JAIVlES, L, f•'OR.D
`B.Sc., JvLR.Phann. S., Ph.D.
`Principal Lecturer in Drug Formulations and Design
`Liverpool Po[ytedmk
`and
`PETER, TIMMINS
`B.Pharm. M.R.Pharm. S2h.D.
`tvfanager, Pharmaceutical Development, International Development Laboratory
`E.R. Squibb and Sons, Merseyside
`
`ELI.JS HORVVOOD LI\fi'fffD
`htbfo.b<::r~ C:hidJ<:~t<· r
`I:blsted Pre<::§; H Jjvb~un or
`JOHN V{~LEV !k SGi\S
`Ne\><;' Y;>rk · Chidwc;wr · Bri:,\:mw
`T~:;<:n::.'
`
`BASF Exhibit No.2014
`IPR2018-01096
`Willowood USA, LLC v. BASF SE
`Page 1 of 16
`
`

`

`Fir~t pubiish,~d in l%9 by
`E.U.IS HORWOOD U.kHTED
`!Yhu·k~~t Cross Htiw;e, Coripn Stre<::!,
`Chkhcl.{tt:r, \V c:-;t Susso:::x, PO 19 1 EB, England
`17,<. p11M'.!·ha's '.">bpf1<m f;; r;;:pmducd Irmn !unws (}i//ison':; drawing of the ancient tdi:ul;e Cros.'<,
`{)if<.i!,'S{:'!,
`
`mstriJm[l.•r:<;;
`Australia and New Zcafomf"
`JACAR./\NDA WILEY LlMiTED
`GPO Box 859, Hri::<b<sne, Qu:.:on;;Lrnd 4001, Australia
`G:mada:
`JOHN WILEY St SONS CANADA LIM1TED
`22 Worcester Road. Ru•dak, Ontario, Canada
`Eumpe and Africa:
`JOHN WILEY & SONS UMlTED
`Haffins Lam~, Chkh~~sk1, West Sussex, England
`North and South America and the rest of the world:
`Halsted Prnss: a division of
`JOHN WILEY & SONS
`605 Third Avenue, New York, NY 10158, USA
`South-East Asia
`JOHN WILEY & SONS (SEA) PTE LIMITED
`37 Jalan Pe:mirnpin ;'/ 05 .. 04
`Block B, Union Industrial Building, Singapore 2057
`Indian Subcontinent
`WILEY EASTERN UMITED
`4835i24 Ansari Road
`Daryaganj, Nt:'.w Delhi 110002, lndia
`
`British Librai·y Cataloguing ln Public<i~iori l:J~1ta
`Ford.J, L
`Pharmac;;utkal thermal analysis
`I, Drugs. chemical analy~ii:<
`L Title
`II. Timmins. P.
`615', 19015
`Library of Congr<;>.'l.'l C£ird No, 88 .. ·J? 189
`ISBN O·· 74S8-·,(fl46-6 {Elli~ Hmwood Umik:d)
`ISBN (~"·Pn.:; 1219 .. 5 (Hnbtcd Pre;s)
`Typeset tn fones by E!li:s Honvood Limikd
`Printed in Gn;Jt Brir;;in bv Th<'. Cnmdot Pr{:~:;, S<:mtirnmpton
`
`COPYiUGBT NOTICE
`/\ii Righ:s Rt:~crved. Nn pnt of tln:<: ptshfo:Mi(m HliiY tw n;p;:(;,:J<ic<-::L
`in '~
`,,,,:.:;;;,,, ,,.,
`trnn~mittccL in mw form or by anv mcm1s, eknrnm;;, m,;d;;:nkd, pht;t<:l.'.:::p:,:;:·i::.,
`wi!lwul :bt: j)('l mi.~.'il<.m <Ji F!!h Hi>rWHOd Limited. ;\Lrktt ('f(:o,:::; ;+:rnw c,;,:p;' i: ::~1< ;'0;'. ' ') :d;,.~:-::::: i\ :;-'(
`SiNCX, bigbnd.
`
`BASF Exhibit No.2014
`IPR2018-01096
`Willowood USA, LLC v. BASF SE
`Page 2of16
`
`

