`Volume 1
`Second Edition, Revised and Expanded
`
`Edited by Kenneth E. Avis,
`Herbert A. lieberman, and lean luthmun
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`AstraZeneca Exhibit 21 13 p.
`InnoPhamia Licensing LLC v. AstraZeneca AB IPR2017-00905
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`
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`
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`ParenterIal
`
`Sum Efiéfiimg “We mi Epndxnmfi
`
`KennAih E. AME
`
`The Univetsity of Tennessee
`Memphis, Tennessee
`
`
`’A As lIeernmu
`
`L @ 1.,
`
`'
`
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`
`5
`
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`
`K
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`.
`
`H.H. Lieberman Associates, Inc.
`Consultant Services
`
`Livingston, New Jersey
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`Lachman Consultant Services
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`Westbum New York
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`Marcel Dekker, inc.
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`New Yen-k A Basel 9 Hang Knng
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`AstraZeneca Exhibit 2] 13 ps 2
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`
`
`Library of Gangress Cataloging - in“ Publication Data
`
`Pharmafleutical dmsaga farms; paranteral medicatians / edited by
`Kenna/t1": E. Avis, Herberi A“ Lieberman, and Leon Lachman. M 21163 ed. .
`rev, anti expanded.
`En
`cm.
`
`Includes bibliographical references and inaax.
`ISBN G-82é%83’3$v2 (v. 1 : am. paper}
`1. Parenteral salutiens.
`2. i‘hm’maceutical technniagyfi
`Kenneth E.
`II. Lieberman, Havbert A.
`III.‘ Lachman, Leann.
`
`It Atria,
`
`[DNLMr 1* Infusimns. Parenteral. 2. Techmlegy, Pharmaceutical.
`WE 35:: P535;
`RSBBLPE'ENS 1932
`615’. Lia-"dew
`‘DN LEW 1'1}ij
`
`im- Library of Cungress
`
`91 »38053
`{ZIP
`
`This beak is printefi 0n acid-free paper.
`
`Cflpyright LC} 1992 by MARCEL IEKKER, INC. Ali Rights Reserved
`
`Neithar thii book my: any part may be repmfiucsd er trangmittad in any farm
`(it by any means, algctmnic m mechanirsal, inclufiing phatompyingt micrw
`filming, and regarding, m by any infarmatiorz manage and retrievaf system,
`withom permissian in writing fmm the: pnhtishan
`
`MARCEL DEKKER, INC.
`2‘20 Madiscnn Avanue, NW Yen-k, New Yark 10016
`
`Current printing (last digit);
`10 9 8 7 6 5 4 3 2 I
`
`
`PRINTED IN THE UNITED STA‘WES OF AMERICA
`
`Astraleneca Exhibit 2| 13 p. 3
`
`
`
`Confiaemtg
`
`I’refaae
`Cantributora
`
`Cantams cf Phavmaeeutical hostage Emma: Parenteral Medicatians,
`Sewncfi Editiang Revisad and Expandad. Valumes 2 and 3
`Cantents 0f Pharmaceuticzal Bflaage: Farms: Tablets, 852mm: Editicm,
`Revised and Expanded. Valumes 1*3
`(laments af Pharmaceutical Baggage mes: DiSperse Systems,
`Vulumes 1 and 2
`
`iii
`xi
`
`xiii
`
`3W
`
`xvii
`
`Chapter 1
`
`The Parenteral Bewge Farm and 11:5 Hismricgtl Davelapmant
`
`1
`
`Kenneth E. Avis
`
`I. The Dasage Farm
`II. Histary Bf Parenterai Medicatians
`flippemfix A: Glossary of “Karma
`Agapandix 1E3: Highiigghts in the Rigatm‘y of
`‘Parentewl Meclicatians
`References
`
`Chapter 2
`
`Parenteral Ilrug; Adminigtratmn: Routes, Ereeautiuns,
`Emblems, Complications, and Brug flelivery Sygtamfi
`
`Richard J. Duma. Michael J. Akin-‘3. and
`Saivmare J. Tame;
`
`Intraductimz
`l. Generai lnciicatiana for Parenteral
`
`Administration :31" Drugs
`H . Pharmaceutical Factars Affecting Parenteral
`Administratifin
`
`UL Specific Relates of Administratiun
`IV. Distribution 63f Farenterally Administered Agents
`
`1
`4
`12
`
`1%
`15
`
`17
`
`1 7
`
`18
`
`19
`
`21
`3‘3
`
`vii
`
`Astraleneca Exhibit 2113 p* 4
`
`
`
`viii
`
`Cantrnts
`
`Vr
`
`Freeautiens, Prablems, Hazards, and
`
`Campiirations Associated with Parenteral Drug
`Afiministratian
`
`VI; Methods and Devices for Drug Delivery Systems
`VII.
`Summary
`Raferencas
`
`Clzaptar 3 Bimpharmaceuties af Injectable Medicatians
`
`Seal Mamie
`
`I.
`
`II.
`
`Intrfiductifm
`
`Physiwchamica}. and Physiaiagieal Faewrs
`Afircting Drug Absmrptian by; Inferticm: An
`Overview
`
`IV.
