.
`
`;
`a:
`h n
`331.
`
`$3
`2::
`
`ma
`
`Liquid
`
`Vapor
`
`Lupin Ex. 1060 (Page 1 of 60)
`Lupln Ex. 1060 (Page 1 of 60)
`
`

`

`edited by
`Harry G:, Brittain
`
`Lupin Ex. 1060 (Page 2 of 60)
`
`

`

`Marcel Dekker,
`270 Madiso.,,~ Avem.~e, New °York~ NY ]0016
`~cE 21.2~696.,9000; t~:~x: 2t2-685-4540
`
`Marcel De, kker AG
`
`44-61-261.-8482; fax: 44-61--26I--8896
`
`World W~de W~:b
`http:i!ww’;.%dekke.r,com
`
`inf:ormafio~L write to Special Sa[es/Pro~%ssio:~al Marketing at the hcadq~-~r~:~rs ~ddress
`
`Neifl~er l.Eis book uor a~.y p;ut may be rep.rodt~ced or tr~.~.smitted h, an~y form or by
`ar.~y msaas, electro,.~ic or mechmdc~.~.i, i~x:.iud[~g pho~ovopying, m.iCrofihnk~g, and re-
`
`(_’,arre, t~ p,ri~:~ting (J, ast digit):
`tO 9 8 ? 6 5 4 3 2 1
`
`PRINTED IN THE L.’N! !
`
`Lupin Ex. 1060 (Page 3 of 60)
`
`

`

`This material may be protec~,ed by Copyright law (Title 17 U.S Code)
`
`4
`Structural Aspects
`and Se]vates
`
`of Hydrates
`
`Purdue Univ’e~r,i~.y
`
`PHARM.ACEUTICAI, IMPORTANCE OF {...R~ S K~LI.,/NE
`HYDRATES
`
`HYDP.ATI!:i THE.RMODYNAM!£S
`.A, Classical H~guchi/Gram Trcat.me~t
`B.. Simitarit.ies and Difi%reE~ces Betwc~::~; P¢)~,ymorphs 8Etd
`Hydrates
`C. Hvdroge~a .Bondi~g in H~ ~r,n
`
`CLASSIFI!CATION OF HYDRATES
`A, Class 1: Isolaved Site Hydrates
`B. Class 2: Cl~amml Hydrates
`C, Class 3: Ion Associmed Hydrates
`
`9
`
`130
`i.:30
`
`14I.
`1.42
`1.45
`1.55
`
`I62
`163
`
`125
`
`Lupin Ex. 1060 (Page 4 of 60)
`
`

`

`BE, HAVIOR O17 HY1)RATES DURING PROC~’;SS[NG,
`HANDLING, AND STORAG/~
`A, Processk~g Induced Tra~~sit:~o~s
`B, :Tra~,s~tior~8 in t,l~e Final Product
`
`VI. S{J.MMAR ~
`
`REFERENt.E5
`
`1,67
`167
`I73
`
`178
`
`ii 79
`
`PHARMACEUTICAL INPORTANCE OF
`CRYSTALLINE HYDRATES
`
`The potential pt.~armaceutical impact: (,q! cba~~ges in I~ydratio,~. sl:ate
`crystali~e dt:ug subs{:ances and excipkmts exists tI:~rot~ghou~ the deve~-
`opme~:~ process. Tl?e: behavior of pha~mace.utical hydrates has become
`the ol~ect of i~tcr~:ash~.g at~e~tiot~ over the Iasi: decade, primarily due
`(dh-’ectly or indirectly) t~:~ tl.~.e pow:~tial impact of i~yd.rates o~. the
`ol?ment pnx:ess arid dosage Ii>rm pefforma~ce. Substances may
`
`tio~s, processing, or over time if 1~1 a metasl:abte t.herm<~dynamic state
`
`~soIated at the disc<wery bench scale synthesis during scale-~,p activi.ti.es
`R~r a hydra~:ed compound, The chc, ice of cou r, geri:,::~~s it~ produce a more
`sol.abIe :sal{: form may also be dielated by tI~e extent and tNpe of hydra-.
`
`be saf*eIy accommodated by t.h.e dosage form [2],
`The physicochem:ical s{:abilit.y of the compou~d may raise
`duri~g preR~r.muk-~.~:io~. Some hydrated com.pou~ds may co~.ve_rt to
`amorpgous :lbrm upon dehydratio:n a~~d some may become ch.emically
`labile, TNs is true of cephradin:e dihydrate that dehydrates ~x:} becom.e
`amorp1~.o~:s ar~.d m~dergoes subsequen~ oxida~:iom Otl?er cc~m.pouMs
`may convert ~?i’om a lower to a l~i.gl~er state o:f" hydratio~
`
`Lupin Ex. 1060 (Page 5 of 60)
`
`

