Nichaias
`
`Layd 2
`
`SDLTL1‘ IEDLTLQR
`
`Amerigen Ex. 1046, p. 1
`Amerigen Ex. 1046, p. 1
`
`

`
`
`
`I am a Pharmacist
`
`,
`
`'
`
`O I am a specialist in med1'cat1'ons
`
`I supply medicines and pharmaceuticals to those who need them.
`
`I prepare and compound special dosage forms.
`
`I control the storage and preservation of all rnedications in my care.
`
`0 I am a custodian of medical information
`
`My library is a ready source of drug knowledge.
`My files contain thousands of specific drug names and tens of
`thousands of facts about them.
`
`My records include the medication and health history of entire families.
`
`$Yfi§}&jcbii£fiEI%El3lEfiIeléth<i%slrt§pEifi -lelcilxiifi-’i1<ilti3§i"l?xi¥i‘EJ’l1ar1nacy from around
`was seals em a.r»;;::...z% -iina‘-:
`H. as?!
`Silt
`’ I W" 6* C””’1?li!’i~‘l?iI30l§iI?l’a‘till?>’5Jl?1l€¢I£?fi=Iii!~t':'.l*
`I am a partner in the case of every patient who takes any kind of
`medication.
`
`I am a consultant on the merits of different therapeutic agents.
`
`I am the connecting link between physician and patient and the final
`check on the safety of medicines.
`
`O lam a counselor to the patient
`
`I help the patient understand the proper use of prescription
`medication.
`
`I assist in the palienfs choice of nonprescription drugs or in the
`decision to consult a physician.
`
`I advise the patient on matters of prescription storage and potency.
`
`O lam a guardian of the public health
`
`My pharmacy is a center for health—care inforrnation.
`
`I encourage and promote sound personal health practices.
`
`My services are available to all at all times.
`
`0
`
`This is my calling 9 This is my pride
`
`Amerigen Ex. 1046, p. 2
`Amerigen Ex. 1046, p. 2
`
`

`
`
`
`I
`
`Pharmaceutical
`
`Dosage Forms
`
`and Drug
`
`Delivery Systems
`
`Howard C. Ansel, Ph.D.
`Panoz Professor of Pharmacy, Department of
`Pharmaceutics, College of Pharmacy
`The University of Georgia
`
`Nicholas G. Popovich, Ph.D.
`Professor and Head, Department of Pharmacy
`Practice, School of Pharmacy and Pharmacal
`Sciences
`
`Purdue University
`
`Loyd V. Alien, Jr., Ph.D.
`Professor and Chair, Department of Medicinal
`Chemistry and Pharmaceutics, College of
`Pharmacy
`The University of Okiahorna
`
`SIXTH EDITION
`
`A Les 8 Febiger Book
`
`Williams & Wilkins
`BMTIMOIIE - °HILAD£LPHIA u HONG KONG
`
`LONDON ‘ MUNICH " SYDNEY ' ?0|<YO_
`I
`A WAVERLY COMPANY
`
`Amerigen Ex. 1046, p. 3
`Amerigen Ex. 1046, p.
`<
`
`

`
`
`
`Executive Editor: Donna M. Balado
`
`Developrnental Editor: Frances M. {(1399
`Production Coordinator: Peter]. Carley
`Project Editor: Iessica Howie Martin
`
`Copyright © 1995
`Williams & Wilkins
`Rose Tree Corporate Center, Building II
`1400 North Providence Ftoad, Suite 5025
`Media, PA19lJ53-2043 USA
`
`
`
`All rights reserved. This book is protected by copyright. No part of this book may be reproduced in any form
`or by any means, including photocopying, or utilized by any informat-ion storage and retrieval system without
`written permission from the copyright owner.
`
`Accurate indications, adverse reactions, and dosage schedules for drugs are provided in this book, but it is pos-
`sible they may change. The reader is urged to review the package information data .of the rnanufacturers of the
`medications mentioned.
`
`Printed in the United States ofAmerfc:a
`
`Library of Congress Cataloging in Publication Data
`
`Ansel, Howard C., 1933--
`Pharmaceutical dosage forms and drug delivery systems I Howard C.
`Ansel, Nicholas G. Popovich, Lloyd V. Allen, ]r.—6th ed.
`p.
`cm
`Includes bibliographical references and index.
`ISBN 0-633-00193-0
`
`96 97 93
`3 4 5 6 7 8 9 10
`
`2. Drug delivery systems.
`1. Drugsv-Dosage forms.
`I. Popovich, : lichotas G. H. Allen, Loyd V.
