+l~'''''~~IIf'II'V and monotroov ;;', 't'lr-I!:i' me. ·'liff ...

- -~ - - - _-_ - - -- -I!.)~ ~ " ~,~~~ ~ ~ ~-~ ~~ . - " ~~ ~ ~~ ~~~ ~I~ yl~JltIVy.,JI ~.i 11;.IJ.I,V vic.; 'IWI.tt""J' .~. !L:~,It~ .. _ ' ~

rnnp ,en~'haln'),y·.· of the hipher 'IrlJ1.'~·~th1 P' form, ]'n ~he case of [CHan ionoev, 'die ,lij', .... f ....

,~ . ..~ _ ~. II'" . . _ ~ - ~ ~ e .. · - ~ L ~ - - ~"~ __ - _ ~ - . _ . _ . . , .. ., . . IF,}" ,. [, 81-

er-mel .'~ m,~' fa' .. ~I :h:PJIi'~ 'th-e :~'n~i'er-m~- el ~']'·lil'iIliit;J ';3'i'i1I~,lb""JI'I' 'p.~tV,_ 'II.'M; 'f'iJ;;,,~ ease o .. 'iI!' monotro p''li.r it:1~e.

II!;. . ~ _ ~""" ~_ ~,~ = I!I.I!!!!!!!! ~ ",!!l!!. _ r.v. II'" ~ ","" ,l~ .II! ~~ !!J.!J,lIIILJJ w~ l' J'. .II~.t U.l .... !!w"-lli..:J!!;" .,~, I. ... ,U,II.I, l.il "J I! '111,11,_,

l;":;'iI"j",i.olli' mel ~~ IIiii ~;T fo 'FiTI 'il..;a; j," ~,~,tI'fI; J'~'!I';'IiJ,l)(J,O ~i' 'm~ ~a.1 ~'~'IfUIT ii30:FjlIIl'j'b" .. ,'llnv .:. ·.-iIif-li,f":'l'll'ii'~Ij9i'....1 Id' isenssi lAin of

I'~ ~;O 11f'1!1l~ If- - _ _~.)~~~.~ ~,~ ~; t· ~,,~,,~,,~, ~ I ~~~~ I~~ ~~ '_ ~I;a:!'~·-~ ~ _I ~i~J!~~~ ~111~,ll.lI.~.:~UJr J"i iLlI~ '~"_lIJ.W~U, . l.",'_'" I.-J!~, lU~.ll IU ,

p' ..... - ... ~ ~I'.,;'[JI[}I ~o'JIl 'i'j;,"" La" Iih."",p"c ·c-·re· e ented ~ .. T. ." .. ~ [?lIl ~ !!IU.S!"", IIJ!Il~.gn~.n.ls !IL_S IIJ.)","vlru p::.:·~ ...... n"""l . lUll' J,OtSC!U'!1 9'~1I1'

S··· :,t'i,m ''V a- res '.··]·]-!I'i'\W ']·III'iII'h"!i!I·I~if"~· ing C·;II'ii.III'II'~'l" "l':" iiC" beeau ie there ~i're' ~'W' i.',j"ij, J'I!f"O" m non ,c;;1i1Mi'e:

"v W ._ .. ~1Ir L;' ". ,v,," . JI W ~!'I!..r,1 1!..r.:l!11ir .. I,I~. VW ~l~ ll. !~.-J!~, ". ~!!i.r'jIU~~. ",. _ j Jib- ,~ ~l. '_, I~, ,,' V ~,_" e- "~'v_._'ls!r~ ~0iI~,

the hoss and the solvent, The :pllil8IJ"e.' no be considered are "the 0;.' [t,vlte· the un-'

,. J 'J .' 'I- ···d· lk.o .... t· ·....iI1 iilb, , .. 111, ent 11' . 'i-~L., , ~,,' . ",' ... : . '~i. I , • ..,,', .' "'f'~ [,,"' , " ", . .t, c, ·[t .. -

,.0 vareo nOS .~ ,anU. me sorven .' JJn me 11I10flei comptex cases 0: severa soivates,

t'l" ",~I,'.'·' -, c' I' t "'h ~ .-~, with diffe " ,to . ., ,.'. ,··t·· .. ~., e th .~.. ... ,' r d

ne u~ erent pnases w ],IIJ,JJ'ill ol rerenr !CO.l],IPOS,tu)ns nave rn:1 enr're,pectn1e .. o-

• & b';'] , ,r.;". .:, 1 ~ " "L d" of; iIl..' •

mains or sta c ] .It)'. rig. ¥, S~1.O'WS SOl11e typu::a. P'1Ii,3s;e·.· aagrams [Oi~ mnary nu .•. ,-

. W- -;~I ~ ., I~ '. t'-11 "b-' I~ f' h h d'

. [.. I -', I - ._ -. II I II . . ,... ,- !inJi' I " . " , I' . ',. .. ~",",... . - . I ;J -,~ -. -~. • .; . ~. I - .

ture nen manu ,~C1UUlil." ta ,~~1;,.,~, ,e I!'O~", tr e occurrence lat. suer P" ase rna-

. , ,"". ,. eds ,t·. be conside ;.:I 'lUI! sid ", ~h"" ,-, .. ,. ~~, ,',,' ··--·c-·.·,·~,-·.~,A t" the salt)

gr a mfi , neec S 1IJ'o e censmerec. ,D[eS\~I" .es I~ e~ IPUJ{~ oompQun!;,jJ, '!I,,[r:.,e.,~ I~ ae sa ,1~."!1

eutectic mixtures between the acidic [and. 'b~ slc components can result. Congruent or incorrugtu!enl melting of the solvate (0'1' of the salt) :m.ay be observed

I{F~' 4:··.J"~I·~d': ')" l· .. eadi "; iIi"".;,:' '''"''''iltl'''''' ·,··,IIf",tiLL.· two eo -: .' '. "'f-''-'''-'' _. ,.·.~I,·,'',-,

\~ I.,g. . .. (if; an,,_, ,e" ea, .lng, ~,O [D, 1111~X~,UU! o.~, ue. '" 0- cnm.ponenls ';Lver med.rung.

'F,:-'-' I~'" ,~, -'" ·~··'I::._ 'l:t·[· 1- I ,~. ·~·'t';'", b" iIt~r' ,i~' 't'li-.l ,J 'h"'·...!' .; .. ,~ ,iW ., .-" , .. ~ jji'1,.. , 'h· ','.' 'd-~"i' ~..JI 'f:' -:::~-

_ or ~xa.n1.JP,.e,~,le eUI~:ec. w.e ,l~!,,"~. eem1 u~e. a,ll",Yu.l,nus ,w.OI11m ,anu 1~I~e .. y'~ ra~!ey ~orm

f· "~ 'b d ""It.. . ...iII [? ,Ii: 1!d 'L '~I 'ii).. , ib.

0' 'terp~ n ~·Uts. :ee:n. Ifen Uey, , ...,J[ ,. rlill:rt.uer.m;Ore~1 ,po~.ymorpw iLL:m ,ca.n. occur IUe-'

t\v[een soh~,a'med fo:r~'ns [18];.

S··~,·eV'er.",;lll- h-; '~I.d'-";lJ'i~'~,S, ["'\'f' ~I 'SlJ]- ,,~.~,Iit'rftJl'[]'0e :m::o!Ji'''!! '~o n.rJj,sI!:"1"b·;~lof.li' ,~M'1iIA 's;[·~n,II!..'lle' ,a·iiJ. ~I'm, :b'·.l~~'-n'i~ . _ _ _ ~ ~ 11 . ~ - g Ii'l!r.i~ V g. ~ _ Yol~~ 1 I~ l. 1 .aIJ' u~ I~VIl.l.!.;;), I .ru.~ ,_~tlj.lIlLlll riY! .• u~DJ, .. ~_ l~ ~~ L. _. _ ¥_,,_,~

condltwornl~. For ,e.x[amp:~e ou;abaine 'w',a o'b tain ed, i'·, ~U1. ~nih: mou '[orm,~ dj,hy'~' d'te.a~,e,!, ~flh'ydrate~ '(;re~r-ah:ydr-ate, oc:~aj\ydra~e;~ and [even a ". a no:m[allycilr,fl~e![ d.e~,

_. d"- ~ ... ':~h ..... ~'" ~ ~ ~ -,'if!' .. ~ - ~ --,~'- ~"r.'~ ~ ][6' 1]

pen. In.,~ on t: ,e~'onll!JUIOn~~ o.~ man:Uta,ctlll~e _~,

Bec,ause arn>r, '~ub~'Lam1ce~]O[ ,3m:e li$U31~.Y dJ~ed be'fore ,a~m,~'~shl [he crllJ~8bIf~,-,

c ,J IJ" .J'

~ ~

,lizaHon. o'f a [o~,v<ruied :[ol!'m 'ii, o:ften :h:nor-oo or oved!ooked [ee pecia,Uy :~f ~h.e

crysmal, h!ad been fj'bb:ined by 'fas~. !cooHnC" In 'nhi:s, re' pect'j) tn,e 'wa~er acti.vilty in. o:rg:am1lico~ve:rnts. :iis[ the !crid"al :pa.fame~ef 'fo.F' the ror.maj~jo.n i()f' hydJ.a't~[

[2,16 '_ 28; TI. :~'Y·.·· drllo.t1.n P h:fl£dra.tes [or oth[er. sOI~'Vate·'·" fnetastabh:~ forms -are fr-e-,

. .,~.. ~'~,J ~~-l:!JIo ~~,.,. ._ ~-.... ~ , .. ' ... ", .'. ,(,' ,. .. 111; .. '.'~

n'I~I;;:'}'Iii"II,IIi"~'\l' oil+'I',t':j;,"'lii'imA -B."·~l.";.-~-[,,,g, '-~ro·"'.;';i!,il".~ . .,-'i c.'o]· .. ,c,":'" ~~,,~,,~'t, .. ", '" .. !It.,. ,~ ,'IIl.,.. [;1'1'[" .... ,- .",,'. ",. '~'["

"'"!11;.1""1~ u!'Il-~,J '11lJ ~,~d ~ 1,II,.r!;JI., , ··!!;;,;!i;..<alllJl.~1J;;; ,P ~ .' I!;;;.'!Q;:I<$ y, ". v,"", ,o',pme!I~. .an,n·, ,al~ I, ,IOI(jJUS,. pfOCe. .. , ,~~,

'l'~ m·"JI,n"':l~ii'"o· ru ,[.,- 1~'v:'!l'il'~11Ia· ~',.c. ~,Lofi' 'i';i'iI';n['4iA'Iii'ii, .... 'V ",.., 'I!!'Jni~rlili'tjfi '~O'~··I"....'1i·a~·::·o,·'n d' '11ii"1'liID' 'iitL'e .... iIi'v .. ,

,",,' ,.t.[Ji!uitl!!I;U .. '~J ,,'ILl' Il..,. ~(1i,hi!~.I11'" 1~1.!I!!i;;.o -.J ..... I~~~""'~,J""'" v_ ,,;:I·vil.'!! ~,,,",, il.'· ,J;J"I ~oJ.' "~no . ~11II, 1.0 ,."n" !I;.,...~".!, ,-

iii"!JlIi ~I m 1 :-",~;;i' ;l!~n. Ip,"f.;f1l;;f"'n,A'l!I f',;lli;. 'If'f' so('ii[~I'U'I;Qi;n~' 'm Ii 'V 'tit Iii·-Ii'~' ~ ,r.r I~'n LlI60·~·~I'. ·a·- ~"Oc :I"ii[n]" ~'lVJ;· !11';i!]id'

1~_~!W ~ lI,~~I',W ~~ ~ [", vw~'lJi,. _ .11 ~,. l~' u,~ orr ~ , 1(, "., lll,AIIi}~. , ~ .:..1, 1~[.ljl[!I' j ~~, __ ,~ • ,Iy J I,. '~" ' .. 1t11V J.' 'J ~~ J ~ ~l,~· I;

~he 'for.rnati,on o;fdle ~nhVd[ouS salt~ a. SO:~''.(lte- .and, Iry'd·~-te("~ Ih('~':'!- n,-, III..~,~:~,~-

.~~ ~ _ ~ ~~~~~. ~ ~ ~~~~ ~~ ~ ,J ~ ~ .. ~.. ..,., . ... . ".' r:::~ .. ~ SJ . ;av~~o ItJe (':Jon

~ .

Copy rig hted m ateri al

81'1,1

o!if'

III ... :Al ~,I!.!!~

100% A, (,8)

T,-,

10QOjb, A

(c)

~~I+A ~ ~BM;t,'a ;

1100% A ~ '1fJ~,% 'B

(Ie')

T

.-=-,.,..,.../ -f B

......

lA .. '

~,Oii'\gl_ A II. U7Q ~ "

(0)1

TO

T

I~"" ~

Fig" 4, Pii'l1}f(! llia''',r;-rll1.IS of b.ituu'y mix,ittl'i[i"S u/tem:rH!l1J.JuW'e vs, t"'lJJnpo • .itiol,1 I{e'.g.~, millilO~e fraction) oftwo cheln~:, '(d' ("()'ll1poUU"t's. I\. I~lrui' lj', $hi'Jw~lw~g I'~'(! flJiJf)t!);'ng b.(!ltav;;orr: aJ) 'si'~nlj'll; e~u'(:,~tr" w,~,~J:" 1~',egN8i/:;l(! J1j'i~cibU;ty ,i:~,r. tA,t!, s,oUd .'i,ti(~'U~', b) cOJl~j'in~,('i:I;S- IlJ'iglt of JffJlid soIUJi:()~l~ (M~ s{:Gbi Ut in rile . olid stare as Vli'd] as in the ~~liqll'idJ sta'le'). It:' .' tU(lc.tic ~~dtli. ptfn£tll mi fi -',rJ:diUJ If.r~ 'lilt! soUf,i ~~,r.a"e" d) f()n7!t~t.io~ '~if~' 'MmplJ~ir,nd ~I?it'~, ,($ ,C'(Jli:g''lle,~U ,"J~\(d6i,ns' po i'd' as C; e). fi;'IFfnat,ion ,yra C,[~\ft~poun,(l'

'wUh Q!l1 J'M'(JJ~,g'rlj\e~~'~' mel'l/ra, ,IJoiJ~1' at p'

Copy rig hted m ateri al

a)

. ,

,P'w'

5

o

Ma'ss chan gle' c{lrli,esIPon:drung '®o ,n mo1i w,aJ~eli

- .

n'

,5~~~""'iiI

n-,

,

[11 ~- ' .......,Ii 1 1-· E!Ii.i.' --l

Or l!..,..........~~~~ __ ......... 10 L----~____.... ~_~ Or . -

r T

,ct IJlw ~i ,< Pw' ,< fJw':f'

. , ... . ... ~ ,

T

IFlu:g. s. Injfueli',r'{1 ojprft'SSfJ''re' {uul' ,t'(!n,ijjf'!l'l1fzr:r-e Oj~ ,tlltl tX)m}1 (J.sitj'(J'i II of tI~e ~ttlhl' ,pltlues jonneii bel:;vee.;~ copp~tt( II) suJf~l.~,rt rf~fjd' w~ter; C:tiSO'",· n ,f~{.;'O [29]. :Pb~s~ dJagr.a:m Qf' pr'~£~~fi~: "S. I~~m: perature, ,(1) sho'w~mig the eq,'~rui~jlbrituti, c{~m"eS !Of ~he: ~n~I'yW',~.ue I(Jir, ':- O]r. :nlOtU:lhydf,are.e. I(n = :1:]., tri,~ ilydm~e (J:~ ~ J ,~ ~~d pe~:lahyd~~'~e I[n =, ,S)., and lhe~j.ogta;~rW.etrLliJ;;: eurve 'olliItai,ned aitt d~f'$ie:~lmllt VamllJeS, of w~[ef' 'Vrilpor p;il[iljia'~ ,[-.e;s~ure (P'~IJ:: ,b) Ibeh]~' .P''!!.I.I:; c) between ,1'\. J and ,P''''\~2; d., 1","1

above P'w .. 2'

• ,At p!:rrtssut1es below ,P'w:,,~ . !only 'OJiJJt equlllbrium is possible, ma,~, between the pe.:ru;alhydmme: ,and, tt1le 8nllydrate,. The cotre ptlRdln,g curve repra ent.ing the WaJlt.elT' consent :"S a 'JIinlc~iO:III, of the tenlpetJT,a!mure detelm:h~Hlu~, 'by thenn.o,grav:~mletry~ is shown in. F:ig' .. 5'J1,; A, mass loss of 36.05'% cortes:pond'rn'ng to .5 mol :H:2[0 o ccurs,

• At pressures between ,/?'w.J :and ,P''W:c'l' the 'Ciorres:~:u:Hldii'ng- thermogra tmetric curve shown ~n FiB' .. ,j'~Jr~ :i,lf.I.vo:,'v,es the :ph~t e transformatiou :00:n1 'the peatahydnue to the monob.ydmle followed by' 'the lri~l'nsformadon 0' ~ the; monohydrate to '~be anhydntte with the ,con,espondi:mg mass loss of 2 8,~,8~ % ,and of 7 ,,2, :~, % re~~em:ill,g t •. the pen'tahydJ,aiI1e", A t ~h ~riph~ p' lot ,ali.

'h ~I 'il ~ b b, ~11'·1il.. .' ",~ 'il

t ';e pres~tiU~e ~Jeve,~ o~ .. P'w., w, , C':Ob~, equmarsa oceur SlWW.!t'l~U,e.QWI:Jy •.

.. At pressures lbO-Vie P'IJ_,2'-' the ther,m,ogra,'virnetr.,i.'c curve cerresponds to the: three successive ,morn.ovm'",iallt 'tran$fortnadol"iS'~ perl~ah.yd:m!te --+, tr~'h~ld:[,at,e ,~, monohydrate ,=-), an'h:ydr,at[e;, (F:ig .. 5,d) w.i:t'h. the m,8SS loss of l4.,4l~

~I 4 42 d~ 7 "'lI!'~ (Il a, 'I,

:1Il" ~;,.' ',., ano ',,' "'~ ]I,if ~ r-e;·· ,:pect~vleIY.

Copy rig hted m ateri al

-., "l: - '.n rphou '" S~: "- ate

..:ii! .. ,.Ji',1I! .-, ',_ 1 v.1 ,',' I v ~iJ! I' ,Pi, !~

The amorphous slate i ,,_ characterized 'by solidifi,Icatwon 'w:n a diso.rdered;,

r an d01m'" rna "t'Ii ner, -, tru ""'~'IIIi'I'a', ll 'V ,;' mi '[:I'l!IIIr~ 't"ln th IE!; 1- jq ui ""~ ~1i'~Oi;'i",P If ,!:i 'n'l!..l:f sieal IP, _,ro, ilnD,(',,,,

, f _~II, _ 'lUI ' !i!i Iii(! I!J,W """,, _, I!!;,,'~ llII.L I, _ _ '.1 ,,' ,1!l.U ,v I!. !I,.. !!I ,~II;.)!I, oJ! "~,,r;,;;.,. '- - ~ ,I(-U J ~,,,",,iIilII, ,,' I "It.""-'

ty of ,3. crystalline substance is plotted ,ag~j nst temperature ;1 sh a;ql dlsoond = n u:ity 'OCC urs at the me~ting point, For amorphou s substance ',- '_ there '~" no meltina; point, a:rnd ~, 'chl:n,~Ie of slope oceu ,~, at the. so-called glass n'an:sr~ti,oT1b ternperature ~g., The g:~_ass transition is, c lu'r-;lctlefiz~di 'by a change of' heat capacity, Below ~hffi<;·. ~emper,a-~~re~ the amorphous 'phase bas certain properties of a crystallin ,!till solid I,DI_ f.1' __ Pi ~ig, ,~·iIC,:." d' efo ,'r~nflI9i11i"i;l["il;m); and is, il::e-rmed '!'(F'1il!!C1,!I'--"!"',''i1''!' A> b ,'-o';i;Je. , I this

w . .J! .. (_, .... 1. "~ • \..if! "u '~II!'O~II~', ~,Q iiJIJ. w .. tL!J~~~I,"~V~~' _~~~~ ,~I&r __ •• ~ _~ _ _ ell~_~,a,J' I., " . "f.', t. l~.~

temperature, ~he substance retains some of the propertie _ of a, :~w"qllm]'id e. R", 1110 .. ~,'ecu~a.r mobility, and is termed 'rubbery'. Above this te;mper,attun~:- the increase in molecular mobility facilitate SIJO~l~llneOUSI crys~.aUill,tru,oWli :irru'LO the crystalline form, 'w'i.~jh an exothermic e'ntha~,:py change a,' ter the glass ~rl.nsi.tion, The use of amorphous forms is attractive, 'parth(;;llilar'~,Y for :s;parlngly 1[01, .. ub'~e compnunds 'because of 'the enbanced 'o~ ubii' i'~y and di ssohnion rate, olv[er ~he cry~tta.~~~~ne state leading to increased bioavailability However, '~he: amorphous state is thermodynamically unstable. The glass transition temperature, 'T''-'N' is lowered bv H~O or ot be w.' additi ves, ',',aciUtaring: conversion to ~Ile rub-

~ J ,__ _'

b " . f ·'~I·· '~I~I'H" ~O"]I 'M' iii 1 ,.Ji

ery state ,and, hence '_:'aC:I,dtaU,UQ' C:r'y'Sn3,~,wlzaU,oD .' _,' "I " ,: oreover, UIllGonK-o~~,e!J,

crystallization can occur' [it any time, and 1.:, accelerated by 'the presence of HiO", The effect of additives 011 ~: can 'be described Iby aJ, modified Gordoi.f;= Taylor equetion ,(Eqn,,, J) ~: here

1~. mix::: (leV' ~ Tit:~ -+ ,K . 'W-'1 ~.J I (Uf III -+ ,K '. lV',;)

(3)

(4)

A- 1- I ":-, -~_',,-"--'m""'JI above the It";--U" damental ,-'h',,: ,". ,',,', ._ ~ 'I" 'I· ,", I' ,',-, "'l", I,' I I, '

, nlenldOn!!;"lJIj, aJ: ,UV!i,.o;~I ' .: liil~ '.:.. ~_,= ,~'_~I~-a~ Pl __ Y.1CO=C!~lemluea ,p,I1'Ope,11 ,1e:!3, afl~

consequences ,of the underlying crystal structure, I'n contrast properties mod-

• iI'" _AI b . '~I ~I u I ":11 d- - .' f? - 11"·' AI • I~ '"

meo .. y ~~lwwrnn~ are :1i',e_£JlteUi to r-e_lucuomIS or crystal i:lint~1I' ;~u"u pamcte seze,

while properties m,odifi:ed b~y maniptru'~1,3ti,ng the crys tal habit are related W, the nature of the (a~)f's,~ai races thalt are expressed. Methods for characte izing poly morphs ,am-Thd solvates ha ve been recemly reviewed I 3 :~. ] '"

Copy rig hted m ateri al

50

D'1L1I .... n'M': 'A-'III"""lm'UTI;("'I' --'L '''A-' m' '!If"C!',. tl= .Ii11.iF\Ji\ .~ l '. "L1.E. . I !IJ-. '. ~I: l ··W.;;.dlllk).,~

'The me hi:ng point of a new organic subs tance is one iOf tbe flrst ~"iii()pe,r=·

,,"- ,--~ ~ -.- - ":1 A - ~ - b . f t . 'i"., . ~ , . '. . 'v ,·"iii 'iL'-1 . ,~ ._. '. ,- ...... ..;1':. r '. ,- '11'-'

nes meas ,ll],reu," ,n, num ", _ 'I ,0 tecnmque -, are a\~ alwalllJ', e, JJ rom, un m,t;U11.Ue .11lI:e .. [ ...

ing te ~tle capil ~,ary method described in dlC various pharmacopoela ., in. which the substance l~'" heeted and 'the' ",~ transition '~_" the llq uid p'IJ..-'J~ :li:.~ ,.r: ... b-

__ , , III ""'II ~ ;,., ,!;.o' OJOI!!.I!J .., I~~~~""" ~ ~!I!..'iY!'~V ~~ ~ ~ _~ !!lit ~J!_ti;l!l= _ ='I!.!'.tlt_ . . . = _ ~ U. I ~ _ "'" Ill, 'Y'

,

--~ td _": -",'I'-I - 'il ' h iii' ~'j]i .. ".... "U--If- -~ -~, B'·'- - ,J'-:If""i~lijl -- 1-[ ,dl' 'd

serve'c v ~.SUd. ",'"1 or _ 'y r .'DII,C~=:' lIla~!e :mlCJrO,OOp'),," ,n..,Ur;U\I)e' I~,,= I·"f irU~{~S~,'1.,I:,lll~ r ' .. LlI,(wlfJ' " .

