Parenteral Medications
`tlolumet
`Second Edition, Revised and Expanded
`
`Edited by Kenneth E. Avis,
`Herbert A. Lieberman, and Leon luchmun
`
`
`
`
`
`Serumconcentrationimuu,-me;
`
`40
`
`Ed 0
`
`M O
`
`—I O
`
`O
`
`
`
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`
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`_L
`__
`
`I.
`
`J
`
`1
`5
`
`1
`8
`
`Time {hours}
`
`__§_
`1t,_
`
`1
`Astrazeneca Ex. 21 13 p.
`Mylan Pharms. Inc. v. Astrazeneca AB IPR2016-01326
`
`

`
`Parenteral Medications
`VIIIIIIIIB 1
`Second Edition, Revised and Expanded
`
`Edited by
`
`Kenneth E. Avis
`
`The University of Tennessee
`Memphis, Tennessee
`
`Herbert A. Lieberman
`
`H.H. Lieberman Associates, inc.
`Consultant Services
`
`Livingston, New Jersey
`
`Leon lutbman
`
`Lachman Consuitant Services
`
`Westbur}; New York
`
`Marcel Dekker, Inc.
`
`New York I Basel 0 Hong Kong
`
`Astrazeneca Ex. 2113 p. 2
`
`

`
`Library of Congress Cataloging -1n— Publication Data
`
`Phalmaceutical dosage forms. parenteral medic-art-ions I edited by
`Eienneth E. Avis. Herbert A. Lieberman, and Leon Lachman. -- ‘End ed. _,
`rev. and expanded.
`p.
`cm.
`Includes bibliographical references and index.
`ISBN 0-B24?-85'if3—-2 (V. 1 :- alk. paper)
`1. Parenteral solutions.
`2-". Pharmaceutical technology.
`Kenneth E.
`II. Iieberman, Herbert A.
`III. Lao-htoan. Leon.
`
`I. Avis,
`
`[DNLM:. 1. Infusions. Par'enteraI.. 2. ‘Technology, Pharmaceutical.
`WB 354 P5Sfi]
`RS201._P3TP48 1992
`615'. 19--de2D
`DNLM.-’DL(.-I
`for Library of Dongress
`
`91 -38083
`CIP
`
`This book is printed on acid-free paper.
`
`Copyright© 1992 by MARC}?-L DEKKEII, INC. All Righu Reserved
`
`Neither this book not any part may be reproduced or transmitted in any form
`or by any means. electronic or mechanical. including photocopying, micro-
`filming, and recording, or by any information storage and retrieval -system,
`without permission in writing from the publisher.
`
`MARCEI. DEKKER, INC.
`270 Madison Avenue, New York, New York [0016
`
`Current printing [last digit]:
`ID 9 8 7 6 5 4- 3 2 I
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`Astrazeneca Ex. 2113 p. 3
`
`

`
`Contents
`
`Preface
`Contributors
`Parenteral‘ Medications,
`Contents of Pharmaceutical Dosage Forms:
`Second Edition, Revised and Expanded, Volumes 2 and 3
`Tablets, Second Edition,
`Contents of Pharmaceutical Dosage Forms:
`Revised and Expanded, Volumes 1-3
`Contents of Pharmaceutical Dosage Forms:
`Ilisperse Systems.
`Volumes 1 and 2
`
`ii.Ea"
`
`JEV
`
`xvii.
`
`Chapter I. The Parenteral Dosage Form and Its Historical Development
`
`Kenneth E. Avis
`
`I.. The Dosage Form
`I]. History of Parenteral Medications
`Appendix A: Glossary of Terms
`Appendix '13: Highlights in the History of
`Parenteral Medications
`References
`
`Chapter 3
`
`Parenteral Drug Administration: Routes, Precautions,
`Problems, Complications, and Drug Delivery Systems
`
`Richard J. Burns, Michael J. Alters. and
`8aIvatore- J. Tm-no
`
`Introduction
`I. General Indications for Parenteral
`
`Administration of Drugs
`11 . Pharmaceutical Factors Affecting Parenteral
`Administration
`
`111.
`IV.
`
`‘Specific Routes of Administration
`Distribution of Pareuterally Administered Agents
`
`IADIDA1-‘
`
`14
`15
`
`1'7
`
`1?
`
`18
`
`19
`21
`-39
`
`vi!
`
`AstraZeneca Ex. 2113 p. 4
`
`

