A HANDBOOK FOR PHARMACISTS
`
`Kenneth A. Connors
`Gordon L. Amidon
`
`SECOND EDITION
`
`ChemicalStability
`of Pharmaceuticals
`
`Valentino J. Stella
`
`ADAMIS EXHIBIT 1012
`Page A
`Page A
`
`ADAMIS EXHIBIT 1012
`
`

`

`Chemical Stability
`of Pharmaceuticals
`A Handbook for Pharmacists
`
`Second Edition
`
`Kenneth A. Connors
`School of Pharmacy, The University of Wisconsin
`
`Gordon L. Amidon
`College of Pharmacy, The University of Michigan
`
`Valentino J. Stella
`School of Pharmacy. The University of Kansas
`
`A Wiley-lnterscieoce Publication
`
`JOHN WILEY & SONS
`
`New York • Chichester • Brisbane • Toronto • Singapore
`
`Page B
`
`ADAMIS EXHIBIT 1012
`
`

`

`A NOTE TO TiiE READER
`This book has been electronically reproduced from
`digital infonnation stored at John Wiley & Sons, Inc.
`We are pleased that the use of this new teclu1ology
`will enable us to keep works of enduring scholarly
`value in print as long as there is a reasonable demand
`for them. The content of this book is identical to
`previous printings.
`
`Copyript 0 1986 by John Wiley cl Sons, Inc .
`.
`All risll•• retcrVed. Published simultaneously in Canada.
`
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`(201) 748-6011, fax (201) 748-6008.
`
`,...,,.c.,,._,c..,.,."',.....,.,, o-:
`
`Connon, Kenneth A. (Kenneth Anlonio), 1932-
`Chemlcal 11&bil11y ol pharmaceucicals.
`"A Wiley-lntendence publication."
`lnclucle1 ~phles and index.
`I. Amidon, Gordon L.
`II. Stella,
`I. Drva 11&bility.
`I. One
`• ill. Title.
`Valentino J., 1946-
`[DNLM:
`Stabilicy-haadboolts. 2. Kinetics-ha.ndboots.
`QV 73.5 C7.Slc)
`
`RS42A.C66 1986
`ISBN CM71-179SS-X
`
`61S' .18
`
`S.S-314.SS
`
`Pnnted in India
`to 9 8 7 6 s 4 3
`
`Page C
`
`ADAMIS EXHIBIT 1012
`
`

`

`To the •e•ory of Lloyd Kennon
`
`v
`
`Page v
`
`ADAMIS EXHIBIT 1012
`
`

`

`Preface
`
`Pharmaceutics instruction in the phar•acy curriculu•
`provides phar•acists wJth (a•ong other kinda of knowl(cid:173)
`edge) a sound theoretical basis for understanding
`che11ical kinetics and 1 ta uses in studying drug sta(cid:173)
`bility. This is a research application of kinetics in
`phar•acy, and it ts entirely appropriate that the
`phar•acist be aware of the aethoda used (pri•arily in
`the phar•aceutical industry) to aaaeaa and control
`drug and dosage for• stability. There is, however,
`another area of phar•acy in which a knowledge of ki(cid:173)
`netics can be usefully applied:
`this is the area of
`professional practice. Teachers of phar•aceutics have
`not been highly aucceaaful, it aeeaa to us, in devel(cid:173)
`oping this application. The purpose of this book is
`to assist the phar•acist in applying kinetic •etbods
`and data to stability proble•• in professional prac(cid:173)
`tice.
`The way fro• theory to practice is not always easy
`or obvioua. Part One of this book treats the calcula(cid:173)
`tions, approxi•ations, and esti•ates that are useful
`in practical situations. Part Two is a collection of
`selected drug-stability data froa tbe literature.
`Although it is clearly not encyclopedic, this collec(cid:173)
`tion •akea readily accessible to the phar•aciat •uch
`of the infor•ation necessary to •ake phar•aceutical
`decisions about drug stability .
`It haa been interest(cid:173)
`ing to le•rn, in the several years since the first
`edition appeared, that research pharaacista in the
`pharaaceutical industry also have found the book uae(cid:173)
`fu I. priaarily because of the data presented in the
`stability •onoaraphe.
`Jn this aecond edition the principal changes are a
`thorough revision of the chapter on oxidation, addi-
`
`vii
`
`Page vii
`
`ADAMIS EXHIBIT 1012
`
`