`
`I11. Applicatinn 13f Pharmacakinafias to Biogharmw
`cautic: Investigations: Pharmacokinatic Madam
`Examgglas at" Bimpharmacautic{Pharmawkmetic
`Prinuigales
`V. Regulamry Consifierstians far Bioequivalenca
`Studies;
`
`VI; Biaequivalence Study @f Twm Inimitable Farmg
`0f the Same Drug
`Summary
`References
`
`VII.
`
`Chapter 63
`
`Prefarmulation Research 9f Parenteral Medicatians
`
`5'0? Mamie} and Shreeram N. Agharkar
`
`I.
`
`Intrudnctian
`
`II. Drug Substance: Phyaicachemiéal Properties
`III. Acuaieramd Stability Evaluatinn
`IV. Gangral Macias 0f Brag Degraflafiun
`V,
`Prefurmulation Studies fur Framing and Peptides
`VI.
`Prefarmuiation Screaming cf Parentrm]
`Packaging Compnnema
`Summary
`VII,
`VIII. Prefarmulatien Worksheet
`
`References
`
`Chapter 5
`
`Formulatian of Small Volume Parenterals
`
`Patrick P. DeLuca and James C. Boylcm
`
`I.
`
`introductian
`
`II.
`Farmulation Principles
`
`III. Cmntainer Effecta an Farmulmicm
`
`IV Stability Evaluatian
`V.
`Pracesa Effects
`Referéncas
`
`41
`
`49
`56
`5'?
`
`59
`
`59
`
`$0
`
`??
`
`993
`
`1138
`
`189
`111
`112
`
`115
`
`1 15
`
`118
`1%
`150
`1551
`
`1.58
`163
`1&3
`
`169
`
`1?3
`
`173
`
`1%
`22'?
`
`23%
`244
`245
`
`Astraleneca Exhibit 2] 13 p. 5
`
`
`
`Contents
`
`ix
`
`Chapter 6
`
`Formulation of Large Volume Parenterels
`
`Levit J. Demorest and Jeffrey G. Hamilton
`
`I.
`II.
`III.
`IV.
`V.
`
`Introduction ‘
`
`Concepts of Formulation
`Formulation Development
`Solution Quality
`Summary
`References
`
`Chapter 7
`
`Parenteral Products of Peptides and Proteins
`
`YuHChong John Wong
`
`I.
`II.
`III.
`IV.
`
`V.
`
`Introduction
`
`
`Characteristics of Proteins and Peptides
`Formulation Principles
`Compatibility with Packaging Components and
`Infusion Sets
`Formulation of Market Products
`References
`
`Chapter 8
`
`Sterile
`
`Diagnostics
`
`Leif E.
`
`Olsen
`
`Introduction
`
`II.
`III.
`IV.
`
`VI.
`VII.
`
`Diagnostic Products Defined
`SteriIe Diagnostics
`Definitions
`
`Aseptic Manufacturing Considerations
`Validation Program
`Conclusion
`References
`
`Chapter 9
`
`Glass Containers for Parenterals
`
`R. Poul Abendroth and Robert N. Clark
`
`1.
`II.
`III.
`
`IV .
`V .
`VI .
`VII.
`VIII.
`
`Introduction
`The Nature of Glass
`
`United States Pharmacopeia Glassware
`Classifications
`The Manufacture of Glass Containers
`Chemical Performance
`Mechanical Performance
`
`The Container and Closure as a System
`Quality Assurance
`References
`
`249
`
`249
`250
`273
`280
`281
`281
`
`283
`
`283
`284
`302
`
`310
`312
`317
`
`321
`
`323.
`321
`322
`325
`330
`351
`359
`359
`
`351
`
`381
`381
`
`362
`369
`375
`380
`380
`382
`384
`
`AstraZeneca Exhibit 2113 p. 6
`
`
`
`:-
`
`Canlents
`
`Chapter If) 05% 0f Plasticg for Parentserafi Packaging?
`
`Jahn M. Ana's. Raher‘t S. N339‘ and
`Charms H, White
`
`Intmductimn
`I.
`Fundamentalg
`II .
`III. Fabricatian Pmcesses
`
`Imgortant Criteria {car Selectian 0i” Plastics
`IV.
`V. Plastics Used in Parenteral Packaging
`VI. Quality Assurance of Parentera? Contaiflew
`Raferences
`
`Chapter 11 Elaatameric Cifisures far Parenterals
`
`Edward J. Smith and Robert J. Nash
`
`I. Elagtomeric Parenteral Packaging Companents:
`A Physieai Descriptmn
`Phyaical Dessrigtion (sf Rubber
`II.
`III. Typas :35 Rubber Usaci in Parenteral Packaging
`IV‘ Ciasura Besign
`V. Rubber Campuunding
`V1. Vulcanizatinn Franzen
`VII. Closure: Manufaczture and Contra!
`
`{Ensure Eesigfi Qualifieatian
`VIII.
`1X . Regulatory Qansifietatims
`X .
`Intarantiun {if 13mg Farmmatiuns with
`Rubber Clasures
`
`XI. Cmntgmpm'ary Closure-Related Issues
`References
`
`Chapter 12 Pamnmra: Praducts in Hospital anefl Heme Care
`Fharmaey Practice
`
`Jam: W. Levchuk
`
`l.
