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`Lupin Ex. 1046 (Page 2 of 26)
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`Lupin Ex. 1046 (Page 3 of 26)
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`1. Introduction
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`Mo~ orgamc ~md iru;.rga’.ak: o.’.~t~}peumb.: of phar-
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`
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`
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`
`Lupin Ex. 1046 (Page 6 Of 26)
`Lupin Ex. 1046 (Page 6 of 26)
`
`

`

`modes of h:~!:er-motec:uL~tr
`
`molecule, restfll:ing fr~ c{.m.sideral>Jy larger dipole
`
`I)tl!Jiig the Sl:tldy tz~ a Slew ccystai
`
`Lupin Ex. 1046 (Page 7 of 26)
`
`

`

`}A ,al....~t,~ !ms been studied
`detail 140], ’l"his compou~M is d].st[nctive i~-~ tha, the
`.[~igh-mdting fi~rt:,:l (pol):morph .I) co~{-ait~s
`
`with the a.mJ(]o r~:itrogeu, ato:m &.L,;~’,2 as
`
`str~ct:~re i~,., "lTh~ :ov:~n~ .... eJf.in~:~ form k~.:, ,.~mo~ p}~ ~.~
`contaJ.t~.s mole(:;u~es of two d~stJuct
`
`]inked L}rroug;h di]’~’e;lx~:n~ hydrogen,, bom!irig arradge.,
`me.m:s. This lalte~: findln:~ ~..p.~<.~,..,A~ an,:)thc:.r
`~spect of the c?.:.,,a]l, ~,,~:~.h... of the
`
`hydrochhydde in t:wo soh.’~{<: :[orms [4ij. ().~c h~rm
`
`(} -
`
`; ............. " ..W " ~ "
`......... , ._:::J... ..rqk~
`[%
`...... [ ii ......... i ..... i.
`
`N.,
`
`,,
`
`})::oya] S(<}et): <:![
`
`Lupin Ex. 1046 (Page 8 of 26)
`
`

`

`[.’S)]II::LIJ!I’V.:J:I:’alt) i’~lbTt~C. {...s,,,dl~ 0I:’ l;tl.~,’, ,m:~I’,wopi~KJoi ~Ol--
`
`turn+ beca~.~se tim : ’<>’] "",
`
`" "..-w i,.~.>,,.: .--.~’-.11,. I~
`
`-
`
`"
`
`.... :-q,,e~,u~->=, rm, h.c.uKu
`
`that :v~rlety of
`
`:iCl’vt’.(], TO ~biiaif:t ~t tl]OI’~ det:~:dlod <;’vait!a!:ior~ OJ"
`
`pre’lierence :{br .porpci~dlcui.ar co~.ii.)rmal:iom~ b~
`
`Lupin Ex. 1046 (Page 9 of 26)
`
`

`

`ai. [.2-.1 have. rcmiov,.’ed 5ricfi.y tl-i~, aspect of pc.ty..
`mo~;pl:~{c l~]t~bt’c%)~.t,,~)r:g~oj~, all( lh¢. iac:~ors
`
`mo-r<s st.:~{~l<: tJlan the. ~.~ .forni. at. roo~:~ tempuratm.’@, but
`
`(lcms{l.y, wilh Ihe su’ucture shll:f.iE~g f’rom an
`an’a}, c>~; moJectA,~s ~thfi<ed t]-uotlgl:] hydr,:.~gen
`
`c~erg3.’- 1 {-~o.ratc~l by l.}li~ pro.ces~ is aJ.~;aost offscl by
`
`.... :tL,, 1LL I}.
`
`morphk: trao81t[oi:] o#
`
`~---Q<;(’ The ~]~se c~]a.i:]}~e was as:~o(:.iatod ~.’it]~ a
`
`1- .,a ....... f]-}llctv~xl by
`the m<.H<: ratio of the coexisting .... ,,~
`..
`;ff I~LiC}] .~][V+q;if" .)]’OU, OT~S jI-tVO.[V]t.ID’, g~
`
`Lupin Ex. 1046 (Page 10 of 26)
`
`

