c-
`.,......,._ :-hn Crnton '~ Uk
`-
`~·IJI1v"~a...tor.UK
`Mt clro<tlon:,., ~
`
`Volume 16 Number 9 September 2004 www.ptemagazlne.com
`
`Features
`
`DRUG DELIVERY
`Physicochemical Approaches
`to Enhancing Oral
`Abso rption
`Powck l Crowley and
`Luig1 G. Martini
`Understanding the physico(cid:173)
`chemical properties of a drug and
`the anatomy and physiology of
`the Gl tract provides valuable
`insight 1nto the possibilities and
`constraints for optimizing oral
`absorption
`
`DRUG DELIVERY
`Smart Skin Patches
`Peter Harrop
`A smart skin patch is a new
`delivery system for drugs and
`cosmetics that addresses the
`problems of inflated doses and
`unwanted Side-effects associated
`with traditional methods, as well
`as providing compliance benefits
`
`QUALITY CONTROL
`Is There Such a Thing as a
`Best-in-Class Lab?
`Benchmarking of QC
`Operations
`Tsvika Bublitsky and Alex Howard
`Changes are afoot in the life
`science sector; the pressure is on
`to retain full regulcltory compliance.
`provide faultless customer service
`and to reduce costs - part1culclrly
`in the areas of R&D and QC
`
`4
`
`MACHINERY
`Intelligent Inspectors
`Hitesh Hirani
`Th1s article looks at how changing
`customer demands have affected
`mspection technology, looking at
`1ssues such as WlP. 21 CFR Part 11
`compliance and the relentless
`push for heightened sensitiVIty
`
`Regulars
`
`From the Editor
`
`News
`
`REGULATORY AFFAIRS
`Brussels Report
`Stepping Back into the River
`Albedo
`
`REGULATORY AFFAIRS
`Washington Report
`Promoting Quality in Drug
`Manufacturing
`Jill Wechsler
`
`Product Showcase
`Product Focus: Drug Delivery
`Classified Directory
`Appointments
`On the Move
`~ Calendar of Events
`
`PHARMACEUTICAL TECHNOLOGY EUROPE SEPTEMBER 2004
`
`3
`
`Next issue October 2004
`
`Solid Dosage
`QA!QC
`Software and Data Management
`
`0001
`
`PSG2009
`Catalent Pharma Solutions v. Patheon Softgels
`IPR2018-00422
`
`

`

`Pharmaceutical
`Technology
`
`EUROPE
`
`Publdhed by
`
`..
`
`....... . O •o
`AOVANSV\R
`
`Corporate Offla
`Advanstar Communications Inc.
`7.500 Old Oak 8out.vlnf
`OevNnd
`Ohio44130
`USA
`
`AllvMsW Coa•-· ~IIIMII Inc.
`
`-
`
`~ P'ubllsMclllr
`AdvMISUI Cornmuniations IU.K) Lid
`Dr ICMIIIabinson
`Tel .-44 1244 393 257
`~Houw
`Park Wet
`~JlGUOfll
`.se.land Road
`MIMglftg ldltor
`Cheslef CH I 4RN
`GutmJnder Marwaha
`United l<lngdom
`Tel..-441244393 2S8
`~ Tel.-+44 1244 378 888
`Fu -+44 1244 370 011
`....... Eeors
`"""-'-~(Wtllld
`CJaudiiTMinef
`General ......
`~-com
`Helen Gardner
`ConiM~e
`dilwrl!fiCII~rlll.stat.com
`Tel. +44 1244 393 263
`Senlcw w. &.cullwt
`SlmGteen
`Tel.-+441244393116
`. . . ~.tat.alm
`i.rop.. We &.c.ath.
`~Oocheny
`Tel. +44 :108 822 6745
`~.(l)fll
`ChW Eacudft Ofllaf
`Joseph LoggWI
`USA 5.llls IIIIMeg8'
`John~
`IEDaatlft Vb l'nlldents
`Tel. •1 541 338 0022
`~S.Oee.rt
`~lftl~.cam
`Oanlet M. Philips
`a....ds.lft~ Scau E. Pierce
`Vanew Wllilms
`&KudwVb~-
`c.ar,or.r. Dec 11 p..nt
`Tel. +44 1244 393 215
`~.com
`EriclUsman
`VP.~ao
`Dlvid W.Momgornery
`1/P."---~
`AdeM O.~Wtwid
`liP. Pllllllhlnt Operlltlonl
`Fr.lnds HRkl
`VP. ChlefTechnologf Olllar
`ll8pra Art . . . . . - - - -- RlckTreew
`
`.................
`,......Dindor
`
`Oeborlll~
`Tel+44 2Q8 822 6746
`cislllrtlol~-.com
`
`JoMnslrong
`Gqphlc Dcllg.-
`...,~ms
`
`AIMI.~Mnes
`ClftuiMioa ..........
`Judy KrmenJey
`
`Subscribe online at
`www.ptemagazlne.com
`
`...__.,"" .-., q J - - ~<I'- f""'l_ ... _
`8 ...... . , ........
`•cur.a .. c..~~"" putllsNr annoc •c.ftX ~btnw«aa"X)'ol ~.on~ ~ot
`
`,._,.., .. - ... tot-"""--- bOA.,.. pbbhof .........
`, __ 110
`,.,...,_.-.pnwd
`,_,u_
`--[- IllS
`-..--.. [ - I~
`
`~ l'honN<out<M Tfdwloiogylu<- • cll<tnl>ut<d h .. ot<!WgoiD
`~!'-'d~_,ELtopt"
`__ .,&..-
`
`lrt·
`
`_..._
`
`(JI
`
`2 _.12. -1
`F• o
`i1l0
`UH
`for ..-..,..... .... ,.,....bodl ........ -"'"'-~-"fOUI/-1 .. _10
`s.-,.