`

`wou!.d represem unique entities that, de.pe~.dbg o~ the dosage
`might h.ave to be :mai~.tairmd throughot~t the mmmfi-tctt~ring process and
`i~. the cli~ic a.r~d would impact on l:he regalatory star-as of the
`pom~d. Most oRe~ ~5is demands that llne, tk~rm (us~Nly crysm-ll].ne) be
`identified and characterized w~th respect to han.dli:ag conditioas during
`the early pre-IND stage of ~:he developmem process,
`As dosage form. devdopmem proceeds, changes ia hydration
`can rest:~k in varia.ble pm.e:acies depe~ding on ha~dii~.g condition,s dur-.
`ing weighing stops, [he ki~etics of the 5ydratio~?/dehydradm~.
`and the e~:~:viromnemaI co~.ditio-ns duri.ng processi~~g, Difl>~rences
`powder flow ca~ rest~k fl:om changes m crystal form m~dior mo:@~of
`
`afl)ct contempt tmiformiU i~ solid processh:~g either i~ th.e mixing pro-
`cess or du.fi:t~g ~ra~-~.sfer ~o other processi~g equipm.em such as tablet
`presses. Aqv~eous granul.ation, patti.tie size reduction, film coating, and
`tablet com.pressio~~. N1 provide opporttmities to "lrap" a. compom~d
`a memstable tbrm. that may ~’rela_x" to a more stable ~k>rm at some
`unpredic~ed poi~}.t ~t~ the lii-~ of a dosage. R~rm Alt<..mak.l:¢, a km~.t~c.all.~
`~fayored b~t Ihermody~mmically tmstahle form may be c<mverted darir~g
`these processes to a more stable and less soIuble
`DtuJng arid afler mamffactm:it~g, moisture from the et~virom:n.en~
`or ~:hat ~ealed m. the package may redislAbute throughot, t the dosage
`form. arid change the ~y,::ka~fi.o~~ state(~0. These cha~ges can, in turn,
`visit the negative consequm~ces discussed ahove for the b~.]k dr~lg
`the. dosage %rm. These cm~. be ma.~.ifest as changes m table!!capsule
`dissok~ti(m rm:es (aad perhaps bioava.ilabiliV), char~ges i~ ~yophile
`co~stimtio~ times, tablet capping, chemical insmbi.!.i.ty, discoloration.
`a~d more. Of cot~rse., the potem:i.a!. :[br char, ges in hydra0on slate also
`exists tbr many pharmaceulicN, exci.pients {such as lactose or
`sium stea’a.te)~
`Such problems are typically magnified as botB symheti.c ana dos-
`age R~rm prodttcti.on ~s scaled u p, This may be caused by solve.m iimita~
`tions, heat i:rm~.s.fer d{ffere~?ces in prod.ucdon equipmeat, changes i~a raw
`maerials a:ad~or raw material suppliers~ chaages in processing times.
`m~d time a~d co,m~oI co~.stra.h~t:s o.a product storage, m name a
`
`Lupin Ex. 1060 (Page 6 of 60)
`
`

`

`The ar~umel~ts just provided detail ~:he potential issues
`hydrates in the development pmce~s. The other co~sideration is the
`frequency with which hydraes are encountered in real life. Focusing
`sm~, t~,~a ........ , it :is ~,m~m~,~.:l that approxirr~atcly one4hird
`of the pharmaceutical act.ires are cap~ible of %truing crysta].l~ne
`draes [3], A search of the Cambridge Structural Database (CSD) shows
`that appmximale~y 1.1% of all the reported crystal strttctures contain
`molect~.lar water [4]. ’rb~s represents over 16~000 com pom~ds, K
`ometa.llic compounds are excIuded, tl~.is "mm-~be.r drops to approximately
`6,000 (3.8%), and the breakdow~ o:1 these according ~o hydration
`bet is shown in Pig. 1., Tl:~is shows tt~e expected t.re~:~d in which monohy-,
`drates are most. [:?:equently eacoulltered, and"~’,,.he.~c. ¯ ’- l.he [?:~,qu~,nc)." " ~ ’ ~ ’
`creases almost exponentially as ~:he hydration number hlcreases, The
`hom.ihy&ate stoichiome~:ry occurs approximat:ely as ff’equent/y as
`iril]ydrate, which should ;serve as a cat, don. to explore .%lly the occ~:~r.,
`fence of fractional hy&ation. That is, an apparent sufichiomeu:y of
`wa~:er molecules could be a partially dohydrated mo~iohydr~tte,
`
`Lupin Ex. 1060 (Page 7 of 60)
`
`

`

`eou.ld be a t~mihyd.ra~e \v~th additional sorptkm d~l¢ io dc.l~,t~, or amof
`
`The symmetry of th~se hydrate, crysla.!s tkfll.ows fairly closely with
`ttr~.at reported h)r organic s~ructure~ ~wer;:dl [5]. Table ! ,>how ~ the
`,~,,.,~.~.. groups, orgmsi.zed by crysta~ ,..5, ,, t~m, accounfi~~g for
`the top approximately "~*’’ ..... ~t~u~.,m~s. P~;~, (ra~mber 1.4) i.s
`
`CP
`s~,c~.,¢,,, that Q~ dl.a~6d sl.~ ac, turc,~ ~en>rall> ol l(. ,~.ca symmetry
`~:ha.~a a,c- "" " tl:~eh" anhydrous cotmterparts [61. This is attributed to tlae ~r<,~l-.
`I.lmt the h:~ghest. ~vmm~.,.~"~ .... ,-v assoc:ia~cd wi/h the ,,, al~.~ molecule i.s
`
`,, -, ~ o~.~,a.}.]~.~ stiacm{ c.,,. Regard~e.~s of the so/valiioI1 state,
`orgamc mo].e~:-..~les }4encrally exhibit: ~ower symme~.ry llama, do i~orgamc
`compomKb, s(} the impact of the symmetPg con.straints imposed by
`~:er does ~{x appem: to be the c{xl.rro[~r~g el.emem:. ~1,!1.111~.I comparisons
`would be .... - "’-’"t .... ~ ~ ..... _ ..
`
`Lupin Ex. 1060 (Page 8 of 60)
`
`

