:ol1su-

ogical

ion of

Chapte
).
hane.

rs de

.tifl Ie

opro-

rique
'aris)

hine-

nans.

I -{rn

Soc
Physicochemical and
emie
eutical Propefties of Drug
ances and Pharmacokinetics
ICTI\L
206.

Res

ium, AMBHEKAR
acid
ride

in-
nlre
:--:ret iations
rcric
{DME, absorption, distribution, J, bioavailability pK,, the negative logarithm of a
i79.
cat- metabolism, and excretion F, absolute bioavai labil ity dissociation constant, K
{P, absorption potential FDA, U.S. Food and Drug pK,, negative logarithm of dissociation
En.
lTP, adenosine s/-triphosphate Administration constant of water
{NDA, Abbreviated New Drug F,.,, fraction of un-ionized form PSA, polar surface area
Application HCI, hydrochloric acid PSAd, dynamic polar surface area
{UC, area under the plasma lM, intramuscular P., permeability of a drug in the gut
concentration-time curve lV, intravenous wall
AUC):, total area under the plasma K, elimination rate constant Q, blood flow rate
concentration-ti me curve K-, the concentration of drug at half SC, subcutaneous
AUMC, area under the first-moment the V SITT, small intestinal transit time
",
CU TVC MAD, maximum absorbable dose SlV, small intestinal volume
C/. clearance MAT, mean absorption time S., intrinsic solubility
C-,concentration of drug in the organic MDCK, Madin-Darby canine kidney t,r,, half-life
or oil phase MRT, mean residence time t-"*, peak time
C-)*"^, plasma peak concentration NDA, New Drug Application V, volume of distribution
C , solubility P or log P, partition coefficient V., volume of the luminal content
dC, concentration gradient Par, agueous permeability V-,-, maximum theoretical transfer rate
ER, extraction ratio P-gp, P-glycoprotein

Throughout its history, the pharmacy profession has been
concerned primarilywith the manner in which drugs pro-
dtrce their pharmacologic effects and the dosage forms
through which drugs are administered. Since the early
It-lth century, efforts have been directed to determining,
understanding, and providing rational explanations of
,Crug effects on biologic systems, but we have been limited
by our abiliq, to correlate the observed physiologic eve,ts
with a reasonable hl,pothesis or concept. Pharmacists, at
one time, were closely involved in formulating a prescrip-
tion written by a physician for a patient. Today, most of the
formulating is done by the pharmaceutical manufacturer.
Early descriptions of drug action were confined to
their reference as tonic or toxic effects. This approach
6t
 6z PART I ,/ PRINCIPLES OF DRUG DISCOVERY

was followed by the concept of receptor theory, which the biopharmaceutical

properties of a drug in a dosage
for decades remained primarily an operational concept form can affect the avaiLniuty and
action of that drug, it
that was useful for discussing the new actions of drugs is prudent to review gastrointestinal
physiology.
on a molecular level (1). Research in receptor theoriei,

l:H,*H,H'.T::ff ::Hf ff i::T

,,,*1,,.,1:j::.s.
attained in the characterization of receptors (2,3).
cA s r Ro rN r E s r r NA L pH ys r o L o c y
Figure 3.1 schematically represents the gastrointestinal
An extension of the. receptor theory of drugaction trict ancl some of the p-bl.-, encountered in consider-
is an increased emphasis on the importance of physico- ation of drug absorpt'ion from
the site following admin-
chemical properties of the drug and the relationship of istration of i drug uiu aorug. f";-;14j.-ihlstomach
such properties to the pharmacologic responses. Beciuse is divided into two" main
paris: the body of the stomach
these properties have an important role in determining and the pylorus. Histologically,
these parts correspond to
biologic action of pharmaceuticals, it is appropriate t6 the pepsin- and hydrocilloric acid (HCl)-secreting area
refer to these properties as biopharmaceuticil pioperties ana ine
of drug substances. Examples of such propertiis inctude mucosa. -.r.rr-r....ting
area, respectively, of the gastric
In the human,"the stomach contents are usually
solubility, partition coefficients, diffusivity, degree of in the pH range of 1.0 to 3.b, with
pH 1.0 to 2.b being
ionization, and polymorphism, which in turn ut. d.t..- the most common range. Furthermore, there is a diur-
mined by the chemical structure and stereochemistry of nal cycle of gastric acidlty in humans. During the night,
drug substances' ,tomach con"tents are, as a rule, more acidic"(pH, -1.3),
Aconsideration of--, ,
these biopharmaceutical properties and during the day, because of food corsum,ption, the
is fundamental to discussing several important aspicts of pH is less icidic. The recovery of stomach acidity, how-
the overall effects. For a given chemiial entity ldrug), 1u.., o..rm quite rapidly. The presence
of protein, being
there often will be a difference in physiologic availabiilty amphoteric ir-r .rut.,..,
acts as an excellent buffer, and
and, presumably, in clinical responses, primarily because as digestion pro.eeds,
the liberated amino acids enor-
drus molecules must cross various biologic membranes ,rorrly increase the neutralizing capacity
of the stomach.
and interact with intercellular and intracellular fluids The small intestine is dividef, anatomlcaily into three
before reaching the elusive region termed the "site of sections: the duodenum, the jejunum, and the ileum.
action'" Under these conditions, the biopharmaceutical All three areas are involved
in the digestion and absorp-
properties of the drug must contribute favorably to facili- tion of food. The availabie
absorbinig area is increased
tateabsorptionanddistributionprocessesto_augmentthe by surface folds in the intestinal
liniig. The surface of
drus concentration at various active sites. Furihermore, these folds possesses villi
and microvill"i, which are tiny,
equally important is the fact that these biopharmaceuti- finger-like projections
that protrude from the epithelial
cal properties of a drug must ensure a specific orienta- hnlig of the i"ntestinal
wall as shown in Figure b.Z. rn.
tion on the receptor surface so that u ..qr.r.. of events pH o1 the duodenal
contents in the humai is usually in
is initiated that leads to the observed pharmacologic ih. .urg. of 5 to 7. There is
a gradual decrease in acid-
gffects' Drug molecules that are cleficient in the requirid ity alon[ the length of the gasrrointestinal tract,
biopharmaceutical properties can display generally mar- ,iti-ut. pH beiig with the
7 to B in the lower ileum. It has been
ginal pharmacologic action or be totallv ineffective. estimated that apiroximately g L of fluid enter rhe upper
Biopharmaceutlcs is the- study of thJ influence of for- intestine per day,
with approximately 7 L ofthis arising
mulation factors on the therapeutic activity of a drug from digestive juices urrh'fl.rid, and. approximately 1 L
product or dosage forms. It involves the study of the relJ- arising fiom oial intake. over the entiie length of the
tionship between somg o-f the physicochemical proper- large and small intestine and the stomach is the brush
ties of a drug and the biologic effects observed aiter-the boidea which consists of a unifbrm coating (thickness,
administration of a drug via various dosage forms or drug 3 mm) of mucopolysaccharide. This coatinf lryer serves
delivery systems' Almost any alteratio, lt-t u drug delii as a mechanical^barrier to bacteria or food particles.
ery system is likely to alter the drug delivery rate and the \Arhen a dosage form containing a drug or drug mol-
amount of the drug delivered to the desired place in the ecules moves from
the stomach thiough tfre pylorus into
body' This includes the chemical nature of the drug (e.g., the duodenum,
rhe dorug. form eniourrt.ii u rapidly
ester, salts, complexes), the particle size and surfaCe
aria changing environment witir respect to pH. Furthermore,
of the drug, the rype of dosageforms (e.g., solution, sus- aig"siivJ;.rlces secreted into the small bowel contain
pension, capsule, tablet), and the excipients and processer *iry enzymes not founcl in the gastric juices. Digestion
used in the manufactrring of the drug delivery systems. and absorption of foodstuff occur simultaneously in the
Drugs, via drug delivery systems, are most often admin- small inteitine. Intestinal digestion is the terminal phase
istered to human subjects by the oral route' cg1-par9d of preparing foodstuff for absorption and. consists of
to other routes of diug administration, especialiy the two processes: completion of the hydrolysis of large mol-
intravenous route, the oral route is unusuaily complex ecules to smaller ones, which are absorbed, and convert-
with respect to the physicochemical conditions exi*ting ing the finished product of
hyctrolysis into an aqueous
at the absorption site. Therefore, before we cliscuss hori soiution or emulsion.
 OF DRUG SUBSTANCES AND PHARMACOKINET]CS 63
CHAPTER 3 / PHYSICOCHEMICAL AND BIOPT{ARMACEUTICAL PROPERTIES

Cholesterol

pH 1-3
Volume ?
Residence Stomach
time ?
Gastric
Deaooreoation
""t" acid

4lBNHt
precipltation
'jilXi"',. > Absorption of acids

___---/ ,,^ ,nuo):

Enzymes
Water
Bicarbonate
Fat absorbed
Complexation
Solubilization
Absorption of bases

Jejunum

pH
Portal vein
7-B

15-20o/o of pool o{ bile salts to feces

- tract and the factors

processes occurring along with drug absorption when drug molecules travel down the gastrointestinal
FTGURE 3.r physiochemical Principles of Pharmacy, znd Ed. New York: chapman and Hall'
that affect drug absorption. (From Florence AT, Attwood D.
r9BB, with permission.) (zr).

Drug absorption, whether from the gastrointestinal
,ru.t oif.o- oiher sites, requires the passage ofthe drug
in a molecular form across the barrier membrane' Most
clrugs are presented to the body as solid o^r semisolid dos-
,g"io.-., and the drug particles must first be released
t'r.-om these dosage forms. These drug particles must
clissolve, and if they possess the desirable biopharma-
ceutical properties, they witl pass from a region of high
concentiation to a region of lolv concentration across
rhe membrane into the blood or general circulation
Fig. 3.3). Knowledge of biologic membrane structure
and its general properties is pivotal in understandins
absorption processes and the role of the biopharmaceu-
tical properties of drug substances'
Biologic Membrane
The prevalent view of the gastrointestinal membrane is
that it consists of a bimolecular lipoid layer covered on
each side by protein, with the lipid molecule oriented per-
pendicular to the cell surface as shown in Figure 3'4' The
iipia luy". is interrupted by small, water-filled pores with
a'radius of approximately 4 A' A molecule rvith a radius
of 4 A or less can easily pass through these water-filled
pores. Thus, membranes have a specialized transport sys-
i.ro to assist the passage of water-soluble material and ions
through the lipid interior, a process sometimes termed
"convlctive absorption." The rate of permeation of such

Drug in Drug in Drug in

formulation l solution blood
t\
C I

Deaggregation, Absorption across

dissolution membrane
FICURE 3.2 The epithelium of the small intestine at different
:vels of magnification. From left to right: the intestinal villi and FIGURE 3.3 Sequence of events in drug absorption from formula
tions of solid dosage forms.
-lcrovilli that constitute the brush border.
64 PART I/ PRINCIPLES OF DRUG DISCOVERY
Exterior
Cholesterol
Peripheral
proiein
Basic structure of an animal cell membrane. (From Smith c' Marks A' Lieberman M,
FIGURE 3.4
Basic Medical Biochemistry. Baltimore: Lippincott williams & Wilkins, zoo4:t59-t63,
small molecules through the pore is affected not only by
the relative sizes of the holes and the molecules, but also
by the interaction between permeating molecules and the
membrane. \A4nen permeation through the membrane
occurs, the permeating substance is considered to have
transferred from solution in the luminal aqueous phase
to the lipid membrane phase, then to the aqueous phase
on the other side of the membrane. Biologic membranes
differ from a polyrneric membrane in that they are com-
posed of small amphipathic molecules, phospholipids,
ind cholesterol. The protein layer associated with mem-
branes is hydrophobic in nature. Therefore, biologic
membranes have a hydrophilic exterior and a hydropho-
bic interior. Cholesterol is a major component of most
mammalian biologic membranes, and its removal renders
the membrane highly permeable. Cholesterol complexes
with phospholipids, and its presence reduces the perme-
ability of the membrane to water"' cations, glycerides' and
glucose. The shape of the cholesterol molecule allows it to
fit closelywith the hydrocarbon chains of unsaturated fatty
acids in the bilayer. It is the general opinion that the cho-
lesterol makes the membrane more rigid. The flexibility
of the biologic membrane to reform and adapt to a chang-
ing environment is its important feature' The details of
membrane structure are still widely debated, and a more
recent membrane model is shown in Figure 3.4.
In addition to biopharmaceutical factors, several
physiotogic factors can also affect the rate and extent
bf gastrointestinal absorption. These factors are as fol-
lows: properties of epithelial cells, segmental activity of
the bowel, degree of vascularity, effective absorbing sur-
face area per unit length of gut, surface and interfacial
tensions, electrolyte content and their concentration in
Carbohydrate
Glycoprotein
]Hydrophilic
I regron
l-Hyoropnonic
reoion
]
]Hydrophilic
regron
protein
Phospholipid
eds'
with permission')
luminal fluid, enzyrnatic activity in the luminal contents,
and gastric emptying rate of the drug from stomach'
Mechanisms of Drug AbsorPtion
Drug transfer is often viewed as the movement of a
drug molecule across a series of membranes and spaces
(Fig. 3.5), which, in aggregate, serve as a macroscopic
lying between
-.*b.ur'l.. The cells and interstitial spaces
the gastric lumen and the capillary blood or structure
between the sinusoidal space and the bile canaliculi are
examples. Each of the cellular membranes and spaces
can impede drug transport to varying degrees; there-
fore, any one of them is a rate-limiting step to the overall
process of drug transport. This complexity of structure
makes quantitative prediction of drug transport difficult'
A qualitative description of the processes of drug trans-
port across functional membranes follows'
Passive Diffusion
The transfer of most drugs across a biologic membrane
occurs by passive diffusion, a natural tendency for mol-
ecules to move from a higher concentration to a lower
concentration. This movement of drug molecules is
caused by the kinetic energy of the molecules. The rate
of diffusion depends on the magnitude of the concentra-
tion gradient (dC) across the membrane and is repre-
senled by the lollowing equation:
3.1 -dc = x.ttc = K(c^,,"-c,,)
dt
where -dc/dt is the rate of diffusion across a membrane;
Kis a complex proportionality constant that includes the
 CTL\PTER 3 / PHYSICOCHEMICAL AND BIOPHARMACEUTICAL PROPERTIES OF DRUG SUBSTANCES AND PHARMACOKINETICS 65