`

`tion of a new chapter on solid-state stability, and a
`triplinc ot the nuaber ot stability aonographs . Sic(cid:173)
`nif icant changes were also aade in the treataent of
`industrial stability-teatinc requireaents and proto(cid:173)
`cols, and for tbia we acknowledire the assistance of
`Pradip K. Banerjee.
`The aonocraphs have been contributed by graduate
`atudents and faculty aeabers in the pharmaceutics
`areas of the University of Kansas,
`the Univer•ity of
`Michigan, and the University of Wiaconain . The affil (cid:173)
`iation of each author ta given, althoucb in aost in (cid:173)
`stances the author will have left the institution to
`take a position elsewhere; should a reader wish to
`correspond with a aonoirraph author, this can be done
`by addressing one of us at the appropriate school.
`All aonoirrapb fiirures have been redrawn, aost of
`thea fro• publ !shed data, and all aources are cited .
`Por the record, K. A. C. was reaponaible for Chapters 1,
`3, and 4, G. L . A. for Chapters 2 and 7, and V. J . S . for
`Chapters 5 and 6 . The caaera-ready copy waa prepared
`bJ the very able Linda Frei.
`
`Madison, Wisconsin
`Ann Arbor, Michigan
`Lawrence, Kansas
`
`October 1985
`
`KENNETH A. CONNORS
`GORDON L. AMIDON
`VALENTINO J . STELLA
`
`vii 1
`
`Page viii
`
`ADAMIS EXHIBIT 1012
`
`

`

`Contents
`
`PART ONI:
`
`PRINCIPLES
`
`Chapter 1.
`
`Introduction
`
`A. Stability Prediction by the Phar•aciat, 3
`B . Other Sources of lnfor•ation. 5
`
`Chapter 2. Stability Calculations
`
`A. Rate Equations, 8
`1. The Order of Che•ical Reactions, 8
`2. First-Order Calculations, 11
`3. Zero-Order Calculations, 15
`
`3
`
`8
`
`B. Te•perature Effects, 18
`1 . Activation Energy Calculations, 18
`2. Q 10 -Value Calculations: Approxi•ate
`Method, 22
`
`C. Shelf-Life EstiM4t1on Methods, 26
`
`Chapter 3.
`
`Interpretation of Kinetic Data
`
`32
`
`A. The Transition-State Theory, 32
`B. Med1u• Effects, 38
`C. Catalysis, 41
`D.
`pH Effects, 43
`1. V-Graphs, 44
`2. Sig•oid Curves, 47
`3. Bell-Shaped Curves, 52
`
`B. So•e Practical Mattera, 55
`1. Using pH-Rate Profiles , 55
`2. Using Activation Energies, 59
`
`Chapter 4. Hydrolysie and Other Acyl Transfer•
`
`63
`
`A. Nature of the Reaction, 65
`8. Catalysis, 69
`C . Structure and Reactivity, 73
`
`ix
`
`Page ix
`
`ADAMIS EXHIBIT 1012
`
`

