kiot
`h raTia
`
`Howard Cu Ans&
`
`Nicholas G„ Papovich
`
`Loyd V Men, Jr
`
`p. 1
`
`SHIRE EX. 2058
`KVK v. SHIRE
`IPR2018-00290
`
`SHIRE EX. 2077
`KVK v. SHIRE
`IPR2018-00293
`
`

`

`I am a Pharmacist
`
`•
`
`•
`
`I am a specialist in medications
`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 medications in my care.
`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.
`armacy from around
`
`•
`
`STAINAdrangeailngidtirgs/r4M aaviug
`fAlt M104141 Alt4.1q
`I am a completimokttimAypicigo
`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.
`I am a counselor to the patient
`I help the patient understand the proper use of prescription
`medication.
`I assist in the patient's choice of nonprescription drugs or in the
`decision to consult a physician.
`I advise the patient on matters of prescription storage and potency.
`I am 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.
`• This is my calling • This is my pride
`
`•
`
`•
`
`p. 2
`
`

`

`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. Allen, Jr., Ph.D.
`Professor and Chair, Department of Medicinal
`Chemistry and Pharmaceutics, College of
`Pharmacy
`The University of Oklahoma
`
`SIXTH EDITION
`
`A Lea & Febiger Book
`
`Williams & Wilkins
`sAormoke • ■4ILADELEHIA • HONG KONG
`LONDON • MUNICH • SYDNEY • tOKYO
`A WAVERLY COMPANY
`
`

`

`I
`
`Executive Editor: Donna M. Balado
`Developmental Editor: Frances M. Klass
`Production Coordinator: Peter J. Carley
`Project Editor: Jessica Howie Martin
`
`Copyright ti)) 1995
`Williams & Wilkins
`Rose Tree Corporate Center, Building II
`1400 North Providence Road, Suite 5025
`Media, PA 19063-2043 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, induding 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 of America
`
`Library of Congress Cataloging in Publication Data
`
`96 97 98
`3 4 5 6 7 8 9 10
`
`Ansel, Howard C., 1933—
`Pharmaceutical dosage forms and drug delivery systems / Howard C.
`Ansel, Nicholas G. Popovich, Lloyd V. Allen, Jr.-6th ed.
`p. cm.
`Includes bibliographical references and index.
`ISBN 0-683-00193-0
`1. Drugs—Dosage forms. 2. Drug delivery systems.
`I. Popovich, Nicholas G. II. Allen, Loyd V.
`III. Title.
`[DNLM: 1. Dosage Forms. 2. Drug Delivery Systems. QV 785 A618i
`1995]
`RS200.A57 1995
`615'.1—dc20
`DNLM/DLC
`for Library of Congress
`
`94-22471
`CIP
`The use of portions of the text of USP23/NF18, 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 context or by obsolescence resulting from publica-
`tion of a supplement.
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`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
`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 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 blopharmaceu tics,
`to 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, biotransforma-
`tion (metabolism),, 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's
`activity within the body. The area of study which
`elucidates the time course of drug concentration
`
`in the blood and tissues is termed pharrreoceki-
`netics. 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. 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 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 fraction 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 may be quite different
`(greater or lesser) than the concentration of the
`drug in the other compartments. This is due
`
`55
`
`p. 5
`
`

`

`56
`
`Dosage Form Design: Biopharnuu:eutic Considerations
`
`Oral
`Administration
`
`Gastro-
`Intestinal
`Tract
`
`Intravenous
`Injection
`
`Circulatory
`Systems
`
`Drug
`
`Drug
`
`Intramuscular
`Injection
`
`immm.4110.
`
`Subcutaneous
`Injection
`
`F....*
`
`Tissues
`
`Metabolic
`Sites
`
`Drug
`Metabolites
`
`Fig. 3-1. Schematic representation of events of absorption, metabolism, and excretion of drugs after their administration
`by various routes.
`
`largely to the physiochemical 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 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 biotransfonned into
`pharmacologically active or inactive metabolites.
`Often, both the drug substance and its metabo-
`lite(s) are active and exert pharmacologic effects.
`For example, the antianxiety drug prazepam
`(Centrax) metabolizes, in part, to oxazepain
`(Serax), which also has antianxiety effects. In
`some instances a pharmacologically inactive
`drug (termed a prodrug) 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,
`
`dipivefrin E
`drolysis to e
`The metal
`is usually ai
`rates in the
`usually via
`may calculi
`(termed ko)
`ination from
`to both me
`which are
`therefore im
`is much les;
`tered orally
`stances, dru
`are occurrit
`rates.
`
`Gen
`
`Before an
`site of actioi
`surmount a
`are chiefly ;
`such as thof
`lungs, blooi
`generally
`composed c
`(b) those co
`the intes tin
`than one ca
`single cell.
`must pass
`types beton
`stance, a do
`gastrointest
`large intest
`circulation,
`which it ha
`sue, and th
`Althougl
`differs one I
`viewed in
`containing)
`tein layer. 1
`biologic me
`passive dif
`transport
`main categ;
`have been ;
`Passive Di
`The tern
`the passage
`
`.6
`
`I I
`
`