`

`The equ.itibrim~ them’..odynamivs of stoichiometr:ic hydrams has bee~
`described by several authors, The overview presented hem is inmt~ded
`both to review Jm basic thm:mody~mmics of crystNli.ae hydrate
`formation/stability and to [fighlighl. the i.n!;rinsb dKI)rences between
`polymo<phic systems and hydrate systems (a discussion of the kh~etics
`of dehydratiorghydralion will be given in Section IV), The following
`description is a hybr.id based on the work of Grant and tSgud:fi [7]
`and ,hat of Ca.rs~e~sen [8].
`
`A. Classical Higuchi/Grant Treatment
`The cq-mhb.~ mm between a hydrate: and ar~ ,mlb~drous erystat (o_r be-
`. _ hy&adcro may be (i¢.,,....t~b~,d by the following relalior~-
`
`where
`
`(1)
`
`l:tere a r~:,p.~c::~tmt,, fl~e activity o:f the. h3.~drate
`
`anhs,<~rat~.~ (aOM~olkt)l). ~. .... .. , respectivdy.. .
`-Wt~en hc ~:,,~.t.~;r activity
`(a [t-LO]) ~.s 5.~:a.~e~ thm~ the ratio
`
`(2)
`
`{.:~.n the, hydrate species is the smbb form. The anhydra{:e species will
`be smbk~, if tlae w-~,-~,... ~,~,:,.~ acl:~vity is ,~.~:o~,~,~, tha:a the ratio in Eq, (2). If the
`pure solids are taken as the standard states for the by&ate and arfl~y-
`dro~-~.s m~l.cnaL, (ie,. as tt~e ;~ta~:e,., with trait activity), ..he~
`a[H;O]" ~md m = 1 for a ~?,om.l~.~drme, So, dearly, ~he ~.L~bfl~D of
`a hydrate re~at]ve to t.h,:.; ar~hydrate :(or bwer hydrate) depends upon
`the activity of water in the va-oor [.aase. o~. the parthd, vapor
`or relative ’, ....
`,-, ~ ,
`~mm:td~tv (the ratio of J~e ~a~.o~: ~res~s~,ro of water to the
`samrati.on vapor [..{~,.,sm.~ a{: th,.,.t tcm.p~,~atm~., ’ ~’ ’ ~s
`’": ~" ........ " ...... .P~Po.~, Tim; straightfl)r-
`.
`
`Lupin Ex. 1060 (Page 9 of 60)
`
`

`

`der.stan~t~ng no~: only tt~e stability of hydrm:~d forms bin, th~
`differe~.c.es betwee~, hydrates a~d polymorpl~s,
`Jtlsl_ as lhe sta~e of hydration depends aport, l:he water vapor
`ity, so will ~}:~e water acti.vity (relative h.umid{ty, RH) i~:~. a closed sysmm
`depe.~~d upon tl:~e state of hydratio~ of tt~e ;{~o~{d phase, These microenvi-
`r(mmer~tal RI-i values cm~ be of sign.~ficance for tlae redisvribution of
`moisture witl~i~ a dosage 12orm. m~d!or package, An excellent ill,~slra--
`ti.oa of this was given by Carste~?se-~ for sodium phosplmt:e [9~,
`2 st~ows t~e relat~ot~ between water vapor press~.re (P) and the m~mber
`of moles of water for tt’~e compound. Here i{ is see,~ that as water
`adde(I to a closed system, the co~npo-und takes it up u:~til it ~o Ionger
`t~as a:~y capacity i.r~ a gbcen R~rm (i,e,, all of t.he sol~d is converte~
`n~.~_.~e~., the RH of t~h,., sys~:ern
`co,}.slarm As more wat:er is added, the Rt-I Nses m~OI the critical vah~e
`is reached {:h.a.~ is stffficicat to init.iate the formation of t.b.e r~exI t~igher
`
`be attained, Ul~:imately, the RH dri~s t~p if the eomp<m~:~.d deli.q~.~esces,
`()~e woul.d not, tt.tere:[k~re, .expec~ t):7~ maintains, a constam: RH witl~
`e:~ces i~ wm:e.r co~~te~t i~ a system re?less il: conlains hydratable compo-
`ae~:~ts ~:o bu:/Sfer the. cl3ar~ges~ The type of behavior M?.ow:~. here is most
`commo~t wit[~, it~orga.n.ic compounds, bui: the principle is the same
`
`2O
`
`10
`
`Fig. 2 Va.por wes~ure---h’v’dratio~ s a:~,~e diagram of .~odim~: phosphate
`d~.~c:ed ,,:villa permission0,
`
`Lupin Ex. 1060 (Page 10 of 60)
`
`

