advanced

drugdehmy
reviews

ELSEVIER

Advanced Drug Delivery Reviews 25 ( 1997) 3-14

Influence of physicochemical properties on dissolution of drugs in the

gastrointestinal tract
D. Hijrter, J.B. Dressman
Insritut
,fiir

Pharmazeutische

Technologie,

J.W. Goethe Universitiit,

Marie-Curie-Strqfie

9, 60439 Frankfurt

am Main, Germany

Abstract
The rate-limiting step to absorption of drugs from the gastrointestinal (GI) tract is often dissolution from the dosage form.
Consideration of the Noyes-Whitney dissolution model shows that drug diffusivity, solubility in the gastrointestinal contents,
the surface area of the solid wetted by the lumenal fluids and the GI hydrodynamics all play a role in determining the in vivo
dissolution rate. Solubility in the GI contents is determined by aqueous solubility, crystalline form, drug lipophilicity,
solubilization by native surfactants and co-ingested foodstuffs, and pKa in relation to the GI pH profile. Compounds with
aqueous solubilities lower than 100 pg/ml often present dissolution limitations to absorption. The dose:solubility ratio of the
drug provides an estimate of the volume of fluids required to dissolve an individual dose, and when this volume exceeds 1 1,
dissolution is often problematic. The surface area of a drug available for dissolution depends on the particle size of the solid
and its ability to be wetted by lumenal fluids. Other physiological factors that can play a role in dissolution include the
viscosity of the lumenal contents, through its effect on the diffusivity, and mixing and flow patterns within the gut. In order
to better predict in vivo dissolution of drugs, dissolution tests which more adequately simulate the physiological conditions
are needed.
Keywords:

Dissolution;

Polymorphism;

Solubilization;

pK*; Complexation;

Wetting diffusivity;

GI physiology

Contents
1. Introduction ............................................................................................................................................................................
2. Factors influencing the saturation solubility (C,) .......................................................................................................................
2.1. Polymorphism .................................................................................................................................................................
2.2. Solubilization by surfactants and its relation to physicochemical properties ..........................................................................
2.3. pK,, and the gastrointestinal pH profile ..............................................................................................................................
23.1. Gastric PH.. ...........................................................................................................................................................

4
4
3
5
6
6
7
2.32. pH in the small intestine .........................................................................................................................................
8
2.3.3. Buffer capacity ......................................................................................................................................................
9
2.4. Complexation ..................................................................................................................................................................
9
2.4.1. w-Donor/m-acceptor
complexes ..............................................................................................................................
9
2.4.2. Cyclodextrins .........................................................................................................................................................
9
2.4.3. Complexation phenomena and solubility in co-ingested food.. ...................................................................................
10
3. Factors influencing the available surface area for dissolution. .....................................................................................................
10
3.1. Particle size .....................................................................................................................................................................
10
3.2. Wetting ...........................................................................................................................................................................
3.2.1. Wetting by the gastric juice.. ...................................................................................................................................
10
3.2.2. Wetting effects in the small intestine .......................................................................................................................
10

*Corresponding

author. Tel.: +49 69 79829680;

0169-409X/97/$32.00
0 1997 Elsevier Science
PII SO1 69-409X(96)00487-5

fax: +49 69 79829694.

B .V. All rights reserved

4
3.2.3. Wetting
4. Factors influencing
5. Factors influencing
6. Factors influencing

D. HGrter, J.B. Dressmm

I Advanced Drug Delivery Reviews 25 (1997) 3-14

versus solubilization ..................................................................................................................................

1I
the volume available for dissolution .............................................................................................................
11
the diffusivity .............................................................................................................................................
I1
the boundary layer thickness and time available for dissolution ......................................................................
II

7. Conclusion .............................................................................
References ..................................................................................

1. Introduction
The lack of ability of a drug to go into solution is
sometimes a more important limitation to its overall
rate of absorption than its ability to permeate the
intestinal mucosa. For many drugs that cross the
intestinal mucosa easily, the onset of drug levels will
be dictated by the time required for the dosage form
to release its contents, and for the drug to dissolve.
We may define a drug as poorly soluble when its
dissolution
rate is so slow that dissolution
takes
longer than the transit time past its absorptive sites,
resulting in incomplete bioavailability.
The aqueous solubility
of a drug is a prime
determinant of its dissolution rate and, in the case of
poorly soluble drugs (as defined above), the aqueous solubility is usually less than 100 pg/ml.
A
further parameter that is useful for identifying poorly soluble drugs is the dose:solubility
ratio of the
drug. The dose:solubility
ratio can be defined as the
volume of gastrointestinal
fluids necessary to dissolve the administered
dose. When this volume
exceeds the volume of fluids available, one may
anticipate incomplete bioavailability
from solid oral
dosage forms. Griseofulvin
provides a classic illustration of the utility of the dose:solubility
ratio. With
an aqueous solubility of 15 ,uglml at 37C and a
dose of 500 mg, griseofulvin has a dose:solubility
ratio of about 33 1 [l]. Thus the combination of its
poor solubility and high dose constitutes a severe
limitation to its oral bioavailability.
From the following modification
of the NoyesWhitney equation (Eq. (l)), the important factors to
the kinetics of drug dissolution can be identified.

where DR is the dissolution rate, A is the surface

area available for dissolution,
D is the diffusion
coefficient of the drug, h is the thickness of the
boundary
layer adjacent to the dissolving
drug
surface, C, is the saturation solubility of the drug,

......
......

12
13

X, is the amount of dissolved drug and V is the

volume of dissolution media.
There are many physicochemical
and physiological factors which can have a great influence on the
factors in Eq. (1) and therefore on the dissolution
rate.