'h- '~I- '. b h · f' d ."~ d" ·th: '. --. .-, '. '~- .' '. th

1Ii'~ I~ m- ~ ~'fi'l- iffIl {F :~ :',R.V:"rNim'· ,0,: I :m"an(U ...• ro- - H ... ·· C, lime :u' '~I'D'D '. I~l- f- . 'I ilil'e~., :,11'1- C :m'::, t~1 n'!lli' WI "

I~. h.r "'"' ~!!l ~'~~ 'boo. _ ~v ~ ~" . ._ ~ " _ ~ ~ ~ ~_ L ~~ . "'" . ~I~ _ ,!!l~ ~ _~ ,L ~~, _ ~.

several reference '~b-~anoes. 'for ilidellti'6cmtion. plllrpose~ r:',~].. If 'Ill:~ion 'i,~:

ri".o'!it_~ ""'r· !iI!.;;.'~loiZi' the eauilibrlum ::, 'm" ...... '-'lIioJl"il. ';!5l't"t.-Jli,fl'" (,0 ,£Ii' 'C' = 'II I 'i!ril'iffiI,.;g1 the QnfL'I!..~,11'i0iiy

I!!, ~!t.'~ '_' "I,lll.;J'~~~ ",,_ "'" ''''-''''tI!I;,I H~ p~. 11_ _ ~ _ L, ."I!;,J!h.V!lilU II i!i!!!J U, ~" ~"'" .r"'" ,~, ... 'l! ~!JII-'UI I~~III_ '~lJI!! _'U~~.~,

h . fusi (~ lv ed . ih 1 -, - ~~ ., 'f' f~ " )"

,- .'. .~. , •. I ,,". ",,' _. ... ... • '. , '. ... " .' .' " .•.. ,', '." '11. .. . : ..", [' I I ",I I' " ", ,. 'il 'I f ,- • • "

cnange aoco.mpanY,tfl.,1 ruston .. ' _,or.m,er.J termee t te atent ,_ teat o~ JJlS10~1. ts

posillJive~, because fusion 1-, endothermic. PO' .ion can be l~iOCO'- 'p\anied b~y' dissociation or' by- decomnosltioa. The vae ':F' 'plre,~iUlf~f H"'iO 'liJl~b . ~ ~Ui:i: :~'mfinr-·

.~' r ,. .iI!.., ,1;' [ y.

- - - - ~ -

. .-~ .' -'-h d-' ". · f 'h d - 1-3'3] D'-"f-f-' .-" t .' ~.,

I,ll' . _. I •• J ,- .-' I' -, I . .,.... ~,-". . . '. I " ,,' .. _', I I" . ,". '", i' -I' '"j']""" , ," ',--' - r., '-.' IIJ' " ,"", __ . '.'

UU1~ ro e tn tne 1.:._l,s,soculJhon 0. ,_~y.c_nles -·!.-~".,I ".lelienUa_CaJUli~nt', cmonm-

etry (D!S, .. ) ,aUOiWS the iChall1,ge of enthal:py doting: melting ~,O be followed and the; thermal processes hnrviolved to, 'be de:t,erm1dned Ill, uandtati'vl(;dy. Because

- !~"'-,.,._.,O'.' -.AI ,,:"]'l"11 involve the ·~:\f~·:II'-r-I"·-~-i-' "",th,·-.·~l· -t'II-~ '-~'I~.11It""·--,p ,-::-:.-",',--,~. ,".:, .~.-

processmg amy nu " mg .tIl_ Ow. _ e . ae e_ osu 10.111 or . ea,!., . ne lIL.JJIcDo' l~O,~Iil~, 1 .an

" .- .-. -." - 'L. 'I ,. f~ . 'I 'II - . ..-11 "~I -- A';II" _.dI b . U

:~·m.p' _1!1_':n.~ properF.y in tne lei torce or ~,'!Ie san ca'1IJ!l"d.'lw~.me" .' .,,'; ul'_ cussen :i:y : teus

[2] '" the counter- woOn plays a dominant role ln determjDi[ii~ '~he 'me. ting 'p~ ·'~nt. of the salt, for' exanlplle~nla.i·~ counrer-ioes such as .;·'hlo,:rid.e iO':_reas.~· 'the~

,,_._ ... ],j,"'_.,., ...... ' .. ~. b ... --"., .... - ofthei 1-'-':' - ,,-';h-'_-,-,,·,,-, . .-:I- ... -,~,"'f-,: T't.·~-" l_m'~'·'iIi·:··- - ,i, ,·'U,,_

me ,",~.ng, pO~.lh!, . ecause 0, rnen . arge c arge censny, . ms . umanon ,~, mus-

t niJted 'by various sillts formed. by a, basic chemical e,~ltjily 'Of melting point 98 (j'e: ru:he melti lIl,g p()rn Il1i~S ;~ulld enthalpies of the cr,ysta Ublle salts are :~b~~,ed ~n l(Jbi.e 1 [41]"

MI~ltJj'IlIG "hit [CC]

,00 ~ ~ I

3,

Sal~: tfo,rrm

2S~1

Copy rig hted m ateri al

'The process o:f dissohnicn in rolves the breaking of '''~'n'~,ed,oniC' an.dllo,F' intermolecular interactions in the so,nd solute, the separation o:~; the so'l,vent

~ ~

molecules from leach O~~iU!!F' to provide s,P ace for the :soh~1i~e, and the formation

"f-" ]~ nter ';Fio't~ on il:" between 'I'!J,. e 0]"' enr 'm ol e ... n:i ''' ;]I riI1i ,..-1 ,j;;L;Ci; n~ ute 'n'~a,;(!ionl]I;!.'II ~ or

. i, ,1.1,[1" ",IJkr.r.IIU ~~dW,[.·. ll:ll~i:l!J U·' .,1f.l! I ....... '!.P. :l, !lJJ,~l.· ':,'J,. "" •. :.. i~ ,j';, }Ul ,,' ~u.l <- lu_~,~lU, u I-I!. ["vll,"~ l ;0.t,~j~~IU ~.~ 'yl[;"

ions, The intermolecular bonding forces in so'~~d, include 'Va" der \faals' forees, 'H -bonds, ,and, ion ic interactions. \.t,n de r 'Wa~t;lx :~, 'lf~es, include dip, ';~I~~(n-, pole forces, d'ilJole~,~'ndllJcied dipol e force .. ·,~ Ind induced. d:pole .. ,i nduced ([pu:~e~ Jorces Ii, e. ~ London d:~ sper ton forces), :H:,= B,onding is the 111l0n di ~l!ctiol1U:a~ ol:f the m,n~erm:o:l:ej'_ular interactions, The ,po,:buri~y 0':( ~ molecule can be expressed In terms of its dipole moment, In general, the '~ollWb"Hty of a substance ill H20! increases with increa ~ :in,g dipole mc):mel1rt:t other file tors, suc:h as melting: poim, beJng e-qu,al :~:'f the solute 11n. ,8 ,:-olu:ti,orn,)on:,ls;~~s olf molecules whh, ;3 :,~,mai~ ~I Of zero dlp . le mO':fil .rnl~-" 'ru'~ 'ru s :said to, 'be: nonpolar ;Ind '~he' irn:teF,lct~lon between solute and solvent is dominated by dj,po:~e .. j[1d:l!:u:ed d.w:po:~e forces and Londo» disper .ion forces .'

In the c ase ,o:f a salt, ~he anractive force, ,F" between oppositely charged particles or i,'on~, is, expressed by CO'~"i,on:lh"'$ Iaw:

where ,(:}'+ and €l- represent the electric charges Oilil. the particles or ion '~ d is the distance between '~'he:ln and ,DI :is 'the' dielectric c'OnsJtan~, of 'the :s,tuJ'Ound,i'ng medi um with re spect t .• 'v,a~c~.n'w'm '} 'f '\1im:cil D :=: l.

The ion-dipole :rum:te:ractio:n, is the force ~hut dominates 'the dissolution 0.:[ salts in 110~,aI~ solvents, In aqueous solution. 'the ions are surrO~onded by (,tt'." hydrated by) as many :H:2,O molecules as possible, The ,a_m,OUD~, . f H20 o.:f crystallizatien affect , 'n'be heat of ~ol,utiIOlll. In ,3, ,cry~~al :h:ydnl'te, , '~be ion~" are already :~~Fglely :bydr,a;led, in the crys tal ,11:a;U;ice and, oon',eqJlue~fl~Jy,!, the ion-dipole mreraetion energy llberaeed on dis solution is con iclc{[,altdy less t~la~m, 'thaJt of the anhydrous .A);~U~,e d:UI.ring: the dig~·, luUo:n precess. More considerations o!f so] ulbni~)? are disc III sed in Chapt. 2.

In rhe case of ,3; sol~d salt, for which the sto~,'c~lic!:m,eti)l '~,S represented lby ,~~,,,tiB,u~ d-is.solut~on rnay be accompanied by disscciatinn of ~~le ions, w'biclh, causes 'the 'ions ro separate; thus:

The ,app,!al~enl[, concentration-based, s6~u:biU:[,y p,('()duc'n K ~ ls given by:

K = [A lpn [B]"

, , '~" '11 ~

" 6)

If h b f' dAI d . h 1 b·'~'· f II nl'·":1 A f,';" ",1 1·'·

in t , e a senee 10:: ,3', ,ue, ions, t :J:! :',10, [WI ~hlly «(' the ,O,thJH~' uennea 3:, t te some

1 . , · , '11 b f' ~ f 'I ' "', ~ 'I]' " ~ ~ ~ f ~ ~ b ., ~ ~ d'" ~ ~ ~ ~ d

",' . " " "", _' '}.,' ," ',',' ,',' ,"" " ,"',", ,--,", ' , --', ","--'- --', , " ,', v "

11'10 al ty, ~. ie" 'el u e 11I.IJUl ,'e,[ 0., U]JO es 0 , e eetron ~,1C c arge '", 0 .eac ,~,OD rsso ,: ,e,· ,

Copy rig hted m ateri al

~, ..J-

'per unit volume oif solution is:

C' :' l1'l[ A]I :: n1:I[B,]1 ::::: I( K s) 111/hlfJ-i!-U ' .' In!~'/I "11 i-n .' nml{,rl.~+.!'I)

{7)

:If dis: Ol~ ution 0 c eurs 'W ~thou't diss oc.htdou" ,t'he SOI:~,u,bi1i:'ty, le.,~ is d,~,[lect~,y given

bv t'h- eo I, cncentratien 0;" the ~~'f!lil'd' issociated :,1\10(;;i,,', iii'~'rii'I''I'~

J" ~w !Ir-" I J ~~r11 '-: 1. ~l J I Iii, .' ~: I ,~I~·.~.lj oil V~l ~l~' ',r..~. ~ ,[~Il~l~'~'

(:8)

The I~h~ ngei ~ III tlhe energy of' the interactiens as a ri olete di" elves i manife "ted as ~he' enthalpy of ,"olrmtruon, '~,','" HSfj~ wru lie the ',' tandard free eueq;y change, , :,0 0 ~ Is related to the solublllty c.:

I~ I{" ] - K' AU,' R" I...,,' dl " S:= ,iI1Ii. ",0 - ,l..:U:"l sui.' ,:, ,:I.

(:11.0)

or

The ~o~[I:b'i~mty of polymerphs is related to 'nhelr tJle.r.mod,yna-mw.c ,acUvi~y, to the escaping tendency .of 'nhe:ilT" molecu ~,Ies,~, and hence to ,the:ii'r melring point, For :n.bo'O,av:in. [2] a, Un~-ar relatlon was found be~''"''t\en '(be' '~,(),g, of the solubllities ,and, the ~imeJdng' points, of ~he thlre-e polymorphic :-OMt"\, The theMlod.ynznn.w_~any sUlbl.le torm at a given t:emper,a~ure and pressure is the form w:rn"tb the lowest 'free ,e:neJlgy ,and, '~he. poorest: so;lu'bUity~

: -o~·' each pO~:~tmo':rp'h., we may ,appl~y 'the V.a:~]i Jt ,Hoff '~q,;i~., J'O 1]01 ·the. r01', n:

] Il.~" H=: I R-;- 'T

,'I,ll .......,.,_ -; .: I,ll!!'

,mes, - '_:, ::sol,' + C

(II)

Copy rig hted m ateri al

CS"

Ei1iIeU'ltllt1~ro"iV

rF'IJli

.,.-

------~' ...

'T

,Frng. 6. ,P,',:(j'l.s of r(jlu'bilft:)~ ;C ~ ~8", l'empe.rll\l:u:wtl T '. olubil~rn~y curves) Jot' t~!(mt,itU'Mp:il ., af.~(l tit{ ;i:c),fIVP'iC S)'J8,~'fMfU

T'

F:~g. ". S(),I'fi~bUil'jl' (l,n'leS ,ryl.\1(.Pjf~te'S~ eNe,mp'lifl~d by t~'f;' dilt:ydfot'e~, t'e'~'r!'h:ldrot'e ,~niJ 1!.e:X(Jh)'~ drc(;u,e' tJ,f ,CQ~'c,ii'~'~ d~ll:tJJriclJ'

lations~hi'p between the polymorphs of anhydrous :f~llll'ms ,Ind, even for ,~()!~: ates or :h'ydra:te.~ [3.3]~

'Wb,e;n compari ng the ~o:~,lJ.'bj I hies of ~:aJ.tSI~ the imlP~ct of' :POl:y:rM.orpbisul has

'iifn L.;iJIi taken '~"l'iIit'_ ·a ..... \If"\if1I;'I"1 n't- ,;;)i,C' for nonele ..... 't''il'if1I;~''!jJI jr,;fI!,C!' D' issolved , po' ri'Ii ..... .t:!ii'ffiili,r~,i"~;_'i"i; ""

1Ii.'0' 1!JJ!I;"o' _~' ,", ,I,ll, JII.I:U.V ,,,,;,~uU,W.1JIIl. it~" ,[ VI , !1:II0.'I, '.a!!!i.A.,.-l.llu.lI,,;" ~w,. "w~~v,~,'" '!Wi -, I~.ulll;,.l!l;"oin'l., _Uiur.Lclii'i1

shiould, 'be :mileasured as a, function of time 'w:heo detenmning the ~o,~,'l1d~i I i.'ty of the diffeFleru forms because transfonuation during ~he measurement Iua,y ocIcur. FtUinhermore;~ for proper interpretation of the results of ,: o:~,ub~U,'ty measuremenss ~he tem;'~mh.lf<e has, '~IO be mmfIJ~adned. ioomV~MU and accuratelv deft -ed.,

- -" . - - ,It'''''' -- - - - -~-- - - ~ - ~~~-- ~~--- ~~- -- - ~_5 n_ --- - __ nt __ =y .. m~ -

Copy rig hted m ateri al

54

·s· .·.'1', bilitv ., 'b '. ... . ... ,",. "d:' 'Ilk "'h" ' .. ' -'AI, 'ik:"'i"·it· . 111, ," "'11.",,, . ."

.... oiueun Y can .• e measure . IU'Y p. ase SO,w.Lihwr.ld,Y a)lla~"ys~"j; .... nere ,a:Jn excess

Oi~~ 'nhe' solid remains in ~QuiUb.rium \~I.~th the 51it1Jr,,~e.d 50~'u'tiotm [34 - ,],1']., Tihf; '·o~ U~:h:Hll is ana~,yzed by g;ria'Virne:Rry~1 high :per£olim,~lfJe liquid ch:Fo:r]l!a'~,oglGa,phy (HP',' •... ), 0(1" ':peckO,:coiP'Y~ Higl1 thrujJ,gn,put ];11f;/[bod'$ of' ':olruib!.iUty determinad,on ,ha,ve; been de.'v'el,oped based (l'1l t:lie :mea' U:liem:eIl1E of '&11 ~ ,Ippe.aac_ lof ,lth~

'I~...iIi ,L,· iLl ~'I!.., .. ], ...... ', ·1' .,'.' 'to. ,'1'-" " .. , .. ] " .. '". '.- '1:.. ... ' .... '-. [3"'S"] [3'f····] ~-"

:. Oilly, ,p~ w:OO if!; lIIJy nepne !ome~ry or 0)' IlLtfl vl.'o~e1. '. pecK()puo~,m~ltry :~. '",'. ". ~ =0

I.~ I :$ol.ubn~,m:y dete,ll'mjfii,ado(f1ls~ soluble i,mprtuide--s; can ~'d,,;nifL_-ant~,'y mnfiuemce

,t'....·· "" I ·.~I, .~, b ,·"m'~'iii'. '. _.., .'.- .. ', "1 ' ,~... ,jj'L.·. . ',., " .. ifl" " ,. ,!',~ " .:11 ,-' ... ' ~',- 'ii' .-'. . I· Ii" 1 .

,.U1C mea;S,l!llrel!J, . OdJI,),h rn,,,y,. ,~'O:f exmm,p, e, Ul ~w.~e case or ,8,1 .PI]e-',pOIJ1i,!! ,meu,I:R.,..

'm ali il'ril Ii' on 'i'lio ~1'1 ilnllllirr g,iii<~ ~irg'jjj:!ii....ill oh ~1"';;Oiii'!i1 ~ ,Jr I'r·t.. iiJj; ii"a:m ;o;Ji1ii+~ 'NIl-a, ;o;Jid.--n/III'II!l'iM' Il"iif" ;]i,..iI"""'1 III ' '1,~'1k Jhlii .. ii'ii, ..... ao. ''';, l"",ll,1II '", .' ~ '. 'IIU,~""", " t.II:J~'llII • 'QIl.I!.;illll ')v 1!l,lII'l,w,. u 'I J.,~, _,~:I}~ ii, ~w,Q~'.I.'Mi,~ ,~~.!I.!I,y Q, . I!!,;, ~I ~ UI !I!;I,,~ ,,:,,~,!I!) 'l;~;l~!I;#

of 9:8,% Pl1FUy i s 20 mgl:m[ 1111. 'tbe suspension, O~,4 mg: IQf the imvudty may be dW,ssol~'Ved.., If 'the 'olubru Uly (if 't~le dro,1 substane e ~>, I ~O mg!m],. ,DO ,opplUlefllt

'''i "1' - ,I'be-,·' 11'·1i\'~: aq-". '~I 'hi'.'j 'I~ 0'" ,dib, o· '.;11, '=' 'II .Ii, '-m'~ ,--:- "'-m'~ '~'"' -! '!I'~ be ~o' 'i ii! 'iffii ,..11 '1' l-,~'~'m - ~~. "'f--:' ,jflil-.';;:i;!;, '-jiI"j.'I,-, _,

,$ 0 U m,lI,b,Y 1I;;;i~. II!l ~,~ t,~ ,II, ~' .. "'i!P :._. "~ ,_, ,it ","'t '~ ~,g~" !I. ,"f~J!! I, , .. "-,, il'" '!.I!!JlII!Ui;;;, !!II.V~,~l!;r.;f· -iii· ~, 11j.~,h •• • 'uIlJU,

bilitv t ilif."h,1 ..ii" 'I "I' JII;,.,,':.'~;" ' ;" 101 '!!:;:;, """,1::'~1 'it'L,,' :'1:11"" . ,m ,111..,.'~1..'''', ". ·'!I'~I b "

.' hhy ~b l, ,f; uJu,g SUIDJ '''lance 1 ' ..•. J! ,m.5'n',~, ~ue Ipparejll,~,O,~,ll1llUb ,I)' W1Lu _ e

O iC: n 4 n 9 a,1 '~I T'!;. ., ",II'" • '1110, • ,0"1;.. ~ '" II,;" I&.,'~ f' 1Il.., ,..!I"'

.,,3 ,of, y," =: us I mgrnu, ',IdS ,ulSCLlSS:lo.n ~~wlgt~~lgll,~,g, 'ttw~we resevance Oi~' ,tne conu:w,-

tions used. b~f comparing Slolu'biHlt~jes," ,Fig's., 81fld 91 emphasiae the in:flhlenee of boih impurltles and. PQ:~Y'morpm';m [,3.5;],.