`

`·;--:::: ·i:::
`
`.·~·.·,·_·.~~-·_·,~~,=~.·.l,: ....... ",,·.· .. ,~,·,.·"'_-.'.,'·.·.·,, __ .'·',==.·.',:·::~ :_,_·_._,_-_,_·.·.·.:. :.·.== ... ·_. :.~ ·:_:_=_,_L.-.: ~-·.·=,',·-~ .'··.'.·.',:.··:··_.~-~--~.-.•.-. ',·.·.·.'.·'_.:.~ · .. '.·.', ... : .. _:_:_._'.· .. -~,~_}_ .. :.:~ ..• ~_; ____ :=_·,_::,· __ ',:=.·.'.:_'.·.',·'.·.·.·:_.·'.·.',·.
`·=~· i···=- ·-= "!';
`. ::. ,=== ~:r ... --~ t $.... t ·;-;~·:..
`.l flt:~l·:·:rtI~:ll ~IlI~~litl~.f ~}lt~ JJH~~ ~~~LttJ;~ ~·-
`·"
`~ ....
`rJhar.n-1a.cc1ntir:alt so~ids
`
`v
`
`:--
`
`,
`
`,
`
`'-.',',' .'.','·'·· .~.~
`~
`
`, "$
`
`, _ ..;..
`
`.&
`
`6,1 JNTRODUCTJON
`The isnhHion of a pharmacrntkal solid is achieved often by me~ms of a pn:ci:pirn\io:;
`\)r crystn!lizatioH from its solution in a solvent or mixwre o.f solvents, Tho rnk :.E
`which ttw ;.;qxmition of Bolid mater.bl fro:m the solution occurs and the naturl.'. of Jh:=:
`~olvfm, th~ conccntrntion of tho drug substance in soh.ltion and temprratm;; il
`whkh solid Bemm.itkm occurs am all factors whkh can affect habit, soiv3t;; nanm.'
`:-i.nd crystalline modification of the separated sohd.
`ln a review, ffaieblian (1975) has difforcntfarnd habit and (~rystal chermstry of a
`drug compound according to the sche.rne in Flg. 6.L fo addition to the da~m
`in.duded in the scheme of Halebfom (197.5) .isomers of organic compounds w1H be
`i
`·h
`I
`1 · ,
`,.. 1 •
`l.
`c :scu:.;:.;cc antJ ~10w· t enna ana ysis IS USfaH1 m tw-:: c~wrncknzatwn m tui.t; type ot
`l 1
`h
`•
`•
`-·
`, ~-
`-
`varfat\on of ~1 ch1.~mical substanc,~,
`While the definition of isomers mav be understood bv th,,;; ma jmi tv of 1 ea den the
`..
`"
`definitions of polymorphism, habit and vmfom; types o:f solvent addition sobs
`(solvates, indusion compounds) may need further durHkatlon.
`A drug substm1ce may occur in several different crystal habits., e.g. prLms. pbtts
`or needles. Where the habit varies the internal molecuh-n orgniz2tion of tlw u.ru::l h
`the same for each h&bit but different crystal faces have devdofKd to diff.::r<nt
`resulting in the different C[ystal shapes. Unfortunately physicz:H::h(:mkal parnmWi!.
`induding thermal arndysis do not show differences between dEL:rcnt
`habh.
`Only their appearance, for example by microscopy., 1-viH diff~rr-nti;ne thur. His
`important to identify the different habib a~ they may hav::; dfffer:.':nt ph;:;·m~::,:d:fr:::l
`properties. For example, Shdl (.196.3) has in<li<:ated dlfk:rrng :>yriq:;;:
`panmt~rnl ::mspcnsions prepared from p!ak habit and nerdk kibli
`j l
`!
`.1.n ;1w (;ase m po1ymorpul&m, scparat.J<.m ot so!K> nl.ilknal L'-urn
`in materiafa of different ~:uibfrs buL in addition; phy:0.c0<hf:1.n
`rnte§ !h;:1t the mokcubr organization within dw :>-uhds b d~
`
`f
`
`'
`
`i,,.
`
`•
`
`..
`
`x' ~
`
`.
`
`.
`
`.._,
`
`~'
`
`j@ m
`BASF Exhibit No.2014
`IPR2018-01096
`Willowood USA, LLC v. BASF SE
`Page 3of16
`
`

`

`Cho::mic:.d •:onwou1 ''·'
`
`r·· . J .. -m-·1
`r"~ ... ~~J~ .............. "."""l
`
`H,d ,](
`
`lnkm;:d :;t»ucttu ('
`
`Crv~:t.:iiline
`
`;\rnorphous
`
`r·"_, ........... ..
`
`1
`
`Single entity
`
`fvfolr1ctd;-1: ildduct~;
`
`Non ·stoichiomet:ic
`inclusion cornpoundc;
`
`Stoichiometric
`~:olvate;a (hy{lrntns)
`
`l
`I" ____ J ____ ~-~-·1
`I
`1---f~·····-~ .. ·1
`
`Chann0i
`
`Layer
`
`Cage
`idathr.l'\te)
`
`Fig. 6. l ..... Outline schcrm.: diffornntiating habit and ciystal chemisuy of a .;Ji1;;mical compound
`(reproduced with pcnnbsion from Hakblian, 1985).
`
`of the physico··chernicaJ methods will definitely confirm the different molecular
`organization within the solid while thermal analytical methods wiH provide useful
`additfonai information.
`Because of the different internal organization within the solid, polymorphs may
`show diffornnt melting points~ solubilities, chemical reactivity or stabihty, These can
`have an impact rm pharmaceutical properties such as dissolution rnte and bioavana ..
`bility. Unfortunately polymorphism fa common among pharmaceutical substances
`and the evaluation of new dmg e:nlities for polymorphi.srn is irnportant in ~~arly
`prefornmlatkm studies.
`Solvatesj often termed pst.:udopolyrnorphs, are formed when the crystaHbdng
`solvent is incorporated into the separating crystals during crystallization,
`
`6 .. 2 THERMAL ANALYSIS IN THE EVALUATION OF fSOMERS
`Byrn (1982) has described the case of configuratkmal polym<)rphisrn, '1-Vhere {hffon~nt
`configurations si.K~h as tautomern or cis~tmns ~somtrn crystallize in separate crystal~
`line forms, The latter example is wd1 .. known within the .fidd of org.imk chemistry but
`the ability to crystallize equilibrating iscimerr; in configurntionaJ poly:morphs fa of
`particular interest as it can allow for Uw i~ofotkm of im'lividnai is<nm:,_rn ..
`Ttw application of tbermaJ arrnJysis in the case of m.i.ch ismw .. .::rn h;;tS bt:cn rarely
`
`BASF Exhibit No.2014
`IPR2018-01096
`Willowood USA, LLC v. BASF SE
`Page 4of16
`
`

`

`135 c
`
`T(C)
`
`fa. 6.2--Comparison of two benzyl ketone p~eparati~n~ by DTA. (A) ~rst preparation; (B)
`~
`second preparation (reproduced with perm1ss10n from Ferran, 1969).
`
`point onsets differ by ll 0C. One sample (B) shows an additional shallow endotherm
`at a temperature below that of the main transition. As microanalysis for the sm~ples
`was the same the possibility of dealing with a mixture of isomers was suggestea.
`For the antituberculosis compound ethambutol Ferrari & Grabar (1971) were
`a~l~ t~ dem~nst.rate the presence of a meso isomer in the p<irent ethaml:m~ni t:y
`DI A. fhe trnxture of the two•faomers could be analvsed bv virtm~ of the formation of
`~solid solution with a minimum melting point at f75''C ~This \Vas a more sensitive
`approach than attempts at quantifying ind]vidual endothenns for the. two comp()-
`nents themselves wh1· ·h
`Id b
`··
`.
`'"',
`ea more routme a.pprnach to the pm<.1H.m.
`· ·
`·,
`c wou
`
`··· __ ·_· __ '.'..:: ... : ............ .
`
`BASF Exhibit No.2014
`IPR2018-01096
`Willowood USA, LLC v. BASF SE
`Page 5of16
`
`