`
`Introdumifin
`
`II. The Frepawfiinn {3f Sterile baggage Farms in the
`Haspita} and in Rama Care
`III. DiSpensing and Comgounding P‘mcessas
`IV. Tenhnolug’y 3f Sterile Cnmpaunfiing in the
`Hmspital thmaey
`V. Clinical: Supply and Use at“ Sterile product&
`VI. Qualify Assurance
`V11 . Canclusien
`
`Appendix: Abbreviated Sequence for Preparing 5-1
`Sraries of Extempomnmuglgr Campaunded LV.
`admixtures
`Refemnces
`
`~
`
`Index
`
`387
`
`38?
`. 339
`393
`
`($07
`422
`c139
`4&3
`
`1145
`
`445
`450
`451
`462
`483
`£170
`4'77
`
`€394
`583
`
`$05
`
`58‘?
`508
`
`513
`
`51 3
`
`513
`52%
`
`532
`547
`552
`5&2
`
`563
`56%
`
`569
`
`Astraleneca Exhibit 2| 13 p. 7
`
`
`
`
`
`Biopharmaceutics @f
`Elnjectbatfle MedEcations
`
`Scat Mtflflia"
`
`Whitehall Labor‘mmries, Hammmnmn, New Jer’my
`
`I.
`
`iNTRQDUCTIDN
`
`Biopharmaceutics is the subject in pharmaceutical sciences that examines the in~
`fluence of physicachemiaal changes in drug and/Car farmulhtimn design on the ab»
`sorption of airtight
`(liver the last three decades, this area a? reaearch has 9"
`merged as cane at? the mast influrantial feactmrs in guiding the dévelopment 63f gharv
`maceutical (image forms. As a result, ihél‘fl has Man a rapid increase in the
`number at“ heientific publicatimhs and textbhhhs on this subject. Pharmacy
`schema thmug‘hout the warm new include hiapharmacautics in bath undergratt
`mate and graduate pmgmms. Mareaver, practical}? every new thug pmduct in~
`trhduced during this period has been} designed based on bitnphmmhceutical data.
`Tm date. most hiapharmaceutical inveStigations have been in suppart at“ or»-
`allgr afiminiatarad desage farms since they are the preduminant QHES usad in mu:w
`rent therapy. Althuugh there have been a significant number of studies reparted
`an the rates of ahsarption. distfibutian, metahafism. anti excretifim of parenteral»
`1y administered drugs, only a few have beam designed to alucidaw which pram
`ertieg of the tnjectian formulation (or injection site influence these rates. The
`Danish pharmachlogist Schau was: cane of the first ta stutty extensively the
`phyhimmgical factors that influence the absorption 9f mugs {mm subcutaneous
`connective flame.
`In a 12361 review article [13, he czitescrihmi¥ tram a pharma-
`cotmgieal viewpoint, haw the rate 01" ahgarption of subcutaneausly administerefl
`hormanes and aruga mum be altered demanding an the effect the injection hem
`can the physiomgiaal conditinn 0f the: cannective tissues, the capillary membrane,
`and the capillary bland flaw at the huhcutaneans site.
`During? the same year, Wagner { 2] reviewed the literatum comprising the
`discipline that had just: been coined biopharmaceuticg by (Earhart?! Levy. He re~
`viewed impartam physiaeuchemical meters influeneing mug ahaarptinn fmm
`variaus madea {Itf administratinn. Besideg cmrectly predicting the impartant
`
`.4!
`
`Current affitiation: Wyeth-Ayerst Lahoramrim? Racimr, Pennsylvania.
`
`59
`
`Astraleneca Exhibit 2] 13 p. 8
`
`
`
`36*
`
`Ma: mm
`
`tale this disciyline wauld serve in the future 9? ylaarmaey, he auggasrad many
`of the areas far study that have influenced biapharmaaeutical investigatians an?
`injectable dosage forms.
`Ballard. apmied this infarmatien ta research on intramuscular injectians
`and, frail} a pharmacauticai viewpoint, yuhlishefi an influential raview article
`dealing with biayharmaeeufieai factars influaming intramugcular and subcu-
`taneaus injeatians [3] . A1th0ug‘h interest continues in this area at" research,
`{as mated by periadie rafiews Hr?) . relatively little new basic infarmaticm has
`been uncmverefl, leaving mam for mare in»de;1th studies.
`Nat Icing aga, mugs, administewd by injectian were assquéi t0 prwvme
`rapid and campleie absm'ptmn, yarficulafiy when wmparafi t0 mall admirfistra»
`tian. During the last 39 years, this assumption has been shown not always :9
`be true. These findings {3* 13] , caugled with mare numemuss axamgies {31‘ in-
`campleta absarptiun fmm Qral dosaga farms, have stimulated reseamh m1:
`(1} drug absurptifln ané haw it is affrzgcted by the design mi” the dusage farm
`(biapharmaceutics); (2) the extent t0 which {bugs are hialggicafiy avaiiahle
`t0 the mam stream relative m the anmunt marsinismrefi {binavailabiiitwg anti
`
`{3} the rates ané extents tea which drugs are absnrbad, distributes}, metahm-
`ligad. and excreted by the: bady (pharmawkjnetics);
`The aim 03? this chamar is to gmvicie the farmulator 63f inieetahla medica»
`titan with a bash undemtanfiing {If the majar ghysiémhemiaai «and physiamgiml
`mama's cuwenfly cansidared “ta play an impurtant male in influencing gammy
`than at” drug‘s administerefi by injefltiun. Selected tapies in pharmawkinetiea
`will be cavered pyimariiy ta demunstrata their utility in the: anaiyais af bia'
`phm'maceutical experiments. The OVQI'QH gaal i3 fur the farmulamr t0 he ahie
`ta apyly this knowledge in designirxg; injeetahle deaage fwmulatians that will
`gravide @redifltable drug dalivary m the patient.