In the car e of salts, 'the: :~eII!tj.o:[aJ'111p: are more CJlJmp:~,1ex. because a san may

'k', .' I -[,·'11' ..41,·, ' '" ,., .,t,' d Dr,!, ,- - .. ,-,., '., -.:- 't,'I~' - ; -'II ' Ib"~'"It, 1 ' ,., '. b' ,«- " ·t!Ll;;.,., '." ·'·bl·"m

ee ~WIi ,~,a_ y 'UI) IlfgC]a~~ '. ::y me "W!.fll'llg L ae SiOJlU ,llll~,y m mn .. lIl.i' "!I me P05S1,h:=

- - .- r

hy '0 tbe~~ddng-ou'n effect I.,ond. less :freqlll~!l1d,:y~ the -saJt~.mlg=:i'lil effect) mU8'n

'11 b ... 1 .. ;" A, - ..41 'lq" 1 ' 1, , ba ',-. '~'" . "d' '11-'111;"" .'., 'H' . ..lI. .'.. 'f"

au 0 . e consiaerec. C"ur POlY ~'3JS~ or po~"yac., •• s, Il,nere are ,P, aomams o·

, . 'ii·g,LI~i m ~'ity' 'f' 0' .p P''J!Ij,(!l.'l11l "n;9!;t""il.iE!i.lII! '~I,tiliA it.'lfl,S 'P~ 'R' .,n~ nlbi~I'~ ~'Iii-'V 'nm" . 'fl' ~ ~ D~ it:!lbRIl1 ~d' 'L.,;j!!i;, 'm" iIt!Ii,g, .~ ~'iia,.J1

", ,Itoui!tj III ~ ~.!I,".: ·..'tt I"-~_I!W~, I'; !,~·'fi.jr~,1J~~1 '''.Lllll,U 'U,II~ ,:.' .. :'_', U~.IU ,lIL~-lI.!~J.' ,r ._:', .. lII.11I~a, ~~l~,VI~ll' '. _J i~~ __ , ~~~. '~.~ ~YIl,~

The p,H: :pro'fi~,e o,f I, base or 1.0. acid may 'be ca~,lcublted, om, ttl basis o:f tbe

,;tj;~

l~~l -

~ II- Ii :1 t i
10 :201 ,40 eo BO '1'00' 1:20 1,40 lTam'l co n,oe(n'b~arUon X' 1m s ubsltanoo: ~id dad I(m,g~!gl :soi~yeiniO

,F~ig. ': '. Phl!'se s..ol.~lJ;iJ:i:')~ Q~'Q,tJ~;d~J of 7m(1~.II:ydroxyp\ml,')"I.')r~jJt,o,,~y/Jr'~ -, ,iN AcO'El" ~dl:o~vi~il!' ~h' i,~.fl'r,j 'l1jlt"e' 'rI' i,.mp~':r~t.{lls in ,rJ~c',~as~,w sh' tfJ1.(Jt ;r,~lu&ilif}l: mDC:iU~ili~g ~.,'ll!lri~y ~"Omllmi. 'D:f .~ fl~~ s;[lmp;I~;..'i' used i~1 'the ,SlttldJ:r ru:s lnd~~a~d h,:Y' i~e jn~[\e~swlll_:g ,g,~:,' illte;1l ~~:y of tlite d:3m:tI, :pO~lm1Iitiiil. Be= hJI!I,' s~'Ium~jo~. rulli:tr~ ~i!i!ta :poirU8, rule en ~iilfll;~ J' ~:,N ~lftCdic3Ili[niIlg OGm,h~te~ dl~_S1ijh,llli:iiO'~, o€' t]~~ ~!lliD.;P~~ ~ddJe·d l~iO the SOillV!eloi. ([I~wn :Fm. ~35].1.

Copy rig hted m ateri al

·6

14

'13 : '

Ii _J i -- I, i .a --
0 20 4n so ,BID 1 00 '11 201 ~,40
. ,', ', ...... A,g. '9',. Plusse ~-OhiIJi:"it:y a.ita(}lsis;> ,rmnsjorm,(lti{in 0/ {lil',igll·'J' s(J{,,~-IJle ili"'~} ta' less .foluf"e.f~"n "ie~, pt!J1d:il~g m~ fhe' tim,(! ,aJww(!'dfol" eCju~'~'iuJ!'{diOJ1 . .6.: 20 h~ D: ti-3 ~I~ 0; ~~.:5 h (redn~'l1 iIC. r,3Sn.

, I •• ~ 1 ik' m ~ (tn,., 'II 'b"I' II:! h d ~ "''':1 '\ ":11 b

_,:c_nOVln mtnnsrc :SOJJlu'hUy ,~~~e 8o,ljul I'll' O'~- tne unc_U~sOCla,~etJ, species) athJJ the

, 'K-' C····· ',e,;, C:-·-'~'·' !ii' I"~ ,~.,.,..:I; 2'''Jj [3-'0'] [':1'9'] '8'" ,~~. ---I'" ·-·.-f·, .~. -.: .~.'I:~l-, ';'-~'f; 'odueed '-l-~,,,--·---,·,-"I!'

"I ~ se~' :t1.QP!l1;" .' ~IU;h • .I: ~,)l,_ 0',.;1 .' .• ' .- y lillJ,~~,tl!i Q e- ~j~~"uy ,~!ll,~nc i!;;J.~ ,C~~, ~,I)I!Yom~-h-

ed, dtra'don methods, the :pH profile 0" the so~ubnity can 'be: obtained ,qu~tle

f:3J;.t·, t'~(;ri,lj; C,·. }~'"?:p',l" 2)" TI'1~ 'n'H'" dom ains o-f "',f9~ir i:~v. m entioned above ,Y'~' ,Al'i ~ ;~i,"_

-- I~~¥~ r.1~'1~;~ __ ~ "_ ~!J ~~~ ,r'= Yv - ~_l _ = ~ _ _1IW1_. -~~J' ~ J~, ~I~. _U~j.~~U gUU _ 'Ijpr~l UJlJ.IIJr.r y __ ~

- -.' 'to, .'. - H' 10······ ,.' , '~- , ~,,- -L '~i ~ ",')I -, ... (1: '. "", "...[1 -, 't.. -~ ,~.''- 'ie'~,., :11 ,t"': - I ,I, -Ii' ~. - - "

en _ In _, -2.' ..... or 1.0 '¥a,~er iF, ,~rnJqIU~u rille c u.~, Ilk't!Jl, ,8,: puar,m,ace U l,~,lca-1 1 or,m,tl_ !I'orn,on _ "

as 'W~:t11 as :~'-n the _~;~'\rl~ntl(:S of cryst ... .'II'~i··."~I~"i,jft;;1rl a'S ,d·~"&;~'e;,", b ..... ·. 't'~~ ·pl'iIl..l~il'~' ,d· ia .g·_:iF'\'liI'-m··',

~ __ ~ __ $ __ 'We~ ~"'"'" v_ 'i".o . '!!.I'_ _ I!l,~__ ~!~~v_Jl", lI;;i.it~!nlliOOl!I. ,"-_u", ~_rulg!!l "'"" .,~ lU,iI. ,

:'. ••• I,'.

of e~'!!I!·c· ,Ii,. i[liIf'IIe·c· ,"',jOiJ " with t-:1h[;Pi; I!:1·O,··,'II'\!!';;:Ji;Hlit· He'I"!I?' ,aa''TIiI'~''1il uolvmerohis ilf-"Ifli, 91'1'lIl..:l 'p:' end ,niiil!lif"ill~I,'!lJ!"~,

.' I _" . at' ~ ~ ~r"': ",'1iP '_ - ~. Hil . ~.L~ .;]! .. W ._ I~~I Wi".;. . I·":.t Y .. b.R iiI I j~ I~U~,J' l!l .i!V~ r~ ~.~ . J~ ~ W 'UL ~IIJJ, , .. :_'.'~.:... UruJIJ

,- --, . - b,,' ,--~- , -,t '11 ,. Ib. - ,t ok' , . "' .-., -., '1' ,t G"'-1'1 ,ttl!" -I~ 1I!..·'~I·',-, • 'M' 1-0',--·

muorf,pnl,.m mU~Sb adiO iJ ' ,;,ae,[l ru.'n~o 3;CiOO un.; , , iene.r,{b"y~, ,Lne SOdh.:d.wny];]) "-2:

co , ., h 't d h drat h d'- ] - d fr - b -- -

,t- .: '~,.'j- ·~r.'.j I '( 'I [ L :. ": i I' ·.·.1:1 -("'_": ", (_.: ~.[.-' "J'.'" ,," '," ['::.: I.,' .:' IV~ 'L"~":' ••.. <' -.- ~ .'~I" ,': J I'~

U. crease 111~, e ran. or .er: Y rate <: an . y .rame <: O. _ ~U0 , rerm, , .. ua excep

tions exist, especially wben the trnil1'-iHon, temperature U,es below the iar.l1b:ie,n~ temeerat lliii'\Qi; 'If'ffi organl ro '-mBA,;; n ;ij {J' ;;~, Q1 coh 01' l'lii L"~rdlF-'lil:i',;l!id ,iW 'RD' " i;[' Uil:"Iii1iII'!!!ii'm ~'I rlJ,l. ,; :~,~,~l~,~._._,_ W,I~~ m .:~ '_ .s .'g_,_.~I~-1 _. I~U,~I~I-" e.g.. ~,~~ IU,--,~V.! '~; " .":"'1 ;U ~w~,',., '~-U.'L.~'" JP. _ [I ~~ .'~~IYJU.JJj~,;,

- -- . - 'iiI- ibl . th _. 'ii!'1i!... - Iil.-..r- ,,..1 - ,. - f':' - .~.. 'F' - -- - Ail - ~- - ;'1 ~... ,[" - - - '. - ~ ~ .. 'I']!.. -- - iii",

more ~ Ow Uv, e tnan ~~ ~iean~ ~yu.ro UlS rorm, ,~- or neoocrorm ~ magnesium, Ui[:.. r£UJl~

order 0:[ the p~" en~_alh.'flrdra.te~, the heir1mlb~tdrllte~ ,and the decahvdrate was not ex-

l_, .s ,fr' lJ J

acdy the same tor ~he SO,:hlfbU:ity and 'w n~ri'n sie di ssetution ra~e (JD'l~) [4·0]. b. '.~

cause ~he metastable Il~g'her h.ydrates 'transform, 'to ~he' stable pennah~ drate

d- ~ sri m '0" If"'\(J~ nta of'" III' with 'H 0- ,;; llii the "0- 'l~'~I'b' . ~ ~ i: IIi'V 11-'f(1'.m; a' if"IIUI'I~'m~ ~ ent

'~ __ -~!Ci IV • i!!,~ J _' ...... I~,·: :_." I, , "]i,--- '-- !II "I, . 1.1i!!;;,.! '. J.'. 11j,J!J[. -!~ hl~'J" u' ,";:": oJ;!O-l!JlI..... !!;.o, ,~L .. -r

- - -

T,lile dis :si~lMd.r;.n 'r3J"~'~ 0 .. ' -,'fl·' powders ;1' "~" 'O--.:Iif:'.'.n,lflIl moo s ~,Q '~]'llii¥-lA, bv t h: f!J; ,nln'w': -th .. ,nn (iIf'L,

_ ~ - -_ ~ ~ v __ . ~ _ v _ ~ __ ~I~¥ 1~ ~ " - - ~ -iJ! 11 ,W, LN;~ ~ . ~ ~I ~1II1!\nl!I)J ,J' . ~ l~ ,~v w _I;U ~1~o~,1

,e'en, :lmle~h.OOI as described in ,C:/1)QP,t .. 2" When comparing ditferent sa1ti UJ~S

Copy rig hted m ateri al

a

.... _._ .,_._. __ . _._. _'-" ~ _. - ._,. -. b

40

[Iii ._ ;>

20

40

an 10'0 ~20 '1140 1Sn 18'11

· - -;:i!i,~,IiJ...n..:1 Ii.. ~,oil th A AI·'I ~ iCi A """"!jj'm.'t.']i, Oe th .:II,~, the dis il:" ol nlt;l~iii'Ii rate ",llpon£i·ii'Ii ~I Oilt'i, ~,iL..o, 'n'!5'ii'"ii'~ .... le m~!I!.~ w~u ~.~~ _".'11,;..0 'l,III ,~U'U ~~ul.""u6.~' ~-li l,t"I~, It . ,'Ii." Il,III .. :.Ji'ili'Q, .'Il.IIIUvlllll ," ... ~ U~"","~.',lIIF' . '_ 11111 I~!I ~~ ,IIY-- 'lciIl.lro,;. .. ' '

,. .. ·0···· .-.~ .-.iIi.... '6 " .....lI ·~.'h~' _...iI .. , A ' ~., . it,""II:' -A·t':·. . 0""1' - .,r-- .• t, .. -- --1

~~ ize, ' .'. n tne otnei nana, tr rns eepenaency I s unuzea ~Ol ;(1 ,~.I, ~,~ 'n rorm to e'. ai-

1iI~IF'M:'i1"iIo 1'rE...R. fI'!i:f~;i'!i"-;'rIi' of lin'I!li"fi"~ cle if"~'!'J'--' .i!liJ,~ .,,1 ~-m··"i·j;;m,,(,.iii"r!'[ii'[-~d ~ifti' 17' '-" •.. -, ,~.I'Ii '[ill-] A-" - for 'if'!;;~Iii~'

'l.l!I,all!J!1Q !!J,~'~"", .... _ ~ iI;;;;]!i;;rI~ ' .. .Ii r~l-~ ,.II!i,.,.o~1I;iO i,;iI ~ .... .::.. 'j .!:i"'-'" YI"",~ L _,'!lJI'.~ l,o;I!l!W_, ~L'!I;;+':___ b!l!. .. 1~8.. .~' I;)' _ 9'. ~., .~ __:''' .Ii'y'", ' !Y"I!.l!I-'

'L,' ~1:·~, " - -" . - _' - -j -, .~ ". ~'bc. <H' of C-i:"~"'" '-~~-;"~----,1Ii .ru.;'-:-,"':il !lib. -, e~~·~1Ii·il'i;. I~'~ '. ~,t· of ,,,'h- ',j!ii; b C'-'~j!ii; =

!L~ ~ ~ 11~,:y mel,.u renl ~In'~S., l!l,u.e iP= . o. nlel ~Hjlfi!i,.,.omell1!!l, ilIlnU ,~ue ~~u ","".Ii..l.'e-c~. v !._ ,,..,..!lJ.I! . .I,",,,f

ha ve to 'be taken 'hl~-O consideration.

T:I:· It·· . :··f!'.·l"--- ':1"'11' . of :,' -I :~. --h··.'_:,...;i! -':;' :--- ;t;.c,- -_cc int .. :- :-,. I ..... c".d·-:'~,,-.,;il .t;.~,- _-~.-·;al .~b,- .

. . ne ranst orma .~ on o ,an an "y orou S; rorm U1 ,10 a U.yl, ~r~,lt7u rorm ,ali1u. rne

I.'·~ ~. .f.', - '. .'''.'''' -' . 'f" ... 11.0, ,', .,', .'- the .,t': .. ,... Ib. - '. '. .,. .,.' Am. .' -', - c-'Ib.-- ~V ·d· F'~ }. 'i'

.. ran : tormanon 0 a, ·UJ.~ mto te rrec ease or acia IS -0. ~en OIlJP" erx Itt .." ·'8 i ,

· ~ r-'I b- d- d-" ,c1" ., h ft-'" ,. d~

~IC' · .. ·-[ __ 1.:· ,-. ,," 1',-,,- ,.~ ~.~ --- ..... -·~I-···'~I'~·I·.·'-- - !""Sa[ -~ 11.-;-. '7'L I ,.,; 113i ,-~.~~ ...• ~-. -,--

~I,.~ ·(tn eX:H mp e o t ne 0 ,', sesve , I. 1550. ,~t-~o.n rates 1m, L te case 0, tJ .an S·.IIHOft I ! ·ur,.·

· ~ f' ,t '"

mg 'hle 'co urse 0 t~le experunent:

l: The anhydrous :form dissolves 'W·~.d-lO'Ut change;

J:I':: the ,amlhydr.o'Us;. :foJrmw transforms into ,3 h:ydl~;t'~e.,:,

Ilt: W lit.- ~ mtaneeus change of ·the anhydrous form into the hyd:~a~e and dissomutio:n of the '~e S ; soluble 11,ydt,u:te ..

The difference, b, between the curves II and III results from the concurrence of the di .,··ol[IJt~lolr'Ii process and the MlUl·.·form!3ltiO.1i11 process.

Fie. .12' deals 'w~.nh a, drug substance ~.itb, :poly.morphi~~ Ibe:h a.v lor [.4· :~. ] '. The (US~ olution :r.a~e of two samples 0:( the drug: substance. lie.pr--e~:ernthlg two :po1y·_, morphs 0:[ almost the same particle size; :i s reflected i.n the dissolution :nOJlte of the d[lUlg product "b: capsules.

The dissolutien rate per un~t snrfaec area, termed the intdni.c d·i SSO:~,ll,~io(n ·I·.alt~ (lD':R;, see Cht$P'l'~ 2'.1 is, ~ ndependten~, of me particle size. )"0 the "disc meth-

Copy rig hted m ateri al

r-. ',' ,"""',

Tlme

Oa,~----------------~------~

o 20 ;4,0 60. 80 '~;'OO '~ ~O 140

Time (min)'

100 SO

20 Jill

'iliiirilfue' ([~~i1)

40

,~"rng. ~ 2" D'issoli,j$,icn.!, ,CUf'il/e'S (l,e;f'iO ,~f.t:~~(J' ("ry:S;'aUi~,e i,f;Otliflo(Jtio.~'M (A :a~~~ l~J of t~ drug: ;n~IJslar1.l:,e' alld ,~jie t:o,rrespOlu1ing cun~eS' (,ri,ghi,O tille' ,d:rf,~'g PI'rJ:tiYlC/:S (ca:ps.lill~e.S)',. ~:' :polynJaorpliTh .A.; 0': pl~ymorph B.

,~,,,41 "j'lb,~, "::",,~,.,."~- ,'~, i"'-~' - '-: ~ ~~ ,,, d 'Iik.,- ,c ., 'C: ~ ~ ,~,' ch :""~ '. d':"" 'i' ' " - .. .Ar- - i ' ' I " " ,'" t disc

oo, tne ,powu,e;r Ul; COnlpreS5e,,~ !~y ,8 ,plUlfWC~~, In a I, I,e [,.0 proouce 8, compa,c, [, lSC

or '~ab:~et., Iastru ments are nnw eommereially a"li/',m I:ajble: for this purpose [42,] ~

O"'~ I' ~c .'~h:, , ,,~,", fac ",,: th " ,.<t~' ',' ~ '" " ,'" ","d [[', 'I 1Ii,1 .', ...4,",,,",. " ]~ " It'", ,. ',' '''d' I,· " , . . ' _,.AI iltlh" " ,',,'

...... if1lJJ,)' one race 011. me urn. ,'C ~.S exposea ~O me u~,::il':SO, uuon t1l6· J.Ulnj! .aWu, 11lJ. e eu =

mulative amount dissolved per un i .. t surface area ·w 5. determined by W.1IIr,1 violet spectrophotometry 'Un:U~. lO'% of the :BoUd, 'm s dissolved, The slope 'of the 'plot of mass dissolved per un'~t surface area i'S, time gives the ]DR :h'l appropriate

1·1"·t" " ""D,I""~,J:,,:2If', 'h'·'-"" in th · .. !M.·.,_.· , •. 'L. ' .. ,...lId," ",' , '~:I.:'.' "~"'~

~L1U. s, e .g. ~ n~el mn ~ em ,. I, C range In I~ te stope 1'", ooservee mnng rue COlU ,-

se of the experi ment then ,8, change in the solid phase exposed to ~he sol vent occ LlFS dllllrim,g the experiment. A so~ i,d phase \vi~h diffeJJiernU state of ioni zation

~ ~

(", ~ 'it"Il..,a. '11I'1il \0' n' ized ,iI\'"-r"-m' )' ~,C' C"w~ Am I '!'lIi,,," 01 ""'0' ,]- :'-"c'm'" ···liI"!iilil"lil'liE.., ',,,",, ..... rn..,,""' ..... = ',;13. m'ifij '0' - ..... '-l!lrF ~'O'lr' a"ii'

e.,g.) Ul""" ~" l .. [, l~" ,~,"'-.JI1,-, ._ ,g,-" .. ~,!I~. ~~~, ~"P' .. y ~,' 'Y!',~ v~~l .... ["""~W~,~,g,[~, ~~"',' C"""_, 111,. v.',~ ''''.,;''1;'-

ample thei ni ti ,~'II A,~"ii:'.' solution '1j'''Ji,it,e for a d 'i11'1[ilJ .,;;0;1 tbstance 'W' as '0'" '0· ,~, me/min .1 e» ,11\-02

. ,ii, "W,l1;"rijo " .',' W .. 1I.!1i.. ed Y.,1Ii iJ!'o:) 'II.!I!'U'IUI',U ,iii. U!I" c .lL'IU!', 1 ,'.~. I!LC' OJ! llI!, .', i:!I'Ii.AII.W,.' ',", ,', ,,;:,,, ,.' , ,,.J' .. " ~ 11111.111. "I.il1iJ1"r,IIL ,.

Copy rig hted m ateri al

'~8'~' ;,j" .

The elf.[tha:~py of the so~ ution proc 58 ~ i . .(J. the heat ,of ~ol[tdon~ ,AH~ol,' can

Ilk" .' ]- ,'-, , ~1, *- d 'f: ", : th - ~ ~- - ~ -~~, -- ~'I . ,~, de e"~ - ~ A-,~ ,-::- ,c- , '-"'f' 'Ii-'h-'_~ -, I "-"-l~' bl ~ ",~c ~-: ..-il,·, - ~ I' ~,~ .JI ne ca .CUJILal~,e, rom ,'. e ILe:mpe.r.fhl!Jl'e 'epenue.lI1,oe. 0" me so UI.~~['lI..y as 'U~:SIC I,,',LW,

in Sect. 3. ,2'" This method ha'" been 'wide' y used; for example, :fO~L-" etoxadrol base and iu .hydroch'~o[idle [43}. However, Holl "t6'(.;-/(. (44," and .B'!u'fge'r '23]1

- , , -'·d'" th '~ ,-,I,L.", slone -' il: ;;.Ih' " '1"·"'" ''','' 'II",,':~ ," ", ..... ,.4: .. - 'itv -'d' 'b" Je",~' '~'ll1Ii ':, ~~" - ,-, ' , -'

'conS.I., , e.r 1,,, a~ hl.1! .. , ope n~, IIJ). ,I ,e . Linear .rreJJ.[m.lOJiI, ,IU ~~,Clle_ .'Y £.lq"1:., .!lU ,~iS too- VM ='

iable, and ,ill.':_, "",U. biect to .: · Si" stomatic errors '0: ..-[- several pl!!!!lY:'"~IIfII~' A'I~I~ '~'IOI noni deal-

",r.lbUll ~[' _w.~U ,Ij. ~ -'~J!\..tl u L·. II..! .. L'-I!i..r. " 1 .atll~ !\r. I U~,!ilI . '" . ~ ~ u g ,~IJ ~~-JILIJ~~, UU'¥ itJl·." Li~I,V. j!tJIi'-f.U

it,y of the saturated ~o~,uHon. resuihing in, inaccurate determination of 'both the

I~, ____:, ~ lit ~ 'f ."".,~. I~I' ,- . ;"'i: ~. _~,AI ~,:k.-, tra -,~ ,--:. "'Ii". ,---; _.~,c' ~::-, ---;." - e"t, '-"'-f" 'iiW = I '~o,.--~- ~ ~:- Tb-L ,-, he _ iIi'~, ,'f? ~,-I ~, It" = ~~, ,,-1:

W we:a~,.o, 50 ~ Ill. HI) IiI ann me ,,[ 111" ~J.U)llI. poim 0 LI:'_ -0 JJ,I. rms, " e . ear O,~, O~,[Ij,~,~OD. 'O,~,

substances can be measured directly 'by solwlion calorimetry, wblJl clearly

.~ -, ~-, " ~ d·, ",. ,- ~"",: , .. 'q~ , "'Iii' ... .'1 " , =[ 'II 0' I ',;,~I ,Ii;i']1 'Th" ··..;t~,"'"· ',~ . . '. .....~,- "... j,!I.;, il,;, - ~

p't-OVl; es ,nrtore S.lgnhlc.anl!!, "!;ttueo.; . ,~, 0 ~ _ ~'.J! e. = • ,e !Ui.tllltremOe IU! .. '1~,W.:. on U~e ueit~",

,o;f solution ,of the two POI,)flnoqJb s is equ:a[ eo the 'tr,QO'tt.iOl1 e nth all ply of 'tit

~ ] - ~~ n I" n b '. - t Th - 1m "d 'I ~

" ", ,', ;r::" ''','' ,,,- ',.'''". -" , "",', "!'" ,'" 'I' -'" '\t' ,,- " -, '-',-, '

po _YlllOqll',.-, a e.ml1JpE;];,3, ure . erose 10 am ien .• ,. re resu _- ':, p.IliO. ,I' e am, ,3., erna-

H'II'e to : .• 'SC for the discrimination between ,eJlantiot[Io;PIY tm:nd :~110n,otropy\O

-,~' 'he ','111" "", .'b'i'-- E''' ' " ""~, "" ',' ,-,' ''-,',', ,', ',,- ''-' , '"'' -,[-~,:. , Q' "', -,' It" ,t( "'o~ ... , I " " ' ." l' ,'., ",_I f"'" ,~;

'\1111,,,,en n je stu stance eecomposer 1II,I~KUl me u:rng,.IJJi]!~,]lliauve ana YS1, '0, poJ.~ -,

',',-' mh .,m, C'~'.!I;; .(":1 ,_.,~~'I!..,,', '&'~" s , ~~lii'~l" '!!..'I' '[L- ,~,.,J,.' ,,··...iIi'I,

.molUlP, " I " SOIII ' aile""", Sl1u ;I,m 0 rpn 0\1 I .~,o.nn" 1Jn. mlXI[lU.res ,n,~·, ueenJ pe.u . .of.m,elW, Ur"""

• ~ ,0 • lorl - '8 ~ d· f '~ - '1]- ,. 'b- 'II -, '" Iorime

< '. .' :' ',.. ", ' •• " " I'"' - ", -'" .. " " " ", f F,' "_.. [' .. '.' [," ',' .,. - -' .. ', [. ;" - ." ~r - • . '." :.' ... I I ";,'. 'i .' "'; .' i"" , . . . - _, I

ing 0 UUOIll, ca. onrnetry. . .t,LlIe" I 0., ,po. ymorp, 11S.mly $0. unon lea ,on,m.e~ry

ha V,DO '"Ib' een revi ewed I[]' 'Q]

:11 'a....... ," _ '.', , ,,!!Or, 1"",, ¥'r I....., ",0 m

Copy rig hted m ateri al

,5
4,
~
'i!f.!i ,3,
,~
IIllIJ
'E' 2
!'::::-,
z-
"0' 1
.
~,
0,
tJ!. 0
.......,.
w' 6 -
· ,
a)
f:
m 5
~ ·
0,
00 4
00
till
::! 3
·
2 '0 ~~~=~=='b~~""':&"' __ ...:.1-_----1

a.

