International Journal of Pharmaceutics 480 (2015) 4854

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International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

Pharmaceutical nanotechnology

Excipient pharmacokinetics and proling

Thorsteinn Loftsson *
Faculty of Pharmaceutical Sciences, University of Iceland, Hofsvallagata 53, IS-107 Reykjavik, Iceland

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 18 December 2014
Received in revised form 12 January 2015
Accepted 13 January 2015
Available online 14 January 2015

Novel pharmaceutical excipients, and new derivatives of currently used excipients, are new chemical
entities and as such have to go through extensive pharmacokinetic and toxicologic evaluations before
they can be approved for use in pharmaceutical products. The high cost of these safety studies, long
development timelines and risks of failure have hampered development of new excipients and drug
delivery systems. Various, relatively simple, methods are used for prediction of pharmacokinetic
properties of new drug candidates based on their physicochemical properties. Similar methods can be
applied to predict pharmacokinetic and ADME properties of new excipients. Simple methods, like the
Rule-of-Five and the Biopharmaceutics Classication System, can be applied for early prediction of
pharmacokinetic and ADME properties of new excipients and drug delivery systems although the aims
can be different. While the objectives in new drug development are to maximize drug bioavailability and
pharmacologic response the objectives in new excipient development can be reduced excipient
bioavailability and enhanced rate of elimination. Here pharmacokinetic properties of some currently
used excipients are reviewed and shown how some of the simple methods used to predict drug-like
properties can be applied to predict desired properties of novel excipients and drug delivery systems.
2015 Elsevier B.V. All rights reserved.

Keywords:
Absorption
Distribution
Drug delivery
Excipient-like properties
Excipients
Excretion

1. Introduction
Pharmacokinetics is the kinetics of drug absorption, distribution, metabolism and excretion (ADME). These four criteria all
inuence drug levels and kinetics of drug exposure to tissues and
hence inuence the performance and pharmacological activity of a
drug. ADME proling and toxicological (ADME/Tox) screenings are
conducted during drug discovery and development processes.
ADME/Tox properties of a new biologically active compound will
determine if it can be developed into a useful pharmaceutical
product (a drug product). However, a pharmaceutical product,
such as tablet or parenteral solution, does not only contain an
active pharmaceutical ingredient (API) but also several inactive
ingredients that are commonly called pharmaceutical excipients or
simply excipients (from Latin excipere meaning to except or other
than [the API]). While an excipient is considered to be inactive
pharmaceutical ingredient it enables delivery of API to a patient.
Frequently, the API makes up only small fraction of a drug product
with the rest being a mixture of excipients such as tablet llers
used to increase volume or weight of tablets, binders and
disintegrants. Sometimes drug release modiers are included to
provide sustained drug release and colorants to give the product a

* Tel.: +354 525 4464; fax: +354 525 4071.

E-mail address: thorstlo@hi.is (T. Loftsson).
http://dx.doi.org/10.1016/j.ijpharm.2015.01.022
0378-5173/ 2015 Elsevier B.V. All rights reserved.

distinctive look. Liquid products frequently contain buffer salts for

pH control, solubilizers, polymers for enhanced viscosity, antioxidants and antimicrobial preservatives. Although a pharmaceutical product may contain much larger amount of excipients than of
the API there is no independent regulatory approval process for
new excipients in the EU and US. It is not known if a new excipient
will be approved until it has been included in a new approved drug
product. Although excipients are by denition pharmacologically
inactive their regulatory requirements are in praxis comparable to
those of new drug substances regarding, for example, toxicological
evaluations and in vivo performance, with development processes
that can take seven years at a cost of between 10 and 50 million
USD (DeMerlis et al., 2009; EMA, 2007; IPEC, 2014; Osterberg et al.,
2011). In this context the pharmacokinetics of a new excipient
should preferably be determined in animals and humans during
new product development. ADME proling should be an integral
part of new chemical development in drug delivery, including
development of new chemicals and novel drug delivery systems
such as nanocarriers and enabling polymers, all of which are
characterized as new pharmaceutical excipients.
Physicochemical properties of excipients, such as their aqueous
solubility, ionization (pKa), lipophilicity, number of hydrogen bond
(H-bond) donors and acceptors, polar surface area, physical and
chemical stability, and molecular shape and weight, will affect
their fate in our body. Good understanding of how physicochemical
properties of pharmaceutical excipients affect their interactions