`

`s~c. 6.3]
`
`139
`
`for a particuhu drug sub::;tanre can ulkr chemical and physical ~~!ability d!H:'. to aht~rt.:d
`readivity <md aha the r;;ne of dis::;olution of the solid substance, A~, the nik of
`,fr.,solution cm be related to the degree of <lbsorptfon, particularly of lc:~s solubk
`cornpounds, polymorphbm may have an dfoct on the therapeutic activity of dnse
`forms whose polymorphic nature was not controlled. Polymorphism is particniar!y
`wkksprend arnongst pharmaceutical compounds and the b~rbitunHes, sulphomi~
`midcs and steroids have been studied in detail both as model compounds for the
`exhibition of polymorphs and in the evaluation of the effect of polymorphism on
`pharmaceutical properties. The purpose of this section is to cover the applkaiions of
`thi:mrnl analysis in the study of polymorphs of pharmaceutical compounds.
`Th~ characterization of polymorphism within a pharmaceutical compound
`should be undertaken at the earliest opportunity during developrnent of that
`wmpound. Should polymorphism occur this ensures that the most suitable poly~
`morph1 such as th.;; one rnost likdy to be routinely produced via scaled~up synthetic
`routes or the one demonstrating the most desirable stability or biopharmaceutical
`properties, is identified. This role falls upon the preformulation scientist working in
`tht'. pharmaceutical and analytical rest~arch groups who may screen for polymorphs.
`This may involve carefuHy evaluating each new lot emanating from chemical.,
`processes or drug-discovery research groups as the synthesis is scaled up or, perhaps
`most usually, by carrying out a polymorph screening exercise as soon as adequate
`material is available, This would invo1ve the crystamzation of the dmg substance
`from a variety of solvents where conditions such as the nature of the solvent~
`temperature of crystallization) rate of cooling, rate of agitation or the nature of
`precipitation solvent are changed. All may potentj,ally in.tfoence the formation of
`polymorphs.
`The end sequence is to carry out a series of physko-chemkal examinations on the
`obtained crystaHine materials for evidence of polymorphism. Traditionally tht:~
`examination methods employed indude lR spectroscopy (of Nujol nmHs)? powder
`X-ray diffraction and thermal methods~ espedaHy DSC.
`In the case of DSC 1 heating rnte might be very important in the detection of
`polymorphism. Tuladhar et aL (1983)i working with phenylbutazcme, indicated that
`three polymorphs of the compound showed singk~ endother.ms on DSC at high
`heating rates whereas addil:ional peaks were discernible at lower heating rates, This
`is due to less stable forms melting and recrystaHizing as the more stable fon.n prior to
`that form then melting, The result is a melting endotherm, a r(.:crystalhzation
`e.wtherm and a final melting endotherrn (Fig. 6.3). DSC alone is not sufficient
`evidence for the existence of polymorphism in such studies and it b essenti<'I~ thHt
`HSM is applied to visuaHy confirm the events suggested by the DSC curves" H is
`particularly important to distinguish between endotherms due to :i.mJting of a kss
`stable form prior to recrystallization and a second f • .:ndotherm due to mt.~hing of n
`more stable form and endotherrns attdbutabl.e to tlesolvatkrn followed by mehing, of
`the desolvate form. This can b~~ done by mounting crystals in silicone oil m!d
`observing via a hoH:;tagt~ micmsi..:ope. An endotherm due to tksolvation wol~kl.
`correlate ;,vilh bubbles of vapour appearing in the monntant around crystaL at th.t:
`appropriate tempernmre. l\'ieiting without loss of solvent wodd show io;:;s uf
`crystatline fonn without the production of any vapour bubhk;s,
`The tkKrmal stability of a poiyrnorphk substm1c1..~ aHows t)'fkS ot polyniuqihnrn
`
`BASF Exhibit No.2014
`IPR2018-01096
`Willowood USA, LLC v. BASF SE
`Page 6of16
`
`