`
`vlti
`
`Contents
`
`V. Precautions, Problems, Hazards. and
`Complications Associated with Parenteral Drug
`Administration
`
`W. Methods and Devices for Drug Delivery Systems
`VII.
`Summary
`References
`
`Chapter -3
`
`Biopharmaceutics of Injectable Medications
`
`Sol Motola
`
`1.
`
`Introduction
`
`1!.
`
`Phyaicochemical and.Phys1olog1ca1 Factors
`Affecting Drug Absorption by Injection: An
`U'V'E1‘V'i9W
`
`III. Application of Pharmacokinetics to Biopharma-
`ceutic Investigations: Pharmacokinetic Models
`IV. Examples of Biopharmaceuticflharmacokinetic
`Principles
`V. Regulatory Considerations for Bioequivalence
`Studies
`
`VI. Bioequivaience Study of Two Injectable Forms
`of the same Drug
`Summary
`References
`
`VII.
`
`Chapter 4
`
`Preformulation Research of Parenteral Medications
`
`Sol Match: and Shreeram N. Agharkcr
`
`I.
`
`Introduction
`
`11.. Drug. Substance Physieochemical Properties
`III. Accelerated stability Evaluation
`IV. General Modes of Drug Degradation
`V.
`Preforlmflation Studies for Proteins and Peptides
`VI. Preformulation Screening of Parenteral
`Packaging Components.
`Summary
`VII.
`VIII. Preformulation Worksheet
`References
`
`Chapter 5
`
`Forrnulstion of Small Volume Parenterala
`
`Patrick P. Dellucc and James C.. Boylan
`
`Introduction
`I.
`IL Formulation Principles
`III. Container Effects on Formulation
`11?.
`Stability Evaluation
`V.
`Process Effects
`References
`
`41
`49
`55
`5’?
`
`59
`
`59
`
`60
`
`77
`
`98
`
`108
`
`I119
`111
`112
`
`115
`
`115
`116
`140
`I50
`154
`
`158
`183
`163
`
`169
`
`173
`
`173
`I'M
`227
`234
`244
`245
`
`Astraleneca Ex. 2113 p. 5
`
`

`
`Contents
`
`inc
`
`Chapter 6
`
`Formulation of Large Volume Parents-rals
`
`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 ?roteins
`
`Yu~Chang John Wang
`
`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
`
`III.
`IV.
`
`VI.
`VII.
`
`Diagnostic Products Defined
`Sterile Diagnostics
`Definitions
`
`Aseptic Manufacturing Considerations
`Validation Program
`Conclusion
`References
`
`Chapter 9
`
`Glass Containers for Parenterais
`
`R. Paul Abendroth and Robert N. Clark
`
`I.
`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
`
`2419
`
`249
`250
`273
`280
`281
`281
`
`283
`
`283
`284
`302
`
`310
`312
`317
`
`321.
`
`321
`321
`322
`325
`330
`351
`359
`359
`
`351
`
`361
`361
`
`362
`369
`375
`380
`380
`382
`384
`
`Astrazeneca Ex. 2113 p. 6
`
`

`
`1.‘
`
`Contents
`
`Chapter 10 Use of Plastics for Parenteral Packaging
`
`John M. Anes, Robert S. Nose, and
`Charles H. White.
`
`Introduction
`I.
`II. Fundamentals
`III. Fabrication Processes
`
`Important Criteria for Selection of Plastics
`IV.
`V. Plastics Used in Parenteral Packaging
`VI. Quality Assurance of Parenteral Containers
`References
`
`Chapter 11 Elastomeric Closures for Pa.-renterals
`
`Edward J. Smith and Robert J. "Noah
`
`1. Elastomeric Parenteral Packaging Components:
`A Physical Description
`Physical Description of ‘Rubber
`11.
`III. Types 01’ Rubber Used in Parenteral Packaging
`IV. Closure Design
`V. Rubber Compounding
`VI.
`vulcanization Process
`VII. Closure Manufacture and Control
`
`VIII. Closure Design Qualification
`IX. Regulatory Considerations
`X.
`Interaction of Drug Formulations with
`Rubber Closures
`
`XI. Contemporary Closure-Related Issues
`References
`
`Chapter 12 Parenteral Products in Hospital and Home Care
`Pharmacy Practice
`
`John W". Levchuk
`
`1.
`
`Introduction
`
`.11. The Preparation of Sterile Dosage Forms in the
`Hospital and in Home Care
`111. Dispensing and Compounding Processes
`IV. Technology of sterile Compounding in the
`Hospital Pharmacy
`1?. Clinical Supply and Use of Sterile Products
`VI. Quality Assurance
`VII. Conclusion
`
`Appendix: Abbreviated Sequence for Preparing 9.
`Series of Extemporaneously compounded IN’.
`- Admixturas
`References
`
`Index
`
`387
`
`387
`. 389
`398
`407
`422
`439
`443
`
`-145
`
`445
`450
`451
`482
`463.
`470
`477
`494
`503
`
`505
`507
`508
`
`513
`
`513
`
`513
`524
`
`532
`54'?
`552
`583.
`
`563'
`566
`
`569
`
`Astraleneca Ex. 2113 p. '7
`
`