`

`Epinephrine
`
`GENERAL
`
`Na•es
`
`Epinephrine; adrenaline; 1-epinephrine: 4(1-hyd roxy-2 -
`(•ethylaaino)ethyl}-1,2-benzenediol.
`
`Structure
`
`OH
`
`HOy~ t-C'"'2NHCl-b
`-
`I
`.
`H
`
`C9H13N03
`
`•ol. wt. 183.20
`
`HO
`Por•s Available
`
`Epinephrine base; epinepbr ine hydrocblor ide: epi nepb(cid:173)
`r i ne bitartrate, C9H13N03·C4HeOs. •ol . wt. 333. 29:
`epinephrine borate (Eppy) , C9H12BN04 1 aol. wt. 209. 01.
`
`Physical Properties
`
`Crystals that beco•e brown on exposure to light and
`air: aeltine point 211-212•c. Optical rotation [ ci]o
`between -50 and -53 . 5°C (5- in dilute HCl) (1). Spar(cid:173)
`ingly soluble in water: soluble in aineral acids and
`alkali hydroxide solutions.
`Insoluble Jn •ost orga nic
`solvents.
`The bitartraie aalt dissolves in water to
`the extent ot 1 g
`in 3 •L (2): the hydrochloride is
`soluble in water .
`The macroscopic acid d 1 ssociat ion
`constants (3) are pK1
`• 8 . 71 and pK2 • · 9.90 at 20° c.
`and the ratio of zwitterionic to uncharged for• is
`about 4:1.
`
`Stability Suaaary
`
`Epinephrine Jn solution undergoes acid - catalyz ed
`raceaization, oxidation by •olecular oxygen, an d
`
`438
`
`b
`
`ADAMIS EXHIBIT 1012
`
`Page 438
`
`

`

`Drua Kinetic•
`
`est
`
`nucleo phil lc aubatitutlon by biaulfite , which i• uau(cid:173)
`a lly preaent aa an antioxidant . Opti•u• atability Ja
`a chieved by aaintainJnc the pH at 3 to C, by excludJne
`oxycen, by JncorporatJne bJaulfJte aa an antioxidant,
`and by protectlnc the aolution fro• lisbt . Opbtbalaic
`a oluti on a can be atablllzed by the incorporation of
`b oric acid, wbicb protects aaainat oxidation and
`bi sulflte attack .
`·
`
`DRUG KINBTICS
`
`Reaction• and Rate Equation•
`
`lpi nephrine in ita doaaee for•• ••Y undereo three
`tap ortant reactiona--race •lzatlon , oxidation, and
`aub atitutlon by blsulflte .
`
`1. R•c••lsatloa .
`In aqueoua aolutlon J-eplneph(cid:173)
`rine raceaises to cll - epinepbrlne , wltb concoaltant
`decr ease ln pbaraacoloslcal activity .
`Schroeter and
`Rieu cbl (C) atudled tbe acid-catalysed racealaatlon
`over the pH ranee o. o to 1.'. The loc k va . pH rate
`prof llea at several teaperaturea were linear, tbe
`aver a1• alo pe value beine -1.21 .
`The •ecbaniatic
`aeanlne of thia result la not clear, but tbe deviation
`froa the expected value of - 1 . 00 (i . e . , a fir•t-order
`dependence on bydroeen ion) aay be an activity coeffi(cid:173)
`cient effect in tbeae very acidic aolutiona . The rate
`constant • at two pB value• are eaplrically related by
`Bq.
`( 1) ,
`
`101 k3 • 101 kl - 1.21(pH3 - PH1)
`
`( 1)
`
`• here kl and ka are paeudo-firat - order rate conatanta
`at PH1 and PH2i respectively. At cs . c•c and pH 1 . 27,
`k • 1. 19 x 10-7 .-1.
`lquation (1) should not be uaed
`to predict raceaization rate• above pl C. The extrap(cid:173)
`ol ated abelf life (t90) for race•laatlon at pH 3 . 5 and
`as•cc ta about 120 •ontha .
`
`2 . Oz1dat1oa .
`a olecular oxyeen
`col ored products.
`ox idation.
`
`Epinephrine la eaaily oxidised by
`and other oxidl1ln1 aeenta to eive
`Tbe catecbol aolety i• the site of
`
`ADAMIS EXHIBIT 1012
`
`Page 439
`
`

