reviews research focus
10 October 2000
Drug–excipient interactions and their
affect on absorption
Kimberley Jackson, David Young and Sonia Pant
Excipient(s) are traditionally thought of as inert but they can have a
tremendous impact on the ultimate pharmacological availability of a
drug substance when added to a formulation. The magnitude of this
effect will depend on the characteristics of the drug and on the
quantity and properties of the excipients. The aim of this article is to
identify the various physicochemical and physiological processes that
can be altered by drug–excipient interactions and to explore
mechanisms by which they might occur. The regulatory implications of
drug–excipient interactions will also be discussed.
▼ Most drugs intended for oral administration
Kimberley Jackson,
David Young* and Sonia Pant require formulation with excipients to allow for
GloboMax LLC adequate administration, to facilitate manufactur-
7250 Parkway Drive ing of the product, to increase the stability of the
Suite 430 formulation, for aesthetic reasons or for identifi-
Hanover
cation. Although excipients have traditionally
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USA
been thought of as being inert, experience has
*tel: 11 410 712 9500 shown that they can interact with a drug to affect
fax: 11 410 712 0737 its absorption and bioavailability. Indeed, some
e-mail: info@globomax.com excipients are added to a formulation specifically
to take advantage of the interaction when it af-
fects the bioavailability of the drug. This article
gives an overview of the physicochemical and
physiological processes [e.g. stability, physio-
logical pH, gastrointestinal (GI) transit time,
disintegration, dissolution and permeability] that
can be altered by drug–excipient interactions. In
addition, we give details of established mecha-
nisms of interaction and, where possible, show
the potential impact of these interactions on the
absorption and bioavailability of the drug.
Excipients have traditionally been classified
according to the function they perform in a
formulation, although many excipients perform
multiple functions. Diluents allow the formu-
lation of a practically sized tablet and can form a
336 1461-5347/00/$ – see front matter ©2000 Elsevier Science Ltd. All rights reserved. PII: S1461-5347(00)00301-1
PSTT Vol. 3, No.
large proportion by weight of a formulated
product when, for example, the active ingredient
is very potent1. (The physical characteristics of
the diluent are important; for example, tri-
amterene was shown to dissolve more rapidly
when it was formulated with hydrophilic fillers
such as lactose and starch as compared with insol-
uble diluents2). Disintegrants tend to swell when
wetted and so are added to a formulation to facili-
tate the breakdown of the dosage form into
granules and powder particles3,4.The newer disin-
tegrants, called superdisintegrants, cause an ex-
tremely rapid breakup of a tablet owing to their
ability to swell to many times their original size5–7.
Binders provide cohesiveness to a powder
mixture to ensure that a tablet formulation will
be compressible and remain intact throughout
its shelf-life yet will still disintegrate in vivo. Dis-
integration and dissolution times can be opti-
mized by varying the concentration of binders in
a formulation8,9. Lubricants tend to be hydro-
phobic substances that act by coating particles to
prevent adhesion of the tablet to the dies and
punches of the tableting machine, to aid in ejec-
tion of the tablet from the die by reducing the
interparticulate friction and improving flow of
the powder mixture4,10. Very small quantities are
often used (1% or less of the formulation)
because too much lubricant can waterproof
the tablet, which can hinder its disintegration,
dissolution and/or bioavailability1,2,11,12.
Processes affected by drug–excipient
interactions
After oral administration of a drug in tablet
form, the solid formulation will disintegrate and,
although dissolution can occur directly at the
surface of an intact tablet, a rapid rate of disso-
lution will typically occur as the tablet is
fragmented. In most cases, the drug in solution
is then absorbed by passive diffusion into the
PSTT Vol. 3, No. 10 October 2000
general circulation and hence transported to its site of action.
Most drug–excipient interactions that have been identified affect
the processes of disintegration and/or dissolution. Effects on
physiological factors or processes such as the pH of the micro-
environment, the stability of a drug substance in the GI tract and
the permeability of GI membranes to the drug can also alter the
bioavailability of a drug, however, a significantly smaller number
of reports have been published on these types of interactions.
Disintegration
Disintegration is the process whereby the dosage form breaks up
into fragments and particles, exposing a large surface area of drug
product to the physiological fluids and thus allowing dissolution
to occur more readily. There are official in vitro disintegration
tests and these are described in national and international
pharmacopoeias such as the US Pharmacopoeia13 (USP) and
the British Pharmacopoeia14 (BP). If a drug–excipient interaction
results in more rapid disintegration, then absorption will in-
crease if disintegration is a critical step for that particular drug.
For example, the antidiabetic drug tolbutamide was spray
dried in combination with a disintegrant [partly pregelatinized
corn starch (PCS)] to form particles composed of a single core
of PCS on which the drug was deposited15. Increased dissolu-
tion was observed compared with a formulation made with
regular corn starch; this was caused by the layer of drug crys-
tals separating from the surface of the particle owing to rapid
disintegration caused by the swelling action of PCS. A study on
the hydrophobic diuretic drug furosemide investigated the
effect of formulations with different disintegrants16.The super-
disintegrant sodium starch glycolate was found to increase the
bioavailability of furosemide significantly in comparison with
other disintegrants.
A drug–excipient interaction that results in inadequate or
very slow disintegration of a drug product will reduce the
bioavailability of the drug if disintegration is a rate-limiting
step in its absorption. For example, when the bioavailability of
six commercial formulations of the antihelmintic agent prazi-
quantel were investigated, in vitro disintegration testing showed
that one generic formulation failed to disintegrate in water and
acidic media, and subsequently failed to dissolve adequately17.
When this formulation was administered in vivo, its bioavail-
ability was lower than those of the other formulations.
When the antibacterial drug sulphadimidine was formu-
lated with various disintegrants including Primojel (sodium
starch glycolate), Veegum and Amberlite, a decrease in disinte-
gration and dissolution times was observed3.The magnitude of
the reduction in these times differed depending on the disinte-
grant used perhaps as a result of the differences in binding
between the sulphadimidine and the different disintegrants.
In a study of oxymorphone derivatives formulated with the
research focus reviews
superdisintegrant croscarmelose sodium, there was extensive
binding of the oxymorphone to the croscarmelose sodium,
which resulted in a slower rate of dissolution18.
