`
`u .
`
`.
`
`_
`
`.
`
`SHIRE EX. 2010 Part 1
`
`IPR2018-00293
`
`r/!2
`
`HQward Ame;
`
`Nichaiag
`
`PQpQWCh
`
`Layd M Mien; Jr,
`
`SHIRE EX. 2010 Part 1
`KVK v. SHIRE
`IPR2018-00293
`
`

`

`
`
`I am a Pharmacist
`
`
`
`O I am a specialist in medications
`
`I supply medicines and pharmaceuticais to those who need them.
`
`i prepare and compound special dosage forms.
`
`I control the storage and. preservation of all medications 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.
`
`$¥mfiMfimfififiiWfiggfirfipgfi-§&\i§’§1c§é§§l¥?1armacy from around
`stilt? ant-1%} a H5 son:a a. r sat: at:
`O I am a comymwoiéibfiflihflsifiéfiififinttit
`I am a partner in the case of every patient who takes any kind of.
`medication.
`
`I am a consultant on the merits of diEferent therapeutic agents.
`
`I am the comecting link between physician and patient and the final
`check on the safety of medicines.
`
`0 Jam (1 coanseior to the patient
`
`I help the patient understand the proper use of prescription
`medication.
`
`I assist in the paiient’s choice of nonprescription drugs or in the
`decision to c0nsuit 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 information.
`
`I encourage and promote sound personal health practices.
`
`My services are available to all at all times.
`
`9
`
`This is my calling O This is my pride
`
`r/!3
`
`

`

`
`
`Pharmaceutical
`
`Dosage Forms
`
`and Drug
`
`Delivery Systems
`
`Howard C. Ansel, Ph. D.
`Panoz Professor of Pharmacy, Department of
`Phannacculics, College of Pharmacy
`The Ur-ir‘zrcrsily of Georgia
`
`Nicholas G. Popow'ch, PhD.
`Professor and Head, [Department of Pharmacy
`Practice, School of Pharmacy and Pharmacal
`Sciences
`
`Purdue University
`
`Loyd V. Allen, Jr., PhD.
`Professor and Chair, Department of Medicinal
`Chemistry and Pharmaceutics, College of
`Pharmacy
`The University of OkiriI-iormi
`
`SIXTH EDITION
`
`A Les 8‘ Febiger Book
`
`__Williams 8; Wilkins
`BAITIMOiE I ”HIIADELFHIA I HDNO KONG
`
`LONDON . MUN=CH - SYDNEY -
`:OKTG
`A WAVERLY COMPAN Y
`
`r/!4
`
`

`

`
`
`Executive Editor: Donna M. Balado
`
`Developmental Editor: Frances M [(1355
`Production Coordinator: Peter I. Carley
`Project Editor”: Jessica Howie Martin
`
`Copyright © 1995
`Williams it Wilkins
`Ruse Tree Corporate Center. Building II
`1400 North Providence Road, Suite 5025
`Media, PA 19053-2043 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 information 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 manufacturers of the
`medications mentioned.
`
`Printed in the United States oj'AmcriaI
`
`Library of Congress Cataloging in Publication Data
`
`Ansel, Howard (1., 1933--
`Phannaceutical dosage forms and drug delivery systems 3' Howard C.
`Ansel, Nicholas G. Popovich. Lloyd V. Allen, Ir.—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. Drugs—Dosage forms.
`I. Popovich, s licholas G.
`Ll. Allen, Loyd V. HI. Title.
`[DNLM1 1. Dosage Forms.
`2. Drug Delivery Systems. QV 785 A618i
`1995}
`R5200.A57
`615’J—dtflfl
`DNLNI;JI DLC
`for Library of Congress
`
`1995
`
`94—22471
`CIP
`
`The use of portions of the text of USPZBE N'FlS, copyright 1994, is by permission 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 mntext or by obsolescence resulting from publica-
`tion of a sopplcment.
`
`PRINTED IN THE UNITED STATES OF m‘vflimCA
`
`r/!5
`
`