T. Loftsson / International Journal of Pharmaceutics 480 (2015) 4854

with our body is of essence to pharmaceutical scientists in their

search for ever more effective excipients and drug delivery
systems. Rules and guidelines that were developed for rapid
proling of new drug candidates, such as Lipinskis Rule-of-Five
and the Biopharmaceutics Classication System, can be applied
during development of new excipients and drug delivery systems
(Kerns and Di, 2008).
Here the relationship between physicochemical properties and
pharmacokinetics of some currently used excipients will be
reviewed and shown how the methods used for rapid proling
of new drug candidates can be applied during development of new
excipients.
2. Pharmacokinetic parameters
When a compound, such as a drug or an excipient, is injected
into the systemic blood circulation (i.e., administered by intravenous (IV) injection) it is rapidly distributed within the body and
then more slowly eliminated by metabolism and/or as intact
compound in urine (Fig. 1). Likewise, an orally (PO) administrated
compound is absorbed from the gastrointestinal (GI) tract into the
blood circulation and then eliminated. Various pharmacokinetic
parameters are used to characterize ADME such as volume of
distribution (VD), elimination half-life (t1/2), clearance (Cl) and
bioavailability (F), and most often the pharmacokinetic processes
follow rst-order kinetics (Loftsson, 2015). VD describes how the
compound is distributed within the body. A compound with small
VD (e.g. 0.2 L/kg) is mainly located in the blood plasma while a
compound with large VD (e.g., much larger than the body volume)
might be highly tissue bound. Elimination t1/2 of a compound is the
time it takes to reduce its blood plasma concentration by 50%. Cl is
another parameter that indicates how rapidly drug is eliminated
from the body. It can be divided into hepatic clearance (ClH) and
renal clearance (ClR), which are the two main elimination
pathways. ClH is associated with metabolism of the compound
in the liver while ClR is associated with elimination of unmetabolized compound in urine. The total body clearance (ClT) is the sum
of ClH and ClR (i.e., ClT = ClH + ClR). Bioavailability is the fraction of a
compound that is absorbed from the GI tract into the general blood
circulation. While high bioavailability (i.e., close to complete
absorption [F  1]) of API is desired after PO administration low
excipient bioavailability (F  1) is favored with most of the
excipient metabolized in the gut or excreted unchanged in feces.
In the kidneys drugs are mainly excreted from the blood
circulation by glomerular ltration (Loftsson, 2015). Glomerular
ltrated drugs may be passively reabsorbed in the peritubular
capillaries. Only unbound hydrophilic molecules with a molecular
weight (Mw) below approximately 25 kDa are ltered through

Fig. 1. Sketch showing the natural logarithm of the plasma concentration (CP)time
prole for a compound after intravenous (IV) injection (solid curve) and per oral
(PO) administration (broken curve).

49

glomerulus. In humans, dextrans with Mw less than 15 kDa are

mainly excreted unchanged in urine with a renal clearance close to
the glomerular ltration rate (GFR) (ClR  125 mL/min = 7.5 L/h),
whereas dextrans with Mw above about 50 kDa are mainly
degraded in the liver to lower Mw products (i.e., metabolites)
that are then excreted in urine.
3. Lipinskis Rule-of-Five and other methods used for rapid drug
proling
Various methods or rules of thumb are used in rapid proling
of new drug candidates to predict their drug like properties, mainly
bioavailability after oral administration. Some of these same rules
of thumb can be applied for proling of new excipients although
the aims can be different. While the objectives in new drug design
are to maximize bioavailability and pharmacologic response, the
objectives in new excipient design can be to reduce its
bioavailability and enhance its rate of elimination from the body
and detoxication.
Lipinski et al. evaluated drug-like properties of couple of
thousands biologically active compounds (i.e., drugs and drug
candidates) and came up with what is known as the Lipinskis
Rule-of-Five (Lipinski et al., 1997). Due to its simplicity, this
method is widely used by researchers to predict not only
absorption of compounds from the GI tract but also
overall drug-like properties of biologically active compounds.
The Rule-of-Five applies only to passive absorption and excludes
compounds that are substrates for biological transporters such
as some antibiotics, antifungals and vitamins. It consists of four
prerequisites that are based on the number 5 and state that
poor absorption from the GI tract or permeation through
biomembrane is more likely when:
 there are more than 5H-bond donors (expressed as the sum of all