Dissolution
A drug has to be in solution before it can be absorbed across
the GI membranes and reach the systemic circulation. Because
many drugs are lipophilic, dissolution is often the rate-limiting
step in absorption. Thus, drug–excipient interactions that alter
dissolution can have a significant impact on absorption.
In vitro experiments were conducted with formulations of
the anti-inflammatory drug phenylbutazone in which possible
drug–excipient interactions were identified for three of the ten
formulations19.Two of these formulations had slow dissolution
rates and low bioavailabilities, but the third formulation had a
slow rate of dissolution yet its bioavailability was ~100%. In a
study of four formulations of the antidiabetic drug tolazamide,
one formulation exhibited fast dissolution and high bioavail-
ability20.Two other formulations showed intermediate dissolu-
tion but, in vivo, one of them had a high bioavailability and the
other a significantly lower availability. These inconsistent
effects on dissolution suggest that dissolution might not be
the rate-limiting step for these drug formulations.
One study evaluated eight different formulations of the di-
uretic spironolactone in which concentrations of talc, magne-
sium stearate and gelatin were varied with each formulation21.
A wide disparity was found between the disintegration times
and the rates and extents of dissolution, yet no significant dif-
ferences were observed in the bioavailability of these products.
In another study evaluating spironolactone formulations, when
calcium sulfate dihydrate was substituted with dibasic calcium
phosphate as the major tablet excipient, dissolution was very
slow yet there was no appreciable effect on bioavailability22. In
contrast to the previous studies, Chao and co-workers found
that the bioavailability of spironolactone was correlated with
dissolution when the levels of microcrystalline cellulose, starch
and calcium sulfate dihydrate were varied among different
formulations23.
An interaction was observed in a series of studies conducted
to investigate different formulations of the antibiotic amoxy-
cillin with various excipients (colloidal silica and a synthetic
fat derivative of glycerin and talc)24–26. When synthetic fat and
talc were the only excipients in the formulation, there was an
increase in dissolution and an increase in bioavailability as the
proportion of fat decreased. However, when colloidal silica was
added to the formulation, increased bioavailability of amoxy-
cillin was observed at high concentrations of silica irrespective
of the fat content.
When the calcium-channel blocker nifedipine was
co-ground with polyethylene glycol 6000 (PEG6000) and
337
reviews research focus
Plasma concentration of NP (ng ml−1)
120
100
80
60
40
20
0 with gluconolactone. In contrast to the effect seen in the
0 2 4 6
Time (h)
Pharmaceutical Science & Technology Today
Figure 1. Increased area under the plasma-concentration–time curve
when nifedipine is administered as a co-ground mixture compared
with a physical mixture. Mean plasma-concentration–time profiles of
nifedipine (NP) after the oral administration of various preparations
equivalent to 10 mg of NP to beagle dogs. Each point represents the
average of four determinations, plus or minus the standard error.
Physical mixture (closed circle); co-ground mixture prepared in the
presence of water (closed square); NP solution of PEG400 (open
square). Reproduced, with permission, from Ref. 28.
hydroxypropylmethyl cellulose (HPMC) in the presence of a
small amount of water, the rate of dissolution of the co-ground
mixture was markedly higher than that of a physical mixture27.
The authors suggested that hydrophobic interactions between
nifedipine and the polymer occurred during the co-grinding
process.When the co-ground mixture was administered to dogs,
there was a tenfold increase in the maximum concentration
(Cmax) and a threefold increase in the area under the concen-
tration–time curve (AUC) of the co-ground mixture compared
with the physical mixture (Fig. 1). In this case, the method of
manufacture of the drug product resulted in an increased inter-
action between the drug and the excipient, causing an increase
in dissolution and a subsequent increase in absorption.
Physiological factors and processes
Drug–excipient interactions have the potential to affect many
physiological processes and factors, such as the pH of the
microenvironment, protein binding, GI transit time, stability
in the GI tract, effects on gut flora, and so on. The potential
outcome of all of these interactions might be to alter the
bioavailability of the drug. Although examples of drug–excipient
interactions affecting all of these processes and factors were
not found during a literature search, it does not mean that
examples have not occurred and these potential areas for inter-
action should be considered if unexpected effects occur upon
the administration of a formulation in vivo.
338
PSTT Vol. 3, No. 10 October 2000
If significant degradation or decomposition of a drug oc-
curs, this can result in less absorption and a lower bioavailabil-
ity of the drug. Chlorpromazine is an antipsychotic drug
known to undergo metabolic transformation in the gut28. The
stability of chlorpromazine was improved when it was admini-
stered as a complex with b-cyclodextrin and this resulted in an
increase in bioavailability. In a study evaluating formulations of
the non-steroidal anti-inflammatory drug (NSAID) aspirin, the
effect of gluconolactone as a direct compression diluent was
compared with the established diluent, anhydrous lactose29.
There was less hydrolysis of aspirin when it was formulated
8 chlorpromazine study, preliminary in vivo studies with the
aspirin–gluconolactone formulation showed no significant
effect on the bioavailability of aspirin.
The pH of the GI tract varies greatly, from pH 1–3.5 in the
stomach to pH 7–8 in the large intestine5,30. Some drugs can
be preferentially absorbed from a particular section of the gut,
although both weakly acidic and basic drugs are absorbed from
the small intestine. Drugs that are weak acids are un-ionized in
the stomach and hence might be absorbed well from there,
whereas drugs that are weak bases might not be well absorbed
from the stomach because they are highly ionized. A substance
that increases the gastric pH would therefore be expected to
increase the absorption of weak bases and to decrease the
absorption of weak acids in the stomach30,31.
The antibiotic erythromycin acistrate is an erythromycin
derivative that is susceptible to conversion to anhydroerythro-
mycin in the acidic contents of the stomach32. Formulating
erythromycin acistrate as a hard gelatin capsule with sodium
bicarbonate as an excipient resulted in an increase in the pH of
the stomach, which led to increased bioavailability of erythro-
mycin32. A study evaluating the bioavailability of the poorly
water soluble drug tolbutamide from four commercial prepar-
ations found that the dissolution of one preparation at pH 6.5
took .900 min (Ref. 33). However, no significant difference
in urinary recovery was found compared with the other
formulations.The authors changed the dissolution testing con-
ditions to incorporate pre-incubation of the formulation in
acidic media, a situation that reflects physiological conditions
more accurately, and this resulted in rapid disintegration and a
more rapid dissolution of the preparation.