,20' ,40 60 eo

Re,lat]v'e humidity (%)

Copy rig hted m ateri al

60

'pu ii, D'~,lI' A.ii"""!~~' ~fC' AL~' f'i A. '~. "11". '.

-·nftftdiy.Il/a:·1.}!Is..":\~JU! 1 JI., .', !k)~IIJ ...... : .•

~ [~ ,mo [m

:E

e-

"'Ci

~ o

~

...,_...

m rn E-

m[

ti,

m[ W[

ta,

:!

J J

III A:

~ l·. l

,I

ll~

, ~I I I

~I j

B

B

.

f

j

'11 I] 20 30 401 501 60 '701 1901 9 III IRellatiye, hUlm'idi'ty (%,)

FIg,. 14., :n!FO' pt1lyf,~'tfJ.'rpis .c, - -. irDIDd. H,) ,n"~~~4'O,!Iil,m'i~g i,~'t() I~,e S-tlW~7i &.'1d~1t~t- _ d.J~,rw-". The '.e~mntJm - :fnrn:l B ~*e[;, up H;iQ! ~t, ~owef re~~tmve humjjd1ru~¥ tb,JrnID the '~ta;b~e '- HI'i, A", The hyd'raro:e' :f-eJrmrnl loses H2!D ail rr.h., valnes 1b~;~;'II(l!I\\Y 20%,.

namic water sorption' 'ysltem [50], the ';\amp;~,!e is placed au a, 'micIO'babJJDC1C

~t.".n-;-:-d exposed to [ill oo,nil[~i:~lUIn'1J,-/ 'iA'FilW' " .. fi !~31~r o a r '. WI~iolh [i"nif'ill. I',ruil'ii'i,i' p ~A~I~'~f-:ii'iI'Illirn~lill

~ ~ _ A ~ _ u 'U __ .~. [I.bI!._ ~ 1j,1i. __ U __ ~ lIv _ _ gii _ 2. _ _ WJljl ~UIIILIJ IlBIJJl~. I . tlJ.l~UJl!.l~!!i..!t lIIUjJlJlJlJIL~U

~' '11 .'(1'; B th- 'h d l ]~ I b

•. 'J • _. I I, ."J '. I' -.' .. ' I,' ._!, , - "0J' - - ," '-,' •• (-.[ •••• t ' [ ~ - I I '_-. '[" ,"' I iri • 1-' '" • -·~._l·"'·1 " ... '~' ,

re !a~l ve , "urr:m - l~y" [-'''1 "e Ie 1,1]1et, o· . 1~I,mp', es ,1;5; ,ml "as " D1(~ CI!D, : e ,aCClll;~

'II ..:I" .... 1

ir,~dje,ly -t'I.!IIUU;!U~

S ,., d Ib. ..;11 ., I . ..,1 ~ lb._..., ~ " f' Ib, . ..;11

,0. '~!' ,~. ta-t,e u,:,''Ur:~.tI,on :ma,), ODCUF' li,;-'auU:lg: 'to t!JW '1L,'O(lj,maJJt~.oD 0'- uy"'Ura.tJes,.

'X" ell'n; -, -, be eoui ed ""n- - '~ I '~~ m

• , .••. I _ .•• f r' ,"" " ... ", . [' I .' ,," "._. ,". ' I . ", "," • I ._ -',' ," ..' I' "" ," [ J

.; ;~:",m,y '_ 1. . ractometers may ue equ rn"p,p,. ,_, W,~,t_,_ ~,peC11, sa,m,p' e ,ce,_ ,_'. '~O,[ e:' ::-

eosin 0' 'iiffL.t:!Ii' sam pile 't',n C-Il1'tr~' '~I p,.J1 temoersture ;!to '1- ..:II LII'II'IIfffii[;,,A'::'tr'l 'TIt· ';i!li3 '~_'III""i"!11 ral ,t:'"v.:ii! ",S; l~lI.b"': ,;:)!i:III:;" >L_~u •. ' ~ ,_IIUdI, !!L;ii, ~,lli;Jl!Ii. ten -r:"':w, ~l!~,II,: ~_!1IJi ,~.hll'lltWJ!I~W·':',i'; "_ '_ e _'~'-'-.w~~!lUL m

changes i,n ~he solid can 'be, monito.F.1ed- and the lextenl !().,' their :re,v!e_,· ,:ibUilty can be ~·;il!1d'~ed, The powder X """o:y difflfactio\l, 'piil't~er-n'l cw[,ecwd dUlf.i:nll h_lUt-, :i:n,g ~l~otJl{ d!ehyd:r,atilolll steps, ![OCr other d!es~)lv,ation st:eps-, '~O be fOIU.owed ,em ... , c'wlendy~ Because ~Olipti(,lO and desoj~ptiron phenOiwfuta ,am accl(Jwpaoied by ~:l~31 ' exchange, :mh::f~:caJO(fj~.m,e!tI.~.'c; mcbl[1,lqru!es, are 'Valw a'b:~,e '€o(l' mUIDli'to(Fing :p,ur~ poses ,[51,] [52].,

Fi:iJ'., J 4 ShOi~VS mhe sorption l' ot'h~lImc-, of two 'Cr}'8l~Ui.oe: mod:i:fi.c3iti,oo[:-· of

= _

It drug subs tance borh of wbic'h tta~n· form in't,o, I hydrl:ted. :~mm, at 25 QC 1'5:31]1.,

'Ulld~r atnbient cOllldidoflJ'/, tile dlermod,Yll1,amieany :.: !toJJJle 'fo(f,m i[ I ~e;. ,: h:y,gro= ~C\OP(~:_-" The ,cf~'ti,ca] hllJ.'mjdl~y ;a;t \vbjcll tltu~~ mass ,chalDg~s a;bru.p~J~.-" corm", spondi ng, ~O[ dlli~ hu:micUty ;I'~ w:hich ~:be 'UmlA\'t.~,lo;rn, [of :hydr[are: 'begin[:- depends 'IJ,:PO(l1, the temperature The hi\Shm' the: '~~nlperl,'n[l!re die ~,OWe\F' is (De c,rit'ru,ca1 hu:midi1ty .. The formatlon of '~~__e. ~phyUine 'm,o'[li)o'b.ydrIJE :a,~ '~~b.e ;':-[lJRaCe of tablets

c if"!i;1n[li"!cl; il'il'l' Ifill 0' alll'il[jI","'!iJ''''llro-- - (1lI' 'fi'IiI..,efinb';ijji~I~;'IiI'iI[;i!l!i' '~i;f;! a- 1FiI[ e:v,g,:ft-ilip--,me ,ltlb,,~t· 'iJ..g[iIl1' bD!DIf'II[ ·t:"'nm"']nb'~ly

:.__.IUI!IIll!l.Qn,~ II;~C [ I!I~U,j I!U . _ .. I!J,W~~v,.rU.,i1'jILh'III;III~ ,Iii;;]. . ~:III un;)'..:~:~,~ .,W.!"" tw:w;":',. ,~-JjD':' -lII;,;!r;;.;~.1II _1;ljv,,·1,; "~ .. W,~

studied ,54- 56,1 ..

Copy rig hte d m ateri al

Different polymorphs usually behave differently [I 8;] '. ,A -,"et,[l~!{mb:~e ,po~y~' morph may mra.n,'Jor.m in~o a crystallfne :hydf,flt!t,!, 'Whelle9r~ ~ih.e /~alb]e :po~y'-' rnorph may not I(,f,.g.." see 1:tl./J,,ie 3). S'O:I,'~la~es :m,3],), tr.an ,:form, into hydmt.e.

bv direct disp ."J acem .ci,iIf'Ij,iii' ofa ,nlllJ'Sloi'I''!i,iii' '1l'f~'nl.t:!i>('I iii, b '1" 'H' 0' ", Thi If> pro P;!:!i;~,ii:' 'Ill !i!'J'Ill";Ci! "t-. ..:II

·:__':rJ' IlllJ· ~ _" ~ _: ll. [ __ ~I,~ . _,~,~ ~~.' ,~,~~ ~I~, IV~ ,~, :,"tv y I~~ ~I~, ,~IU~:~~ '. ~': ,2··.···! '_ ~,~ -e- .. 1 ,~~~~ ~I ":" '-"'f~~~' ·I!I;..:.·· ,Q

.. '" "t·'.... d for obt ~- ~ - . ~'~rd- n - II'h-" ~ To .. --, ii 'tl· rwi b - - .. - .- - - 1[' -., .... 1 [.c7111

memo ' . ..or on am nnn.,g n)1 ~ra, es L: ;a!~, C,3'nrno~ 0 nen :l e .... e mann ac urea ,.;_;' ill"

\"ilh .. · .. ' " " '\' . '," ,J- ~-,c' .,;II .. .: 'I"-_'~ ,~: ,': _ .Iil"", ·'-·C'C",..-li ,.i.,,~, ·~I .. ,'~·" Ii'" '_ ."CO the . .d 'ii..",,: · .. t·'-IIil"~·'·-1 ,-- ,"

Ill' "en severer 11,II.yuf,;!i.l;!eS are ~,or:me!Ul,. ~.~ we ~l"edC.s, o~ _ ne ue~ ~yy,r,a'II,Jon JUlO-

'e'-- es 'i"'i"ii~OiV b f.iI; 'd,-,e,'B~"i!'f!;,,-'t" from th ,- '~l..;' '~lii;"C' of the hvd ~I't"""'O"'" sten ,- r., 'ii·IiI..,;j:'iI; .. ;- ... .,,I> S'.J L ,I,.!,I",;' • ,Ii;j , I.u IIiOO,F'"",riI ~ .. fi,rn. . ",,;: it\.l:ru ...... d, 0 " ~ W WJW. ~I~I n •. ' .. ~,p~, a .mn !l-I!l~~' ca e

of ;i'Ii""1ii'f'iii"'i"ii'ilJe'''1 hvdrochlo -\"':I,~ l[c.,Q,] for ~'; ,'h·~,··iIl,.,., 1('l'I"- ".,,-, "': ~,'t'~ :" .-, ,'!'f: 'lI~r 10":' 1"'>' ,,:~: ... "", ~'i'

!!..;I',. W W~ ... W Ue .,. ,11,1 J' ~tIV"",, ,11,un uC .,J.!I Q ~.'.f '\!iI W c~ ~ . l.C .sur;p ,.U)n. 0 _' '~:-;~'2 .. ' ooe U 1'8 lin .. "'" 0

. ,. " • ','''1 Ii!.. , '~ii-.. ·..:11-· Til-. '~I·," PI "-.. "- I d .. _, 'II - - -H'-' '0"" • - -" ...

s~e:ps 'v,~a: ~ le ~ ~lelrml:1 nY'urate,. ,~, ~Le lie~u ~'t~.n~: m;o:nol:~yl.: .. r~tle .1)0151 ~ .. '.' ,_c "i' .. ' Ul, one sb~,p

yielding the an hydFate~ Due to [the diffe:fient kinetics (}I'f their tlran'·:for.n1'3!Ulon· ~, the anhydrare, h .. em rnhydrwte~ and monohydrate can ,COi- exist ~or an appreciabl .. e period lof ~i'lJll1,e" Hydrate I ha;V'!8 'be-en ~he :,ubjec~, o'f several reviews (.e.,g .. ~ [519]'.,

Fig. .15 ru ~ I ustraaes the comp;~ex.ily of hydration ;and dehydration processes ru n the water-sorption isotherms of three '>I1J1l, of I, basic dJf.ug [4:1.] '. The h:ydm~'

!p!'IiJii'I-1IJ '[1.'Jj Q ill 0' ."if· ''!iII'f',Q; , ~I'I~' tak 'e""" 'U iIi'Ii moisnrre reversibl v corresnond '1· 'm· p' to 'Cii wei oL,.·

'O[~l ,l!j l .• lIJ~JWI ... II ~~ :'':Q. JIIlr I~~IL' . ~ . Itt.'" ~IUIj.W'll.},W,1;;:! Illy \r.r I, "-".~ ·.ll ;,w.··· oJ I~UI I, J ~ ~~v, J [ .. ,]1 l 0 .IU ,~JJ _'._ '".II.~I:II,ll

change that exceeds 22'% at saturation. The hyd[l!gI0raJ tartrate salt is a1-'0

1,· e : ,~·".",""L':":' "".'I'~~'b··~"·'·!J· ' lisht h 't'n ",., F· the ~ . ...4.- •.. L,'!I."'AI h

II ygI OSCO'P~ .. C exm .• : n mg a s l~, 1.~. ,. ,y:~h~rleSltt . I. or :. e UYU,I, 'OC~.lUo.lil:~e san, a

strong by· tere J, is observed dllJe to the formation of a s't:aJb]l~ hydral:e:,. The

'L·o:1i'S' e and the hvdrosen m '!:II 'I eate salt W';;:Ji,~ no ·,t, '!'II'~ ;]i,l'll L·U0'M····· coni r> This exam

u~"· .... 11.], " IlL .l .... "',j Illij., ." ·1~~:I.lJj "I ,Q ,~(11. ~ ~ i:)~-~ I', ..... ~w I~ llllj,.~ " IU~ r~" JJ ~'~')' [~_,[ .. ~ .. :... ~u~.~,~ I!I "~ ~ IJ ~ 1 .'~ .~,~"lI:~'

ple 1] lustrates rbe ~.m·pOdiEU!lC.e of the s~ud:\f of the :hv2:-r(t~:·crp" j .. city ... · of salt can-

,J " [J' J'II.;;;;r.I.,.

did .

1 ates,

.-.

00

00

m "'1!1ii"'Ii E LU'

,~' u

'15 15,

,~ . ,i;,}

o.a···~···~~~~~--~P-~~~~~

o 110

30 40 5~1 6iO

Re latiiiv,e hI.Jm:idmt,y (:%)1

nt'll, ;~v

Copy rig hted m ateri al

611

,,g,,

~ f phase u',anS:[o:nnltW()nS, we~~ based ~~ o~~ly' IOrID f ~J,mlld.:yn~mDic ,mmes" stable ,cr-t,'£id fO!Fmr, ';bou:~d 'be obtained ,q1Jll'~.~ e~·iUy:., 'Hofweve;Ii.~, :tJin~ti,c f9iCU)([S

Copy rig hte d m ateri al

1 .. (2)

where A. hi the frequency factor ·\vhich is related to the entropy of activation according to EJJ'in~ ':' a:rud Polanyi c and .R' and T ha eve been defined previously (£q"+. 91: .• " The ,ac~'h\',amioru,~enJer:gy barrier may be: reduced by catalysts, impurities, and/or crystal defects, :M:ost transformaaion processes '~rnl 'Wile solid .. tate' 'm:nvo!~ve n!!u::~e3Uon nroeresslon of a erowth zone and regression of an unre-

- - - - - - .. - ._ .... - -~, ~'~. b I. ,,~ ., ,10 ' ", " ,""" ., '- ~" ,,, , ". ,,:s , " ,,-,' ",

d Wlt.. "'h bili -& lid Ai '" f

aete .core. '". nen compenng t:: e .' taul tty Ow: so. :~, s ounng storage, many 'i .ac-

ton" :ph~,Jt a role, such as !emper,a~ure~ :patt~,cle' : ,I e, ~he presence of seed ,"uclei of '~~le product, aetivat ",on. energy for the change, and diffus,:~on of '~he mo~ecu·~es,.

Til influence 0':( nuclei (seed (~ry:s:nal··,) ,of the stahl"e form in a sample C"_,· a metastable form is, demonstrated in, the fo;~ low ing example. For the sub-

~ '" ~ ed ,. F - I , b b f 't 'bJ iir

stance exempnt iee U]J , ' I:g" .,2,;] two batenes 0 ~. ie metastable torm 'were sto-

red 'Lunder different conditiens :~or sltaJt;Uity ~e1 thllg'", The .DSC' seam showed '~hat the ieeond batch contained traces o:f the stable form, whereas no "table

form .... ould be detected in ,,,:III,.'iIliIi' first batch A·· Iter 5··· vears 'i"ll;.'e iI:'1Jli' ..... ond basch Ilhli,,"lIi...:l Ill.". ,.. '~yi':!l [UJj. '., '!!i.?- U/." l,,~ ... v'~i .: ;.1;, ~:W.W~ lll.i. j' '. UalIL,.:·· ,~t,. :. '. ,~, Li ' . .'lJj, ':.. ,J,I~'~I :.;i - ,=W w. :ci~I!ir.'~u',. JU [, .,., tIJ.j J" W lIJelUJ

transformed to the s~aJb~"e 1'"o:rm at a Fate: that depended on the tempe;FaJtlu'e", whereas no transformadcn of the metastable form tOI the sutbl", for,1llI1 was observed In ~he first batch at al'~ . :ton,ge temperatures. AJteJt storage of the second 'batc'h for 3, years a!t: ,30o[e· 50% 0:': the :s~(~b'le form was :f.ound 'by :X: .. ra,y di'ffta~J_:metr~y arrud 'by :[R ~p~Ct[108CO:py [41 I' 64J :H:owe;v,el',. :if10 trace of the stable forr-n W'~'·, :f.ound by X-ray dl:ffractom[etIfY In all samples of the first bateb. S;lmp;~es {)If d~e second. batch, when stored in ,3], deep-freezer : ~O[[' 5 years, .... ontained .... ''''' em, ·0···'(· the ' ,to:li,II!...~le· form . estimated bv X·'" 'ra'\~' diffra .... tom iIi:nJ'~; T·I"'e

[~y, . ~~ '[ .. J~U [b.[~I;.l IJ,·:3r.(.{ ' .. ' ·.,l , IlL ,J.'. 1 ~)LrUjll).',W' .. l ~,[t..JillJ, ",:.' , ',_ ~~jllL .I. ,~_~l~.'-·UI ' _: ',J': ,'.' ",~; .! [J .:-;: J J l'-~.¥lL[ :'" " J. I.~ l~_~ j' '[. "J :;.,:,'~

dif"" erent behavior of the batebes is expl ained ·by the :plre- enee of the small amount of seed nucl,lei, of the stable form W n the second batch, This le)t3mp;~le ernphss ,I zes the need fer sensitive methods to' di:ffen:::ntiate and to detect poly-

" 'I" ru tu

morp :l"! m nux ures.

Transformations ru,a,y be: accelerated by the presence [o:f a. ~ol,v~,!:iIt~ such ~s, "20,. So,,lvent -media: ed ,lnafl:sjo't"I"Ult,iOJ'ts' occur by I, coatlnuous di s ol udon~ [crys~~:n~la,t~l()n process, This '~.ype of 'tr~U:lsfonmalwon ulay OOCU'F during erys'~aIUza.don Of grMula;nion~ Hydrates ~:nay be formed by thi process i'n: mixtures involviag moisture. Solvent-mediated transfosrnatioes m~;y occur 'w.hen measuring ',~,olub~l,i~ies; such 'that; after some time , :l"lec1]{stl:~~izlti,orn of ~., more stable state :niIJa.y be comp;~e~:e (F.i8,',. .l'6l,

Table 2 summadze l~o~,ubUlty measurements om ·~OUlf forms ~ ,A" B,~, IC" and D'", [o,f :MKS 4192 as functions of time and an diffeare:nt telTIperatnre·,-[60l., After

Copy rig hted m ateri al

64

.

,

Cs ------~" ...... _-

I - .........

CA::~~~~~-~~~~'-~-~~~~-~-----

r

'l1m,e

fig. :16. Co,u:,erll:',"~a.rj'()/~ 'V.; ". dr"~~ P,~'()IS showiR,' ,tl~'e ,p.os.ti:ble .fi~d~'ibiU{.y .b't"!tn~f'o,r ,of st.ab~' OJ (A) lUll1' n.u:tl1.fjjl'(J'l:Jb? (B) rJ,f..~'/yl.1~o.rrp.lI~~ or ,psetf-do,(}I~pn()"'fJhsj re.'ipectil.tl)" A~ the thne i~~di{:Uited .1'*,.