*"on"!1,,,1",,on C
.o
o-
a
-o

o
o
(d
E.

oo
o
Low
concentration
Concentration (Dose)

FIGURE 3.6 Effect of drug concentration on the rate of absorp-

tion when passive diffusion is operative.

ooo ui^h Because absorption by passive diffusion is a first-order

OO& concen't'ration process, the rate of absorption (dC/ dt in Eq. 3.2) is
directly proportional to the concentration at the site of
absorption (C.,). fne greater the concentration of drug
at the absorption site, the faster is the rate of absorption
(Fig. 3.6). The percentage of dose absorbed at any time.
ir iii. however, remains unchanged.
A major source of variation is membrane permeability,
which depends on the lipophilicity of the drug molecule.
This is often characterized by its partition between oil and
water. The lipid solubility of a drug, therefore, is a very
important physicochemical property governing the rate of
f,a OO Low transfer through a variety of biologic membrane barriers.
ces
O concentration
Figure 3.7 illustrates the role of partition coefficients in the
,PiC FIGURE 3.5 (A) Simple diffusion. (B). Membrane channels. (From Smith
een C Marks A, Lieberman M, eds. Basic Medical Biochemistry. Baltimore: 100
ure Lippincott Williams & Wilkins, zcr,4t59-r63, with permission.)
are O)
f _^ o Secobarbital
LCCS
E5U
area of membrane, the thickness of the membrane, the E
o
ere-
partition coefficient of the drug molecule between the .N
c
Pentobarbital O
:rall
lipophilic membrane and the aqueous phase on each .T
c
nfre
side of the membrane, and the diffusion coefficient of = Cyclobarbital o
cult. o Butethal o
the drug; C^0, is the drug concentration at the absorption o
:ans-
site; and Co is the drug concentration in the hlood. E10 Allylbarbituric o
c acid
The gastrointestinal absorption of a drug from an .o
aqueous solution requires transfer from the lumen to =(5v
talo
irane
rhe gut wall followed by penetration of the epithelial o-
Phenobarbital
o
mol-
membrane by a drug molecule to the capillaries of the (u

s\stemic circulation. On entering the blood, the drug dis- =

ower
tributes itself rapidly in the blood. Because of the volume o
esis =
differences at absorption and distribution sites, the drug
: rate
concentration in blood (Co) will be much lower than the Cl
o Barbital
:ntra-
concentration at the absorption site (C.b,). This concen-
€Pre-
tration gradient is maintained throughout the absorption 0.5 L
0 20 60
process-that is, (C o" - Cb) . As a result, the concentration
Percentage absorbed
gradient (dCin Eq. 3.1), is approximately equal to C,0,,
so Equation 3.1 is written as: FIGURE 3.7 Comparison between colonic absorption of barbiturates
in the rat and lipid-to-water partition coefficient of the un-ionized form
)rane; 3.2 _dC =K C.
of the barbiturates. (From Schanker L5. Absorption of drugs from the
cs the dt colon. J Pharmacol Exp Ther t959;rz6:z83-z94,with permission.) (6).
66 PART I/ PRINC]IPLES OF DRUG DISCOVERY

Extracellular

rr'iir
f luid

IlI I II
I ta' High
concentration

I Energy
Low
concentration

o
Cytoplasm

FICURE 3.8 Active transport. (From Smith C, Marks A, Lieberman M, eds. Basic Medical Biochemistry. Baltimore: Lippincott Williams &
Wilkins, zoo4:r59-t63, with permission.)

drug absorption process frorn the colon and that a good
correlation exists betr'veen the percentage of drug absorp-
tion and the partition coefficient of an un-ionized drug.
Carrier-Mediated or Active Transport
Nthough rnost drugs are absorbed from the gastrointes-
tinal tract by passive diffusion, some druss of therzrpeutic
interest and some chemicals of nutritional value, such as
amino acids, dipeptides and tripeptides, glucose, and folic
acid, are absorbed by the action of transporter proteins
(i.e., a carrier-mediated transport mechanism) (Fig. 3.8).
In this Spe of transport, membranes have a specialized
role. The usual requirement for active transport is struc-
tural similarities betr,veen the drug and the slrbstrate nor-
mally transported across the membrane. Active transport
differs frorn passive diffusion in the following u,a,vs: 1) The
transport ofthe drug occurs against a concentration gradi-
ent; 2) the transport mechanism can become saturated at
high drug concentration; and 3) a specificitv for a certain
molecular structure can promote competition in the pres-
ence of a similarly structured compound. This, in turn,
can decrease the absorption of a drrg. Active or facilitated
absorption of a drug is usuallv explained by assuming that
transporter proteins (i.e., carriers in membranes) are
responsible for shuttling these solules in mucosal or sero-
sal direction. The number of apparent carriers in mem-
branes, howeveq is limited. Therefore, the rate of transfer
or absorption is described by the follor'ving equation:
Equation 3.4 indicates that apparent first-orcler kinetics
is observed. Under these conditions, there are sufficient
numbers of carriers available so that a constant propor-
tion of solute molecules presented to the membrane are
transported across the rnembranes. As the solute concen-
tration increases, the number of free carriers is reduced,
and the proportion of solute molecules transferred across
the membrane is reduced until a maximum saturation is
reached, lvhen C ,r, K,,
3.5 Ab:o'prio,,n,"=4(l=1,.
-dt
Equation 3.5 indicates that a further increase in solute
concentration lvill not result in an1, further increase in
the rate of absorption (Fig. 3.9). The capacitv-limited
characteristics of carrier-mediated processes suggest
that the bioavailabilitv of drr.rgs absorbed in this rnan-
ner should decrease nonlinearlv rvith increasing doses.
C
o
o-
o
0
_o

dC
3,3 ,\bsorption rate = = q,,". c/i(,,, + c o
0)
dt (s
tr
where Cis the solute concentration at the absot ption site,
and V (the maximum fheoretical transfer rate) and K*
"*
(the concentration of drug at half the I1,".) are constants.
Lon, doses or conce ntrations, ruhen K >>> C, redttce
Equation 3.3 to:.
Concentration (Dose)
d(: 1-,,".
r_
tlt K.'C =K.o 3.9 Relationship between drug concentration and rate of
3.4 FICURE
absorption when an active transport process is operative.

_f
.-H.\PTER 3 / PHYSICOCHEMICAL AND BIOP}]ARMACEUTICAL PROPERTIES OF DRUG SUBSTANCES AND PHARMACOKINETICS
f herefore, the use of a large, single oral dose of these
-.r'r-rgs is irrational, and if larger daily doses are neces-
:-ir\'. one should use divided doses. Examples of sub-
::.illces that are actively transported include amino
..iids, methyldopa, fluorouracil, penicillamine, and
-tr odopa.
Convective Absorption
- ire absorption of small molecules (molecular radii
,;ss than -4 A) through water-filled pores of biologic
::lerlbrane is referred to as convective absorption. The
.'.,te of absorption because of this mechanism is equated
. , tire product of a sieving coefficient, the rate of fluid
,: \{ater absorption, and the concentration of solute
.:r the luminal content. The sieving coefficient is indi-
,'.cth, related to the relative sizes of the pores and the
-:r,t1ecules.
In 1967, Higuchi suggested that
-'"-Pnrn AesoRpttoNr
.-:ghly ionized compounds, such as quaternarv ammo-
:-u1n compounds, can possibly be absorbed by an ion-
:,air mechanism (5). In vitro, a relatively large organic
.nion can combine with a relatively large cation to form
,n ion pair of neutral properties, which will then cross
,.- water-organic solvent interface and transfer to an
,,,rganic phase.
PHYSICOCH EMICAL FACTORS AFFECTI NC
DRUC ABSORPT]ON
The pH-Partition Hypothesis on Drug Absorption
)rr,rg absorption is influenced by many physiologic fac-
,,r-s. Additionally, it also depends on many physico-
hernical properties of the drug itself. Some investigators
"-12) concluded from their research that most drugs
..:'e absorbed from the gastrointestinal tract by a process
,r passive diffusion of the un-ionized moiety across a
:pid membrane. Furthermore, the dissociation constant,
.:pid solubilitl,, urrd pH of the fluid at the absorption
.-te determine the extent of absorption from a solution.
T].re interrelationship among these parameters is known
-,s the pH-partition theory. This theory provides a basic
:rarlework for the understanding of drug absorption
i-om the gastrointestinal tract and drug transport across
:he biologic membrane. The principle points of this the-
-ir\- are as follows:
1. The gastrointestinal and other biologic mem-
branes act like lipid barriers.
2. The un-ionized form of the acidic or basic drug is
preferentially absorbe d.
3. Most drugs are absorbed by passive diffusion.
4. The rate of drug absorption and amount of drug
absorbed are related to the drug's oil-water parti-
tion coefficient (i.e., the more lipophilic the drug,
the faster is its absorption).
5. Weak acidic and neutral drugs are absorbed from
the stomach, but basic drrgs are not.
67
\Vhen a drug is administered intravenously, it is imme-
diately available to body fluids for distribution to the site
of action. F{owever. all extravascular routes, such as oral,
intramuscular, sublingual, buccal, subcutaneous, dermal,
rectal, and nasal routes, can influence the overall thera-
peutic activity of the drug, primarily because of its dis-
solution rate, a step that is necessarv fcrr a drug to be
available in a solution form. \[hen a drug is administered
orally in a dosage form such as a tablet, capsule, or sus-
pension, the rate of absorption across the biologic mem-
brane frequently is controlled by the slowest step in the
following sequence:
Dosage disxnu&!, Drtrgin absurrrr,,n Drug in general
) ,
form solution circulation
In many instances, the slowest step, or the rate-limiting
step, in the sequence is the dissolution of the dnrg. \Alhen
dissolution is the controlling step, any factors that affect
the rate of dissolution must also influence the rate rl1'
absorption. This, in turn, affects the extent and duration
of action. Several factors can influence the dissolution
rate of drug from solid dosage forms and, therefore, the
therapeutic activity. These factors include solubiliq' of a
drr.rg, particle size and surface area of drug particles, crys-
talline and salt form of a drug, and rate of disintegration.
The absorption rate of drugs is also affected by inter-
action or formation of complexes in the gastrointestinal
tract. Generally, such complex formation reduces the
concentration of free drug at the absorption sire. Recanrse
the complexed drug is absorbed either slowly or not at
all, the net effect is the reduction of concentration of
drug at the absorption site and slower rate of absorption'
lonization and pH at Absorption Site
The fraction of the drug existing in its un-ionized form in
a solution is a function of both the dissociation constant
of a drug and the pH of the solution at the absorption
site. The dissociation constant, for both weak acids and
bases, is often expressed as the pK, (the negative loga-
rithm of a dissociation constant, K"). fne Henderson-
Hasselbalch equation (Eq. 3.6) for the ionization of a
weak acid, FI-A, is presented below.
3.6 pH - pK ='o*-P]{q-
lun-ronl/eol
Assuming that c{, is the fraction of ionized species and
that 1 o, is the liaction remaining as the un-ionized
fbrrn. Equation 3.6 is writ.ten as
J.l pH-pK.=1.c*
or
3.8 .L = antilog (pH - pK,)
1- o"
68 PART I/ PRINCIPLES OF DRUG DISCOVERY

or
From Equation 3.8, the fraction or percentage of the
uU*ornrbt. and nonabsorbable forms of a weak acid can
(PK,-PH)
be calculated if the pH condition at the site of adminis- 3.12 1|=."1,r.s
tration is known. Analogously, the dissociation or basicity
constant for a weak base is derived as follows: From Equati or.3.12,one can calculate the fraction or
per-
.."og.tf .Usorbable and nonabsorbable form of a weak
3.e p4+p4=p4 ;;r; i? the pH condition at the site of drug absorption is

p(' is the negative logarithm of dissociation con-

krro*. Figure 3'10 shows the p{ valu-e1 of several drugs
where
and the f"Ltir. acid or base stringtn of these compounds'
stant Jl- r,Jater. ,q'lthlugh thi dissociation constant of
a
The relationship between pH and pd and the extent
weak base is described by the term -(' it is conventron-
of ionization is given by Equations 3'8 and 3'12 for weak
ally expressed in terms oi \,brcr;uuse of the relationship
acids and *.uli bus.t, respectively' Accordingly' most
expressed in Equation 3.9.
weak acidic drugs are predominantly in the un-ionized
' [lonized] form at lower pfr of thi gastric fluid and, therefore' ate
3.10
pK, - pH =l"slu;ionir;l absorbed frorn the stomaih as well as from the intestine'
Some veryweak acidic drugs, such as phenytoin
and many
barbiturates, the p,K"valuei of which are greater than B'0'
Again, assuming that u is the fraction of ionized spe- at all pH values' Therefore'
are essentially un-ionized
.i?, urrd that 1 I cr is the fraction of un-ionized species' for these weai acidic drugs, transport is more rapid and
Equation 3.10 becomes
independent of pH, p.ouidtd that the un-ionized form
is lipophilic ot .tottpblu.. Furthermore, it is important
3.11 p&-pH=r"S* to ,rot. that the friction un-ionized changes dramati-
cally only for weak acids with p{ values between
3 and
7. Th...'for., for the weak acids, i change in the rate of
transport wiit pH is expected, as shown in Figure 3'11
Acids B
Strong
Weak (13). Although the transport of weak,acids with p{ val-
ues'less than-3.0 should iheoretically depend on pH'
the
fraction un-ionized is so low that transport across the gut
Cromoglycic membrane is slow even under the most acidic conditions'
Most weak bases are poorly absorbed, if at all' in the
Acid
Oxazepam
Penicillins stomach, because they aie present largely in the ionized
Salicylic acid "Nitrazepam form at pH 1 to 2. iodeine, a weak base with a p{ of
AcetylsalicYlic Diazepam ,pp.o"i*utely B, will have about 1 in every 1 million
acid Quinidine, Quinine
ChlordiazePoxide
Warfarin