`

`even l:hot~gh the mm;~ber of stable hydrates 1.bat lb~:m.
`
`Hydratc.s a’~d po!ymorphs ar~ typically disc~.~sed tc, get]~.er (as i.~
`
`iza:km of pharmace~tk:als~ many of the be~mviors of poIym.orphic
`terns are at l.ea~: appare~.tly siva.red by compounds ~hat cm~ exist i.n
`o~ crystal]ine :~;tat,e::~ of hydratio~~, For the pm:poaes of t.his chapter,
`
`hydrates. Members of bot.l~, polymorphic at~d bydrm:e sys~:ems have di
`ik:~’ent c-rysla] structures a~d exhib:it different x-ray powder diffracd.o.t~
`patterns (XRPD), thermograms (DSC or TGA), i:~frared spectra,
`iufion r~vc.es, hygroscopicity~ e~.c, ~m:erconversio~? between polymorpt~s
`or t~ydrat.es may occur as a function of iemperamre and!or pressnre
`be solution media~:e& The po~:.e~~.~ial %r i~terconversio~ dm’i.r~g pro
`
`polym.otphs and. !~ydrates, Given ~:l~is long list of similar behaviors.
`a~x~ t?.v(iral.es be a :~d~:es,., :A in the
`
`The diffi:rences between polymorphs and t~ydrams are
`The bas~.s :li>r all these di.fferer~.ces is ~:ba.t pc, lymorpb.s are differe~ crys.-
`~.M struc[ures o I~ the same mol.eculesis) while t~ydrates are crys~Ns of
`dr~g molcct~le wkh different nt~m.bers of water molect~Ies. As discussed
`above, the hydration state (arid d:~.em:li>re the sm:~emre) of a erysta[Ii:~e
`h.y~Ira~e is a f~mciion of tl~e wamr vapor pressure (water activity) above
`ihe so]it!. Polymorphs, however, are typically onty agfecl:ed by changes
`in. water vapor pressure if wat.er sorpti.o:i~ allows motec:u.lar moOo~,
`;~ reor~anization in.to a di~:~::renl pol.vmorpl~. (i~e..,
`a soluti.o~..medmted t.ra.ns~Srmation), This d.ist.~nctio~ is pa.rl;icu~arly
`portant in defir~i~g ~he relalive free energy of hydcaes, A sh~pl.e (only
`o~.e molec~.le) anl~y&x)us cryslalih~e %rm is a o~.~e compo~en.t system,
`and the free energy is, prac~ica!ly, specified by temperature a.i;~.d, pres-
`sure. A crystalline hydrate is a two~compone.at system and :is specKied
`
`Lupin Ex. 1060 (Page 11 of 60)
`
`

`

`that the ac~:~vity of t.he pure solid is uni~:y,
`Consider ff~e tbermody~,amic stabi!.ity of a phase that crystaBizes
`from water. K the phase is a~.hydrous (a:ssu:mi.ng no specific interaction
`be[ween, d~e molecule ~md the wal.m’), wher~ the phase is removed
`lhe solvent it is u.st:~ally stable a~ ~hal temperature (i,e,, fi~e free energy
`o[ tl-~e phase is ind.ependem of the solvent of origin), If the phase
`hydrated, whe~. i~ is ~:moved from the solven~ the sima~i.on chm~ges
`completely, AI1 that can be known ~s tha.~ the phase was thm’modynami-
`only s~ab!e a~: a water act.ivitv of approximalely rarity. Although it
`a rule o[’ t!:mmb that ~he higher the hydratior~ state lhat forms at a
`pera.mre the more thermodynamically slable, Grant et al, [10] have
`ported, lhe opposite behavior. Once removed fi:om the win:or, the acfi.wty
`of wamr needed to mN.ntain t:he %rm (the critical acti.vily) had to be
`determir~ed by other mcdx~d.s, Thes:e may include water vN)or sorpfion
`daa or a titration, of/he amount of waer in a cosolveng system
`A typicai constanl pressure G-T diagram (Kee energy vs, mmpc;ramre,
`recalling tha ~G/~7’~ ..... S~ for a polymorphic s-vstem is reaffy
`gous m a logarithm solubility vs, reciprocal teng~erat.ure plot (la X
`liT) fl>r a system of hydrates (Figs, 3a and b), Alternatively, a G..--T
`plot %r a hydrm:e sys~:em a~: cons~.ant warm: activity is ana].ogous, The
`relatkmsh.ip be~weea~ t?ee energy and t~he ideal solubilily of a ~:}/id.
`see~. flom the fbllowing
`
`AG = ..... R’F In X
`
`R R T
`
`where zk$~- a~d ~.kH: are ~:he entropy and enthalpy of fusion at the melting
`point, respectively, and R i.s the gas ~..onstam. A plot of 1~ X againsl:
`1!T should yield a straight ii~e wffh a negative sl.ope equai to .... ~:~H~iR
`that
`" ’~ ..... ¯ 1 A~
`and an mt ~.c.q) ~ o:t"~.~. r, - for each. phase, This conciuskm assames ....
`the enthalpy of sol.ufion is equal ~:o the enthatpy of mekh~g at ~Se melt-
`ing poinL A more general expression may b:e derived, but lhe reciprocal
`.....
`dependence of solubility ;;m(;~
`
`Lupin Ex. 1060 (Page 12 of 60)
`
`

`

`~~ TRIHYDRATZ
`
`3,2 3.3 3.4
`
`..... ’~’"," ~m.[..,.~.a~m<.. p]o~ R:~r ,un~..~c~:lm.~ anhydrate and trihyd.rate
`(reproduced: wi~h permissJ,:)n).
`
`G-.’/.= pioi:, the .intersection of cm:ve~ generated for two differe.:at crystal.~
`liae lit-roses repre:set~s a poin~ of eq~]aI iYee energy aM a tra~sidon tem.-
`perature,
`There are .ma~-~:y implications of tl~e :relatively more complex
`turc of hydrates. As wal:er is i.~:~cluded or lost :[rom tI:~e crystal sm~.cmre,
`tkere mu.st be a ch:m~ge i~. tt~c vokm~.e of the m:~i~ ceil (co~ected :R~r
`~:he mtmber of molecules per u~~it cell) a~: ~east as large as the
`
`Lupin Ex. 1060 (Page 13 of 60)
`
`