`........ t t-I'NII~omotb;c+441244l70Sil
`Dl<o<t-Um:ContKtRobo<lfui.,.. r .. ,...1:144ln•l6 f .. ,...12 ... ltlll6
`Dhfoley...........,CO<U<tS....Gt-1 Tfl ..... 11 ... 191116 F,,.,.. 11 ... 1&Jll6
`... ...U~To' .... 1011116,.} F., _...1011216741
`_ _ ,
`a-.._, _
`·••n\..,.,\A'h1iUMI.Tfj ..W1244~ll1S r ...... U44JI))S6
`t
`
`Pharmaceutical Analysis
`How well
`your product
`performs
`
`depends
`on how
`well we
`perform.
`
`• Method feasabif1ty,
`deotelopment and validation
`• GMP and ICH·comphant
`stiibility studies
`
`• CMC Support
`• Batch release for clinical
`trials/commercial products
`• Specialty seMc:es
`- Inhaled products
`-Nitrosarrunes
`-aosure and container
`analysis
`-Extractables and
`leachables
`
`~ ~lof 41MtK.Wi '"ltd~ .-net~ IUue'S .... .-.c.lS(IO~
`Cot-cocl s.-> .........._ , ...... t 1 ... 191 liO fa. .... 11 .. l8l116
`
`Coprtghl 1004.Adnns..,~(UI() Ud.A.Irltl>u~
`
`COY~
`~'"901 ACnl"'9 ! ... ""'t'tWdliUn'l bf'tllctranll: tnHn\hi ~ Ot,...
`trJftWt!rt) 6f N~t1tlll) to lOt!W OChft vw ol U\ts ~UtoOn i ~~P•t'\Out ttw
`wt lttn p.H~UMM\ ~f tb~ COPJfl~i'\t o-~ t"J;ttp:t in KC?fdant• ••H'l L~
`. . - -d ..... ~~,,.,...,.l<t'UI<II911oo~ll>o"'""~
`•"..,'"-"' INCOO>'V~l .. ,.""9~ 90 r - c - . -
`t..-Wl•CIIP.U<.
`
`P'iO P¥1 f tM ptbouan tr\k'l bt rtprOdu<.td in ¥'rf tNttfWI bf'l'tt .l"'().,dt'\9
`
`~~
`4ocJiC.t~0'"1for ~ COP1f19N ~1 ~to~~.,.,~ Gf tM
`publiutten lhO\Itd ~ fOfwlfdf<lln "'''""9 to ~tn1Ut0M Otpt. .44vati11M ~
`(Of'!"'f''"WMCll•Of'l\ CUI() ltd. Adv""UM Hot.M. Pitr\ WHl Sto~~ Ro.d Ctwittt
`(HI4'1'< ~W¥1>oft9'Thtcloon<joi..,~OCtlft• ........ .,•~
`...,..,., ........ -·<Mcs.n. ... ...._....,.,.,..,._
`
`·~e~
`
`10 -......,....
`.... .., .
`
`4
`
`SEPTEMBER 2004 PHARMACEUTICAL TfCHNOlOGY EUROPE
`
`0002
`
`

`

`Physicochemical Approaches to
`Enhancing Oral Absorption
`
`This article reviews various physicochemical approaches that may be employed to enhance
`absorption following oral administration of solid dosage forms in humans. This article also
`examines strategies based on capitalizing or neutralizing physiological processes.
`
`O ral ab-.orpt1on dfi.:i.:n~~ can h..• innuen.:.:d hy
`
`SCII!ral factor.. acting mJ.:p.:nJcntl~ or in Ctlll·
`ccrt These mdudc tho.: ph)stc:uchcnuc.tl properties uf
`the admmister.:d agcnt. human ph)slolo!!.Y· pathulug)
`(includmg d1....:asc state). thc ~a~ the Jrug i' pr<.-scnto.:d
`(formulat.:d) and J'<"s1hll th.: amount that i~ .1Jnun·
`ist.:r.:d (dos.:). Otho.:r mnuo.:ncc:s induJc ttmc ot
`administration. whether the patient 1s n .. -..ting or
`act11c and hud1 J'<hlliun. f~lr c:xamplo.:. recuml'>cnl m
`standmg. Opumumg ah,t>rptton J't:4Uir<." kn,w.JcJge
`of ho" thes.: l<lrtahh:s .1tfcctthe drug or formula
`tion. How.:, cr. it ma1 take many )l!ilrs !>don: such
`compreh.:n,ll.: kno11led!!.e can be ~lean.:d on
`compouhd·,pi!Cific beha1 •ours.
`In the ah.,.:nce of o,uch dctatleJ tno,J!!hl 11 rna\
`neces~ary. particular!~ with novelthcrap.:ut1c
`agcnb hemg doo,ed tu human' for the ftrst timt: to
`de,1gn a tormulauon l>a,cd on gene: ric con~1dcr:t·
`tton~ of t.u:tnrs affectmg ah,orptt~\ll.thc ph\,Ktl·
`chcmtcal propertt~\ of th.: ag.:nt hcmg atlmumtcr.:d
`and 111 11111 urn 11111 finding' in ammah ur ammal
`tto,sue. Such a o,trat.:!!\ t:.ln help 1dentih the
`optimum fnrm of the drug and cJ,ml\ po-'tt'ttltttc'
`and ltmitation~ for man1pulatmg lh prupertlc\ tn
`opllmtzc dcltver).
`
`H.:nce. good undeNandinl?, ot the phy,tc<xhemical
`prop.: rues of the drug and of the an atom\ and
`phy,iology ot the gamointestinal (G I) tra~t pro~id~--.
`1 alunhle ins1ght on the po~sibilitics and constramt~
`for opllmtzing oral ahsorpllon.
`
`Solubility enhancement
`Sum.: material~ arc ahsorbed h\ active trans{'<lrt
`acn."' the mtcstmall>amcr. hut aho;orption h~ pa'Sh e
`diffu~ion i!> pwhahl~ far more pre.-aknt.l Rc!!ardJ.:,,
`of the mudc: of tran.,port. ho\\.ever it is r.:a,nnahlc: tu
`conclude that. in th.: \a~t majorit) ot casco, thc dru!!
`mu'>l h.: 111 the soh a ted \Late tn dtffus.: mtn anti .~ero"
`the ent.:rOC\ tc!> lminl?, the mtcsunallumcn Thu" ,nJu.