`Ill. Title.
`[DNLM: 1. Dosage Forms.
`2. Drug Delivery Systems. QV 785 A618i
`1995]
`RS200.A57
`615’.1—::1c20
`DNLME DLC
`for Library of Congress
`
`1995
`
`94-22471
`CH’
`
`The use of portions of the text of USP23 I NF18, copyright 1994, is by perrnission of the USP Convention, Inc.
`The Convention is not responsible for any inaccuracy of quotation or for any false or misleading implication
`that may arise from separation of excerpts from the original context or by obsolescence mulling from publica-
`tion of a supplement.
`
`PRINTED IN THE UNITED STATES OF AL-TERJCA
`
`Amerigen Ex. 1046, p. 4
`Amerigen Ex. 1046, p. 4
`
`

`
`
`
` 3
`
`Dosage Form Design:
`
`Biopharmaceutic Considerations
`
`As DISCUSSED in the previous chapter, the biologic
`response to a drug is the result of an interaction
`between the drug substance and functionally im-
`portant cell receptors or enzyme systems. The
`response is due to an alteration in the biologic
`processes that were present prior to the drug’s
`administratiort. The magnitude of the response
`is
`related to the concentration of the drug
`achieved at the site of its action. This drug con-
`centration depends upon the dosage of the drug
`administered, the extent of its absorption and
`distribution to the site, and the rate and extent
`of its elimination from the body. The physical
`and chemical constitution of
`the drug sub-
`stance—-particularly its lipid solubility, degree
`of ionization, and molecular size—determines to
`
`a great extent its ability to effect its biological
`activity. The area of study embracing this rela-
`tionship between the physical, chemical, and bi-
`ological sciences as they apply to drugs, dosage
`forms, and to drug action has been given the
`descriptive term biophenrzaceutics.
`In general, for a drug to exert its biologic effect,
`it must be transported by the body fluids, tra-
`verse the required biologic membrane barriers,
`escape widespread distribution to unwanted
`areas, endure metabolic attack, penetrate in ade-
`quate co'n,centrat'.on to the sites of action, and
`interact in a specific fashion, causing an alter-
`ation of cellular function. A simplified diagram
`of this complex series of events between a drug’ s
`administration and its elimination is presented
`in Figure 3—1.
`The absorption, distribution, biotransforma-
`tion (InetabolisIn),_and elimination of a drug
`from the body are dynamic processes that con-
`tinue from the time a drug is taken until all of
`the drug has been removed from the body. The
`rates at which these processes occur affect the
`onset, intensity, and the duration of the drug’ 5
`activity within the body. The area of study which
`elucidates the time course of drug concentration
`
`in the blood and tissues is termed pharmacoki—
`netics. It is the study of the kinetics of absorption,
`distribution, metabolism and excretion (ADMCE)_
`of drugs and their corresponding pharmaco-
`logic, therapeutic, or toxic response in animals
`and man. Further, since one drug may alter the
`absorption, distribution, metabolism or excre-
`tion of another drug, pharmacokinetics also may
`be applied in the study of interactions between
`drugs.
`Once a drug is administered and drug absorp-
`tion begins, the drug does not remain in a single
`body location, but rather is distributed through-
`out the body until its ultimate elimination. For
`instance, following the oral administration of a
`drug and its entry into the gastrointestinal tract,
`a portion of the drug is absorbed into the circula-
`tory system from which it is distributed to the
`various other body fluids, tissues, and organs.
`From thesesites the drug may return to me circu-
`latory system and be excreted through the kid-
`ney as such or the drug may be metabolized by
`the liver or other cellular sites and be excreted
`
`shown i.n Figure 3-1, drugs
`as rnetabolita.
`administered by intravenous injection are placed
`directly into the circulatory system,
`thereby
`avoiding the absorption process which is re-
`quired from all other routes of administration
`for systemic effects.