OHs and NHs),

 there are more than 10H-bond acceptors (expressed as the sum

of Ns and Os),
 the molecular weight (Mw) is over 500, and
 the log Poctanol/water is over 5.

The physicochemical rational for the Rule-of-Five is based

on the fact that in aqueous solutions H-bonds are formed
between water and dissolved molecules and these H-bonds
must be broken when the molecules partition from the aqueous
exterior into a lipophilic membrane. The more H-bonds there
are the more difcult it becomes for a molecule to partition
from the aqueous exterior into a membrane. The molecular
weight refers to the size of the molecule and the fact that the
diffusion coefcient of a molecule as well as its solubility
decreases with increasing size. Increase in lipophilicity (e.g.,
increased log Poctanol/water) of a compound will also decrease its
aqueous solubility. Furthermore, if log Poctanol/water of a compound
is greater than 5 then dissolved molecules will partition into the
lipophilic membrane but will have less tendency to partition from
the membrane on the receptor side into the aqueous internal
layers. The Rule-of-Five is based on oral absorption but with some
modications it can be applied to predict permeation through
biomembranes in general (Table 1). Although there are numerous
exceptions from Lipinskis Rule-of-Five it still gives important
information of how physicochemical properties of a compound
direct its fate within our body.
The Biopharmaceutics Classication System (BCS) is based on
the fact that close to half of drug failures in development can be
traced to poor dissolution or poor permeability (Amidon et al.,
1995). According to the BCS, orally administered drugs are divided
into 4 classes (Table 2) based on their solubility and permeability

50

T. Loftsson / International Journal of Pharmaceutics 480 (2015) 4854

Table 1
The limiting Rule-of-Five values for oral bioavailability as well as for transdermal, ophthalmic and pulmonary drug delivery. Modied from (Choy and Prausnitz, 2011).
Route of drug administration

Mw
(Da)

Log Poctanol/water

H-bond donors

H-bond acceptors

Oral drug delivery

Transdermal drug delivery
Topical drug delivery to the eye
Pulmonary drug delivery