`

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`.~c
`
`Of h~.h~[b~th~g t:he ntx:~c:a:~io~ ~t,d!or growt[~ o}: the
`~mwa~a:/ed j?oiymo~:pbs..For the {~i:st: tirade;, the role
`
`pattert?, it: w~:,.s p,’¢dk::tcd that: il)e ;~tharnid.o
`0 f ’" " ’ >
`
`growi~g [i~ce ~-~{: form I witbot~t dis;upH,~g the.
`
`possible with the ot}~:~r %rrns, i~,:;o:qgora{J.o~ of
`
`their growth (:Fia
`.. :h. t:~xl?~rinaentatly, it was
`
`the co~tqbiBath:~rt oJ: c~rysu~l n::Ot’pi~fogy .g~d
`
`and stability ir~. the t:’rea~n;_~e of additives.
`
`)kE/C I~.~ ~:md TRIPOS force-fi~:~ki:g were. used
`al.I..~ 4 ~mt.. ~dditivcs which ,:.ou]d mh~tic ~hc.
`Se].ect ’ -~ -’ ’o " ’" .’~
`a~td [g ccn~)Jrrnt~i~J:c~s.~ Four additives we:’e, chose.r1
`
`ly, Jt was proven thr4 the additive.s, by vh’me of tt-JeJr
`
`Lupin Ex. 1046 (Page 12 of 26)
`
`

`

`a
`
`b
`
`, ,..- ,-.:..c,. ., :..,:<.,,
`
`,.,). cot!p.llag i;b0-, highly
`
`Ths commcm l:~c.hnJ.qtms o{’i:e4; {’all t:o ds It ......... ~a
`
`Lupin Ex. 1046 (Page 13 of 26)
`
`

`

`ppm
`
`be.on p~:opo~;ed ~o be in the keto4autorwzrD
`Using NMR aad c.~:ystal struch~rc data ].t was
`
`combi~adon c,f s,:fiM,sia[c NMR spect:roseopy
`X--ray cryst~.(ilography provided suro,~g evidct~cc ~.ha~:
`bo~h fom~s ~~1’ ace:tobe.xamide exist i~ t.{?c .keto,.
`
`Lupin Ex. 1046 (Page 14 of 26)
`
`

`

`fo.rmJ.r~g crvs~aJ]Jne hv~J.rat~s [6% The a,~tor
`
`voids mid because of i~s muh:idirecdonal
`
`which water is lo::a ized
`
`hydrates, in which die metal kms ase coordhmted
`
`(cid:128)he work of Co>: et .~. ..
`
`.......... ,<.esl~gatcd ~s{rtg single
`crv.sta] X-rap’ difiSac{:ou:~:etrv,
`
`The changes :i~J. the PXItI)
`
`surnmndi:ng reJ:~:rf~{v¢ JmmM.ky (RI[) wore explained
`
`c~o,,moT[yn sodkm~. ~’ ..,’:
`
`.~ .... ., ~ .... -~.
`was ~{.~ r~::~ a~ { .,.J K by v.h.~n ~{: ffi, ].], ]hb work.
`.
`[?
`
`~, -/’<-- . ..... .,J: P..
`ih:e two cy<:lic t:~lOio[Jes, ch;:t~,gcd {20 ;:tcco:mmod;~tc
`]a{l:Jce e;xDa~]s~on or con[ract~or~ J:esulch~g
`
`Lupin Ex. 1046 (Page 15 of 26)
`
`