`

` 3
`
`
`
`-.'__.'.-—r..-.-._.-.-...._-#-
`
`._-.-..-.._.t.
`
`
`
`Dosage Form Design:
`Biopnarmaceutic Considerations
`
`A5 otscusseo 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
`administration. 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 absurption 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 sblubility, 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 binphmmaceutics.
`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 concentration 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, biotransfomia-
`tion (metabolism-Land 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
`eiucidates the time course of drug concentration
`
`in the blood and tissues is termed piisrmncoki—
`nettcs. It is the study of the kinetiCs of absorption,_
`distribution, metabolism and excretion (ADME)
`of drugs and their corresponding pharmaco-
`logic, therapeutic, or toxic response in animals
`and man. Fmther, since one drug may alter the
`absorption, distribution. metabolism or extre-
`Lion of another drug, pharrnacoldnetics 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 elimina lion. For
`instantze, following the oral administmtion of a
`drug and its enby into the gash-ointestinal beer,
`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 these sites the drug may return to the 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
`
`as metabolites. As shown in Figure 3—1, drugs
`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, each 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 circulation. 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 my be quite different
`(greater or lesser) than the concentration of the
`drug in the other compaxtments. This is due
`
`55
`
`r/!6
`
`
`
`
`
`___.,....In.__.._._...-_,_...._...-_..-.._........_._....._._....,_,..._:._..__-___.._,..._..._._...._
`
`
`
`
`
`
`
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`
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`
`
`
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`
`

`

`
`
`56
`
`Dosage Fmrt Design: Biapharmaceutic Considerations
`
`
`
`Orol
`
`
`Administration
`
`Gastro—
`
`Intestinal
`
`Tract
`
`'t
`
`
`
`
`
`
`
`
`intravenous
`
`Injection
`
`Circulatory
`
`djpivefrin E
`drolysis to e
`The metal:
`
`is usually or
`notes in the I
`usually via
`may calcul:
`(termed kcll
`ination from
`to both me-
`which are
`therefore in».
`is much Ies:
`
`tered orally
`stances, dru
`are accurrir
`rates.
`
`Gen
`
`Before an
`site of actioi
`surmount a
`
`are chiefly i
`such as tho:
`
`lungs, bloo:
`generally cl;
`composed r
`lb) those co
`the intestin
`than one ce'.
`
`single cell,
`must pass
`types befor‘
`stance, 3 £th
`gastrointest
`large intest
`circulation,
`which it he
`sue, and th
`Althougt
`differs one I
`
`viewed in ;
`containing)
`fein layer. l
`biologic tnr
`passive dil
`transport
`1
`main categn
`have been .-
`
`Passive Di
`The tern
`
`the passage
`
`
`
`r/!7
`
`
`
`C O :
`
`(DL.
`
`O X
`
`l_Ll
`
`l__1
`
`Systems
`
`'tU
`
`Drug
`
` Intramuscular
` Tissues
`
`
`injection
`
`
`
`Subcutaneous
`
`lnjecticm
`
`Metabolic
`
`Slles
`
`Drug
`Metabolites
`
`
`
`
`Schematic representation of events of absorption, metabolism, and excretion of drugs after their administration
`Fig. 3—1.
`by serious routes.
`
`largely to the physiochemjcal 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 compartment 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 concentration of the drug in the cone
`pa rtment 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 biotransformed into
`pharmacologicaily active or inactive metabolites.
`Often, both the drug substanCe and its metabo—
`litels) are active and exert pharmcologic effects.
`For example,
`the antjanxiety drug prazepam
`(Centraxl metabolizes,
`in part,
`to oxazepam
`(Seraxl, which also has antianxiety effects. In
`some instances a pharmacologically inactive
`drug (termed a pt‘atimg) may be administered
`for the known effects of its active metabolites.
`
`Dipivetrin, for example, is a prodrug of epineph-
`rine formed by the esterification of epinephrine
`and pivalic acid. This enhances the lipapl'ljlic
`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.
`
`

`

`
`
`130ng Form Design: Hiaphnnmcculic Considerations
`
`5'}
`
`is converted by enzymatic hy—
`dipivefrin l-ICl
`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 pharo'lacokineticist
`may calculate an elimbiation rate constant
`(termed ltd) 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 adrrunistered 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 administered drug can arrive at its
`site of action in effective concentrations, it must
`surmount a number of barriers. These barriers
`
`are chiefly a succession of biologic membranes
`such as those of the gastrointestinal epithelium,
`lungs, blood, and brain. Body membranes are
`generally classified as three main types: (3} those
`composed of several layers of cells, as the skin,-
`(bl those compared of a single layer of cells, as
`the intestinal epithelium; and (:3 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-
`oantaining) 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.
`
`I Passive Diffusion
`
`The term passing riijj’usian is used to describe
`the passage of (drug) molecules through a mem—
`
`
`
`brane which behaves inerlly in that it does not
`actively participate in the process. 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
`ocuuring 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 (dcfclt) is propor-
`tional to the difference in drug concentration on
`both sides of the membrane:
`
`dc
`‘a = Pic: — C2)
`
`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—
`meni with the greater concentration of drug and
`thus the transport of drug proceeds trom come
`partrnent 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, clue to the
`rapid dilution of the drug in the blood and its
`subsequent distribution to the tissues, for practi-
`cal purposes the value of C1 — C2 may be taken
`simply as that of C1 and the equation written in
`the standard form for a first order rate equation;
`
`.
`dc
`-a — FL}
`
`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, Le, dou—
`bh‘ng the dose doubles the transfer rate. The
`magnitude 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-
`
`ration
`
`r/!8
`
`