Tolbutamide
Sulfadimethoxine Propoxyphene
Reserpine
Acetazolamide !80
o
Phenobarbital Kqnamycin .N
C
Liddeaine
ThioPental
PhenYtoin Quinidine, Quinine
f60
tr
Meperidine
l*c
TheoPhYlline 40
Procainamide o
Glutethimide Ephedrine
Io
Amphetamine
L20
Nitrazepam Tolazoline
*oxazepam Mecamylamine
Guanethidine pH

FIGURE 3.rr For very weak acids, pK values greater than B'o
are predJminantly un-ionized at all pH values between r'o and
.Caffeine
8.o. Profound changes in the un-ionized fraction occur with pH for
z'o to B'o'
an acid with a pK" value that lies within the range of
weak Strong
Although the fraciion un-ionized of even strong acids increases
the absolute value-remains low
The pK values of certain acidic and basic drugs'
with hydrogen ion concentration,
FIGURE 3.ro at most pH-values shown' (From Rowland M, Tozer T- Clinical
Drugs denoted with an asterisk are amphoteric (13)'
(From Rowland
Pharmacokinetics: Concepts and Application' Pharmacokinetics: Concepts and Application, znd Ed' Philadelphia:
M, iozer T. Clinical
Lea and Febiger, 1989, with permission') (r3)'
zndEd'Philadelphia:LeaandFebiger,r989,withpermission.)
 . {PTER 3 / PIIYSICOCHEMICAL AND BIOPHARMACEUTICAL PROPERTIES OF DRUG SUBSTANCES AND PHAR]\,{ACOI(INLTICS 69

lecules in its un-ion ized form at gastric pH 1 .0. Weakly

' ...rc drugs with a pK of less than 4, such as dapsone, diaz-
::,-:111. and chlordiazepoxide, are essentially un-ionized
'r.r-rr-rgh the intestine. Strons bases, l,l,hich are those Absorbed from Rat Intestine
r,r,ith 7o

-,;i r.:rlues between 5 ancl 11, shor,v pH-dependent absorp-

. r. Stronger bases, such as guanethidine (p4 > 11 ) aie nK pH4 pH5 pH7 pHS
k :'.ized throushout the gastrointestinal tract and tend to Acids
S
: :r()orly absorbed.
S
Ti.re evidence of the importance of dissociation in drug 5-Nitrosalicylic acid 40 27
i. :'-rrption is found in the result of studies in which pH at Salicylic acid 3.o 64 35 IO
t : ebsorption site is changed (Tables 3.1 zrnd 3.2). Table
k Acetylsalicylic acid 3.5 4\ 27
- clearly shotvs the decreased absorption of a weak acid
!i ::H 8.0 compared to pH 1.0 (13). However, an inclcase Benzoic acid +.2 6z 36
d lH 8.0 promotes the absorption of a weak base with Bases.
e . ,,,--ticallv nothing absorbed at pH 1.0. The data in Table

Y
- also permit a comparison of intestinal absorption of Aniline 4.6 40 48 58 6t
,1ic and basic drugs from bufl'ered solutions raneing
t. Aminopyrinq 5.o 21 35 48 52
rn pH 4.0 to 8.0 (14). These results are in agreemenr
. :-. the pH-partition hlpothesis. p-Tolu id ine 5.3 to 42 65 64
d The pH-partition theory provides a basic frarne-
Quinine 8.4 9 l1 41 \4
ll r'k for the understandins of drug absorption and,
lt . :retimes, is an oversimplification of a more complex
i- .ess. For example, experimentally observed pH-
d irrption curves are less steep (Fig.3.12) than those predominantly in the un-ionized form in the gastroin-
)f .r.cted theoretically and are shifted to higher pH val- testinal tract. This is attributed to the low lipid solubility
1 ... for bases and lorver pH values for acids. This devia- of the un-ionized molecule. A guide to lipid solubility
l- r:. observed experimentalll., has been attributed by or lipophilic natlrre cif a drug is provided by a prop-
.e . : r1'al investisators to factors such as limitecl absorption erty called the partition coefficient (P) . Therefore,
rt , ,nized species of clmgs, the presence of an unstirred this parameter influences the transport and absorp-
S.
-.r,sion layer adjacent to the cell membrane, and a tion processes of drugs, and it is one of the most
iC
--.rence between luminal pH and cell membrane widell used propelties in quantitati\e srrucrrrre-a( li\ity
cl '-ece pH. relationships (15) (see also Chapter 2).
rf
ll
- : d Solubility
r-;-roN CoErrrcrenr Some drugs are poorly absorbed
.r oral administration even though they are available

q)
c$
cc
C
o
850
o
a
-o
r:rds

_.-i-lfosalicylic acid o

. ', :'osalicylic acid 2.3 52 t6

pH
!. :vlic acid 3.o 6t 13 12 + 4 5 6 7 8 e +10 11

-- :pental 7-6 46 34
PKa PK"

FICURE 3.rz Relationship between absorption rates of salicylic

acid and ephedrine and bulk phase pH in the rat small intestine in
: - lne 4.6 56 vivo. Dashed lines represent curves predicted by the pH-partition
:--: lu id ine theory in the absence of an unstirred layer. (From Winne D. The
53 47
influence of unstirred layers on intestinal absorption in intes-
I - rine 8.4 r8 tinal permeation. In: Kramer M, Lauterbach F, eds. Workshop
l: -.:romethorphan Conference Hoechest, Vol 4. Amsterdam: Excerpta Medica,
9.2 t6
t977 :58-64, with permission.) ( r6).
 7o PART I/ PRINCIPLES OF DRUG DISCOVERY

The movement of molecules from one phase to It must be clearly understood that even though drugs
another is called partitioning. Drugs partition themselves with greater lipophilicity and, therefore, partition coef-
between the aqueous phase and lipophilic membrane. ficient are better absorbed, it is imperative that drugs
Preservative emulsions partition between the water exhibit some degree of aqueous solubility. This is essen-
and oil phases; antibiotics partition from body fluids to tial, because the availability of the drug molecule in a
microorganisms; and drug and other adjuvants can parti- solution form is a prerequisite for drug absorption and
tion into the plastic and rubber stoppers of containers. the biologic fluids at the site of absorption.are aqueous
Therefore, it is important that this process is understood. in nature. Therefore, from a practical viewpoint, drugs
If two immiscible phases are placed adjacent to each must exhibit a balance between hydrophilicity and lipo-
other, with one containing a solute soluble in both phases, philicity. This factor is always taken into account while
the solute will distribute itself between two immiscible a chemical modification is being considered as a way of
phases until equilibrium is attained; therefore, no further improving the efficacy of a therapeutic agent.
transfer of solute occurs. If we consider an aqueous (w) Examples of polar or hydrophilic molecules that are
and an organic (o) phase, we write according to theory. poorly absorbed following oral administration and, there-
If the solute under consideration forms an ideal solu- fore, must be administered parenterally include gentami-
tion in either phases or in solvent, the activity coeffi- cin, ceftriaxone, and streptokinase. Lipid-soluble drugs
cient can be replaced by the concentration term to yield with favorable partition coefficients generally are well
Equation 3.13: absorbed after oral administration. Often, the selection
of a compound with higher partition coefficient from a
D_
C series of research compounds provides improved phar-
3.13 C macologic activity. Occasionally, the structure of an exist-
ing drug is modified to develop a similar pharmacologic
Equation 3.13 is used conventionally to calculate the par- activity with improved absorption. Chlortetracycline,
tition coefficient of a drug. In Equation 3.13, C", the con- which differs from tetracycline by the substitution of a
centration of drug in the organic or oil phase, is divided chlorine at C-7 , substitution of an n-hexyl (hexethal) for
by the concentration in the aqueous phase. The greater a phenyl ring in phenobarbital, or replacement of the
the value of P, the higher is the lipid solubility of the sol- 2-carbonyl of pentobarbital with a 2-thio group (thiopen-
ute. It has been demonstrated for several systems that the tal) are examples of enhanced lipophilicity (Fig. 3.13).
partition coefficient can be approximated by the solu- It is important to note that even a minor molecu-
bility of the solute in the organic phase divided by the lar modification of a drug can also promote the risk of
solubility in the aqueous phase. Therefore, the partition altering the efficacy and safety profile of a drug. For this
coefficient is a measure of the relative affinities of the sol- reason, medicinal chemists prefer the development of a
ute for an aqueous or nonaqueous or oil phase. The effect lipid-soluble prodrug of a drugwith poor oral absorption
of lipid solubility and, hence, the partition coefficient on characteristics.
the absorption of a series of barbituric acid derivatives
is shown in Table 3.3. The term partition coefficient is
more commonly expressed exponentially as log P.

Tetracycline Chlorotetracycline

Ph C,H^ C2H5 .n-C6H13

o--X-;o o--'X--o
Barbital 9.7 t2 tr
HNYNH
IT
HNYNH
Apobarbital 4.g L7
o o

:!:TYb'"r ., ,1,1 ,.-.,,,', 1o Phenobarbital Hexethal

:i:$,!!i|si6iiii1;tt:il:i::iiiliiitlti:ltill:i:iilqrriliilt:iliiti:::lii:ii:ii:::i:iitii,,,,,,,i,,'',,,:,1:l?a l

Butethal t r.7
CzHs Crau D\
24 o--><..-o
HN- -NH
tr
i:1:qvdobaiulr,ari:iir:'iul:i:ii:i'...t:ltti itttt ilri'atriittltlt fl
HNYNH
.}
Peiitobarrbital z8.o '':lttiixa'ix.laii3o D

Pentobarbital Thiopental
Secobarbital 5a.7 4o

Hexethal. . 'tdo FIGURE 3.r3 Drug pairs in which chemical modification enhances
lipophilicity.

J.
5-c&bry mry#
 .I.\PTER 3 / PHYSI']OCHEMICAL AND BIOPHARMACEUTICAL PROPERTIES OF DRUG
ugs Estimation of Drug Absorption
-,',1:en
oef- clifferent chemical entities are being investigated
Lrgs :- iheir potenrial as drug candiclates, dosige ford per-
ielf- : :'nrance is one of the possible contributing factori to
na : ,rr bioavailability. Historically, the concept of bioavail_
and , ,ilin'is closely, ilnot solely, associated with dosage form
OLlS - :r tormallce. Because
poor bioat ailability in particular is
'ugs -.,--reasingly an issue in
the drug discov..y ur-rd develop_
ipo- .-rnt process, application of the bioavailability principlis
hile ".:-,1 techniques has been extended to include animal
rof ..:dies in the selection of potential drug candiclates for
--eir full developmenr (17,18).
are -\s the drug tratels dor,vn the gastrointestinal tract fol-
ere- r'ing its oral administration, part of the dose cannot be
uni- ,,- rilabie for absorption for a number of reasons. These
Llgs -clude its chemical degradation, physical inactivation
,.ell :.arlse of binding and complexation with substances in
ion -r intestinal tract, incomplete dissolution of the dosage
ma : ,:-nt, rnicrobial rnetabolism, insufficient contact time in
har- r-e gasrrointestinal tract, poor solubility and poor per_
rist- : rability across the gastrointestinal mucosa, and meiab_
rgic .,sm tvithin the gut wall. Of the absorbed close, some of
ine, ,::e drug is metabolized in transit cluring its first passage
rfa .:rough the gur wall and rhe liver. Unchingecl diug th"at
for :'raches the hepatic portal vein can be extracted bi the
the -,r er via metabolism or biliary excretion. Thus, the bio_
ren- .,,aiiability (f) of an orally administered dose of a drug
i. --,-rr.nprises the individual fractions that survive ..u".u-l
lcu- :,arriers encountered by the drug cluring its first passage
r o1' -:'or-r-t gut lumen to the sampling site, urd it is deicribed
this I!lr. in general. bv rhe lollowing relarionship:
rfa
ion 3.14
f= F^FII;
i'here -F, 1,', and
{ are the fractions of intact drug
.ibsorbed (F,1 that escape irreversible elimination as thi
rtnrg passes sequentially from the gastrointestinal tract
across the gur wall (1i) and rra\rerses the liver ({) into
slstemic circulation. thus, bioavailabiliry of a riiug is
eqnal to or less than the fraction absorbed. dependlng
on the extent of rnetabolism and loss during the absorpl
tion process. Therefore, poor bloocl levels o? a dr.,g .an
be a consequence ofpoor absorption or ofgood ab"sorp_
tion accompanied by extensive metabolism.
There appear to be several common misconceptions
^ the drug structure, it is relatecl in a iornplex rnanner.
t20) regarding the nature of absorption. Among these
misconceptions are that intestinal abiorption, permeabil_
in', fraction of drug absorbed, and in ,o-. .u."r, et en bio_
availability are equivalent properties and, consequently, are
rr.sedinterchanueably. Another common misconception is
that absorption and permeabiliq, are cliscrete fundamen_
tal properties of a drug molecule and can be predicted
soiely from its chemical structure. In realiq,, however, drug
absorption is quite a cornplex process dependent on dru[
properties such as solubility and permeability, formulatioi
physiologic variablei such as regional perme_
t::g.r,.ild
ability differences, pH, luminal and mucosal enzymology,
and intestinal motility, amons others.
r
SUBSTANCES AND PFIARMACOKINETICS
71
Publication of the so-called ,,Rule of Five,, (2i) has
senerated widespread interest regarding applying calcLr_
Iated physicochemical propenies in rhi drug dilcoren
process to separate ollt poor drug candidates before bet-
ter drug candidates go into clinical trials. Accorcling to
the Rule of Five, poor intestinal absorption is associiiecl
with and attributed to the molecule poisessing any rn-o of
the following properties: moleculaiweight gieater than
750 daltons, number of hydrogen bonJdoiors grearer
than 5, number of hydrogen boircl acceptors great;r rhall
10, and calculatecl log Pureater than S. fnese suidelines
have been proven to be very useful for approxi-mate prc_
dictions of intestinal drug absorption. ihe critical iole
of_lipid solubility in drug absorption is a major guiding
principle in the drug discovery and clevelopment prcr"-
cess. Because the lipid solubility of a drug moiecule is the
sum of the individual partition coefficients for each of its
functional groups (see Chapter 2), the prediction of lipid
solubility (calculated CLog p; see Appendix A for tables
of CLog Pvalues) can be estimated.
A recent examination (22) of the relationship of
molecular surface properties with biologic performance
of a molecule has been revealing. Mosi notably, it has
been demonstrated rhar polar surface area (pSA) of a
drug molecule has a strong correlation predicting drug
transport from human intestine and across the clrug mem.-_
brane. The PSA is defined as the sum of the Van dei Waals
surface areas for the polar atoms, oxygens, nitrogens.
and attached hydrogen atom (or the number of H_boncl
donors and H-bond acceptors) . (See ww.r,r,..molinspiration.
com for calculating the PSA.) The pSA is a major hetermi_
nant for oral absorption and brain penetrati,on of drugs
that are transported by the transcellular route (movemeit
across cell membranes). This property shoulcl be consicl_
ered in the early phase of drug screening. Another related
parameter, dynamic PSA (pSAd), has surfaced (23) as a
parameter of value in predictins rnembrane permeabil_
ity and oral absorption in htrmans. Interpolalion of the
sigmoidal plot for 20 selectecl .orrpo.rrd. sugsests thar
yhen tle !,SAd is greater than 140 A!, irrcompleL absorp_
tion (< 10%) results, and.when the pSAd value is less thin
60,f ; drug absorption will be in excess of g0%.
A drug's absorption, as reflected in its bioavailabilint
is a fairly complex process, and although
it is related to
Failure to appreciate and understand theseiomplexities.
in an attempr to build models, can provicle a piediction
of marginal and lo'lv confidence. Boih fraction absorbed
alcl bioavailability are measllres of the extent of absorp_
tion. Permeabilitl., on the other hand, is related to the
rate of absorption (20):
3.15 J= P,. SA. dC
the absorptive flux and is equal to rhe perme_
I1:.../l
ability ({) of intestinal mucosa to the drug, the iurface
area available (SA), and the drug concentration gracli_
ent (dC) across the mucosa. Factors that can influence
 72 PART I / PRINCIPLES OF DRUG D]SCOVERY