`
`11. PHYEWGCHEMICAL AND PHYSIOLQGECAL FACTQRS AFFECTING
`GRUG ABSQRPTIQN BY iNJECTlC‘N: AN UVERVWW
`
`An intravascular (intraveneeus) inieetian places; a (hug directly inm the b100d~
`Stream, bygxasaing wnvantit'nal phyaicmhemiaal and physiolagical influences.
`Injectian 631’ a drug intn an axtravascuiar site (all others) leads t0 the initiatinn
`0f events that caliectively maxim up :he absorption @FQGQSS. Bepending {m the
`type 9f farmulatian administered, varying degrees of a delaot are established.
`Eventua] drug aésurptiun intc; the bloodsfmam is: influenced by several physica-
`
`chemical and ghysiological faetars, the two cansifiemd mast imper‘tam being
`passive m‘ffuaion and mead flaw [iii-13] 1 The relative importance cf these
`facmm depandg (m "the capmary bed await}; at the iniectian site, ma phyaicai
`farm nf the drug, anti the arug's molecuiar size.
`fiance an exmflina’tion 0f
`these and other influential physieoehemical and phygioiagica} faemrs is impel?“
`tant in gal‘aviding the pharmaceutieal formmamr with infarmatian that can be
`used to damsign farmulafions yielding acceptable absarptian aharaaterisfics.
`
`A. Physicachemica! Facmrs Affecting Drug
`Absorptmn by Injection
`
`As stated, no absarptian meg; is necessary when a drug; is afiministered direct
`1y mm the blmadmmam; therefnre. them are no phyaimehemical factars to
`
`Astraleneca Exhibit 2113 13* 9
`
`
`
`Biflphcmmtmsmiéas of Injectczhle Medicarian
`
`61
`
`affect at Eat'ytitszt. Drugs given his; extravascular injectian require an ahsmp»
`tion step befare they hat: enter the bleedstt’eam. Even drugs that are aflmiw
`tattered by the tutti-3.5mm} (intrathaeat) and intraharéiac Nantes and are in very
`class pruxtmtty tn the htoxtdstream mutt first underge meal Fanatrattan and
`parmeatiun and than panetrate 19:31 capinarias in artist: to reach the bimodd
`stream. at flthat‘ axtravascular sites, such as intramusaulat‘, suhautahaaus,
`and intratlermal, the: {thug is expased ta 3 reiatively await lflcalizatt regitm.
`Fran} auch t‘egians, the (thug; travels to the bland or lymphatic circulatimt
`{01113: far highvmhlecularwwight mater-states} by means at physiea} yenetration
`and permaattan praehsses which are assuuiateati with passive diffuathn and par“
`titieantng thmugh the capiilary mamhrane and mm tlta hlcwtstt‘eam.
`
`Drug Solubility
`
`A majar Erhysitmchemieat criterian far absorhticn by passive diffusien and par“
`titianing is cirug seluhilit‘y‘ Regardless at the dhsaga farm afiminiatered, a
`drug must he in mluttart in an aqueous systam fflr it ti: he expasatt ten pmces-
`$25 that will eventualty resutt in 33.5 absorption mm the hlcociatraam.
`$31113;
`the fracttmt at drug in satutian is; availgthle for ahaorptiun. Drugs that remain
`in shtuticim at the injectttsn Sim are generally absmhazt quickly and easily, all
`other influencing; facthra hating camtat‘st.
`A critical diffarenee hatwattn the pH 3f the administered drug solutien and
`the physiolegtcal 53H at the injectien site {audit}? shiuhihty of the drug in a.
`casclvent vehicle and in physihlugica‘l tissue fluid} can cause an ungraatteted
`decrease in. ahsarption due tea precipitation «of the drug at the injaettan Etta-t
`Phenytcin, a chmmerciaj brand of diphenylhydanmtm is a very insaluhle free
`acid and. is fhhmulated as; the Stadium salt in a talution sf 40% yragylette 3131001;
`10% aleahel, and water far tnjectian. Thg pH must he adjusted w pH 12 with
`shtiium hydraxide ta sciuhtiize the Ctr-11g. Than propyiene glycol helps ta 391w
`hiltze the tree mid fractihn available at this hit. When intestafl trite muscle
`tissue the large diffarenee in 9H causes canversien cf the satiium salt ta the
`less gamble free acid which hracipitates in tissue fluids at the injectian sites.