`

`'40
`
`Epinephrine
`
`HO~Cl«lHC!tHHMe -2H
`
`On
`~
`0
`
`CHOHCIV<HMe
`
`h
`
`1-2H
`
`HO
`
`:::::_....
`
`t:tO
`
`HO
`
`OH -
`<
`
`0
`
`0
`
`H
`
`H
`
`adrenolotin
`
`adrenochrome
`
`The discoloration resultinc fro• oxidation is u na c(cid:173)
`c eptabl e phar•aceutically .
`Sokoloski and Hicuchi ( 5)
`found that the kioetic a of oxidation by 02 were c o•(cid:173)
`plex, an d they •easured initial rates to overco•e tb ie
`co•pl e xi t y, but even tbe initial rates displayed c o•(cid:173)
`pl icated kinetic behavior .
`Tbe orders of rea cti on
`with respect to oxyeen and epinephrine depend upon t he
`reactant concentrations as shown in Table 1 .
`
`TABLB 1 . Order Dependence of Initial Rates in Oxida (cid:173)
`tion of Epinephrine by 02 (5)
`
`Order with Respect t o
`
`Concentration Conditions
`
`Epinephr ine
`
`Low epinephrine; low o2
`Hieb epinephrine; bicb 02
`Hieb epinephrine; low 02
`Low epinephrine; bich 02
`
`>1
`<0 .5
`<0 . 5
`>l
`
`1.0
`0.5
`1. 0
`0 . 5
`
`ADAMIS EXHIBIT 1012
`
`Page 440
`
`

`

`Oxidation can be prevented by reaovinar oxyaren froa
`tbe aystea, and aapuls of epinephrine solution are
`uaua 11 y pa eked under nit roeen. Ant !oxidants, •oat
`coaaonly aodiua b!aulfite (see belo•), are usually
`inc orporated. Oxidation appears also to be proaoted
`by light, and storaare in the dark is therefore helpful
`( 8).
`The rate of oxidation increase• •1th increased
`pH, and since the rate of raceaisation decreases •ith
`inc reased pH, there ia an optiaua pH at which raceai(cid:173)
`zat ion and oxidation can be balanced to ainiaize loas
`of intact drue by theae two routes; tbia i• approxi(cid:173)
`aate ly pH 3 . 0-S.8 (7), which 1• conaistent •1th USP
`requ ireaenta (1) .
`s. R••ct1oa w1tb B1suJl1t•. Solutions of epineph(cid:173)
`rine are routinely stabilized with the antioxidant
`sodiu • b1aulf1te or a related aalt.
`The report by
`Schr oeter and Hteuchi (8,9) that btaultite react• with
`epine phrine to fora a pharaacoloeically inactive
`aulf onate was therefore ot arreat intereat. Thia
`react ion ia a nucleophilic substitution on c•rboni
`
`r
`·~
`
`) "°9-~ ... ·
`
`The species in an aqueous solution of bisulftte are
`r elated by these equilibria (10):
`
`HO
`
`S02 + H20
`
`H2S03
`
`B2SOs
`
`K1 ::ii. e• + BSOs-
`
`HSOs-
`
`Ka:::. a+ + S032-
`
`2HS03-
`
`Ko:::. S2052-
`
`Aqueous aolutiona of aultur dioxide (902) are foraally
`equ ivalent to aulfurous acid (H3S03), which, however,
`la not detectable aa such.
`It• aalta are bJaulfite
`(HS03-), sulfite (S032-). and aetabhulfite (S3052-,
`
`ADAMIS EXHIBIT 1012
`
`Page 441
`
`