500
335
500
500

5.0
5.0
4.2
3.4

5
2
3
4

10
5
8
10

characteristics (FDA, 2009). In the BCS a given drug substance is

considered highly soluble (i.e., having high S) when the highest
dose strength is soluble in 250 mL water over a pH range 17.5 at
37  C and highly permeable (i.e., having high P) when the extent
of oral absorption in humans is >90% of an administered dose (in
solution), based on mass-balance or related to an intravenous
reference dose. Highly soluble drugs that permeate biological
membranes rather easily are termed Class I drugs and so on. While
Class I drugs have the optimum physicochemical properties for oral
delivery, excipients for oral preparations (e.g., disintegrants and
solubilizers) that fall into Class III will have the optimum
physicochemical properties since they will mainly be excreted
with feces after they have had their desired effect. Excipients in
Class I will be absorbed and have the potential of causing systemic
side effects, and non-hydroscopic compounds in Class II and IV
(includes compounds that poorly soluble in water) are likely to be
ineffective and can be rather useless as excipients. However, some
excipients that are poorly-soluble in water, like ethylcellulose used
for controlled release lms coatings, are very effective.
The Biopharmaceutics Drug Disposition Classication System
(BDDCS) is based on drug solubility and metabolism (Wu and
Benet, 2005). It is based on the observation that drugs that possess
high permeability (i.e., BCS Class I and II drugs) are primarily
eliminated by metabolism (ClH > ClR), whereas drugs that possess
low permeability (i.e., BCS Class III and IV drugs) are primarily
eliminated unchanged with the urine after being absorbed into the
general blood circulation (ClH < ClR). Furthermore, they observed
that there is a strong correlation between extent of metabolism
and the intestinal permeability rate (i.e., drugs displaying high
permeability according to the BCS also display extensive metabolism according to the BDDCS). Thus, while the denition of highly
soluble (i.e., having high S) in the BDDCS is identical to that of BCS
(i.e., drug is highly soluble when the highest dose strength is
soluble in 250 mL water over a pH range 17.5 at 37  C) the
permeability can be replaced by the extent of drug metabolism
(i.e., drug is extensively metabolized when 90% of the drug dose
is metabolized) (Chen et al., 2011).
4. Physiochemical properties and pharmacokinetic parameters
of some known excipients
Excipients (i.e., inactive pharmaceutical ingredients) follow the
same basic pharmacokinetic principles as drugs (i.e., APIs) and
their biological fate is also governed by their physicochemical
characteristics. The main difference is that while wealth of
pharmacokinetic data is available on marketed drugs such data

on currently used excipients is rather scarce, especially pharmacokinetic data in humans, although some data is available.
Table 3 lists physicochemical properties of 26 common, mainly
low-Mw, pharmaceutical excipients and their pharmacokinetic
parameters in humans. On the average, the excipients have similar
Mw as marketed drugs (about 350 Da) but they are more
hydrophilic with average log P value of about 0.5 compared to
about 2.3 for marketed drugs (Meanwell, 2011). As expected,
relationship between the physicochemical properties of the
excipients and their pharmacokinetic parameters are similar as
that of drugs. Excipients that violate Lipinskis Rule-of-Five (e.g.,
the cyclodextrins [CDs], maltose and polyethylene glycol) display
negligible oral bioavailability. Very lipophilic excipients (e.g.,
b-carotene, chlorobutanol, lycopene, tocopherol and tocotrienol)
have relatively long t1/2 and are cleared slowly from the body. Very
hydrophilic excipients (e.g., the CDs, glucose, glycerol, mannitol,
propylene glycol and sorbitol) display small VD and thus, are
mainly distributed in the blood plasma. Most drugs and excipients
are xenobiotic compounds and as such treated as other xenobiotics
in both humans and animals.
Polymers such as dextrans, cellulose derivatives, polyethylene
glycol (PEG) and polyvinylpyrrolidone (PVP) are pharmaceutical
excipients that are commonly found in both oral and parenteral
products. Dextrans consist of mixtures of closely related polysaccharides, mainly (>95%) of the a-1,6-glucan type with branches
a-1,2-, a-1,3- and a-1,4-linkages. They are, for example, given in
aqueous parenteral solutions to patients as plasma expanders. The
t1/2 of parenterally administered dextrans are governed by their
Mw (Table 4). Dextran 1 (average Mw about 1000 Da) is readily
excreted unchanged in humans by glomerular ltration with t1/2 of
about 1.9 h while dextran 60 (average Mw about 60,000 Da) is
excreted much slower (t1/2  42 h) (Klotz and Kroemer, 1987).
Dextrans with a molecular weight below 15 kDa are mainly
excreted unchanged in urine with a renal clearance (ClR) close to
the GFR, whereas dextrans with a molecular weight above
5060 kDa are mainly cleaved in liver to lower Mw metabolites
before being excreted from the body (Arturson et al., 1971; Mehvar
and Shepard, 1992; Mehvar et al., 1995). Small amounts of
parenterally administered dextrans are excreted with the bile or
by other means via the GI tract (Kaneo et al., 1997). Dextrans are
very hydrophilic and relatively large molecules with numerous
H-bond donors and acceptors and thus, according to Lipinskis
Rule-of-Five are not readily absorbed from the GI tract. In general,
dextrans do not readily permeate biological membranes. Similarly
the t1/2 of other water-soluble polymers decrease with increasing
Mw and number of substituents (Klotz and Kroemer, 1987). PVP is