For some drugs, one of the tasks of the pharmaceutical sci-
entist is to formulate the drug in such a manner that it will be
preferentially released in a certain part of the GI tract. The
H2-receptor antagonist ranitidine, which is preferentially ab-
sorbed proximal to the cecum, was formulated with sodium
acid pyrophosphate as an excipient to make an effervescent
tablet34. When it was tested in vivo, the extent of absorption was
found to be approximately half of that seen with the regular
PSTT Vol. 3, No. 10 October 2000
Table 1. Summary of studies involving cyclodextrins
Drug Cyclodextrin Effect on dissolution
Spironolactone SBE-b-CD, DM-b-CD Increased
Atovaquone SBE-b-CD, HP-b-CD Increased
Oxazepam b-CD Increased
Griseofulvin b-CD Increased
Ursodeoxycholic acid HP-b-CD Increased
Cinnarizine SBE-b-CD, HP-b-CD Increased
Naproxen b-CD Increased
Tolbutamide b-CD Increased
Abbreviations: b-CD, b-cyclodextrin; HP-b-CD, hydroxypropyl-b-cyclodextrin; SBE-b-CD, sulfobutylether-b-cyclodextrin; DM-b-CD, dimethyl-b-cyclodextrin; ND, not done; NA, not applicable.
tablet formulation. Investigations revealed that the small in-
testinal transit time of the effervescent formulation was much
more rapid than that seen with the tablet formulation.
Similarly, a study investigating another H2-receptor antagon-
ist, cimetidine, formulated with either mannitol or sucrose
found that mannitol formulations reduced the small intestinal
transit time of cimetidine compared with sucrose, which led
to a reduced oral bioavailability35. It has been suggested that
both sodium acid pyrophosphate and mannitol act as small
intestinal cathartics even at these low concentrations, which
results in a decrease in small intestinal transit time36. However,
the effect of mannitol had been shown to be concentration
dependent and therefore using a lower concentration of
mannitol in a formulation might not affect bioavailability37.
Mechanisms of drug–excipient interactions
A review of the literature on drug–excipient interactions shows
that the mechanism of the interaction is often not clear.
However, there are several well-documented mechanisms in
the literature, and these are described here with examples to
illustrate the effect.
Complexation
Complexing agents interact, usually reversibly, with a drug to
form a complex5,31. When in the complex, the drug is not free
to dissolve because it must first dissociate from the complex31.
In many instances, the drug complex will dissociate upon
coming into contact with GI fluids, releasing the drug sub-
stance, which can then be absorbed across the GI membranes.
Complexing agents such as cyclodextrins are often used to
increase the bioavailability of poorly water soluble or unstable
drugs. Cyclodextrins are cyclic oligosaccharides that are com-
posed of a small number of dextrose units. The inside of these
molecules is lipophilic and the exterior is relatively hydrophilic.
It is this lipophilic interior of cyclodextrin molecules that allows
the formation of inclusion complexes with hydrophobic
research focus reviews
In vivo study Effect on bioavailability Ref.
Rats Increased 43
Dogs Increased 47
ND NA 89
Rabbits and humans Increased 44
Humans Increased 45
Dogs Increased 46
Humans No effect 48
Rabbits No effect 49
drugs38,39. Cyclodextrins can be used to increase absorption
and bioavailability by increasing the rate and extent of drug
dissolution, by increasing the permeability of the mucosal
membrane or by increasing the stability of the drug38,40. There
are numerous articles in the literature reviewing the use of
cyclodextrins in the pharmaceutical formulation of oral
products38,40–43.
A summary of some studies that have evaluated the use of
cyclodextrins as complexing agents in oral formulations is
shown in Table 1. Studies conducted with numerous different
drugs such as griseofulvin44, ursodeoxycholic acid45, cinnari-
zine46, and atovaquone47 in combination with various cyclo-
dextrins all demonstrate marked improvement in bioavailability
caused by increased dissolution. Figure 2 shows the twofold
increase in Cmax and AUC observed after administering a bile
acid (ursodeoxycholic acid) complex compared with a com-
mercial preparation. However, complexation with cyclodex-
trins has not been shown to increase the bioavailability of all
poorly soluble drugs. Even though the extents of dissolution of
the NSAID naproxen48 and tolbutamide49 were increased by
complexation with cyclodextrins, there was no corresponding
increase in bioavailability48,49.
Complexation of a drug can also result in decreased bioavail-
ability. For example, the antibiotic tetracycline forms an insol-
uble complex with calcium carbonate, which results in slower
dissolution and less absorption50. Similarly, the anti-epileptic
drug phenobarbital was shown to form an insoluble complex
with PEG4000 (Ref. 51). Formation of the complex resulted in
decreased dissolution and decreased absorption to approxi-
mately one-third of that for phenobarbital alone. In a study
evaluating commercial formulations of the steroid pred-
nisolone, five preparations showed increased in vitro dissolution
compared with the powder alone52. This was attributed to the
formation of complexes with water-soluble excipients in the
formulations. However, in vitro experiments showed that these
complexes had high molecular weights and might be too large
339
reviews research focus
8 an NSAID, was formulated as an absorbate with kaolin, an
6 when the adsorbate was formed, drug crystallized on the sur-
Plasma level (µg ml−1)
4 Adsorption of drug molecules can render the drug unavail-
2 was added to tablets containing cetylpyridinium chloride,
0
0 60 120 180 240
Time (min)
Pharmaceutical Science & Technology Today
Figure 2. Increased area under the plasma-concentration–time curve
of ursodeoxycholic acid (UDCA) when complexed with a cyclodextrin
compared with a commercial preparation of UDCA. Mean UDCA
plasma concentrations (n 5 6) after oral administration of tablets
containing 425 mg UDCA in an inclusion complex with
2-hydroxypropyl-b-cyclodextrin (closed square) or of commercial
tablets containing 450 mg free UDCA (closed triangle). Bars represent
the standard deviation. Reproduced, with permission, from Ref. 46.
to diffuse through GI membranes. Thus, although dissolution
increased, it is possible that the in vivo bioavailability would be
lower.