`

`Dosage Form Design: Biopharrnareutic Considerations
`
`57
`
`dipivefrin BC) 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 ka) 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 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 dassified as three main types: (a) those
`composed of several layers of cells, as the skin;
`(b) 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-
`co ntaining) 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 dearly defined processes
`have been ascribed to drug transfer.
`Passive Diffusion
`The term passive diffusion is used to describe
`the passage o f (drug) molecules through a mem-
`
`brane which behaves inertly 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 (Le., 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 (dc/dt) is propor-
`tional to the difference in drug concentration on
`both sides of the membrane:
`
`dc
`-- =
`dt
`
`
`
`P(C1 —
`
`in which Cr 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 in the blood and its
`subsequent distribution to the tissues, for practi-
`cal purposes the value of C1 — Ca may be taken
`simply as that of C1 and the equation written in
`the standard form for a first order rate equation:
`
`dc
`dt
`--
`
`P
`Cr
`
`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, ie., dou-
`bling 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
`
`for-
`tated
`sm a
`into
`tlites.
`tabo-
`fects.
`Tani
`Tam
`s. In
`ictive
`tered
`
`teph-
`hrirte
`2hilic
`ce its
`e eye
`t eye,
`
`

`

`58
`
`Dosage Form Design: Biopharmaceutie Considerations
`
`Lion 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 biblogic cells are also permeated by
`lipid-insoluble substances, it is
`water and
`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 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 plc,
`or dissociation constant, of the drug (whether an
`acid or base). The concept of pK is derived from
`the Henderson-Hasselbalch equation arid is:
`For an acid:
`
`pH = pK, + log ionized conc. (salt)
`b unionized conc. (acid)
`
`For a base:
`
`pH = pK, -I- log
`
`unionized conc. (base)
`ionized conc. (salt)
`
`Since the pH of body fluids varies (stomach, =
`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
`unionized concentration (acid)
`ionized concentration (salt)
`
`= log
`
`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 plc 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 3-1
`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 Electrolytes*
`
`% Unionized
`If Weak Acid
`pK,-pH
`If Weak Base
`-3.0
`0.100
`99.9
`-2.0
`0.990
`99.0
`9.09
`-1.0
`90.9
`-0.7
`16.6
`83.4
`-0.5
`24.0
`76.0
`-0.2
`38.7
`613
`0
`50.0
`50.0
`+0.2
`61.3
`38.7
`+0.5
`76.0
`24.0
`+0.7
`83.4
`16.6
`+1.0
`90.9
`9.09
`+2.0
`99.0
`0.99
`+3.0
`99.9
`0.100
`* From Doluisio, J.T., and Swintosk-y, J.V.; Amer. I.
`Phann., 137:149,1965.
`
`Table 3-2. pi(
`Drugs
`
`Adds:
`
`Bases.
`
`a pH value In
`may be de.finc
`ionized. For
`value of aboi
`present as ior
`amounts. 1 lc
`reach the bloc
`out the body
`through infra
`sorbed from i
`gastrointestic
`the general
`may be easil:
`acid, with a p
`ciated in the
`would likely'
`the circulatic
`tions if mem
`plished or at
`is not reach!)
`The pH of thi
`ences the rate
`button, since
`and therefor
`under some c
`If an union:
`
`8
`
`

`

`iach,
`1; blood
`ug from
`dictate
`and the
`a given
`
`id:
`
`id)
`t)
`
`itive ex-
`d under
`ticularly
`ly fluids.
`a of 4 is
`Inci juice
`in would
`t that the
`partides
`sorption
`La the re-
`the drug
`'able 3-1
`Cation of
`ome rep-
`rug sub-
`
`-1, it may
`onized at
`
`cation of
`
`Weak Base
`99.9
`99.0
`90.9
`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: Biopharmaceutic Considerations
`
`59
`
`Table 3-2. pKa Values for Some Acidic and Basic
`Drugs
`
`Adds:
`
`Bases:
`
`Acetylsalicylic acid
`Barbital
`BenzylpeniciNin
`Boric acid
`Dicoumarol
`Phenobarbital
`Phenytoin
`Sulfanilamide
`Theophylline
`Thiopental
`Tolbutamide
`Warfarin
`Amphetamine
`Apomorphine
`Atropine
`Caffeine
`Chlordiazepoxide
`Cocaine
`Codeine
`Guanethidine
`Morphine
`Procaine
`Quinine
`Reserpine
`
`3.5
`7.9
`2.8
`9.2
`5.7
`7.4
`8.3
`10.4
`9.0
`7.6
`5.5
`4.8
`9.8
`7.0
`9.7
`0.8
`4.6
`8.5
`7.9
`11.8
`7.9
`9.0
`8.4
`6.6
`
`a pH value which is equal to its plc. Thus pKa
`may be defined as the pH at which a drug is 50%
`ionized. For example, phenobarbital has a pKa
`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
`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 plc of 7.4 would be largely undisso-
`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-
`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 equilibrium on
`each side of a membrane due to different degrees
`of ionization occurring on each side. A summary
`of the concepts of dissociation/ionization 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 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
`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 ac-
`
`11 9
`
`