`Simultanequs (iilutian flf ttm prahythns glymt with tihsue flaw cantrihutas ten
`free atria precipitatiana Mast 0f the drug is therat‘m‘a avatiahie unit; stewiy,
`depending: gredominantty 0n the dissalution rate flf {tighenythydantain crystats.
`Thua campleta ahsm'ptiwn takes 4 ta 5 days [1121‘ Similar reductions in hic—
`attatlahility (tut: t0 drug precipitatimt chused by pH and saluhility changes
`have been repurtad fur Diashpam Injecticm [11} , Ctflwfiiaaegmxide Injectian
`[12] I, and Digaxin Injactian {13] .
`
`Passive Diffusimn
`
`Passive diffusion invmlves the spamaneous mavemém 0f solute maleculet-B in
`32311113011 fmm an meg hf higher mneentrafion on rme sirie Bf a samipermeahle
`membrane t0 an area of Iawer moncentratihn on the other Side Of the membrane.
`
`{:1 the hiamgiczal system, a cirug in scalution passes from the extracellular t0
`the intracellular tiSsue fluids. by passive diffusisn.
`The rate of passage {3f a (thug thmugh a hioicgical membrane by passive
`diffuhian is affected "by several physiemhamical factcars, such as concentratian
`gradient, Fartiticm coefficient, 332mm;hh‘titm‘:g macromniecmar binding, and 05*
`molality. in additian ti} flifferences in physical form at {ht-3 macfitzatifln.
`
`AstraZeneca Exhibit 2113 pt 10
`
`
`
`62
`
`Motolo
`
`Concentration Gradient. The rate at which a drug molecule crosses a semi~
`permeable membrane by passive diffusion is described by Fick's law, expressed
`by the following equation for the unidirectional case:
`
`g3 - DA‘IC1 w CZ)
`
`dt
`
`i
`
`(1)
`
`where
`
`33% = Flux or amount of transfer of Substance per unit of time
`D
`" diffusion constant
`A
`-
`surface area available for diffusion
`
`Cl = concentration of diffusing substance in extracellular fluid
`02 2
`concentration of diffusete in the intracellular fluid
`9.
`=
`thickness of the membrane
`
`For any particular membrane where A, end it are constant, the diffusion rate
`is controlled by 9(01 ~ C2). The magnitude of the diffusion constant B is in~
`fluenced by the physicochemical properties of the drug molecule and the char”
`acteristics of the membrane.
`
`For any given drug in it contained in vitro system, the rate of passive
`diffusion is controlled by the cencentration gradient (C 1 ~ Cg) that exists be—
`tween both sides of the membrane. The rate at which drug molecules move
`from side 1 to side 2 will decrease as the magnitude of C2 decreases and apprw
`aches C 1i When 01 equals 02 the system is at equilibrium This is described
`mathematically as follows:
`
`me no)
`legwl2
`
`gel
`(it “D
`
`(2)
`
`(3)
`
`However, the concentration gradient (C1 - C3) does not become a rate-limiting
`factor in vivo because of unidirectional movement of the drug through the
`membrane.
`In this case, as the drug reaches the other side of the membrane
`it is removed by the blood, leading to distribution, metabolism, andlor excre-
`tion. Therefore, Cl remains considerably greater than C2 at all times until
`the transfer is complete. This is referred to as a "sink“ condition and Bones
`tion (2) reduces to
`
`m__ M
`
`(4)
`
`Partition Coefficient. The distribution of a solute between an aqueous
`
`environment and a. lipid membrane is analogous to the distribution of a solute
`between two immiscible solvents such as water and oil. This type of distribu~
`
`AstraZeneca Exhibit 2113 p. 11
`
`
`
`Biopharmaceutics of Injectable Medicatian
`
`£33
`
`tian, aaflad partitianing. plays an impartam role in passive diffuswn. The
`equatian that describes gaartitimui‘ng is:
`
`(2
`Partition coefficient (PC) = K s: 33
`b
`
`(5)
`
`where , by canvention ,
`ca
`:
`cancentration {at salute in the Gil 2231' lipid phase
`at:
`:- concentration 13? naniunized salute in the aqueous phase at a dew
`fined pH
`.~.~ partitian cmefficient
`
`K
`
`The influence 9f the partitian eaeffieient £311 passive diffuaian 3f .3 drug through
`a biolagica} membranea- can be illustrated by censicitaring the relative transfer of
`drugs with high arid 10w partitian cmefficientsn. A drug with a high partitiwn
`coefficient amid saluble) will pass readily fmm the agueaus phase intu time
`membrane, whereas one with a law partitim: coefficient {water gamma} wflj
`remain in the aquemus pham and net pass appreciably mm the mambmne. As
`stated earlier, in a biulegiea} system. diffusiun takes piazza 5.3 a uxfidimctioual
`process; this is aqually true for the pracess of partitianing. The drug with
`a higher yartitian caefficient will exhibit a higher ram {sf diffusium 2:101de
`Thus ligidwsaluble drugs are abserbéd £1116 distributed mQre rapiefily than are
`watgrwsmluble drugs.
`
`innizaticm Whereas partitiwning 61’ neutral malgculee takes place in reia~
`ticfm ta their Gil-water solubility, this is neat true far ionized drugs.