`The various body locations to which a drug
`travels may be viewed as separate compart-
`ments, eadl containing some traction of the ad-
`ministered dose of drug. The transfer of drug
`from the blood to other body locations is gener-
`ally a rapid process and is reversible; that is, the
`drug may diffuse back into the circlilafion. The
`drug in the blood therefore exists in equilibrium
`with the drug in the other compartments. How-
`ever, in this equilibrium state, the concentration
`of the drug in the blood may be quite different
`(greater or lesser) than the concentration of the
`drug in the other cornpartments. This is due
`
`Amerigen55Ex. 1046, p. 3i‘-
`Amerigen Ex. 1046, p. 5
`
`

`
`
`
`56
`
`Dosage Form Design: Btopharmaceutic Considerations
`
`Orol
`Administration
`
`
`
` Gastro-
`
`lntestinol
`
`Troct
`
`
`
`
`
`
`
`intravenous
`
`Injection
`
`
`
`Intramuscular
`
`
`Injection
`
`
`
`Subcutaneous
`
`injection
`
`Circulatory
`
`Systems
`
`Excretion
`
`
`
`Tissues
`
`Metabolic
`
`Sites
`
`Metabolites
`
`djpivelrin I-I
`d1-olysis to e
`The metat
`
`is usually in
`{rates in the I
`usually via
`may calcul;
`[termed Rail
`Lnationfrom
`to both me‘
`which are
`therefore im
`is much lest
`
`terecl orally
`stances, dru
`are OCC'DI‘ri_‘t
`rates.
`
`Gen
`
`Before an
`site of action
`surmount a
`
`are chiefly :
`such as tho:
`
`lungs, bloo:
`generally cl:
`composed r
`(b) those co
`the intestin.
`than one cel
`
`single cell.
`must pass
`types beforn
`stance, a (in
`gastrointest
`large intest
`circulation,
`which it ha
`sue, and th
`
`Althougt
`differs one 1
`
`Viewed in ;
`oontainingl
`tein layer. l
`biologic me
`passive dil
`transport
`1
`main categ.
`have been ;
`
`Passive D1’.-
`The tern"
`
`the passage
`
`Fig. 3-1. Schematic representation of events of absorption, metabolism, and ercretiort of drugs after their administration
`by various routes.
`
`largely to the physiochernical properties of the
`drug and its resultant ability to leave the blood
`and traverse the biological membranes. Certain
`drugs may leave the circulatory system rapidly
`and completely, whereas other drugs may do so
`slowly and with difficulty. A number of drugs
`become bound to blood proteins, particularly the
`albumins, and only a small fraction of the drug
`administered may actually be found at locations
`outside of the circulatory system at a given time.
`The transfer of drug from one cornpartoient to
`another is mathematically associated with a spe-
`cific rate constant describing that particular
`transfer. Generally, the rate of transfer of a drug
`from one compartment to another is propor-
`tional to the concentrration of the drug in the com-
`partment from which it exits; the greater the con-
`centration,
`the greater is the amount of drug
`transfer.
`
`Metabolism is the major process by which for-
`eign substances, including drugs are eliminated
`from the body. In the process of metabolism a
`drug substance may be biotransformecl
`into
`pharmacologically active or inactive Inetabolites.
`Often, both the drug substance and its metabo—
`lite(s) are active and exert pharmacologic effects.
`For example,
`the antzianxiety drug prazepam
`{Cent.rax) metabolizes,
`in part,
`to oxazepam
`(Seraxl, which also has antianxiety effects. In
`some instances a phaxmacologically inactive
`drug (termed a prod:-ug) may be administered
`for the known effects of its active metabolites.
`
`Dipivefrin, for example, is a prodrug of epineph-
`rine formed by the esterification of epinephrine
`and pivalic acid. This enhances the lipophilic
`character of the drug, and as a consequence its
`penetration into the anterior chamber of the eye
`is 17 times that of epinephrine. Within the eye;
`
`Amerigen Ex. 1046, p. 6
`Amerigen Ex. 1046, p 6
`
`

`
`
`
`Dosage Form Design: Bioplmrmacsutic Considerations
`
`5?
`
`dipivefxin HCl is converted by enzymatic hy-
`drolysis to epinephrine.
`The metabolism of a drug to inactive products
`is usually an irreversible process which culmi-
`nates in the excretion of the drug from the body,
`usually via the urine. The pharmacokineticist
`may calculate an elimination rate constant
`(termed keg) for a drug to describe its rate of elim-
`ination from the body. The term elimination refers
`to both metabolism and excretion. For drugs
`which are administered intravenously, and
`therefore involve no absorption process, the task
`is much less complex than for drugs adminis-
`tered orally or by other routes. in the latter in-
`stances, drug absorption and drug elimination
`are occurring simultaneously but at different
`rates.