`

`60
`
`Dosage Form Design.: Biopharmaceutic Considerations
`
`Dissociation Constants
`
`Among the physicochemical characteristics of interest is the extent of dissociation/ionization
`of drug substances. This is important because the extent of ionization has an important effect
`on the formulation and pharmacokinetic 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 level
`of ionization of the drug for solubility and stability purposes. In the pharmacokinetic area, the
`extent of ionization of 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 dissociation/ionization concepts.
`The dissociation of a weak acid in water is given by the expression:
`HA
`FP' + A-
`NNA] K2[1-11A- ]
`At equilibrium, the reaction rate constants K1 and K2 are equal. This can be rearranged, and
`the dissociation constant defined as
`
`K1
`Ka — K2 —
`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:
`
`[H- ][A- ]
`[HA]
`
`BR'
`The dissociation constant is described by:
`
`+ B
`
`[H+][13]
`Ka — [BM
`The dissociation of a hydroxyl-containing weak base,
`B + H2O OH- + BH'''
`The dissociation constant is described by:
`
`[OH- ][BH1
`Kb -
`[B]
`The hydrogen ion concentrations can be calculated for the solution of a weak acid using:
`[H4-] =
`•\/
`}aC
`Similarly, the hydroxyl ion concentration for a solution of a weak base is approximated by:
`[OH- ] = Kbc
`Some practical applications of these equations are as follows.
`EXAMPLE 1
`The K. of lactic acid is 1.387 x 10-4 at 25°C. What is the hydrogen ion concentration of a
`0.02 M solution?
`[H+] = \/1.387 X 10-4 x 0.02 = 1.665 x 10-3 G-ion/L.
`
`EXAMPLE 2
`The Kb of morphine Is 7.4 x 10-7. What is the hydroxyl ion concentration of a 0.02 M solution?
`[OHJ = V7.4 x 10-7 x 0.02 = 1.216 x 10-4 G-Ion/L.
`
`D"-*
`
`outside
`
`rr
`
`Fig. 3-2. Active tra
`drug molecule; C repri
`(After O'Reilly, W.I.: ,
`
`five transport, as a s
`transport, denotes
`feature of the solut
`the membrane aga
`that is, from a solu
`one of a higher ca
`an ion, against an
`dient. In contrast
`diffusion is a spec
`having all of the ab
`the solute is not to
`tion gradient and n
`Lion inside the cell
`Many body nut
`acids, are transpoi
`the gastrointestim
`Certain vitamins,
`and vitamin B6, an
`dopa and 5-fluoroi
`mechanisms for th
`Investigations
`often utilized in s
`the body) animal
`body) transport ir
`culture models of I
`tive cells have be
`transport across in
`sive and transport
`conducted to inve
`rates of transport.
`
`Dissolution
`In order for a dr
`be dissolved in th
`p. 10
`
`

`

`Dosage Form Design: Biopharmaceutic Considerations
`
`61
`
`D -4
`
`outside
`
`membrane i
`
`inside
`
`Fig. 3-2. Active transport mechanism. 13 represents a
`drug molecule; C represents the carrier in the membrane.
`(After O'Reilly, W.J.: Aust. J. Pharm., 47568, 1966.)
`
`Hoe transport, as a subclassification 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 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
`diffusion 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 amino
`adds, are transported across the membranes of
`the gastrointestinal tract by carrier processes.
`Certain vitamins, as thiamine, niacin, riboflavin
`and vitamin B6, 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 vivo (in
`the body) animal models or a vivo (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 pas-
`sive and transport-mediated studies have been
`conducted to investigate mechanisms as well as
`rates of transport.
`
`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 dissolution, 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 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 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
`
`4,1,E
`
`•-fLeN
`444.1. fixiXd.5
`
`VODEM:no
`I..
`] -7I
`
`&Hui 6..0
`
`I
`
`II)
`Cr COY
`
`mp, •m Try e
`
`IT6MA.C14 S.1, PM 3 II
`
`oroicia5.5
`
`rwAftsriE • U. CRON
`
`6C$t Ent's.; Mew
`
`JCW.Lai II /0 .1 51
`
`5111, 0 I 0 COI ow
`
`ECTwO
`
`ization
`t effect
`:lotion/
`drug.
`n level
`ea, the
`bution,
`ton in
`Bowing
`
`and
`
`!towing
`
`ed by:
`
`ion of a
`
`°lotion?
`
`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.
`
`p. 11
`
`

`

`62
`
`Dosage Form Design: Biopharnzaceutic Considerations
`
`is slow, as may be due to the physiochemical
`characteristics of the drug substance or the dos-
`age form, the dissolution 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 emptying time) and in the small in-
`testines for 4 to 10 hours, alth