Cyclodextrins as Functional Excipients: Methods

to Enhance Complexation Efficiency

THORSTEINN LOFTSSON,1 MARCUS E. BREWSTER2
1

Faculty of Pharmaceutical Sciences, University of Iceland, IS-107 Reykjavik, Iceland

2
Pharmaceutical Development and Manufacturing Sciences, Janssen Research and Development, Johnson & Johnson,
B-2340 Beerse, Belgium

Received 19 December 2011; revised 16 January 2012; accepted 18 January 2012

Published online 14 February 2012 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23077
ABSTRACT: Cyclodextrins have gained currency as useful solubilizing excipients with an ever
increasing list of beneficial properties and functionalities. Although their use in liquid dosage
forms including oral and parenteral solutions is straightforward, their application to solids
can be confounded by the added bulk that is contributed to the formulation. This factor has
limited the use of cyclodextrin in tablets and relates systems mainly to potent drug substances.
Increasing the ability of cyclodextrins to complex with drug through a manipulation of their
complexation efficiency (CE) may expand the use of these materials to the increasing list of drug
candidates and marketed drugs who may benefit from this technology. This brief review assesses
tools and materials that have been suggested for increasing the CE for pharmaceutically useful
cyclodextrins and drugs. The relative importance of impacting the drug solubility (S0 ) and
phase-solubility isotherm slope is discussed in the context of drug ionization and salt use; the
impact of polymers, charge interactions, and charge shielding; and the coincidental formation of
other complex types in the media. The influence of drug form as well as supersaturation is also
discussed in the context of the responsible mechanisms along with aggregation, inclusion, and
noninclusion complex formation. 2012 Wiley Periodicals, Inc. and the American Pharmacists
Association J Pharm Sci 101:30193032, 2012
Keywords: cyclodextrin; complex; solubilization; complexation efficiency; dissolution;
solubility; preformulation; inclusion compounds

INTRODUCTION
Cyclodextrins are pharmaceutical excipients that
can solubilize various poorly soluble drugs through
the formation of water-soluble drugcyclodextrin
complexes. Cyclodextrins are cyclic oligosaccharides
containing six, seven, or eight ("-1,4)-linked Dglucopyranoside units (giving rise to "-, $-, and (cyclodextrin, respectively). These three so-called parent cyclodextrins, as well as their complexes, can
have somewhat limited solubility in water, especially in the case of $-cyclodextrin. Thus, a number of water-soluble chemically modified cyclodextrin
derivatives have been synthesized.16 Cyclodextrins
and cyclodextrin derivatives of pharmaceutical interest are depicted in Table 1. Cyclodextrins generally have a rather favorable toxicological profile, esCorrespondence to: Thorsteinn Loftsson (Telephone: +354-5254464; Fax: +354-525-4071; E-mail: thorstlo@hi.is)
Journal of Pharmaceutical Sciences, Vol. 101, 30193032 (2012)
2012 Wiley Periodicals, Inc. and the American Pharmacists Association

pecially in comparison to other pharmaceutical excipients, such as surfactants, water-soluble polymers,

and organic solvents.3,7,8 Because of their generation
by bacterial digestion of starch; their hydrophilicity
(log Koctanol/water ), which is in most cases less than
7; their high molecular weight (MW); and the large
number of hydrogen donors and acceptors, the oral
bioavailability of cyclodextrins is very low meaning that they act as true drug carriers. Toxicological studies have shown that orally administered cyclodextrins are practically nontoxic because of their
low absorption into the systemic blood circulation.8,9
Even when given via parenteral administration, hydrophilic cyclodextrins are primarily eliminated unchanged from the body via renal excretion with a total
plasma clearance that is close to glomerular filtration
rates.7,1012 In patients with normal kidney function,
about 90% of the cyclodextrin will be excreted within
6 h and about 99% within 12 h after intravenous administration. Cyclodextrins are listed in a number of
pharmacopoeias and are accepted as pharmaceutical

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LOFTSSON AND BREWSTER

Table 1.

Some Cyclodextrins That Can be Found in Commercial Pharmaceutical Products69

Cyclodextrin

MSa

Oral Bioavailability Solubility in Water at Room

in Rats (%)
Temperature (mg/mL)

Synonyms

MW (Da)

"-Cyclodextrin

Alfadex

973

145

$-Cyclodextrin

Betadex

1135

0.6

18.5

2-Hydroxypropyl$-cyclodextrin

0.65 Hydroxypropylbetadex

1400

>600

Sulfobutylether
$-cyclodextrin
sodium salt
Methylated
$-cyclodextrin
(-Cyclodextrin
2-Hydroxypropyl(-cyclodextrin

0.9

2163

1.6

>500

1.8

1312

12

>600

1297
1576

0.02
<0.1

232
>600

a The

Gammadex
0.6

Current Usage in
Marketed Products
Oral and parenteral
formulations.
Oral, buccal, and topical
formulations.
Oral, parenteral, rectal,
and ophthalmic
formulations.
Parenteral formulations.