`hilit) and rate of dl,~>lution of tho: drug arc of maJOr
`importance and man\ approaches to ab-.urpllnn
`enhanccm.:nt cnnt·em tho.: optimization of thew
`propcnte\.
`Pt'>nrly soluhle Jrutts present a maJor cho~tt.:nge in
`dosa!!O.: form t.lo.:ll'lnpmcnt. In "mplc teml'>. a mate
`nnl muo,t be 111 o,olutton tf 11 i' to pa'' from the mtt:'
`unc tu thc <y,tcmt..: \\\tern At the o,ame time
`hpophthcll) i' treqLh.:ntl\ asstx:lated 11 11h ht!!her
`actlvitv. or rcccpwr o,p.:cificll~ and is mvanahl\
`incorporated 111 nwlecular structun:s hy th.: medtcmal
`
`SEPTEMBER 2004 PHARMACEUTICAL TECHNOLOGY EUROPE
`
`Patrick J. CrowleY'
`os a voce pre<•~ton I~
`product lone extensoons
`depanment of pharmaceuucal
`de~lopm~nt GoaxoSrnoll>Khne.
`1250 Sooth Coll"9evol~ ROdd,
`Collegevoll•!. Pennsyl•anoa
`
`19426. U~A
`Pau • Crow~<~ (om
`
`Luigi G. Martini
`os a manaqN wothon thl> mategic
`technologoes dep.~nment of
`pharm.tc~hcal dewlopm<'flt
`GlaxoSmothiOone, UK.
`
`'To whom all conespondf'nCe
`
`<hould ~ addrh~
`
`0003
`
`

`

`ch.:mbt. l.o.>w atJu.:ou' soluhdn)
`(which 1' usually ;N,ocmteJ with high
`lipophtlicll)) and poor bmavailab1lil)
`arc often a con,.:qucm·.: ol 'uch mol (cid:173)
`ecular de,ign. lmpro•mg ab~orpti(m
`in ,uch C<ls.:s may mean us1n~ a form
`of the drug with opt1mum solubiht).
`or employmg a vehidc in which the
`compound~~ soluble. Optimuing
`solubility may entail using a more
`soluble salt or polvmorph (if one
`exist~). ore\ en the amorphou~ form
`of a compound. Each approach ha>
`advantag..:' and complication' and
`~uch opuons may not alwa)s he
`a\ailable. depending on the molecular
`composition and phys1cal beha\ 1ours
`of the material under consic.kration.
`
`Salt forms. Agh.~rk.~r found that the
`solubility of the fr..:..: hase form of
`the antima larial. n-(2-pip..:ridyl)-~-:1.
`o-bis(trifluorometh) 1)-9-phenan(cid:173)
`thrcnem..:thanol wa, 7 f-Lg/mL.2 The
`hydrochlond..: salt in comra;t had
`solubdny of approximately
`30 fLg}mL w h..: rea' a valu..: of
`1-..;oo 1-1-g;mL was allained for thc
`dl-lactatc.: salt. Tctracyclinc and ery(cid:173)
`thromycm 'ails also exhibn differing
`>olubllitic• (Table I). Baslln cl a/.
`also found that ;orne salts or thc
`cardiovascular compound
`RPR 127963 afforded sigmficantl;
`improved •olubilitcs compared with
`thc freo: base (Table II ).'
`Enhanced soluh1ht) docs not
`m:cc~rily translate: to bcttc:r ill 1·im
`absorption Thcro: ar..: several report'
`of salts with differing solubihllt:s
`bc:having no tliffero:ntl) in bioavail(cid:173)
`ahl.lity stud1es. ~<Better solubrlit) rna>
`simply be a pH effect that is neutral(cid:173)
`ilo:d in the gastnc or intestinal milieu.
`"-1lh soluhrlity changmg to rcnect local
`..:nvironmental pH. Conversely. it is
`also feasible that the pH cngcndero:d
`by a salt in its micro--em ironment
`facilitat.:s dis.olution. The: salt acts as
`its own buffer so to ;peak. Once in the
`solvated state. the dynamics of trans(cid:173)
`port or reprecrpitation may be such
`that there i\ a net cnhancemcm of
`amount di,~olved and absorbc:d.
`The countcr ion can he important
`for other re<~~on-,. M<~ny drug. ~ub­
`stance~ arc urgarue ha'>cS. and
`h) drochlorides aro: usually the fir~t
`(~ometimc~ only) salts considered
`when seeking a more soluble form.
`However. the presence of chloride
`ron~ in g.1stnc acid may well depress
`
`-olublilt~ 111 111 ,, bc..:au-.c of cnmmnn
`mn dfcch •. - Cun't:<juenth. ah,orp(cid:173)
`llnn ma~ not 1-\C impr<l\cd
`llrc "-t•r~ h\ F n~cl ·r a/. 1~
`rt:\L'altng. mth1' nHllc\t.~lll..:
`hydrochlunJc and mt:S) late 'a Its of
`two nO\cl prlllt:lll ~mase mh1hrtors
`were more soluhk than other s;lits.
`hut '~hen b10a' ailabilit) in beagle
`dog' was cvaluntetf the mes:.late
`salts of both cump<•umh hat! hetto:r
`hlo;narlabthllt:o; than the h)-dn>chlo(cid:173)
`ridcs (Figure I ).
`Th1' m.l) h.l\l' been bo:cau.sc of
`better ~olubllrl) ol the mesylatc salts
`(fiv..: times more o;oluhlc than
`hydrochlondc l. but a common 10n
`effect \~Hh the hydrochloride '>alts
`cannot he rulcJ out. lntcrcstingly.
`these authors estahh,hcd (from a
`r..:•iew of rcccntl) approved com(cid:173)
`pounds) that mcs) late -;alt; arc now
`bcmg more \\ldely u~d. It would be
`of interc'>l if 'uch mcr..:a,mg popu(cid:173)
`larit) was J r.:sult ,,t better in 1·i1·o
`pertormam:e
`Inc potcnu.rl for ab;urption
`enhancem..:nt h) s~1lts could be use(cid:173)
`full> cxplurcJ 111 small animal in I'IVO
`studieS. part"ui,HI) 111 cases" here
`human stullrcs Jre mll po:..sihl.. or
`appropnah:: for c\ample. at the
`compound selection stag.: in drug
`dbcovery pro~rammcs. Animal
`studies. whrlc not necessarily
`predictmg ah,orpti<'n ct!icicnc' m
`humans rna} pro' ide useful rank
`order rating' un thc eftt:cl' of
`different ~alh ..