Other in vitro studies investigated the effect on membrane
permeability of adding polysorbate 80 and sodium lauryl
sulfate to chlorpromazine formulations53. In both cases, a
decrease in permeability was observed. Polysorbate 80 has a
very low critical micelle concentration and so the decrease in
permeability was attributed to formation of soluble micellar
aggregates. However, in the case of sodium lauryl sulfate,
which has a higher critical micelle concentration, it appeared
that an insoluble complex was formed between the lauryl
sulfate anions and the chlorpromazine cations.
Adsorption
The adsorption of drug molecules onto the surface of excipi-
ents can reduce drug particle size and increase the surface area
of drug available to the dissolution medium16,54,55. Both of
these effects might increase dissolution and, as a result, bio-
availability. In a study of the weak acid dicumarol, magnesium
hydroxide and magnesium oxide enhanced its absorption in
dogs as a result of increased dissolution56. This was attributed
to the formation of a more readily absorbable dicumarol–mag-
nesium chelate or to an increase in pH of the microenvironment
340
PSTT Vol. 3, No. 10 October 2000
caused by the addition of the excipients. When indomethacin,
increase in dissolution was observed compared with a simple
mixture of the two components54. The authors suggested that,
face of the adsorbent particles, increasing the surface area of
drug available for dissolution.
able for dissolution and diffusion and this might, in turn, re-
duce bioavailability5. When the lubricant magnesium stearate
there was a marked reduction in antibacterial activity owing to
adsorption of the cetylpyridinium chloride cations by stearate
anions on the surface of the magnesium stearate particles57.
Similarly, the use of colloidal magnesium aluminum silicate,
aluminum hydroxide, starch and talc in formulations with
dicumarol resulted in decreased absorption of dicumarol at-
tributed to the adsorptive properties of the excipients56. A
similar potential effect of talc was identified for the anxiolytic
agent chlordiazepoxide using membrane permeability studies,
although the quantities of talc used were larger than would be
expected in practice58.
Potential bioavailability problems were identified for chlor-
promazine through in vitro studies that showed chlorpromazine
adsorbed to the surface of talc and kaolin resulting in reduced
membrane permeability53. Similarly, the benzodiazepine
diazepam, which exists predominantly in the cationic form at
low pH, was found to adsorb to the negative sites on kaolin
and talc59. The authors did not investigate the effect of this
binding on the dissolution and bioavailability of diazepam. A
substantial electrostatic interaction has been observed in vitro
involving croscarmelose sodium, which is negatively charged
at pH.2, and the cation of a weakly basic antihistamine, chlor-
pheniramine maleate60. However, when croscarmelose sodium
was added to a formulation of another weakly basic drug,
phenylpropanolamine, which is used in cold preparations,
no effect was observed in vivo, indicating that this type of
interaction might not occur at the low pH of physiological
fluids61.
Adsorption can be reversible and might not affect the
bioavailability of the drug. When several other drugs, such as
griseofulvin, indomethacin and prednisone, were formulated
as adsorbates with colloidal magnesium aluminum silicate, a
marked increase in dissolution of all drugs was observed62. It
was thought that the drugs bound to the surface of the col-
loidal magnesium aluminum silicate by weak van der Waals
forces. The hydrophilic and swelling properties of the colloidal
magnesium aluminum silicate facilitated wetting of the
drug and therefore the bonds were easily broken to release
the drug again.
PSTT Vol. 3, No. 10 October 2000 research focus reviews

Table 2. Summary of studies investigating the use of solid dispersions

Drug Excipient(s) Binary or Effect on In vivo Effect on Method of Ref.

ternary system dissolution study bioavailability preparation

Piroxicam PEG4000/6000 B Increased Rabbits Increased Fusion 64

Norfloxacin PEG6000 B Increased Rabbits Increased Melting 65
Norfloxacin PEG6000 B Increased Rabbits Increased 66
Nifedipine PEG4000 and PEG4000/PC B and T Increased Rats Increased Solvent 67
Oxodipine PEG6000 and PEG6000/Tween 20 B and T Increased ND NA Melting 68
Griseofulvin PEG6000 and PEG6000/Tween 20 B and T Increased ND NA Melting 68
Ibuprofen PEG4000 or PVP B Increased ND NA Melting and 69
solvent
Rev5901 PEG400 and GP T Increased Humans Increased Not stated 73
Rev5901 PEG1000 and GP T Increased Dogs Increased Not stated 74
Mefenamic acid PEG3350 and PEG3350/Tween 20 B and T Increased ND NA Melting 70
Ciprofloxacin PEG6000 B Increased ND NA Melting 63
Rev5901 PEG (various grades) and T Increased ND NA Melting 75
polysorbate 80
Indomethacin HPC-SL and HPMC B Increased Humans Increased rate of absorption; Solvent 71
no effect on extent of
absorption

Abbreviations: PEG, polyethylene glycol; PC, phosphatidylcholine; PVP, polyvinyl pyrrolidine; GP, mixture of glyceryl and PEG1500 esters of long chain fatty acids; DMPC,
dimyristoylphosphatidylcholine; HPC-SL, hydroxypropyl cellulose-SL; HPMC, hydroxypropylmethyl cellulose; B, binary system (drug plus one component); T, ternary system (drug plus two
components); ND, not done; NA, not applicable.

solid dispersion is formulated, crystals of the drug in combi-

Solid dispersions
The formulation of hydrophobic drugs as solid dispersions is a
significant area of research aimed at improving the dissolution
and bioavailability of hydrophobic drugs. Solid dispersions
consisting of two components in the solid state are referred to
as binary systems. The two components are a water-soluble
carrier and a hydrophobic drug dispersed in the carrier sub-
stance63. Several different methods have been used to formu-
late solid dispersions and the particular manufacturing method
used might influence the in vivo effect of the drug.
A summary of selected studies using solid dispersion
methodology is provided in Table 2. Different molecular weights
of PEG have been used to formulate solid dispersions with many
different types of drugs, including piroxicam64, norfloxacin65,66,
nifedipine67, oxodipine68, griseofulvin68 and ibuprofen69. In all
cases, an increase in dissolution of the drug from the solid dis-
persion was observed compared with either the drug alone or a
physical mixture of the drug with PEG. This latter effect shows
that the interaction of the drug with PEG to form the solid dis-
persion is at least partly responsible for the increased dissolu-
tion. In the studies that evaluated the solid dispersions in vivo, a
corresponding increase in bioavailability was observed.