Ophthalmic and nasal

formulations.
Parenteral formulation.
Parenteral and ophthalmic
formulations.

molar degree of substitution (MS) is defined as the average number of substituents that have reacted with one glucopyranose repeat unit.

excipients and food additives by various regulatory agencies. For example, monographs for the parent "-, $-, and (-cyclodextrin can be found in the
United States Pharmacopoeia (USP)/National Formulary and all three are included in the US Food
and Drug Administration (FDA) generally recognized as safe list. 2-Hydroxypropyl-$-cyclodextrin is
compendial in the USP and European Pharmacopoeia
and both 2-hydroxypropyl-$-cyclodextrin and sulfobutylether $-cyclodextrin are cited in the FDAs list
of pharmaceutical ingredients. Furthermore, these
cyclodextrins have gained similar status in both Europe and Japan. Currently, cyclodextrins can be found
in over 35 commercially available drug products, including tablets, parenteral solutions, eye drops, ointments, and suppositories.6
A major obstacle to pharmaceutical exploitation
of cyclodextrins is their formulation bulk. In solid
dosage forms, cyclodextrin can only be used as solubility enhancers for potent drugs and drugs with
medium potency and only if these drugs have relatively high complexation efficiency (CE) (Table 2). The
CE of a poorly soluble lipophilic drug can range from

zero, when no complexation is observed, to infinity,

when every cyclodextrin molecule present in solution
forms a complex with the drug. Importantly, the value
of the CE in aqueous media is rarely greater than 1.5
with an average value of about 0.3, indicating that on
average only about one out of every four cyclodextrin
molecules present in a given complexation medium
is in a complex with a drug molecule.13 The formulation bulk of low potency drugs and drugs displaying
low CE will often be too large for a single dose tablet
(Table 3). Frequently, an increase in the drugcyclodextrin complex molar ratio will lead to an increase
in drug bioavailability. Optimum drug bioavailability is frequently obtained with a minimum amount
of cyclodextrin, that is, by including material sufficient to produce desired effect but avoiding excess
amounts of cyclodextrin. Thus, enhancement of the
CE is of importance to pharmaceutical formulators.
Here, methods that can be applied to enhance the CE
are reviewed. Although the examples used relate to
cyclodextrin containing media, many of these same
methods can be applied to other complexing agents
and other types of solubilizers.

Table 2. The Relationship Between Drug Potency, Complexation Efficiency (CE), and Formulation Bulk, that is the Weight of a
DrugCyclodextrin (DCD) Complex Containing the Drug Dose, Assuming Drug Molecular Weight of 400 Da and That of the
Cyclodextrin to be 1400 Da
The Weight of a Dry Complex Containing the Drug Dose

Drug Dose
High potency drug (5 mg)
Medium potency drug (50 mg)
Low potency drug (500 mg)

CE = with DCD
Molar Ratio of 1:1

High CE with DCD

Molar Ratio of 1:2

Medium CE with DCD

Molar Ratio of 1:4a

23 mg
230 mg
2300 mg

35 mg
350 mg
3500 mg

70 mg
700 mg
7000 mg

a The average CE of 28 different drugs was determined to be 0.3, indicating that on the average only one out of every four cyclodextrin molecules are
forming drug complex assuming 1:1 DCD complex formation.13

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CYCLODEXTRINS AS FUNCTIONAL EXCIPIENTS

3021

Table 3. The Relationship Between the Drug Dose, Complexation Efficiency (CE), and the Dosage Bulk upon Complexation with
2-Hydroxypropyl-$-Cyclodextrin (MW 1400 Da)

Drug
Acetazolamide
Alprazolam
Digoxin
Econazole
Flunitrazepam
Miconazole
Naproxen
Sulfamethoxazole
Triazolam

MW (Da)

Common Oral
Dose (mg)

S0 (mg/mL)

Slope

K1:1 (M1 )a

CEb

DCD Molar
Ratioc

Dosage Bulk
(mg)

222.2
308.8
780.9
381.7
313.3
416.1
230.3
253.3
343.2

250
0.25
0.05
150
1
1000
500
800
0.25

0.64
0.07
0.99
0.37
0.00
0.09
0.12
0.39
0.03

0.197
0.055
0.303
0.145
0.110
0.080
0.282
0.359
0.017

85
250
6800
180
1100
260
780
360
200

0.246
0.058
0.435
0.170
0.010
0.087
0.393
0.561
0.017

1:5
1:18
1:3
1:7
1:100
1:12
1:4
1:3
1:60

8200
20
0.3
3200
450
42,000
13, 000
14,000
60

a According

to Eq. 9.
to Eq. 12.
c According to Eq. 13.
The dosage bulk is the weight of drugcyclodextrin complex containing the drug dose. The table is based on data from Ref. 13.
b According