`
`General Principles of Drug
`Absorption
`Before an adiifinistered drug can arrive at its
`site of action in effective concentrations, it must
`surmount _a number of barriers. 'I'hese barriers
`are chiefly a succession of biologic membranes
`such as those of the gastrointeslilial epithelium,
`lungs, blood, and brain. Body membranes are
`generally classified as three main types: (21) those
`composed of several layers of cells, as the skin;
`(bl those composed of a single layer of cells, as
`the intestinal epithelium; and (c) those of less
`than one cell in thickness, as the membrane of a
`single cell. In most instances a drug substance
`must pass more than one of these membrane
`types before it reaches its site of action. For in-
`stance, a drug taken orally must first traverse the
`gastrointestinal membranes (stomach, small and
`large intestine), gain entrance into the general
`circulation, pass to the organ or tissue with"
`which it has affinity, gain entrance into that tis-
`sue, and then enter into its individual cells.
`Although the chemistry of body membranes
`differs one from another, the membranes maybe
`viewed in general as a bimolecular lipoid (fat-
`containing) layer attached on both sides to a pro-
`tein layer. Drugs are thought to penetrate these
`biologic membranes in two general ways: (1) by
`passive diffusion and (2)
`through specialized
`transport mechanisms. Within each of these
`main categories, more clearly defined processes
`have been ascribed to drug transfer.
`Passive Diffusion
`
`The term passive diffusion is used to describe
`the passage of (drug) molecules through a mem-
`
`brane which behaves inertly in that it does not
`actively participate in the proms. Drugs ab-
`sorbed according to this method are said to be
`passively absorbed. The absorption process is
`driven by the concentration gradient (i.e., the dif-
`ferences in concentration) existing across _ the
`membrane, with the passage of drug molecules
`occurring primarily from the side of high drug
`concentration. Most drugs pass through biologic
`membranes by diffusion.
`Passive diffusion is described by Fick’s first
`law, which states that the rate of diffusion or
`
`transport across a membrane (dcfdt) is propor-
`tional to the difference in drug concentration on
`both sides of the membrane:
`
`in which C1 and C2 refer to the drug concentra-
`tions on each side of the membrane and P is a
`
`permeability coefficient or constant. The term C1
`is customarily used to represent the compart-
`ment with the greater concentration of drug and
`thus the transport of drug proceeds from com-
`partment one (e.g., absorption site) to Compart-
`ment two (e.g., blood).
`Because the concentration of drug at the site
`of absorption (C1) is usually much greater than
`on the other side of the membrane, due to the
`rapid dilution of the drug i_n the blood and its
`subsequent distribution to the tissues, for practi-
`cal purposes the value of C-1 — C2 may be taken
`simply as that of C1 and the equation written in
`the standard form for a first order rate equaflon:
`
`The gastrointestinal absorption of most drugs
`from solution occurs in this manner in accor-
`
`dance with first order kinetics in which the rate is
`dependent upon drug concentration, i.e., dou-
`bling the dose doubles the transfer rate. The
`magrnihide of the permeability constant, de-
`pends on the diffusion coefficient of the drug,
`the thickness and area of the absorbing mem-
`brane, and the permeability of the membrane to
`the particular drug.
`Because of the lipoid nature of the cell mem-
`brane, it is highly permeable to lipid soluble sub-
`stances. The rate of diffusion of a drug across the
`membrane depends not only upon its concentra-
`
`mtiim
`
`1 for-
`tated
`sin a
`into
`ilites.
`tabo-
`fects.
`
`zpam
`spam
`
`nctive
`tered
`ilites.
`
`reph-
`
`_:|hi.Lic
`ce its
`e eye
`3 eye,
`
`Amerigen Ex. 1046,
`7--
`Amerigen Ex. 1046, p. 7
`
`

`
`
`
`58
`
`Domge Form Design: Bzbphammceutfc Consideralimzs
`
`tion but also upon the relative extent of its affin-
`' ity for lipid and rejection of water (a high lipid
`partition coefficient). The greater its affinity for
`lipid and the more hydrophobic it is, the faster
`will be its rate of penetration into the lipid-rich
`membrane. Erythromycin base, for example,
`possesses a higher partition coefficient
`than
`other erythromycin compounds, e.g., estolate,
`gluceptate. Consequently, the base is the pre-
`ferred agent for the topical treatment of acne
`where penetration into the skin is desired.
`Because biologic cells are also permeated by
`water and lipid-insoluble substances,
`it
`is
`thought that the membrane also contains Water-
`filled pores or charmels that permit the passage
`of these types of substances. As water passes in
`bulk across a porous membrane, any dissolved
`Solute rnolecularly small enough to traverse the
`pores passes in by filtration. Aqueous pores vary
`in size from membrane to meulbrane and thus in
`
`their individual permeability characteristics for
`certain drugs and other substances.