It has been proposed that PEG acts as a disaggregant in a
physical mixture, reducing the electrostatic charges between
the drug particles, thereby facilitating dissolution68. When the
nation with the PEG are formed.There might be a correspond-
ing decrease in particle size and a resulting increase in surface
area, or there might be a decrease in the force of interaction
between the drug molecules, both of which would cause a
further increase in dissolution64,68.
Although PEG has been the most frequently used hydro-
philic carrier, other water-soluble carriers have also been used,
such as polyvinyl pyrrolidine (PVP) and HPMC27,70,71. The
commercial use of solid dispersions has been limited by diffi-
culties with manufacturing and stability. However, the overall
effect of formulating a poorly water-soluble drug as a solid
dispersion in a water-soluble carrier appears to be to increase
dissolution and, where tested, to increase bioavailability. This
indicates that this technique does have value in pharmaceutical
manufacturing if the problems can be overcome. However,
there are examples in which it has not resulted in improved
absorption.When indomethacin was formulated with hydroxy-
propyl cellulose-SL, a 30-fold increase in dissolution was
observed for the solid dispersions compared with the drug
alone71. This resulted in a faster rate of absorption for the solid
dispersions but the overall extent of absorption was comparable
to that observed for the pure drug.
Only binary solid dispersions have been discussed so far but
ternary systems can also be formulated.These include a second
excipient, such as a surfactant, to increase dissolution further.

341
reviews research focus
The addition of surfactants can often markedly increase the
dissolution rates of hydrophobic drugs by increasing contact
between the drug and the dissolution medium72. Surface active
agents that have been included in solid dispersions for this pur-
pose include Tween 20, phosphatidylcholine, polysorbate 80
and sodium lauryl sulfate67–70,73–75. All studies found increased
dissolution and those studies that included in vivo data also
reported increased bioavailability. The surfactant probably de-
creases the interfacial tension between the dissolution medium
and the drug particles, thereby facilitating wetting of the drug
and increasing dissolution. One study postulated that the
surfactant acted to prevent a drug-rich layer forming on the
surface of the solid dispersion, which was impeding dissolution
of the formulation75.
Chemical interaction
Several different types of chemical drug–excipient interactions
have been reported in the literature. To illustrate the potential
consequences of an unexpected drug–excipient interaction,
consider the occurrences of phenytoin toxicity that were ob-
served in the late 1960s in Australia in epileptic patients taking
phenytoin sodium preparations76–78. Patients presented with a
variety of symptoms associated with phenytoin toxicity includ-
ing double vision, vomiting, ataxia, psychiatric disturbances
and high plasma phenytoin levels.
It was found that toxicity occurred when patients who were
stabilized on phenytoin were changed from a formulation con-
taining calcium sulfate as the major excipient to a formulation
containing lactose instead. Use of the formulation with lactose
resulted in much higher blood phenytoin levels than observed
with the calcium sulfate formulation. It was thought that
calcium sulfate might interact to form an insoluble form of
phenytoin that could not be absorbed across the cell mem-
branes of the gut wall, although this was not shown conclu-
sively to be the case76,79,80. An alternative explanation for this
effect was incomplete release of phenytoin sodium from the
capsules in the presence of calcium sulfate dihydrate. However,
a previous in vivo study had shown that almost all of the admini-
stered dose could be accounted for76,80.This shows that careful
consideration must be given to reformulating an established
drug, especially a drug with a narrow therapeutic index, such
as phenytoin.
When silica gel was added to vitamin formulations contain-
ing ascorbic acid, the decomposition of ascorbic acid in-
creased, possibly as a consequence of the trace metals such as
iron and copper present in silica gel, which can catalyse the
decomposition of ascorbic acid in solution81. However,
bioavailability was not affected. Other investigators found that
the polymer chitosan inhibited the release of the NSAID
diclofenac sodium from matrix tablets at low pH, possibly
342
PSTT Vol. 3, No. 10 October 2000
through the formation of an ionic complex between the diclo-
fenac sodium and the ionized amino groups of the cationic
polymer82. An in vitro study found that chlordiazepoxide, which
can exist in cationic form, formed an ion pair with the anionic
surfactant sodium lauryl sulfate, resulting in decreased mem-
brane permeability4. Finally, when ibuprofen and ketoprofen
were formulated with the organic base N-methylglucamine, an
increase in dissolution was observed with both of these
NSAIDs83. Ibuprofen appeared to form a complex with the
N-methylglucamine, but the authors also proposed the forma-
tion of water-soluble salts as a potential explanation for this
effect83.
Regulatory implications
Although the previous sections of this article describe how
drug and excipients might interact to alter absorption, the lack
of an in vivo effect has become even more important to the
regulatory agencies and the pharmaceutical industry. In recent
years, in the USA, there has been a significant amount of inter-
est and effort in defining formulation changes that will not sig-
nificantly alter absorption. This interest has led the FDA, the
pharmaceutical industry and academia to investigate scientifi-
cally and to discuss how formulations can be changed without
altering the in vivo response. This led to the FDA guidelines on
scale-up and post-approval changes (SUPAC).
In 1995, the FDA issued a guidance document governing
changes to immediate release formulations84, SUPAC-IR and,
in 1997, a similar document was issued governing changes to
modified release formulations85, SUPAC-MR. The purpose of
the guidelines was: (1) to decrease the amount of information
and in vivo studies required when insignificant (from an in vivo
point of view) changes in the formulation were made; (2) to
define different levels of change and the information required
for various changes; (3) to pre-define some significant and in-
significant formulation changes to the pharmaceutical indus-
try; (4) to ensure that critical and non-critical formulation
variables would be investigated using the appropriate scientific
approaches; and (5) to ensure that formulation changes would
be made without compromising the safety and efficacy of the
formulation.
The science for these guidelines was based on the experi-
ments conducted at the University of Maryland (MD, USA) in
conjunction with the FDA, as well as the collected knowledge
of scientists within the FDA, pharmaceutical industry and aca-
demia. The University of Maryland–FDA collaboration investi-
gated various compositional and manufacturing changes made
to a series of formulations and quantified the effects that these
changes had on the in vitro and in vivo activity of the drug; vari-
ous different drugs were used in these studies (e.g. piroxicam,
propranolol, metoprolol, naproxen, naproxen sodium, ranitidine
PSTT Vol. 3, No. 10 October 2000
and diltiazem). The results of the experiments conducted with
the NSAID piroxicam and the beta blockers propranolol and
metoprolol have been published86–88, and the results of the
other drugs have been presented in other forums.