`

`
`
`53
`
`Dosage Form Design.- Biophormaccutic Considerations
`
`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
`tl'eatIuent 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 channels that permit the passage
`of these types of substances. As water passes in
`bulk across a porous membrane, any dissolved
`solute molecularly small enough to traverse the
`pores passes in by filtration. Aqueous pores vary
`in size from membrane to membrane and thus in
`
`their individual permeability characteristics for
`certain drugs and other substances.
`The majority of rings 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 undissoctated 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 pig,
`or dissociation constant, of the drug (whether an
`acid or base). The concept of pK, is derived from
`the Henderson-l-lasselbalch equation and is:
`For rm and:
`
`ionized cone. (salt)
`PH = 1919 + 10%m
`
`For a base:
`
`Since the pH of body fluids varies (stomach, 2
`pH 1; lumen of the intestine, = pH 6.6; blood
`plasma, =3 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:
`
`PK: _ PH
`
`__ l
`_ Us
`
`Imionized concentration (acid)
`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 and having a pK, of4 is
`assumed to be in an environment of gastric juice
`with a pH of l, 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—1
`presents the effect of pH on the ionization of
`weak electrolytes, and Table 3~2 otters 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 iotfizod at
`
`Table 3—1. The Effect of pH on the Ionization of
`Weak Electrolytes‘
`
`it: Unionized
`
`pKa-pH
`-3.0
`— 2.0
`— l .0
`- 0.7
`- 0.5
`— 0.2
`0
`+ 0.2
`+ 0.5
`+ 0.7
`+ 1.0
`+ 2.0
`+ 3.0
`
`
`if Weak Acid
`If Weak Base
`0.l 00
`99.9
`0.990
`99.0
`9.09
`90.9
`16.6
`53.4
`24.0
`76.0
`33.7
`61.3
`50.0
`50.0
`61 .3
`33.7
`76.0
`24.0
`33.4
`16.6
`90.9
`9.09
`99.0
`0.99
`99.9
`0.100
`
`.—
`a
`P” T pK 4
`
`‘ ——_-___"—'_
`log unionized conc. (base)
`ionized conc. (salt)
`
`’ From Doluisio, ].T., and Swintosky, I.V.; Amer. l.
`Plot-m, 137:149, 1965.
`
`
`
`[)5
`Table 3-2.
`Drugs
`
`Acids:
`
`Bases:
`
`a pH value in
`may be deflm
`ionized. For I
`value of also.
`
`present as ior
`amounts. Ilc
`reach the blot
`
`out the body
`through intra
`sorbed from i
`
`gastrointestic
`the general
`I
`may be easil'
`acid, with a p
`ciated in the
`
`would likely
`the circulatir
`tions it mem
`
`plished or at
`is not reach];
`The pit of th:
`ences the rate
`bution, since
`and therefor
`under some r
`If an union
`
`r/!9
`p8
`
`