`

`442
`
`Epinephrine
`
`.. 1.76 and pK2 = 7 . 20
`PK1
`aho called pyrosultite).
`at 25°C for sulfurous acid, and the diaerization con (cid:173)
`stant Kn = 0 . 07 M-1 . Because of these equilibria , so (cid:173)
`dium bisulfite, aodiu• sulfite, and sodiu• •etabi sul (cid:173)
`fite aay all be used as antioxidants, and it is no t
`always clear which species is taking part in a
`r eac(cid:173)
`tion.
`At pH values above 5, the reaction between epineph(cid:173)
`rine and b isulfite is overall second order . At lower
`pH
`the kinetics are first order in epi n ephrine but
`zero order in bisulfite: aoreover, in the presenc e of
`biaulfite the raceaization is inhibited. These obs er(cid:173)
`vations were accounted for with the followinr kine tic
`sche•e, where B- OH repr esents epinephrine and E+oe - la
`the in~ipient carbocation that is conjectured to be a
`co••on intermediate for the k2 (race•ization) step and
`the ks (bisulfite diversion) step.
`
`)
`
`dl-E-OH
`
`!-E-OH
`
`ks
`
`)
`
`k,(S~
`
`E-SG.l-
`
`The rate equation for loss of 1-epinephrine is
`
`Application of the steady-state approximation to the
`inter•ediate gives
`
`ki(l - E- OH)
`k 2 + k 3 (so3 2-)
`which . coabined with Eq.
`( 2), yields
`
`( 3)
`
`ADAMIS EXHIBIT 1012
`
`Page 442
`
`

`

`Dru1 Kinetic•
`
`''s
`
`where koba is the pseudo-first-order rate constant for
`l o•• of l-epinephrine. Equation (S) is consistent
`with the observed kinetics.
`Epinephrine and boric acid for• a 1:1 producf
`accordinir to Eq. (f), where R la the epinephrine aid~
`
`chain. HOXJR
`
`1-bB<>s •
`
`I
`HO ~
`
`o:(JR
`HO-BF ~ I
`-\
`Rieirel•an and Fischer (11) showed that boric acid
`bil izea epinephrine aeainat biaulfite attack .
`also report that sulfite attacks adrenochroae to
`a c olorless adrenochroae aulfonate (6).
`
`\
`
`+ 2Hi0
`<•>
`ata(cid:173)
`They
`fora
`
`pH-Rate Profile
`
`It baa already been pointed out that the race•ization
`reac tion is acid catalyzed, the 101 k va. pH-rate pro(cid:173)
`file having a slope of -1.21.
`Fieure 1 is a pH-rate profile for the loss of bi(cid:173)
`eul tite in an epinephrine tolution (9).
`The aig•old
`curve can be accounted for with Bq. (S) and the condi(cid:173)
`tion k·2 <<< ks(S032-). Thie suggests that the reac(cid:173)
`tion is aa shown above, that is, the attack of sulfite
`on p ositively char1ed epinephrine, or its kinetic
`equivalent, the attack of bisulfite on the zwitterion
`of ep inephrine.
`
`Activa tion Bnerey
`
`The Ar rhenius activation energy of the race•izatton ia
`23.2 kcal/aol (4).
`Th e activation ener1y of the biaulf ite reaction at
`pH 6. 50 in a phosphate buffer ia 24 kcal/•ol (9).
`HaJra t wala (12) studied the reaction of aetabisulfite
`( 0.05 •) with epinephrine (0.001•)
`in 1 and 2• Udo(cid:173)
`c aine at pH 4 . 0 and 4.4, findine AH+• 23.6-2S.9
`kcal/•ol and As+ • -20 e.u.
`
`Other Data
`
`The bi aulf ite reaction rate is insensitive to ionic
`·a tren.eth, and ia ali1htly increased by acetate at pH
`
`ADAMIS EXHIBIT 1012
`
`Page 443
`
`