permeabiliq/ include structural characteristics of a drug,

inc_luding size, shape, solubility, charge, and surface arel.
It has been argued (24), on a theoretical basis, that
a lundarnental relationship exists between the rate
measured as a permeability coefficient and the extent
of absorptiorr. ihlr has led [o rhe greater interest and
increasing use of the in vitro permeability model to
serve as an experimental surrogate for predicting oral
absorption potential of drr-rg .urrdidut.. in drug d"iscol,-
ery programs. Additionally, although in some instances
(24,25).it has been possible to direitly correlate absorp_
tion lvith permeability, more often poor correlation
exists (20,26), as illustrared ir.r Figuri S.14. At times,
good absorprion is observed lor poorly permeable com_
pounds. These poorly permeable but well-absorbed
compounds exhibit high aqueous solubility, generally
exceeding 2.5 mg/ml (20,22). This suggests tf,at aque_
ous solubiliq/ can help to compensate-ftr the pooi ir-,
vitro permeability observed.
Estimating the extent of oral clrug absorption and
variation in drupJ absorption, thereforE, can bL of great
value in the selection of a potential therapeuric
Eqent
and in identif,ving ways to optimize the oral a.rg ,i.tir_
erv in patients. This can be facilitatecl by der.e"loping
the predictive oral drus delivery models. Iir turn. these
models permit rhe esrirnation of drug absorption r,r.irhorrt
performing in vivo studies in humans and impart better
understanding of the,rate-limiting processei affecting
drug- absorption, rvhich can assist irr developing strate"_
gies for the development of oral drug delivery. Tii"..
o..
three physical barriers to drug absorption: the dissolu_
tion resistance, the aqueous boundary layer resistance,
and the membrane resistance (27-29).'
100
. Although physicochemical properties, such as solubil_
ity and permeability, and other pioperties, such as meta_
bolic stability and toxicity, u.e inrpoitant inclividually, the
interrelarionship of these properties is rvhat evenir.rally
determines the in rrivo performance of a drug. In pui_
ticular, the role of solubilitv is dependent on the" potency,
which will determine the close. In other words, low solu_
biliq, is problematic fbr a high-close drug; howeveq ir can
be more acceptable for a lor,r.dose drug.
Measurement of permeabi I ity
Although a variery of models (subcellular fraction, cell
monolayer model, isolated intestinal tissue. and intesri_
nal perfusion) are available to predict the permeability
of a drug, the cell monolayer model and iat intestinal
perfusion techniques are the most commonly used
techniques.
Cell Monolayer
These models consist of cells grown on permeable inserts.
Transport of compounds across the iell monolayer is
used to quantitate the permeability of a new chemical
entity in a rapid rnanner. One of the most popular cell
lines is Caco-2, deri.r,ed frorn human colon adinocarci_
noma cells. The monolayer exhibits ion conductance ancl
possesses transepithelial electrical resistance indicative
of
fully formecl tight junctions rhar restrict the paracellular
transport of a chemical entitv. Although Caco_2 cells are
the most commonly usecl ceils, Madin-Darby canine kid_
ney (MDCK) cells are becomins more widespread in use,
in part because of the shorter culture time (4 to 7 days
vs. 21 to 30 clays for Caco-2 cells) needed for their use
in
permeability experiments.
Excellent correlation for permeabilitv coeflicient
between MDCK and Caco-Z ..11, *u, observed for 5b

compound
o
ll
compound I I
ll 1
compounds with known human intestinal absorption.
Regardless of rhe type of cells used in determining per_
meability measurement, establishing the correlation
I
I
:a
o\
Il between the perrneabiliry coefficient incl the fraction of
drug absorbed in vivo validates this approach.
r60 Several clones of HT 2g cells have teen used (30) to
0)
I study different aspect of intestinal druu absorption. An
t
840
-o
o
I'T
1r
enterocvtic HT 29 clone, HT 2g_19_C1, *r, propored as a
model to studv intestinal permeability. The limitation of
the cells is that these cells grorv r.er1.slowly, and a large
ilr I number of cultures failed to develop acceptable barrier
i.' characteristics.
10 20 30 40 Biopharmaceutical Drug Classification
permeability (x 10 6
cm/sec)
It is clear fiom the cliscussion thus far that the physico-
FICURE 3.r4 Poor correlation between oral bioavailability chemical properties, such as drug solubility ancl'clrug
and permeability as measured using Caco-z cells for three permeahiliry. have a crirical role in rhe drug ahsorption
com_
pounds. (From Burton p, Coodwin Vidamas et al. predicting process. The following biopharmaceutical drug classifi_
J, L
drug absorption: how nature made it a difficult problem. cation system (30-32) has been developed to optimize
J
Pharm Exp Ther zooz;3o3:B89-895; and from Hilgers AR, the development of an oral dosage form taking into
Smith
DP, Biermacher JJ, et al. predicting oral absorption
of drugs: a consideration two rate-limiting factors, clrug permeabil_
case study with novel class of antimicrobial agents. pharm
Res ity and drug dissolution, the litter of'which is related to
2oo3;2o:1t49-r r55, with permission.) (r9).
drug solubility.

f
 H.\PTER ]/ PHYSICOCIIEMICAL AND BIOPHARMACEUTICAI- PROPERTIES OF DRUG SUBS]'ANCES AND PHARMACOKINETICS
73

F l-iss I Dnucs (Hrcn Soruarrrry AND HrcH Prnvrnarrrrv) Class
t- . drugs provide both rapid dissolution and high mem-
:'lne permeation. This class includes small-molecule
I .:,.c1rophilic drugs that are not ionized in the gastro-
t-
-,testinal tract. Examples include acetaminophen,
t-. -,iproic acid, ketoprofen, disopyramide, verapamil,
l- ::'(lpranolol, fluconazole, and metoprolol. Class I
n 1:''.rgs are well absorbed and are affected bv a limited
.:: of interactions that alter drug absorption. Because
:-,stric emptying frequently will control the rate of
..-:,sorption for this class of drugs, interactions that
l1 rtlar-sastric emptying rvill delay druu absorption. This
i- . ir.nportant for class I analgesic drugs, for which a
. -ioicl rate of absorption and quick rise in the plasrna
t).
.:rel to tvithin the therapeutic ranse is needed to alle-
a1
.d :1te pain quickl,v.
ll Dnucs (Low SoLuerrrry nno Hrcn Prnrr,tenaurrv) For
--.ss
.:rmediate-release formulations of many poorly water-
ts.
. iuble clrugs, the dissolution rate limits drug absorp-
.- ,n. Alons with this limitation, a greater impact on drug
is
a1 ., sorption will be observed with high oral doses. For
::\.irrpleJ the antifungal drug griseofulvin and the car-
:11
:--,c glvcoside drug digoxin are both poorlv water solu-
ci-
rd ' t and possess similar dissolution profiles, which limit
of '-.r rate of drug absorption. The extent of griseofulvin
r,,.orption, ho'weveq is incomplete for typical dose of
aI
.re
: t ) rlS, whereas a normal, 0.25-mg oraladose of digoxin
id- .r',r:r11)' provides a fairly cornplete absorption. Other
ie, : \.11nples are diazepam and nifedipine.
I\S -\u.interactions that increase drug solubiliW and dis-
' ,,lrtion rate in the gastrointestinal tract will exert a posi-
in
-"c effecton the gastrointestinal absorption of this class
: drugs. The absorption of this class of drugs is often
'11t.
Crnss IV Dnucs (Low Sorusrrrry nuo Low Prnurealrrrv) Poor
aqueous solubility cannot necessarily impart high lipo-
philicitv and, therefore, hish membrane permeation
fcir a drug. Class IV drugs possess both low solubility and
low permeabilitv, both of rvhich are undesirable for good
drug absorption. Examples include furosemide and
paclitaxel. Drugs in this class, however, still are admin-
istered orally if the plasma concentrations obtained are
sufficient to produce the desired therapeutic effect and
the drr-rgs do not possess a narrow therapeutic index.
Role of Transporters in Drug Absorption
The oral route of drug administration remains the most
popular and convenient route of administration, despite
its many shortcomings and challenges. Although the
advantages associated with oral administration far out-
weish the limitations, a major limitation fbr oral absorp-
tion relates to the interactions of drugs with intestinal
membrane transporters and metabolizing enzymes (33).
The rapidly growing awareness of transporters affectins
the rate and extent of intestinal drug absorption has
attracted attention in drug discoverl, and development
(Chapter 5). Intestinal membrane transporters affecting
the rate of oral absorption are the influx peptide trans-
porters (PepT1, PHTs, and HPT:1), bile salt rransporrer,
phosphate transporter, nucleoside transporters, organic
cation/anion transporters (OATP and OCTP), and fatty
acid transporters. Transporters affectiltg drug efflux
into the intestinal lumen include P-glycoprotein (P-gp),
MRP2, BCRP, and N[RP3. The primary inresrinal enzyme
affecting the absorption of drugs is C\?3A4, as u/ell as
the phase II enzvmes, glutathione transferase, glucuro-
nyltransferases, and sr-rlfotransferases. Thus, inhibition

55 :.-.hanced in proportion to the fat content of the coadmin- of these membrane transporters and/or metabolizing
.:ered meal. This is attributed to the increased gastrointes- enzymes and modulation of the expression of these mem-
)11.