`
`Crystal forms. ~kdll"tnal compounds
`may c·ustrn a 'anet1 ot crystal forms
`that can have d1ffcrrng aqueou~
`solubiliuc .... Rrhofla, in has thrco:
`polymorphs \\llh solubilities varying
`from !Ul6-1.2 mglm l 1_•1
`B1oa,allabilit) of vannus morph1c
`fo rms of cimetldine \\as shown to
`correlate with dis~olution ratt.:s
`sul!gt:sllng__that soluhllll) might be
`important for oral ;rhsorption.tn
`Kimura t'lul obtamcll diffenng
`pla<>ma I..: vel<, 111 d\ll,!' when dosed
`w11h diffen:nt pol}morphs of the
`poor!\ ,olublc h)'poglycaemic agent
`tolbutamide (fable lll)llflll'im
`performance reflected in ''irro
`differences in dissolution rat.:s and
`solubihtic~ between the form.,__
`Pol}•morphs with the lowest free
`cn~:rgy (lo"-o:st solubility) are usual!}
`most stablt: in thermoJynamrc terms;
`
`ORAL ABSORPTION
`
`mor..: ,,,luhlt: hlflll' t..:nd to tran,t orm
`to the lo" cnl'rg) \tat.:. Such tram(cid:173)
`form.ruun can occur during stora!(C
`prcx.:"m~ 111 C\l.!n dunng Ji~snlu­
`tinn II 111" ma~e' pol} mmph sd.:c(cid:173)
`tion fur \Oiuhrhty cnham:emcnt an
`uncertillll pnH.:c,s. Tht.: more soluble
`form mh!ht hew me lcs\ \oluble 11 ith
`time b.:cause of revl!rsion to the
`mon: thamod) namicull) stable
`form." lth ab,nrption be mg. compro(cid:173)
`mised"' a consequence It is impor(cid:173)
`tant. therefore. that any promising
`crystal fom1 "thorough!) a.'s.:s~cd to
`confim1 that:
`• It can bo: prepared con~istcntlv n) a
`n:ahstic and reliable process.
`• The preferred form can be readily
`idt.mtilled hy a technique suitable
`for routine quaht) control.
`• It dncs not transform to a less
`useful fonn on \to rage. during
`processing c1r :rft..:r incorporation in
`the llchag..: form.
`• It docs not transform to the less
`solublo: state after mgcsuon but
`prior to absorption; that is. in the
`Gltmct cnvrronmcnt
`Modest 1mpr01o:mcnts in 'olub1lity
`or dis\olution rate may be of littlt:
`ben.:fit111 I'IHI. Poole et ul. claimed
`that shght differences m solubility
`anJ di~solution rate of the anhydrous
`
`Tetracycline (base)
`Tetracycline hydrochloride
`Tetracycline phosphate
`Erythromycin
`Erythromycin stearate
`Erythromycin lactobionate
`
`1.7
`10.9
`15.9
`2.1
`0.3
`20
`
`~!'-;r~·:~ .. ~::o_:..rt~·tt·':(~\~l--.~-z;,~":::.
`, ......... ·.::I\,.,._,., ........ ~.-~- ...... ~.-..-,.,~~.. ......... ~ .... -.
`.. _.
`l .-....aolu.......,
`.
`
`.
`
`..
`
`-.
`
`Compound/form
`
`Solubility in water (mg/ml 1 )
`
`RPR 127963 (base)
`Hydrochloride salt
`Mesylate salt
`Citrate salt
`Tartrate salt
`Sulfate salt
`
`Below detection limit
`3.9
`108
`0.8
`0.9
`so
`
`PHARMACEUTICAL TECHNOLOGY EUROPE SEPTEMBER 1004
`
`19
`
`0004
`
`

`

`O RAL ABSORPTION
`
`anti trihytlmte form~ of the anti(cid:173)
`bact.:nal amp1cillrn lead to dlffer(cid:173)
`enc.:s rn ural h1oavailahJiity in dog~
`and humans •~ Howc,er. a later
`study u~rnl! unformulated drug
`showed thdt hoth form-. "ere bioe(cid:173)
`qmvalcnt. '>Ug_ge~ting that the resulh
`from the Pooh: stud~ mu~ht be
`ascribable to formul<lllon differ(cid:173)
`enccs.I'Thc work b..- t\[!uiar and
`Zelmcr pro' ide~ further elucidation
`on ,olul11hty diffcrence" They
`showed. u''"l! polymorphs of mefe(cid:173)
`namic acu.J and chloramphenicol.
`that when free encr)!} differences
`(renecung soluhllit) values across a
`range: of temperatures ) were mode~t .
`bioa' ail.thihty differences would not
`be expected. \Vhen differences arc
`large they can o~ffect ah,orpllon.IJ
`
`Amorphous forms. Amorphous
`materials can he more soluble and
`
`have.: laster tl"'nluuon rate' than
`cryst~lline form' hccause of lower
`solvauun cncruv Amorphous no,o(cid:173)
`hwcm di,~olvc' rapidly and" well
`absorbed rn humans. Inc cry~talhne
`form, by contrast. •~ k'i..'> soluhk. has
`slower diSM)Iuuun rate<;, and ..:xhihits
`poor and o:rrali( hl()ava•lahlht\.''
`Amorphous materials have the
`~arne potential disadvantag..:s as
`poly morphs or P'eudopolymorphs in
`that they may transform to the less
`soluble crystalline statc.1ne molec(cid:173)
`ular mobility (and associato:d tcndcncy
`to transform) of <.~n a morphous solid
`is" function of the differential
`between storage temperature and its
`gla"-S transition temperature (T g)· It
`has ho:o:n claimed that storage at
`tcmperaturcs of 50 C belowTg is
`required to avoid crystallization.lh
`lnerefore. the I ~ for most amor(cid:173)
`phous solids ~hould be greater than
`
`44
`85
`80
`
`II
`IV
`
`'Taken from~ II.