`Ianizatian
`has a grufound effect can drug ahsnrptim. diatributien, and excretiam. The
`degree of innizatian af an acid 9r base is detarmined by the ionization canstsant
`at? the campcaund, pKa, in additinn t0 the pH , temperature, and innit: strength
`3f the solutiaan. Since in a biulflg‘iwl system temper-Mum amfi imnic Btregngth
`are essentially canstanta their influence can be neglected.
`The ralatiunship between pH and pita can be readily seen by the follzswing
`derivation.
`In water, a weak acid, RA. “signifies (or dissaciates) according m
`the fallowing equatian:
`
`HA + new -«= 1430* + A”
`
`The equilibrium canstant far the reaction is written conventionafiy 5:35
`
`[330*] {A1
`"eq = W
`
`(a)
`
`,
`"”
`
`Since the molar cancentratimn 01? water (55.3 mal liter"1 at 35%;) is much larger
`than any mf the ether values and remains essentially mnfitam during the ram»
`titan, one can write
`
`[H303 m1
`Kaq [H23] = K1011 t W
`
`(3)
`
`AstraZeneca Exhibit 2113 p. 12
`
`
`
`64
`
`Mctcfc
`
`Taking: the logarithm cf bath 51'.ch cf Equaticn (8) and trancpcsing lag Kicn
`and 10g {Eggpfl tc cppccitc sides yields
`
`-
`
`+ n .,
`10g [H30 }
`-—
`
`.-I_A:_1
`10g Km“ +13% [HA]
`
`(9)
`
`Zly employing ccnvcnticnal definiticns for pH and Erika, Equation (9) ncccmcs
`
`, Mr!
`_ .
`pH wpKfl 4-1ng
`
`W
`(10)
`
`Equaticn (10) , kncwn as the Benderscwi-iaccclhach cguaticn. is very useful
`in predicting the inniznticn pmgcrticc cf weak acids. and bases, garticulcriy
`with rcsgicct to their ability in partition infra lipicis.
`A similar cquaticn dcccfibcs the icnizaticn of a weak base, but by canvcm
`tion, the rcacticn is written as the icnization 0f the: prctonatcd weak huge. EH4":
`
`391*" + can} 13 4- H20
`
`yielding
`
`2
`
`gal-I w pKa + lag
`
`
`[E]
`
`[BN3
`2
`
`(11)
`
`(12)
`
`when; the symbcl 13K decignates the: ianizatian 0f the prctonatcd base-
`Several whviaua gut imgortant relatiflnships between pH and pKfl can be
`seen thmugh inspecticn cf Eguaticn {Iii}: pcfliculcriy as they affect partiticnw
`ing:
`
`1.
`
`thn the ccnccntraticn cf acid [Hm equals the ccnccntraticn cf the
`anion [A'] in a sclution ci‘ a weak acid, thc ratic [A‘UEHM = 1. Since
`
`10g 3‘. == 5}, pH 3: Mia.
`2. The degree; cf icnimticn of weak, acids and Bianca changes rayidly as
`the difference between 1:23 and [Mia bcccmcs greater anti} thc 9H value
`«of the scinticn is 2 units away fmm pica, at which time further changes
`in pf! haVc little effect on the degree cf ianizaticn cf the acid air base.
`This canccpt can be easily dcmcnstrctcd by rearranging Equation (ll)
`turn the fem
`
`*‘
`pH pKa
`
`:
`
`
`claw}
`10g[HA1
`
`(13)
`
`and examimng the difference in the ratio lag {3‘1 Him} as the differ—
`ence, @H - 193:3" gees through changes frcm 2 tn {3.81 as shown balms:
`
`
`“
`_
`[A‘]
`pH PKa m leg {HA1
`
`2
`
`Ionized form MS]
`
`== 138
`
`Ncmcnizcd form [HA1 2
`
`1
`
`1
`
`IE)
`
`1
`
`E}
`
`'1
`
`[3.1
`
`1
`
`£3.01
`
`1
`
`1 10130
`
`Thcrcfcrei if there were a 3 unit difference bcthc-n pH and 9K8.
`cue wauifi (1111;: see less than a 1% further change in ionization.
`
`AstraZeneca Exhibit 2113 p. 13
`
`
`
`Biopharmaceuties of Infactabig Medication
`
`65
`
`3. Whgn dealing with ionized and lienianized forms at“ a drug, the rela~
`timship to lipid suitability and partitiim inefficient becomes apparent.
`The neutral {namunmeéj} fraction Elf the <1ng is inure readily parti~
`tinned init} the nanpalar ligicl membrane. During yartiiiuhing (if the
`nanianiaati molecule the fractimn of remaining ionimd drug mpidly
`eQuflihrates 80 that norfianizeci drug is again farmed and available £01?
`partiiianing. This dynamic pix-Guess takes place until the entire drug“
`partitions through the membrane.
`
`When the pH of a medium causes most at" the drug to be in the ianizecl farm
`(alga. , medium [3H s 7 for an acidic drug with piia : 5) , slow alasclrption can
`be expecteti since the partitianable nanicanizeci farm ehnstitutes anly a small
`fraction {if the total drug, less than 1% in the case abave.
`A rank Qrder demonstraticm 0f the effect of medium {)H and drug pKa on
`Eartitioning is shawn by the fallawing hygpothetical examgle. A beaker can"
`mining: a buffer selution is separated equally into two campartments by a Sam?