`

`n~'('e··n "'fphbriylbut:izone polvmorph E, obtained at 4~Cmin ·I (rcprnducedwith
`... ,
`.,
`l 10°~)
`I·x« {\ ~··.-·VJ ·"~" ,,
`,,
`•
`,
`pcrmis;;icn from Tuhldhar <'tc1 ., .. 0:> •
`v· · ·•
`
`•
`
`.
`
`·
`
`•
`
`.J. •
`
`.1
`
`to be defined, namely ernmtiomorphk and monotropic polymorphism (Kuhnert(cid:173)
`Brandst&tter; 1971). Enantiomorphic polymorphs can be encountered below the
`melting point of either polymorph. Hence storage of the less stable polymorph of a
`compound will result in conversion to a more stable po!ynwrph on storage below the
`melting point of either. An example of enantiomorphic polymorphism is that of
`forms I and n and forms I and III of gepirnne hydrochloride (Behme et aL, 1985).
`This was discernible by thermal arialysis as endotherms on DSC traces which
`correlated with melting behaviour on HSM. The endotherms are due to solid-solid
`transitions as the less stable polymorphs convert to the more stable form. Condition·
`ing samples of the lower stable polymorphs at temperntun~s below their melting
`poi~ts sh~wed the loss of DSC endothenns for the less stable polymorph (Fig. 6.4).
`fyp1cal ?SC tr~~es for the newly crystallized lower stable polymorph sho\.V the
`sohd~sohd. trans1t10ns at low scanning rates (L5~10°Cfrnin) but at higher temper<.!'
`tl~re scannm~ rates only the melting endothenns of the n~o polvmorph& i:ould n.e
`d1scerned (Fig 6 ") ~I'h h. l
`·
`Hli"
`· e tg 1 scannmg rate traces show exotherrns due to recrys"~ '"
`zatmn of the more "t"ble 11 It'
`,, ~~1 •)Sc
`f
`·
`~
`1e mg. orm from melts of the less stable tonn. ~tb .. t
`1 ~ •
`1
`•
`··
`"' ""
`1.X~ trnvwur ran b
`. · · d
`. ·
`.
`'H'-'M
`·
`e conswere typical of enantiotmpk poivmoP)hs. The rnha() 01 ··
`.
`, ..
`. ·
`~.'.
`m tvaluatmo polymo
`, 1 ·19s:;)
`1 •10
`rpm"m is wen mdicated t)v me work nf Lhhmt: d a~. {
`;
`u·d
`1::
`~ 1 eorecor<l1.1Ht of t1 ,
`,.,fi<l in
`, 1
`"·
`··
`..
`·
`·
`.
`Krma1 events on the. mu::roscope hot sn.tc w~~s u:-;'". '. ....
`interp. t'
`~"
`re mg complex mehi. :; lri .. ·
`.,. ,, ... ,. .. ·.1, . ~"i~wn;-;
`.
`. ··
`· ·
`ng e mvmur pnor to which sonw ~o.ml··:-,dh• ,raL
`had occurr' i (B· h.
`.
`.
`ca
`~~ me et al,, 1985).
`..
`,
`. A further recent S'rm ~l"
`~ ·
`~''\·:O;;;:i
`.
`. . .
`1985). The .DSC . ,':,'I 1; ot en~nt1otrophy is metock>pnrmkk txv:;::: ;,·dg ".:
`. , tr dee, for men'"'
`. +..-: h co·:H1:J
`.
`. ~
`.
`.
`·1 '}
`.A--1 ;ie:o(·' "nd lA ,. i4
`. .
`' c,l,,nramh.se t:~''>:'" ,s,,,~;"""'i two (;>:it,, .. u '· ..
`·t0·-1 W'C i bn.
`.:
`.
`. O .. h,"'
`·""~'"' :' v<.<
`~"' .
`t on ~oo!mo and· , ... , .. ~p.;,t<n<) i onf
`/
`,.:.-dH.0:. ,;.;.
`).>.\'.'::
`
`• • • ,
`
`,
`
`•
`
`•
`
`. • •
`
`/
`
`\.
`
`..
`
`•
`
`.
`
`,
`
`·...-
`
`• •
`
`fA
`
`!";:-
`
`•
`
`"
`
`Dn;;;;;;: .. · .. HU ... u.:.:u.u·•~u ..
`
`-~
`BASF Exhibit No.2014
`IPR2018-01096
`Willowood USA, LLC v. BASF SE
`Page 7of16
`
`

`

`141
`
`0:kfo::::
`fi;~;-~1ifii'J
`
`I
`I
`
`l .......... ~ ...
`
`• ...... -.>.
`
`~m ........ www~,,,,.......,=-,,,,..~,,..,,,.,,.,,....,.,,.,,,,..=:'=~
`180
`240
`
`Fig. 6A - Difforcntlal scanning culorimetrk s.:anli of a sampk of Oepirom: bdore and after
`heat treatment for 3 hour:> at 150°C which produced form H. ThC'. temperature sc<1.rming rat<) W<•s
`2ffC min 1 (reproduced with permission tmm Be.h!11e et al., 1985).
`
`exotherm only was seen on cooling) only one endotherm~ the higher tem1wratun::
`one, was seen. Thermomicroscopy confim1ed the lower temperature en<lotherm as a
`soHd~·solid transition and the higher temperature one as a melting cndotherm.
`Storing the cooled sample pan for three days at 22')C resulted in the original thermul
`behaviour, demonstrating the reversible natme of the enamiotrophy .. Monotropk
`polymorphism is where one polymorph is stable throughout the: temperntm:f'. rnnge
`up to the melting point of the highest mehing. pniymorph" Metodoprnrnkk hydro,
`chloride has been well charn,~terizcd in exhibiting this beh~wimn: (Mitchdl, 1985), By
`heating rnewcloprnmide hydrochloride monohydrm('. under a vacuum irs a DSC pan ..
`dehydration is brought about (73··~75'~C) and metodop:rnmidc hydrochlorlde form H
`crysta!Hzes from the rm:-.H: (85-.. ·89"'C), Form H then m~Jts (1.54···15tt) as H~e tern.per:.\
`nne is im:rca":Ped and form! crystallizes frmn this mdt O 56- ·l.58"C}, Furtb;;~r b:>1frng
`
`BASF Exhibit No.2014
`IPR2018-01096
`Willowood USA, LLC v. BASF SE
`Page 8of16
`
`

`

`rr'h
`! .. '6
`
`Temperature i Cl
`
`Fig 6,5-... Differential scanning calorimetric scans of a sample of Gepironc form I recordc~ at
`different temperature scanning rates (reproduced with permission from Behme t:t aL, t 98:; ).
`
`results in the melting of form I (186-18W'C). Form I cannot be recorrvt.;1te('. to th~
`metastable form n easily and spontaneous conversion on storage of the solid doe)
`not occur.
`.
`A large nu1'.1ber of studies on polymorphism, most of which ind ude so mt. fo~m ~t
`H~7rm~l.analysi~, have been undertaken. Some are listed in Table ii}, Tl'. is hst 1::,.~~:
`exna1btlve but includes "'O
`f th
`;
`•. ''" .,,1rUv 1
`,, me o · e more useful references, com::er1tn1°1•t- c
`!· , ., ·
`.
`. 1•
`,(i,J) on s1gm!lcant and marketed compounds.
`
`BASF Exhibit No.2014
`IPR2018-01096
`Willowood USA, LLC v. BASF SE
`Page 9of16
`
`

