NOVARTIS EXHIBIT 2017
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 1 of 6
`
`

`

`: ','
`'~:'1.,
`, .. ,
`.:'
`
`;
`
`i
`i
`j
`i ,
`i
`I
`~ II
`
`i
`
`I ,
`
`',.: "", ,i,,"';_:',"'"
`."
`
`,
`
`·· .•...•. R(:?~ington' s
`, ',.';' ',: ,""
`Pharmaceutical
`Sciences'
`
`,
`
`18
`
`; . . ' . . .
`
`NOVARTIS EXHIBIT 2017
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 2 of 6
`
`

`

`I
`
`18TH
`
`EDITION
`
`Remington's
`
`ALFONSO R GENNARO
`Editor, and Chairman
`of the Editorial Boord
`
`NOVARTIS EXHIBIT 2017
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 3 of 6
`
`

`

`,t
`
`Pharmaceutical
`
`Sciences
`
`1990
`
`MACK PUBLISHING COMPANY
`
`Easton, Pennsylvania 18042
`
`NOVARTIS EXHIBIT 2017
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 4 of 6
`
`

`

`1'1
`
`. ' .. -'
`Remington's Pharmaceutical Sciences . .. a treatise on the theory
`and practice of thepharmaceutica! sciences, with'essential
`information aboutphormoceuticol and medici~ol agents; also a gUide
`to the professional responsibilities of the pharmacist as the
`. , !;!rug.iQformatian sPecialistpf the health team "." ktextbaok
`and reference work for pharmacists, physicians dildother
`practitioners of the pharmaceutical and m~diciii ~(jence~ .
`'.-.' ~,.,'
`. -'
`.. \' ,-
`
`.~'.
`
`"
`
`,'- ..
`EDITORS
`
`: -~
`
`..... ;.;
`
`',' '.
`AUTHORS'
`
`Alfonso R Gennaro, Chairman
`, '.
`' ..
`Graftan D Chase'
`Ara Der Mardero~ian
`!,., ','
`.. ~"
`Stewart C Haryey.
`
`, '_<1
`
`Daniel A Ho~sat
`
`, ''Fhomas Medwick
`
`. ;Edward G Rippie
`
`Joseph B Schwartz
`
`Ewart A Swinyard
`
`Gilbert L Zink
`
`The 109 chapters of this edition of Remington's Pharmaceutical·
`Sciences were"written by the editors, by members of the
`Editoriaiiloaid, and by other autho;;Usted Orlf>~ges ix to xi .. ,
`
`i'.'·',
`
`"
`
`:j-'
`
`Managing Editor,
`
`John E HOOVer
`
`i .,
`
`Editorial Assistant '
`
`Bonnie Brigham Pocker
`
`Director
`
`Allen Misher 1985-1990
`
`. Eighteenth Edition - 1990
`
`Published in the 1Z0fh yeor of the
`PHILADELPHIA COLLEGE OF PHA~MACY AND SCIENCE
`
`.' '.,
`
`. J","
`
`i _,.;'"
`
`., ~_, I
`
`" ".:.'-
`
`",
`
`NOVARTIS EXHIBIT 2017
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 5 of 6
`
`