`
`3 B
`
`iopharmaceutics of
`Injectable Medications
`
`Sol Motola*
`
`Whitehall Laboratories, Hommonton, New Jersey
`
`I.
`
`INTRODUCTION
`
`Biopharrnaceutica is the subject in pharmaceutical sciences that examines the in-
`fluence oif physioochemicsl changes in drug and/or formulation design on the ab-
`sorption of drugs. Over the last three decades, this area of research has e-
`merged as one of the most influential factors in guiding the development of phar-
`maceutical dosage forms. As a result. there has been a rapid increase in the
`number of scientific publications and textbooks on this subject. Pharmacy
`schools throughout the world now include biopharmaceutics in both underg-1-ad—
`uate and graduate programs. Moreover, practically every new drug product in-
`troduced during this period has been designed based on biopharmaceutical data.
`To date, most biopharmaceuticsl investigations have been in support of or
`ally administered dosage forms since they are the predominant ones used in cur-
`rent therapy. Although there have been a significant number of studies reported
`on the rates of absorption, distribution, metabolism, and excretion of parenteral-
`ly administered drugs, only a few have been designed to elucidate which prop-
`erties of the injection formulation or injection site influence these rates. The
`Danish pharmacologist Schou was one of the first to study extensively the
`physiological factors that influence the absorption of drugs from subcutaneous
`connective tissue.
`In a 1961 review article [1] , he described, from a pharma-
`cological viewpoint, how the rate of absorption of subcutaneously administered
`hormones and drugs could ‘be altered depending on the effect the injection had
`on the physiological condition of the connective tissues, the capillary membrane,
`and the capillary blood flow at the subcutaneous site.
`During the same year, Wagner [2] reviewed the literature comprising -the
`discipline that had just been coined biopharmcoentios by Gerhard Levy. He re-
`viewed important physiocochemical factors influencing drug absorption from
`various modes of administration. Besides correctly predicting the important
`
`it
`
`.
`Current affiliation: Wyeth-Ayerst Laboratories. Radnor, Pennsylvania.
`
`59
`
`AstraZene.ca Ex. 2113 p. 8
`
`