`

`there is study
`.... ,~,-~ :e
`o~" the water moI,..~ul ..... (!5-40
`[12i,
`knowr~ to the ai~.thor comparing the re]ati.ve vo.h.m~e change, between
`potymorpbic pairs vs. hydrate pairs, it must be assumed [:ha1 the trm~d
`is l:a:s~ for hydrates. " "’- ~’
`accommodate {he addk~onal vo}m.ne occgpied by the water motecules,
`The obvious problen~, for pharmaceutical development is that the
`
`it is for this maso~ that knowledgo of the water
`acdve :sabstar~ces m~d excipients is so cri.gcal,
`
`Hydrogen E~onding in Hydrate~
`
`The abithy o[ water to form hydroger~ bonds and hydroge~~ bo~d.ing
`nmworks gives it unique behavi.or w~:~ respect to colliga, iw properties
`sm:h as boi.li.r~g at:~d malting poh~ts. Similarly, hydrogen bo~:tdi.ng be.-
`twem~ wa~:er molecules and drug molecules in th.e solid state dictates
`~{:s role i~ the structure of al~ classes o~’ crystalline hydrates (i,e.,
`abilftv of water [o form cocrvstaIs wi/h the drug molect~le), WaI.e,r will.
`of course, be h ydroge~ bouded whenever physical I y possible, ’Phis may
`take ti~c [0rm of hydroger~ bondi~g ~x~ other water" molec{:des, wifl~
`ti(maI groups (m other molecules, or to anions, Hydrogen bonding
`other water molecules i.s common both in tl~e crystal ?attice m3d in inter-.
`st.iOa! cawues or channels. Hydroge:n bonding {o other moieties and
`a~ions i~~ crystalline hydrates is primarily wi.~hin fl~¢ lattice. In addition.
`{:be lon.e pair elecu’ons of the water oxygen may be associa~:ed with
`metNlic cations present: in many salts, i[’l~is interact:kin is largely e~ec--
`trostafic i~ harare for the me~al cations con?.~.no~.’~. 1o pharmaceutics (Na,
`m.a~a-g~ ~up metal kms lack the d-orbitais of
`energy that are necessary to form coo~d.m,tt~ covale{~t or coordin.mkm
`bo~ds ~:hai ~on;s of the transition series fom~. wilh oxygen. It
`stm:ed that Mg([I) has a coordination nomber of 4, but this is a result of
`packing (or geometric } restrictions arising when fitting warm: mo!.ecul.es
`around the c.ation in response to the electrostatic attraction, Since these
`~’bonds" are mostly e lectt’ostatic in ~-~at~,tre, they are no~: preperiy
`scribed by a mo[ec-ular orbkaI but are bes~ defined by classical electro-
`statics ~.I.:,]. These b(mds" ~., _.. often stronger th,:,t,, hydrogen bonds
`but exist with less direcfional dependence.. A l)’p{cal, water hy<kogen
`
`Lupin Ex. 1060 (Page 14 of 60)
`
`

`

`bond is on doe order of 4_> k~,a!o’mol, w[~ereas a sodi.~ml-oxygen l.o~e
`pair elect.rostatic interaction ca~: be t~m" Io fi.ve times stm~ger, These
`bonds also exert: their iilflucnce tl:~ro-ugh hydrogen hoods i~. the form
`of coope’rative e2focts~ The specific characteristic~ of the hydrogen bo~d
`are pmser~ted here in~ the %rmai~s:m of Falk and Knop [6],
`The ubiquitous hydroge:~x boixd~ng of waker is largely a resu{l:
`its being both a ixydrogen bo~ad don.or and acceptor, .[t may participate
`~.t~ as .rarely as :(our hydrogen ~ -" " ,’ v ..... ~, ~
`:[Br each b::me pair or~ ~}le oxygen, CIassi~ca~io~. scI:~.ernes based, solely
`on t[~e ~.ype o.[ coord~nati.(m of ~:he wa~er oxygens, have Ueen. proposed
`[G]. As e.acl~ bond .is :~’or:med. i.t, makes the otller si.[es more attracd.ve
`as parmers for addid.o~al bor~ds, EIydroge~ bor~.d acceptors mus~ be
`electronegadve arid incl.ude one oJ" ~}m foliowi~?g: ox.yge.n atoms
`ott~er wa~er-molecules, oxygens, and ~b:rogen re:ores :from other
`tional gr(mps, a~ad chl.orh:m a[oms, Hydroge:~ bored do~.~.ors inch~de pro-
`toas on nitrogen, oxygen, and sulfur, of the type, s ~suatly Rmad o~.
`water, Ncof~oJ.s, amines, a~:~d tl~e like,
`Free. w,-,-’,.,,.,.,,.,. ~.v~.~por), . . has an ()b~ bono. length of 0.957 A and an
`HOIt angle of 104,52", As soor~ as the n~o]ect~Ie starts imm’acti~g with
`oilier mol.ecules through hydrogen bor, ds, coo~x[inadom or otSer elec-
`Vosta~ic "bonds", t}~e molecule is di.slorted 9:ore its t57ee co:n.~r.mad<m,
`The :~k>rmation of hyd.roge~.~, bonds weakens th.e OH bo.~ad, ~stmlly
`suI~h~g ir~ an increase m it:s Iengtl.~. This i~.crease cm~. be up m 0,01
`fo~: a:~ <.xce~.u,m,J.Iv s~r(mg~ hyd.roger~, bo~.:~d, b~: i~ ~.s more typically
`~he order of 0,01 m 0.02 A for organic hydrat~s wJ.th hydrogen bond
`le~.gd~s of 2 7 to 2,9 ~t -~,:.. ,- .....
`The limits o[ ieng-fh of a hydroge~:~, bond are defined al: the lower
`e~.d by the va~ der Waal.s radii of the two atoms and at d:~e upper e~ld
`:~tSil:rarily. by the lengih of ihe weakest hydroger~ bond obsm:ved, 32his
`ca~. be see~ more quantitatively by expre;ssi.ng the hydroger~ bo~~d dis,--
`tances sl~ow~ h~ Pig, 4 i.~ terms of the va~-~ tier Wools ra.diL
`
`’~.) < t.(iH)+ r(Y)- 0,20 A.
`
`4)
`
`a~~d since ,,’(i-t) = I..2 .~,
`
`Lupin Ex. 1060 (Page 15 of 60)
`
`