`

`into a cylinder and extruded with ,a measured force. The
`amount extruded is a measure of the consistency of the
`ointment.' , '. .
`.
`, Ointments have a considerable degree of structure which
`requires a minimum of 48 ,hours to develop after prepara(cid:173)
`tion. 'As:rheo~6gical "data on a freshlY'made ointment may
`be erron'eous, such tests should be performed only' after the
`ointment has achieyed equilibrium.
`.
`.
`Slight changes iirtemperature(1 or 2°) can affect the
`con:si!?te'ncy of an oin#nent greatlYi hence, rheological stud(cid:173)
`ies on' ointments _must be performed 'only at 'constant' and
`controlled temperatures.
`. Among' the other tests performed during the stability
`study of an ointment are a check of visual appearance', color,
`odor;'-viscosity, softening-tange, consistency, homogeneity,
`paitiCIe-size'dist'rihutiim-aitd sterility.
`"
`Undissolved 'components 'of an ointment may change in
`crystal form or in;siie with time. ,Microscopic-examination
`or an',X-ray .diffraCtion·measurement may be used to moni(cid:173)
`tor these parameters.
`In some instances it is necessary to use an ointment base
`that ,is less than ideal in orde1,' to Ilchieve the required s4tbil(cid:173)
`i&. --For'example; drugs that hydrolyze rapidly' are-more
`stable in,a hydrocarbo~~base than hi a base containing water-,
`. ev.::n thoilgh they m~y be' more effective':iri t~e latter.
`
`lncompatibmty .
`
`Obvious sources of pharmaceutical instability include.the
`incompatibility of various- ingredients within a formulation.
`Numerous'examples are described in other sections,'of-.this
`book and- the literature' is,replete- with illustrations. Thus,
`the subject,nead not be treated,jn detail here.··
`While undesirable reactions between ·two' or more_ drugs
`are said -to_result in a ~'physical,". "chemical" Or '~therap'eu­
`tic'" incompatibility, -'physica,l incompatibility is somewhat
`of a misnomer. ,It,has been' defined as a physical or chemical
`interaction between two or more ingredients which leads to a
`visibly recognizable change. The latter may be in the_ form
`of a gross precipitate, haze or ,color change.· .. -.
`..',
`On the other hand, a chemical incompatibility is 'classified
`as a reactio'n-in which,-avisible change does not occur.' 'Since
`there' is. ·no : visible' evidence of deterioration,. this -type, of
`incompatibility requires trained, knowledgeable-personnel
`,,'
`',.
`'.
`.
`to rl(cognize it, should it occur .-,'
`,A -the:t:apeutic incompatibility has been defined as an un(cid:173)
`desirable, pharmacological interaction between two, or more
`ingredients which "leads to (1) potentjation of thetherapeu·
`tic effects oHhe,ingredients, (2) destruction of the effective(cid:173)
`ness of one or:.more of the ingredients or· (3) ,occurrence of a
`toxic" man:ifestation within the' patieIit~
`
`Oxidation-Reduction-
`Oxidation is a prime cause of product instability and of(cid:173)
`ten, but not always, the' addition 'o{dxygen or the removal of
`hydrog~n is ilJ.volved. When moleGu,Jar oxygen is involved,
`the reaction,.is known as ,autooxidation because it occurs
`spont'8.neously: th.ough slowly, at room temperature.
`,Ox~9.~tion,' or.~he loss of electron!?,_from an ~tl?m, frequent(cid:173)
`ly involves .I:r.~~c radicals and. subsequent chain react~ons.
`Only a verY,small arp.ount of oxygen is required to initi~te a
`chain reaction. In practice, it is easy to remove most of the
`oxygen f-rom.a container, but very difficult to re~ove it all.
`Hence" nitroge;n and c~rbon dioxide frequently are used. to
`displace the headspace air in pharmaceutical containers to
`help minimize deterioration by oxidation.
`'
`As an oxidation reaction is co:mpIicated, it is difficult to
`perform a kinetic study on' oxidative processes within a gen(cid:173)
`eral'stability program. The redox potential, which is con(cid:173)
`stant and relatively easy to determine, can, however, provide
`
`STABILITY OF PHARMACEUTICAL PRODUCTS
`
`1507
`
`•
`
`valuable predictive information. In many oxidative :reac(cid:173)