`permeable lipid membrane (3% Fig 1) that alluws only the nonitsnizad weak
`acid (Elia == 5) to pass thmug‘h. A quantity 6f the weak acid drug is dissalved
`in a negligible mlume @f buffer solutim; the solutimn is than quialily injected
`mm the left campartment, resulting; in El hcmeg‘eneaus saluiiiin in that cmnpart'
`merit.
`
`After each equilibriiim partitianing step takes glaze (Le. , HA par-tithing
`thrwugh thil" membrane, leaving A” and H“? hahinsi) , the buffer salution on the
`right side of the membrane (Sirius: beauming enriched with HA) is replaced with
`fresh buffer. The spacias N on the left side reequilabrateg with 3"" iii farm
`more HA and the pmeass is mpéamfl until eventually all the drug is pariitianefii
`as HA.
`
`Referi'ing: in the I—Ianeieman—Hagselhach equatimn [qu (10)] . cansizier the
`following ”Ewe cases, which will demonstrate the effect 91‘ pH and {3K8 0n partiw
`tioning.
`
`
`
`Figure ‘I Beaker cantiiining buffer solniicen in which a semipermfiiahle lipid
`membrane gepamies the sniutinn intm two compartments. Weak acid HA placed
`in the left sicie equilibratea awarding m EQ uatien (6), allwwing wnly HA t0
`pariitian through the membrane.
`
`AstraZeneca Exhibit 2113 p 14
`
`
`
`55
`
`Mfflifllfl
`
`Case 1: Buffer salutian on thh sides 9f the membrane at pH 5.
`
`In this
`
`case Equaticzn (16:!) indicate that lag [A"}I[HA] a 1; thus [AC1
`== [HA].
`
`Thus 50% at“ the mtg; weak acid is in the neutral fm‘m HA, able ta partitifln
`tthugh the membrana. The remaining ignited pertien, A”, is unable t0 pal”
`titican intc: limit.
`The hypethatical graffiti: for the system, based an the gareent of HA re~
`mafinirzg in the left: campartment versus the number 01‘ aquilihratians 53nd buf»
`fer solutitm replacements 9f the right comgartmenti. is shown in Figure 2. At
`pH 5 following fmur ecgmlibratims, only 5% A" remains in the left cnmgaartmem
`(aypmximataly 94% of HA has partitioned).
`
`Case 2: Buffer anlutimn in both compartments at E3“ ?. Equatifln (10)
`new indiuates that lag [if] I {HA1 1 1%. Substituting; these
`values into Equation (ID) yields
`
`7m5+1€3glgg
`
`Therefme anly 0:353 0f the 1:01:23] drug, HA + A“ , is in the farm
`HA, able to be partitimned.
`
`The hypmhetical pmfile for this system under the conditians stated is shown
`in Figure 2.
`In this case at pH ?, after four etauilihraticms 95% HA remuns in
`the left campartment amt: only 4% has been able t0 partition thmugh the mem~
`brane. Since 0. 99% 0f the ammmt of HA present can gartition during each
`equflibratiun, we can calculate that it weuld take 95 equilibrations (he. ,
`9M3. E39) ta partitiun the same amount at“ HA 515 was partitioned, by faur equiliv
`bratians at pH 5 in cam I.
`
`
`
`EQUIUBRXXTWNS
`
`Figure 2 Hypotheticai cage (31‘ camparativa partitioning versus number of @thilb
`brations for weak gem HA 031% 5), par‘titimning through a lipid membrane
`from buffer aulutimns at pH 5 (Q) and pH 7 (fl).
`
`AstraZeneca Exhibit 2113 pt 15
`
`
`
`Biapfzarmflccutics {if I njecmhle Medicatian
`
`6?
`
`These examples are meant tc sum the relaticnahip betwcen inrmulaticn
`pH, firug pig; and the amuumts of gartiticnabie naniunized weak acid 01* weak
`base species available fur absoruticn frcm an injeciabla scluticn flusage farm.
`
`Binding 10 Macmmulecules. Biological fluids ccntain macrcmcleculcs such
`as pmtcins which may have affinity fur certain drugs“ These macmmciecifias
`are generally- was largc 10 pass through biclogical membranes by filtration,
`ncr dc they have the lipid scluhiiity requircci fur passive aiii‘fusian. Therew
`fore, they are canfincd within their immeciiatc bcunziaries. When a drug be-
`ccmes adscrhcd stir campicxcci cm Such macrcmclcculw, its effective “free“ (3031*
`centraticn of diffusablc farm becames lowered. The equatiun describing this
`reacitcn is
`
`‘3}
`firug + macmmalccule M drug * macrcmmecule 0531113312}:
`1"2
`
`where
`
`k1 =1 atiaarpticu rate ccnsta’int
`k2 : descrgtiun rate attractant
`
`The] equilibrium constant is then cxgzresscd as
`
`K m {drug -— macrcmclecule]
`'- {drug] {macmmciecule}
`
`(1%)
`
`(15)
`
`where K, the associaticn constant. presumes a quantitative measure (3f the
`affinity mi“ the :irug far the particxflar macmmaieculc‘ Significant binding to
`macramciecuias such as serum protein reduccs the ccncentratiun cf frec drug
`in the. tissue fluids and hence reduces thc rate 0f passive diffusion by luwer~
`mg the cancentration grafiicm in acccréiance with Fick’s law [3%. (1)] . Since
`binding." is an equilibrium {Bracers and thus readily rcrersible, thc drug can
`eventually be dammed,
`It is impmrtant tc ncte that pretcin binding reduces
`the rate (if {)asaive ciiffusicn but (1083 not prevent it‘ Pratein binding has a
`significant effect on passive diffusian when the drug is bound by mere than
`33% because the desmrpticn ratc fI‘QIIl the drugwpmtein complex is usually slow-
`er than the diffusion rate 0f the drug through membranes.