`
`60
`
`Mo told
`
`role this discipline would serve in the future of pharmacy. he suggested many
`of the areas for study that have influenced biopharmaceuti-cal investigations of
`injectable dosage forms.
`Ballard applied this information to research on intramuscular injections
`and, from a pharmaceutical viewpoint. published an influential review article
`dealing with biopharrnaceutical factors influencing intramuscular and subcu-
`taneous injections [3] . Although interest continues in this area of research,
`as noted by periodic reviews [4- 7] , relatively little new basic information has
`been uncovered, leaving room ior more in-depth studies.
`Not long ago, drugs administered by injection were assumed to provide
`rapid and complete absorption ,. particularly when compared to oral administra-
`tion. During the last 30 years, this assumption has been shown not always to
`be true. These findings [B-13-1, coupled with more numerous examples of in-
`complete absorption from oral’ dosage forms, have stimulated research on:
`(1) drug absorption and how it is affected by the design oi‘ the dosage form
`(biopharmaceutics);
`(2.) the extent to which drugs are biologically available
`to the blood stream relative to the amount administered (bioavallability); and
`(.3) the ‘rates and extents to which drugs are absorbed, distributed, metabo-
`lized, and excreted by the body (pharmaoolcinetics).
`The aim of this -chapter is to provide the formulator of injectable medica-
`tion with a basic understanding of the major physieochemioal and physiological
`factors currently considered to play on important role in influencing absorp-
`tion of drugs administered by injection. Selected topics in pharmacokinetios
`will be covered primarily to demonstrate their utility in the analysis of bio-
`pharmaceutical experiments. The overall goal is for the formulstor to be able
`to apply this knowledge in designing. iniectable dosage. formulations that will
`provide predictable drug delivery to the patient.
`
`ll. PHYSICOCHEMICAL AND PHYSIOLOGICAL FACTORS AFFECTING
`DRUG" ABSORPTION BY INJECTION: AN OVERVIEW
`
`An intravascular (intraveneous) injection places a drug directly into the blood-
`stream. bypassing conventional physicoehemical and physiological influences.
`Injection of .a drug into an extravascular -site (all others) leads to the initiation
`of events that collectively make up the absorption process. Depending on the
`type of formulation administered, varying degrees of a depot are established.
`Eventual drua: adsorption into the bloodstream is influenced by several physica-
`chemical and physiological factors. the two considered most important being
`passive diffusion and blood flow [14-16] . The relative importance oi‘ these
`factors depends on. the capillary bed density at the injection site, the physical
`form of the drug. and the drug's molecular size. Hence an examination of
`these and other influential physicoohemical and phyfiological factors is impor-
`tant in providing the pharmaceutical formulator with information that can be
`used to design formulations yielding acceptable absorption characteristics.
`
`A. Physiooohemioai Factors Affecting Drug
`Absorption by Injection
`
`As stated, no absorption step is necessary when a drug is administered direct-
`ly into the bloodstream; therefore , there are no phyaicochemioal factors to
`
`Astrazencoa Ex. 2113 p. 9
`
`

`
`Biophormeoeutica of Injeotcble Medication
`
`61
`
`affect absorption. Drugs given by ext:-avsscular injection require an absorp-
`tion step before they can enter the bloodstream. Even drugs that are admin-
`istered by the intraspinal (intrathecal) and intracardiac routes and are in very
`close proximity to the bloodstream must first undergo local penetration and
`permeation and then penetrate local capillaries in order to reach the blood-
`stream. At other ex-travascular sites, such as intramusmjlar, subcutaneous.
`and intradermal, the drug is exposed to a relatively small localised region.
`From -such regions. the drug trsvels to the blood or lymphatic circulation
`{only for high-molecular-weight molecules) by means of physical penetration
`and permeation processes which are associated with passive diffusion and par-
`titioning through the capillary membrane and into the bloodstream.
`
`Drug Solubility
`
`A major physioochemical criterion for absorption by passive diffusion and par-
`titioning is drug solubility. Regardless of the dosage form administered, a
`drug must be in solution in an aqueous system for it to be -exposed to proces-
`ses that will eventually result in its absorption into the bloodstream. Only
`the fraction of drug in solution is available for absorption. Drugs that remain
`in solution at the injection site are generally absorbed quickly and easily. all
`other influencing factors being constant.
`A critical difference between the pH of the administered drug‘ solution and
`the physiological pH at the injection site Landior solubility of the drug in a
`cosolvent vehicle and in physiological tissue fluid.) can cause an unpredicted
`decrease in absorption due to precipitation of the drug at the injection site.
`Phenytoin. a commercial brand of diphenylhydantoin, is a, very insoluble free
`acid and is formulated as the sodium salt in a solution of 40% propylene glycol,
`10% alcohol, and water for injection. The pH must be adjusted to pH 12 with
`sodium hydroxide to solubilise the drug’. The propylene glycol helps to solu-
`bilize the "free acid fraction available at this pl-1. When injected into muscle
`tissue the large difference in pH causes conversion of the sodium salt to the
`less soluble free acid which precipitates in tissue fluids at the injection site.
`Simultaneous dilution of the propylene glycol with tissue fluid contributes to
`free acid precipitation. Most of the drug is therefore available only slowly,
`depending predominantly on the dissolution rate of diphenylhydantoin crystal.
`Thus complete absorption takes 4 to 5 days ‘[10]. Similar reductions in bio-
`svailability due to drug-precipitation caused by pH and solubility changes
`have been reported for Diazepam lrzjcction [I1] , Chlordiazepoxide Injection
`[12] . and Digoxin Injection [13] .
`
`Passive Diffusion
`
`Passive diffusion involves the spontaneous movement of solute molecules in
`solution from an area of higher concentration on one side of a semipermeable
`membrane to an area of lower concentration on the other side of the membrane.
`
`In the biological system . a drug in solution passes from the extracellular to
`the intracellular tissue fluids by passive diffusion.
`The rate of passage of a drug through a biological membrane by passive
`diffusion is affected by several physicochemical factors, such as concentration
`gradient, partition coefficient, ionization, macromolecular binding, and os-
`molality. in addition to differences in physical form of the medication.
`
`Astraleneca Ex
`
`.2113 p. 10
`
`