Table 2
The Biopharmaceutics Classication System is based on the aqueous drug solubility (S) over the pH range 17.5 and permeability (P) through GI mucosa.
Class

High High Water-soluble drugs (high S value) that are well absorbed from the GI tract (high P value) and in general, have the preferred physicochemical
properties for optimum oral bioavailability. Primarily eliminated by metabolism
Low High Drugs that are poorly soluble in water (low S value) that are well absorbed from the GI tract (high P value) once dissolved. Primarily eliminated by
metabolism
High Low Water-soluble drugs (high S value) that are poorly absorbed from the GI tract (low P value). Primarily eliminated unchanged
Low Low Drugs that are poorly soluble in water (low S value) that are poorly absorbed from the GI tract (low P value). Primarily eliminated unchanged

II
III
IV

Characteristics

T. Loftsson / International Journal of Pharmaceutics 480 (2015) 4854

51

Table 3
Physiochemical properties of some common low-molecular weight pharmaceutical excipients and their pharmacokinetic parameters in humans.
Drug

Physicochemical propertiesa
Mw
(Da)

S (mg/
mL)

Ascorbic acid
Aspartame
Butylated hydroxyanisole
b-Carotene
Curcumin
Chlorobutanol
Edetic acid (EDTA)
Glucose
Glycerol

176
294
180
537
368
177
292
180
92

330
10
0.2
<0.001
0.0003e
10
100
640f
>500

2-Hydroxypropyl-bCD
Isopropanol
Lactitol
Lycopene
Maltose
Mannitol
Menthol
Phenol
Polyethylene glycol 3350
Propylene glycol
Riboavin
Saccharin

1400
60
344
537
342
182
156
94
3350
76
376
183

>600
Miscible
180
<0.001
520f
650f
0.5
80
670
Miscible
0.07
3

Sorbitol
Sucralose
Sulfobutylether bCD sodium
salt
all-rac-a-Tocopherol
a-Tocotrienol

182
398
2163

770f
300
>500

a
b
c
d
e
f
g
h

430
425

0.02
<0.001

Log P

H-bond
acceptors

t1/2 (h)

4
4
1
0
2
1
4
5
3

6
7
2
0
6
1
10
6
3

10c
3.5
2
3
890
1.7
>5
240
3
1
0.31.4
0.2
0.51.2
0.20.3

11
21
0.2 1
4.7
9
15
0
4.8
8
3.3
6
3.2
1
1.5
1
< 5
2
-1
2
0.1
5
0.9 1

40
1
11
0
11
6
1
1
80
2
10
4

3.3
6
0.2 5
10
15

6
8
53

2.8
0.5
3
15
3.1
1.7
0.8
3.3
1.9

<

Pharmacokinetic parameters

11
10

H-bond
donors

1
1

2
2

1.9
2.58
650
1.4
1.2
4.7
3.5
5.8
4
1.0c
1.1

VD (L/
kg)

0.2
0.5

0.5

0.5
0.6

0.3
13
1.41.8

0.2

50
4.4

0.9
3.3

0.2

F (%)

References

80100c
Negligibled
6090
22
<10

(Hornig, 1981)
(Puthrasingam et al., 1996)
(Castelli et al., 1984)
(Burri et al., 2001)
(Heger et al., 2014; Prasad et al., 2014)
(Tung et al., 1982)
(Osterloh and Becker, 1986)
(Hahn et al., 2011; Heller et al., 1958)
(Olbermann et al., 1977; Sommer et al.,
1993)
(Kurkov and Loftsson, 2013)
(Slaughter et al., 2014)
(Grimble et al., 1988)
(Burri et al., 2001)
(Tahara et al., 1990)
(Cloyd et al., 1986)
(Martin et al., 2004)
(Campbell, 2003; Capel et al., 1972)
(Pelham et al., 2008)
(Kolloffel et al., 1996)
(Zempleni et al., 1996)
(Colburn et al., 1981; Sweatman et al.,
1981)
(Nau et al., 1992)
(Robersts et al., 2000)
(Kurkov and Loftsson, 2013)

5
100g
100
0.53
100
2
<2
0h
740
<90
90f
0.2
100
96c
85
2590
<15
Negligible
5080

(Proteggente et al., 2005)

(Yap et al., 2001)

From (ACS, 2014).