`

`Table 6J w·· Examples of drugs whose polymorphism har: been recently studied by
`thermal analysis
`
`.-•. •.•.•••'>"•",..._._•.•.•-•••"•···•"•"•"•"•-.-.-.-.-.•.•.•.•••-•••••••••••••••••••••••••••••._•••••••••.•.••.•.•.•.••o_•.•.•.•.-.......,. .......
`
`•"•"•"•"•"•"•"•"•"•"•"•"•"•"•"•"•"•"•"•"•,...,,_ ••••••••••••••--·•• ••••••••••••••••••••••••••••"••••u••••••••••••••n••••••••
`
`143
`
`" ···-'"~~ ...................... .
`
`Chk>roquine dipho~phate
`Cimetidifie
`Ck•trim:izok
`Cor1ison<:i ;\Cetate
`Disopyrnmkk
`Enabpril makate
`fo<li)methacin
`
`Lora:.Mpam
`M::protiiine hydrochloride
`
`wfoprnb~mate
`Methyipredisolone
`Metodopramide
`Metoclopramide hydrochloride
`Nifedipine
`Oxazep24m
`Phenobarbitone
`Phenylbutazone
`
`~~~3£P.0~~;~_ ....................................................... , ..................... ~.:!~.l--~.~:~~'.' -~·.•.•·· . .-·.
`Umi;(h; <;! ul. (198:'.i)
`;\cd;~~olan:kk
`Grafe! d. (19154)
`Atdohcxamiur
`Aus\il1<)1in
`Lindenbaum t'I al. (1985)
`Lefebvre et ul. (1986)
`Carbim:1;i2-cp1n,~
`C1:l•}t!!mpl"«cnicoi pahnhMe
`Bodm ( 1970)
`thktdl;:i2 . .::pn1d<le hy<lrod1loride
`Simmon!S n al. (19"10)
`Chlcrpwpamidc
`Buq&er (1975)
`Ford & Rubin~tein (1977)
`Simmon~ et al. (1973)
`Van .Aerde et al. (1984)
`Shibat;i et al. (1933)
`Borka & Valdimarsdottcr (1975)
`Carles"> et al. (1966)
`Gunning et al. (1976)
`Ip n al. (1986)
`Ford & Rubinstein (1973)
`Kaneniwa <.~t al. ( 1985)
`Masse et al. (1985)
`Chan & Doelker (1985)
`Kuhnert-Brnndstatter et al. (1982)
`Cle.ments & Popli (1973)
`Guillory (1967)
`Mitchell (1985)
`Mitchdl (1985)
`Eck;-;rt & Muller (1977)
`Masse et al. (1985)
`Mesky et al. (1968)
`Tuladhar et al. (1983)
`Muller (1978)
`Matsuda et al. ( 1984)
`Kuhnert-Brandstatter & Volknklee (1985)
`Kuhnert-Brandstatter & Volknkke (1985)
`El-Dalsh et al. (1983)
`Salole & Al-Sana.i (1985)
`Yang & Guillory (1972)
`Yang & Guillory (197?.)
`Yang & Guillory (1972.)
`Yang & Guillory (1972)
`Maury et al. (1985)
`Yang & Guillory (1972)
`Moustafa ;;t al. (1971)
`Yang & Guillory (19l2)
`Yang & Guillory (l 972)
`Gouda et ar (1977)
`Guillory (19&7)
`Moustafa & Carle~~; (1969)
`Shami r:t al. (197?.)
`Lag as & Lnk 0 9fU)
`Yang & Guillory { !972)
`Goldberi; & Be.:kn- (19ll7l
`Leary fl ~~i. {J98n
`·
`Ucd;i et al. (1982)
`B<.".ttinetti f!{ al. (_~916,_~2!.~L].?.~9.L ......................... ~ ..
`Y.!ml~lhop~~!!~ ........................................... ~..........
`"The n::ferences cited rnntain iht~ mo3! ;;omprchcnsivc data ,1n pdvmmµhhm of th.: 1xsm1x1irnd in
`<JUc~tinn where thermal unalvs.1s has bc('.ll i.J~d ;:b r>nc nf the charactcrl2atinn meHw& {Jf is the ::mh
`liternH.ite reference. Wht~re W'orc \han one paper i~ dted thi~ rndkatc:'i that the p11p1:r;; are wmplim<.0n\M:;,.
`r<ilhl'.r ttrnn ;;uppkmcntnrv. e.g. different gsp:::cts ot po!ymNplmm were inv;.:,;\ig:cit<::<'. ~nd tkrmd
`;m:ilytki! dnla included. Aspirin ba':' been deHberntdy qdudd imm tht' ti~t t;:,·<.:m.Vit of::l1t ;:,:entrov<:r'>i:.il
`miture of its polymorphi;;1rL
`
`Piroxicam
`Proprnnolol hydrochlm·i1.k
`Spirono!acetone
`
`Sulphabt;m;amide
`Sulphaethidok
`Sulphagmmidine
`Sulphamethazine
`
`Sulphamethoxazole
`Sulphamtahoxydiazine
`Sulphamethoxypyridazine
`Sulphapyridine
`
`Sulpll;ithiazole
`
`Snlphisoxa;;:o!e
`hmoxifen dtrnte
`Tolbutumide
`
`BASF Exhibit No.2014
`IPR2018-01096
`Willowood USA, LLC v. BASF SE
`Page 10of16
`
`