`The majority of drugs today are weak organic
`acids or bases. Knowledge of their individual
`ionization or dissociation characteristics is im-
`
`portant, because their absorption is governed to
`a large extent by their degrees of ionization as
`they are presented to the membrane barriers.
`Cell membranes are more permeable to the un-
`ionized forms of drugs than to their ionized
`forms, mainly because of the greater lipid solu-
`bility of the unionized forms and to the highly
`charged nature of the cell membrane which re-
`sults in the binding or repelling of the ionized
`drug and thereby decreases cell penetration.
`Also, ions become hydrated through association
`with water molecules, resulting in larger parti-
`cles than the undissociated molecule and again
`decreased penetrating capability.
`The degree of a. drug’s ionization depends
`both on the pH of the solution in which it is pre-
`sented to the biologic membrane and on the pK,,,
`or dissociation constant, of the drug (Whether an
`acid or base}. The concept of pK,, is derived from
`the Hertderson-Hasselbalch equation and is:
`For an acid:
`
`inized n.(alt)
`PH=PKa+1°8
`
`For :1 base:
`
`Since the pH of body fluids varies (stomach, a
`pH 1; lumen of the intestine, = pH 6.6; blood
`plasma, = pH 7.4), the absorption of a drug from
`various body fluids will differ and may dictate
`to some extent the type of dosage form and the
`route of administration preferred for a given
`drug.
`.
`By rearranging the equation for an acid:
`
`PKa _ PH
`
`_ 1
`
`unionized concentration (acid)
`03 ionized concentration (salt)
`
`one can theoretically determine the relative ex-
`tent to which a drug remains unionized under
`various conditions of pH. This is particularly
`useful when applied to conditions of body fluids.
`For instance, if a weak acid having a pK,, of 4 is
`assumed to be in an environment of gastric juice
`with a pH of 1, the left side of the equation would
`yield the number 3, which would mean that the
`ratio of unionized to ionized drug particles
`would be about 1000 to 1, and gastric absorption
`would be excellent. At the pH of plasma the re-
`verse would be true, and in the blood the drug
`would be largely in the ionized form. Table 3—l
`presents the effect of pH on the ionization of
`Weak electrolytes, and Table 3-2 offers some rep-
`resentative pK_., values of common drug sub-
`stances.
`
`From the equation and from Table 3—1, it may
`be seen that a drug substance is half ionized at
`
`Table 3-1. The Effect of pH on the Ionization of
`Weak Eleclrolytest
`
`‘ll: lfnicrxized
`
`pK,,-pH
`-3.0‘
`— 2.0
`- 1.0
`- 0.7
`-- 0.5
`— 0.2
`0
`+ 0.2
`+ 0.5
`+ 0.7
`+ 1.0
`+ 2.0
`+ 3.0
`
`If Weak Acid
`0.100
`0.990
`9.09
`16.6
`24.0
`33.7
`50.0
`61.3
`75.0
`33.4
`90.9
`99.0
`99.9
`
`If Weak Base
`99.9
`99.0
`90.9
`33.4
`76.0
`61.3
`50.0
`33.7
`24.0
`16,6
`9.09
`0.99
`0.100
`
`PH = PK’ + log
`
`unionized conc. (base)
`ionized conc. (salt)
`
`*From Doluisio, ].T., and Swintoslcy, I.V.; Amer. I.
`Pliann, I37:149, 1965.
`
`Table 3-2. pl!
`Drugs
`
`
`Acids:
`
`Bases:
`
`a pH value ‘Sh
`may be defint
`ionized. For -
`value of aboi
`
`present as ior
`amounts. Hc
`reach the blot
`
`out thebody
`through intra
`sorbed from a
`
`gastrointestic
`the general 1
`may be easilj
`acid, with a p
`ciated in the
`would lil<ely'
`the circulafir
`tions it mem
`
`plished or at
`is not readil)
`The pH of tht
`ences the rate
`bution, since
`and therefor
`under some r
`If an union‘
`
`Amerigen Ex. 1046, p. 8
`Amerigen Ex. 1046,
`8
`
`

`
`
`
`'—“'
`_1_ach,
`3; blood
`ug from
`' dictate
`and the
`
`a given
`
`id:
`
`Ell
`ll
`
`itive ex-
`cl under
`
`ticularly
`ly fluids.
`(a of 4 is
`tl‘lC juice
`in would
`i that the
`
`particles
`asorptjon
`la the re-
`
`the drug
`Table 3-1
`zation of
`ome rep-
`
`rug sub-
`
`-1, it may
`onized at
`
`sation of
`
`Week Bose
`99.9
`99.0
`90.9
`33.4
`75.0
`51.3
`50.0
`' 33.7
`24o
`16.6
`9.09
`0.99
`0.100
`
`V.; Amer. J.