Common logarithm of the calculated partition coefcient between n-octanol and water.
Dose dependent.
Well absorbed from the GI tract but undergoes extensive rst-pass metabolism.
From (Pandey et al., 2011).
From (Bouchard et al., 2007).
Active absorption.
Polysaccharides and oligosaccharides must be digested to monosaccharides before being absorbed into the blood circulation.

essentially not metabolized in the body but excreted in urine by

glomerular ltration. The excretion rate decreases (i.e., t1/2
increases) with increasing Mw. PVP with Mw below about
10,000 Da is readily excreted unmetabolized in the kidney by
glomerular ltration, PVP of Mw up to 25,000 Da is completely
excreted within one day but it takes eight days to excrete PVP of
Mw 37,000 Da (Wessel et al., 1971). Consequently only PVP with
Mw below 10,000 Da is used in parenteral solutions (Robinson
et al., 1990; Schiller et al., 1978). Negligible amounts of PVP are
absorbed from the GI tract.
Glomerulus is the semi-permeable ltering unit of the kidney
that lters urine from blood plasma at the rate of 125 mL/min (i.e.,
GFR is about 125 mL/mL in adult humans with normal kidney
function). In general, the glomerular lter allows water-soluble
molecules of Mw less than 7000 Da to pass freely but then the GFR
decreases with increasing Mw and approaches zero for molecules
with Mw of about 70,000 Da, that is the Mw cutoff (MWCO) of
glomerulus is about 70,000 Da (Lote, 2012). Plasma albumin (Mw
68,000 Da) is only able to pass through the glomerulus lter in
minute quantities. However, the log t1/2 log Mw relationships for
water-soluble polymers are sigmoidal displaying a sharp t1/2
increase at some observed MWCO of the semipermeable glomerulus membrane lter that is frequently at about or slightly above
10,000 Da. For example, in mice the t1/2 of PEG increases from
about 18 min to one day as the Mw is increased from 3000 to
30,000 Da with sharp increase in t1/2 when the Mw increases above
10,000 Da (Fig. 2). In drug delivery nanoparticles are frequently

dened as solid particles with diameter less than 1000 nm (Durn

et al., 2014; Stefnsson and Loftsson, 2010). For example, the
diameter of polymeric nanoparticles is typically between 200 and
800 nm. The size of nanoparticles, their surface charge and

Table 4
Partial structure, physicochemical properties and pharmacokinetic parameters of
dextran after parenteral administration to humans. Data collected from (ACS, 2014;
Arturson et al., 1971; Klotz and Kroemer, 1987; Mehvar et al., 1995; Mehvar and
Shepard, 1992; Terg et al., 1996).

Parameter

Dextran 1

Dextran 60

Dextran 70

Molecular weight (Da)

Approx. number of glucose units
Calculated log Poctanol/water at 25  C
Approx. H-bond donors
Approx. H-bond acceptors
t1/2 (h)
VD (L/kg)

1000
6
13.0
20
31
1.9
0.14

60,000
360
< 13
1080
1800
42

70,000
420
< 13
1260
2100
67
0.10

52

T. Loftsson / International Journal of Pharmaceutics 480 (2015) 4854

6. General observations

Fig. 2. Logarithmic relationship between the molecular weight (Mw) and the
elimination half-life (t1/2) of polyethylene glycol (PEG) in mice. Reproduced with
permission from (Yamaoka et al., 1994).