`
`62
`
`Morale
`
`Ccncentratfen Gradient. The rate at which a drug molecule crosses a semi~
`permeable membrane by passive diffusion is described by Fields law, expressed
`by the following equation for the unidirectional case:
`
`fig M DA(C1 W C2)
`dt
`R
`
`where
`
`(1)
`
`gig“
`D
`A
`
`-"= Flux or amount of transfer of substance per unit of time
`tr» diffusion constant
`-
`surface area available for diffusion
`
`C1 = concentration of diffusing substance in extracellular fluid
`C2 =
`concentraticn of diffusate in the intracellular fluid
`.9.
`=
`thickness of the membrane
`
`For any particular membrane where A and 2 are constant, the diffusion rate
`is controlled by D(C1 — C2). The magnitude of the diffusion constant D is in~
`fluenced by the physicochemical properties of the drug molecule and the char“
`acteristics of the membrane.
`
`For any given drug in a contained in vitrc system, the rate of passive
`diffusion is controlled by the concentration gradient (C1 ~ C2) 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 C3 decreases and apprtr
`aches C1. When C1 equals C2 the system is at equilibrium. This is described
`mathematically as follows:
`
`9.9:
`fit
`
`._~
`
`13 C ** C
`.‘.,.3_,,,2l
`2
`
`when C1 2 C2,
`
`9% 3
`Cit
`
`D
`
`(2,
`
`(3)
`
`However, the concentration gradient (C1 - C3) does not became a rate—limiting
`factor in viva because cf 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, C1 remains considerably greater than C2 at all times until
`the transfer is ccmplete. This is referred to as a “sink” condition and Equa~
`tion (2) reduces to
`
`~----— —«—~
`
`(4)
`
`Partition Coefficient. The distribution of a solute between an aqueous
`environment and a lipid membrane is analogous to the distribution of a salute
`between two immiscible solvents such as water and oil. This type of clietribuv
`
`Astrazeneca Ex. 2113 p. 11
`
`

`
`Biophormccoutics of Inieotobla Medication
`
`63
`
`tion, called partitioning, plays an important role in passive diffusion. The
`equation that describes partitioning is:
`
`Partition cociflcient (PC) = K =
`
`ca
`33
`
`(5)
`
`where, by convention.
`a
`concentration of solute in the 011 or lipid phase
`c: = concentration of nonionized solute in the aqueous phase at a de-
`fined pH
`= partition coefficient
`
`K
`
`The influence of the partition coefficient on passive diffusion of a drug through
`a biological membrane can be illustrated by considering the relative transfer of
`drugs with high and low partition coefficients. A drug with a high partition
`coefficient (lipid soluble) will pass readfl? from the aqueous phase into the
`membrane. whereas. one with a low partition coefficient (water soluble) will
`remain in the aqueous phase and not pass appreciably into the membrane. As
`stated earlier. in a biological system. diffusion takes place as a unidirectional
`process; this is equally true tor the process of partitioning. The drug with
`a higher partition coefficient will exhibit a higher rate of diffusion. dq ldt.
`Thus lipid-soluble drugs are absorbed and distributed more rapidly than are
`water-soluble drugs.
`
`Ionization. Whereas partitioning of neutral. molecules takes place in rela-
`tion to their oil-water solubility, this is not true for ionized drugs.
`Ionization
`has a profound effect on drug absorption, distribution, and excretion. The
`degree of ionisation of an. acid or base is determined by the ionization constant
`of the compound, pita, in addition to the pH, temperature. and ionic strength
`of the solution. Since in a biological system temperature and ionic strength
`are essentially constant, their influence can be neglected.
`The relationship between pH and plia can be readily seen by the following
`derivation.
`In water, a weak acid, HA, ioniaes (or dissociates) according to
`the following equation:
`
`HA 4» H20 '|*H3_()+ + A’
`
`The equilibrium constant for the reaction is written conventionally as
`
`_IH3o"1 _IA']
`“eq ‘ :Tmm',fi
`
`(6)
`
`"3
`
`-Since the molar concentration of water (55.3 mol l:'Ltar‘1 at 25°C.‘) is much larger
`than any of the other values and remains essentially constant during the reac-
`tion, one can write
`
`[H.30+'.| [A'l
`_
`Kaq [HBO] = Kim = ——f,n-_—]——
`
`ca)
`
`Astraleneca Ex. 2113' p. 12
`
`