`
`Dosage Form Design: Biopharmnceutic Considerations
`
`59
`
`Table 3-2. pI(, Values for Some Acidic and Basic
`Drugs
`
`Acids:
`
`Acetylsalicylic acid
`Barbltal
`
`Bases:
`
`Benzylpenicillin
`Boric acid
`Dicoumarol
`Phenobarbital
`
`-
`
`Phenytoin
`Sulfanilamlde
`
`Theophylline
`Thiopental
`Tolbutamidel
`Warfarin
`
`-
`
`Amphetamine
`Apornorphine
`Atropine
`Caffeine
`
`Chlordiazepoxide
`Cocaine
`Codeine
`Guanethidine
`
`Morpldne
`Procaine
`Quinine
`Reserpine
`
`39K.
`
`3.5
`7.9
`
`2.3
`9.2
`5.7
`7.4
`
`3.3
`10.4
`
`9.0
`7.6
`5.5
`4.8
`
`9.8
`7.0
`9.7
`0.8
`
`4.6
`3.5
`7.9
`11.8
`
`7.9
`9.0
`3.4
`6.5
`
`a pH value which is equal to its pK,. Thus pK,,
`may be defined as the pH at which a drug is 50%
`ionized. For example, phenobarbital has a pI<,,
`value of about 7.4, and in plasma (pH 7.4) it is
`present as ionized and unionized forms in equal
`amounts. However, a drug substance cannot
`read-L the blood plasma for distribution through-
`out the body unless it is placed there directly
`through intravenous injection or is favorably ab-
`sorbed from a site along its route of entry, as the
`gastrointestional tract, and allowed to pass into
`the general circulation. Utilizing Table 3-2 it
`may be easily seen that phenobarbital, a weak
`acid, with a pI<,, of 7.4 would be largely undisso—
`ciated in the gastric environment of pH 1, and
`would likely be well absorbed. A drug may enter
`the circulation rapidly and at high concentra-
`tions if membrane penetration is easily accom-
`plished or at a low rate and low level if the drug
`is not readily absorbed from its route of entry.
`The pH of the drug's current environment influ-
`ences the rate and the degree of its further distri-
`bution, since it becomes more or less unionized
`and therefore more or less lipid—penetrating
`under some condition of pH than under another.
`If an unionized molecule is able to diffuse
`
`through the lipid barrier and remain unionized
`in the new environment, it may return to its for-
`mer location or go on to a new one. However, if
`in the new environment it is greatly ionized due
`to the influence of the pH of the second fluid, it
`likely will be unable to cross the membrane with
`its former ability. Thus a concentration gradient
`of a drug usually is reached at equilibriurn on
`each side of a membrane due to different degrees
`of ionization occurring on each side. A summary
`of the concepts of dissociationfionrkafion is found in
`the accompanying Physical Pharmacy Capsule.
`It is often desirable for pharmaceutical scien-
`tists to make structural modifications in organic
`drugs and thereby favorably alter their lipid sol-
`ubility, partition coefficients, and dissociation
`constants while maintaining the same basic
`pharmacologic activity. These efforts frequently
`result in increased absorption, better therapeutic
`response, and lower dosage.
`
`Specialized Transport Mechanisms
`
`In contrast to the passive transfer of drugs and
`other substances across a biologic membrane,
`certain substances, including some drugs and bi-
`ologic metabolites, are conducted across a mem-
`brane through one of several postulated special-
`ized transport mechanisms. This type of transfer
`seems to account for those substances, many nat-
`urally occurring as amino acids and glucose, that
`are too lipid—insoluble to dissolve in the bound-
`ary and too large to flow or filter through the
`pores. This type of transport is thought to in-
`volve metrlbrane components that may be en-
`zymes or some other type of agent capable of
`forming a complex with the drug (or other agent)
`at the surface membrane, after which the com-
`plex moves across the membrane Where the drug
`is released, with the carrier returning to the origi-
`nal surface. Figure 3-2 presents the simplified
`scheme of this process. Specialized transport
`may be differentiated from passive transfer in
`that the former process may become ”saturated”
`as the amount of carrier present for a given sub-
`stance becomes completely bound with that sub-
`stance resulting in a delay in the "ferrying" or
`transport process. Other features of specialized
`transport include the specificity by a carrier for
`a particular type of chemical structure so that
`if two substances are transported by the same
`medianism one will competitively inhibit the
`transport of the other. Further, the transport
`mechanism is inhibited in general by substances
`that interfere with cell metabolism. The term cc-
`
`Amerigen Ex. 1046, p. 9
`Amerigen Ex. 1046, p. 9
`
`

`
`
`
`6|]
`
`Dosage Form Design: Biophamraceutic Considemtrhns
`
`
`
`Dissociation Constants
`
`Among the physicochernicai characteristics of interest is the extent of dissociationfionization
`of drug substances. This is important because the extent of ionization has an important effect
`on the formulation and pharmacokinetic parameters oi the drug. The extent of dissociationi
`ionization is, in many cases, highly dependent on the pH of the medium containing the drug,
`In formulation. often the vehicle is adjusted to a certain pH in order to obtain a Certain level
`of ionization oi the drug for solubility and stability purposes. In the pharmacokinetic area, the
`extent oi ionization ot a drug is an important affector of its extent of absorption, distribution,
`and elimination. For the practicing pharmacist, it is important in predicting precipitation in
`admixtures and in the calculating of the solubility of drugs at certain pH values. The following
`discussion will present only a brief summary of dissociationiionization concepts.