composition will affect their pharmacokinetics. Studies have

shown that nanoparticles with hydrodynamic diameter less than
about 6 nm are rapidly and completely excreted by glomerular
ltration while larger particles are excreted more slowly (Avgoustakis et al., 2003; Lu et al., 2010; Marcato, 2014). In general,
polymer particles less than 8 nm in diameter are mainly excreted
vis glomerular ltration (i.e., by renal clearance) while larger
nanoparticles must disassemble to form smaller particles and
low-Mw metabolites before they can be excreted from the body
(Longmire et al., 2008).
5. Metabolizability and drug design
The ADME properties of drugs and drug candidates can be
improved through chemical modications. For example, Bodor
introduced the soft drug design where ADME/Tox properties of
biologically active compounds are improved thorough chemical
modications (Bodor and Buchwald, 2012). Soft drugs are
characterized by a predictable and controllable metabolism to
nontoxic products after they have achieved their therapeutic role.
Oxidative pathways are avoided as much as possible, since
oxidation frequently leads to the formation of biologically active
metabolites that can lead to adverse effects (Bodor and Buchwald,
2004). Chemically labile linkages such as ester linkages are
introduced into biologically active compounds. This makes their
metabolism much less dependent on saturable metabolic pathways. A typical soft drug is inactivated through simple hydrolysis
to form a highly hydrophilic and biologically inactive metabolite
that is then readily excreted from the body (most often in urine)
without further conversions (Loftsson, 2015). The soft drug
approach has been used to design soft excipients such as soft
antimicrobial agents (Thorsteinsson et al., 2003).

While drugs need to have some lipophilicity to be able to

permeate biological membranes and reach their target,
pharmaceutical excipients should generally be rather hydrophilic
and possess limited ability to permeate the skin barrier and
the GI mucosa, although many excipients are lipophilic (Table 3).
Methods used for rapid proling of new drug candidates can
be used for rapid proling of new pharmaceutical excipients
and drug delivery systems but with emphasis on inability to
permeate biological membranes, favorable toxicological prole
and relatively rapid excretion from the body (Table 5). Excipients
should be biologically inactive, unable to interact with drug
receptors and produce pharmacologic response, and unable to
modify enzymatic activity. There are, however, some exceptions.
Many antimicrobial agents, such as the parabens, have to be
somewhat lipophilic to be able to permeate bacterial walls and
reach their target. Antibacterial agents used as preservatives are
biologically active compounds that target microorganisms.
Various antioxidants, such as tocopherols, are lipophilic and
used to protect lipophilic drug molecules against oxidative
degradation in certain lipophilic drug products like ointments
and creams. Some excipients, such as nonionic tocopheryl
surfactants, are able to enhance oral bioavailability of drugs by
inhibiting the efux pumps of the GI mucosa (Wempe et al.,
2009). Finally, numerous drug products (e.g., suppositories and
many dermal products) are lipid based and contain lipophilic
excipients like vegetable or mineral oils, surfactants, fatty acids
and fatty alcohols. However, hydrophilic excipients are frequently
favored over lipophilic and poorly water-soluble ones since
hydrophilic excipients are normally more biocompatible and
often easily excreted from the body (Fig. 3). Following are some
general observations and list of preferred physicochemical
properties of novel pharmaceutical excipients and drug
delivery systems.
Novel excipients designed for oral drug products should
preferably not be absorbed from the GI tract. From the Rule-ofFive we know that drug molecules that have Mw above 500 Da, log P
value above 5, more than 5H-bond donors or more than 10H-bond
acceptors are poorly absorbed from the GI tract (Table 1).
Furthermore, Table 3 shows that large hydrophilic molecules with
numerous H-bond donors and acceptors are very poorly absorbed
from the GI tract. Thus, if orally administered excipients are
lipophilic their Mw should preferable be above 500 Da and their
calculated log P value above 5, since large very lipophilic molecules
are, in general, poorly absorbed from the GI tract. On the other hand,
if the excipients are hydrophilic their Mw should be above 1000 Da,
their log P value should be below 0.5 and they should contain large
number of H-bond donors and acceptors. Excipients with Mw below
500, log P value between 1 and 5 and low number of H-bond donors

Table 5
Favored physicochemical properties of novel excipients for pharmaceutical products.
Type of drug delivery

Mw (Da)

Log P

H-bond donors

H-bond acceptors

Oral drug delivery:

Lipophilic excipientsa
Hydrophilic excipients

>500
>1000

>5
<0.5

>5

>10

Topical drug delivery to the eye:

>1000

<0

>3

>8

>5
<0.5

>2

>8

<0

High

High

Transdermal drug delivery:

Lipophilic excipientsa
Hydrophilic excipients
Parenteral drug delivery:
a

Soft design preferred.