`
`64
`
`Mo tolo
`
`Taking the logarithm of both sides of Equation (-8) and transposing log Kion
`and log; [H 30''] to opposite sides yields
`
`—1og- '[FI_3O+] = —1og Kim +- log
`
`IA-1
`[HA]
`
`(9)
`
`By employing‘ conventional definitions for pH and pita. Equation (9) becomes
`
`.
`__
`.
`A-
`pl-I _ pita + log {E3-3-
`
`-
`(10)
`
`Equation ['10) , known. as t-he Henderson-I-Issselbach equation, is very useful
`in predicting the ionization properties of weak acids and bases, particularly
`with respect to their ability to partition into lipids.
`A similar equation describes the ionisation of a weak base, but by conven-
`tion, the reaction is written as the ioxiizstion of the protonated weak base, BH"':
`
`133+ + on’: B + H20
`
`yielding‘-
`
`pH = pit; + log
`
`[B51
`[EH 1
`
`(11)
`
`(12)
`
`where the symbol p'K'a designates the ionization of the protonated base.
`Several obvious but important relationships between pH and p'Kfl can be
`seen through inspection of Equation (10), particularly as they affect partition»
`ing:
`
`1. When the concentration of acid [HA] equals the concentration of the
`anion [A‘1 in a solution of a weak acid, the ratio [A'] IIHAI = 1. Since
`log 1 = 0. pH = pita.
`2- The degree of ionization of weak acids and bases changes rapidly as
`the difference between pH and pita becomes greater until the pH value
`of the solution is 2 units away from pita, at which time further changes
`in pH have little effect on the degree of ionization of the acid or base.
`This concept can be easily demonstrated by rearranging Equation (10)
`to the form
`
`pH - pita =1og [Egg]
`
`[13]
`
`and examining the difference in the ratio log [A'] {[1-L5,] as the differ-
`ence, pH - pfia. goes through changes from 2 to 0.01 as shown below:
`
`A-
`2
`pH—pna=1og[[T§=
`Ionized forn1[A'I
`= 100
`
`Nonionized form [HA1 =
`
`1
`
`1
`ID
`
`1
`
`0
`1
`
`1
`
`0.1
`1
`
`10
`
`(1.01
`1
`
`1110
`
`Therefore-. if there were a 3 unit difference between pH and pita.
`one would only see less than a 1% further change in ionization.
`
`Astraleneca Ex. 2113 p. 13
`
`

`
`Biophonnoceutics of Injectohle Medication
`
`65
`
`3. when dealing with ionized and nonionized forms of a drug, the rela-
`tionship to lipid solubility and partition coefficient becomes apparent.
`The neutral (nonionized) fraction of the drug‘. is more readily parti-
`tionod into the nonpolar lipid membrane. During partitioning of the
`nonionized molecule the fraction of remaining -ionized d-rug rapidly
`equilibrates so that nonionized drug is again formed and available for
`partitioning. This dynamic process takes place until the entire drug
`partitions through the membrane.
`
`when the pH of a medium causes most of the drug to be in the ionized form
`(.e.g‘., medium pH = 'l for an acidic drug‘ with pita = 5') . slow absorption. can
`be expected since the partitionable nonionizod form constitutes only a small
`fraction of the total drug, less than 1%1n the case above.
`A rank order demonstration of the effect of medium pH and drug plia on
`partitioning is shown by the following hypothetical example. A beaker con-
`taining a buffer solution is separated equally into two compartments by a semi-
`permeable lipid membrane (see Fig. 1) that allows only the nonionized weal:
`acid (pita = 5) to pass through. A quantity of the weak acid drug is dissolved
`in a negligible volume of buffer solution; the solution is then quickly injected
`into the left compartment, resulting in a homogeneous solution in that compart-
`room.
`
`After each equilibrium partitioning step takes place (i.c. , HA partitions
`through the membrane. leaving A‘ and H+ behind) , the buffer solution on the
`right side of the membrane {side becoming enriched with HA) is replaced with
`fresh buffer. The species A‘ on the left side reequilabratcs with H" to form
`more HA and the process is repeated until eventually all the drug is partitioned
`as HA.
`
`Referring to the Henderson-Hasselhach equation [Eq. (10)) , consider the
`following two cases, which will demonstrate the effect of "PH and pKa on parti-
`floning.
`
`
`
`Figure 1 Beaker containing buffer solution in which a semipermeable lipid
`membrane separates the solution into two compartments. Weak acid I-IA placed
`in the left side oquilibrates according to Equation (6), allowing only I-IA to
`partition through the membrane.
`
`Astralenoca Ex. 2113 p. 14
`
`