`

`nw },;nwrn! ti.':rm ol crystalline rnak'daL o;nH1ining solvent of 1.systd!izatfrm L
`;;1.1lv:~itc::-; ... wlK're hvd.rntl.:s an: u pnrticular cH:>(: ~,vhen the soi vent ('.rmopped h Watrr.
`:\nhvdr;~L;:; <H«': :;;dw:rH·fnx: (:rystaHhw rnatfrifib ahhough tht ti::crm
`i~, strktb
`!~dh.:;,,tiv<: of a t.rvstd form wl'.Kn; watn of c:ryt~tr.llhzatk1.n b ab11i;.::nt, Solvatcs ffrny b;,:
`rmw<: Pr k;::.;; st<~hk~ sogrw requiring k.•rdng conditions to producf dt':iolvation,
`1«>,nking in production of a nrw crystal form frorn l:ht.'i anhydrom; ::olkL Oth1~r
`sr'h ::it<::3.dt::'>i;h::i.k n:ndilv but have :an anhydrntt form Viith the same cry.shg! ',:tn.icHm;
`;t~ dk sohHk: (ao; ::mggc~ted by X··rny diffrndkm pattern). Such deHoiwtt<:d c:y;:;tiJ!~
`h~;:.;(.li!V hctomt:; r;;::,;;oivated, c,g, on t~xposure to an atmosphere of solvent vapour (4
`hlgh l~mnidhy atmosphere for wakr), Some solids He between the iwo (";xtremc:::,
`rc:idHy attrncting rhe solvent of crystalHzation but converting to a different cry::;t;l
`form in d<)ing so. Where a different crystal form is produced on desolvatim1)
`resolvatfrm has to b{.'. accomplished by dissolution and recrystaHization,
`Thenmd analytical methods, DTA, DSC, HSM and TG, are all vahmble tonbfo
`assfatirw in the drn.mcterizatkm of solvates. An extensive sh!dy of drng rnbstanct~
`was un~iertaken by Kuhnert~Brandstatter (l97l) empfoying HSM, showing that 11
`large number of classes of drug substances form hydrates and solvates includingµ.
`bctam antibiotics, sulphonamides, cortiwsternids and xanthine derivatives, Com·
`pfox desolvahon behaviours for a variety of substances were dassified utilizing HSM
`in conjunction with DSC, evolved gas analysis (EGA) and T'G by Kuhnert·
`Brandstattcr & ProhJl (1983a, b ). Further general examples of the application of
`DSC, TG and HSM to the analysis of pharmaceutka.I sohrates have been given by
`Brown & Hardy (1985), 111ese authors used DSC on samples cooled beiow the
`fre.;;zing point of water in an attempt to detect the melting of ice derived from
`;dustered water' in the materiaL Adsorbed monolayers of water and tightly bound
`hydrate water wm not show in the DSC endotherm for the melting of ice. A solvate
`may be differentiated from a wet sample because in the former solvent Joss occur~
`over a narrow temperature rnnge(s) whereas in a wet sample the !oss slowly occurs
`over a wide range. Bnmcone & Ferrari (1966) demonstrated the potential of DTA in
`a..11aiysing for the pn~sence of solvent In studies on si.dphm-nonomethoxine a shallow
`endothcrm at 120"C was apparent when scanned at atmospherk pressure bm under
`reduced pressure the endotherm decreased to 66"C, Table 62 indicates a partial list
`of important drng substances (or those exhibiting classical bdrn:viom on thermal
`arm!ysfa) Hmt form hydrates or other soivates. Some examples am dfacussc:d forfot:.r
`below to demonstrate the use of thermal anaiysfa in this fiel;;l
`Niazi (1978) examined th'~ crystal forms of the antitumour agent rnercaptopudm:
`using techniques including DSC. Endotherms for the dcsolvation and the melting of
`the mono.hydrate are seen on the DSC scmm for thi~ compound, A. h~:aHreattd
`sample of the monohydrnte showed no endotherm for the ioss of water of cryst:lHw·
`tion (Fig. 6.6 ), DSC w~1s used to cakulate the entha.tpy of dehydratim1 (}§ SJ7
`tcai i 't1()j ,
`. lJll
`\,.
`The macrolide antibiotic erythrnmydn appearn to show a rn.unbt::r nf hydr:;k~
`tlrnt have been ev<J.hrnted by various physkai tn:hniqucs) notably thtr.ma1 gnalys.i3
`(Pelizz.a et al,, 1976; A.1kn et al., 1978). \Vhibt anhydrous~ clihyd:nHt' and rnnnotyJ
`rate forms are indicated, the role of water in the Mrunnre of t:rvthromv::::in
`appears to be ont uf a loos;; as~ochition with the \Vater bt::inn eas;lv L?st c;nd
`again (Allen et al., 1978).
`····
`··
`
`!;.
`
`BASF Exhibit No.2014
`IPR2018-01096
`Willowood USA, LLC v. BASF SE
`Page 11 of 16
`
`

`

`Sec. 6.4J
`
`145
`
`Table 6,2 -·· Ern:mpl.es of hydi«~tes and solv~it<::;s recently studied using thermal
`analysis
`
`Compound
`
`Refe.rence
`
`,;-,-..-.;oo•oo•o'•"·~-~··•••OOOOOO•••oooooooooooooooo'o'o
`
`.-.-o'oooooooo•O•OOOOOOOOOoo_ooo._o_.~~·.·.~--~o000HOOOOOOOOOOOOOOoo_O_O_O_O._ooOo~o•••,•'
`
`Calcium glu~~eptate
`Ct'phak~xin
`Codeine hydrochloride
`E:rythromy~:in
`
`Ferrous :'iulphme
`Magnesimn stearate
`Magnesium palinitate
`Ivkrcaptopurine
`Ivletronidazole henzoate
`Piroxic<lm
`Spironolactone
`Sulphamethoxa:wle
`Testosterone
`Theophylline
`Trimethoprim
`
`Suryanarnyanan & Mitcbdl ( 1986)
`Otsuka & Kam..~niwa ( J 983)
`KulmerH3nmdstatter & Pron (1983a}
`Pelizza et al, (1976)
`Allen et aL (1978)
`Murthy et al. (1986)
`Mitchell (1984)
`Miner & York 0985)
`'
`.
`Miller & York (1985)
`Niazi (1978)
`Hodgaard & Mwdkr (1983)
`Kozjek et al. (1985)
`S"•1•)I•· _r;, Al S"i"'r''l, (1 oxs\
`C.I «,
`.... ,( ... }
`Abdallah & El-Fattah (1984.)
`Frukjaer & Ander.sen (198:?)
`Sernjuddin (1986)
`Hettinetti et al. (1978)
`
`(''·'-'IX
`
`-
`
`---·-··•••••••••··---··••••m•••••~~~•·••••••••••••••••••"'"•••••••••••••••••••••••••••·•.-.. _. .. _._ .... ~
`
`.~
`f
`
`' 1
`
`Fig. 6.& -···Differential sc&nning cakirimetry ~e?in~ <)f merci:ipwpurinc .. Key: wp, m:igfrw1 drug;
`bottom, fi,;at-tH:atcd '.'ampit~ (hd<l i.lt 'WI.PC for :m mins) m r1::rnn nf smnrk m \he tur Si:an
`{reprnch.iccd ,,,,.ith pcnnis'2<ior. from Nb?.i, 1978\
`
`BASF Exhibit No.2014
`IPR2018-01096
`Willowood USA, LLC v. BASF SE
`Page 12of16
`
`