er- ,:rir1 fluid volume from a coadministered meal, stimulated brane transporters and/or metabolizing enzymes are
. -1!trointestinal secretions, and biliary solubilization effects key factors affecting the rate and extent of drus absorp-
o11
of .i--at increase the dissolution rate. Furthermore, increased tion. Drug molecules recosnized by OATP-B inclucle bile
;-i-itric residence tirne as a function of the caloric density acids, bilirubin and bilirubin glucuronides, estropen and
to
-,,errnits greater time for drug dissolution. androgen sulfate conjugates, digoxin, pravastatin, f'exof-
\l
enadine, thyroid hormones, and other lipophilic organic
l-rss lll Dnucs (Hrcu SoruelLrry nruo Low Prnueaerrrrv) anions. The PepTl will transport peptide-tike drups, such
tsa For
l'ugs high water solubility, the inresrinal
possessing as B-lactam antibiotics (penicillins and cephalosporin.l.
of
rge .:rerlbrane permeation rate is often the rate-limiting angiotensin-converting enzyme inhibitors, rennin inhibi-
ier i:ep in drug absorption from immediate-release dos- tors, thrombin inhibitors, and di-/tripeptide prodrues of
-,fe forms. Many drugs in this class (e.g., acyclovir and antivirals (valacyclor.ir) .
-hlorarnphenicol) also show region-dependent absorp-
r,-rn rvith better absorption in the upper small intestine. Efflux Transporters
rco- Therefore, any interactions that compromise upper More recently (33-37), the role of efflux rransporrers
rllg .ltestinal absorption can result in a significant decrease in influencins the permeability and the overall bioavail-
ion :l oral bioar,ailability. Conseqr,rentl,v, these drugs show ability of drugs has emerged and gained considerable
sifi- .,- sliarp decrease in absorption rvith a coadministered attention. Among these transporters is P-gp, which is
ize :real that is independent of fat content. Meals tend to expressed on the luminal surface of normal intestinal
nto jecrease the absorption of some drugs in this category mucosa. Unlike absorptirre transporters that increase the
Lbil- rs a result of simple physical barrier that compromises uptake ofa substrate from intestinal lumen, P-gp impedes
1to .he availability of drug molecules to the upper intestinal uptake by returning the portion of drug entering the
:rer-nbrane. mucosa back to the lumen in a concentration-dependent
7+ PART I ,/ PRINCIPLES OF DRUG DISCOVERY
manner. Two types of P-gp have been observed in
mammals: drug-transporting P-gp and phospholipid-
transporting P-gp.
The localization suggests that P-gp functionally can
protect the body against toxic xenobiotics by excret-
ing these compounds into bile, urine, and the intes-
tinal lumen and by preventing their accumulation in
brain and testes. Thus, P-gp can have a significant role
in drug absorption and disposition in human and ani-
mals. An increasing number of drugs have been shown
to be substrate for P-gp, including HIV protease inhibi-
tors and verapamil, which is also an inhibitor of P-gp
and, thus, can increase the intestinal permeability of
other drugs
P-gp is a cell membrane-associated protein that trans-
ports a variety of substances. It has been studied exten-
sively as a mediator of multidrug resistance in cancer, but
only recently has the role of P-gp expressed in normal
tissue as a determinant of drug pharmacokinetics and
pharmacod;.tramics been investigated.
P-gp is a 170 kDa protein product of the MDRIgene. It
is a dimer consisting of 1,280 amino acids, with 12 trans-
membrane segments arrd 2 adenosine 5ltriphosphate
(AIP)-binding domains. P-gp requires binding of AIP to
both ATP-binding domains for the transport function. A
proposed mechanism by which P-gp secretes substrates is
illustrated in Figure 3.15.
Unlike most other transport proteins that recognize
a few structurally similar substrates, P-gp recognizes
a broad range of pharmacologically and structurally
diverse compounds. In general, P-gp substrates are large,
lipophilic compounds that tend to be cationic at
t-no\
)o^
oo-
P-gp
lntracellular Space
Substrate
Cell
Membrane Secretion of
Drug
Extracellular Space
FIGURE 3.r5 Proposed mechanism by which P-glycoprotein
(P-gp) secretes substrates. (r) Passive drug uptake across cell mem-
brane. (za) Formation of hydrophobic channel (pore) between the
intracellular and extracellular space. (zb) Flippase activity, whereby
the drug is flipped from the inner leaflet to the outer leaflet ofthe
cell membrane. (zc) "Vacuum cleaner model," in which the drug
interacts with P-gp in the lipid bilayer and is subsequently secreted
back into the extracellular space. (From Matheney C, Lamb M,
Brouwer K, et al. Pharmacokinetics and pharmacodynamic implica-
tions of P-glycoprotein modulation. Rev Ther 2ooL)T.:778-796,
with permission.)
physiologic pH. An evaluation of 100 structurally diverse
compounds revealed that P-gp substrates have a relativelv
high number of electron-donating groups (i.e., O, N, S.
F, Cl, or groups with a fi-electron orbital of an unsatu-
rated system).
In recent years, the role of drug transporters in the
intestinal epithelium as major determinants of drug
absorption has been recognized, and P-gp and other
transporters have been implicated in modulating the
absorption and/or intestinal elimination of drugs.
Reduction in the small intestinal transit time (SITT) of
a drug can decrease the peak plasma concentration and
area under the plasma concentration-time curve, the
rate and extent of absorption, and, therefore, the bio-
availability of a drug. Another potential consequence
of increased transit has been proposed for digoxin and,
possibly, other drugs that are substrate for P-gp in the
small intestine. Because intestinal permeability of such
compounds can depend on the relative activiqz of P-gp
in the intestine, factors affecting this activity can also
affect absorption. One determinant is drug concentra-
tion, which will influence the degree of saturation of the
transporters. Another consideration is the specific activ-
ity of the transporters with the intestine itself. Evidence
suggests that P-gp is not homogenously distributed
throughout the intestinal tract but, rather, increases in
abundance from the proximal to the distal small intes-
tine. Therefore, drugs that can be substrate for P-gp but
that are partly permeable can be well absorbed in the
duodenum and proximaljejunum, which have little P-gp.
Drugs that inhibit P-gp can alter the absorption, disposi-
tion, and elimination of coadministered drugs and can
enhance bioavailability or cause unwanted drug-drug
interactions.
Prodrugs
Prodrugs are bioreversible derivatives of drug mol-
ecules that undergo an enzymatic and/or chemical
transformation in vivo to release the active parent
drug, which can then exert the desired pharmacologic
effect. In both drug discovery and development, pro-
drugs have become an established tool for improving
physiochemical, biopharmaceutical, or pharmacoki-
netic properties of pharmacologically active agents.
The rationale behind the use of a prodrug is gener-
ally to optimize absorption, distribution, metabolism,
and excretion (ADME) processes. Prodrugs are usually
designed to improve oral bioavailability due to poor
absorption from the gastrointestinal tract. Prodrugs are
now an established concept to overcome barriers to a
drug's usefulness. About \Vo to 7% of drugs approved
worldwide can be classified as prodrugs, and the imple-
mentation of a prodrug approach in the early stages of
drug discovery is a growing trend. A few examples of
noteworthy blockbuster prodrugs are omeprazole, sim-
vastatin, lovastatin, enalapril, clopidogrel, valacyclovir,
acyclovir, and oseltamivir (Fig. 3.16).
 CHAPTER 3 / PT]YSICO(]HEMICAL AND BIOPHARN4ACEUTICAI, T'ROPERTIES OF DITUG SUBS]]ANCES AND PHAI{MACOKINITICS

HoY'/Yo barrier permeability, marked presvstemic rnetabolism,

^ (-o and toxicity (39).
YI*
.r,oli\r
n.cllfa p, (
tr cH3r'\r'^YcHs Strategic Considerations
r,, oH'c-/'r-cH'
(rLr>s'cHft +c''W
Beaurnont et al. (43), in a recent revierv on the desisn
H of ester prodrugs, conclude with the recommendations
l-ou*tutin (Mevacor, R = H) that the prodnrg strategJ should only be considered as
Omeprazole (Prilosec)
Simvastatin (Zecor, R = CH3) a last resort to impror,e the oral bioavailability of impor-
tant therapeutic agents. It can be considered in parallel
lvith classical analoging as soon as a problem becomes
r'\ct -,'\-s
Yi*'
zlpparent.
One prodrug stralegy that is often applied to improve
the solubiliry of drug candidates is to introduce a promoi-
H.C'o ety containing phosphate, sulfate, or succinate groups,
Oseltamivir (Tamiflu) Clopidogrel (Plavix)
which can ionize in relevant biologic rnedia. Srategies to
impror,e the permeability by prodrug formulation can be
o
oYoin'"J' usecl to develop prodmgs that have increased passir,e diflu-
,n\ry. sional permeabiliq, propertie s across the enterocytic rnem-
,rn \rAr) f.y-*'--"Jt(l brane cornpared with the parent compound or to develop
\/ ctt" Y - prodrugs as substrates for absorptive intestinal mernbrane
--)L"-.,
A t'""1
I co2H
transporters such as the peptide transporter PepT1.
Regardless of the strategv used, however, a prereq-
,/alacyclovir (Valtrex) Enalapril (Vasotec) uisite is that the drug candidates contain functional
;ICURE uroup(s) such as carboxylic acid, alcohol, thiol, or amine
3.16Commercially available blockbuster prodrugs and
,"eir structures. functionalities that can be applied in the forrnation of
bioreversible linkages beh,veen the promoiety and the
drug candidate. The most frequently applied prodrug
linkase is the ester linkage; however, manv other linkages
The term "prodrug" or "proagent" was first introduced
can also be used.
rr Albert (38) to signi$, pharmacologically inactive chemi-
Thus, drug candidates that are alcohols, amines,
:a1 derivatives that could be used to alter the physicochemi-
thiols, or carboxylic acids are fbrmulated as the corre-
.rl propt'rtics of drugs. irr a temporary mannel'. to increase
jreir usefulness and,/or to decrease associated toxiciqr. sponding ester, amide, thioester, and ester prodrugs,
respectively. Conventional ester linkages are, in general,
Since Albert discussed the concept of prodmgs in the late
rapiclly cleaved in the gastrointestinal fluids and thus
,950s, such compounds have also becn called "latenti-
characterized by very short half-lives in vivo due to ester-
-.ted drugs," "bioreversible derivatives," and "congeners,"
ase-catalyzed hydrolysis. In cases r,r,here the prodrug link-
rut "prodrug" is now the most commonly accepted term
age is hydrolyzed in gastrointestinal fluids, the prodmg
:i9-41). Usr.rall1,, "prodrr.rg" implies a rnetabolizable cova-
formulation does not necessarily increase the oral bio-
I .rnt link between a clrug and a chemical moieq,, although
.,,inre authors also use it to characterize sorne forms of salts
availability of the parent drug candidate.
t
: ,,1 the active drug molecr-rle. Approximately 19% of all
:irarketed prodrugs are activated by hy.drolysis, and 23Vo Type of Prodrugs
.,r.e bioprecursors (i.e., lacking a promoief) actir,ated by a Hard Prodrug: A hard prodmg is a biologically active
',iosrnthetic reaction (42). compound with a hieh lipid solubility or high water
The prodrug approach sained attention as a tech- solubility having zr long biolosic half-life. Examples
:rique for improving drug therapy in the earlv 1970s. include cocaine and heroin.
\urnerous prodrugs have been designed and developed Soft Prodrug: A soft drug is a biologicallv active com-
:rnce then to overcome pharmaceutical and pharmacoki pound that is biotransformed in vivo in a rapid
:.rctic barriers in clinical drug application such as low oral and predictable manner into nontoxic moieties.
'irrg absorption, lack of site specificity, chemical instabil- Examples inch-rde insulin and adrenaline.
':r.. toxicity, and poor patient acceptance (e.g., bad taste, Carrier-Linked Prodrug: A carrier-lirrked prodmg is
' ,dor, pain at injection site) (42). a compound that contains an active drug linked to
Prodrugs provide a rationale and opportunities to a carrier group that can be removed enzymatically.
-'each targe t physiochemical, pharmacokinetic, and These prodmgs are generally esters or amides, and
'.-,har-macodynamic properties. They are designed to over- such a prodrugwould have greatly modified lipophi-
barriers such as insufficient chemical stabiliry poor
,--,rr.ne licity duc to the attached carrier. The active drug is
.,,lubility, unacceptable taste or odor, irritation or pain. realized by hydrolytic cleavage either chemically or
.:rsufficient oral absorption, inadequate bloocl-brain enzymaticalh,. The prodrug should be biologicallv
 PART I/ PRINC1PLES OF DRUG DISCOVERY
76

an l-lysi-
the parent ester prodrug of acyclovir; lisdexamfetamine'
inactive. The chemical linkage between orJdr.rn of amphetamine that is slowly hydro-
the ""r#ia.
drug and its promoiety -'tt p" bioreverslble; its i:)";;; ^";Jn"iJ**.' ind methvldopa'ina the prodrug of
be sufficiently stable to allow brain to
;;;e*g ,no.ia fbrm' The ,1";rld;;;i,',. tt.'ut is decarboxylated
formulation into an appropriate dosage ;"il;i;;;;-i".' rn' recognition that di- and tripep-
a bipartite
carrier-linked prodrug it t'fai'iata
into intestine by their PepTl
of one carrier attached ;til;;;;rrrpo,tta f'om developmen^t-of prodrugs
tire
;;;r"g that i^s comp"rised
prodrug is carrier connected t^.unsporte, has led to the
(36)' For exam-
io a.rgl A tripartite ;;#;J;t di- or tripeptide analogues
to a linier that is connected to a drug' J"'rogue or mithvldopa increased
niop.".*r"rs: BioprecY"ott..:t".. inert molecules ;';:i;.;;.p,iJvi by more thall
of the active the intestinal absorption"ot- methyldopa
oitultl.a by cheinical modification a moiety 20-fold.
Such
drug but do not contain a carrier' drug
the parent
has almost the same lipophilicity
as
redox OF
and is bioactivated genlraly by enzymatic FACTORS AFFECTING THE ABSO-RP-TION
metabolism.
are
iiRnbI inonn soLlD DosAcE FoRMS AND
ilt""I Prodrug: Two, usually synergistic' drugs SUSPENSIONS
other' A bipartite or tripartite pro-
atta.hed to Jach via tablet' capsule'
When a drug is administered orally
a."flt one in which the carrier is a ryr-rergistic drug or suspension, tl,e rtie of absorption is often controlled
with"the drug to which it is linked' hv how fast the drug parricles dissolve
in the fluid at
dissolution rate
Major Objectives of Prodrug Design
;(.';ii; oirJ*i"itt'ition' Hence' the in the following
step
solubility' drug insta- i;';il the rate-limiting (slowest)
lmpnoveo Btonvntrnstrttv Aqueous
absorption' targeted-. active sequence:
iili.r. oassive intestinal an d
tv'
;ilrJ;o,i;;. i"t,, *i,ti"" problem;,.r lste p.alatabili Drug in 'or'i'-"1i"
metabolic switching are well-established factors limiting
iYlifi
pi.$r',d,",
Solid---';, -- ) t"tilft"n scrrr, Drug in.systcmic
circulation
bioavailability that need to be circumvented'
aqueous solubil- Ifthedissolutionofthedrugissloworcontrollingthe
lupnovto Aqurous Soluslrtrv Inadequate is the rate-
ir" it u" important factor limiting parenteral' percrrta- ,u* oi ulrr"rption (Step I)' thin dissolution
dissolution' such
;:;t;"; 5.* iiouuullabilitv' In iuch cases' a prodrug a",.r-l"i"g'rt.p' Futttts controlling will then control
;;;;;gy can bring great pharmaceutical and pharma- ., tJ"frifi,y' ionization, or surface area'3.'17 describes the
(e.g., esters the overall dissolution process' Figure
."f.i"Zti. benefit] Lnu.g.a promoieties.
aminoacyl cgnju- ;;";p;;" of aspirin fiom solution and from two
differ-
;.h .t phosphates, he'iisuciinates'
promoietie's ent qpes of tablets'
tes. dimethylamino acetates) and neutral absorption is
It is clear from Figure 3'17 that aspirin formulations'
c,a
grvcors) can be used (e'g" cerecoxib
t..;:';;i;;ii.;,i;;;OnJ of the potential problems in this more rapid from soltition than from
tablet
and valdecoxib). of aspirin is an indication that the
;;;.";;h is ttrat solubilizing gtot'pt can sometimes gen- inft ..eifa absorption limited' A general
rate of absorption it ai"otlti"n rate
erale toxic efFects.
enhanced
IrvrpRovpo Pesstvr lt'iresrtNnr AssoRPrloN Providing
absorption is
iif"prrili.i,y for increased passive intestinal
a prodrug
the most fiequent rationale when adopting are
prodrugs
,,***, (approximately 49% of all marked
activated bY hYdrolYsis) '
Other'pharmaceutical applications of
prodrugs o
.o
(slow-release
inchrde protection against fast metabolism 960
of odor' -o
orodrugs), improvement of taste' improvement
for preparation of solid dosage
:;;;;;%i pt-'y'ri.rt form irritation' and
5+o
o
i";# (4),'reduction of gasirointestinal 0)
TL
-reduction
- of Pain on injection
-are 20
g..u.rr. irodrugs designtd- !o improve- the
parent drug'
oermeability and oial absorption of the
il;;;;;." iifia soluble ihan the parent drug and 10 20 30 40 50 60