`
`Dsmmiaiity. A salutiun is QSGDsmotic with tissue fluid when the tatai num~
`her 01‘ dissalveti particles in the; twc systems are equm.
`In general, injectable
`precincts are formulated to be ismsmctic m reduce the guauibiiity cf irritation
`that cam result if agmutia differencca between tissue fluid 91* red £31on cell
`
`cantenta and the iniecticn product are great. The effect of large differencea
`in mlutiun osmmlality an pausive diffusiun can he dcacrihed by cansidering the
`fallewing canfiitians;
`(l) hypmsmmic, (2) iscosmotic, and {3} iiyperusmctic.
`When an injecticn sclution is hypaosmctic. it contains fewer salute particies
`
`ihan (ices the tissue fluizii Bascfi cm the law cf osnosis, salvcnt games frcm
`
`a regiun of lawer concentration of solute t0 (me cf higher concentratien it: re-
`duce {ha prescure differentiai caused by the dissolved solute particle imimiance.
`Therefcrei the extravaascular injecticn of a grossiy hypucsmctic scluticn
`wmuid cause the movement of fluid away frum the repcfiitory injectian aim.
`1n
`
`AstraZeneca Exhibit 2113 p 16
`
`
`
`68
`
`Mamie
`
`this case, the apparent concentratign 0f drug wmult‘i increase, resulting in an
`increase in rate at“ passive diffusimn. Cunwraalyg the extravaamdar injectiun
`
`(3f a git-assist hypermsrmtic solutian causes an influx at fluid to the repasitm-y
`injectian site, resulting; in dilution {If drug cancantration and an agparent de-
`erease in rate (if diffusicm.
`Inamasing the uamolality at atmtiine mlutions Lay
`the additian Elf aithar pmlidnxine ehlm‘ide 0r sadium chloride led ta an appar»
`ent reductiun in intramuscular abStDrptian, determined by ita «effect an redur
`timn at heart rate [UL When an ismsmutic salutian is injected, there is 110
`
`fluitfi flux either ta; or away fmm the iniectian site, hence n0 demenatmble
`effect an passive diffusimn.
`It is important to differentiate between the terms isotanfc and ismsmatie.
`They are synonymoua anty when the tiissmlved solute cannm pass thmugh
`membranes 01‘ red blueci cells. Hmwever, when such passage times mount, as
`with aquaaus aaiutiuns of urea, mammal, m- heric: acid, the salution acta as if
`it: were pure watar and bath salute and salvgmt pass thraug‘h the membrane
`intu the mat blamt sails; causing them to await and burst {hemalysia} . The
`sviutim was cansitiered isutonit’: based cm saciium chlm‘itie equivalent calculav
`titans m as datarminaé by its freezingwpmnt detiressian; hawewar! it was ac»
`tually hypatanic 0r hygmmsmotic with respmt t0 red blatant cells. The term
`iaatanic 511011143. be used only to describe salutions having equal osmotic pres-
`sures with respetzt ta 5; garticutar memm‘ane. Therefme, it is imgartant ta
`examine the asmatic bahavicr at new tirug substamea toward. refit bleed cells
`mature deciding whether an adjustment is t0 be matte.
`In order to make an
`isacizamatic aqua-(ms salutiun (if a nanosmcatic cuntributing substance such as
`urea, an external agent such as sodium chlorida, sarbitoi, or other emetic
`pmfluaing substance mugt be added at its ismmnic level. such a5 0.9% sodium
`chinricte.
`
`£631“ the; sink canditian (Cg = I) it
`Volume Df Enjectian. 1’er F‘ick's law,
`was shown by Equatian (4) that «it; hit 2 Kij When the vmiume V1 of drug
`aalutien at the absorptigm site remams Hearty mnstant, the rate of passivg
`diffusian will be equal m
`
`A
`9:11,; w.
`'4‘.
`at w—th
`
`(it)
`
`where A1 is the ammunt at? drug at the site at any time. Thus the diffusion
`rate is inversely propertmnal t9 voiume V1, and absmptmn rates should in—
`crease when volumes tiecrtease {3] . Smaller injected valumfis have began re««
`ported ta enhance drug absorptiezm {18! . Anfithél‘ way at expreafiing this is
`to consider the rattan 3f tissue sutfaee area m volume of injectitm. An increase
`in injection volume with a relatively cenfined area regatta in a towering 0f the
`tissue surface area—twvulume ratia. Sinm passive diffusion is directly gren