`

`;i.:·.-·
`
`Fig. 6.7 -··· DTA curves of cephalexin hydrates at heating rates of lO')C!mirmte. Key: A,
`cephalexin phase IV monohydrate; B, cephalexin phase II dihydrate; C, cephaiexin I:hase Il!(cid:173)
`hemihydrate; D, cephalexin phase V rnonohydrate: E, non-crystalline solid cephi.ilexm ~ihy,_,.
`rate (reproduced from Otsuka & Kaneniwa, 1983 with permission of the publishers).
`
`The use of thermal analysis in the studv of Pharmaceutical exdpient,, such"
`i~a~n~sh11? stearatc and. I~ctose, which ar~ ab~ capable of forming solvak&, an.:
`d1sct1ssed m greater detm] m Chapter 9.
`
`BASF Exhibit No.2014
`IPR2018-01096
`Willowood USA, LLC v. BASF SE
`Page 13of16
`
`

`

`Ch. 6j
`
`147
`
`number of proc:edmes including the dclH1<.;r:ih: addition ol H truce irnpurity has been
`developed.
`l l
`• ' h ,
`. J' '
`l .
`l •
`' j
`l' •
`f
`.
`Cry;:;tals o <~( 1pK <Jn<:.. rnouJtH'.'i. m t ms \V}lY \a· lpli.:: acHJ .,emg u~;t::u as a .mo>: e}
`I' '
`J
`compound) lrnve been evaiu;1kd by cornpkrnentnry physirn .. rhemicat tcchniqtH:s
`lndudim.: DSC when.' the heat of fusion wa::. determini?,d (Chow et al., 1984. l 98Sa} .
`.
`.,,,.
`Rdnkd f<Hty adds were used in the case of adipic add but Chow d al. (1985b)
`mili1ed a synthetic impurity of acetaminophen (pmfHX~tamol),, nmndy p··~·H.:t~toxyace··
`rnnilidt\ to 'poison' crystals of the r.mrent compound and rnodify th~~ir pharmacemi~
`cA properties. A.gain complementi1ry physko~chemical measurements including
`kitt of fusion determined by DSC was utilized to drnrncterize the vmkms products
`obt;:tinr:~d. 1n further \Vork on adipie acid (]10w et al. ( 1986) indicated that DSC was a
`mz~rn ~ensitive indicator of crystal imperfections than the often applied measurement
`.,f <l 'f'S' 1'tv
`L •. vi:. <
`, •
`Further developing thfa work York&. Grn.nt ( 1985) proposed the development of
`11 disruption index for such solid solutions whereby heat of fusion data obtained by
`DSC could be utilized to characterize the disorder created in a crystal structure by
`such poisoning. The value of such an index remains to be ascertained as work in this
`field progresses.
`
`RE.FERENCE§
`Abdallah 1 0. & El··Fattah, S. A. (1984)Plwrm. Ind., 46i 970--971.
`Allen, P. V., Rahn, P. D., Sarnpu, A. C. & Vanderwielen, A. J. (1978) J. Phann.
`Sci., 61, 1087-1093.
`Barton, J.M. (1969) Po~ymer, 10, 151-154.
`Behme, R. J., Brooke, D., Farney, R. F. & Kensier, T. T. (1985)1. Phann. Sci., 14,
`1041-1046.
`Bettinetti, G. P., Giordano, F., La Manna, A. & Ghrneppetti, G. (1976) J. Phann.
`Pharmac., 23, 87---88.
`Bettinetti, G. P., Giordano, F" La Manna, A. & Giuseppeui, G. (1978) Boll. Chim.
`Farm., 117, 522--529.
`l:'d
`. I)
`l
`.
`., p
`('' d
`B •
`P & ,.,
`(1C>O'') }'/ r'
`,•annaco 1.!,. 0CL, ~,;;1,
`ettmettl, (J . . , nor ano, .1:«
`· ~erom, ~ . . .100
`706--714.
`BorhL L (1970) Acta Phann. Suec., 7, J---6.
`Borh:, L. & Valdimarsotter, S. (1975) Acta Phann. Suec., !2, 47~.S4.
`Brancont\ L. M. & Ferrari, H.J. (1966) Microchetn. J., rn, 370~392.
`Browni D. E. & Hardy, M. J. (1985) Thermochirn. Acta, 90, 149-156.
`Bu r
`,~·:s 1 ~?--1 , 1
`· A (19''~) t'-. · vh
`·
`rgei,
`.
`1 •.• ;KL,. ann'" ~;;, ::i~
`iJ .
`Byrn, ~iL (1982) Solid state stability of drugs, Academic Press, New York
`Carless,J. E., Moustafa, M ... /\. & Rapson, H. D. C. (1966).J. Phann. Phannac .. 18,
`l 90S-.,-1 <J7S.
`Ch'm I' l"" "' D ·'lk·
`J')"' ! d fJ!f· ··,
`<-» (·1no~• [)
`'' ~ ii~ ... '<.~)
`'· \., ~x. _ o~ .. eL. x: ...
`. 1.{~nn., 1.~., .. 1" ...... ""
`·
`. Yo.,} .. rug . ti . . n ..
`• c
`,
`J lLi' h j' . • h l\ ·
`... ,
`{) i· u; · 1 go4) '
`.,
`"" ..
`·
`Ch · K. "-"
`{ "'}
`·ow, .. i.,...,o, .. ,1v1.e c1nKae, .1l.,&brant, .... ,, ·n.(.< .. o·,.mt.v.f'wrnL, .. ~V,
`t''
`
`·:s~
`
`P
`
`•
`
`Chow, A., K Y., Go, J., Zhong&han, \"J./., Mehdizadeh, M., & GrnnL D. J. V./.
`098.'fa) Int. J. Phann., 25, 41·55.
`
`BASF Exhibit No.2014
`IPR2018-01096
`Willowood USA, LLC v. BASF SE
`Page 14of16
`
`