`The dissociation of a weak acid in water is given by the expression:
`HA -—r H*‘ + A"
`K1[HA] H K-2lH+][A']
`
`At equilibrium, the reaction rate constants K, and K2 are equal. This can be rearranged, and
`the dissociation constant defined as
`
`K _ Q _ [H*]lA"]
`*‘ _ K2 _
`[HA]
`where Ka is the acid dissociation constant.
`
`For the dissociation of a weak base that does not contain a hydroxyl group, the following
`relationship can be used:
`
`BH*' H H’' + B
`
`The dissociation constant is described by:
`
`K = lH*][Bl
`“
`lBH*l
`
`The dissociation of a hydroxyl-containing weak base,
`B + H20 -—» OH‘ + BH*'
`
`The dissociation constant is described by:
`K, , mien
`{Bi
`
`The hydrogen ion concentrations can be calculated tor the solution of a weak acid using:
`[H"] = \/E
`
`Similarly, the hydroxyl ion concentration for a solution of a weak base is approximated by:
`roar] = x/E
`
`Sorne practical applications oi these equations are as follows.
`EXAM PLE 1
`
`The K2. of lactic acid is 1.337 X 10"‘ at 25°C. What is the hydrogen ion concentration of a
`0.02 M solution?
`
`[H*] = V1.33? x 10-4 X one = 1.665 x 10-3 G—ioniL
`
`EXAMPLE 2
`
`The Kb of morphine is 7.4 X 10“. What isthe hydroxyl ion concentration of ai).02 M solution?
`[OHI = V7.4 X 10“? X 0.02 = 1.216 X 10“ G-ioni’L.
`
`Fig. 3-2. Active trrr
`drug molecule; C reprr
`(After O'Reiliy, WJ.: .
`
`tive t'r::msport, as a s
`transport, denotes
`feature of the solut
`
`the membrane age
`that is, from a solo
`one of a higher co:
`anion, against an I
`client. In contrast
`
`diffusion is a spec
`having all of the ah
`the solute is not tr:
`
`tion gradient and 11
`tion irlside the eel]
`
`Many body nut
`acids, are transpo:
`the gastrc-intestine
`Certain vitamins, a
`and vitamin B5, an
`dopa and 5—fluoro1
`mechanisms for th
`
`Investigations r
`often utilized in s
`
`the body} animal 1
`body) transport 11'
`culture models of]
`tive cells have be-
`
`transport across in
`sive and transport
`conducted to inve:
`
`rates of fzransport.
`
`Dissolution
`
`In order for a C11"
`be dissolved in th
`
`
`
`Amerigen Ex. 1046, p. 10
`Amerigen Ex. 1046, p. 10
`
`

`
`
`
`Dosage Form Design: Biapharrnareuffc Considerations
`
`61
`
`For instance, a drug adrrlinistered orally in tablet
`or capsule form cannot be absorbed until the
`drug particles are dissolved by the fluids at some
`point within the gastrointiasfinal
`tract. In in-
`stances in which the solubility of a drug is depen-
`dent upon either an acidic or basic medium, the
`drug would be dissolved in the stomach or intes-
`lines respectively (Fig. 3-3}. The process by
`which a drug particle dissolves is termed dissolu-
`tion.