~'I -' '," '-.' .. -- ~~. .",1 : ~ 1- .. II' • ,,- . .7 ·'r:' 1,1;..·.,· . '1'0 I-,~k b·.'1 , ,f,' - - . 'If iI..' . I~ • , '~r. -;, ~-:- •• It- -,- 11\ ~~I ,- "['1- - .,Ii:' - .. -, ,,-. , Ii'''' 'i'iI:.. ,

11t:iQ.I,U!u'th,eu, 'Ou,lhl:~,1Ji iIi)" !LUi!; IIlme i,~.t.!:h_a !J'~ ,1,QI'liI1llih.," "ul~_l'Cu ~, , .. :JJlillJe![Il"S~ urn,~-eu WI.· 1, 1re:ll.'eI-e:l'lioe: ~)O, me

su~:b:ie form starts to ,e~ys[:ailllil.e.;, ~lli];e;oob:y ,ll(p,p:roac.q, 1 'he cO'nlCle~UIDtrndon. ,@f the lower : o[ulbUilJ '@ir the 5'tab~e form, Cr'ys~ruUz.~ruiQn ~ay OCCII!lIJ£' b)! ,:p'on~~eous, ni!lli~10a~kiml 01 IC~_rru Ib~ wmld~ced b,Y

.. 'eedlil~g with the stable :~~:mm.,

Tablc' 2. Soiu,bilil:V ~W'ea'9U,~"e~lien$' of lW KS 4'92 ,f1;fJij1t/t(Jrr~;'~'s~ afui ()J.M:~~'it'lft'ie~~ Qf E~]ich P()I"mo,rpJ~ wil:'l~! ,t-lu! ,SltlbJ.l1' ,l;'o,.n,~' ,fil" ,ij" ,H20 [,50]

Po~JmcrrJbs M.tures,
~ =
Tel1ilpI:3'itl'Il''e Ttilil~.e ,f\ B C D' i-1 .Oi c + :0 0 + D
I '_. ___ .' ~' J • _ : • : I
~ ~
~QC] l[lmmmnl,~,
~IO - 'j",! L71 2.161 t'7' :~.SJ ] ,61 l.Ll
~ •• ' ,I ,[II', .•
:20' 20 "716, '~ i6' 2JJ2, t71i]1 .~.S,5 IJj[) , , 00
..... ' ,~": ..... l
40 2.77 ~ .If,S, " 10'7 ~ .,8.1 :~I.JOOI ~ et 1.6,5
I~{) 2.'9,61 :rn .1'16, J,Im3 " 21 ~ .I~I ]".11 2.21
I .. . 01 •• .- ~'HI~' ...
301 20 2:.,'91,8, m.53, 2,71~ 234 ~ 7'{) 1.59 204,
~. ~ '_', - ,I!, ~ .. _: . ~11!' .
40 3J]~]1 't5!g " 81 2; '-'I ~ 168, 1.66 1.'96
_.1".-.._ .:_". ,III _'".
~o 3 '" ~ ,161 ~ ~fI 2.3'1 .~ .,1,]i9' 1,.:n~1 1.60
1.:·'1,'] [ J~, L!'!
40 20 ],.'61 43'1
_ ~= l.""!'
40 3 ,= ,411'3
'.:) :
- ,_." . equi libraaicn, the aqu,ecnJ~: :phorSe was H!Tru:m]yzed. Form I, Is the least soluble form and ~,S'I' therefore, the :lillOst stable '~Oftll" .Afrte'F.' m 0 m,~ n lor 40 min. no ob .. , v:~o'Cus d. :~'f1elJ\encles 'wa'i'\e '0·-· bserved amone the measurem ents, i!"1r\1'iii;P; :Si!1I'IOftliP- experi ..

_ _ ~ _ '1]#._ ~ ~_ _ ~ _ . 'U~'~,~ lL .. ~ ~~ _.I.t!IiP. .. ~~IUII L.=-J! III 1. ~JI}lli11!" IY! n:.l~JjL~ ~A ~-~ l

ment w-as repeated with for.m,·· A~ < .. , and D~ each C-1DDtaJmng some Oi nle ~,es~., sol uble fo,:rm B.. The decreases in 'Khe ~~I:~,11~,'~til'~dep, 1~I~m-- - ,nn,1 ;:t:'iI",gl~~' the infl ~ ~1;;i!'ifiI';f!(.'I;.

_ _ _ _ _ _ _ _ ~ _ _ __ ~~ ~ ~ UIJJ~ _ ~I._ Y~l .. Vt!lJg~ U, ~.l~~ ~l~lw Jj J • lfU~~ILIJ~~

Copy rig hted m ateri al

65

8

7' .'

10

o!'1i~ ~!rJ

"llii'lij ~u·

Fig,. 1 j., 1~'ifl~~lHICft ,()j ~'etJ~p~'r,al~~'re ,QU ,',~'e kine,''ic~ii of a ._fjo·t~'''e,w.~$~nletf~'(Ju!d tron~_if_~n,71(1~'i(),rJ, r'~l: f(Jr~· rJ\f .. d(Jl,im~ ,of a)l';l. 1',.u"''''stigal,ij~·;j'a'l ,d'r,t~g: ,sf,rb·~t(!'JU::';io i~t I~:i~,~' Cf)'st,'(;~'I'Un," ~"~m;lificri1:i(}u'; '''J'(I~li,riO,!i'l!illJy lhe ,il':'IOI~'c~n'mt,i\{JiI~ 0/ dis,'!;o.lve(;f SUbSI'(l$!Ci afl'er Ol'\~e' day ,if SI'Orog,e. 'fuU s'Y~imThbo~ and b'roke:~1 ~:ine~: :siab!:e: forml;, ~~U.'ij"~~ :symbc~s. and 'fuUI U[les:; ~~lejtu£~8ble form: solvents: 0': M:i.g:iyol 8 I 2"

,O':~ oolybe~ n oil, Ii; :mbnul'e ,ra:f leq~utl, parts of' M'i..Glyo~ :8 ~:2 ,amd saybe'ilm oi~:" .

O· :'f~ seed it" n,1ir '1:11.;iJi; 1;::0;[-' able fo rm , w' hI' ch 'Ji,C .... a,11 erate the solvent ·m·· ed ; 'Jj,iil:ed trsn r[I for

'. II. ~"""" ... ;;) !I •• J!',~, ,Jlh, .. ;;;!!i ,(l., ". ~,I,.,i" ,,,,.' .'.'" ~,,_ 'Ii,r""",~,11I;-.o ,~:I,!"", III-, '_ o::i!!I, .. .!I',W~·IIi...oIIIll.;"" ,,~.< ,III,"'_~III-:.·:, !Il.!Ji,;¢l1... ,i!jo "U',,,";'

maeion [60],

The influenee of temperature on the :lPh;a.: e transformation is demon strat-

d b -L, nl h · F'"'' 1·i7·· .. ..~ ." 'md f-' 'iIJ..,~ h th

en . 'y ~ue exampie sr own. In ·i ~ if,I'~ .. , "or an mves ,'tJl.gau.oltlj .". mig 0' W~iLiC,', tn.:

. table crys~fd~iJDJe, form 'was obtained for the 'first time oni~Y' after sID,r,age of

]''"., 1 , •. ...:1 fo -" 'I] 't:"· . '.,. I[ ill'm] A· .' ".;1" ~r ,«, " .. ". ". "" ,=, ,'Rj' '1l..,"I:,' '. L. ..... :t, "." th ". . . Ii' L. ~i ". L~,q:lJ.nu ,Or.Iil1I[ i~t 1.o11lS,,"t'.lIJ. m,~ .". greer uh,,~e.re~~ce In SOwUllJ,h~l.y 11JC~,Wee~I' I e "'~lluw,e

and the ·it:·"iI,,,,'~'I·· ,~., "I, '1LL.·"b'··· ", ob .,-,";II,',,'th"·, .. j[i'li,", 11', ., ... , .... ,',.' •. , .. "',.,,.,

ann 'l, e metastame terms nas eeen o serveo In ~_l,;_, ca .. se, !lil!l suspensions pre-

pared with the three sol v ents, it was, found. dw.a:t the big'her the s~.or,a,ge; temperaJi.'lU"Ie; is, the faster the ," .olub.~li.ly decreases, departing from '~;he: :irnitimU:y' b'~~h value '.'1" rh m .. t' .. ·.-,,·', b-~'il f;-·- - 'Tk, - n te -f' 'I ;,-., nsfor -- '-"ru-' - ,',: ,-),.--:il.~r .~- .~~ itIL,~__ .. __ w,_-, o~ c e ~ __ (%LH8~llte ,",orm. ~ ctd,~ ~aJ~ 0, b,ans,~o..J manon 1., acce,Ie;.ra~~U,

bv "".~'- .. - ",.-.;'.-::", ,~,'ij,.,-, 'it· .-.-,,·:··.- -'_·t" .," T··I];.:, ,t, nsforr 11-"···'· ,n., ilmost , ,'11;'1·' ~,:!"

y merea ing me tempera ure, . ne d~an~,. orma ~on I,S a most co.mp.~,e~}e ,~l~ Ile,£'

Olne··· :d ~v in ,;:;'11,'1 iIil'lf'!i·el"" "~n"", rt'" 'he'II":1 .g,'~ ~'O'I o:C' iiI'iJL.aril'\Cli;~ ~n"":i'i'i, III'h-·' ...... , ..... ',0, ri'ii' ;fi'n'~'f·3'f;~ on" ,f" nf" ~- ,- b

,I , .. '." ,!i:lII'J ,Ii,,, ,i::iJl1lJ,0"J!1t"_ .1111" 1't,ll'1rJ,¢, ..' U 'Q'I!-.;l_ ..... '~; 'fl1. !1.~, ..... II!,'"",~ ¥V,!,!I! I~_ L!Io,;.o '!!..<'_ .J!I! """!!l~I~" '!i_;~l . ,, __ ,,~, IV ~I[W ,-'

stance i! solution remain unchanged u~er ,3. frllrther week of equiUbra!Uon,. 'Thi' examele 'U'I!1~tr··-3't-·- '1IIrh.-,. 't'h-L - '··d'··-·' -.",;',!il': .. - -'11+,' .. -, -, of ,t'h·l- - :S:~' ·'b~ - for -- -··f-· A .. , ...

.. ~ ,_ ~ I,:: .::_ . P'=:_' 1 __ ,:.,~ , '!i.!J,~S ~_l;a~ ~,e l'eJil,dJ!lC;31!l.lOn 0 t,: 1.;; .:.,1.,;1; ~~,Ie "orm 0 a IIU,rug

, . .-,. - 'ii...,~.~,:.-" :. -', - ,- nd I ,~ib.., 'k" -iW'~ ·4: .. of ,'t".,. ., ·:I~, ' 'Ir-c:' 1,,' tv "f-' .,;T·,~,. rI' "j;:L, ·1 ,..;w', ,Iii'-'.':..· f'" ~J' ,

S lJ),uSII,all1,Ce ~Ul·. 1~_ueIllO __ ~.IeL.!lge (J , ~ ~ so.~ [II ul.d . .y ., 3tC,~,II .. I,~iljl~ t.~~e pre!.,JlllIC,,!lo'rn, 0, ~!11e,

'h ' I Ii;;,. "~I; t, 1Ll.. ' ] s; ]"

P', ;-,:YS1C,;;b, sta U':~ iI!j,'ty o,~, a p,w:war,mac:eu~Jca, rormu ,It~onl,

Trb. 'I: "is " ' ·iii'l sta 'b'''·]· , .',.'.' .. , .. :f;' " ..... I· 'lit -.iI'· .. , /~,L, - .' ", .. - 'r-' t'·I'" t'I'r". , ,,'il' L'II· ,

nere ,I i;,,! a IW,elf3lS, , ,f, lone 0, ,,,U,[pe,Fsa,il,l.!llJldOIl1: '\.;\ hlt!!, respec c' I~,O me SdIJu,le

.. ~".. L" ,:r - , '1 hi . 'lI.." ., - .. . .~,. ,~~' _. Ii' ~ 1 ~.... 'iii"~ _. - ~ . - ~I ._.' - -- Iii-.,-

pO~,ylno.rpu'u;:; rorm, tV _]C,~~ ts ,Impo,~, ~~n~ :nill cry: "a~ izanon precesse 'ull. ,en t}1Y'

,. ,. -- - = -

coeling (Fig, l8), If ~he .:' olubU:ilY curve of a metastable form is, in. ~he 111, eta-

stable zone, the first crystal obtained \~:iJ'~ I, be the metastable form. TnlWl.~ 'thi~,

.. . ·,t·· t 'LeI· f' .. 'W~ 'I 'l . . , ,it ]11." ,., nd 'iI'I!..~, L.I . ,Ii'-- , :~ 1]- -'I' -, ...., '~,Iili' ~~ ,

me astae 'C rorm .:b, (~ry!J,al!lz:e'!i' ane me stante rorm wu not appear, 1.11 ~111e~

Copy rig hted m ateri al

/. 6

To

:i~. 18. Cryst(~'iUms,i'O'Ijl ffont supe'rj~'I;!~'ta(rir!d ,$,!!tlu,~li£ll,~~ hl~ corJ\Ul,~8'. :P.IDo(]: ~f !}ol;lJlbru~;i'~y e: , '~l'\, 'ieMF' ,penmre of ~:\lI'O ~:~y.oqlh ~ st~'b;le /l., ;nd '1ilile~:;l·t~'ble :8 '~v~j;tb ~be 'o.h!lm~iJEy CIlI1f¥1e lD:f '~@JIm, B :I}@!~~l~d. lI:V~.~~, Wnm:~ '~ry ,mm]:l~tlin~1 .~ta'SIID[lhUii[y ~Ol!l(t" CIO~Ulllg , 'maWit ~t ,.~

, ransform ilion i,fDJ~O ~lh~ , table form is IDimiwd by the kineties of djl isolution ,~nd ,g:Fi ·wth l[ Ei5] [66] '. Dif-n~i~lllt'iJes :hl o(bt;~iQi~~ el~y'~ a~: ": 01= a plttiJclllllu' :[~JI]~[w;UL, wh:~,ch we:,Je obt;arn,n;e~, ait an eaJr1l:icr time are discllI,g'ed by ,D~~'ld'tl and B(!',m'St-'~''!

6:1]~

Amorphous 0.[' pmi:aU:y ,amorpb,OiI!l,~ : 'JoHd s :ma:,y resu ~:£ fFom ve:ry rapid preIC:ilpi:ttadlonJ, dry:i:n"g; milling freeze (h~ying, Of' . hock coonnl fRJim 'the me[t, 'O.rfl1l~f:lli. 'ii'~'~, presence '01:.' se d', ~If'~ ;8 GnJ'. ,t8Jnl.ii'iffi'~ '~O.·""il11 ,Ii'nl jk;§; ,m'niil~wp'-::b'-m"· -:iilii'il' ·~'I,~r· rep-

_ ~ !, ~ww _ ~'_ _ ~J _ _ _ _ _ __ u ",,;;~_!!J.II~~~_ il'! It.ll~~ U~ 1!U!I,~lIi# l!lll!!I~c!!IU ~"-' I!JJ.!!;!!! ",~,'!!i#.

_' "

resent a '~me,:1nJ10r.)i" '01- the crysls.f ine "UiJ'te, e .. r:pec,~;ally' af~er d:rying so ,'V,mmd

forms. Amorphou c, substances are ,ge:n,e[,aU,y :b:ypos:c[llpi.lc ~ they have b:~,g'b SOil-

b ., ~ ,. d ~. ., ~ ~. '~I" ...al ~I 'b~ .' ., 'Ii.. ,",~'.'~' 11

ruJ.1 ~l~,y :an, , o(ruoa.va~,liaJul~,d'ty" ;mu, ,gOOY, ta r~)eU:illil :pro:penleS'r llJiut are ilWllli,~:]JCUI.~t ~o

[Ilid ll, ,A,11IlO~lh,OiIiJ,S :forrms are U8JI,[I,OUy less ,taJb,le C:l!lemj,iCSUy and. p:hy' ~ih!aJ'~,y d,UJt ~o! '~he~r molecu ~,.. Fnob:i:~:~.'t)f" dl,e~t tend 'ft,o Il:lID' fORD, :~'miblli ICry' ·:t9JJUm:e, :~nmJi);.: upon ShOif;3(I;'e, :hliJlm:~,d.i:l1lc:aUoJll; and helm'in,O' ~

ICry8IlaJ~:ru.zamioro, of ,am amoqJ1to:U1s, so!U,d proceeds gJenerdl, fa'E ,am, ~em:p'er:~tLlre·, Ibove the glass uan .,:it~.ion 'te:lll1rper;a'EOre,. ~. ·hj!c~, is dep,ro_·. sed by' the Ilre:!ene e o:f H:JO~ The I.mJorpboo~ :[o.1'm, m"ilY CQfst~IUize balta 000 or ;aoordler olf di 'f~ :fer~nl~. p'~,ymll)rph', depending o:n the tem,pe.f.,I'tom aDd, h,umicU,'tty-, :IS was ob ... served in 'lhe case of :i:ndo(me~ll:uu:[n, [1" 1[6:8,J~ The amoflPihous, content orf'micronized solids is important because rec~ry. 'tIIU~'a;~io(ft [l[nodJllces ,31:gg[,omera:Les and C)O~~ ,elqueill~ly intj1·ea~ es the 'pl.!lti,c]eim, as de.mul'ii;",tt'llood, 'by· ,O,tsfA,ka: [169' _, The h:y,grij~co!p].'cUy oif bmqllJ;hll[, sow,um is, ,re~~,ai~ed, 'no, 'the: 1111ilqlboU', ,co.nte]l!t ['0]'"

Copy rig hte d m ateri al

Deh.ydra.tl1on, and 'hydtado:u proces ~ es largely depend on :kJn,eU,c' factors.

~ - - - ~

'h d 'ff'~'~ ,. f~ 'H'" 'O~: ~'~ ~'~ d·'fcf~· d ~ ~~ ~ . . ti ~ .

_, ". J _" ," ' •• r; . . ....• .'_ [' ,- ..... ", ' . _, [',", IW .]. -"'. - 'I I .. "-r" .. - " .. " -," -, I'" or ,.

sue, as 1.1 " -(I' 100. 0. '2:.'" mo eee es, as ~"~,,e. IS ""WI ,~LS10!ll ano runs, ormm on

:~ - [i'h" '" ,'~i.~dl t" '["'" ,",1 ~,L" 1'1' "ir" .~, " d ',' " nd ,,' ,tL, , ',' ,It' ". 'C'~" •• , ,:' " 1[7" 1i] 'Q\ti", .. " c' '.' ", ',' " ,

~n k" ,Ie ~(),~,~,1", ~,h.a Je'i an.lW· !))Ue,re,l,o,re-;,. "epen." on !!'ue _P3 , JIC~,le s~ze " ,IJ, ,. ,F,w,ncesses.

i,[Ilvolving a high input of :mechal1l'icfll en,e~G:Y:~ 8'L1C'h as. ,the shear creased duriog milllng 3:nd. the pressure o!ppUed during ta:ble'ltn.g, "'131, are cepa <Ie cif in-

dr ,~'~ '-, ,'- '" ." 1"" - ii"~'(]I' .-L,., ',II'ri>'''- ,~"",~ " "i'.'~ -,~, A·".-iI" ", '. iib .. 'iii' ".dI b ~ J'_. '~~L "~~,~

I lJICI,!I1g or !i!~.ceed~J';th.lr[t. pnase 11!lI, ansreemauons, "; ,S llLcm.o,I!lS,u a~!eu '~.J "Q,,,,!Qd!'M " ,,,IJ

foe fo i1- edil 1'["'''i~1 'fbjfi;, iII·v·n~,.;. of mill employed and - ;tb.;a; added excipients g~ ·i:'E!I''liii:t,.,

II;.}.', ,~,I '" I.~' II" ,~ '~JII, !l,_~,W!""" llJ.-,j.' .r-' .... ., I, ,.1, "LU,U, ..... ~IIII)~,'V.J v . ' 'u I, 11I,j,ll" .... iQ_lJ!i!!i;;. , """,A',,",,,., .~,I,,"",u" "II'"",;YL,

ly influence the transfeematlon.

The solid .. -state propenies of the dfUl,g 8ub.J9Jl1.c1e", its (HIt. forms 'po'~y ... morphs, and sO'~,"I3Jte!~t; SlJu;:.Jl a, the solid-solid, solid .. liquid, liqlilid=U,;(~JllJIid~, and solid .. -ga eq:ui~'rn'bria and transformadons, are derw ved from 'nhe ther.mOQ)ffJam .. ic phase diagrams, wbich expres s ~he influence '0" temperature 811d pre' sure, Expeditious product developmenr requires rapid recognition of the form that, ls ~heFrnnod,Yfila'micaUy :s:tab'~,e: under a range of relevant ~e:mJPf!':riIJmFeS a:rud water vapor pressures. The characteri zat~(l~ and s~JUdy of pol )"m,orp:hs and :pseudo;-poly morp'hs is Iqu:~te complex. It is 1L1SIlIIlllly important '~O know whether the solid under study is a, mixture of phases a metastable form, or a :':tab:~e form at '~he 'te:m:,eratlllr-e ,and. other ,colDl(Uti.ons. o:f :n~er-est However, the kioetic factor in solid-solid ttans:fonnad;o,m,$ complicate 't'true' interpretations, Therefore, s~rV'end methods should be applied to the study of soUd phases and, their trans,:i'~i.on~,~ These methods have been described in, Sec« .1.. Chemical ;ftna'~:y'sis. after 'traitlts:~bfmfllUo:n avoids ml~'~leooing: hl~,erpretatio:[ii/: dii_,at ,could, arise 'from iso:tl1·erizatio(n~ dimerization, an.dJol:r decomposi~ion,. Thermal ana~,:y~ical method s jn w hich a phY:SI,'cl'~ property I suc:b as the now of heat ener = ,g)' OJ' weight, I' :mn,em' sured as a function of tempe,[jll,t~ul'llie~ or as function 'of time, '\vh1~!e 't'he sub 'lance is :ubjected to a. temper,at,u:~e program, are ,e· pecially valuabje for 'dlC study of polymorphi .. lll and pseudo-polymorphism [I 8;] [,5.3]1 rl,41 1['5].,

D!w'fferem:tiai~l :slcan:nlng;: calori me:try I(DSC •... measures the heat flo',",' dq/dt. '~ml~~) and oU' of a sample. ICe.:'. relative 'to, a reference cell in ,aJ, ,contr'o,li!ed, al-

'm-~ io sp iiI-.';;;.;n~ over .!iiJo def ~]. ned tern iperatu ~ range 'W;,,.,Ib";"IPIi '!'lim avail a Ib.;~l.;fi, 'I~g.:ni(l!!\a 'I,.;.,a,

_~.' '.;:II,·,w ~""',L!~ 'v' ~ ~, M U!I;;.o', ,UII!.'·· !:,""", ,.", ... tilit ... '~,!!i;;- ... '"_ '': . ~ '.~: iII,Uh.1!ol Q,IILII ,'_,~ ~,W : l!JJ,~"", ,II. ,All ~bli;" U!!;,o""

tween -50 to >.3'00 Q,C'" ,Fig',. ,19 Sb"OW", ty,p:icalleven~:· in, :DSC'~ t: .ir; change of heat c.a:PI;city at glass tT,ans,i~io:m, Iud changes in. enthalpy, nam,e,:~y exothermic

'l'II·· ..;III.'L. '" ~ ,. d 'I!.. ,. Ai 0, ,. E

cry I sta .1:IJ:latlo!lll~ encotnermtc menmg, ML_ e>UJibler.mlc uecompo· ,~Uon" ., :'Y'ef)!