2. Factors influencing the saturation

solubility

((-2
The saturation solubility is a key factor in the
Noyes-Whitney
equation, as, together with the concentration of drug already dissolved and the thickness of the boundary layer, it determines the concentration gradient across the boundary layer, which
is the driving force for dissolution.
Various physicochemical
and physiological factors
influence the saturation solubility of a drug in the
gastrointestinal
tract. These include its crystalline
form, its lipophilicity and the ability of the drug to
be solubilized by native surfactants and co-ingested
foodstuffs, its aqueous solubility and pK, and the GI
pH profile.
2.1. Polymorphism
Many drugs are able to crystallize
in several
forms, each having a different energy and thereby
differing
in physicochemical
properties
such as
melting point, solubility,
heat of fusion, density,
refractive index, etc. Methods of obtaining metastable forms of a drug include recrystallization
from
different solvents, melting or rapid cooling. Polymorphic form has been shown to influence the
solubility and therefore the dissolution rate of numerous drugs, for example chlorpropamide
[2] and
novobiocin
[3]. Enhanced dissolution rate through
appropriate polymorph selection does not, however,
always lead to improved bioavailability.
Although
the solubility of the metastable form of the analgesic
diflunisal was twice as high as that of the stable form

D. Hiirter, J.B. Dressmun ! Advanced Drug Delivery Reviews 25 (1997) 3-14

(14 ,uglml vs. 26 pg/ml), no statistically significant

differences
in the in vivo plasma profiles were
observed [4]. In other cases, the bioavailability
of a
drug may be increased by selection of an appropriate
polymorph, but for reasons other than an increase in
the drug solubility. In the case of chloramphenicol
palmitate, the rate of enzymatic hydrolysis differs
among polymorphs of the ester. Since only the free
base of chloramphenicol
is efficiently absorbed, the
conversion rate of the ester to the free base will be
the controlling factor in the overall rate of absorption

L-7.
The biggest problem with the use of metastable
polymorphs to improve dissolution is the eventual
conversion of the higher energy, higher soluble form
to the crystalline
form with the lowest energy.
Commercial
exploitation
of metastable
forms is
limited by the possibility
of interconversion
of
polymorphs
both during
manufacture
and subsequently during storage of the dosage form.
2.2. S&biEization
to physicochemical

by surfactants
properlies

and its relation

Solubilization can be defined as the preparation of

a thermodynamically
stable solution of a substance
that is normally insoluble or very slightly soluble in
a given solvent, by the introduction of one or more
amphiphilic
component(s)
[6]. A relationship
between the extent of solubilization
and the lipophilicity of the compound has been observed by several
authors [7-lo]. Collett and Koo [7] found a linear
relationship
between the 7~ values of functional
groups on substituted benzoic acids and their aqueous/micellar
partition coefficients into polysorbate
20. Tomida et al. [S] demonstrated linear free energy
relationships between the octanol/water
(log P) and
aqueous/micellar
(log P,) partition coefficients into
BrijS 35 of 34 benzoic acid derivatives. Although
the majority of compounds could be described by
one line, two additional, parallel lines were needed to
describe the behaviour
of the nitro and cyano
derivatives, and the dicarboxyl derivatives. In the
case of steroids [9], Barry and El Eini found that for
four steroids there was a general relationship
between the free energy of solubilization
and the
polarity of the steroid. However, the behaviour of
dexamethasone,
a fluorinated steroid, did not fit the
relationship
so closely as the other three steroids

studied. In more extensive studies, Tomida et al. [lo]

found that it was necessary
to use two linear
relationships
with the same slope but different
intercepts to describe the relationship between log P
and log P,. The main structural difference between
the two series of steroids was the presence of a
fluorine atom at the C9 position. Fluorinated steroids
were better solubilized than the corresponding
steroids which contained no fluorine atom. The authors
attributed these results to incorporation of the fluorinated drugs into the more hydrophilic outer region of
the micelle [lo].
In the small intestine,
drug solubility
can be
enhanced by amphiphilic bile components
such as
bile salts, lecithin and monooleins.
When these
substances are present in concentrations
higher than
their critical micelle concentration
(CMC), micellar
solubilization
of the drug can occur. Solubilization
into simple bile salt micelles has been reported for
many poorly soluble drugs, including griseofulvin
[ 111, giutethimide [ 1 I ], digoxin [ 121, Ieucotriene-D,
antagonists [ 131 and gemfibrozil [14]. Increases in
solubility of up to IOO-fold upon addition of physiological concentrations
of bile salts to aqueous media
have been observed.
In several cases, the solubility of drug compounds
in bile salt solutions was further enhanced by the
addition of lecithin, monooleins,
long chain fatty
acids and/or
triglycerides.
Addition
of lecithin
causes an increase in the molecular
weight of
micelles from 6000 to 150 000 Da [ 151. In most
cases there is a correlation between size and solubilization capacity of mixed micelles, but this is dependent on the mechanism
by which the drug is
solubilized. The ratio of bile salts to lecithin may
also influence the extent of solubilization.
Rosoff et
al., for example, showed that the greater the molar
ratio of lecithin to bile salt was increased, the more
the solubility of diazepam was enhanced [ 161.
Mithani et al. [17] developed a model to predict
solubility enhancement
by bile salts based on two
physicochemical
properties of the drug, namely its
log P and aqueous solubility. Eleven compounds
with widely varying structures were included in the
correlation. A linear correlation (Fig. 1, Eq. (2)),
[SRI = 0.64 x log [P] + 2.09
r2 =0.95,

was

observed

between

(2)
log P and

the

D. H&u,

J.B. Dressman

I Advanced

4.5 !
4 l
305 i
34

2 4~0,oo

25 (1997) J-14

2.3. pK, and the gastrointestinal

log SR

2,5

Drug Delivery Rwiews

1 ,oo

2,00

3,00

4,00

5,00
log

Fig. I. Correlation between log SR (solubility ratio) and log P

(partition coefficient)
for 1 I steroidal and non-steroidal
compounds (adapted from [17]).

logarithm of the solubilization

defined in Eq. (3),

ratio SR, which

is

where SR is the solubilization

ratio, SC,, is the
solubilizing
capacity of bile salt micelles (moles
drug/mole taurocholate) and SC,, is the solubilization capacity of water (moles drug/mole water) for
the drug. An interesting feature of this correlation
was that only one correlation line was required to
describe the results, despite the diversity of drug
structures.
In addition to partitioning behaviour, other factors
may be important
in determining
the extent of
solubilization. The molecular weight of the drug can
come into play, because the volume available to the
drug in the micelle is limited, especially in the case
of simple bile salt micelles. Specific interactions may
also be important. In spite of its higher partition
showed
that
coefficient,
Miyazaki
et
al.
phenylbutazone
has a lower affinity for bile salt
micelles than indomethacin
[18]. An explanation for
the unfavourable
solubilization
of phenylbutazone
was found in the repulsion forces between the cyclic
mesomeric anion and the negatively charged carboxyl-group of bile salts [19].