`
`66
`
`Morale
`
`In this
`Case 1: Buffer solution on both sides of the membrane at pH 5.
`case Equation (10) indicate that log [AC] III-1&1 = 1-, thus IA']
`= [HA] ..
`
`Thus 50% of the total weak acid is in the neutral form HA. able to partition
`through the membrane. The remaining" ionized portion. A’ , is unable to par-
`fition into lipid.
`The hypothetical profile for the system, based on the percent of HA re-
`maining in the left compartment versus the number of equilibrations and buf-
`fer solution replacements of the right compartment, is shown in Figure 2. At
`pH 5 following four equilibrationa, only 6% A‘ remains in the left compartment
`(approzdmately 94% of HA has partitioned) .
`
`Case 2: Buffer solution in both compartments at pl! '7. Equation (10)
`new indicates that log [A"_] MBA] = 100. Substituting these
`values into Equation (10) yields
`
`'r=5+1og¥
`
`Therefore only 0.99 of the total drug. HA 4- A", is in the form
`HA. able to be partitioned.
`
`The hypothetical profile for this system under the conditions stated is -shown
`in Figure 2.
`In this case at pH '?_, after four equilibrations 96!; HA remains in
`the left compartment and only 4% has: been able to partition through the mem-
`brane. Since 0.99% of the amount of HA present can partition during each
`equilibration, one can calculate that it would take 95 equilihrations (i.e. ,
`9430. 99} to partition the same amount of HA as was partitioned by four equili-
`hretions at pH 5 in case 1.
`
`
`
`I
`e
`EDUILIBHATIDNB
`
`1
`
`Figure 2' Hypothetical case of comparative partitioning versus number of equili-
`brations for weak acid I-IA (pita 5). partitioning" through a lipid membrane
`from buffer solutions at pH 5 (A) and pH '2 (0).
`
`Astraleneca Ex. 2113 p. 15
`
`