DSC '.:mudy 8hcHlld, include 5C~n!) ,aI, difler,t.il't 'he&t~ ng rates b~ClIJUJ'~Je D,Se is a

dvnamic 'm" . eth .... ..J1 2r~id fi,O' :il'·'d'~ -sta '~'I~ 'ti- ~-,'.~ .. fo :'~'~,~ "'lI1't"I~' -~ I~ WII;"li ~ 'b,,::.:,i'_.I~ ,t:Iii-.,·~,·· ~ ~ _ • .:t.,! ',~ -~ ~ ~ '--,;'~~'c~ __ ~~ ~.:_~~UU.~ ~.IL ~,d_ 5, \\'" \\r~U1SJJ'.rm~L,~,on>il,;.,.~Ud~ ue,~n,g uwer.muu'yflIam~

.' ]'~l dn kineti I'll ~II . ..:1 TI!.. DSC' ~~l d'· ~ ,. I' ill>L,

U::I, ,(1 .. ' nven, are kmeuca .IY 'co.Ill'~ro.~!l'e!iJl", " .ne ,'~. seans w'h:;__ trrer 1:~~ me sam-

ple under '.' ~ ~dy is stable or metastable at, a:mb:ien~. tempCF,i~uF!e ' ,8,'·· shown In

1:1' U·'

Copy rig hted m ateri al

:6'Q

-e. .. ()

PHlAltMACEUT.~CAL ;SALTS;

Endo,

{JI '\

~,~.

~ 'ii"

~~\' ~,

~~ -

,

,

,~ ,(), ,', , ..:ml,p;. [17'] ..1,6; , '" , ·I·~I II l' 't 'iii" ii''I,.;,;' ,'11" "" " ,L,,· , ] "II"'": ' ,'t-.,~ 'f"

I.gs. '';;';''j.Q anu (]_,' , • , ,ue sc,ans :~nUS:r.a~e ItU,e :pchym,UI])~wlC ,F!e,:a,,,; .o1]I',IJ11,:PI 01.

'["\\V'O" ',~~II']"F1,C S A> an ... il, B,-

. . .11IV~, ]lll ~.II..!, 1" U ~

The 831m,pIe studied is the s.lab:~e: form A" 'which gives the endother ... mie solid pha se tran ~iti,on ,,'~' ]3., (see ,,' ilJ'" j Q. ),' fOi,~OI.o,wed, by the melting endother.m of form B"

TD6. ~ tud · , d '. i:II6., _ [. jb'~" 'f" , "" A 'lib. f ,t'" t'· " " t:· , .

~ ie sampie ;s, 'UU:U~l~ is me sra ,I,we rorrn ' "f. mn, ror xmenc reason ',,,

the SO,~ id '[['anSrOnll~,t~,On. A -+ ,8 does not OCC'IJ,r.:. Instead j fO'l",m A melts,

The sample ~n~dw!d is the 8~lb[ie 'form A, whleh melta.Porm B crystallizes fOOiM n~e~ 'melt: '~~id~, ,an ,exo:therm'ic peak, a'nd fOil'rn, B '~fu~~~ts ,at,

a h ~ O'iIi.. er tem 'P' eransre

[~_ ,.IJIlI~~lm,· .. 11i"_", , .. ,. 1[(_.~IILIltJ,~IIi'

" ,'he s ample studied :i s the metastable 'form B. \I,,,hic:h become .... stable at a, hrn,,=:her ~e:mpenture' above 't'~e tl,an ... ,[dlon tempera .. ture,

: n exothermic :pe.ak ICO,l,FEF ponds to the~'oIUd. b',an(·,fb,:rm_~l'nj,oin B '9' A" followed by successive t~aJIJ~'~Dfmadon A '~' B and me'-dns of B".

Scan j;. The sample ~.~nudwled is the 'meta~;iajJb~,I~ ferm B,., The 'DSie' Lean shows its m,elth!l,~ end ~dlefm,

Sean 1.

'" .;H ,".. 3,'

ocan s.

Case' of ,'fI:OJ~'ot.rop,' I~Fi8., 2(JI~.b· ,.

Scan 1. The sample studied 'w s the : ~:tlb_le :fo,mt ,A , and it, meldng enciJ.oM'wenn is, observed.

Copy rig hted m ateri al

nD,O'-:'D~'R-.' -],·m ~(': S':IPL, ECTION AND U,~JE

,Ir·~ .. £"l(;fi ""~ I;'.r~f. .,IC._ ~ _' _ ~ ,~, _ __ ~~

a,) CD



~A .

~---+-"""",,,,,,,,,,,,,,,,,,,;,,,,,,,,,,,,,,,,,,,,""~~lh

1:f· .' A.' " T~, a

I" IUi~

1 L_____

Endo, f,;,."

+0

®

,

, ,

- 0
'_
"'C
~.
fi;
-g i
........ 'e!) B ~ I
3\: I
;
0 •
II;: r~
,~
m
~
L b),
G) A
, ,~ig, 20", 'rJl~(J'relic"{jt DSC G'UI!"'ii,'e$ (If P(J,")~ii~(tt--pJt$,; ~) "N:Qli,tiottvlJicaU)'-rfticd"(!-d _poiym',(}Ipils; b) ,m,fJ';i~'tril)p,i;f."aily'_'"el(J.';e:d p.O'ly',ru),rJJi~'S', :PCt'i"f d.etaUs;, see test,

- _

The sample s~ud.'~ed is th'e metastable form B t. which transforms exotthe:r,mJi,e~U.y li.n the so':~'wd state Into 'the; s~alb]e form ,A,. 'Form A, melts am, a bwgher temperature,

The san~pl:~e S~u(U,led :is tthe: mem's;~a'b]e form, :B,,~, wbw(~h dots not transform i.nto! A 'but: melts, endothermically .. From the melt, the stable ,c:rysti~Une form A, appears, 'with an exothermic peak, Then, A, melrs ,at a, higher temperature,

Similar interpretations a;plply 'no all methods that involve heating (e" g .. '~J hot .. -stage ,optical microscopy, hot .. stage lR 0,( Ralfl£lf!: m:~,icroscO,PY" t:e,mpl;}ra-

'11.,,3 .' 'ii-..]- 'X'.-:I '" ,fc'b - )

ture ... reSO'f'\{CU il):r v a._r~av ,e,m te~.upe:.r,af,ure, ... ray U~ir~:I-,ac~,oi:mie~.ry, •. ,

.Fig., ,2,1 shows an example of a, DISIC curve, 'w:hl,ch, is, observed in. the ease of enanriotropy, This is, not ~.h.e case for the :hyd~Fochiio:tide ~~HIU of a drug cancl.~date; presented 1:0 ,Fig, 2'2'~ 'The form A, melts, .and, various olher foems grow'

S 2.

.' 'lie -.- .

C-8Jrn '. '.

S'-C."'lnll'il, 'l ··".".iUUI J,.

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70

a)

o '"Oi

te.

W

ill

W

50

15

'1- eo

"u···

tzs ~lU

1'15

Fi ~'''" 2]" DISC C~~I1;',es o,r.tw,o "}OlW~'lOI'nllS. ;\, ' ,a)1 ajul B {b). ,(J,i'a,_tvbl,llrJ!I"Ocailt - [:I. :8;]'. PO,IVlffiO'mlliru ,8

[b J I' w' J!~ .'] __ '11' 1I,r,'

ulndet:goos an enant ~ou·op':ic trans~doml to polymorp~~1 A !,t t ~ 40~ 150 ~c.!,

from rhe melt, although they may not be pre ·en~ in the lorigrunait solid s:a.mp;~I~s

. '- =

studied as resulti ~:g from the X-ta:y diffraction wHa1Y'~'~' '.

n is difficult to distinguish between :mon.o'tool~Y and enantictropy in the case of Fig. 2'OI,~a,! SC;iUl 51' and Fig. 2'01'10, Scan I, as well as Fig, ,1',0\,,,,!, Sean J, and F ifj',. 20,b- Scan 3., The int,erp,retntion of the :DSC 'C1Jn~Vf;!, i '. facilitated by

fl,-,.· B' - '~ .. rn ,~-' " iitll] -, .·,iIt f" " ' •. '., ' ~I " [2'-1111 ~ ,. ,iIr ;ii-!b. . lb.,·' L., ., _ .. '1It--·"'· ,i":, . 1Il-.., " the

tile ,., ,l"gel S enl~illJal,py ot , uston rute / JI" h. me u~,gwwe,I=',~De,~. mg rorm nas ., e

~ ] . ~ h 't bo 1- '~ 1 . d ,'..~. 1'1 A' d

. ..' ..- ",- . . ~ . ,".. " ",[ - 'u _ . . _; !' . :", ," ."d· ' .. ' • '... . ~ • - _.' I, I . I "" . I, L~. '. I"" I , I .' . ,".",.1., I···.. .' .. '. I' ",:' ',. • • ..' 'f '. , .

ower me 1~11.:g; ent a py. botn "O,[lnSI are re ate elru~!Ult!lOLr()p,u:a:y., ·s- emon-

t:',t~IIi"'!O~I'I,,;!;',d' I in Table ,-3·.'-:·,~ for ,~~ benzi socuinoline b- vd rochloridc [' ,P,] ~ tbe ' melting .n,IIi'1I""'

~ .~ gl. JIW .L. I' [!1.I. , r ~ , . g ~lII.lIJw~. V, ... lIJIUIj'lU!,W.w. l!!i.J ~.J- . ~,lLIJlu ,mJ..~ ,0 ~I ~w~w.. , .. ~.I. llUIUJ r !\\.rIILi

.'~-~ ~'I- ~ ~ - ~ '-~ 'llil-I~ ~ hi ~ h ~ -~ ~~ ~,~ h. -+-~ ~ '.~~ -- - - B" e ~ 1- ~ ~~- ~ - '-1~~ ~ -~ th ~ - - ~'I~--·'· - - - - ·.'h- '~- - f~'A'

" ... ' .. '" . ., '.' p.... , - - - - D' ,- ~ .. ' .., . "W' . - " - '.'" - . . '; 0"'" -' , ,., , ' .

tna ply (]1, ~ e ng ,: er-me tmg orm .' is : ower ~ ~.an t e me nng ent a PY 0 .', l,~

The refo ire, the ~'\l-Vi~ forms are allfli 9In'it'~in~'ro·~ ·"'p~, .... 'rmI1'~I'v 'l"JO;II.r'!iI"'_""~~ ~111!~:'th' '~nl('I'TJ" A',', ,"i-g,iIl.,.:~I,Q be-

w w _,,!!;,r . , " :~,u ~ _ ,~ .. , v III. V~, ,,11,,-, iIllIi· ,..... !!;.o ,II ,L RJ_U 'L-III,'V Ill.. , -1I,!I;,.!I;!lI _~',J ,'!!;,o!i1.t!Ii}U:::U"n ,W,l, _ ll'v,iI, J, ., ",'Lt_~lti.UIlO,.o .- '""'

111'0' w· the 'i"'iiT'"'li,rn .'., ~ iii' ~ o'-in' 'p-Fii'~11!l iii' M···· ·,""...11~ flcati o··-:n· 'B- '~Q' :h' ''!lJ'om····~J .... ,n:ni!' .': ;lJj1"i"ii d und ,::!!;'fn-~ .-'.n.~_

~. ". !lW W" loW i[IIi.I.lI-· ,W d.·." " , ,'!WI III, . ,1[.. ·~,lIlJ"UdLl,!li..niu;'·,,,, ,., ,III i:) ; I ,1 ,~ ,c ifi,II,.o'V!t'"',~I.·~ ~~I.: ~;, ,IU"", ~ ~,vro,...-·, ,ii "'_ v~,

vent-mediated transition '1'0' A in alcohols st ambiem te r'npe[,a'~)llr~,.

'11",. ~,!b". -- . I .' ' I': ;'.- trv (T~"O"-:- ~ TO' ~ -~::-, A.)' th ". ",'l\."., ... "f-' th '-. " .' ,,·.of- - ',', , . .- "'1 :'

,1111 mermog a.v,~mely .-,~ ",n,. I.. e enange 0 me mass o~, a, S8J11P e 1S

d t · d i - h 'b '~ f' ~' f' .. .- dI- ,-, - '.

I .'. ',-.-'" ~'~-,' . ,~,~. :' " . ,.-~ .. " - .. ":' .-,~" .- , " ~ ,~ ',: .~ .,.-, ... -{ .~: - -: '-. -__:~= "~r'l- , :-~. '-, :,' -c ,,-,~ ... ~-.~,

eter 1lI111n,e _, III a, u ermo na ance as ,8 rune non 0._, temperature ,an_ or u me,

Most insuuments record. the percentage '0,1 mass chaege and the derivative curve (DTG)'1 which shows the 'rate of the :m3JS~, ch8n,e,e wi:~h respect to temperature or time. Fig. 23 shows 'the DS,IC and LJ(] ~~caln:s, of a salt obtained 3(,

h ,..;1,-"., .- ' .. 'c,-O·:····H' "'~II ~,", _AI ~-d~" Iil"~ ith-'" ~ ---'~ ·~-'·O··u·jl.Jr '01 '. ~ .j".. l~

, l!JIJ,a~e or as, an ,lCrt_",_,,~ SO.wl,a~e ,y,epen_.rnn~ on I~. e ratu:"1'JUJlt"lJ'2"" lIW ~I~e :n -

vent '~n Fli ~rit'!I the temeeran 1 ~ of rflJ fo; .PiflI']- 'r "'"" - ~"' h--

:' .... ,I,~. ~ 0;, ,'Uj uw il . III ["'" IL:",", , :":F .... ,<U",ll~,-~ '_', ,~; ~j'~!I;~<_,~:Wi.;.id:'!Y":n,.

S ] it- • .. ., -, II - • ,~, ~, .- , . ..m~' iii· ~~... 'm _ .. , ~. ~ ]~ -~'~ ~- - - Ii' - ~ -~ ~ ~ - ~ ~ - ~ ~

0: ,U'~~M)m1 nuerocasonmeuy ,Inu .~'SIOI~~~e~Uua~, 'mlCfi lea, · .. 'nme~_ry are compie-

... , "i" . ~ .,,,_ - . " , ' , ' " "T~h' '~I 'Jej'" ',' '~I' _..,.- iii''''' ~ .. ,- '~. ]-1-'" .,.;4, II'h-- 'I),'~ ,ur"'I-menrary l~eCIIJ,lJrnll,qt:U;:s., .ne ,~,a[,~er vorumes 0'" me 'CamplJ[e, ,t, H~' 3Ji[ii,u u e ,~~l.&M,I~r

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01"
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,
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m,
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l 2
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0
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:)i(:
WI
3 1S

100

12:5

150

IF:ic~ 22, ,DS.' SeemS( of dblrN! .batd~(!'~· IrJI a d'r.UI: c'tluiJidili'e. Codit' 2105-J9'? il)'d,"(}chl()r;j~dit. ~l Jd~nilc1r ql,wlii]i .acC'o.rdi:uS' 1;0' ptJwi.ler .)!:~,r[lY diffr(;l,CI~Ij.'(1m (form .A.} bi'~'J' Sh()iIIL'1i:ng diffi' '~"e~l~' .bella vior

I.. ,U W~rJl1 1.P' .i':',], 'j ['I Q] '~') A.,~" ", '11.'- 'liT ,.,jf' 'f'" -, ,A. .,11-.., -!~.~,- ~j! .', . - .' - ,r,'. ,--" .. C··! ,Jli..t ...... " , ...ill ,i::,- , .) QuO '. ,I'" ,.8 ',', t . dl~. , ' ,;o...IJ nnJeif me, ~,m~ 0111 "orm, ell,. U~e eIill~n'i I,QIW,Pl(:: .I:Omriil < .I. 'Ou,aruiliilelll! ,lrom:

tllm,{':: mHeB::, 2> iiIJ :l1l~'la.s~,abl·e i(Qif.m. .B·. .;ilJ:l!ilrill~lIft}'pI:ic to tbe stab~]e form A~ ~s. (Dbta:i ned ';~mm. the melt; J) O~ I,.y 'Ihe :me~~ing pe;mk, ,of ihe 'WQ(un ,A., i:s ~b[eMV~~.

Copy rig hted m ateri al

1'2

Taib:lf! J. Songlf ,Ph:ys,~'cat Pmpe.rt,~es 01 T1/L1'O Crys~Qlllitle ,FOmlS l'ff a ,lIe,M'tiS:€JqJ~ln(JJi~,i'e' Hydro .... dd'o,ri:ae ni~t1", A,~ Ei;'(J"'IIti{},t'~"Op~(;{}J;~l)!' R!e~~~lf!.tl [~,,;'1

'!IlL. ',_ ,~,

,~lI!Jl)peil!-'~Y

" I[g~]

,'".p',. ,-~,-

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70 1 :3,0 1 QO

l8Mlipa ratu rl@; f~'C]

2'£0'-1

.... iJ.'.'-'

701 130 '11 'QO ,200

TemlpSIratlLlf9 r~iC] ,~

'P1 g. 2:t :Le.ft iDSC (""awe' 0/ ~' ,~:ydr:lJJ/.(j' I(CU~ ;I) ,and tJ,' so$ImJ:e (CU!Flj/l b-). R:iaiirut:: t~~'I! c{Jlrre:spo"uJ'.= ,~,~g' m ,c,~~n)',e'.r., ,en~~I:,r"~1l ,~'e' fJ-():sili'(,m, at tJ~t! lleJ~)ritmt,~(J~,r, a~~id' ,$f!!;JWI:!~'1,~(J.'n ,lMQ-k~ to' be eOl.npllnid' [ ~,Bl·

Copy rig hte d m ateri al

' ......

i!'Ii!i J.-_'.

I).

::r:

1:::)(.0

an illf.U

G'n, Uu

1100

I'

'F~g. 24·. ,rue C[U1!'£'~' l~'UJ,' l'e,~';'i:tjeratm'e rf!~YJI11,e:d X~'nJ1)1 diffi'ac.r;(!J,''llnltJs of ,'!i'e .1~'I.U";W1ll,d.e.I·il'I(Jli~,re M.K.S 4"92'

<;Ii solvent .... areful ·o-b·'~oi."il-r·tI{lj;t-·;:,ii'1i;Iij1, or '~'~'A '~m--''''' In '-'n:' = "\0'1- ld ~:-. ,,- d.'-~' - ;;;,- t .-.-~ ..:il :-.oO.. e. c·_, --.!It ,it~. ,i:!i'v_ .... ~.l!!J. !I;;;~.~"'" I~~' ,g~_'lf~I-.~vn-· IIl,WW'V 1[""", ,J::U l, g .S,· 1. 1· a, ' In;C~, anu le,u,lC,~erullll.

·wa.'li' to :s;tw:dl\-r the ehasc trnn sfonnation. However . as emphasized bv B'1iJF.n~

- - -J - - - - -" - ~ - !r- - -- -~ --- - ---- .. - - -- - - .. ,. - - - -" _(I. . Ji·.t" .

et a't·, [76i]~ the cleare -t mdicationof the existence of polymorphs a;nd solvares

.~~, d er '1- ved ·l'ii'iO·IIT11ol XC:" ra v crvst >Eli iUO- '. pI';,j;·nlll'lli"I- .... · ex arnin 0 iii'I' '0'11 o'f': sin i!0I,'I.... lI""iIi,;},~·t·~,1,~

h!J; . -,'IW. ... '!jf~' m.I!' '.,111.11',.- .-a.i' -. j a 'iilJl!I.'_'·~.":'~.!o.fill.w .. ~ ~. -,~I . I " I~'!l- '._ ' .... _'. o:j!.~._'_.,~._.11!# ''''''III'i';'iI'!;.-~'-'!i •.

Studies of hydrat,e formatlon widl water-sorptiori isotherms have been

d':l' !P..t"<'I"!I:".~.;!i;..-1 'rlin, Sect 3···: ~ The ,~'Y Qm---n,·lla. zivcn ';;'[1' Fig '5,; fo '-'I~ tetracaine ~l"Y:"d: ·I1',;i"Ii; .... '1_1Ii·~IO· =

_ l~,~~ ~ ~)i~~llJ, ~.~ ~ ~I [ ~'5!" '.' 'i4"J1!; , ~ W'l!r.~ ~A~ r,~IIJr' c v. 'IJrI.lIJ.1 ,I. 1(" [~l .• :,'_ ~ :. I··" .. j ~~!~J. ~.(_'_lIll.. ,W.W _' -," ill V.~l .lIKW:, _' -

ride :i.'~'~:u~trat,e~ ~he compi:~txi~.y· of inve stigations 0'( POlY:~110Illhi' m ... 110 obt.a_~·n the relationships between s ix nO;~·lj.(m(n-ip'h', a tetrahy drate, I nruo.'[}ohvdria·~-e- ;~md

- - - - - - - _. - - - - ,_: - • _._ . - ~2iI' ,J' .. l . ~ •• .• • _ •.. .' •. .:!!I - I . ., I, . J' . . ,f •

a hem :rn·hy.dr'-~a·~,p. ,0'. ,f '1~11'~'c-i.!ii';i'ifie fij".lj'~.ffiO·. chloride ~""'D·~." several ~'·""-'i-Il":·lI.L.ir'il'1· OI11;iJi;. were li'iIiQ,;f"' .... ·

__ __ _ _ _~ _ __ _ __ r;".< _ ~!..~ g ,y~~,~",", ~~,,;r U.IIL' ,",lJW.v~.,!liJ1Ij;.o' ~ i 0JII, . !I;.,o'f "w.w. I~"",UU ""lU'!I;.o . W'",,". _ .Ill'!!..!'"",

l' ~- -~, -,. 'DIS--:-C'- "- ''T'',O' 'FR" -, _- - - 'I" ..... '.- .' -. ". , ,il· . - . ..:1 _'-. . ..... -, _". _. ". . ..... .Ai ·X····

e-'SsIJ~y" . ,-' .~ Jj! r, J[~ : -.pec~IT!OSCO,P'y~ regmar auu temperaiare re ,'0. \~l~.!J. ",.--r.ay

di ffractemetrv, and solubil i[y~.·.. studies i 0 different' '.01 vents N',o 'no'h-rmo1"mh]'~m

---=------ ~--- "',,.1' _H - -, _;. .. •• _ •••• _" - • -'" '·-.F·-·,1 __ .... I!" __ -_s_.J_.

was observed for me tetli,aca.'~'Fl:e 'base; it e~f.