pH prqfile

The solubility of weak acids and bases is dependent on their ionization constants, K, and the pH of
the dissolution medium. The intrinsic solubility can
be defined as the solubility of a compound in its free
acid or base form. For weak acids this is approximated by the solubility at pH values more than one
unit below the pK,. As the pH value increases, the
solubility of the acid increases due to the contribution from the ionized form. At pH values exceeding
pH=pK, + 1, a linear relationship
between
the
logarithm of the solubility and the pH is observed,
until the limiting solubility of the ionized form is
reached. The inverse relationships
exist for weak
bases (Fig. 2a and Fig. Zb).
The pH of the gastrointestinal
fluids is, therefore,
one of the most important influences on the saturation solubility of ionizable drugs. The pH varies
widely with location in the gastrointestinal
tract, as
shown in Table 1 and Table 2. Typical values in the
fasted stomach are pH l-2 while in the upper small
intestine the pH usually lies between pH 5 and pH
6.5.

2.3.1. Gastric pH
There are complex variations in pH between the
fed and fasted state. Upon ingestion of a meal, the
gastric pH at first increases because of buffering
effects of food components.
In response to food
ingestion, however, gastric acid is secreted, and by
3-4 h after the meal intake, the fasted state pH has
usually been reestablished (Fig. 3) [25].
Weak bases like ketoconazole (pK,, =6.5; pK,,=
(pK, = 3.7)
[27]
and
2.9)
WA, itraconazole
dipyridamole (pK, = 6.4) [28] will be less soluble in
the stomach if given immediately after food intake
because the gastric fluids are less acidic. This effect
will however, be partly offset by the longer gastric
emptying time in the fed state, which will afford
more time for the drug to go into solution.
Note that the pH of the lumenal fluids is also
dependent on other factors like age, pathophysiological conditions such as achlorhydria and AIDS, and
concurrent drug therapy such as HZ-receptor antagonists and proton pump inhibitors. In the case of
poorly soluble weak bases, especially the imidazole
antifungals, ketoconazole and itraconazole, elevated

D. Hiirter, J.B. Dressman I Advanced Drug Delivery Reviews 25 (1997) 3-14

Table 1
Average pH values in healthy humans in the fasted state at various

(a)
log

sites in the upper GI tract

Location
Stomach
Duodenum
Jejunum

(mid distal)

Ileum

Average pH

Reference

1.3
6.5
6.6
7.4

t201

I201
1211
1211

Table 2
Average pH values in healthy humans in the fed state in healthy
humans at various sites in the upper GI tract

(b)

10

Location

T
PKa

PH

Stomach
Duodenum
Jejunum
Ileum

@I

(mid-distal)

Average pH

Reference

4.9
5.4
5.2-6.0
7.5

1201
1221
1231
1241

6
t

f
PKa
Fig. 2. (a) The solubility of a weak acid is enhanced
increasing pH, according to the following equation:

PH
with

*(I +&)

s = s,,

where S is the pH dependent solubility, S, is the pH independent

solubility and K, is the acidity constant (case example 10~).
(b) The solubility of a weak base is enhanced with decreasing pH,
according to the following equation:
S=S,,(l

+F)

where S is the pH dependent solubility, S,, is the pH independent

solubility and K, is the acidity constant (case example IO-).

gastric pH in AIDS patients leads to a reduced rate

of drug dissolution and consequently
to malabsorption
[27,29].
By contrast,
the solubility
of
fluconazole, a weak base with a pK, of 1.5 [26], is
sufficiently high (6 mg/ml [30], dose:solubility
ratio
about 17 ml) that its administration
to patients with

0-1

hOINS

Fig. 3. Gastric pH in the fasted state and after food intake (pH 6,
458 calories and 400 ml total volume) in 10 healthy volunteers.
(Reproduced with permission from [25]).

elevated gastric pH does not lead to dissolution

limited absorption.

rate

2.3.2. pH in the small intestine

The small intestine pH at first decreases in response to a meal with the arrival of acidic thyme
from the stomach but later the fasted state pH is
reestablished
as a result of pancreatic bicarbonate
output (Fig. 4).
Poorly soluble weak acids with pK, values less
than 6, e.g. furosemide
(pK, =3.9)
[28] and indomethacin (pK, =4.5) [28] are relatively insoluble

D. Hiirter, J.B. Dressman I Advanced Drug Delivery Reviews 25 (1997) 3-14

PH

5
0
-1

rl

Hours
Fig. 4. Duodenal pH in the fasted state and after food intake (pH
6, 458 calories and 400 ml total volume) in IO healthy volunteers.
(Reproduced with permission from [25]).

in the preprandial gastric juice and dissolution occurs

first in the upper small intestine. However, in the
case of very weak acids like paracetamol (pK,=9.5)
[28] or hydrochlorothiazide
(pK, =8.8)
[31] the
variations in pH in the gastrointestinal
(GI) tract are
irrelevant to the solubility because these compounds
are always in the free acid form over the physiological pH range.
2.3.3. Buffer capacity
For the dissolution of weak acids and bases, the
pH of the boundary layer is especially significant.
This value can be quite different from the pH of the
bulk solution, depending on the buffer capacity of
the bulk solution and the pK, and solubility of the
drug substance. Fig. 5, adapted from Ozturk et al.
[32], shows the differences between the bulk pH and
the surface pH for the three weak acids indomethacin, 2-naphthoic acid and benzoic acid with
pK, values around 4.
The pH at the surface of the dissolving
solid
influences the dissolution rate of an ionizable compound in a manner that exactly parallels its influence
on the surface pH. As seen in Fig. 6 there is a
pronounced
plateau region where the surface pH
depends more on the pK, of the drug than on the
bulk pH. The extent of the plateau region and thus
the effective surface pH depends on the solubility of
the drug as well as its pK,. The surface pH remains
suppressed, and therefore the plateau region is more
pronounced,
for compounds with a relatively high

Fig. 5. The relationship between bulk and surface pH for different

weak acids in unbuffered
media. (A) Indomethacin;
(B) 2naphthoic acid; (C) benzoic acid. (Reproduced
with permission
from [32]).