should be rapidly converted to the pitt"t compound Time (min)

or site of
;;"ril[ ut rorptio, from the gt't *ull' liver'
pivampicillin' 3.17 Absorption of aspirin after oral ad.ministration
of a
u.,ior-tl Examples of prodrug-s include
FIGURE
in solution (o), in buffered tablets p)' or in regular
that is more ;;;;i";:
the pivalate ester prodrug oi ampicillin absorbed iJUf.,r'pl. (From Kwan KC' oral bioavailability and first-pass effects'
iiprit"i"ur. and, therefoit' efficiently with permission') (r8)
compound
^ot"valacyclovir' an r-valyl
(35); Drug Metab Drug Dispos tggT)25lr32g-r336'
than the parent
 CHAPT'ER 3 / PIIYSICOCFIEMICAL AND BIOPI.IARMACEUTICAL PROPERTIES OF DRUG SUBSTANCES AND PHARMACOKINETICS

Diffusion layer compared to Cl. Under this condition, Equation 3.16 is

reduced to:

dc _ DSC,
Diffusino molecules 3.17 d.t h
-
Equation 3.17 describes a diffusion-controlled dissolu-
tion process (4), which can be visualized as sholvn in
-Gastrointestinal contents Blood
- circulation
Figure 3.18; when solid drug particles are introduced
to the fluids at the absorption sites, the drug promptly
saturates the diffusion layer. This is followed by the dif-
fusion of drug rnolecules from the diffusion layer into
Diffusino molecules the bulk solution, which is instantly replaced in the diffu-
sion layer by molecules from the solid crystal or particle.
Gastrointestinal This is a continuous process. Although it oversimplifies
membrane the dynarnics of the dissolution process, Equation 3.17 is
a qualitatively useful equation and clearly indicates the
t. FICURE 3.r8 Dissolution from a solid surface.
effects of sorne important factors on the dissolution and,
d
therefore, the absorption rate of drugs. \A4ren dissolution
lt
is the rate-limiting factor in the absorption, then bioavail-
.e r'elationship describing the dissolution of a drr,rg was
ability is affected. These factors are listed in Table 3.4.
o
o irst reported by Noyes and \Arhitney (14).The equation The Noyes-Whitney equations (Eqs. 3.16 and 3.17)
lerived by those authors is as fbllows:
demonstrate that the equilibrium solubility (C") is one
of the major factors determining the rate of dissoh-rtion.
d,c
-1.16 Changes in the characteristics of solvents, such as pH,
7=6'(a-c,l affecting the solubility of the drug, affect its dissolution
rate. Similarly, the use of a different salt or other physico-
te '.b.ere dr:/ dtis the dissolution rate, Kis a constant, Sis the
chemical form of a drug, rvhich exhibits a solubility differ-
e- .lrrface area of the dissolution solid, C is the equilibrium
ent from the parent drug, usually affects the dissolution
:h .,,,lubility of drug in the solvent, and C is the concentra-
rate. Increasing the surface area ofa drug exposed to the
ol :ion of drug in the soh,ent at time ,.
disscllution medium, by reducing the particle size, usually
IC The constant Kin Equation 3.16 has been shown to
increases the dissolution rate. In the discttssion to follorv,
)r- ' c equal to D/ h, where D is the coefficient of the dis- some of the more important factors affecting dissolution
.',h-ing material of the drug and /z is the thickness of
and, therefore, absorption are presented in greater detail.
is :ire diffusion layer surrounding the dissolving solid par-
ts. :.,:les. This diffusion layer is a thin, stationary film of a
Dissolution
1e - ,lution adjacent to the surface of a solid particle (Fig.
'al ' 17) and is satr.rrated with drug (4); in other words, pH and Solubility of Weal< Acids and Bases
le drug concentration in the diffr.rsion layer is equal Solubility is another factor determining the rate of dis-
, f.., the equilibrium solubility. The term (C" - q) i" solution. As solubility increases, so does the dissoiution
l:uation 3.16 represents the concentration gradient for rate. One way of increasing solubility is to use salts. Salts
:le dmg between the dilfusion layer and the bulk soh.r- of weak acids andl'veak bases generally have much higher
, ,n. If dissolution is the rate-limiting step in the absorp- aqueous solubility than the free acid or base; therefore, if
- n process, the term Cl in Equation 3.16 is negligible the drug is given as a salt, the solubility can be increased,

Equation Pa'ra!:l!!ai Effect on Rate

..r'r:l::ltrtl,ra:.1 df.:Sitlntii5ht.rr.,

oiffusion coefficient of drug) May be decreased in the presence of substances that increase viscosity of the medium (-)

area exposed',t6-rgqlVeril): :r'':rtr.': r,:r,lntie'ase'd,,br,micioniraliqri:arr,d.:inlllamqipihqLrt,!rugslr'r r; (t),:,:i

:rickness of diffusion layer) Decreased by increased agitation in gut or flask (*)

sol u bi l ity',inr:diff tliiqlrrrl4yEd .:'r Thai::ifrweik,e!:ectrolrietalieiell,6l,-qliaxgg:,inrr.H,rbtuee'qf:rppiopriaiedrug::51!qr.,r ,

(.),(+1
r:af ,bLiffei:ingi.edig ritr'irlrr':'r"r:i::r:'
..i.'
fluid in stomach, by removal of drug by partition or absorption (*)
- :cncentration in bulk) Decreased by intake of
78 PART I/ PRINCIPLES OF DRUG DISCOVERY

and for a weak base:

f
:
50
d,c _K'C"(l+lH-l) s
3.23
dt K^
I
o c,i_ I
Equations 3.21 through 3'23^show that K' is
kc equal ,to
da suggest that the
i
_c
UC ;3/ i. Equations 3.22\td' 3'23 clearly
.E increasing
fo dir.otrrtion rate of weak bases decreases with
6{
ocD nH. Hence, the dissolution rate of weak bases is opti-
i-E 20 Ir;in g";tric fluid, but for weak acids' it is at a mini-
acids
r mum. Furthermore, the dissolution rate of weak
particles move to the more
10 i.t|..u.., as the solid drug 3'18
a- ;ik;i;" regions of the gaslrointes-tinaltract' Figure
rates of weak acids as a func-
ilirrr,ru,., ihe dissolutiLn
1"2o4-678e10 11
Ji"" (45). The absorption t :tl: of weak acid
"ipn "f
pH
o. nut. tu, il. explained by using the following figure:
FIGURE 3.r9The pH-dependent dissolution of salicylic acid
Ionized
(n), and phenobarbital (Q' (From Gibaldi
1o;, Uenz-olcicid + Dissoluriotr
form ofweak acid
Ed'
ivtl'aiopn".rnuceutics and Clinical Pharmacokinetics' 4th
with permission') (45)' or base
ttritua.tpf,ir, Lea and Febiger, r99r,

(Fig' 3'19)'
and we should have improved dissolution Kl
This factor can lead to q,itt different peak plasma con- -----------)
'K2
centrations after oral administration'
The solubility of weak acids and bases is a function
of
tfr" pff of the medium. Therefore, differences in the dis-
where K,, and K, represent the rate constants
associ-
solution rate are expected to occur in different
regions and ionized spe-
of 'rveak acid is ated witli the formation of un-ionized
g""t"intestinal tract' The solubility li., of a compound, respectively' The ratio of these two
"irft.
obtained by the dissociation constant of a
rate constants representi
."*p"""a. The absorption of--the. un-ionized species
3.18 C.= tHAl + tAl of a'molecule disturbs the equilibrium of the process'
where [HA] is the intrinsic solubility of the un-ionized
i" ..g.1" the equilibrium, some of the ionized species' which
therefbre, are converted into un-ionized species'
..ia il . , C,) ana [A-] is the concentration of its anion'
con- are then absorbed through the membrane'
This process'
which .u., 6. expressed in terms of its dissociation of the
that being a continuous onel permits the absorption
stant. Ka, and C,: is,
Therefore' a drug mol-
un-ionized species to take place'
KC ecule will eventually be absorbed'
3.19
c -c " +----!--"
tH-l The relatively poor dissolution of weak acids at the
of
pU oigu.,.ic fluid further diminishes the importance
'tfr. ,to"*u.n as a drug absorption site' Although gastric
In a similar manner, the solubility of a weak base is
it is
obtained by ubro.ptiorl of weak ulid* tutt occur from solution'
untlt ity that much of the drug dissolves and is absorbed
J.rti.rg'th. short residence time as a solid dosage form
3.20 .=".t-qH] in the" stomach. A study by Ogata et al' (46) propo.sg.d
that the critical value of solublHty that separates acidic
J.rrg, frorn the absorption sites-(stomach or intestine)
is
By substituting Equations 3'18 and 3'19 into Equation mglml HCl when 1 g of drug is
3'.20 for the teim C", the following dissolution
rate equa- upfi""i*^t ly 30 in 0'1 N
uh'.rri.rirt...a'orally."Those authors found that if the
solu-
tions are obtained: drug is less than 3 mg/ r.r.L, practically no absorp-
frifi,y
For weak acids: "f " irithe stomach' Changes in the gastric pH
tion occurs "1:"
dc _ K'(C,,+ K^C")
ult., th. solubility of certain dru[s and can affect the dis-
3.2r
d,t solution and absorption rates' A patient with achlorhydria
[H.] rapidly
hu, u t iglr"t gastrii pH and absorbs aspirin more
On the other hand' similar differ-
than a rr?r."ut subject.
or to the absorption
ences were ,ot o6r..u.d with respect
dc _ K'C,,(l+ K") .ut", of acetaminophen, a much wiaker acid' the solubil-
3.22 i.y l}*fri.f, wouldte unaffected by changes in
pH (47)'
dt [H.]
 CHAPTER 3 / PHYSICOCHEMICAI- AND BIOPHARMACEUTICAL PROPERTIES OF DRUG SUBSTANCES
AND PHARMACOKINETICS 79