Copy rig hted m ateri al

74

c-pH- -Al- m,~.If ,~" 'C' iC'UTiiiC-' AL~ iliZ"Al' ~~ _', _ ... ~. ~_J~\tl1l·. ~., " ~ ~ .. ", :~. :"L1IIJ d:

t49-1150eC 100 J;g

. i ~

I _ CQ@Ung

I "",,'-i'V'Ol" i"ifii '!;;;I~_!!!:::::!I

~,26~'C I l' ,J~g I

I I

~

'92% Wa~eJ r.h

FrtIQ.'Ormll tern,p~~tLir,e:

Fig", 25. l?:'t,l:"~'j',~i(JJilJj~,'i.ip'S.· bt,;W'€'1 ~t~ s~t ,c,~",I:!JI'Ci:~'U~j\' form'S. cUi: ",jjj)fjtpho[~'-'I' jfJt-m. (j~1'd' i:'li"{1!> - ,'fjyiltl.!/:(t'(/ forms of tetracain« h)'d.'r(:u:hJ.;(!).lri,l~, Am: amQ~ph!O~s f[amm~ T; ~:erulll"ahydJr.~t""'i M::: mOf]ohydr~de~ M:: !mte:l1lih~d~-at-e,

X-· 'n,J;C'V, .. F'·:.\f:~~""""'O'IJl' D"-'S"le' ;(10,,",£1 T'G'-'-:' a- ,-.-~-~~-, "",,~fj::-li~I'~1 'W' hen decldine ,-- '~'Oi"- jC

~ ,-,lr\.:I;~ Ul"Lr~~I!l,_.,·~l~,,;_ ". ,~IlL_ ,11 ','- ',~_!!!,II;;;< vl"",r), U'li;,':)~JI! ':. ,",-gn '!!;,'lI;;.m! lll,s -tiI,p- n a,

sa~~ form, By these techniques typica] questions, w':llliich can 'be answered 'by

", '0]· - ~ - ~ • "h- 1- " --. d' I' d d '.

... r. . - I, .', ~,' " I?- " -. • ,,- - ',011, . 1"'Iii' .• ,,~ • - '! - I .. - - .' ',.', • ~,- " .". - .. J H - - .

~ U rn,ma, , : e In ves uganons, are: is t . e so ven~, retame , o-r reiease -"-' un .'. er C1erLi;IlO

dj"-" th '~- I] - ~1' th h '. th

..... ,-1'.-", •. ·'E . se .. ,,] '1' '··c· .. ',', .. 1 I. -'-'I'~ :i=j-'] L.' .•.• r.1 n .... I,"' .,-',-,,~ ~' .•••. :-,-

con _ mons; are u e S3. ts eqju,a. .y crystau .• ne; are u .. "ley ~L.y'~rilsco_plC., are u _ley

'b"1 luri - -h -. - hei 'I '-tru·, b h '. ., h f-'

, , , - " - -- , '0' ' "'.!!j ,., '".- ' . - ,-, ' , I' -, - ',' , -''' -" ',..- ' , '" ' • -, , '" ,

SUI I' ie c unng S~ol,F.a~e'i' w, at ts t. e~11' po",ymolrp~Jc ··eL~;aVlO,F,~; U~ tne manu_,ac-

tured salt a uue salt ow' a eutectic mhllure:;, does the salt .re~mlil] undissociat-

d ,',-, the , ""I,',A state ,'", 1E-ib.'-, ,"1'-' - -- "'; tical 'f~:" .--: ,'II,-'f;' 1-1 [[':::3':] T' .111-."', -"·1'-'" tu

'e ,.. 1.n. 'i.. .'e .s:o.~u. s. ~h,~ 1.11 1~lne P', :u~rmacel],III,~CaL. . or.mUJ.~,a~Ullll. " .,JI _. ,. "ue ,e.x,pen:'"'"

ments described. few the study of polyrnorphs allow to establish the relation-

"I ,~'" ii1.., "i" ,- , -" -.]'. '~jj;; ,t· 'ilk·. t~ ,;111...:1' D" - 2~'·£ 'n'~ ~, 'D' "'g"·:'c'-" , - ,~ --, 're Ii'~ ~

S,l~,IPS eetween severe sans ro ee ~hlb,)!leu". r'~8',. ,>v snows ,:' curves ,0,,_, Il,W'O'

S'!'im ~¢ 3~' ,., and "I,~ 'II form ~1 ~V' ''1Ii 1r--ii'j,O 'b:,IlfIo'~ ,e candi ~L~,tt,e 'W :,It'h' fum 9.:r-~ic,_-' acid _ 'Ir.,iI!niltk

~ g~ ~iJi'~J '. 'i! ~ g.,~. _ ~,~ J '~l ~/ l!J .,~~U, I!JJ~' g u, UIC:i I!JJ~. ~ ~ ~:I.~, 1I1UQ~~ '. e- ,III.: . !~t J.lW ,w.. '~11J !I! Uv!~lI.~,

salts could be ,crys;na.~~ized :rFUn1. the same solvents, depending up-n~ he con-

_. I it=i! I

d-· '. " '~'~- ~ '. 'E ·"~"·b· f 1 'n' f' th lts .

,[", .. --:'.--:':;' .. -,: ~_ . .:..~,::_;.I. ~"I"~.'" -.~. .~ -,~, ~I--~' '1._,--: ~ .. r,:. • .~.~I '. :'_ .~- ..... _. _ : .• : .• : .... ,'. :'~"~ II

" ~. non S 0- 'c.ry.~mW,_ll,ahon"" qu.~ _11 .. r,a~10n 0_, _.' ,. ~n~ xtures 0,"- . -e two "a ts U~,

1l:i'['Q" ""'H' ,-,', ;' '-P' "O,-,""H' s~" '\V ':0.4 the nefere '{""-'l- -,,~. - -t"'~]" ""itt',,, :r' ;1.' ... · 'm "I fu . iI' .

& ,[, .-, . or 1-,: II 'c. w wwo,.~ ,~u,u~ pu~ fl en' ~,a ClyS ;3.1 J:zal~,lO,rn1i O. . cUil,e .1Il ,; .1, liuwa;ra'le

salt [[53] ..

(i"., . ··ta,biUl ... ' Beba;vjcn~

Solid-state reactions 'fall wn~ol three categories; .' o:~~.d .. o~id reaction, solid .. ,g3"'" reaetious, and sO:~ . .''',d tJT.an[<onn;at~,ons.. So~'~d, transformation ... have been dis[cussed, m Sect. 5, For example, tolbutamide can 'und}crgo an enalil;UOiRropwl{'~ transitien at, 40 QC [[75~" Jf the chosen polymorphic 'form is sensitive to ,3,

chanae of temnerature oressure or mn0;i,,!s-hrl'fie: 'm" . ethods "~ni'" q' uantif ~-nl~~ ~1ii'iI1 of

_ __- ~ _ ~ ~ ~ ~ ~ ~_~ ~ ~ _ ~l lzr~ _~ __ ~ ~ ~ ~ _~~V~!IJJ.~~~~ .§!, ~IU;Jf. u.S lI.Vt!l ". 'Y~_ ~;l.I,~!I!w~~~ji!~r.~VIIUlJ 'lW'll

Copy rig hted m ateri al

prtOPERT.~E$" sarcno ... '. AND US'IE

'7':::;:'

. ,.)1

, f) ...

..... ",

1

d)

- ~

'~ b)1

-.' ,____ ....

;J -

eo

100

1:20

Tem pera~lJIre f~'C) .- '

Fig. :26. D'SC C'!M1)1fS f;,f Itr,i./JtU~I-e,'_';; 0/ U'1f() di/f:e,r:en.I,' ft,m~(U~$,~e Jj,t;#~f o[ ~' IJlj~~iC' ,i~~ ves,~i,cu'io',i'(Ji ,'lr~ft: si&i'bsl'uJ\,ce., a) ~~:m~'lIi'ate salt A (bas'el'ac:id 1: I}; b) f[Jlm~nl'~e sj!.IJ~lt B (ba·. ela~:id 3:,2);, c) '~I: 1. mliix:= il'JIll e 'F' .1'1..1 d DI' I "'b . iii' AI ' . iu::lO· 'M ! iDi...iF'IiiUl• "') ~I. '! ' ,!,~, .... 'f'" ··';1 '1I!l1 I!t~ ,.,.- ··d'· -,) 'II., '~I ",_.Ii _. 0' n ,~U D'" ~qu~1 . r,n~:eu U1j, w.;;;, ,., or ~-lrl~ un ~ Ii ~.,~ nuJ'{IL)!jr.~ Illl. J.\. ,ru1tu, ,iIUI ~ crm]!Ii1L ; il, l~ co' ~

[ll1IliIJ~,x:iure of A and B,;. p] aced ditrectrny ~W!!J ~e sample ~~:~ f) ~;, [ nl'iX®lli!Jf~ '!Dif A ~nd Jil, ~qonibr~~~d

~mli ·cO:Et"

1Ii'k,a, cha ri'i"j1'ol!i,';;-; m;:!!!ijfi,AI '("·0" b .. edev '.a.l~ n "~~~ For th ~ , .-~ ~ Co ,'~ "n," e ·-:b ~ . 'Ii!!!; .~ ,- C"~ " ~ - n ... -{I,·',~ .~, ~~·t·~~ --:.::-, .

I~,U""", '''''',,,; 'PI!!,I!~"";o!' !!!!!,..;.""",u '_ .' UII;,;r"C: v'PI/;"tU!L, ·.1 lUS pUqJv I"",,,~ pua.~-pu[,,,-, mvurn~l.ca w.on"

have '~O 'be produced, 'VaJuabl:e methods for Iqual1li~it2l,'li,ve analysis are :pDi\1vder X'~·:r.ay diffractometry [79] l6411~1 ,R'al,1tean, spectre OOP'Y (,8iO][,~, dJftu"e reflectance lR. spectroscopy '80~ or atte Wltm at ed, re:necm.11.'ce spectroscopy [:8,2]" . solid-state Il'C-:NM,R spectre coply with hi~h-pow,er proton decoupling; cross-polarizadolO (CP'il1 and maaic anale spinniag IM'ASI [[1611 n-:83~ '1':84],~ The Hllll1Ji~~', of de:",

. - ~ . ~ - J - ~ ~ ~ - - - - -~~ . -~ ,~. ~~ -~- - ~iI:'i '\ - '" . _" .. JJ .l. J ~ . ~ ~ . .,.. ,. 11. , , ...

rection and the quaH~y (lif the. results obtained depend [atg,e::~.y on the sensitiv-

"lit _. ~ ~ d ~. ,- U' ..- ~'m ~1It' 'v';' iii· "f·· ,th~ .-. . ," or'·· "1 ~ ;" ~ , dl it·· .. ~I' ,j', . 'Ie'. U '... '~'h

l~,y .an ... ' on . lie SE;,w.eC1!l.1.· ~.l~y 0 . ~·.e Slona. ~u;,slg.n.e: IlO !eaC,l !lOm1," ror ;~jb I. nl~~· =

~I u, • f 1 '~I· •• 1 f' ''II h Id b .'....lI

oas, 'h'le preparanon 0' t ae sampres :~;s a enuca . : actor, Jl'[ ". aotua ee aseenamed

that the prepared forms 8JJie phss e .. pure 3Jlld :si~3Lb~e enough, if metas~wb~,e, ~,o! sur-C:\fi ve the experl mental conditions eMp;~ioye{L The; method s lUI.·· :e;j, should,

't .. c •. 'I .. · '. ,', to '~ .. '. ~d:' ~. tic ,,,,~, . . ''Iil u bilit I' .. ' ,or' , ,·',t . b.'ll ..,f!. ~, .. ',,, ·~·h . ,fl.,·· ,.

taee IU 0 conssaera ion me :I. at ,~,['liI;.y 0. S[W,h,(lo',le rererenees, I' UC. as me m-

dividual polymorphic forms, ,ru~mue:rna1: references, external references, or peak.

Copy rig hted m ateri al

'The sa I n 'IfO~nl1iJ mav m ~1 fluence the che ni cal stabi lltv 0'" ' the sol ~ d sta te,

~ _ it _ ~ w __ ,; __ ~ ~ _ _ _ _ _, _ 1 _ _ <'! _ __ .I I. ,J' _ _ _._. 1. ,i.]I ~

W~dkU'18' [.:8,8] studied the solid-state s~;;wbnity:_,f :rOtif salts ,and tine fre ~- base of x:i..~Ob~U:11: and observed a salt dependent s~abUity beha vlor, The counter-ion CtljmIJ react chemically \i\fith the melee ule of the dnJlg: substance by esterifica- 0011, amidarion, ,and/o:,' the ,Micha~el :n~actrulon. For a drug substance candidate 'S,' ~:rn:~ hive '[_(l; Bfil,1ne-ri Z:2],'t rn In IIIiII , ,g correl ;fiit': ~;'~'ii was ,if"~i'l,lIlf'N,A, between 'irIL~'e, stabi ~1'm1;V ]' n

~ I: ~ _ _ ~ v. -,t.J!= _ L: t! t! _ ~ ~ ~ __ . _ Vl!! ~ ~J " 'I!ie ViI.!:J 'I!r'~Qli.!I"!...1! J.! . ~~. ,~,~ ~~ wlJl !lJ~' .f¥' \r.I:~IIJ.I ~w,w,. ~ .. ,_~ . ,1j,W lJj,111 J' , "

the presence of moisture and the p,:H: of the salt [4, t ]1" Furthermore, If the salt

form i '~'b'l di '. -' d vari -.' .' tl ill- ]-.. d mi 'R' ,

,- ~ 'if4i1,' - . • [~ , • ~ • - ,_. - - • • - • -- H - -- ," - - ~ - ~. -. - - ~ -

orm 1-,: ery so UI_, ,e,,~ ,1,SSOCI,aJ!tlon" af:i.~ vanenons ~n tne oca '~le nncro-p .'

with the excipients can OCCU'f' in til,e :fOI'ffl,tda-niol1, :re~n:dtimlg, run variations in s,nrub'ru Umv beha:vior 'w'i th the exc w'('lients,~ W1"u~~n comeari ns salt candidates. 1 ~ is

~ ~ ~ - - - - -';' - - ~ ~ ~ ~ - - ~ -~ - - -.!IF- -, -, - • - - , - - - - - -, - - .It'" , - 0' - " -, -, - - , ~' , 1

advis able to compare ~he p"H: of solutlons Oil' suspensions ,of the : alt :fo.[n~'" taking rn nto acccunt the ~ nflueace u'f [Ji'H of' file sna\biH~y profile of the compound (s~abw ~ i ny~p H' profile),

Chemic-al reacdvlty ~n the Stolid. state is cosrelated '"1'~,'~h the nature 0:( the c'ry-: vstal line modifications 'Wal'kl.i,;t 0 et al 1[8911 feu III d fba~ th e t~_IO ,cr\J'~;E~11 ~hle

~~ ----- --- --- -- - -"' JIl>::..!F. _ ••••• -a .. 1 _ •• i! ." 11 ... _" . 1 Ii_ ,. l_ ••• __ ' 'J.[.;."J.----~--,-.-.-

Im,ocU:fi.'cJ]lrn'():I1li$ of fenretinide behave ouite differentlv, A'ner.4 weeks at .'50, •• :',

- ~ ~-- - ~~~- -~ ~ - ~ - - , "ill --- - - --, --_ .. ,j""./J" ,,,J_~,,, . ~ ~"--'--~. '-~'~' ~- '~

the stable -(0 [L11, showed :1i1.0 detectable degradation, wherea the unstable fo(rm,

h 0' we d 8' oz: -",~I.o; (jll'-':.:i·-4i,·c,~,'· - , , [~" -, ~, ,."~,, _ .. - - r~' -- - ,,' - c' 1- II,JI . 1).. , , ... 1 ., 'I" :" "'f" ~,,~', 'i"!

;, ,,,' _~:, I .,~,. 1:0 'lW~ ~J uY~h,WOJ1lj" n ,a SeJ10twS !exI.l11.p ejl 1~lle .w~yuIiO, ;),,51clS 0., an, ,~Ii1:·e51id-

t'a',(lru'] ·0' n 81 cnm~ ~ neund ~ ad.-l '['0' (ti, itn v 1 {'>...:I esrad "1i,it,~ £'it n 'iII1r,","..;I'~I'I'iI"'i'i' fo r r-I,.r~; ..... '~ 0 -,~ it"nill- ~ .,;gl ei. J_,., '~, . c=:;,~ "'" _ yv. ~ ~ :_, w'"".' .. , ''1:, 1~,._.J,n..:,!;" UIIi:,c., ~I:' i.-]oI",h.i,U, ,~' O'U'I!;'~'~ l' - r \\1< ~ ~l~',Ll '. Il'lio.' di;"'i ll'!U!I

form W:~i!.1 much Iess stable than 'liiir'e oth er [9 .•.. 01-

___ ~ ~ ~ g~ ~ ~ ~I~ ..... ~ ~fR ,WIIj.r '_~!II W IIJ.AIl.W... u. _ ,f~ • JI m

The amorphous stare is very reactive, According 'Lo ZO'R;'rtlfi 1[7·~11 30], the

ch em ica 1'1' IJ-"l'!i activ ~I't'\! ;', Ifill rh e m.; iflI~I'~j'ijd' state sho '~'-~j'I';--:i en !I'li,"'~I~, '~u~' to iifllwiill" c"t '1:I'l~' a I~" of '['I"Ii Q 'l!rlJ~I,['IJlj¥ ... l lJj'WI~}~~l. · ... ,WLJ 1.~,W 11i.~.',,, Wl~,!~IU.lk" [~'·I~~J~r·~. ~,.!:__)~.,y ·~!Ij~R" IW!~ ,._~. '11,,1 ~'IQ~ ' .. ,I,._J~ ~i., .-1.11W

Copy rig hted m ateri al

77

'Taib:le. 4. 1~,!fl're~,(!'1.ICe ,()il' NU"1p-t:nlllILlU't'~ ,Ug,l11~ ,(lJ'lcl BU~llr;d:[.ty O:~~ the SI(lbil~t)1 of ~'Ite A'if.iOlp/~'Il'.1!\u£ (uul CI')'sl(l~'li'u! Fotn~s oj ,(,il' .Pep'lide D't1-:tfj Cu~!didt~l'e

L" - 'hili' ':!i,no' I., 'I ~, h , ,~lg,'Ii: ,,1 '!.,II. , . rii.. , 'X" .,

,!O

19

L3

am erehous C' iii,~,iI',.;:i, T~J:.,~~,A::; '111 u i[I~~lte~' . ,tt: ,~b'e·. d ,li ~Q;f' ~ FIi,tr'"a; .0' :f": reactivi ~v betwee n the

Utlll.ll,U ... ,If' . ~ UI.~ i:!Iill.lc~tL-'-".1 ,l:·4-_iII.U~!b "f.' ,L. J. ~Wj. WI . ~ raL:~~~.. .lI.l11I!!i.?o I ~,I.JI~1!r .,~ ~g~. ~ _ ~J.l ~!~ _ _._ _ _ _!J _

1"'- '.,' 't, ~l;' " , " .. ..:1 . , ,.',,'.' . '6 ,,'," '~', ·t, '.' _-·,"f' , 'i'-' i'~ t;'d' ~ 'd:' 'I' " .~.~., 'd'r A,~,t·,~· '~"" the ~ ,~~ ,~, ~

crys, "a~· JDe ane amorpnous states O. ,8. pep ~". e I. rug caru mare, in e a nor-

,.iIl... ... r-. ",.,.,' both ':L."[L'" ... ..J:'~, hvdrochloride '." .,'., '1'",j;.'IIi,.:il' Howev

,p~~ou s suwec O~U hJ.'C II"J~ls!e alliiu Its ,; ,'Y',mc,u on . ,e; were veIY un' ,l,alU'.IC., ," ow'e·, ' ...

er, 'rne. base could be, obtained a.'s, a C:FF~bilr~.'~.'m.e matedal '\ ·lth a '<tdDst:a:nttiil1 g' "I:"1il

~ r~' .

In .s~a.b~·lj:fy ~.4+ 1.]1.,

W·.'·::h'--: ~ ,~. ',J·c,. ' ,',' ,.,: ~, ,c .. ~ .. ' ·~,'~I· ,~,~,t· .oJl .--, sn ·,·4 "'rIi, ..... ~,"II.",t"" 111'·", t .... '.. d -. , "0 '"1'"''

>, , "en pe~ rormmg ~cc~;~eFa~ey or st resseu SI~~I).',t~.~ /f rests on, 3. !. _- ,nl~,~ n 18

,CO:ilI1ll10n 'no em'ploy [c'hrOltllUlo.gmphy as, a, s~ab:ilrutY"-hldicI!Un.i and p'~nii:ty ~:i ~'U ..

". ,.,. ':--- t ,.-.- ,~,~ . "r~'IIi'[b" ' ".j '0- .' • f:'i;>· c ,", , "'~';h' _._, ", -'il ',' ,- .", '"",, '-,', ···f .... ,· ..... ,] .. , ; t·,,, .' 1·', ':: ted t - .