Fig. 6. Initial powder dissolution rate for danazol (normalised for

solubility at the given bile salt concentration)
and contact angle
with the dissolution medium, as a function of sodium taurocholate
concentration.
(Reproduced with permission from [SO]).

intrinsic solubilities, e.g. benzoic acid than for drugs

with lower intrinsic solubilities, e.g. indomethacin.
Co-ingestion
of foodstuffs and liquids with high
buffer capacity may alter the dissolution
rate of
susceptible
ionizable
drugs in the stomach. The
buffer capacity in the small intestine is, however,
governed mainly by secretions, especially pancreatic
juice. Any increase in the buffer concentration in the
small intestine would increase the total solubility and
therefore the dissolution rate of weakly acidic drugs
because the pH at the drug surface would be nearer

D. H6rrer. J.B. Dressman I Advanced Drug Delivery Reviws

to that of the bulk lumenal pH. In pathophysiological

conditions
such as cystic fibrosis, in which pancreatic secretions are significantly reduced, both the
pH and the buffer capacity in the intestine may be
substantially lower than in patients with normal GI
function. It is also worth mentioning here that, since
the intestinal juice contains significant
levels of
bicarbonate buffer, in vitro dissolution tests results
that are obtained in unbuffered or weakly buffered
media are unlikely to reflect in vivo dissolution
behaviour of ionizable drugs.
2.4. Complexation
2.4. I. r-Donor/r-acceptor
complexes
A classic example of solubility enhancement
by
complexation
is the complexation
of caffeine with
salts of benzoic- or salicylic acid via a r-donorlrracceptor mechanism. Nicotinamide has been reported
to enhance the solubility of poorly soluble drugs
such as diazepam [33], progesterone [33] and some
anti-cancer nucleosides [34] by a similar mechanism.
In the case of progesterone
the solubility
was
enhanced
almost 600-fold, in comparison
to its
aqueous solubility, using a 3.3 M concentration
of
nicotinamide.
2.4.2. Cyclodextrins
Another possibility
for improving
solubility by
complexation
is incorporation
by cyclodextrins.
Cyclodextrins
are torus shaped oligosaccharides
composed of glucose molecules, which can form
inclusion complexes by taking up a guest molecule
into the central cavity. A feature of these complexes
is that they are stable in aqueous solution. (Y-, p- and
y-cyclodextrins
contain six, seven and eight glucose
units respectively.
The (Y, with an internal diameter
0
of 6 A, is too small to complex with most compounds of pharmaceutical interest. The p has a rather
low aqueous solubility
(1.8% in water at 25C)
because of the formation of stable intramolecular
hydrogen bonds, and this limits the degree to which
it can be used to improve the solubility of drugs. It
has been shown, however, that inclusion of drugs
such as cinnarizine
[35], piroxicam [36], fenbufen
[37] and ibuprofen
[38] in /3-cyclodextrins,
and
benzodiazepines
and digoxin [38] in y-cyclodextrins
can result in a very significant increase in their rates
of dissolution. How the increase in dissolution rate

(1997) 3- I4

translates to an increase in bioavailability

depends on
whether the rate and/or extent of absorption
is
limited primarily by dissolution when a conventional
dosage form is administered. For ibuprofen, a compound which is thought to be completely absorbed
from the usual dosage form, there is a modest
increase in the rate, but not the extent, of absorption.
In contrast, when diazepam is given as the y-cyclodextrin complex, both the rate and extent of absorption are increased. The results for digoxin are even
more impressive. When administered
to dogs as
conventional tablets, the AUC was only one-fifth that
of tablets containing
a 1:4 digoxin:cyclodextrin
complex.
Recently,
hydroxyalkylated
derivatives
of pcyclodextrins
have been developed. Not only do
these derivatives have a better aqueous solubility
than the parent cyclodextrins,
but they also have a
lower toxicity than methylated and other derivatives.
In the case of carbamazepine
1391 a 2500-fold
increase in aqueous solubility was reached by complexation with HP-P-CD. For thiazolobenzimidazole,
a combination
of pH adjustment and complexation
with HP-P-CD was required to effect the desired
increase in solubility
1401. The bioavailability
of
cinnarizine
was significantly
enhanced,
when administered
in a capsule, by 2-hydroxypropyl-flcyclodextrin (HP-P-CD),
an effect attributed to the
more rapid dissolution rate 1411. Further solubility
enhancement
could be achieved by substituting the
/3-cyclodextrins
with maltosyl- or glucosyl groups,
as demonstrated for lipophilic vitamins 1421 and the
phytosterol
fucosterol [43]. The toxicity of maltosylated cyclodextrins has been reported to be lower
than that of unsubstituted cyclodextrins
[44].
2.4.3.

Complexation

co-ingested

phenomena

and solubility

in

food

The solubility of the drug in the GI tract can also

be enhanced when the drug is highly soluble in a
coadministered
food component.
For example, the
solubility
of dicumarol
is five times higher in
defatted milk than in buffer at 37C [45]. The main
milk protein, casein, is responsible for the significant
increase in dicumarol solubility and bioavailability.
When a freeze-dried
formulation
of dicumarol in
defatted milk was administered, the resultant plasma
levels were five times higher than those after administration of the control formulation (Fig. 7) [46].

10

D. Hbrter. J.B. Dressman I Advanced Drug Delivery Reviews 25 (1997) 3-14

3.2. Wetting

TIME, hours
Fig. 7. Plasma concentrations of dicumarol in 4 subjects after oral
administration
of 300 mg dicumarol (. .control formulation;
formulated as a freeze dried formulation
with defatted
milk (Reproduced with permission from [46]).

Griseofulvin
absorption is also enhanced by concomitant food intake, especially after ingestion of
heavy fat meals. However, in the case of griseofulvin, the amplified bile output and the prolonged
gastric emptying time may also play a role in the
enhanced bioavailability
[47].