`

`
`
`
`
`id)
`ll
`
`itive ex-
`d under
`
`ticularly
`Iy fluids.
`(,1 of 4 is
`tric juice
`in would
`1 that the
`
`particles
`isoiption
`is the re-
`
`the drug
`‘able 3-1
`cation of
`once rep—
`
`rug sub»
`
`—1, it may
`onized at
`
`ration of
`
`Wm]: Base
`
`99.9
`99.0
`98.9
`83.4
`76.0
`61 3
`50.0
`38.7
`24.0
`16.6
`9.09
`0.99
`0.100
`
`V.; Amer. I.
`
`Dosage Form Design: Biophmccutic Considerations
`
`59
`
`Table 3-2. pK. Values for Some Acidic and Basic
`Drugs
`
`.—__________PE
`Acids:
`Acetylsalicylic acid
`3.5
`Barbi lal
`7.9
`
`Bases:
`
`Benzylpenicillin
`Boric acid
`Dicournsrol
`Phenobarbital
`Phenytoin
`Sullanilamide
`
`Theophylline
`Tlliopcntsl
`Tolbutamide
`Warfarin
`
`Amphetamine
`Apomorphine
`Atropine
`Caffeine
`
`Clflordiazepoadde
`Cocaine
`Codeine
`Guanetbidine
`
`Morphine
`Procaine
`Quinine
`Reserpine
`
`2.8
`9.2
`5.?
`7.4
`8.3
`10.4
`
`9.0
`7.6
`5.5
`4.8
`
`9.8
`7.0
`9.7
`0.3
`
`1L6
`8.5
`7.9
`11.3
`
`7.9
`9.0
`3.4
`6.6
`
`a pH value which is equal to its pK.. Thus 13K.
`may be defined as the pH at which a drug is 50%
`ionized. For example, phenobarbital has a pK.
`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
`reach 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
`gaso‘ointestional 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 pK. of 7.4 would be largely undjsso-
`dated 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-
`butiori, since it becomes more or less unionized
`and therefore more or less lipid—penetrating
`under some condition of pH thanunder 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 equilibrium on
`each side of a membrane due to different degrees
`of ionization occurring on each side. A summary
`of the concepts of dissucictionfion'mafion 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 membrane 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 sol}
`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
`mechanism 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 sc-
`
`r/!;
`
`

`

`
`
`Dosage Form Design: Biophmmceutic Considerations
`
`——.———_—_——_—_—___
`
`Dissociation Constants
`
`Among the physicochemical characteristics of interest is the extent of dissociationiionization
`of drug substances. This is important because the extent ot ionization has an important effect
`on the formulation and pharmacoltinetic parameters of the drug. The extent of dissociation}
`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 levet
`oi ionization of the drug for solubility and stability purposes. In the pharmacokinetic area, the
`extent of ionization of a drug is an important effector 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 dissociationfionization concepts.
`The dissociation of a weak acid in water is given by the expression:
`HA H H“ + A—
`KtlHAl H K2[H+][A‘}
`
`At equilibrium, the reaction rate constants K1 and K2 are equal. This can be rearranged. and
`the dissociation constant defined as
`
`K = a = [HillA‘]
`a
`K2
`[HA]
`where Ka is the acid dissociation constant.
`
`For the dissuciation of a weak base that does not contain a hydroxyl group, the following
`relationship can be used:
`
`8H" H H* + B
`
`The dissociation constant is described by:
`
`K = lH*l[Bl
`"
`[Bi-F]
`
`The dissociation of a hydroxyI-containing weak base,
`B + H20 H OH‘ + BH"
`
`The dissociation constant is described by:
`Kb = [OHTJIBHW
`{Bl
`
`The hydrogen ion concentrations can be calculated for the solution of a weak acid using:
`[Ht] = this
`
`Similarly, the hydroxyl ion concentration for a solution 01 a weak base is approximated by:
`[W] = M
`
`Some practical applications of these equations are as follows.
`EXAMPLE 1
`
`The KB ot lactic acid is 1.387 X 10"“ at 25°C. What is the hydrogen ion concentration of a
`0.02 M solution?
`
`{W} = V1.33? x 10-4 x 0.02 = 1.655 x 10'3 G-toan.
`
`EXAMPLE 2
`
`The Kb otmorphine is 7.4 x 104. What isthe hydroxyl ion concentration of a0.02 M solution?
`[OI-II = V7.4 X 10“? X 0.02 = 1.216 x 1l2l‘4 G—ionKL.
`
`Fig. 3—2. Active tro
`drug molecule; C rcpt-r
`(After O'Reiliy, WJ.: .
`
`lice transport, as a 5
`transport, denotes
`feature of the solut
`
`the membrane age
`that is, from a solo
`one of a higher co:
`an ion, against an I
`dient. In contrast
`
`diffusion is a spec
`having all of the ah
`the solute is not b“:
`
`lion gradient and n
`lion inside the cell
`
`Many body nut
`acids, are transpor
`the gastrointestim
`Certain vitanlins, e
`and vitantin Be, an
`dope and 5—fluorot
`mechanisms for th
`
`hivestigations r
`often utilized in s
`
`the body} animal 1
`body) transport 13'
`culture models of]
`live celis have be:
`
`transport across in
`sive and tramporl
`conducted to inve:
`
`rates of transport.
`
`Dissolution
`In order for a (11'
`be dissolved in th
`
`r/!21
`p. 10
`
`'.'.'.I
`
`
`
`