`

`444
`
`Epinephrine
`
`5. 0. At pH 4. 7 sodiu• metabisulf i te was report ed to
`react slightly faster than sodiu• bisulfite (13).
`Soae observations of solid-state stability of epi(cid:173)
`nephrine salts have been reported (14).
`The lo ss of
`•ass of the hydrochloride, bitartrate, •aleat e , and
`fu•arate salts at 95°C over a 20-day period s howed
`t~at the fu•arate and •aleate salts were the most
`ther•ostable ones.
`
`1
`""' l
`
`- 4.0
`
`-4.5
`
`- s.o
`
`- 5.5
`
`-6.0 ..._ _ _ ...._ _ _ .__ _ __. _ _ __.. _ _ __
`6
`8
`4
`5
`7
`3
`
`pH
`pH-rate profile for loss of
`FIGURE 1. Epinephrine .
`biaulfite in an epinephrine solution at 68°C.
`Initi al
`concentrations: epinephrine 0 . 082 M: bisulfite 0.01 92
`II.
`
`FORMULATIONS AND COMBINATIONS
`
`Deeradation Reactions
`
`The reactions of epinephrine with oxidizing agents a nd
`with salts of sulfurous acid have been described
`above.
`
`ADAMIS EXHIBIT 1012
`
`Page 444
`
`

`

`Por•ulatlon• and Co•bl natlon•
`
`''5
`
`Colloidal silver preparation• pro•ote tbe decoapo(cid:173)
`
`el tlon of epinephrine , with up to •o• lo•• after 8-18
`Epinephrine hydrochloride in 5• dextroee with ter(cid:173)
`
`h (15) .
`
`butallne sulfate was studied in the preaence and ab(cid:173)
`se nce of a•inophylllne (16) . Bpinephrlne oxidation
`we• feater in the presence of ••inophylllne, presu•(cid:173)
`abl y because of the bieher pH in tbl• ayete•.
`It was
`au11 e sted that epinephrine not be co•bined with basic
`dr u e • like a•inophylline in laree-volu•e parenteral
`aol utlona . Epinephrine hydrochloride was found to be
`phys ically co•patlble with a•ikacin up to 2• h
`in
`larce -vo l u•e parenteral solution• ( 1 7) .
`Oxy•ix, a for•ulatioD used aa an aeroeol in pul•on(cid:173)
`ary condition a, contain• ascorb ic acid, cupric sul(cid:173)
`fate , aodiu• percarbonate, and excipienta.
`It was
`fou nd that epinephrine concentration dec r eased rapidly
`in t his ayate• ; however. after so min at least so• of
`the added epinephrine waa still unchaneed , and thi•
`was c onsidered a clinically ueeful reeult (18 ).
`
`Stab ilization Method•
`
`Despi t e the labile nature of epinephrine, it l a poaal(cid:173)
`bla t o prepare pbaraaceutlcally acceptable f or•ula (cid:173)
`tiona . The pH should be hleb enoueb ao that race•lza (cid:173)
`tion l a not •ienificant, and
`low enoueb a o that t he
`rates of oxidation and blaulflte attack are neellel(cid:173)
`ble; t he pH s to 4 ranee aee•s opti•al . Oxyeen should
`be exc luded if possible, and atora1e in the dark la
`advis able. Sodiu• biaulf i te o r aodiu• •etabiaulf i te
`(ofte n about 0.1•) •ay be added aa antloxidanta .
`Under a uch conditions 0.1• epinephrine solution in
`aapula can have a shelf life of 5 yeara or •or e (19).
`The ab elf life in •ultiple-doae vial• and screw-cap
`bottles tenda to be aborter and •ore variable .
`Ophtbal•ic epinephrine aolutiona are ao•etiaea buf(cid:173)
`fered t o a h11ber pH than ia deal r able for opti•u•
`atability. Sterilizati o n by f i ltration o r by beatine
`a t ea•c for so •in cauaed no detectable deeradatlon
`( 20). Boric acid ia uaeful in ophtha l•ic for•ulationa
`because of l ta phyaloloeical c oapa t abillty ,
`l ta util(cid:173)
`ity for adjuat•ent of lsotonicity, and lt a f ortuitoua
`a tabiliz ine action on epinephrine (21,22).
`
`ADAMIS EXHIBIT 1012
`
`Page 445
`
`