An example of these findings is the investigation of 19
piroxicam formulations in which excipients and manufactur-
ing processes were varied86. Three formulations representing
slow, medium and fast dissolution were then administered in vivo
in addition to the innovator product. In vitro dissolution profiles
were found to be markedly different for the various formu-
lations but no apparent differences were observed in vivo. The
results of these experiments showed that these drug–excipient
interactions only affected the in vitro dissolution of the drug.
The changes in excipients evaluated in these studies did not
appear to be critical variables in the manufacture of this
particular drug.
Conclusions
Traditionally, excipients have been regarded as inert. However,
there are many instances in which excipients have been shown
to have a significant effect on the biological availability of the
drug. Many of the drug–excipient interactions affected the
process of dissolution. In fact, an interaction between a drug
and an excipient that alters the dissolution of some hydro-
phobic drugs has been shown to have a marked impact on the
absorption and bioavailability of that drug. This is certainly the
case where dissolution is the rate-limiting step in absorption.
A drug–excipient interaction can be actively used to the ad-
vantage of the formulator to increase the bioavailability of the
drug (e.g. complexation with cyclodextrins or solid dispersion
technology). However, there are also many cases in which an
interaction might not be expected and might adversely affect
the bioavailability of a drug (e.g. where the mechanism of the
interaction is surface adsorption or increased GI transit time).
This article has referenced only published literature describ-
ing drug–excipient interactions and the effect or lack of effect
on absorption. As we know of other confidential drug–excipient
interaction studies that have not been reported in the litera-
ture, it is highly likely that the information reported herein is
just a small portion of the scientific investigations that have
been performed in this area. A more complete review of this
scientific area will, however, only be possible when the propri-
etary information is made available by the pharmaceutical
industry, and this might never happen.
References
1 Gennaro, A.R., ed. (1990) Remington’s Pharmaceutical Sciences (18th edn),
pp. 1633–1639, Mack Publishing Company, Easton, PA, USA
2 Yen, J.K.C. (1964) The dissolution rate principle in practical tablet
formulation. Can. Pharm. J. 26, 493–499
research focus reviews
3 Aboutaleb, A.E. et al. (1983) Effect of various disintegrants on the availability
of directly compressed sulphadimidine tablets. Pharmazie 38, 473–475
4 Lieberman, H.A. et al., eds (1989) Pharmaceutical Dosage Forms (2nd edn),
Marcel Dekker
5 Banker, G.S. and Rhodes, C.T., eds (1996) Modern Pharmaceutics (3rd edn),
Marcel Dekker
6 Wade, A. and Weller, P.J. (1994) Handbook of Pharmaceutical Excipients
(2nd edn), American Pharmaceutical Association and the Royal
Pharmaceutical Society of Great Britain
7 Bolhuis, G.K. et al. (1997) Improvement of dissolution of poorly soluble
drugs by solid deposition on a super disintegrant, II.The choice of super
disintegrants and effect of granulation. Eur. J. Pharm. Sci. 5, 63–69
8 Itiola, O.A. and Pilpel, N. (1986) Studies on metronidazole tablet
formulation. J. Pharm. Pharmacol. 38, 81–86
9 Lin, S-Y. (1988) Effect of excipients on tablet properties and dissolution
behavior of theophylline-tableted microcapsules under different
compression forces. J. Pharm. Sci. 77, 229–232
10 Chowhan, Z.T. (1993) Excipients and their functionality in drug product
development. Pharm.Technol. 17, 72–82
11 Proost, J.H. et al. (1983) The effect of the swelling capacity of
disintegrants on the in vitro and in vivo availability of diazepam tablets,
containing magnesium stearate as a lubricant. Int. J. Pharm. Sci. 13, 287–296
12 Bolhuis, G.K. et al. (1981) Interaction of tablet disintegrants and
magnesium stearate during mixing, I: effect on tablet disintegration.
J. Pharm. Sci. 12, 1328–1330
13 US Pharmacopoeia and National Formulary(1999) The United States
Pharmacopoeia Convention, Rockville, MD, USA
14 The British Pharmacopoeia (1999) Spottiswoode and Co., London, UK
15 Takeuchi, H. et al. (1987) Enhancement of the dissolution rate of a poorly
water-soluble drug (tolbutamide) by a spray-drying solvent deposition
method and disintegrants. J. Pharm. Pharmacol. 39, 769–773
16 Rubinstein, M.H. (1980) The effect of disintegrants and processing on
the bioavailability of frusemide from compressed tablets. Drug Dev. Ind.
Pharm. 6, 105–119
17 Kaojarern, S. et al. (1989) Comparative bioavailability of praziquantel
tablets. DICP 23, 29–32
18 Asakawa,Y. et al. (1981) Drug–disintegrant interactions: binding of
oxymorphone derivatives. J. Pharm. Sci. 70, 709–711
19 Lovering, E.G. and Mainville, C.A. (1977) Correlations among
dissolution, permeation and bioavailability of phenylbutazone
formulations. Can. J. Pharm. Sci. 12, 48–50
20 Welling, P.G. et al. (1982) Bioavailability of tolazamide from tablets:
comparison of in vitro and in vivo results. J. Pharm. Sci. 71, 1259–1263
21 Concheiro, A. et al. (1987) Dissolution rate and bioavailability of
spironolactone tablets: effect of various technological factors. Drug Dev. Ind.
Pharm. 13, 2301–2314
22 Clarke, J.M. et al. (1977) Factors influencing comparative bioavailability
of spironolactone tablets. J. Pharm. Sci. 66, 1429–1432
23 Chao, A.Y. et al. (1976) In vitro and in vivo availability of spironolactone
from oral dosage forms. J. Pharm. Sci. 65, 1630–1634
343
reviews research focus
24 Llabres, M. et al. (1982) Quantification of the effect of excipients on
bioavailability by means of response surfaces, I: amoxicillin in fat matrix.