'c8!.JJng assay (t 111;)1 ~e ufll.l,1 II !!o,er ,~so~, " ermar exposure -0. samp .es to ere v ate '; rem-

.' ,Iii-., •• h'L 1 "",A h "d' . '" 11'A h ~ ,.

peratures '\-VI;tj-~ lor 'Wl'n . 'ou~, an e evated humic Uy" ,~i SO',du-p,_,:a·,,:e 'tr,ans:I!,'Ofrn!la:lJl.ons

occur under ~UIC~. ,coud'itJo.rn.s, llh.e, res uhs :ma:y not, reflect the behavior uDelet

a]] , d' , . F' 'I '. hi I . ", ~ d hi 'h'L h'L ~ ~ , .. - ;'d'

Ire S'lDIi,a_glf ,co:rn;·~uons ... or eX,am[l,e.!, ,an ,3, ,,~g_l temperasure ana ~UI __ , __ lIlJm'~c_,-

,·it·,· .. ,t ~." ... ,;t' ... ' "",,·t,·'·,· of '" '." ,IL' I' ,;to., '~'~~ = .. ·. '1\~~'1"~],"',:" ,t'--:,~,~~ .~~ --,~. '-'-"r'~'t- "'"

,IIL)!.II a ,F,~II.S10n:rn~, 1.0111 0 . an amorpnous ,lIl.Ol!'m to a, erys ra ume .it O'nll m~,y resun ru 1i1,

erroneous ev a~,u,at~,on of the chemical stabil U:y cif the amorphous form, if the

!i'li':!!'m' ,,~ =- '~,--:- :t,~,~ '~, ,'r, it'OO' Ji,;.";;iiI.. 'm'· ~'~'f '~I'n' .... '~m'·~··· ~\~i''ili'' leadina ,t'ft 'iii'fll"~~'C' tion '~"~n ~ilii"Ilu[I··1i tate

"-'!;o'\~~_,pemj!l,ur~ ,I ' '''. ,~d"g~~.. = __ ',,",I,dlll~ '""~'_" ~""'II!cI,III, ,. au.~,· ~ IiIU ,W.'''''~· uu.", ,~L I, b_1"",III!j,1!. ,!!JIi, .. WiI, !W-

ti ""'- 'h·,"'",b". ','_ ' .. :~'. , ,-'1.1.., . : .... ' ~b.,., [ ,~.~"'..:II ."~ It"", "M:'" ',' ." .' , .. ,: '1,""'- ': .'. et .' . .', ,', ',,' be ., : 'AI ~..-.. ":'. "~

m.L a . ngner rate tnan lrnl me souo s!lI.a!~·., , , icroca . onme ry ma.ye U sec 1IO,.U' ex.

amine the different sta'biHty behaviors ajt moderate temperatures I '9~. I [92-~.,

Tb bi I" ~ 'I' h ..:11 'b.' t1 f '~I" Ib, l.. d' !pC

'.1 ue stat ~~ lily nl~ 'pO,ly:morp' • s unner h!I,e In: i nenee 0" ,~'~"gut can IUe ~l~~~'eJi'-en~

as demonstrated for chloroq'udrn.e diphosphate .• '93 '1., Even for ethoxyeinnamic acid" different photolytic degradation pnJduc:IS were obtained :[or reach, C·.i')f ~ - talline 'modifi,c3rti()-n:' ~he; a'~'fQm1 eave one de~radat.mon product, whereas '~he

. I: , ,-, ... , - . =.",!,. , - -. -- ~I -, - , ,.- . - b'"' . ,- - .- . - - .- , ~.- - --, ,-,

p,.;fonll ,g,a;ve. ~, ~e,cQnd degradation prOO,uct~ N~) degradation p,roduc'l: was

'found. in the y;.fo.rJu [9'4]~ The above examples emphasize that the. sUI.bHity 'belliuw;v~.or.' of s~,dt caudidsres in the: solid state needs to be ,carefw.1Jy evaluated,

MOrWeculat IJIJJde:Uin.g bY' computational techniques pla,y . 3JJrID increae ingly :~:m'portfU]I~ r-o:~e~ not ord:y i.n the de~~d,n -0:£ dmlg; subseanees but ,at 0 :bl ~:he

Copy rig hted m ateri al

if"~'ilIiild"''N.I 0',- ,~:IiJ",~,jlr' ~·O' ,'II'~id'_i!""h;jj;'~JtfI; nfilif)p'~tF.;!l~~'iI', Th ,~, 10' 'ih"';!~i;,;i"!;t~l''''JiO' n{tiJ1 these 'p"~d;,{'ioi"~" lao it':f:':Ii~j,'iL,~,

~I~f~ . J" "'~~~IJ. ,~"'1i .. J,~.~ 0!L~~~ ~l~ u ··¥,1J,!L1._~!1 ,~. _'!._i~ -1U ~~I~; "" ~ UJj, 1,,_I:L~~·.. .\~,'-i .. ' 1 !I, IIi."J I'_IJ, "" ~~~~WJl~W

'_ = = _. '_'

", A, .. II' , . ' .. ...ii,. " .' , ,,"I ,.- ,",F::. c',;' " "ttl I t. ',.' '[":Ik., - .. 'fI:h- '-"/"'-~" ,.:' c. '-', ~ ""- ere . 1 ,}i "Co ,-: ,-"".-. :- -,- "-'~ no'f' 9,,", ,"c.~ "-" ,-c C .- ";-

Ol,W ~,S"O reauce '\~"gn.ru,lLu:a,1i1 y, ne o~. erwise me ···aSJ~g allj];lJlItnl~, 'IUl'" expenmen-

~i';(fj,'! lifiI.'"F.<F'i'"" reouired 'W~':':':']"ii'~;~I;::;' prediction 0"'''['" crvstal '('!'~''"'i"'~of!ii~~I'llre'Cl ''l!IiA"·AI it.'I,L.,p'i'r '~'IIl-..;:!Ii:t;"mo"'_

!11(llt~. ~ll'uJ"'lvo 1'~~llIULi. ~U'i ._.. ."Jlt~,~ . ',Ij,I!i.r.i ... i~,~llJ.:1u, I ..•.•• ~~'J.' ~~n liI1IjUIU"'_'~U . .' .. ~ gc I U IL.JJi!!i..f.Ji t.Jltl~JL _ ~ £ •• : '

AI.., ,- - ,~. ,t, ·ii..}'~~iiP· - .,- ..•. it''L., '. '~i '0' 'it,' ". 0 '1 n,;!ii;" [n£.·] 'L..' 'f,' " '" .. I' ,'", '

,y,y,namH: 'l~ajl)',h.I.",y rem aJl ns I~HJe ,~,OInJ~,='!Jie[m ~:O3l "'J. :;:/."0. ~ I, ener ~,I:.lmmmry 0'

",b~ p'-' II"Dea'lfiI:iIi' stams n'f" 't;-h'l~ If." '-n~ 'd' 'I'V~A''1I1'jQ;.'II-Ii'Ii'l~ n flji' '~i iD;'~ 'd~ ,; It'!' ilJ~'''~IOin '11..'jQ;ii"<II!ii,

I!U~,""': .,~l"".'"iiil;;;~~:~I~ :~!!b~L",~ I!Y!': ~._,_'~, I~~F,IJ: '~i UI~'¥'!I!i,~,'!Y!',10 !I:iI~ jIL~I""'!I! ."., !L~' ,~J! '!If"",." ,W.WII;::;roL!!i";,,,

D~,U~;fl~Iii'iII:i' 'ty," pe .. , 0,.· ',f" ;iil'fiiil,~il"tii'rirtiliIf'iI;~""'lIl'ma!iiI" 'f~iiii!D~i~, are present ';;'HI 'n~e "'8i1l"io.~u~ l~It1rIl1~-

IJl"n,,\!j li;.rn'l,. . .' M,.; . . 1t~1!! ~ ~~~ IV ..... _" ill_lim = '!Y',~_ !I;;£~_YI. """ It ~_ =_ _ ,I!!,~~ _=_ _ . _= = _ OJ! _

I~ "

mres adopted by :~no,~ecu~e;s, ,~.D the ~oUd .S'la!te~ These intermoleeolar forces in-

~I"d··' ~.1 -. "J'.", 1:]11 ,~ 'ti-I&"it~ ,- ';""fi'-'--- "Ifi"-,,- 'H" bonds 11- "ttPfi-Ii'-'t~' . .""itn---

C,w u : e: "UI;l ae ~ rr:aa,;! a nrac, I,Jl ve ,~.lIl!li,er,ll!e,~lO(ns~, - .Olly':·. e\I~Cw us~a, It Jln,~mc,,,,,,

• m"' ]1 C' H" 0" 'H' 'b d" ..-Ii b, A,:: ""~ "

m'rnons'!1 non-ctassrca I' ~. '."iii,,';;' 1:_' .' ,""" I: one !1og~ aOU, 'Sw:iu,orm wI18Cb,OD:albJ. CO:FlJtac'ts repre-

'en ing 'nhe r-e,ul;~'v,e forces, The ]a'tlice efta(1Y:~, or ICry: >til 'bin;dj'llll,e[1l~,lyjj' i calculated la$SM:mi,~g: tlu1im~ drue im,lu,mcdom ene~gy bem,w'een, two mO:~lecUll,e8 is tile

r - h ". .- . "' bet 'h "" " , '. .' ",0 "Th" 1

! - [ .·.1 ~ 1 ". ._' - .• I •. -,. o· .. . ..,. t· 1 '( .. /. • .. .., ( •..• ". • .' I '. . ·f: _ ..•. - ., .

sum, 0' ~. ~,Ie ~ n~ef,icuon Icne1"J,U!S ·etwee;m. t, e CO.nS~ltLJIlent atom, p,au:,'S,., , , . eo co _ =

culated bllID[:ioe ener-gy can 'be Ibr-o:-i. en down iotu the specific i nteraeti om , ,al(]!:lllg,

.' iIi'Ii",., '1, . di .. ,.It ' .~ f- 'rib,. '!"""I1'1;'~"'t"""", .,,"..:1 ,",-"ttl·"'tf'liI.,, ".' iII'n;·· =,-,'t, .. ·, c;e' .,,,".-IM-;·"k"b:·'c .. ,.-,

p'allJ"Ij;.~CU at ," rrecuons ,aJ1I.lu, "uJJ.!l.UCr PIUJI,I~J, onea ~1iI,L\O U.We ,aiJ!LU,m-jl,I]!O\f11, COm1!,i,lI.ID.UU ,00"1;,

-- ] ~I .... 1 ~ '~I '~I' w 'L, ~'" 'L, '" d ~ h

The ca ,Clh,a~eU '~,In1~,ermO',W,eCUw;M' In.'Ve:[ICU!O;n' , lean, ee 'l,'lu:rlWJer examiner U:8\IJnlg: t " e

Co, • ,Ii,,' .' .,[".,il:' ,..-m 'j;." . . ,"~I '1).,.'1, '" 'iiFiL· 'C" --lbl'-"_!;d' ,.:;!; S·· !!L-' ,,- ~I-.--- -·,r .n. 'r "L ..... "",.:i" 'C·' l!(1IDI)

v,aSI~, ,aJmourn ,. o~ 'l;Ja .. a, ;aViu,~,aul,e In. !~ue I,:. m1~Q,' ,~ __ ge " i~r"C,;ur:a,~ ,ua~~'1:Qu,l;~ \,~ ,.;)',: " .. 1.-

It is possible to l~ite;_lFp!f"e:t. ~~)'~id-'· ,'ta~e 'p,fOrp"e:flti _ .. ' im ~er,m:, :(d~ pa:cki,nl ,aJ1J]d Inter-

""-. c:il· .", l,~1' ;'- ,-J - "I ,." ,--,. A: "," ... _k.,"-. ',-,--A slice --e;"'i' c"'-- '~~ :'81 - I ":8(1- 'm-'-

~11o.~eCU,~Ia:~ n~te:nJ:cUOins., ·uaCililment ,an!i.!l, ,~l'C =- eDsf1Je8::JU11~" t_" CUilM~ .. · , ~r-om

the .. '. '~I ", . "iii" '~I . ,lit," -"if" -- -,".A '1';iiJ." - ,;n'"--'t-I -c- oreholos ", . .,. ~,,- It"';1.~··-· - -'Ik a be ,.---;P!i

. ie ~,rn,rn1g,~e'"'crysl~m.W structure, ana u,~6 ~;ry/a!l mu,rpl·.II). Igy C'AIil Jl~mu.y .. e pre-

... 1 i,r;,~'<ifi.";11 m"u I' nde: , ,il'lfiI ijl}' 'iiFiLa, d 'lj ~aoi'\t3lniil> ,il':illi.;":l~~ '0. "'If .. the l .... ru.,ilf.orni,'11 momh .... '~ Fiilar~,{'io~'~1 ,lirlil"ri,~i'f'ril'i,n .... , U~,!lsrl~y,!! Dl .,lI/.~~~_._Jj,~~~ I~W,~~ ·~,~,lll~t~_,_'~, J!~~~ ... ~ _JJi~ ~~II· .~~.IJ. _,=~u~',rlUJ!~v._ .. -~,~aW ,~,lIJ·~~'~~w

ulations, based Ion t~e ,gluw~b o,f defined : ace ;~,~ IcaJll 'be PJildilc~ed f'Or 'th'

ls.,' . ,!If.'. "1' , 'iii"' . ,. ,,f" "-'h"" 'I' .: .... "f' dd"'IIt,', ,,- -, " ,t'b" fj' "-1' .- . stall ,-'tit: -. -

Cwwo" ce o,~, sor Yien,~, 01' ror tr e c toice 0 ,3· ... mves um me . ma C,F,YSl.;{'t, ]Jzaj~~on,

:Fro,:m ~he :5,i,ng:'~e~cr-, S~I:~, s:&mctlll,re pMll" . del' X=ralf di: ,'flilCU.oD [J\(lUer.llli may 'be III''!]: 11- C'- ~ 1- 1iilI1'i'.ri,'i!ld' and ,- com '-p. !i!!il;'i".if!i!,,,,l wit" 'Il.. ,j,'it..," e ~', 'f'i~lji'im.if!i!'if'I,'iij)ji~~ ·p'\!:!iI't~~·'ii'n·· ~ Til e D' J~ ~I:f R--:-i'-'N old

I;;.rai . III ~,L!Ii;"I. u ",""v ~1I!;;i"'1UJ" " = .lUI u,~ _ ~ ~It"'~ ~~_~~I!i,g_ . y!,!.i,J!I.~ _ = _'"'_ ~" """ v_ _f __ tJ _

, =

,8lrnd, ,McnT. tie Cart:o' ,3Jlgorirthms w~tb -; rl!]j~ta'ble; · ,ofl\\,f:IJI~ 'C8:11 PfOV ~de the ,s}ooem-

,t1.o:"n' .no€.' ~lp.lliiiili"~I'\I"; IfMi''mi't-..ti; C' '1I""\i!'C"it'Q ~ I,' ,;t· m" I' I,e" :t" 111,~'~," ,n'.('li"'Ii;~IIiI~R!iI'~ L,~11t'01 ..J~,;f"'~iFIIII" ;::. <;II, m ",,"..,1 '11'1,1 iifIi: nil' . lI.. '" u~, ~I[ ,It'-·w U.A~lIl.lI,~,lILUI~ . , ,J.' .;;)·l,iA~, .,... U_W.·!ti.n-~!ll IF v!~J "'~l'l~u,r ~~,.J r,.· ~ UI~!lir.II~ VI' It AI, , 0 ,uUu.J~ y,~,

the ICeri'I.'~ so'ft\~are pack~ge. o:ff~~d, 'by ,A.ccB,le'fJ's (io.mlle;,dy ,M()lec,~~lCJ'r S'i;~ft,,-,

,~. 1 1""'('1)" 'D. .JII"' ,'" :I: . 'h'" ". 'b AI '~I • d"

LJt.jI;Q',l~',Of1j ·,~iC'., ", i!fl:,~i "I~ r",rleUll;~C:nl,o:n'S O',~: t, 'I S '~.ype are ,'.a 'eu om. ,wJaiU:~ce [e:rne:rgy:, ,aJm:· ,

~ !1'ffi i'iII_ 'iiiili..'e a;;n't'iIi'nnl'NJ' c-mp-IIfIi,;::;.n'ii" "T"i'b'e' ,iiFib.elll"_ ...... ..:IIVlm'i!Jllm;']· Ffi' iIil'ii\mb":l" '111"'·tv ,; n!f~ C'O'!1111f'1,,;:i; ...ale

1",~":I,!l,>!',I!I'-''''' !!!.~rn· ' .... ' ,I ~,UlFj. 1JjJII • :"V,III.Iiw,I:U:'.. ~.W,· ' !~U, .. Ulll,Im,IIlJifU,J'u~". ,!i.. ;,ill~ 1,11 ',J ,I;" 61,. '.' YJIII!I;,o-, l!II\~

'jp.~ ,:", ":1, II!.., ~' 'iii'lir" 'G" f~b,. ,(- , .', , I ' '.' 1<",-,.' ',' 'Iik,', .,,'&. ,,,A, "j ;.' " 'Id" " . 'b'"" 'Iii'L, ,,,L., '~IiM't';'·"·,, ',"'" or,·

~,el,ml,neu lUI) l~ne,l;01U.3, ,,,m'eee:I[~e:rgy~ W~dC.u ue,peu: S o.n ,O!~JU, U,lIIe ~iaJIj.""~loe, em;ergy

'!JidFII1d: ~Jn>ftm"· ,'nv_ '1Il'pe,AI;~(':t'~'O'-'ln',,",,1 '0" t'{'b~ 'ii'.el- ~t"iVI~, i!:1'~'!iili'b-c:lil-1,t1iJ' lii"lii' p-~ A~V'm'-- 0:: FfNih, ~ ,gl~'_ ,~IJl;;;'~Ii'I.~' nlii'l~_

D __ ,lJI ~" ~, ·,l~·,J·11l c·" fJ!JY.>IJ~. lI,·_ Il~~ .", IUllw IJ,~ ~I. JIj, ~ ~ ill IIJ. GI; .. III ~. lJ· Y. . ulJ.' I , . _ ~ rl , !iJ! AlI~, u_~;~, ~ .v.w, ~'t

d' L. h 'Iii.., '~I ," Ib. • ~' ..,[11. .... "...:11"'

lex peete _ j to lUe more ,aCC'I.!Uil9ile W' •. ieD bwe :en,rtr.o,p,' :re'~lH'tJ.()(IlS~'~]l~S ,are, ifIDe, ,11(WCO :ru~1ll

~~e c,aJcu ~,aUOins," M:olecular d:wQamj.'c~, ma,y···.· '~ro\r[d.e~ a U'~leflLd. :me~tu)d fol" dje~eF;-

!J. , ,~

m'~'llj,ng I,aldoe ailltropi,e'>", USl p,e, e~nted the cloou1ter-c'w,flll '/of~.w,.-e' packa,g:e -':Powde,rSo~,v,e;i ,H'n tile 1,~~·t.',r'ljrJtio\~'Za,i Unt'r:)~t.o/ C,~"st"l,l:(),',~vpny 1(IUIC:r)1 ,":n GlarF go'w; ,A,ugu.s~ :~ 9i99" This, .·i[)f~,w',are :i' I des:igned to d!emm1i:FJJc 'nlbe cry s'la], ': ,;tmc= ~,:u:res of t1exi'ble :rrlolecul[e' ~" ,or {~o'mpl:~e,x cry ~·,'tals!, ::';l1lcl!l 1[', ,,;aU' :', or b.ydraliJe'" \from dle 'powder X -f,a:.y dift'rlCti,o:1l 'pat~em [~l11. SOi "nWu,e of [hi, 'type "'llOtdd,

'F:'!!Ii .... '; 1"1 tg'lIrp 1I""I1f"ii'19fii'IilOZil,[":j to nIFIIII·· nf-:: th- .,..~ 'to' nl,j,A ;Q,~,IjlJj!"',"", ,- 'hll'1l111 .... *"I'Ire- -, ~ nr - - ,~'~,'htl' T' ""il..p iIil'ib.o:- ri 'ttl'" 'WP

,~ig~~, II ·u~~ II!iro·UIJ[llllll~·eAll,W;~JUII.lII_·~1 yl, 'J'JI!i.I ~Ju' Illl!l,~.;]IIIJ.,!mII~ ·~lLIj.u~'LU: ,I··.·~l 'u, ":1GI.1,~..:l!'i' . ,~1,,-, .;]I~~~,. W,I~, ~ . I W

I,~'~,o,~ed :fOlf' 'toda::~i;'s djr!ll~D d,~:v,e:i.l()nnle,nt mnluillies ~be use iof mn:vm:n,lced, '~oo:~,s

l~" C ,r ,

'[" h IIJ •• :~I iir.' . ..lI ~l ~ . ...:1 d ";11 "' '"

W',l:l:C , , e:n'.hiwe :w:,as~ auu, w'e~. -:w:OIlJ,II:~,[[Ie.: uec:~, i,o.'I!l;S;~

Copy rig hted m ateri al

79

[ 1..~ S. M.. Berge, L. D. BI~lhley~, ~Dd n C. M.~mihkJfuLo1LWse~ J: Pilhl·;~m. S -'.i,. 197" .. 66~ ~ -19,

[2] J. L lVeUsl~ ~Phanmacell.ti,,~.~.l :Pfi~f(Dm~Ril ati:o:[ill" Srn1is, :HOFWIOOd, Series in P:hm.rm~ce[fti.c~d

"iii" ..... ~·iL.Il~ 0- n'nfF'!U' 'C·-il..·; chest .... r. ~ ,ifII;QiO ,W "-r!WDJIl ~ " ... ~'!J~~'" ... ~~III~'. ~Qi. j~ ''!! til. :~~qDOl.

[3]1 ,S., R. B:ynl., 'Solid .s~~te C~~l~~stry of Drugs' ~ Ac~dtm1~c :PJ1e~..:. :~,:' 'C;,lq Y~l!ik;, N",Y.! ~'982. [4]1 G'. ,R., Desiraj!u~ !IOrgarric SoU,OJ Stade Cbe:mwstry';, Blsevier, Am'S~enmam~ 1981.

[-.;(::JI m ifiJI'-'I-'UII"~~ -~ ''\'J M' ~-- , .. J~H.r.. - - - s .: '~:,m.;£;n; ,;:0 g" ~I ~I -919"

~ .Ji ~I. nil ~m,~:tlIn,:·: .. _, ,c!;......r:one,,- .. u oF .r\[Qrn~'.-C'. .II! 7U(:;;!!'" ,J-Q'I . '~w -., ,;,;'.'

[6] J. H:~d~b~ii~~, J:. Pha¥F~,~'l. S' ~,i.. 191j',S:,. 64" ~ 1691~ ~ 288,-

[7] .B,. C,. H~]iiI(:o[Jt~ G'. ZOigrt;~fi;~ J. Ph{Jn7,j~ Sci. mm ~·61,~ 1- ~ 2",

[,,;:n_ ·!mI'·V 'Ji:l'll,r;;m:"'fiI_ • ~lli'r~~I"",:I'ur,'·.'1 ';;0 eects 0-' ,;j;:' hvd ~!'~o['. and p"..'IIVlIi'lj!'j,'.- ~il"ii' i'P'o~'!i.\I,mor-nhi!!,lm rn~rnl ,P~m ar-

o JI ~. ~,p. l'¥1.Ijv l ~ i! !iJ!~: ~_~., _ ,~~ rJF] ~~-'!r . fIi~ ~l' ~J' .~ ~~,~~o ~~ ~U L'E¥J! _ Mit ~ ~JH.IJ _ _ w,~· ~ ~ ~ ~ ~ i':i' ~ ~_.1Il"!~ ~ ~_~ _ ~ ~ ~

nl;a~e~~'k~~ Solid;,~,",. ~d, H" 0". B:ritt~~" M~JllOe;I, D'ekkel~. ,:, 'ew YQlt;, :[ 9~', 125- rn 8 t,

[9] O. J. W. 'OriclJllit. 'Theory and oligi.!fD. of poly.[)tphism" i,iIfiI: !'Po]y.,o~:h ism in P,h~~aceu·

. 'I'~ '1' . ..:1 '. 'c.":11 'lUll n 'B "'.- , 'M'" 11 n '-k~"'·N 'v' ·i~ 'I Ci{lO ~I "l'l

U~~L "j1!iJ'J!'lu;,:,_' ~ .Q1;J. V!!!. 'U, : ··I[1~.UIJn.1 .. ll_fiCe:l! lIVe ~rl' ,__; ..... 'eW!I!: Of.K, ~,'-;, ~;i'. ~'~ ..J',;J.

I[ ~IO] D. 'G~roll; u~bo·,PI~amr(;~'-p,~')Jbt, Teclm. 1"8:1, .107" ~,j ~ =] (~).

I~ ~ rn ~ .R,. 1, elMk, C/~en.1~ Soc. ,n'el'. 1"5, 24, 1 :87·- ~ '95;",

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[~5J D. Di.'Jch~il1i,e, G. :p!o,:litc~he~l~ S-',f£;t'I(fS Tl1'ctini(J.i'UJ~' el' .I?r-tJI'Jellii', "5' P~!anii{l.c.eut,iq'l:~e:s (S. T. ,P:

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[~161 'Guide~l~mm,e' Sped'ficii!IJt~on ,Dra:il: 'Q6A, 'Decision Tree: ~n\N!-:Mig~tU'mIJ,g: tile :UiCood to set aeceptenee ,crheri,a for .rlo~ymoij)hbrm in dlrug subs ranees and drug p.r@d'uds" ~ :hwternatiolul Conference ali H:u,morti:Z_:.iIl;uO[l, (JeH),. 1'99'8,.

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