`

`~somorph~c. Fig. t1 s[~ows the sigr~L{~crlnt c.hanges i;~
`
`CJlf.tl}geS, :l’h~’, ~acorpo~";r~tior~ Of W~ttet" illtO the orvsl:ft
`
`cW.’.~mtlogr~:@y>~. ’l’be c~msid~rable hyg~.oscopici~:y of
`
`crysta! s~.ructures of: the hydrated, and non,hydrated
`
`h~u.~ the solids. The ;a~es o.{: dehydration a.ad reb"dra..
`tio~ are h,~rgely d.v:term.i.t~d by d~e size of the water
`c ~m-~r~oJs and Ot~e s~ ..... ~I.L <-rP !re hydrc~ger>bos~d.i~g
`
`,c.~,-_.~t~ng ah~dv with dJ.f-i:ere~c solvate(t
`i’cvms of r..-Iv.sh~.e, mu~ohydrv~chle.d.de (!.M) was
`cc, uductcd by Batxtyop,ldb;<,’ay er. aI. [74j. [.,H w~s
`
`a dlhydrxlc at a,, i: ..... 0,65 with r~,,<0.45: a~x[
`ml.xed r~oJva~:e.s a~: bo.tcrmediatc Ya.ltms o[- a .~ and a.,,,
`
`(b)
`
`Lupin Ex. 1046 (Page 16 of 26)
`
`

`

`1"7
`
`ctctrJ.E,
`
`atK{ acce,]e, rat~xt ~t;:d)ilitv {c5t:~ &~’e }ikclv ~o ocotlr-via
`
`....... I,..f.v,~,c,. ~q:u~j) tl~e, sokttkm phase Io pro.-
`
`the l.>Xl~)
`
`Lupin Ex. 1046 (Page 17 of 26)
`
`

`

`18
`
`tbr predictb% @c c:’y.’..’..~.al s,:r~,:ct~me::~ o:iJ hydrr, tes -:rod
`s<) l’,q tte8,
`
`m+d hot stage microscopy, IISC, TGA. Karl
`
`(~e~’ X.n:~y di@’actome.t% and iufl’ared spectroscopy,
`
`w]JJ al:~o b~:~ discus, seal m detail i~ lat~.q cb.api.e:.L
`
`measm<, the .heat:.+ of:’ dehydration r:u~d heat
`
`St~ryanarayarm~ 179.~. f:n F.ig. {2 it is showr~
`
`tech+fiquo pes:nia;~vd the ws.uer liberated cm deJ~ydra.-
`
`Predicting the fbJ:ma/km of soivates or hydrates ot
`
`or sotveJ.~i ]ncorporak~d ]~to t.{~e cry~t.aI laKice of ~t
`
`@ermo~ravmle~rv m~d inJTrarcd specFo~copy
`can permit ~de@:ificadon o!’ d:~e sol.veto inc
`
`~]~.t~.~-~ has bee~. t~se.d ~,:~ study .l%vmc]]aLed r~r~+t~c;f,s
`st~d.~ f:t.7 cap:sules ;.rod t’abRl:s f~0i,
`
`molecules in the: crystal lattice+ whereas other crwla.{
`
`so t:.[~a{ no c~:m~p@er prog~rams are cutTou.tly available
`
`presented a..’:~d dis:cus:~ed I]1,22] !:hat c~@ he
`
`Lupin Ex. 1046 (Page 18 of 26)
`
`

`

`secdons we wil] address SOT~80.g d~C.SC:: iSS~:~.SS a~.~d.
`
`Lupin Ex. 1046 (Page 19 of 26)
`
`