J. Pharm. Sci. 71, 924–927
25 Llabres, M. et al. (1982) Quantification of the effect of excipients on
bioavailability by means of response surfaces, II: amoxicillin in fat–silica
matrix. J. Pharm. Sci. 71, 927–930
26 Llabres, M. et al. (1982) Quantification of the effect of excipients on
bioavailability by means of response surfaces, III: in vivo–in vitro
correlations. J. Pharm. Sci. 71, 930–932
27 Sugimoto, M. et al. (1998) Improvement of dissolution characteristics
and bioavailability of poorly water-soluble drugs by novel cogrinding
method using water-soluble polymer. Int. J. Pharm. 160, 11–19
28 Ammar, H.O. et al. (1995) Improvement of some pharmaceutical
properties of drugs by cyclodextrin complexation. Pharmazie 50, 805–808
29 Nasir, S.S. et al. (1977) Application of gluconolactone in direct tablet
compression. J. Pharm. Sci. 66, 370–379
30 Howard, C.A., ed. (1985) Introduction to Pharmaceutical Dosage Forms (4th edn),
Lea & Febiger
31 Blanchard, J. et al., eds (1979) Principles and Perspectives in Drug Bioavailability,
S. Karger, Basel, Switzerland
32 Marvola, M. et al. (1991) Bioavailability of erythromycin acistrate from
hard gelatin capsules containing sodium bicarbonate. Pharm. Res. 8,
1056–1058
33 Tuttle, C.B. et al. (1973) Biological availability and urinary excretion
kinetics of oral tolbutamide formulations in man. Can. J. Pharm. Sci.8,
31–36
34 Koch, K.M. et al. (1993) Effect of sodium acid pyrophosphate on
ranitidine bioavailability and gastrointestinal transit time. Pharm. Res. 10,
1027–1030
35 Adkin, D.A. et al. (1995) The effect of mannitol on the oral bioavailability
of cimetidine. J. Pharm. Sci. 84, 1405–1409
36 Adkin, D.A. et al. (1995) The effects of pharmaceutical excipients on small
intestinal transit. Br. J. Clin. Pharmacol. 39, 381–387
37 Adkin, D.A. et al. (1995) The effect of different concentrations of
mannitol in solution on small intestinal transit: implications for drug
absorption. Pharm. Res. 12, 393–396
38 Stella,V.J. and Rajewski, R.A. (1997) Cyclodextrins: their future in drug
formulation and delivery. Pharm. Res. 14, 556–567
39 Duchene, D. et al. (1986) Cyclodextrins, their value in pharmaceutical
technology. Drug Dev. Ind. Pharm. 12, 2193–2215
40 Rajewski, R.A. and Stella,V.J. (1996) Pharmaceutical applications of
cyclodextrins, 2. In vivo drug delivery. J. Pharm. Sci. 85, 1142–1169
41 Loftsson,T. and Brewster, M.E. (1996) Pharmaceutical applications of
cyclodextrins, 1. Drug solubilization and stabilization. J. Pharm. Sci. 85,
1017–1025
42 Thompson, D.O. (1997) Cyclodextrins – enabling excipients: their
present and future use in pharmaceuticals. Crit. Rev.Ther. Drug Carrier Syst. 14,
1–104
43 Kaukonen, A.M. et al. (1998) Water-soluble b-cyclodextrins in paediatric
oral solutions of spironolactone: preclinical evaluation of spironolactone
344
PSTT Vol. 3, No. 10 October 2000
bioavailability from solutions of b-cyclodextrin derivatives in rats.
J. Pharm. Pharmacol. 50, 611–619
44 Dhanaraju, M.D. et al. (1998) Enhancement of bioavailability of griseofulvin
by its complexation with b-cyclodextrin. Drug Dev. Ind. Pharm. 24, 583–587
45 Panini, R. et al. (1995) Improvement of ursodeoxycholic acid
bioavailability by 2-hydroxypropyl-b-cyclodextrin complexation in
healthy volunteers. Pharmacol. Res. 31, 205–209
46 Jarvinen,T. et al. (1995) b-cyclodextrin derivatives, SBE4-b-cd and HP-b-
CD, increase the oral bioavailability of cinnarizine in beagle dogs. J. Pharm.
Sci. 84, 295–299
47 Studenberg, S.D. et al. (1996) Comparative pharmacokinetic and
bioavailability studies of atovaquone in dogs, I. Cyclodextrin
complexation. Pharm. Res. 13, S–457 (Abstract PPDM 8257)
48 Otero-Espinar, F.J. et al. (1991) Oral bioavailability of naproxen–b-
cyclodextrin inclusion compound. Int. J. Pharm. 75, 37–44
49 Kedzierewicz, F. et al. (1993) Bioavailability study of tolbutamide
b-cyclodextrin inclusion compounds, solid dispersions and bulk powder.
Int. J. Pharm. 94, 69–74
50 Shargel, L. and Yu, A.B.C., eds (1985) Applied Biopharmaceutics and
Pharmacokinetics (2nd edn), Appleton–Century–Crofts, Norwalk, CT, USA
51 Singh, P. et al. (1966) Effect of inert tablet ingredients on drug
absorption, I. Effect of polyethylene glycol 4000 on the intestinal
absorption of four barbiturates. J. Pharm. Sci. 55, 63–68
52 Northern, R.E. et al. (1973) Dissolution–dialysis method of assessing
in vitro drug availability of prednisolone tablets. Am. J. Hosp. Pharm. 30,
622–627
53 Nakano, M. (1971) Effects of interaction with surfactants, adsorbents,
and other substances on the permeation of chlorpromazine through a
dimethyl polysiloxane membrane. J. Pharm. Sci. 60, 571–575
54 Alsaidan, S.M. et al. (1998) Improved dissolution rate of indomethacin by
adsorbents. Drug Dev. Ind. Pharm. 24, 389–394
55 Monkhouse, D.C. and Lach, J.L. (1972) Drug–excipient interactions. Can. J.
Pharm. Sci. 7, 29–46
56 Akers, M.J. et al. (1973) Alterations in absorption of dicumarol by various
excipient materials. J. Pharm. Sci. 62, 391–395
57 Richards, R.M. et al. (1996) Excipient interaction with cetylpyridinium
chloride activity in tablet based lozenges. Pharm. Res. 13, 1258–1264
58 Lovering, E.G. (1974) Drug permeation through membranes, IV: effect of
excipients and various additives on permeation of chlordiazepoxide
through polydimethylsiloxane membranes. J. Pharm. Sci. 1224–1227
59 Naggar,V.F. (1981) An in vitro study of the interaction between diazepam
and some antacids or excipients. Pharmazie 36, 114–117
60 Hollenbeck, R.G. (1983) Estimation of the extent of drug–excipient
interactions involving croscarmellose sodium. J. Pharm. Sci. 72, 325–327
61 Hollenbeck, R.G. (1988) Bioavailability of phenylpropanolamine HCL
from tablet dosage forms containing croscarmellose sodium. Int. J. Pharm.