`

`
`
`Dosage Font-r Design: Biophflnmceutic Considerations
`
`61
`
`I
`
`
`
`For instance, a drug administered orally in tablet
`or capsule form cannot be absorbed until the
`drug particles are dissolved by the fluids at some
`point within the gastrointestinal 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-
`tines respectively (Fig. 3—3}. The process by
`which a drug particle dissolves is termed dissolu-
`tion.
`
`As a drug particle undergoes diSSOlutiDl'l, the
`drug molecules on the surface are the first to
`enter into solution creating a saturated layer of
`drug—solution which envelops the surface of the
`solid drug particle. This layer of solution is re-
`ferred to as the difiusr’on 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 d rug 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.
`it 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 becomes 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
`
` hunlrlll
`
`[50”! “US
`
`
`
`
`IYLCRUS
`51 L l II. lull! I
`l
`
`wonhuu
`UH a-Tt
`
`Y‘INSUEISE (OLD!
`QSEIJI'DIMD
`
`KIND”
`"tsunami mum
`I w l-II
`
`JEJUNUH [IN [51
`
`IIFEMOBI -—
`Llflllflll} CGLDH
`
`ILIUI /
`HECTIJH
`l
`
`I
`outside membrane
`1
`
`.
`.
`msrde
`
`Fig. 3—2. Active tnmspori mechanism. D represents a
`drug molecule; C represents the carrier in the mmhmrte.
`(After O'Reflly, W}; Aust, J, ”term, 47563, 1956.}
`
`tioe transport, as a subclasgification of Specialized
`transport, denotes a prorrss with the additional
`feature of the solute or drug being moved across
`the membrane against a concentration gradient,
`that is, from a solution of lower concentration to
`one of a higher concentration or, if the solute is
`an ion. against an electrochemical potential gra-
`dient. In contrast to active transport, facilitated
`drfi‘usion is a specialized transport mechanism
`having all of the above characteristics except that
`the solute is not transferred against a concentra+
`lion gradient and may attain the same concentra—
`tion inside the cell as that on the outside.
`
`Many body nutrients, as sugars and amino
`acids, are transported across the membranes of
`the gastrointestinal tract by carrier processes.
`Certain vitamins, as thiamine, niacin, riboflavin
`
`and vitamin 85, and drug substances as methyl-
`dopa and 5-f1uorotuacil, require active transport
`mechanisms for their absorption.
`Investigations of
`intestinal
`transport have
`often utilized in site (at the site] or in ofoo (in
`
`the body) animal models or ex vino (outside the
`body) transport models; however, recently cell
`culture models of human small-intestine absorp-
`tive cells have become available to investigate
`transport across intestinal epithelium} Both pa5~
`sive and transport-mediated studies have been
`conducted to invratigate mechanisms as well as
`rates of transport.
`
`c
`
`(is
`
`l l
`
`|
`l
`
`t
`
`o—avlC )0
`
`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. Anatomical diagram showing the digestive sys—
`tem including the locations involved in drug absorption and
`their respective pHs.
`
`r/!22
`
`
`
`ization
`t effect
`:iationt
`
`a drug.
`:1 level
`ear, the
`bution,
`rtion in
`
`Ilowing
`
`ad, and
`
`tlowi rig
`
`Ising:
`
`ed by:
`
`ion of a
`
`olution?
`
`
`
`

`

`
`
`62
`
`Dosage Form Design: Biophermcceuh'c Considerations
`
`is slow, as may be due to the physiochemical
`characteristics of the drug substance or the dos-
`age form, the dissoluiion process itself would
`be a rate—limiting 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 result in a drug’s incomplete
`absorption and its passage, unchanged, out of
`the system via the feces.
`Under normal circumstances a drug may be
`' expected to remain in the stomach for 2 to 4
`hours (gastric onptying time} and in the small in-
`testines for 4 to ll} hours, although there is sub—
`stantial variation between people, and even in
`the same person on different occasions. Various
`techniques have been used to determine gastric
`emptying time and the gastrointestinal passage
`of drug from various oral dosage forms, includ—
`ing the tracking of dosage forms labeled with
`gamma—emitting radionuclides through gamma
`scmti