`

`The factor o[ 0,2 reprcsem:s the combi~ed experimentai and statistical
`
`a.~d sma.ll o:rga~dc t~ydrat.~s [6], Of the 1.29 compounds studi.¢d., onb,*
`<me i’a~{ed t~.i.s criterion. Often the }-~ydrogen bo~:~.d le~gths are give.r~ as
`t.~e O~Y (e.g., oxygen---.oxygm:~ or oxyge,>-.ch[orine) dis~.a:aces, be-
`ca.~.~se i,~ x~ray digfr:acti<m st-t~dies it i.s o~:’ter~, di[fic.~.~lt or impossible m
`locate accural:dy t~e hydroge~ arums d~e m {:heir i.r~.{~erem!y low scat-
`termg aM ttaeir relatively high m,)bi~ity. Because of the large cross
`sections, hydroger, a~oms are o{:ten located by ~e~,tro~ d:~ffraelion stud-
`ies. Ut~der ~Sese circumsta.t~,ces, crys~allograpl’~ers will report: lt~e O ....... Y
`dis~:ance they k:~mw m be re~iable, and geome~:ric constraims m~U Nso
`be applied m suct:~ data.
`
`(5)
`
`As the d.ectroslatic bored stre.~.g*la of the do~or ~o tl’~e wate.r oxyge:a (X)
`i~.~creases, ~:he le~.gth of ~1~.c H ...... :Y bo:~d decreases, This cooperative
`efl?~ct is atso sem~ as the ~mmber of ~udroge~i bo~,~ds per wa~er moleca~le
`increases. Hydroge~ bo:a(ts pre:l?~r to be linear bu{: may adopt a range
`of m~.gtes at the expense o:f fl:~e stre~gth of tl~e bo~ad [6,15~,
`All of these a.spec~s o:[’ water t~ydroge~.a bond~.ng are eviden.t in
`tl3e in:flared spectra of crystall~:~e hydrates, When a :m.olecn}.e absorbs
`
`Lupin Ex. 1060 (Page 16 of 60)
`
`

`

`inkared radh,~:km, this energy is used ~:o exci~:e ihe molec~.~e into higher
`vibrafimm~ e~e~2~y level s~ates, The occupancy of these h:~ghe.:r s~ates
`manifests itself in greater degrees of moiecul.ar v~bratio~.. The freque~>
`ties at whic]~ the molecule absot~)s a-~ a fa~.cti.o~ of the mass of the
`bo~:~.ded atoms, the geometry of the molecule, and ~]:~e force constant
`(sW~ngth) of the bond. Thi;s relath:msNp can be described by a~Mogy
`m cI.assical mechanics thro~gh Hooke’s law, which states that. the ~re-
`quency of mo~:io~a (v) for a harmonic osdllator is i>,,ersdy proporlJon.aI
`to ~he square root of lhe reduced mass of the sys~:em (~.). The force
`co~stant (L in ~mits o:g dyaicm) i.s ~he WoportionaliV constant. Thus
`
`I
`
`.h~:,,~ c is ~he velocity of iight i~?. units o1! orals, A’" IllU~.t:~ted
`5, water in crys~alline hydrates has r~ine, pole:ntial degre, es of freedom:
`two sl:retcl:~ing modes (symmetric a~d ,~.~ ~ ~ mn~A,~ ~,.. ~, one be~di:ag mode,
`three vibmtiom:d modes (hi~~dered rotatkm), and l:hree hindered
`
`FI{~. 5 ~ ff.,t,~cm,.I modes of water° Shown are the h~terrml modes: (a) sym-
`reel:rio stre{cb.. (b?.. be~d{~g, (d} asymme~.ric su:etch, a~d the lib~’atkmal. . mcdc-s- -~ ’ ’
`(d) wag, (e? ......
`twist:, a-~d if): rock. No~ shown are the~ ~ ~h~ee~ ,:’- ~hindev,~., ~d transiatiormi
`m:odes~
`
`Lupin Ex. 1060 (Page 17 of 60)
`
`

`

`tio~ml modes. These vi.bratio~ml modes and theh" characterislic
`tion :[reque~cies are p~wented in Table, 2 and contrasted vAtg those of
`water vapor.
`The dominant t~ature i~ the ]n:fi’ared spectrum of a.hydram is band
`system associated with the O-H s~rei.c}fi~lg freque~cies betwee~a 4000
`and 3000 cm< These peaks are mmsual.Iy imense due to the effect of
`hydroge~ bor~dir~g on the chmlges in dipole momer~t that are associated
`with the wave Rmctions describing the mobcular mo!:iom I[ m~ O-H
`st,’etd’~ing bm~d is not observed, then. no water is assoc,iamd wi.~:h the
`compotmd, When prescott, the co~tributing OH groups "a"ms~. be. Woperly
`assigned to ,:Sstingu[sh water from a].coholic, phenolic, hydroxide, or
`other inter[e, rh~g absorlxions, TNs i.s acco~g~lished by first assigning
`em:rgy vabes m the known structure of the molec~:de I)rom tables,.
`resolved, ~he prese,~ce of an HzO bm~di.~g [):ecttm~cy around 1600 cm
`is proof that the sample contait~s water, Comparing ihi.s to the I.R spec-
`trum of the. m~h~d~:, us material or the ud~ d~<,d sampb shows which
`peaks i~ the region are due {ml.y +::o water, The IR spectra of
`be,~k:rre m~d a[~er dehydration exhibits s~Jch behavior,
`Table 2 al.so shows thai the OH stretching frequm~cy of water
`occurs a.t lower wave ~mmbers (l.o~.ger wavekmgth and lower e~ergy)
`m the cUsm] thar~ in. the vapor. This is d~e m tlm reduct:io~ of the
`co,?stant (f) by {meractkm of the water with ~eighborhag groups, ix}.
`partic,dar hydrogen bondi~g and kme pair imeractions involving the
`wm;er oxygem Tge weakenim;~ of the {x~xl ~e,..aks h~,. a sligh~ -b
`of the bored length, in the ra:~ge of 0.01 to 0,0x: [151, Ih~s s.hiR i.~
`
`Table 2 Vibratiorml Modes o.[ Water m Various Phases
`
`B endi ag
`Rotatio.~./libm~ioe
`Tra~asl a~i~m
`
`3755°8 (symme:t~ic)
`3656°7 (asymme~ri.c)
`t 594,6
`
`~
`
`2850-3625
`
`1498 - 173:2
`355- ] 080
`200-490 "
`
`Lupin Ex. 1060 (Page 18 of 60)
`
`