3. Factors influencing
for dissolution.

the available

surface area

A rough estimate of the wettability of a hydrophobic drug by a given medium can be obtained
from the contact angle at the liquid/solid
interface
and the structure of the drug. When a compound is
not very well wetted by water, that is to say its
contact angle is high, native surfactants in the GI
tract may assist wetting of the drug by the lumenal
fluids, so that the ability of the fluid to penetrate
between particles and into pores is increased. It is
worth noting that most media used in in vitro
dissolution
testing (SGF, SIF, water etc.) do not
contain surfactants and therefore fail to address the
possibility
of wetting by native surfactants
and
thereby the associated enhancement
in dissolution
rate.

3.2.1. Wetting by the gastric juice

Gastric juice is an important dissolution medium,
especially for weak bases. Finholt et al. [49] examined the surface tension of human gastric juice
and concluded that the surface tension of human
gastric juice is nearly independent of pH and secretion rate, lying normally in the range from 35-45
mNm-. Further experiments showed a linear relationship between the surface tension of the dissolution medium and the dissolution time in the case of
phenacetin.
As there was no improvement
in the
solubility of phenacetin with increasing surfactant
concentration,
it was concluded that the main effect
of the surfactants on the dissolution rate was the
decrease in the interfacial tension.

3.1. Particle size

An important factor determining
the dissolution
rate is the particle size of the drug. The dissolution
rate is directly proportional to the surface area of the
drug, which in turn increases with decreasing particle
size. Micronization to particle sizes of about 3-5 ,um
is often a successful
strategy for enhancing
the
dissolution rate, for example in the case of griseofulvin. The effective surface area also depends on the
ability of the fluid to wet the particle surface. When
the dissolution medium has only poor wetting properties, micronization
sometimes
results in a decreased dissolution
rate due to agglomeration,
as
reported by Finholt for phenobarbital
[48].

3.2.2. Wetting effects in the small intestine

The bile salts in the small intestine play a very
important role in wetting of poorly soluble drugs.
Typical concentrations of bile salts in the fasted state
are 3-6 mM, levels which can decrease the contact
angle very significantly [50], as shown for danazol in
Fig. 6.
In the case of phenylbutazone,
which has a contact
angle of 90 with water, addition of bile salts to the
medium resulted in a large increase in the dissolution
rate. On the other hand, bile salts had little influence
on the dissolution rate of indomethacin, which has a
contact angle with water of 28 [51].

D. Htirter, J.B. Dressman I Advanced Drug Delivery Reviews 25 (1997) 3-14

3.2.3. Wetting versus solubilization

The relative importance of wetting and solubilization to drug dissolution depend on drug structure and
the type of surfactant present. For a series of steroids
it was shown that increases
in dissolution
rate
resulting from addition of bile salts to the dissolution
medium varied with partitioning characteristics.
At
values of log P in the l-2 range wetting was the
predominant mechanism. Although the solubility of
hydrocortisone
(log P = 1.6) was not substantially
improved in the presence of bile salts, its dissolution
from the powder form increased rapidly with increasing bile salt concentration. This effect was attributed
to wetting. For very lipophilic compounds, such as
danazol (log P = 4.53), however, solubilization
accounted for virtually all of the increase in powder
dissolution rate [52].
The picture becomes somewhat more complicated
when lecithin is introduced into the system. In the
case of hydrocortisone,
wetting effects were almost
eliminated by the addition of lecithin, whereas for
the more lipophilic
danazol, the contribution
of
wetting to the enhancement
of dissolution
was
significantly increased [53].

4. Factors influencing
dissolution

the volume

available

for

One of the ways in which food intake influences

the dissolution rate is through the increase in volume
of the GI contents. Fluids ingested with the meal can
increase the available gastric volume by as much as
1.5 1. Not only do the ingested food and fluids
directly influence the volume in the upper GI tract,
they also stimulate secretion of gastric acid, bile and
pancreatic juice. Furthermore,
ingestion of hypertonic substances can stimulate net water efflux across
the intestinal wall into the GI lumen.

5. Factors influencing

6qr

where D is the diffusivity, T is the temperature, 7 is

the viscosity of the medium, r is the radius of the
drug molecule and k is the Boltzmann constant.
The dissolution rate of benzoic acid in methylcellulose solutions was shown to be inversely proportional to the viscosity of the dissolution medium.
Dissolution
studies carried out in polysorbate
80
solutions of increasing concentration, showed that at
high polysorbate 80 concentrations,
the dissolution
rate decreased, even though the solubility was enhanced [54,55]. A dramatic increase in viscosity was
identified as the reason for this initially surprising
result.
The viscosity of the gastrointestinal
fluids, and so
the diffusivity of the dissolving drug can be increased by food intake. The extent of the effect will
depend on the food components,
i.e., the type of
meal ingested and the composition and volume of
coadministered
fluids. Water soluble fibres such as
pectin, guar and some hemicelluloses
are able to
swell and increase the viscosity of aqueous solutions.
Reppas et al. [56] showed that for hydroxypropylmethylcellulose
(HPMC), a semisynthetic,
non-digestible cellulose derivative,
a linear relationship
exists between the input and the lumenal viscosity.
These water soluble fibres may be present in the
food, or given supplementary
to the diet to treat
obesity or constipation.
The diffusion coefficient is also reduced by micellar solubilization,
since the effective diffusivity will
be that of the micelle rather than of the drug
monomer.
In the case of danazol, the diffusion
coefficient was decreased from 2.7 X 10mh in 0.1 M
NaCl to 1.67X1O-6
cm2/s in 30 mM sodium
taurocholate.
In a 15 mM sodium taurocholate
(NaTC)/3.75
mM lecithin mixture the diffusion
coefficient was only 2 X lo- cmls, nearly lOO-fold
slower than in NaTC only solutions. The reason was
the enormous increase of the micellar diameter from
40 to 2275 A in the mixed micelles [53].

the diffusivity

The Stokes-Einstein
equation describes the relationship between diffusivity and viscosity, showing
that the diffusivity, D, is inverse to the viscosity, 7,
D=k*T

11

(4)

6. Factors influencing the boundary layer

thickness and time available for dissolution
The two
important
absorption
segmental

types of contractile patterns that are most

to the transit of dosage forms and the
of drugs are the propagated
and the
contractions. Propagated contractions, as