CYCLODEXTRIN COMPLEXES AND AQUEOUS

SOLUBILITY
In aqueous solutions, cyclodextrins form inclusion
complexes with poorly water-soluble drugs by taking
up a lipophilic moiety of the drug molecule into the
somewhat hydrophobic central cavity of the cyclodextrin (Fig. 1). In dilute solutions, such inclusion complexes are dominating or even the only form of drug
cyclodextrin superstructure. However, cyclodextrins
are also known to form noninclusion drugcyclodextrin complexes.1421 As the cyclodextrin concentration
increases, the cyclodextrin molecules and their complexes self-assemble to form aggregates that often
range in size between 20 and 100 nm in diameter.2126
The aggregation and the size of the aggregates increases with increasing cyclodextrin concentration.
Excipients that solubilize and stabilize aggregates,
such as small ionized molecules (e.g., salts of organic
acids and bases) and water-soluble polymers (e.g., cellulose derivatives) can improve the magnitude of the
CE. To explain the mechanisms underlying this effect,
we first need to review briefly the phase-solubility theory of Higuchi and Connors,27 understanding that the
theory is based on the formation of soluble complexes,
be the inclusion, noninclusion, or a combination of the
two. Furthermore, the relationship is not indicative

of what form the complexes are, that is, individual

complexes or complex aggregates; only that they are
water soluble.
The Phase-Solubility Theory
If m drug molecules (D) associate with n cyclodextrin molecules (CD) to form a complex (Dm CDn ), the
following equilibrium is suggested18,27 :
K m:n

m D + n CD  DmCDn

(1)

where Km:n is the stability constant (also known as

binding constant, formation constant, or association
constant) of the substrateligand (or guesthost) complex. The stability constant can be written as follows:


DmCDn
n
K m:n =  m 
D CD

(2)

where the brackets denote molar concentrations. In

general, higher order complexes are formed in a stepwise fashion where a 1:1 complex is formed in the first
step, 1:2 (or 2:1) complex in the next step, and so on:
D + CD
D/CD

(3)

D/CD + CD
D/CD2

(4)

Consequently, the stability constants can be written

as follows:


D/CD

K 1:1 =   
(5)
D CD


D/CD2
 

(6)
K 1:2 = 
D/CD CD
Figure 1. Schematic drawing of a drugcyclodextrin complex formation and self-assemble of complexes to form complex aggregate.
DOI 10.1002/jps

If the intrinsic drug solubility, that is, the drug solubility in the aqueous complexation media when no
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3022

LOFTSSON AND BREWSTER

cyclodextrin is present, is given as S0 and a formed

complex is represented by D/CD, then
[D] = S0

(7)

[D]T = S0 + [D/CD]

(8)

where [D]T represents the total drug solubility, assuming 1:1 DCD complex formation according to
Eqs. 3 and 5. A plot of [D]T versus [CD]T for the formation of 1:1 DCD complex should give a straight line
with the y-intercept representing S0 and the slope
defined as follows:
K 1:1 =

Slope
S0 (1 Slope)

(9)

If one drug molecule (n = 1) forms a complex with

two cyclodextrin molecules (m = 2), then the following
equations apply:
[D]T = S0 + [D/CD] + [D/CD2 ]

(10)

[D]T = S0 + K 1:1 S0 [CD] + K 1:1 K 1:2 S0 [CD]2 (11)

indicating that a plot of [D]T versus [CD]T (assuming

that [CD]  ([D/CD] + 2 [D/CD2 ]) or [CD] [CD]T )
fitted to the quadratic relationship will allow for the
estimation of K1:1 and K1:2 .
Dissolved drug molecules can form water-soluble
dimers, trimers, and higher order aggregates as well
as be associated with other excipients present in the
aqueous complexation media. Frequently, only individual drug molecules can form complexes with dissolved cyclodextrin molecules. Dimers, trimers, and
water-soluble oligomers are often unable to form cyclodextrin complexes.13 Under such conditions, the yintercept will not be equal to S0 and this can cause
considerable error in the value of K. A more accurate
method for determination of the solubilizing effect of
cyclodextrins is to determine their CE, that is, the
concentration ratio between cyclodextrin in a complex
and free cyclodextrin. CE is calculated from the slope
of the phase-solubility diagrams, is independent of
both S0 and the intercept, and is more reliable when
the influences of various pharmaceutical excipients
on the solubilization are being investigated. For 1:1
DCD complexes, the CE is calculated as follows:


D/CDn
Slope


= S0 K 1:1 =
CE =
CD
(1 Slope)

(12)

And the drugcyclodextrin molar ratio in a particular

complexation media saturated with the drug can be
calculated from the CE:
D : CD molar ratio = 1 :