`

`446
`
`Epinephrine
`
`REPBRBNCBS
`
`1. Un1ted States Pbarmacop•l• (20th Rev.), USP Con (cid:173)
`vention , Inc ., 1980.
`
`2 .
`
`f'b• lferclc Ind•z ( 1 Oth Ed . ), Merck and Co•pa ny ,
`Inc . , Rahway, New Jersey, 1983 .
`
`3. R . B . Martin, J. Pbys . Cb•• · • 16, 2657 (1971 ).
`
`4 .
`
`5 .
`
`6 .
`
`7 .
`
`L . C . Sch roe t e r and T . H i g u ch i , J . All . P b ar•.
`A•soc . , Sc1 . Bd . , 41 , 426 (1958) .
`
`T·. D. Sokoloski and T. Higuchi , J . Pbara. Sc1 .,
`6J, 172 (1962).
`
`s. Riegelaan and B . Z. Fischer, J. Pbar•. S c1. ,
`5J , 210 (1982).
`
`P . c. M. Hoevenaa r a , Pbar• . Weelcblad, JOO , 1151
`(1985) .
`
`8 . L . c . Schroeter, T . H1&ucb1 , and
`IL B. Schule r,
`J . All. Pb•r•. Assoc . , Sc1. Bd., 41 , 723 (1958) .
`
`IL
`
`T . Higuchi and L. C . Schroeter, J. Am. Cb•• ·
`Soc . , 82, 1904 (1960) .
`
`10 .
`
`L . C.Schroete r, Sal~rir D1oz1d•, P e riraaon Pres.a,
`Oxfo r d, 1966 , pp . 17 - 20 .
`
`11. S. Riegel•an and B . z . Fischer, J . Pbara. Sc1 .,
`6J, 206 (1962) .
`
`12 .
`
`B . R . Hajratwala , Drug Dev. Ind . Pbar•., 3, 6 5
`(1977) .
`l3. B. R. Hajratwala, J. Pbar•. Sc1., 64 , 45 (1975).
`I . P . Lee and H. Burton, Drug Dev. Ind . Pbara.,
`1, 397 ( 1981) .
`
`14 .
`
`15. F. Modrz e jewaki , K. Ko•orow s ka, and T .
`Nalolepsza, Par• . Pol•lc• , 20 , 33 (1964) ; Intern .
`Pb•r• . Abstr., J , 787 (1964) .
`
`ADAMIS EXHIBIT 1012
`
`Page 446
`
`

`

`rps
`
`Reference•
`
`447
`
`16. D. W. Newton, 8. Y. Y. Fun1. end D. A. Willia••·
`A.8. J. Bo•p. Pbara., 38, 1314 (1981).
`17. B. c. Nunnin1 and A. P . Granatek, Carreat Tber.
`R••· CJJn. B6l>·• 20, 417 (1976).
`
`18. G. H. Kronber1 and B. ft. Takaan, J. Pbara. Sc1.,
`62, 823 (1973).
`
`19 .
`
`P. Lund1~en and s. Strti•, Acta Pbara. Saec., 3,
`273 ( 1966).
`20. D. G. Sixaaitb, W. M. Watkin•, and G. o. Kokwaro,
`J. ClJa. BO•l>· Pb•r• .• 1, 20& (1982).
`
`21.
`
`J. N•rch and K. ••rch, Daask. T1d••tr. Fara., 39,
`117 ( 19815).
`
`22. N. Ha•nett,. J. Bo•J>· Pbara., 33, 70 (1978) .
`
`- Kenneth A. Connor•
`(Wlaconatn)
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`ADAMIS EXHIBIT 1012
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