D. Hiirter. J.B. Dressman / Advanced Drug Delivery Reviews 25 (1997) 3-14

12

the name suggests, tend to propel the lumenal

contents towards more distal locations and act over
distances of up to 20-25 cm. Segmental contractions, by contrast, travel only over very short distances (l-4 cm) but encourage mixing of the lumenal contents.
In the fasted state, the proximal
GI tract is
quiescent with the cyclic appearance of short bursts
of intense propagated motor activity. During the
quiescent state (Phase 1), owing to a lack of contractions, the fluid is essentially stagnant and hence the
boundary
layer thickness
is wide. However the
transit time of the drug and therefore the available
time for dissolution is prolonged. The intense motor
activity (Phase 3) serves to clear the proximal
gastrointestinal
tract of undigested residues and to
prevent overgrowth of bacteria. However, this is an
essentially propagative pattern and owing to the short
residence time, does not favour dissolution. Phase 2
behaviour is intermediate between that of Phase 1
and Phase 3 behaviour.
In the fed state there are few long range propagating contractions
in the proximal part of the gut.
Rather, motility patterns that facilitate mixing and
short distance movement
of the thyme prevail.
Coadministered
food causes an enhancement
in
segmental contractions associated with an increase in
mixing efficiency, in other words, the boundary layer
thickness becomes smaller. Therefore, efficiency of
dissolution and absorption are probably greater in the
fed than the fasted state. This is illustrated by studies
on the rate of glucose uptake from solutions in an
intestinal loop model, which showed that absorption
is most efficient in the fed state and least efficient
during Phase 3 motor activity in the fasted state (Fig.
8) [571.

Volume60
Absorbed
45
% 0,
lnl?,ale
30

mean
Fed

Fasling

TraIlSIt
The

Fed

Faslmg

7. Conclusion
The foregoing discussion shows that the physical
chemical properties of a compound have a strong
influence on its dissolution
in the gastrointestinal
tract, and hence on whether or not dissolution will be
the rate limiting step to its absorption. Furthermore,
the extant physiological conditions in the GI lumen
can have a profound effect on the dissolution
of
certain drugs. The poor match between physiological
conditions and those used in in vitro dissolution test
systems is the primary reason for the inability to
predict in vivo dissolution from in vitro data. Current
dissolution
media are not designed to accurately
reflect the physiological conditions in the upper GI
tract. In standard apparatus a volume of 900 ml
dissolution medium is typically used, even though
the gastric volume in the fasted state may be as little
as 20-30 ml. In addition, surfactants are usually not
added to the dissolution medium, and when they are,
the concentrations
tend to be unphysiologically
high
and the surfactants used often have solubilization
capacities, CMCs and wetting quite different from
those of the naturally
occurring
bile salts and
lecithin. In the case of weak acids and bases, the pH
is an especially important factor for dissolution. The
pH values of the dissolution media, e.g. Simulated
Intestinal Fluid USP XXIII with a pH of 7.5 do not
reflect the physiological conditions in the upper GI
tract and there are still fifteen USP monographs in
which the recommended
dissolution
pH is even
greater than pH 7.5. It is also clear that the hydrodynamics in the upper GI tract are quite different
from those in standard pharmacopeial apparatus. Our
ability to predict dissolution limitations to the oral
absorption of drugs in the future will be contingent
on improved design of both the test equipment and
the media that are used in dissolution tests.

l.--lL
II

15

Anticholinergics,
such as the anti-Parkinsons
drug
trihexiphenidyl
[58], increase the transit time and
therefore hence time available for dissolution, but
probably
increase the boundary
layer thickness,
thereby reducing the driving force for dissolution.
Motility-inducing
agents, such as cisapride, increase
propagative contractions and because of the resultant
decreased transit time, do not favour drug dissolution.

111

Fig. 8. Effect of motor pattern in the fasted and fed state on

absorption and transit time in the case of a glucose-electrolyte
solution introduced into an intestinal loop. (Reproduced
with
permission from [59]).

D. Hfirter.

J.B. Dressman

I Advanced

References

121

L31

[41

[5l

[61
I71

181

PI

[ 101

[III

[I31

ll51

1171

1181

Katchen, B. and Symchowicz,

S. (1967) Correlation
of
dissolution
rate and griseofulvin
absorption
in man. J.
Pharm. Sci. 56, 1108-l 110.
Al-Saieq, S.S. and Riley, G.S. (1982) Polymorphism
in
sulphonylurea
hypoglycaemic
agents: II. chlorpropamide.
Pharm. Acta Helv. 57, 8-I I,
Halebhan, J. and McCrone, W. ( 1969) Pharmaceutical
applications of polymorphism.
J. Pharm. Sci. 58, 91 I-929.
Dresse, A., Gerard, M.A., Lays, A., Tempero, K.F. and
Verhaest, L. (1978) Human pharmacokinetics
of two crystalline and galenic forms of diflunisal, a new analgesic.
Pharm. Acta Helv. 53, 177-181.
Aguiar. A.J.. Krc, J., Kinkel. A.W. and Samyn, J.C. (1967)
Effect of polymorphism
on the absorption
of chloramphenicol from chloramphenicol
palmitate. J. Pharm. Sci. 56,
8477853.
Attwood, D. and Florence, A.T. (1983) Solubilization.
In:
Surfactant Systems. Chapman and Hall, London, p, 229.
Collett, J.H. and Koo, L. (1975) Interaction of substituted
benzoic acids with polysorbate 20 micelles. J. Pharm. Sci.
64, 1253-1255.
Barry. B.W. and El Eini, D.I.D. (1976) Solubilization
of
hydrocortisone,
dexamethasone,
testosterone and progesterone by long-chain polyoxyethylene
surfactants. J. Pharm
Pharmacol. 28, 210-218.
Attwood,
D. and Florence, A.T. (1983) Pharmaceutical
aspects of solubilization.
In: Surfactant Systems. Chapman
and Hall, London, pp. 298-299.
Tomida, H., Yotsuyanagi, T. and Ikeda, K. (1978) Solubilization of steroid hormones by polyoxyethylene
lauryl ether.
Chem. Pharm. Bull. 26, 2832-2837.
Bates, T.R., Gibaldi, M. and Kanig, J.L. (1966) Solubilizing
properties of bile salt solutions I: Effect of temperature and
bile salt concentration
on solubihzation
of glutethimide,
griseofulvin and hexestrol. J. Pharm. Sci. 55, 191-199.
Kassem, M.A., Mattha, A.G., El-Nimr, A.E.M. and Omar,
S.M. (1982) Study on the influence of sodium taurocholate
(STC) and sodium glycocholate (SGC) on the mass transfer
of certain drugs. Digoxin. Int. J. Pharm. 12, l-9.
Karat%, T.T. and Gupta, V.W. (1992) Solubilization
and
dissolution
properties
of a leucotriene-D,
antagonist
in
micellar solutions. J. Pharm. Sci. 81, 483-485.
Luner, P.E., Babu, S.R. and Radebaugh, G.W. (1994) The
effects of bile salts and lipids on the physicochemical
behavior of gemfibroail. Pharm. Res. 1 I, 1755-1760.
Shankland, W., (1970) The equilibrium
and structure of
lecithin-cholate
mixed micelles. Chem. Phys. Lipids 4, 109130.
Rosoff, M. and Serajuddin, A.T.M., (1980) Solubilization of
diazepam in bile salts and in sodium cholate-lecithin-water
phases. Int. J. Pharm. 6, 137-146.
Mithani, S.D., Bakatselou, V., Tenhoor, C.N. and Dressman,
J.B. Estimation of the increase in solubility of drugs as a
function of bile salt concentration.
Pharm. Res. in press.
Miyazaki. S., Yamahira, T., Morimoto, Y. and Nadai, T.
(1981)
Micellar
interaction
of
indomethacin
and
phenylbutazone
with bile salts. Int. J. Pharm. 8, 303-310.