The relationships between dissolution rate and hydro_

gen ion concentration, described in Equations 2.22 and,
:3.23, are approximations and tend to overpredict the dis_
solution rate of both weak acids in the smail intestine and
rr.eak bases in the stomach. In reality, the hydrogen ion
concentration of the bulk is not equal to the hydrogen Hydrobromic
to
he
ion concentration of the diffusion layer.
ng
Salts
,ri-
ri- The objective of drug discovery is to identify substances
ds
:hat are highly active in biologic systems. Screening for
re rotential drug candidates is performed in solution at
18
:ricromolar and nanomolar concentration levels.
IC.
Drug substances can be administered byvarious routes,
id :ncluding oral, which is the most frequently chosen route;
e:
:larenteral by several modes of injection (intramuscular
I\Il , intravenous lIVl , subcutaneous tSCl , and others);
-r[anasal inhalation; and topical to the various areas
,f the body surface, to name just a few more important
:'lltes. Various pharmaceutical dosage forms are formu_
-,ted to administer drug substances by these routes. Each
irrsage form requires rhat a rypical set of reievant param-
:ierS of the drug substance lie within a certain range,
.'cvond which the developmenr of said dosage foim
.,ecomes increasingly difficult and eventually impossibte.
!so. in a mutual interdependence, the selection of dos-
ci- =1e form and the applicable technology depend on the (i.e., the pK of the acid should be at least two unirs lower
)e- :,lr sical chemical properties profile of the chosen salt. than that of the base). This corresponds to a situation in
,{o -\pproximately two thirds of the drug substances are which both compounds, brouuht together in water, are
.a : rakiy acidic or basic entities, and therefore, salt forma- ionized to a degree of at least 902o. Sirong mineral acids
ies - -:,n provides a significant opportunity to alter the phys_ such as HCI (pK. = -6) or H,SO4 (pf" = -S) can form solicl
SS. . ,chemical properties of drugs in the solid state without salts with the weak base atazanavir, having a pK as low as
TS, '.:ering chemical integriry. The decision whether to 4.25, whereas amemprs to isolate a salt with either acetic
ch :--rrsue a salt form is usually made early in the develop_ acid (p{ = 4.76) or benzoic acid (pK = 4.19) woutd fail
SS, .r-er1t process on the basis of known properties of the with such a weak base.
he -rcharged molecules. Salt formation will often be consid- The final decision on the selection of a salt of a drug
ol- .:ed rvhen the drug has one or more unfavorable prop- substance is based on data collected from analytical anJ
.:Jes, including poor dissolution, low aqueous solubility physical characterization of a certain number of pre_
he 1{) pglml-), poor chemical stability, hygroscopicity, low
pared salts. The data are evaluated primarily against the
of '-,t1tins point (< B0'C), poor crystallization (foims oil or requirements set by biopharmaceutical and thlraper.rtic
ric .:::orphous solid on crystallization attempts), or displays considerations for the use of the drue, pharmaceutical
is :--',rltiple poll,morphs. A sisnificant number of counter_ and chemical-technologic aspects in view of the devel_
ed ,1s are suitable for pharmaceutical salt selection
studies opment and manufacturing of dosage forms, and the
TN : rreakly acidic or basic drugs, and therefore, there is a synthesis and isolation of the drug substance. The most
ed .,rad range of opportunity to obtain different salts with frequently encountered issues while selecting a suitable
lic ::proved and desired physical chemical properties. salt are discussed belou,.
is The selection of suitable counterions for inclusion For injectable solutions, high solubility of a drug under
iis - a salt selection search is dependent on safety con_ the conditions close to physiologic pH of 7.4 is essential.
Iu- -,.irtarions. For example. chloride and soclium ions For a small-volume injectable such as IM and SC, the solu-
?- .:e regarded as safe to administer and well tolerated. bility should be as high as possible to accommodate the
SO -,-,unterion selection often uses pK talues of the acid dose to be adminisrered in 0.5 to 2 mL for SC or up to
iis- .--d base involved to estimate the likelihood of
successful 5 mL for IM administrarion. The solubility requiremenr
ia .;" i formation. tbr IV injections is less stringent because volumes up to
lll' Based on the pK values, a series of salt formers can 20 mL can be administered.. With lower solubiliq, drugs,
er- :-en be selected from those frequently used pharma_ one has to resort to infusions ofvolumes of up to 1,000 mL.
)11 :.ltically (Table 3.5), whereas orhers must be iejected. Injectable solutions of drugs require pariicularly high
ril- ::,:,rn experience, to form a stable salt, the pK" values of chemical stability. Ideally, a drug subsrance must with_
,-- acid-base pair should differ by ar leasr two pK
units stand heat sterilization in solution and subsequent storage
8o PART I / PRINCIPLES OF DRUG DISCOVERY
for up to 5 years. For those drug substances lacking such
optimum stability, it is possible to circumvent heat stress by
sterile filtration. Naturally, for injectables, solid-state drug
properties are of minor importance as long as they do not
hamper processing or the dissolution of a lyophilizate.
For solid dosage forms, the most critical step, after
swallowing a unit dose, is the release of the drug sub-
stance. Solubility and, therefore, dissolution can control
or limit, respectively, this important process. Therefore,
a solubility that is reasonably high in relation to the drug
dose is desirable.
In selecting a salt form for a product that is applied
topically, it is a prerequisite that it (salt of the drug) must
not cause local irritation, whether the target of treatment
is the skin surface, dermal tissue, or underlying organs
(e.9., joints, muscles, tendons) or even if systemic effects
are intended. Weakly acidic to neutral pH values (-5 to
7.5) are tolerated best, and deviations from this range
should be avoided. Choosing the right salt form of a drug
can offer the following advantages: Annoying polymor-
phism problems can be circumventedl high hygroscopic-
ity resulting in deliquescence can be avoided; amorphous
material can be turned to a crystalline salt; taste and smell
problems can be minimized; the melting point can be
raised to improve mechanical properties (e.g., for mill-
ing), to the extent that liquid bases or acids are turned
into solids; and local irritation can be avoided (e.g., for
inhalation)
With drug candidates exhibiting absorption diffi-
culties, investigations can even include in vivo studies
in animals (e.9., rat, dog) with experimental formula-
tions to identify the most suitable salt form or solid-state
form. Sometimes such a search can address the state of
distribution of the active substance in an experimental
formulation (e.9., micronized, nano-sized, amorphous,
suspension, emulsion, microemulsion), and so the bor-
derlines between chemical technical operations and
pharmaceutical formulation and processing techniques
can become quite diffuse.
Solubility and Dissolution Rate
Chemical stability includes potential interaction between
drug entity and counterions and stability in the presence
of pharmaceutical excipients (drug/excipient compati-
bility); stabiliq, of the morphic state in bulk form; stability
in solid and suspension dosase forrns; hydrate formation
and stability during storage and processing; chemical
stability of hydrated versus anhydrous forms (influence
ofreleased hydrate water during storage); and uptake of
water of hydration by anhydrates in solid dosage forms
with consequences for mechanical properties.
Regarding molecular weight, large counterions can
surmount the tolerable drug amount to be packed into
a solid dose unit; in contrast, for extremely low-dose
drugs, a larger molecular weight can improve handling
and content uniformity.
The dissolution rate of a particular salt is usually
different from that of a parent compound. Sodium or
Benzoic acid 4.2 2.7 t4 z8
l366iii ititit:til::i:iii::tt:ilii:ii'il::iitiiiiii:ill itilltiitilX#ililiililiii::iatio iiiiiiiililtii:l:
Phenobarbital o.24 22
7.4
l:.::9 t!itl:i ;i:.il:itt:tilrti::tit:r:t:tirii,it?8,q;i::tlllxt9?,q.:t:::::l:,l::ltit,:l
'ta. i
Salicylic acid 27.
3.o 53
lt:l:56i{iiii'rii:!rli.l:i]rr,rilll::ii:r,i:rrl,l:rrrii:ri:rr,a7o 2,5oo ria:lt:ri::,a,:,:tir:itiriiiilt:rlr::ilr:
ii*],,{,9:rl::talltiia.i
Sulfaih'iazole' --o.5 '' 8;5
73
potassium salts of weak acids dissolve more rapidly than
the free acid. The same is true with HCI or other salts of
weak bases. Table 3.6 illustrates the dissolution rate dif-
ferences between some weak acids and their sodium salts
(45). The differences in the dissolution rates of salt and
parent compound are explained by taking into consider-
ation the pH of the diffusion layer. At a given pH, regard-
less of salt or free acids/bases, a drug will have a fixed
solubiliqr. The classical dissolution equation predicts a
slower dissolution of a salt of a drug, and the concept of
a diffusion layer becomes useful.
For sodium or potassium salts of weak acids, the pH
of the solution in a diffusion layer is greater than the pH
of the diffusion layer for the corresponding weak acid.
However, the pH of the solution in the diffusion layer
for hydrochloride salts of weak bases is always smaller
than the diffusion layer of the corresponding free base.
Therefore, effective solubility and dissolution rate of
soluble salts on drug absorption are available in the lit-
erature. The potassium salt of penicillin V yields a higher
peak plasma concentration of antibiotic than the cor-
responding free acid.(48). Sodium salts of barbiturates
are reported by Anderson (49) to provide a rapid onset
of sedation. Some salts have a lower solubility and dis-
solution rate than their parent compounds. Examples
include aluminum salts of weak acids and pamoate salts
of weak bases. In these particular examples, insoluble
films of either weak acids or pamoic acid appear to form
in the dissolving solids and further retard the dissolution
rate.
Surface Area and Particle Size
The surface area per gram (or per dose) of a solid drug is
changed by altering the particle size. For example, a cube
that is 1 cm on each side has a suiface area of 6 cm2. If this
cube is broken into cubes with sides of 0.1 cm, the total
 .:I \PTER 3 / PHYSICOCIIEMICAL AND BIOPHARMACEUTICAL PROPERTIES OF DRUG SUBS].ANCES AND PHARMACOKII,\ETICS
..": tace area is 60 cm2. If the particles are broken r.rp by
.:lrrling, then irregular shapes with even larger surface
:--ii1s are created. Cenerall1,, as the surface area increases,
"-.t drug will dissolve more rapidl),. Therefore, many
'- ,,rrh'soluble and slor,vly dissolving drugs currently are
: -.r'keted in a micronized or microcrystalline form. The
-:, ,blems of lor,r, water solubility and particle size were
,, fr-rlly appreciated, but they have resulted in reducing
r : therapeutic dose of some drugs without sacrifrcing
' -.rapeutic efficacy. For example, since the original mar-
. ::ing of spironolactone, its dose has been reduced from
' I to 25 mg as a result of a reformulation that includes
-cronization. The bioavailabilitv of digoxin increased
. n 40Vo to approxirnately 80% to 97% by reducing the
- -,r'ticle size fiom 100 to approximately 10 nm. A similar
'::ult has been obtainecl for griseofuh,in.
rolymorphism
,l:r-rr. pharmaceutical solids can exist in two or more crys-
-,..-ine forms called polymorphs (50,51). Polymorphism
. :I-re ability of the same drug molecule to crystallize
:',:,:r irrore than one different crystal structlrre that has
a11 ,--.ifferent arrangement a:ncl/ or conformation of mole-
of ..,es in the crystal lattice. However, once they are in the
tif- . -,-rtion phase, polyrnorphs share a common form. The
its --.ierent arrangements of atoms within the crystal unit
nd -..1 can have a profound effect on physical and chemi-
er- -.- properties of the final crystallized compound and
rd- :r tl.re final drug product. Amorphous solids consist of
ed ---.ordered arrangements of molecules that do not pos-
ia -..s a distinguishable crystal lattice. Solvates are crystal-
of :re solid adducts containing either stoichiometric or
.. ,nstoichiometric amounts of a sohrent incorporated
rH rihin the crystal stmcture (50,51).If the incorporated
:H . h'ent is water, the solvates are commonly known as
id. .-.-. c1rates. Polymorphs and/ or sohrates of a pharmaceuti-
ier ,..1 solid or pharmaceutical excipients (e.g., lactose) can
ler .,,re different physical and chemical properties, such
.se. .. r.neiting point, chemical reactivity, apparent solubil-
of , ',. and dissolution rate. These properties of a drug sub-
1i t- :.-rnCe can affect the intended shelf life (stability), rate
ter : clissolution, and bioavailability/bioequivalence of the
or- --:.rr.g product. A metastable (amorphous) pharmaceuti-
.tes li solid form can change crystalline structure or sol-
.
.set eie /desolvate in response to changes in environmental
iis- -,lnditions or shelf-life storage. When such differences
rles ,l physical properties are sufficiently laree, bioavailabil-
alts .:"' is altered, and it is often difficult to formulate a bio-
b1e :quivalent drug product using a different polymorph.
,rm Ihe Biopharmaceutics Classification System criteria of
ion :.igh solubility and rapid dissoh.rtion should be consid-
=red in product development decisions when polymor-
-:,hism exists. Drug substances rvith different physical
-,rrm include warfarin sodium, famotidine, and raniti-
gls line, and those r,vith solvation or hydration state include
-rbe -crazosin hydrochloride, ampicillin, and cefadroxil.
rhis Some drugs that exist as polymorphs can have differ-
rtal :nt solubility properties and, thus, different dissolution
8r
characteristics. Chloramphenicol palmitate and ritona-
vir provide good examples of how polymorphism can
influence drug dissolution and, thus, drug bioavail-
abilitl'. Chloramphenicol palmitate is a broad-specrrum
antibiotic known to crvstallize in at least three polymor-
phic forms and one amorphous (metastable) form, B.
The most stable form, known as form A, is the polv-
morph that is marketed, whereas the metastable form B
is approximately eight times more soluble than form A,
thus providing an eightfold difference in bioavailability.
This large difference in bioavailability creates the dan-
ger of fatal dosages \,vhen the unwanted polymorph is
unwittingly administered because of alterations in pro-
cess and/or storage conditions. The HIV protease inhib-
itor ritonavir (Norvir) rvas withdra\,vn from the market
because an undesirable polymorph of ritonavir had
been produced during its shelf lif'e. Ritonavir was fbund
to exist in only one monoclinic form during develop-
ment and early manufacturing. This form, called "form
I," was not sufficiently bioavailable in the solid state by
the oral route, requiring the initial product (Norvir)
to be formulated as a capsule filled with a hydroalco-
holic solution containing the dissolved drug. Two years
after the product launch, several lots of Norvir capsules
started failing dissolution specifications. Evaluation of
the failed lots revealed that a second crystal form of
ritonavir, "form II," had precipitated from the formula-
tion during its shelf life. "Form II" was 50% less soluble
compared to "form I," resulting in failure of batches in
the dissolution test, aff'ecting its bioavailability and caus-
ing the eventual withdrawal of the product from the
market. Substantial time and effort wenr into identify-
ing and correcting the problem. To ensure a continu-
ous supply of this life-saving drug, a liquid formularion
had to be introduced in the marker until the issue of the
polymorphic form nas resolved. Hence, an inadvertent
production of the "wrong" polymorph at the crystalliza-
tion stage or any transformations of one dosage form to
another during processing (e.g., drying, milling, eran-
ulation, compression, spray drying, or fieeze-drying),
storage, and scale-up can result in pharmaceutical dos-
age forms that are either ineffective or toxic. This high-
lights that identification of different solid forms of a
drug substance and determination of their physical and
chemical properties, thermodynamic stabilities, and
conditions or kinetics of interconversion are essential
for ensuring reproducible behavior of drug products.
Estimate of Dose Absorbed
Johnson and Swindell (52) proposed a simple predictive
model that relates the aqueous solubility and absorption
rate constant (K,) to deterrnine the maximum absorb-
able dose (N4-{D):
3.24 MAD = I<CYI
where K is the first-order absorption rate constant; C Vis
a consrant. and I is the time.
.aJ}ffrll-
8z PART I/ PRINCIPLES OF DRUG DISCOVERY
Hilgers et al. (26) argued that Equation 3.24, pro-
posed byJohnson and Swindell (52), assumes that the
drug absorption occurs under highly unrealistic condi-
tions, such as the intestine is exposed to a saturated solu-
tion of a drug of interest for a time equal to the normal
SITT. For interrelating permeability and solubility of a
drug to estimate the absorption potential (30) as NUL{D by
using the predictive model, Hilgers et al. (26) proposed a
modified equation:
3.25 MAD = S' K" ' SrV' SITT
where Sis solubility and SfV is the small intestinal volume.
Briefly, the MAD calculates the total mass of drug that
could theoretically be absorbed if a saturated solution of
a compound with solubility S in the SIV were absorbed
with a first-order absorption rate constant (K,) for a time
equivalent to SITT.
The absorption rate constant (K^) was determined
from Caco-2 permeability value with the assumption
that the value of K and rat ileum permeability values
are approximately equal and, consequently, that the esti-
mated rat permeability (P.) was converted to an absorp-
tion rate constant (K.) from the following relationship:
3.26 K"- P" (A/r)
where Vis the volume of the intestinal lumen and A is the
surface area. For the rats used in this study (26) , A/ Vwas
equal to 10 cm-r.
Using Equations 3.24 and 3.2b for estimating the oral
absorption of oxazolidinone antibiotics data obtained
in rat and comparing the predicted MAD to the actually
administered dose, Burton et al. (19) and Hilgers et al.
(26) reported the relationship illustrated in Figure 3.20.
It is clear from Figure 3.20 that better prediction of
MAD is achieved when solubility, permeability, and dose
are taken into consideration. Despite this, drug perme-
ability is an important determinant of drug absorption;
therefore, it is informative to explore mechanisms con-
tributing to permeability in the light of structure-based
models for absorption prediction.
The relationship between the estimate of MAD and
the fraction absorbed is hyperbolic (28), analogous to
the relationship between drug permeability and fraction
absorbed. Incorporating the solubility term in Equation
3.24 yields a more realistic value of estimate of MAD for
poorly to moderately soluble compounds. Therefore, the
concept of MAD serves to combine two major determi-
nants of oral drug absorption (i.e., intestinal permeabil-
ity and solubility). In turn, the value of MAD can provide
a practical guideline in the early drug discovery program.
If the dose of a potential drug candidate is projected to
be greater than the calculated estimated dose absorbed,
this serves a cautionary notice that the following should
be examined: the potential for solubilization in the gas-
trointestinal tract, and the formulation variables that
could ultimately result in an increased solubility or drug
100
80
Itl compound ll
-I
LL 60 T
E
o I
o
940 1, .€)
o 1
cYmpound lll
20
I
g-
"o
^l^-vn
20 40 60 Bo 1oo
Predicted fa (%)
FIGURE 3.zo A better correlation between observed bioavail-
ability and predicted bioavailability when both aqueous solubility
and permeability parameters of drugs are used to predict the frac-
tion absorbed for three compounds. (From Burton P, Goodwin J,
Vidamas T, et al. Predicting drug absorption: how nature made it a
difficult problem. .j Pharm Exp Ther zooz;3o3:889-895; and adapt-
ed from Hilgers AR, Smith DB Biermacher,J, et al. Predicting oral
absorption of drugs: a case study with novel class of antimicrobial
agents. Pharm Res zoo3;zo:rr 49-tt55, with permission.)
dissolution during the gastrointestinal transit to increase
the fraction absorbed.
To reach the systemic circulation, a drug must move
from the intestinal lumen through an unstirred water
layer and mucous coat adjacent to the epithelial cell
structure. Movement across the epithelial layers takes
place by two independent routes, transcellular flux
(i.e., movement across the cells) and paracellular flux
(i.e., movement between adjacent epithelial cells). The
solute molecules then encounter a basement membrane,
interstitial space, and mesenteric capillary wall to access
the mesenteric circulation. Any and all of these micro-
environments can be considered a resistance to solute
molecule movement, each with an associated permeabil-
ity coefficient. Therefore, the overall process consists of
a number of resistances (i.e., reciprocal of permeability)
in series. Furthermore, the influence of drug structure
with permeability in these different domains is differ-
ent. For example, permeabiliq, in an unstirred water
layer is inversely related to solute size, whereas paracel-
lular permeability is a function of both size and charge.
Furthermore, cations exhibit greater permeability than
neutral species, which in turn manifest greater perme-
ability than anions.
With respect to transcellular permeability, the relation-
ship of solute structure with permeability depends on the
mechanism. Historically, a passive diffusion pathway is
assumed for most solutes. Nevertheless, a great number of
solutes are identified as being associatedwith active absorp-
tion and secretary processes in intestinal epithelial cells.
Additionally, although active transport involves specific
interactions behveen a solute and transporter, passive dif-
fusion is dependent on solute partitioning into the cellular
 ]-PTER ]/ PHYSICOCHEMICAI- AND BIOPIIARMACEUTICAL PROPERTIES OF DRUG SUBS-I'AT'C]ES
AND PIIARN,{ACOKINETICS 83