>500
>300
<15,000

T. Loftsson / International Journal of Pharmaceutics 480 (2015) 4854

53

Fig. 3. Schematic representation of metabolic pathways of excipients and their excretion after entering the systemic blood circulation. The main objectives of phase I
reactions are to increase hydrophilicity of excipient molecule and facilitate phase II conjugations. The main objectives of phase II reactions are formation of highly polar
conjugates that are readily excreted from the body.

and acceptors are frequently well absorbed from the GI tract

(Table 3). While buccal absorption appears to be somewhat similar
to GI absorption the nasal mucosa is a bit more permeable and might
resemble the eye cornea regarding excipient permeation.
Topically administered excipients to the eye should preferably
be somewhat large (Mw above 1000 Da), hydrophilic (log P below
0) molecules with large number of H-bond donors and acceptors
(Table 5) since small (Mw below 500 Da) and lipophilic molecules
(log P below 4) with few H-bond donors and acceptors are
frequently well absorbed into the eye (Table 1). Very lipophilic
excipients do not mix well with the aqueous tear uid and can
cause blurred vision.
Skin is less permeable than mucosa and stricter
physicochemical limits apply for optimum transdermal drug
permeation (Table 1). Thus, dermally applied excipients are
generally less likely to be absorbed into the systemic
blood circulation than, for example, orally administered
excipients. Very hydrophilic molecules (Mw above about 300
and log P below 0.5) and somewhat larger lipophilic molecules
(Mw above 500 and log P above 5) do not readily penetrate the
skin barrier (Table 5).
Excipients administered by parenteral injection, especially
those that are administered by IV injection, readily access the
general blood circulation. In this case absorption of the excipients
into the general blood circulation is not an issue but rather their
excretion from the body (Fig. 3). Excipients that are readily
excreted from the body without oxidative metabolism are less
likely to cause side effects than excipients that are slowly
excreted and undergo oxidative metabolism. Hydrophilic
low-Mw polymers (log P less than 0 and Mw less than about
10,000 Da) with numerous H-bond donors and receptors have
small VD (i.e., are mainly located in the blood plasma due to their
inability to permeate biological membranes) and are readily
excreted by glomerular ltration with t1/2 of about 2 h (Table 3). As
the Mw increases above 10,000 Da the GFR decreases and fraction
of excipient that is metabolized increases. Hydrophilic dextran
molecules of Mw 1000 Da are mainly excreted with urine with t1/2
of 1.9 h while larger 70,000 Da molecules are mainly metabolized

with t1/2 of about three days (Table 4). Thus, excipients

for parenteral administration should if possible be hydrophilic
(log P below 0) and preferably have Mw below about 15,000 Da
with numerous H-bond donors and acceptors (Table 5). Larger
and more lipophilic molecules should be biodegradable and
preferable undergo hydrolytic metabolism (i.e., be soft excipients)
since these are more readily excreted and less likely to cause toxic
side effects.
Nanoparticle drug carriers that enter the general blood
circulation need to be eliminated from the body after they have
delivered their drug load. Nanoparticles with hydrodynamic
diameter less than about 6 nm are rapidly and completely excreted
by glomerular ltration. The GFR decreases rapidly with increasing
particle diameter above 68 nm and larger nanoparticles have to
be disassembled before they can be excreted. Polymeric nanoparticles must be disassembled and/or cleaved to form hydrophilic
low-Mw polymers that can easily be excreted from the body by
glomerular ltration. Lipophilic excipients used to form nanoparticles should preferable be soft and undergo enzymatic or
non-enzymatic hydrolysis to facilitate their detoxication and
excretion from the body.
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