`

`·= ... ~.:.:_.
`
`'.•
`
`' -:'1":,$..
`
`.
`
`,.
`
`..... ~
`
`;i..~;1 ~?~ ·'
`
`Cho\\.,.\. H·l., Cfo)W, P. K. h.,, 7.ho.ng*-ltHU1, \V. & Grnnt, D. J. \V. (1985b) int. l
`. ?4,
`Chow, K. Y ... (h;,J .. & Grant, D. J. W', (1986) Drug lk·v. Ind. Piw.'t'm,, Lt247~264.
`Ck:*;rits; J. A. & PopH, S. li (197.1) Can J Phann. Sci., it 88···92.
`'
`· ~, (~'··;~') 1·
`I
`·~ ·~ ·1 .. 'l ''·) ··
`• l rwnn. /1na . , ~,11, ·'··.;,
`(nf(d;J, J. \L, f\ion1h:~'.:;, J. & Rrve:~, v.
`.,.,1.
`~
`~'1· o.
`···.(,~l:i,
`E(:k~.:rt, T. & A1u1kL J. (t9Tl)Arch. Phann ... 310, Lh~··lliL
`El·D:fr.:h, 5. S., H·SJ.yed, A .. A., BadawL A, A,, Khatt<~h; F. L & Fmili, A. (1983)
`!'),., .•. ,,. f),,,; [.,..; J-,;J:m·p• 9 1rr7._Qq4
`:.. "=' ···=.·<
`Fz:rrnxi, ·u .. (1%9} DTA in phanm1rnutkaJ sdenccs, in nwrma! analysis, vol L
`h:•stn..um:niati<m, organic materials and polymeri Acndemic Press, Ne~v York)
`41-··64.
`f\:rr;:1ri, H. & <Jrnbt,~r, D. G. (1971) Microchetnical J,, 16:, 5··13.
`Ford, J. L. & Rubinstein; M. H. (1977) J. Pharm. Pharmac, W, 209---2U,
`Ford, l L. & Ruhinstdn, M. li. {1978) Pharm. Acta Fldv., 531 327~332.
`Fmkjaer, S. & A.mkrsen, V. S. (1974) Arch. PhatnL Chemi. 5'ci. Ed., 2, 50--59.
`GoidbertL t & Be,ke1\ Y. (J 987) J. Phann. Sd., 76, 259-<~64.
`Goud~" M. W., Ebian 3 A. R., Moustafa, M.A. & Khalil, S. A. (1977) Drug De1>.
`Ind. Plwrm., 3, 273--290.
`Graf, E,,, Beyi.~r, C, & Abdallah, 0. (1984) Phann. Ind., 46, 955-959.
`Gummy} J. K. (1967)J. Pharm. Sci., 56, 72-7(i
`Gunning, S. R., Freem;..u1, M. &. Stead, J. A. (1976) J. Pharm. Pharmac., 28,
`75g..,J6L
`Hakblian, J. K (1975) J. Pha1·m. Sci., 64, 1269--1288.
`Hodgaar<l, A. & MweHer, N. (1983) int l Phann. Sci., 15, 213~221.
`lp. D. P., Brenner, G. S., Stevenson, J. M., Lindenbaum, S., Douglas, A. W.,
`Kkin, S. D. & McCauley, J. A. (1986) lnt. J. Phann.~ 23, 183-··19L
`Kaneniwa, N., Otsuka~ M. & Hayashi, T. (1985) Chem. P!w.mt Bull., 33,
`3477~3455,
`Kissinger, ILE, (1957) AnaL Chem.~ 29> 1702~1706.
`Koz.Jek; F,, Golk, L, Zupet, P., Palka! K, Vodopivec~ P. and JapelL M. (1985)
`Acta Pharm. Jugosl., JS, 275 .. 281.
`Ku!mert .. B:ran<lstattcr, l\t (1971) J1termomicroscopy in the analysis of pharmaceuti,
`N . 'V k ·'IA4')
`p
`cas, ~ ergamon ressj . ew .ior , ,)r · ..,.
`l >)
`Kulrnert~Rrnndstatter, M. & Proll, F. (1983a) Mikrochim. Aaa, 2, 463-176.
`Kulmert~Brandstatter, M. & ProHi F. (1983b) .Mikrochint Acta> 3., WJ.w300.
`Kuhnert··BrnndstaHeri M. & Vollenklee, R. (1985) Fresenius Z. A.nal. Oiem., 321,
`l64· .. J69
`Kuhnert-Brandstatter, M., \Vurian, L& GeHer, M. (1982) Sci. Phann.) Sfi, 208-216.
`Lagas, M. & Lerk, C. F. (1981) int, 1. Phann,, 80 H-24,
`Learyj J. R., Ross, S. D.