`
`As a drug particle undergoes dissolution, the
`drug molecules on the surface are the first to
`enter into solution creating a saturated layer of
`drug—so1ut1'on which envelops the surface of the
`solid drug particle. This layer of solution is re-
`ferred to as the diffusion layer. From this diffusion
`layer, the drug molecules pass throughout the
`dissolving fluid and make contact with the bio-
`logic membranes and absorption ensues. As the
`molecules of drug continue to leave the diffusion
`layer, the layer is replenished with dissolved
`drug from the surface of the drug particle and
`the process of absorption continues.
`If the process of dissolution for a given drug
`particle is rapid, or if the drug is administered
`as a solution and remains present in the body as
`such, the rate at which the drug becoms ab-
`sorbed Would be primarily dependent upon its
`ability to traverse the membrane barrier. How-
`ever, if the rate of dissolution for a drug particle
`
`PHRHYNK
`
`ESOFHIGUS
`
`
`
`FYLU HUS
`E M. L EL 3 UEIEI
`|1IUDDENUv
`(uh 5-‘-|"I
`fi5CENI'llN5
`CDLUN
`cecum
`[nu 1'-Bl
`MWENHIK
`
`H
`
`S‘I|'.'MACHlBH|1fl3I
`1
`},n-nucazas
`TRANSVEESE COLON
`DESCENIJING COLON
`JEJUNUM Ian 6.5!
`swnom COLON
`
`7
`
`ization
`leffeot
`riationl
`
`3 drug.
`n level
`ea, the
`bution,
`ltion in
`Ilowing
`
`ad, and
`
`ullowing
`
`l3lI'lQ1
`
`ed by:
`
`ion of a
`
`olution’?
`
`outside membrane
`
`inside
`
`Fig. 3-2. Active transport meal-mm'sm. D represents a
`drag molecule; C represents the carrier in the membrane.
`{After O'Reilly, W.j'.: Ausl. I. Pl1arm., 47:568. 1965.)
`
`tine transport, as a subclassificalion of specialized
`transport, denotes a process with the additional
`feature of the solute or drug being moved across
`the membrane against a concentration gradient,
`that is, from a SUl.L‘ltl.O1'l of lower concentration to
`one of a higher concentration or, if the solute is
`an ion, against an electrocliernical potential ‘gra-
`dient. In contrast to active transport, facilitated
`dlficusion is a specialized transport mechanism
`having all of the above characteristics except that
`the solute is not transferred against a concentra-
`tion gradient and may attain the same concentra-
`tion inside the cell as that on the outside.
`
`Many body nutrients, as sugars and a.1Iu'no
`acids, are transported across the membranes of
`the gastrointestinal tract by carrier processes-
`Certain vitamins, as thiamine, niacin, riboflavin
`and vitamin B5, and drug substances as methyl-
`dopa and 5-fluorouracil, require active transport
`mechanisms for their absorption.
`Investigations of intestinal
`transport have
`often utilized in situ (at the site) or in vino (in
`
`the body) animal models or ex oioo (outside the
`body) transport models; however, recently cell
`culture models of human small-intestine absorp-
`live cells have become available to investigate
`transport across intestinal epithelium.‘ Both pas-
`sive and transport-mediated studies have been
`conducted to investigate mechanisms as well as
`rates of transport.
`
`Dissolution and Drug Absorption
`In order for a drug to be absorbed, it must first
`be dissolved in the fluid at the absorption site.
`
`Fig. 3-3. Anatomioal diagram showing the digestive sys-
`tem including the locations involved in drug absorption and
`their respective pHs.
`
`Amerigen Ex. 1046, p. 11
`Amerigen Ex. 1046, p. 1i1 .'.|
`
`-e
`
`

`
`
`
`62
`
`Dosage Form Design.‘ Bfophermaceutic Crmsidemtions
`
`is slow, as may be due to the physiochemical
`characteristics of the drug substance or the dos-
`age form, the dissolufion process itself would
`be a rate-limit:ing step in the absorption process.
`Slowly soluble drugs such as digoxin, may not
`only be absorbed at a slow rate, they may be
`incompletely absorbed, or, in some cases largely
`unabsorbed following oral administration, due
`to the natural limitation of time that they may
`remain within the stomach or the intestinal tract.
`
`Thus, poorly soluble drugs or poorly formulated
`drug products may rmult in a drug's incomplete
`absorption and its passage, unchanged, out of
`the system via the feces.
`Under normal circumstances a drug may be
`i expected to remain in the stomach for 2 to 4
`hours (gastric emptying time) and in the small in-
`testines for 4 to 10 hours, although there is sub-
`stantial variation between people, and even in
`the same perso