47, 89–93
62 McGinity, J.W. and Harris, M.R. (1980) Increasing dissolution rates of
poorly soluble drugs by adsorption to montmorillonite. Drug Dev. Ind.
Pharm. 6, 35–48
PSTT Vol. 3, No. 10 October 2000
63 Frances, C. et al. (1991) Preparation, characterization and dissolution of
ciprofloxacin/PEG 6000 binary systems. Int. J. Pharm. 77, 193–198
64 Bhattacharyya, M. et al. (1993) Formulation and in vitro–in vivo
characterization of solid dispersions of piroxicam. Drug Dev. Ind. Pharm. 19,
739–747
65 Fawaz, F. et al. (1996) Bioavailability of norfloxacin from PEG 6000 solid
dispersion and cyclodextrin inclusion complexes in rabbits. Int. J. Pharm.
132, 271–275
66 Guyot, M. et al. (1995) Physicochemical characterization and dissolution
of norfloxacin/cyclodextrin inclusion compounds and PEG solid
dispersions. Int. J. Pharm. 123, 53–63
67 Law, S.L. et al. (1992) Dissolution and absorption of nifedipine in
polyethylene glycol solid dispersion containing phosphatidylcholine. Int.
J. Pharm. 84, 161–166
68 Veiga, M.D. et al. (1993) Dissolution behaviour of drugs from binary and
ternary systems. Int. J. Pharm. 93, 215–220
69 Ghosh, L.K. et al. (1998) Product development studies on the tablet
formulation of ibuprofen to improve bioavailability. Drug Dev. Ind. Pharm.
24, 473–477
70 Owusu-Ababio, G. et al. (1998) Comparative dissolution studies for
mefenamic acid–polyethylene glycol solid dispersion systems and tablets.
Pharm. Dev.Technol. 3, 405–412
71 Chowdary, K.P.R. and Suresh Babu, K.V.V. (1994) Dissolution,
bioavailability and ulcerogenic studies on solid dispersions of
indomethacin in water soluble cellulose polymers. Drug Dev. Ind. Pharm. 20,
799–813
72 Niazi, S., ed. (1979) Textbook of Biopharmaceutics and Clinical Pharmacokinetics,
Appleton–Century–Crofts, New York, NY, USA
73 Sheen, P. et al. (1991) Bioavailability of a poorly water-soluble drug from
tablet and solid dispersion in humans. J. Pharm Sci. 80, 712–714
74 Serajuddin, A.T.M. et al. (1998) Effect of vehicle amphiphilicity on the
dissolution and bioavailability of a poorly water-soluble drug from solid
dispersions. J. Pharm. Sci. 77, 414–417
75 Serajuddin, A.T.M. et al. (1990) Improved dissolution of a poorly water-
soluble drug from solid dispersions in polyethylene
glycol:polysorbate 80 mixtures. J. Pharm. Sci. 79, 463–464
76 Bochner, F. et al. (1972) Factors involved in an outbreak of phenytoin
intoxification. J. Neurol. Sci. 16, 481–487
77 Tyrer, J.H. et al. (1970) Outbreak of anticonvulsant intoxication in an
Australian city. Br. Med. J. 4, 271–273
78 Cacek, A.T. (1986) Review of alterations in oral phenytoin bioavailability
associated with formulation, antacids, and food. Ther. Drug Monit. 8,
166–171
79 Neuvonen, P.J. (1979) Bioavailability of phenytoin: clinical
pharmacokinetic and therapeutic implications. Clin. Pharm. 4, 91–103
80 Bastami, S.M. and Groves, M.J. (1978) Some factors influencing the in
vitro release of phenytoin from formulations. Int. J. Pharm. 1, 151–164
81 De Ritter, E. et al. (1970) Effect of silica gel on stability and biological
availability of ascorbic acid. J Pharm. Sci. 59, 229–232
82 Sabnis, S. et al. (1997) Use of chitosan in compressed tablets of diclofenac
research focus reviews
sodium: inhibition of drug release in an acidic environment. Pharm. Dev.
Technol. 2, 243–255
83 de Villiers, M.M. et al. (1999) The dissolution and complexing properties
of ibuprofen and ketoprofen when mixed with N-methylglucamine. Drug
Dev. Ind. Pharm. 25, 967–972
84 US Department of Health and Human Services (1995) Guidance for Industry:
SUPAC-IR: Immediate Release Solid Oral Dosage Forms. Scale-up and Post-approval Changes:
Chemistry, Manufacturing and Controls; In Vitro Dissolution Testing and In Vivo
Bioequivalence Documentation, US Department of Health and Human Services,
Food and Drug Administration, Center for Drug Evaluation and Research
85 US Department of Health and Human Services (1997) Guidance for Industry:
SUPAC-MR: Modified Release Solid Oral Dosage Forms. Scale-up and Post-approval Changes:
Chemistry, Manufacturing and Controls; In Vitro Dissolution Testing and In Vivo
Bioequivalence Documentation, US Department of Health and Human Services,
Food and Drug Administration, Center for Drug Evaluation and Research
86 Piscitelli, D.A. et al. (1998) The impact of formulation and process
changes on in vitro dissolution and the bioequivalence of piroxicam
capsules. Pharm. Dev.Technol. 3, 443–452
87 Eddington, N.D. (1998) Identification of formulation and manufacturing
variables that influence in vitro dissolution and in vivo bioavailability of
propranolol hydrochloride tablets. Pharm. Dev.Technol. 3, 535–547
88 Rekhi, G.S. (1997) Evaluation of in vitro release rate and in vivo absorption
characteristics of four metoprolol tartrate immediate-release tablet
formulations. Pharm. Dev.Technol. 2, 11–24
89 Moyano, J.R. et al. (1995) Study of the dissolution characteristics of
oxazepam via complexation with beta cyclodextrin. Int. J. Pharm. 114,
95–102
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