`

`fl~e O1t stretct~i~g fl’eque~-~.cy of w,’-.~.ter can be ased t.o evaiuate the im:er-
`action e~ergy between wa~:er a~.d the o~her molectdes. Specifically, the
`N.gher is the degree of waler hydrogen bo~di~g~ the lower the ft"e-
`que~.~.cy will be of the OH strelch. In :[~.c~:, good. correlation betwee~
`OH stre~chi~g fl’eqae~cy a~d fl~e le.agth of hydrogen bo~ds is available
`l;or i.r~o~Narfics m~.d w~ry sma11 orgaaic crystals [14]. While r~pulsive
`lattice energy re:ads ~o i~.crease this frequency, it typict.~).Iy yields only
`a ~,e:ry smalI shift. In large molecular crystals, [~owever, ::/:~e energedcs
`become more complicated a~d the correlador~ i:s t~ot as good. A.dventi
`dous adsorbed wa~er tends t:o have broad peaks in. lhe lower part of
`lhe fla:que~:~cv range, The broade~ing is due to the vibrafio~al
`between waer molec~fles, and the lower t}:equencms are due m the mui-
`r. pie hydrogel:~ r~on.ds, .[[us "’d~.spers~.o:~ of stretchi~:~g t:]:equencies" is
`analogo~s m the broMeni~:~g of DSC peaks due to ll?e mutli pie energetic
`en.vironmem: fl?a[ adven [:il.ious water ca~ experi.et~.ce. If the water
`pi.es {ml.y one !:ype of crystal site, {.he DSC a~d IR peaks shouht be
`sharp relative to fl’,ose of adve~.tlti,::ms wa~ea’. This is see~ in the
`li~. exa.mpie, of tSe classification sectio.l~. The O---l-{ stretching peaks
`from w~aer it~ the crystal [a~:dce will occur a~: various frequencies de..
`pending upo~ the: s~:re.~.gth of t.he hydroget~ bonding.
`ir~ addidon ~o shiRs it~ frequer, cy and peak shape, peaks may
`come split owi~g ~o the interaction of the two water hydroge~.s if they
`participate in difl?~rent hydrogen? bo~?ds. Therefl::~re in some crystalline
`hydral:es there may be two or more peaks associa~:ed with ~he OH
`stretchi~i~g mode,
`Metal ca.dons at’~kct the infrared absorptio~, behavior i:a several.
`ways. First,, if lb.:., waler oxygef:~ :is hotrod a!: *h ~ ~ ,,
`" ,:"
`~....~. m~,r hydration sphere
`of the cation, po~.arization of fl~e elecm:m de~.sib~ causes stronger l~ydm-
`ge~. bonds Io be fl~rmed.. This effect will iower tl~e OH st-~vtch~g
`quer, cy i.r~ a m.am~er proportionam m tl~e degree of b<md
`a decrease that ca.t~ be up to 640 cm ~ i.a i~mrgmfic compounds [6,I 51.
`Second, ca.ion-wa~:er inter:act~or~ ca~ h-~crea.~4e the bending fl’eqnencies
`(which are ob:~erved in fee 1.600 cm ’~ region) by as much as 50 cm’~,
`Fin.ally, the bo,~ds %treed be~:wem~, the cati.o.a arid tSe atoms in its ironer
`coordi~mtio~ spl~ere will be o!~ser~,ed as low<ITreque:acy modes below
`400 cm-~, ¯
`
`Lupin Ex. 1060 (Page 19 of 60)
`
`