`

`0-’.)
`
`(el)
`
`do.n> 8c~d~ a.s fc~.rmf-4km of a polytnorl4)ic forr~
`~h’in w.i.h a much gre;:l:er al]inh.v ft-~r
`fommt:.[on of’ 7.1 crystalllrJe h)/drm~ i.~ tl~e.
`
`aSl-dJ.iu particles i.he:r~;bv provldh~g m~
`
`str,.t.CtLtr~.. Th.ic ~xample c]eady indioa~#~ ~hal
`
`wa~.er vapor.
`
`of co, staiD l.hat mf-~7 R>..organi;(e mt.o ~ differeJ.u lattice
`a.ttrang~m~cm r~:~sulth}g h~ a l:~hz~so chang.~=. Tim
`
`srnal.l regions c,f high ~er.Bperat.m:c ~ ho~ .~;pot%}
`
`drug -m.ol~m-~)b.s [16]. ’-l]}e c..lteci, ot low lemper;
`8t~ci~ ~1$. (hrrirJ<-, frcscf-z<~:---chv{~ ~, on lhe crvst.a lt7ne form
`
`can s.mni.ficm-at~v limJl t.[~e dE’yinT r~te, while
`
`pro,::.e:sses h]volv.mg r~q)id solidJicadoL~ o7
`
`efYecf_~ io lhe at.omi:¢er, Siva), do,-i~-:U2 1cads t.o
`
`Lupin Ex. 1046 (Page 20 of 26)
`
`

`

`2J
`
`~k]du.g p oce-s’kJ.r~ is l:~Jghty ultdosirable, The
`
`aflc.~{m:~ ma~y pllysico--.chcm]cat
`
`¯ :, ,.<,,.+ :~?
`
`interco~ver{, 13~m e~ al. 1II] sugg~sted tha{: tb.e
`way (:o deal v,,id] t.t)i8 problem J.8 pa)b~.cbly by
`
`Lupin Ex. 1046 (Page 21 of 26)
`
`

`

`su:aight line. " * ~
`.M~.d~..m computer c~m~r~.~[ted X-ray
`..
`
`x.,~ ~ o~2’ mull ico.npo~.~em mix tmes using the co n’Jete
`powder diKracth-m profib:-~att~-" dmr~ a 1;,~m.,-.,,’, ~
`
`cial r~eu.rat ~aetworks (ANNa)in q~.mufitative X-.ray
`
`ranif.ktine 53;,drocl-~br.[de even wl}.cr~, the weight
`
`0.0! [95]..:kNNs have beer~ u.~ed mostly h-~
`of pat.mn~ recog~:~i.do~~, and modeling, and is ther-:::~bre
`dcc~)!?.~,m~ the pattern ir~. difffactior~ data
`f?om polymorphk,, mixtures. ’17t-m ANNs :noda,J
`d.icmd coi~ce.nl~:at-ion precisely, accura.tely, arid with
`
`two kaowu, ra~:}itktine hydrochlorMe
`ftwms h?. a. mhtu.re (Fi~,,. ~.. !4"<.. This m~:thod
`the problen->; assochm:::d with pref%rred orlcn~
`am:i ov’er!.app.i~ag X--ray liJ.ms. The samc~ group
`
`comb:h-la:i:(.m witt-, ])RIFT spectroscopy to am~ yz<~
`po]ymorp[~ic pm:ity o~ c-o’sta!!i~e mni.fidine
`
`being wi.de~y used to q~mrmt~tivety estimate
`perc.e,~t~.~ge oi o~e po~ymoq:,h b~ a lr~ix[ure of po~:y--
`morphs. ]:;T-.Ra.man spe:ctrome~_ry oK~z,m nmm, advan~
`t.age.s, the most pmrn~em being, mi.rJma.i sa.mple
`
`tot brea~ce h:om water "l’wo po].ymor[~hs
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`
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`
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`
`Lupin Ex. 1046 (Page 22 of 26)
`
`

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`comes d~e ih:~c ste.) J.n predJ.c.t.~on. SJngl~ crysta~
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`
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`
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`
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`
`a~d the use o{ cornb~nat.io~~ tecJmTc~uos, facilitale ~:he
`
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`Lupin Ex. 1046 (Page 23 of 26)
`
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`Lupin Ex. 1046 (Page 24 of 26)
`Lupin Ex. 1046 (Page 24 of 26)
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`Lupin Ex. 1046 (Page 25 of 26)
`Lupin Ex. 1046 (Page 25 of 26)
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`Lupin Ex. 1046 (Page 26 of 26)
`Lupin Ex. 1046 (Page 26 of 2
`)
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