.rr-ia llembrzlne and the diffusion coefficientwithin the
:-t)rane. Both processcs, horvever, are influenced by
- hr sicochemical and strrctural characteristics of the
- Factors iniluencins plasma membrane partitioning
' lute size, lipophiliciEl hydrogen-bonding potential,
- large characteristics, rvhereas the diffusion coeffi_
-:
;s clcpendent on size or total rnolecular surface area.
:rer&l, a non-PSA fzrvors partitionins.
: :' solutes that exhibit rtrarsinal (or-a lack of) mem-
. :tffinit\., permeabilitr. is lo.l,r,, resulting primarily
: paracellular diffusion of the solute. As the pro-
, r' ol tire solute to partition into cell membrane
'...ies! so does the permeability, as a result of the sig-
,,lt irrcrease in surface area of the transcellular path_
: rlatir.e to the paracellular route. This increase in
:,rabilitv will approach a plateau, the so-called ,,aque_
. ' lrndary laver-limited situzrtion," in u,hich diffusion
ii rhe cell is verr,'rapicl relative to diffusion ofthe
= rlrrough the unstirred lvatcr/mucous layer.
ihe case of ionizable solutes. permeability is also
l.i)c1tdent. A neutral, uncharged species is capable
. -,lsccllular diffusion, rvhereas a charsed species is
.- tecl to the paracellular-pathrvar.. Thus, the observed
.-r.rbilitv of strch molecules is clependent on the rela_
,nccntrations of charged and neutral species.
- .:slltan et al. (53) developed a1t equation to cleter_
. :ire absorption potential (AP) of a clnrg by taking
rnsi<leration sever:rl of its phvsicochc-mical prop".-
r:cluding intrinsic solubility ({) of the un-ionizecl
-i of a clrug, fraction of un-iouized forni ({,,,,) of a
- .,r a specific pH, voh.rme ol.the luminal content (I,),
c.rbilitr. of a drug in the gtit rvall (p ), and the aqrie_
rl[reability ({o) ot u drug. The equation is:
r =(! ) rrrt
[".J'' '[ .J
:I ,. is the fraction absorbed and X- is the adminis_
. ,:l,jse. With the asslrmption that, in'many cases, the
pernrcabilitv ratio (i.e., P,,/ P^,) of a drus is proportional
to its membrane-\,\rater coefficient (1r), which can be cor_
related ro the 1-octanol-urater partition coefficient (p),
Equation 3.27 rvas simplified to:
,tl=roefr,.,
3.28
+)
lthere AP is a dimensicinless parametcr.
Using Equzrtion 3.28 and selecting clrues that rep-
resent a r,r,ide range of absorption characteristics, from
poorlv absorbed compounds to rhose that are virtually
completelv absorbed, the utility of the Ap pzrrarncter as
a predictor of the liaction absorbed was assessed (53).
The physicochemical properties, such as the partitior.r
coefficient, solubilitH fraction zrvailurble in un-ionized
fbrm, dissociation constant, fraction of dose absorbecl,
and calculated dimensionless parameter Ap fbr drugs
selected in this stud1, (53), are reporred in Table 3.7. The
observed correlation betr,veen the fractions absorbecl ancl
the AP is illustrated eraphically in Figure 3.21.
From Table 3.7 and Figure 3.21, it is quite appar-
ent that for the compounds selectcd in this study l8:;,
the dimensionless parameter Ap manifests a strong cor-
relation to the fraction absorbecl. Negative Ap values
correspond to poor druu absorption. For the range of
AP virlues betu,een 0 zrnd 1, an increase in Ap value cor-
relates lvith an increase in fractiou absorbed, u,hereas
AP values greatcr than 1 inclicate complete rlrug
absorption.
SUMMARY
At one time, it \,\ras common to assunte that the biologic
response to a drug r,vas simply a function of the intrin_
sic pharmacologic activity of the drug molecule. Toda1.,
when assessing the potenc)/ of most drugs, consideration
is gi1,6n to plasma clrug concentration-response rather
than dose-response relationships. The conientration of

r
l-

s (mg/ml) Do19 {mg) pr(, r;., (p,tt 6.5) AP. %ABS (range)
:1

7.3 200 95 1 - 1.5 t7 fz z3)

--:-:rhrazide .o..4 : ?5o 6;7, 0;6 .'.' ,' :o:89 ?5 (1o-4o)
I-
c -- :::julvin o.or5 250 l a36 43 (3s-5 r)
:
S -.:-c:hlorothiazide o.85 o.6: . 25 8.8' o.q s o.7 67 {5o-9o)
I : -:-,:cin 295 o.o14 100
F 9.2 o.99 1.O 9o (8o-roo)
!. :-::-isone 26, c,'235 '
-:. 't,g qq
C
, .:, r o.o24
3.13 ,90
-eflPF
84 PART I/ PRINCIPLES OF DRUG DISCOVERY
Fraction Absorbed
E
1.0
DT
0.8 T1
t lntroduction
CI
-_L
B into two phases: a pharmacokinetic phase, in which the
i
IJ
0.4
r1 0.2
1.0 0 1.0 2.0
Absorption Potential
FIGURE 3.zr The relationship between absorption potential
(AP) and fraction absorbed for seven representative drugs (see
Table 3.7). A, acyclovir; B, chlorothiazide; C, micronized griseo-
fulvin; D, hydrochlorothiazide; E, phenytoin; F, prednisolone; C,
digoxin (Lanoxicap). (From Dressman ,lB, Amidon CL, Fleisher D.
Absorption potential: estimating the fraction absorbed for orally
administered compounds. .J Pharm Sci t9B5;74:588-589, with
perm ission.)
a drug in the plasma is dependent on the rate and extent
of absorption, which in turn is influenced by the physico-
chemical properties of drug substances. Drug absorption
can markedly affect the onset and intensity of a biologic
response to a drug. Clinically significant differences in
the absorption of closely related drugs, such as linco-
mycin and clindamycin, penicillin and pivampicillin, or
secobarbital and sodium secobarbital, are invariably the
result of significant differences in their physicochemical
properties.
Dissolution is simply a process by which a solid sub-
stance goes into solution. The determination of disso-
lution rates of pharmaceutical substances from dosage
forms does not predict their bioavailability or rheir in
vivo performance; rather, it indicates the potential avail-
ability of drug substance for absorption. Therefore, it is
essential for pharmacists and pharmaceutical scientists to
know and understand the importance of dissolution and
its potential influence on the rate and extent of absorp-
tion and availability for drugs.
Factors affecting the dissolution rate of a drug from
a dosage form can be related to the physicochemical
properties of a drug, formulation of a dosage form, and
dissolution apparatus and test parameters. Additionally,
a brief introduction of the role of intestinal transporters
and metabolizing enzymes (C\?3A4) in drug absorption
was provided. The role of intestinal permeability in drug
absorption process, techniques of measuring intestinal
permeability, and methods that permit the estimation
of fraction of dose absorbed by considering the physi-
cochemical properties of a drug also were discussed.
Additionally, the biopharmaceutical drug classification
based on the two physicochemical properties of drugs,
solubility and permeabiliq,, and the implications of these
properties on drug absorption were covered.
PHARMACOKINETICS
The events following drug administration are divided
ability to adjust a dose, alter the dosage form, and alter
the frequency and route of administration are related to
the drug concentration-time relationship in the body;
and a pharmacodynamic phase, in which the drug con-
centration at the sites of action is related to the magni-
tude of effects produced. Once both of these phases have
been defined for a drug, a dosage regimen for a drug can
be established to achieve the optimum therapeutic goals
in individual patients and to predict what can happen
when a dosage regimen is changed.
The sites into which drugs are routinely administered
are broadly classified as intravascular and extravascular.
Intravascular administration refers to the placement of
a drug directly into blood, either IV or intra-arterially.
Because the drug is placed directly into blood, it is
imperative that a drug administered intravascularly be
given as a solution. The extravascular routes of admin-
istration include oral, IM, sublingual, buccal, SC, der-
mal, rectal, and nasal routes. To enter the blood, a drug
administered extravascularly must be absorbed from
the site of administration. In addition, if a drug is orally
administered through solid dosage forms, such as tab-
lets or capsules, then the drug must first dissolve at the
site of administration. Therefore, the dissolution of a
drug is essential before absorption occurs. However, no
such absorption step is required when a drug is admin-
istered fV.
Pharmacokinetics is the scientific discipline that deals
with the mathematical description of biologic processes
affecting drugs and affected by drugs. In addition to sig-
nifying the relationship of ADME processes to the inten-
sity and time course of pharmacologic effects of drugs,
pharmacokinetics describes the time course of a drug's
ADME processes, which take place following the admin-
istration of a drug. Therefore, it is necessary to describe
and analyze these processes and their effects in relation
to their rates, rate constants, or time course. A qualitative
description of these processes is quite insufficient and
seldom leads to adequate and accurate characterizations
ofthe effects ofdrugs on the body and effects ofthe body
on the drugs. Pharmacokinetics is a quantitative study
whose purposes are:
l. To develop mathematical expressions that permit
one to describe the temporal changes of the drug
concentration;
2. To determine constraints that describes ADME j
processes succinctly; I
3. To make predictions and extrapolations based on I
the mathematical expressions; and T