`tions,' the rate is proportional to the concentration of the
`oxidizing species but-may, be independent,of the concentra(cid:173)
`tion of the oxygen present. The rate is ,influenced by,tem(cid:173)
`perature, radiation ,and· the presence of-a ·catalyst. ,.An in(cid:173)
`crease:in,temperature leads to an acceleration, in the rate of
`oxidation.. If the storage temperature ,of a preparation can
`be reduced to 0 to 5°" usually it can be assumed that the'rate
`of oxidation will be at least h,alved.
`Trace amounts of heavy metals such· as ·cupric,~,chromic,
`ferrous or ferric ions may catalyze: oxidation reactions .. As
`Ii,ttle ,as·.o.2 mg of copper ·ion per liter considerably reduces
`the stability of penicillin. Similar example!?, include the
`deterioration, of epinephrine,. phenylephrine" lincomycin,
`isoprenaline and procaine hydrochloride. Adding.ch.elating
`agents to"water;,to sequester, heavy metals:and working in
`special manufacturing equipment (eg~ glass) are some means
`used to reduce the influence of heavy metals'on a formula':
`tiQn-, Parenteral formulations sho.uld nO.t come ~n ,contact
`with heavy metal ions during tliei:r manufacture,:;packaging
`or.storage.
`.
`,,~, "'<
`:.Hydronium ·and hydroxyl. ions ,catalyze oxidative ·r.eac~
`tions. The rate of. decomposition for' epinephrine,: for exam~
`pIe, is more ,rapid;in a·.netltral':or 'alkalin,e solution,:with
`maximum stability (minimum oxtda_tive' d~coDiposition) 'at
`pH 3.4. There is a pH range. for maximum stability for.any
`antibiotic and vitamin-:preparation which:usuaJly can he
`achievedbY'adding an acid, 8lkali or bUffer.
`Oxidation may be inhibited,;by the use. of antioxidants,
`called negative catalysts. They are.very effec~ive ~n,stabiliz­
`ing phar_maceutical products 'undergoing.aJree:radical-me,.
`diated chain reaction .. These substancesj -whi,ch are ,easily
`oxidizable, act by possessing lowet,oxidation potentials than
`the active ingredient.· Thus;tltey undergo prefe.rep.tial deg(cid:173)
`radation or act-as chain inhibitOJ;s of fre.e radicals·py provid(cid:173)
`ing an electron a1;ld receiving the e~G~ss enetgy possessed by
`the activated molecule.
`. . , . . . .
`The ideal antioxidant should be stable and. ~ffe,ctive over a
`wid~ pH range,-,s.olqble in,its oxidiz,ed form; colorless,,,n,on(cid:173)
`toxic,. nonvolatile, nonirritating; effective in low ctmcentra(cid:173)
`tions', .thermostable and compatible with th,e c.ont,aine:r .... _clo~
`sure,!?ystem and fO,rmulation ingredients.
`.. ,The commonly used -antioxidants ,for .aque.ous:,:l;iyste,ms
`include sodium sulfite, sodium metabisulfit!3', sodi,um 'bistil~
`fite, sodium thiosulfate·and ascorbic acid. For<oih;ystems,
`ascorbyl-palmitate, hydroquinone" propyl gallate,'nordihy:(cid:173)
`droguaiaretic acid, butylated hydroxytoluene, butyl.ted hy(cid:173)
`droxyanis6le and alpha-tocopherol'areemployed."
`Synergists, which increas~ the.activitY'Of-antioxidants"a,re
`generally organic.compounds that compl~x small amotmts of
`heavy metal.ions;(see Chapter 14).. .These in.clu.de.the eth'
`ylenediamine tetraacetic-- acid r (EDTA) derivatives, ·dihy(cid:173)
`droethylglycine, citric,.tartaric, gJuconic:and sac,chark acids.
`EDTA has, been uS,ecl:to stabilize ascorbic.ac~d.,_oxytetracy­
`cline, penicillin, epinephrine.and:predni_solone. :,' ;.
`Reduction reactions are much less ,comm.opJhan oxidative
`processes _ in pharmaceutical, practi~e~':, Examples include
`the reduction of gold, silver OJ{ mercury salts byJight to fo,rIP
`the corresponding free metaL
`
`Hydrolysis ,.
`
`Drugs, containing an ester or ~ amide linltage are prone to
`hydrolysis. Some example_s inclU.de Go,eai.ne, physostigmine"
`procaine, tetracaine, thiamine and benzylp,el1icUlin.
`. I 1:'he rate of hydrolysis, depends o.n. the t~mperature l,md
`the pH of the,solution, A much quoted,rule;of-thumb is
`that, for 'each 10° -rise in _storage temperat\lrej,~the rate of
`·reaction doubles or triples. As this is an,empiriG.ism,· iUs not
`applicable always. . .
`, ":.;:~,' .
`
`NOVARTIS EXHIBIT 2017
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 6 of 6
`
`