Drug

Delivery

Reviews 25 (1997)

3-14

13

[I91 Stella,V.J. and Pipkin, J.D. (1976) Phenylbutazone

kinetics. J. Pharm. Sci. 65, 1161-1165.

ionization

rw

Russell, T.L., Berardi, R.R., Bamett, J.L., Dermentzoglou,

L.C., Jarvenpaa, K.M., Schmaltz, S.P. and Dressman, J.B.
(1993) Upper gastrointestinal
pH in 79 healthy, elderly,
North American men and women. Pharm. Res. 10, 187- 196.

Pll

Evans, D.F., Pye, G., Bramley, R., Clark, A.G., Dyson, T.J.
and Hardcastle, J.D. (1988) Measurement of gastrointestinal
pH profiles
1035-1041.

WI

Dressman,
T.L.,

in normal

ambulant

human

subjects.

J.B., Berardi, R.R., Dermentzoglou,

Schmaltz,

S.P., Bamett,

J.L.

Gut, 29,

L.C., Russell,

and Jarvenpaa,

K.M.

(1991) Upper gastrointestinal pH in young, healthy men and

women. Pharm. Res. 7, 756-761.
U., Pedersen, N.T.,
~231 Ovesen, L., Bentsen, F., Tage-Jensen,
Gram, B.R. and Rune, S.J. (1986) Intraluminal pH in the
stomach,
jects

duodenum

and patients

Gastroenterology

and proximal
with exocrine

jejunum
pancreatic

in normal

sub-

insufficiency.

90, 958.

[241 Borgstrom, B., Dahlquist, A., Lundh, G. et al. (1957) Studies

of intestinal digestion and absorption in the human. Journal
of Clinical Investigation 36, 1521-1536.
1251 Malagelada, J.R., Longstreth, G.F., Summerskill, W.H.J. and
Go, V.L.W. (1976) Measurement of gastric functions during
digestion of ordinary solid meals in man. Gastroenterology
70, 203-210.
Ml

Blum, R.A., DAndrea, D.T., Florentino, B.M., Wilton, J.H.,

Hilligoss, D.M., Gardner, M.J., Henry, E.B., Goldstein, H.
and Schentag, J.J. (1991) Increased gastric pH and the
bioavailability of fluconazole and ketoconazole. Ann. Intern.
Med. 114, 755-7.57.

T.. Yeates, R.A., Laufen, H., Pfaff, G. and

~271 Zimmermann,
Wildfeuer, A. (I 994) Influence of concomitant food intake
on the oral absorption of two triazole antifungal agents,
itraconazoie and fluconazole. Eur. J. Clin. Pharmacol. 46,
147- 150.
w31 Martindale, W. (1982). Dissociation Constants.
Pharmacopeia.
The Pharmaceutical
Press,
XXIV-XXVII.

In: The Extra

London,
pp.

G., Tom, W., Lake-Bakaar,

D., Gupta, N.,
P91 Lake-Bakaar,
Beidas, S., Elsakr, M. and Straus, E. (1988) Gastropathy and
ketoconazole
malabsorption
in the Acquired
ImmunoDeficiency Syndrome (AIDS). Ann. Intern. Med. 109, 471473.
[301 Brammer, K.W. and Tarbit, M.H. (1987) A review of the
ptarmacokinetics
of fluconazole (UK-49 858) in laboratory
animals and man. In: R.A. Fromtling (Ed.), Recent Trends in
the Discovery, Development and Evaluation of Antifungal
Agents. J.R. Prous Science Publishers, Barcelona, pp. 141149.
[31] Deppeler, H.P. (1981) Hydrchlorothiazide.
In: K. Florey
(Ed.), Analytical Profiles of Drug Substances Volume IO.
Academic Press, New York, pp. 405437.
[32] Ozturk, S.S., Palsson, B.O. and Dressman, J.B. (1988)
Dissolution of ionizable drugs in buffered and unbuffered
solutions. Pharm. Res. 5, 272-282.
[33] Rasool, A.A., Husnain, A.A. and Dittert, L.W. (1991) Solubility enhancement
of some water-insoluble
drugs in the

14

[34]

[35]