`
`3
`2
`3
`
`226
`590
`576
`
`----~
`
`7~ XO C 11 the\ arc to ro;m,1in 'tahlc
`111 tho; morphic scn~c: at amhicnl
`stora)!c. Exc1p1ents \\ith a much
`hr!!hcr I,_ can sometimes he added 10
`.,tahihtc a drug in the ilmorphou.,
`state. For instance. polyvmylpyrroll(cid:173)
`done ( P\'Pl (T c of :!SO C) inhibits
`tho: Cf}'>talhLallon of
`mdomcthacin.lto
`C'ry.,talhzation IS the preferred
`technique of the organic chemist fo r
`i'>olatton m a pure state, and pro-
`' 1des a const~tent phys1cal form.
`lsolatron may be more difficult 1f an
`amorphou~ fom1 IS preferred.
`"Up'>tn:am" purific<ltion. or reprc(cid:173)
`ctpitatton following origmal isola(cid:173)
`tion mthe Cf)~tallin.: state may be
`neccssaf}. This \\ill add to cost and
`complexny.
`Whereas it may be advantageous
`from an ahsorption perspective to
`select a particular salt. polymorph or
`materialm som.: other physical stat!!.
`oth..:r sch!ction cntcria must not he
`ignored. With respect to counter ions
`in salt'- the potassium ion can be <.1
`Gl1rntant unless the dO'>c is lo"
`Other cattons. such as magnesiUm or
`calcium. can innuo:nce G I tract
`moulit~ and affect absorption where
`GJ tract restdence time is important.
`However. the dose of counter ion~
`may he too low in most cases to
`evince undesirable effects.
`
`3500
`
`3000
`
`2500
`
`"' E 2000
`"' "' Ci
`..J
`E 1500
`.._
`0\
`:::1.
`
`1000
`
`500
`
`LY333531 (HCI)
`
`LY333531 (Mesylate)
`
`LY338S22 (HCI)
`
`LY338522 (Mesylate)
`
`... -fr ..
`
`---.t.-
`... Q ...
`
`-----
`
`8
`
`16
`
`24
`
`32
`
`40
`
`48
`Time(h)
`
`56
`
`64
`
`72
`
`80
`
`88
`
`96
`
`20
`
`SEPTEMBER 2004 PHARMACEunCAL TECHNOLOGY EUROPE
`
`0005
`
`

`

`ORAL ABSORPTION
`
`Dtll~tcnt '"II' nugh t .1!"1 .:ont.un
`Jiffcr.:nt rc,il.lualtmpunuc,
`"ccau" nl 'olul•lllly. p.trttt tnnm!! <II
`cr)'talltt.lliun clkct' Junn~ i'ol.t(cid:173)
`llC>n. nr Jiffc:rcnt tmpurllh> in the
`r..:agent prm ill till! the ,J.:,m:d
`cuunh:r ton. ,\ pr..:krrcd 'all ma\
`not he \tahh: or npttm.tltor pr<•(cid:173)
`cc~~lll!! to product bc:c.tuse of mot'(cid:173)
`tun: \l>rptiun llcm o r n•mpactic•n
`prop..:rtte'. or nth.:r such pharma(cid:173)
`ceutical beha' iour'- In the c\amplc'
`)!I' en 111 I able II. the 'ullatc , ,tit \\ ib
`chosen because solubtht\ w;h ade(cid:173)
`quate ;111J the phy-,tcal characterh(cid:173)
`tic; ''ere better than fnr th.: mnr.:
`soluble mesy latc salt. ln.: 'clccuon
`of a preferred tvrm ha' 1\l be a mul(cid:173)
`tidisctphnary cxcrcisc. cn,unn!! that
`ach antai(C' for unc iacct nt th<. pro(cid:173)
`gramm.: ,trc mll ncgativcd h\ mtro
`ducing. other problem,
`
`Cocrystal formation. l ,.., ol thl'
`cry,tallinc lnrm nl ,, drug c.m lle
`ad"mt.tt:t:Olh from purity. ,tahilit)
`.md pr<lCC'-'lllt: per,pcctin:,. !nus
`mctl1<xh of n:tatrllnt: cryst.Jiluut~
`"h1bt enhano.:mg solubilll) .tnd
`bioa\ ailahtht\ ma\ he WU1th cons1d
`enng. Inc recent ur-urge nt tnkrc:st
`111 wcrystallom tation rct1ects th1s.
`Pwpcrtlt''> 'uch as 'nlubilit\ l'an he
`mlluenced b\ cry,tal packm!! and thh
`m tum ..:an be mllucn..:ed by the CI)S(cid:173)
`talline ali!!nmcnt o f drug mokcuks
`"llh \lruelurall) ..:umpkmcntary
`'truCLUfC'<.
`H)drngcn llond donor. can.
`th.:rdore. llC ,,ligned \\1th hydrog~n
`acc<.:phlr.. In thts conte'(l 11 appear\
`that drug molecul.:s with appropriate
`anude grouP" can ali!tn.m the
`cry,tallographic sense." ith 1.4-
`dicarbo\\ lil aciJ., 'uch a~ citric and
`
`•1 ..... ",<:~ ~~M~~ .P- ~ ~ ... ~·-¥· i..-
`.. -:-· .?·.r~:~:....- ,J. .. -:·~r ..... :---~. .
`;L '·,.; •. Q!~ani~,so_t~nts_us~_inparanteAII,..,._IIdons.•
`Solvent
`Compound solubilized
`
`-
`
`~-
`-.
`
`·-·,..
`:
`
`~
`.
`
`- __
`
`Cremophor
`Ethanol
`Glycerin
`Polyethylene glycol 300 and 400
`Propylene glycol
`Sorbitol
`Polysorbate 80
`
`·Taken from refetence 24.
`
`Miconazole. paclitaxel
`Diazepam, phenytoin
`Epinephrine, idarubidn
`Lorazep<~m. etoposide
`Phenobarbital. hydralazine
`Nicardiptne. triamcinolone
`Dexamethasone. docetaxel
`
`:
`
`:
`
`. .