`

`IlL CLASSIFICAT~ON OF HYDRATES
`
`The comNnatio!7~ of the vibrati.o~ml mod.e {n[ormaJom the hydrogen
`bonding character~stics, and the ~l~ermody~mmic reh~ionsI:Jps serves to
`-~brm a dear p~cture as to why water can and do{~s pm:ticipate i.r~ hyde:ate
`forma~i.on with drug mobcules. The possible structu.res that may
`from s’~.ch, imeractions are q~:fite diverse. For practical purposes,
`idemiflcatio~ of types or c~asses of poss{bb re.salting su:uctures is use-
`fuL Water is small enough to fill many cornmo~J.y occm~J.ng periodic
`"voids" gormed when larger molecule:s are packed, and. it interac{:s
`tI~rougb hydrogen bonds [o overcome som.c ~~f the em:ropy of mixing.
`I h., ab~hty of wa.ter ", .... ~ " ..... " ¯ ’~ ’""
`"-am.all.’ size,., allows them ~_,"~ fill larger periodi.c sl..a.~es" ",’" ~" conlMrm]ng to
`different ~hape;5. The chm:a:{:eris~5.cs give water a dmmebor>like qu.al-
`ity (also seen m proteb, hydratkm), which gives rise to "motifs
`water arrangements in crystai
`
`clas,..l~1<:,d by either ~,!.~mA.t~l ~ or
`energedcs [6]. The idea of ghe strt:cmra] classifmation scheme presem;ed
`here is to divide the by&ares into three classes Jfmt are discer~:Jble
`by ~he commonly avai!able analytical iedm.iq~,.es. The cIassi r:icatio~ of
`crystNline hy&’ates of p~a.rm.~.k~e~.~tical interes~ by their suucttu:al
`acteri.stics is the mos~. conunon, imuitive, and {:~sefiff approach., A good
`classification system should direct, the p:t’efom?,ulation/formulation sci-
`em:ist to the chamcmristics of the particular class that will help in
`’ "
`[’y:b~g a r~ew ,_ampk.., in se.lectb.g the ..... r*~" .. .
`1..,t~.,c..~ form of the su.~stanc{.., at~.d
`i~. es~imatin.g bott~]darv con.diOons ~Br safe handlieg (TaNe 3).
`
`(.’lassifica~ion of Co’stalli~e Hy~]rates
`
`Description
`
`I
`2
`
`Lattice cham~.eIs
`Expat?.ded ehan.r~els (~(m-stoichiometric)
`
`Dehydrated hydrates
`MetaIdon eoordhmted water
`
`Lupin Ex. 1060 (Page 20 of 60)
`
`

`

`An ex.ampIe o£ each cla:ss and I£e analytical m.anifesmtions of i~:s
`crystallkle stn~cm:re will be, p,,’.e.se~ted in ~:he succeeding seci:io~s, For
`~h:is sectiom each class will be exami~ed wi!:h respect i~o a specific ex.-
`ample for which si~igle crystal structure, DSCiTGA, XRPI), and IR
`data are available, Startk~g with d~e pacldng diagrams from the solved
`strucl:ure, the da/t-t from the or.her medaods will be compared to thai
`expected based o:a i:he information presem.ed in the disc~ssions above,
`
`A, Class 1: Iselated Site
`
`Lupin Ex. 1060 (Page 21 of 60)
`
`

`

`Stt~ct~ra~ Aspects of Hydrate= and 8oivates
`
`~ 43
`
`cephradinc a.r~d fore" motec~l¢~ of water, The diagram shows ~so].a,ed
`
`water molec-~Ies hydrogea bol:~d with each other, a~.d with the carbol~y!,
`carboxyl, m~d amlde groups o,~. ~he two cepl~,radh:~e m.olecgles,.
`No axis ca~ be draw~ between sq~:m:ate water pabs wkhom: pass.*
`i~~g thro{:@~ a~ im:erve~.h~g portion of the cephradi~e mo!ecu.k:. This
`means ~h.a~; a pah: of water molecules o:~:~ the surface may be easily
`
`Lupin Ex. 1060 (Page 22 of 60)
`
`

`

`Fig. 8 (a) Meas~.~:ed a:t~d (b) caIculated x-,ray powder d-iff-!"actior~ p~-i~terns t-or
`
`losL b~l: the crea.tion of the h.ole does r~o~: l.eave other water
`accessible, Si.milarly, ~.~o r~,atwo.rk of hydroger~ b<mds exisIs soIety
`volvi~g wat~:~" molecul.es on mly axis t.hrough the crystal. The (iiagram
`has been co~sh.’ucted to show the water molecales wilb ,heir ,~,a~:~ der
`W~als dimensions while the (frag is in a stick representation. Areas
`,hat may appear void. between pairs are actually filled by i.he electro~
`cIouds of the .~eighboring arums, Si~ce each pair is located in the same
`environmen% it is expected that the i.nlerac~ion e~’~.ergy bei:ween eaclq
`water m.ol.ec’al.e and its r~eighbor be similar {.low energy dispersio.~a),
`This st:rt]cmre sbou]d yield sha’p DSC e:t~d:o~]:~erms, a ~.arrow TGA
`weight l.oss range, a.~:~.d sharp O-H sh:etching frequencies m the
`specmm:~ (.~a’igs, 9a an~t b ~md. 10). The DSC thermogram shows
`h~completely resoived, bu{. sharp, entl.o~hm-ms at approxh:na~ely 1.00°Co
`and the TGA t:herm.ogrm~?, shows the anticipated sI~a~i> weight Ioss over
`a similar rm~ge, Ir~ additi.o~~, l~e onse{, of d.eJ.~ydration observed i,~. the
`DSC curve is quite sharp, ’rt~e diffuse reflecta~ce i~frared (DRIFT)
`
`Lupin Ex. 1060 (Page 23 of 60)
`
`

`

`145
`
`spectrum of cepllradi.ne dihydrat{~ shows sharp O-}{
`p~ox~mately 3520 ai~d 3425 cm ~ d~.a{: a~’~> abse~~t .h-~ the a~hy{.h:otf.s
`~:iai. [1~7]. The thes~mal a~d spectroscopi.c data are, seex~, to be: c<msistm~t
`witl~ the kt~.own singte-crystal slr~c{:~’e, Were the si~gle
`ture not availab:Ie, the ge,,eral [i:atures of lt~e water associal:i.<m
`h~:ve been deduced usi~g t-l:~e ~:ati.o,~.ale previously developed.
`
`cha:m:~els, where tl~e w~ter
`l~-Iydrates, in tm.~, ~..l:as~, c’ ~,~,n.tam" ": w",.~.{:<~r 0" :in l~{tice ....