[36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

D. Hbrter, J.B. Dressman I Advanced Drug Delivery Reviews 25 (1997) 3-14

presence of nicotinamide and related compounds. J. Pharm.
Sci. 80, 387-393.
Truelove, J., Bawarshi-Nassar,
R., Chen, N.R. and Hussain,
A. (1984) Solubility enhancement
of some developmental
anti-cancer nucleoside analogs by complexation
with nicotinamide. Int. J. Pharm. 19, 17-25.
Tokumura,
T., Nanba, M., Tsushima, Y., Tatsuishi,
K.,
Masanori, K., Machida, Y. and Nagai, T. (1986) Enhancement of bioavailability of cinnarizine from its P-cyclodextrin
complex on oral administration with D,L-phenylalanine
as a
competing agent. J. Pharm. Sci. 75, 391-394.
Woodcock, B.G., Acerbi, D., Merz, P.G., Rietbrock, S. and
Rietbrock, N. (1993) Supermolecular
inclusion of piroxicam
with P-cyclodextrin:
pharmacokinetic
properties
in man.
Eur. .I. Rheumatol. Inflamm. 12, 12-28.
Miyayi, T., Inoue, Y, Acarturk, F., Imai, T., Otagiri, M. and
Uekama K. (1992) Improvement
of oral bioavailability
of
fenbufen by cyclodextrin complexations.
Acta Pharm. Nerd.
4, 17-22.
Dressman, J.B., Ridout, G. and Guy, R.H. (1990) Delivery
system technology. In: C. Hansch, P.G. Sammes and J.B.
Taylor (Eds.), Comprehensive
Medicinal Chemistry, Volume
5. Biopharmaceutics.
Pergamon Press, Oxford, p. 632.
Brewster, M.E., Anderson, W.R., Estes, K.S. and Bodor, N.
(199 1) Development of aqueous parenteral formulations for
carbamazepine
through the use of modified cyclodexttins.
J.
Pharm. Sci. 80, 380-383.
Tinwalla, A.Y., Hoesterey, B.L., Xiang, T., Lim, K. and
Anderson
B.D. (1993)
Solubilization
of thiazolobenzimidazole
using a combination
of pH adjustment
and
complexation
with 2-hydroxypropyl-P-cyclodextrin.
Pharm.
Res. 10, 1136-1143.
Jarvinen, T., Jarvinen, K., Schwarting,
N. and Stella, V.J.
(1995) P-Cyclodextrin derivatives, SBE-P-CD and HP-PCD, increase the oral bioavailability
of cinnarizine in beagle
dogs. J. Pharm. Sci. 84, 295-299.
Okada, Y., Tachibana, M. and Koizumi, K. (1990) Solubilization of lipid-soluble
vitamins
by complexation
with
glucosyl-P-cyclodextrin.
Chem. Pharm. Bull. 38, 20472049.
Acartiirk, F., Imai, T., Saito, H., Ishikawa, M. and Otagiri,
M. (1993) Comparative study on inclusion complexation of
heptakis(2,6-di-O-methyl)-Pmaltosyl-P-cyclodextrin,
cyclodextrin and P-cyclodextrin
with fucosterol in aqueous
and solid state. J. Pharm. Pharmacol. 45, 1028-1032.
Okada, Y., Kubota, Y., Koizumi, K., Hizukuri, S., Ohfuji, T.
and Ogata, K. (1988) Some properties and the inclusion
behavior of branched cyclodextrins. Chem. Pharm. Bull. 36,
2176-2185.
Macheras, P.E., Koupparis,
M.A. and Antimisiaris,
S.G.
(1990) Drug binding and solubility in milk. Pharm. Res. 7,
537-541.

[46] Macheras, P.E. and Reppas, C.I. (1986), Studies on drugmilk freeze dried formulations
I: bioavailability
of sulfamethizole and dicumarol formulations. J. Pharm Sci. 75,
692-696.
(471 Welling, PG. (1977) Influence of food and diet on gastrointestinal drug absorption: a review. J. Pharmacokinet.
Biopharm. 5, 291-334.
[48] Solvang, S. and Finholt, P. (1970) Effect of tablet processing
and formulation
factors on dissolution rate of the active
ingredient in human gastric juice. J. Pharm. Sci. 59, 49-52.
[49] Finholt, P. and Solvang, S. (1968) Dissolution kinetics of
drugs in human gastric juice - the role of surface tension. J.
Pharm. Sci. 57, 1322-1326.
[50] Bakatselou, V., Oppenheim, R.C. and Dressman, J.B. (1991)
Solubilization
and wetting effects of bile salts on the
dissolution of steroids. Pharm. Res. 8, 1461-1469.
[51] Miyazaki, S., moue, H., Yamahira, T. and Nadai, T. (1979)
Interaction of drugs with bile components I: Effect of bile
salts on the dissolution
behavior
of indomethacin
and
phenylbutazone.
Chem. Pharm. Bull. 27, 2468-2472.
[52] Naylor, L.J., Bakatselou, V. and Dressman,
J.B. (1993)
Comparison
of the mechanism
of dissolution
of hydrocortisone in simple and mixed micelle systems. Pharm. Res.
10, 865-870.
[53] Naylor, L.J., Bakatselou, V., Rodriguez-Homedo,
N., Weiner,
N.D. and Dressman, J.B. (1995) Dissolution of steroids in
bile salt solutions is modified by the presence of lecithin.
Eur. J. Pharm. Biopharm. 41, 346-353.
[54] Braun, R.J. and Parrott, E.L. (1972) Influence of viscosity
and solubilization
on dissolution rate. J. Pharm. Sci. 61,
175-178.
[55] Wurster, D.E. and Polli, G.P. (1964) Investigation of drug
release from solids V: Simultaneous influence of adsorption
and viscosity on the dissolution rate. J. Pharm. Sci. 53,
311-314.
[56] Reppas, C., Meyer, J.H., Sirois, P.J. and Dressman, J.B.
(1991) Effect of hydroxypropylmethylcellulose
on gastrointestinal transit and luminal viscosity in dogs. Gastroenterology 100, 1217-1223.
[57] Eeckhout, C., De-Wever, I.,Vantrappen,
G. and Janssens, J.
(1980) Local disorganization
of interdigestive
migrating
complex by perfusion of a Thiry-Vella loop. Am. J. Physiol.
238, 509-513.
[58] Banakar, UV., Lathia, C.D. and Wood, J.H. (1991) Interpretation of dissolution rate data and techniques of in vivo
dissolution. In: UV. Banakar (Ed.), Pharmaceutical
Dissolution Testing. Marcel Dekker, Inc., New York, p. 212.
[59] AGA Undergraduate
Teaching Project, GastroenterologyLiver Disease. Unit 10B. Alimentary Tract Motility. MilnerFenwick, Inc. MD, USA, Fig. 58.