`
`Btophormoceutics of‘ Injectcole Medication
`
`6.?
`
`These examples are meant to show the relationship between formulation
`PH, drug PKL. and ‘the amounts of partitionable nonionized weak acid or weak
`base species available for absorption from an injectahle solution dosage form.
`
`Binding to Macromolecules. Biological fluids contain macromolecules such
`as proteins which may have affinity for certain drugs. These macromolecules
`are generally too large to pass through biological membranes by filtration,
`nor do they have the lipid solubility required for passive diffusion. There-
`fore, they are confined within their immediate boundaries. When a -drug be-
`comes adsorbed or compiexed on such macromolecules .. its effective "free" con-
`centration of diffusable form becomes lowered. The equation describing this
`reacitaon is
`
`kl
`Drug + macromolecule if drug - macromolecule complex
`N
`
`where
`
`k1 = adsorption rate constant
`kg. = desorption rate constant
`
`The equilibrium constant is then expressed as
`
`= [drug - macromoleculel
`[drug] Imacromolecule]
`
`K
`
`(14)
`
`_
`(153
`
`where .14, the association constant ,. provides a quantitative measure of the
`affinity of the drug for the particular macromolecule. Significant binding to
`macromolecules such as serum protein reduces the concentration of free drug
`in the tissue fluids and hence reduces the rats of passive diffusion by lower-
`ing the concentration gradient in accordance with Fisk's law [Eq. (1)1. Since
`binding is an equilibrium process and thus readily reversible, the drug can
`eventually be deaorbed .
`It is important to note that protein binding reduces
`the rate of passive diffusion but does not prevent it. Protein binding has a
`significant effect on passive diffusion when the drug is bound by more than
`90% because the desorption rate from the drug-protein complex is usually slow-
`er than the diffusion rate of the drug through membranes.
`
`Osmolslity. A solution is osoosrnotie. with tissue fluid when the total num-
`ber of dissolved particles in the two systems. are equal.
`In general, iniectablc
`products are formulated to be iaoosmotic to reduce the -‘possibility’ of irritation
`that can result if osmotic differences between tissue fluid or red blood cell
`
`product are great. The effect of large differences
`contents and the
`in solution osmolality on passive diffusion can be -described by considering the
`following conditions:
`(1) hypoosmotic. (2) isoosmotic. and (3) hypcroamotic.
`When an injection solution is hypoosmotic. it contains fewer solute particles
`than does the tissue fluid. Based on the law of osmosis, solvent passes from
`a region of lower concentration of solute to one of higher concentration to re-
`duce the pressure differential caused by the dissolved soiute particle imba1ance..
`Therefore. the extravaaoulsr injection of a grossly hypooamotic solution
`would cause the movement 01 fluid away from the repository injection site.
`In
`
`Astralencca Ex. 2113 p. 16
`
`

`
`68
`
`Match:
`
`this case, the apparent concentration of drug: would increase, resulting in an
`increase in rate of passive diffusion. Conversely, the extravasoulsr injection
`of a grossly hyper-osmotic solution causes an influx of fluid to the repository
`injection site, resulting in dilution of drug concentration and an apparent de-
`crease in rate of diffusion.
`Increasing the osmoielity of atropine solutions by
`the addition oi‘ either prolidoxine chloride or sodium chloride led to an appar-
`ent reduction. in intramuscular absorption, determined by its effect on reduc-
`tion of heart rate £17]. When an isoosmotic solution is injected, there is no
`fluid flux either to or away from the injection site, hence no demonstrable
`effect on passive diffusion.
`It is important to differentiate between the terms isotonic and iaoosmotic.
`They are synonymous only when the dissolved solute cannot pass through
`membranes of red blood cells. However, when such passage does occur, as
`with aqueous solutions of urea, alcohol, or boric acid, the solution acts as if
`it were pure water and both solute and solvent pass through the membrane
`into the ‘red blood cells. causing them to swell and burst {hemolysis} . The
`solution was considered isotonic based on sodium chloride equivalent calcula-
`tions or as determined by its freezing'—point depression; however, it was ac-
`tually hypotonic or hypoosmotio with respect to red blood cells. The term
`isotonic should be used only to describe -solutions having equal osmotic pres~
`sures: with respect to a particular membrane. Therefore, it is important to
`examine the osmotic behavior of new drug substances toward red blood cells
`before deciding whether an adjustment is to be made.
`In order to make an
`isoosmotic aqueous solution of a nonosmotic contributing substance such as
`urea, an external agent such as sodium chloride, sorbitol, or other osmotic-
`Drodueing substance must be added at its isotonic level. such as 0. 9% sodium
`chloride.
`
`Volume of Injection. From Fick's1aw, for the sin]: condition (02 = 0) it
`was shown by Equation (4) that dqfdt = K01. when the volume V1 oi’ drug
`solution at the absorption site remains nearly constant, the rate of passive
`diffusion will. be equal" to
`
`.
`A
`%- = K .31
`I
`
`(13)
`
`where A1 is the amount of drug at the site at any time. Thus the difmsion
`rate is inversely proportional to- volume V1, and absorption rates -should in-
`crease when volumes decrease [3]. Smaller injected volumes have been re-
`ported to enhance drug absorption [18] . Another way of expressing this is
`to consider the ratio of tissue surface area to volume of injection. An increase
`in injection volume with a relatively confined area results in a lowering of the
`tissue surface area-to-volume ratio. Since passive diffusion is directly propor-
`tional to surface area, an increase in injection volume should cause a lowering
`in the rate of passive diffusion. A physiological reason to keep injection vol-
`umes small is to help minimize or reduce pain caused by hydrostatic pressure
`on surrounding tissues.
`
`Differences in Physical