`. ..
`-
`.
`.
`.
`. ·..
`"....
`.
`Dissolution profiles of ltraconazole forms in 0.1 N HCI at 2S"C. •
`
`...
`
`_.
`
`8
`
`6
`
`"i
`
`0 x 4 <
`
`:=-
`
`2
`
`0
`
`0
`
`100
`
`300
`200
`Time(mtn)
`
`400
`
`Commercial form (amorphous)
`
`Cocrystal with succinic aCid
`
`Cocrystal with L malic acid
`
`-+- Crystalline material
`-+- Cocrystal with L tartaric acid
`
`tartan.: a..:ld'. "hl(h .m.: 'uit,thlt:
`m,Haia"-. tr<.>m .1 <;;Jfct\ pcf'p<.:<.:ll\.!.1'
`·The IX'I\Ifl~ ,ofuhlc f'<'<>rh t>in,l\ .ul(cid:173)
`ahlc anliiUill(alllrawn.ttulc h<td com(cid:173)
`parJhlt: Ji-,,,J(Utlllll pwhlc' "ith the
`amorphou' uptimall~ bioenhanccd
`conunerc1al product" hen prcscntcd
`in COCI) 'tal forms '' ith th.: L lnrm~ of
`malic and tartan<.: a~1d~ (1-igure 2).1h
`Such cr.~tall·neinecrinl! technology i~
`potent tall~ \en promi'lll!! for f'<'lO.lrl~
`soluble drug..'
`
`pH adjustment. I i a cumpounJ is
`ioni1ahlc 11 rna\ he posstblc to
`tncrcaw ,u(uhtht\ b~ Jdjlblln!! pH.
`Compounds \\llh pKa b valuc~
`between '-II. namely weak actds
`and has.:' may ha\e snluhiht)
`cnhann:d 111 th" \\a\ ' '' II a drug
`is poorly scllulllc at lu\\ pH. Ills
`concet\ahk that co-admimstration
`or coformulatJcln \\ith .tn acid-neu(cid:173)
`tralizing material proviJc, a gastric
`cnviwnmcnt more conJuci\ c to
`better solubiht) and dissoluuon rate.
`Ele\ation ol !!a.stnc pH could abo
`reJuce pres)-.tcmu; del!radauon of
`acid labilt! compound-..lc;JI:in!,!. more
`a,aJiahk for abwrptlon.::11
`MagnesiUm and caklllm carhonate
`can be used as comprt:)>slon aids m
`tablet formul.lll<lllS. It'' feasih!.: that
`thetr actd-ncutralizing effects cuuld
`be capitalued on to enhance absorp(cid:173)
`uon of acid labile compounds or
`tho<;e "'ith poor ~olubilit~ at ll<lrrnal
`ga\lric pH Some ant.lctd~ ha~c abo
`been sho" n to mcreasc the rat.: of
`pas.~age from the stomach to tht! small
`intestine. conscquent to cit:\ atmg gru;(cid:173)
`tric pH.::' Thts can ha\e theoretu.:al
`benefit. not on I~ for acid-unstable
`drugs or acJd-m<.Oiuhlc drug<, hut also
`'ol.hc:re m~Teased rate ol1bsorption
`can ha' e therapeutic hcncfit
`Such pos,ibilities mu~t be carefull>
`con'>Jdered. howe' er An} effect IS
`like!) to be related w the amt•unt o f
`matcrial utilited. Inadequate quanti(cid:173)
`lit!' m.t~ lead to margmal or no ben(cid:173)
`.:fit: con\'crscly. cxcc~st\'e amounts
`might ~timulate acid rchound
`Ph) stologJcal cffecL' may ai\O play a
`part. Magnesium carbon.tte has laxa(cid:173)
`tive propcrti.:~: by contrast calctum
`carbona te 1s a known wnstipatmg
`ag.cnt Such effects on G ltrm:t
`moulit} could comphcate all,tlrption
`proccs~es. Antactds may also act as
`adsorhcnts. making less dru!! avail-
`able for dissolution anJ adsorption z:!
`
`. 'I
`,
`I
`I
`
`l2
`
`SEPTtMBER 2004 PHARMACEUTICAl TEOINOLOGY EUROPE
`
`0006
`
`

`

`ORAL ABSORPTION
`
`AtJ,,u plillll cnhan.:o.:m.:nt
`. 1ppn •.u.:h.:' 11.1'-t.:J on altering pi I m,11
`11..: dilllo.:ult lO ~luth pro:dJmcalh 1n
`ammal modo.:l<i. Dllt.:rcncc., 111 ~a,tno.;
`volum.:s. ac1Jlly ,md phy\lolog.~ an:
`likely 11> com plical.: rc,ponses. 'lberc
`may ho: no ahc::rnat1'e hut to cxplorc
`f'<l'>'lhihllcs in human Phase:: I ~tud1c'.
`
`Solubilizing vehicles. !be least com(cid:173)
`plex wav to pn.:,ent a material to the:
`G I tract for a~~lrpllon 1S to admm
`1ster 111 soluuon. thcn:b~ rcmovmg
`an~ d1,soluuon ~tagc Occas•onalh
`non-aqut:o~ (organ1c) ~ohen~ arc
`u~ed to ~olubiliLe drugs for par.:nh:ral
`u-.e. ll<>e in oral products ll> con(cid:173)
`'>lraint:d and complicated by mam
`I acto,.... They may not exert sufficio.:nt
`'>Oiubilillng act1on to b.: of practical
`,aJu..: unless the dtl'>C of drug" lnw.
`Otht:nHsc the volume of 1ehiclo:
`n.:qutrcd cannot b.: rc:adily com.uno:d
`m a con,enio.:nt dthc unu. LitjUJd
`filled gelatin cap-,ult!s off.:r (Xl'''hlh·
`ties for compound' when the drug
`dose i.-. approximately 40-60 mg. but
`only a hmited number of non(cid:173)
`aqueo~ solvenLs can be employed fur
`such pn..><;entauon"
`
`Some: '~nthct1c alummthllic.:;llc' nr
`''hc.:atc' C<tn ah~•rh ''!!mlic.mt
`.tmounh (up 1<1 and t:\ce.:Jmg .111
`.:qual 111.1" 1 ol c.:nam ''rf.!.tnic 'ol(cid:173)
`'ents '' h1bt rct,timng the propcrues
`of a solid Dru!!, Ji~sol1.:d m the
`orgamc ,ohcrll and tho.:n ab..t>rheJ on
`the s•hc01 pn" ide<; a form that can he
`filled into cap..ulc~ and O:\c:n com-
`pr.: o:J to l.Jblct'" ~..1 !be drug IS thus
`"tn solullun." hut can he lormulat.:d
`a;; a "'hc.J c.Jn-..II!C: iorm. lb!' approach
`requiro.:' that th..: drug h.1~ high solu(cid:173)
`bilny (and gt'llxl stahtlity) in the
`cho.,.;n o rganic -.oh <!nl. and that the
`Silicate 111 turn h:1.s h•gh .tb..orption
`capahtlit) for the >OI~ent. These
`requ•rcment~ re,trict the! .lpplicabtlit}'
`to pot<!nt mc:d•cinal agents (d~o.: not
`greater than 10-20 mg) that have high
`soluhtht;. >Uilahl<! of organ it; solv<!nt~
`Orgamc -;ol\c:nts can ha1o: long(cid:173)
`term cffc.>ctson Gl mucn'-llfthc mcd(cid:173)
`tcalll'n L\ ttlr chroru~ U.\1!.. c\<!n tf Jc,eb
`emplo>cd comply \\ith lntemauonal
`Conference on Harmonization (ICH)
`guidelines. It b also pc.N•hle that pre(cid:173)
`etpiwtilm of drug from soluuon ma)'
`folio" admmtstration. when the
`mat<!n.il encounters the aqueo~
`
`extenor
`
`HO
`
`t
`
`LipopihC
`cavity
`
`~oduc<>d wllh ~mos~'''" from Cyt>.>x.tnc
`
`il
`
`envuonm<.nh in th.: ( rltra.:t. Thu" .
`th.:rc.: rna~ be hlllc or nu <~bsorpll\111
`enh.111c.:mo.:nt rahlc I\ outhnc' -.~•1
`1c.nt\ used in commcru.ll parc:ntcral
`formulauuns. whtch with the aho~e
`caveats might al'o b.: considered for
`oral tleJi,c:ry.~J
`
`Complexation. Cycltxlextnn'l can
`rru~"tde a no' el wa) to get mall(cid:173)
`molecule drugs in a mol.:cular Jbpcr(cid:173)
`sion. lbese cyc:lic gluco'e pol~ rners
`have hydrophilic "outer surtac..:s"
`and hydrophobic into:nor ca\ttlc~ that
`can accommodate! molecules of m01~~
`between 40U-500 (Figure 3).
`If interactions be t,~ecn drug and the
`pendant group-, \\ithm the ca1it) arc
`strong. a stable molar complex b
`formed. The compound "hJde.. .. 111 the
`cavity and the comple~ assumes the
`-;olubiliry of Lhe cyclooextrin
`Dissociation of the t'Omplex ··releases"
`Lhe drug in Lhe mokcular state.
`Table V summarucs bioa,ailabihty
`data. expressed as "area undc:r cunc: ..
`(AUC) for an azole antifungal drug
`dosed to animalo;, euher parenterall~
`or orally. as a hytlroxypropyl
`cydodextnn com pie\ or as a di~per­
`sion in aqueous methylcellulose.!.~
`The cyclooextnn complex afforded
`better ab~rption than the convcn(cid:173)
`uonal s~pension m all cases.. but the
`d1fferenuals varied" ith animal
`species. Data from mice and monke)'s
`suggest Lhat a~orption is s•gnificantly
`enhanced whereas Improvement was
`more modest in the dog and rat Such
`findmgs e'Ct:mplif) tht.: uncertain tic:;
`of accurately predJcting absorption in
`humans usmg animal modt.:ls.
`The original (alpha. beta and
`gamma) cyclodcxtrins havt.: limited
`application for o,olubility enhanccmem
`bt.:cause thc:y themselves arc not par(cid:173)
`ucularly soluble. the reb} limiting the
`overall dose that can be contained in a
`conventional unll 'uch as a tablet or
`ca~ule. Derivall.ft.:d cyclodc:xtrins
`such as the: hydrmypropyl or ~ul­
`fobutyl ether forms are much more
`o,oluble Some have bt.:en subjected to
`comprehensive ~afcl) screening and
`do not seem to have undes1rable
`features such as ncphrotoxicHy or
`properu.ll} to cau...: erythrtx.yte
`hcmoly~i' that were associated wtlh
`earlier cyclodextnn-;.'llte sultobutyl
`form in particular has excell..:nt
`wlubility. (ca 50 g.: 100 ml). so can
`"carry" a lot of drug. !b
`
`SEPTEMBER 2004 PHARMACEUTICAL Tt:CHNOLOGY EUROPE
`
`0007
`
`

`

`ORAL ABSORPTION
`
`I ol ,1 pan~~:ul.1r c~ .:lnJc\lflll tn I•,·
`'unable: h•r .ll~"''rp!lon cnh.lnl·,·mcnt
`11 mu't not nnl~ .JccnmmoJ,,tc the
`J ru!! 111 .. mnlc.:ular Ul\pcr,ltln ·· hH 111
`h• cnh.mc.: '" l ubll11~. but mu't .11-,1
`-rdc.I'C .. the Jru!! b~ ..:Llmplc\ Jl"o(cid:173)
`l:iati\Hl rn the (j I lr.Jct. r(l() ~tahlc .I
`comple\ can he prohkmatll"JI
`lrapanr ,h,m.:J thai when cydndc\·
`tnn .:ompl.:xe-. of the h) pnutu.:
`1Uip1dem were dosed to rat~ the
`mdu..:ti1m penod for ata\1.1 wa~ pm·
`longed compared with contrnlo,. I he
`effect 11as ascnhed to com ph!' Ul\'>0-
`cJallon bcmg rate lrmillng to ahsorp(cid:173)
`llon ~7 Complex format1o n can.
`therefore. fl<'"ibl~ affect pharnr.tlo·
`l.metiL-.. and compmm1-.,o:: ah"lrptlt•n
`1f the cumplc\ 1s too -.tahlc. In dfc..:t.
`c~ cloJexuin-.. hkc all o ther
`,.1pprn.1.:hc:, uo not alway' ,oh c
`"'luhility-rdato::d problems.
`In 'umma~ a numb.:r of 'tratcgu.:'
`can he wns1dercu lor \Oiuh1lily
`enham:ement when: this IS n..:ce''·'~·
`TI1e L-onundrum for thc ph.lmw.:eul!Lal
`technulogbt concern· " hether 'u..:h
`.1pprnachcs arc: warranll:u. There 1s
`fairl:r gencral agreement that ~~hen
`<H~ucuus solubility at physiologll41lh
`rcle•ant pi I i.., less than I -5 mg.ml at
`'7 ( · there is potential for soluh1lll\
`.md 01 solut10n-rdated alhorptmn
`
`p1nbkm'- ., ~ 1 1!~ lllklt:llL~. ,(•·[" to
`unpro1c "'luhlln1 m l.!ht xul "·I·
`r.tnh:d "hen '"luhil111 h ltmu tfJ.1n
`thl'- I hm ..:lcr. l.u.:tor' ,uch .l' 'llc--pc(cid:173)
`clt i,· .1h'< •rptu•n. dnmnJ!Ion h.ill '1"(cid:173)
`.md CICll d11\C mil\ ,i!'(l !'<: lll1pt•fl,m!
`\ddii Hlllall\. Ill\ hkt:JI that m,,_J..:,t
`\Oiuhilit~ IIKrC,I\C\ lll.l\ df..:d IItie: nr
`no m1prm..:ment. particularly "ho:rc
`\IIIUnlhl} I' \<.:1"> ltm r ach Cil'l! mu-;t
`he jUd!.!ed Ull II' mail' .md \(UUIL'd
`.lt:<.:on.linl.!h.
`
`Maximizing dissolution rate
`llll: '-.tliC\· \\h11nc1 C4ll,llitlll
`quantitilll\ch d..:-.t:ni1L' the: tactor.
`contnnutllll! 111 d1"uluunn rat~
`
`Noyes·Wh•tney e-quation
`
`dW
`dt
`
`DA(C,-Q
`
`L
`
`Nh~re
`dW dr " d1ssolution rate
`A • surface area of rhe dissolvmg solid
`C " concentration of drug m the bulk
`dissolut•on medium
`c, .. concentration 'n rhe diffus1on layer
`surrounding the d1ssolvmg sol1d
`(5.aturaled -alut onl
`d1ffus1on coeff1C1enr
`
`o
`
`d1ffus10n layer rh•ckn~s
`
`Unmilled naproxen
`Nanopartide naproxen
`
`126
`187
`
`335
`23.7
`
`15228
`19062
`
`•Taken from reference 34.
`
`350
`300
`
`400 l
`250 l
`200
`150 ~
`100
`
`z
`i
`~
`v
`=> <
`
`so ~
`0·
`
`~0~
`c..,o'.;>
`
`l11c lL'rm' I) .md I l".lnl't: uHNdo.:r..:d
`unmutahk. l't:ml! nutcn.1l 'fl<!.:llk In
`pr;~t:ue.tl term'! 111 111 "l l ' ,,Ill pra!,!(cid:173)
`lll.lllcall\ h.: ..:on,1dcro.:d to l't: tern 11 11
`I' .t'-'Umcu tiM! d1"uh ed mah:nall\
`,,h,orh.:d 4ll1cl.l~ lnu-. < ~ (11hrch ..:;1n
`h.: consid..:r..:d l!l h.: th..: ..... uura!lun ~ol­
`uhlllly) .md \ 1\urf.lco.: area ,,t -.nhd
`cxj10'>ed lilt he di-.,u!uuon mcd1um)
`.Ire the pnmc dnver.. for Ul\\olutton.
`lncrc;.~sin!l euh..:r ur hoth uKn:a>c\ th..:
`ratc of pa...-ugc lmm ,<,I ILl tu soh a teLl
`...tate Ill 'lluatitHI\ ~>'here th..: rate and
`..:\lent of .tlN!rp!lon can h.: 111nuenced
`h\ the df.;.,oluuun r.llc.
`Surface area enh.mcement is ma.-.t
`n:adi!v .1ff..:cted h1 reducrnl! particle
`\Ill!. Rcducuon w ffiiLTI.lli-,1/I!U parti(cid:173)
`cle~ lx><,..t..:d .tb<>.lrption ol the anll·
`fungal .1gent. gri....:ofuh 111 rn human'
`comparanh: pJa,m.l h:1 cb h.:ing
`nhtaim:d ~~oith half the dthe o f
`microni1cd drug ct1mp.1red with tht:
`nttn-nm:rumJed form. 1 \h.:roni1.ation
`1s a m~llur..:. ~~oell ch.~ra..:tenlcd tech(cid:173)
`nology and. arl!uahl\. ought h.: consld(cid:173)
`er..:d when .1queou' "'!uhi!it) "[c:s..,
`than appro~ lm;uch I m~mL. 1~
`I lowever. it doc ... nut m:ce\saril)
`guarantc..: llllpmveLI ab:.orptiun. Small
`particles can form •l!t!:!regat..:' and
`dispel'><.: pomJ~ II Jt may nt: nect:>.Sary.
`therefore. tt> adu d!'>per;anh or oth.:r
`ph~'\ICJJ \l,lhl[iiCI'.
`\lore recently~ tcchnollll!les from
`the reprographic ~nd photll)!raphlc
`rndu,tn..:' ha•..: h.:en uuh1ed w
`provide ~ul'lmicron parttc!c~ of C\ t:n
`gn:atcr surf .tee area than microniLed
`matenal. rahlc \ I ~hOI\\ the effect of
`using 'uch nanopart1clc\ on all<.Orp(cid:173)
`tion of napro,en in rah. ~
`Nanopan1culate matcna! pro-.tded
`higher peak pla,ma level' and shorter
`ume to peak, a!thou!!h 01erall ab:.orp