(CE + 1)
CE

(13)

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 9, SEPTEMBER 2012

Equation 13 shows that CE of 1.0 gives D:CD molar ratio of 1:2 and CE of 5.0 gives molar ratio of 4:5.
Examples of CE in pure aqueous solutions at room
temperature are shown in Table 3. Table 3 shows that
the value of K1:1 for the acetazolamideHP$CD complex in pure water at room temperature is 85 M1 ,
indicating that about 90% of the HP$CD molecules
will be in a complex in an unsaturated aqueous solution containing equimolar amounts of acetazolamide
(MW 222.2 Da) and HP$CD (MW 1400 Da). However, in 20% (w/v) HP$CD aqueous solution (i.e.,
0.14 M) saturated with the drug ([D] = constant
= S0 = 0.003 M), only about 20% of the HP$CD
molecules, or one out of every five HP$CD molecules,
will be complexed with acetazolamide. This solution can be lyophilized to produce a solid powder of
acetazolamideHP$CD complex. Tablets of acetazolamide commonly contain 250 mg of the drug that
corresponds to 8200 mg of the acetazolamideHP$CD
complex powder. Even if the CE can be enhanced to
produce a acetazolamideHP$CD (1:1) dry complex
powder, the formulation bulk of this medium to low
potency drug would be very high (i.e., 1250 mg).

ENHANCING THE CE
The CE is the product of the apparent solubility of
the poorly soluble drug in the complexation media
(assumed to be S0 in Eq. 12) and the apparent stability constant of the complex (K1:1 ), assuming formation
of 1:1 drugcyclodextrin complex. Thus, according to
Eq. 12, the CE can be increased by either increasing
the value of S0 or the value of K1:1 , or both values
simultaneously. In many cases, the true magnitudes
of S0 and K1:1 remain constant while their apparent
values increase. For example, the intrinsic solubility of an acid is the solubility of its unionized form
(HA), but the apparent solubility at a given pH is
the total solubility, that is, of both the unionized and
ionized species ([HA]T = [HA] + [A ]). Likewise, the
apparent solubility of a metastable amorphous drug
is much higher than the equilibrium solubility of its
crystalline form. Thus, itraconazole is converted to its
amorphous form to enhance its cyclodextrin solubilization in parenteral and oral solutions.6 Cocrystals
and polymorphic forms can also result in enhanced
apparent solubility and better cyclodextrin solubilization of poorly soluble drugs. As cyclodextrins and cyclodextrin complexes are able to self-assemble and
solubilize drugs in micellar-like fashion, pharmaceutical excipients that stabilize and solubilize nanoparticles and micelles, such as polymers and low MW
organic acids, are also able to enhance the CE. Frequently, such enhancement is associated with apparent increase in the value of K1:1 .
DOI 10.1002/jps

CYCLODEXTRINS AS FUNCTIONAL EXCIPIENTS

3023

Figure 2. A pH-solubility profile in pure water and a phase-solubility profile for phenytoin in
aqueous buffer solutions containing 0%6% (w/v) 2-hydroxypropyl-$-cyclodextrin (HP$CD) at
25 C. The figures and table are based on data from Ref. 28 and unpublished results.

Drug Ionization
Normally, the more lipophilic unionized form of a
given drug molecule has a greater affinity for the
somewhat hydrophobic cyclodextrin cavity than the
ionized form and, thus, the unionized form has a
higher K1:1 value. However, ionization of a poorly
water-soluble drug will increase the S0 value and
if the increase in S0 is greater than the decrease in
K1:1 , then an increase in the CE will be observed (see
Eq. 12). For example, phenytoin is a poorly soluble
drug with a pKa value of 8.06 in pure water at room
temperature.28 Unionized phenytoin has CE of 0.08,
indicating that in aqueous solutions only one out of
every 15 cyclodextrin molecules forms a complex with
phenytoin (Fig. 2). Thus, cyclodextrin solubilization of
phenytoin in aqueous formulations was not practical
and the only way to prepare a parenteral phenytoin
solution was to use mixture of water and organic solvents and at the same time increase the pH to values
above 10.29 Increasing the pH from acidic to 7.55 results in partial (about 24%) ionization of the drug
and consequently increases the S0 . This, in turn, increases the CE from 0.08 to 0.15 with one out of every
eight cyclodextrin molecules forming a complex with
the drug. Increasing the pH further to 11 results in
almost complete (over 99%) ionization of the drug and
increase in the CE to 14, meaning that almost every
cyclodextrin molecule in the solution forms a complex
with the drug. The ionized forms of all four drugs
shown in Table 4 have lower K1:1 value than the corresponding unionized forms. The ionization increases
the S0 value but decreases the K1:1 , but the increase

DOI 10.1002/jps

in S0 is more than sufficient to compensate for the

decrease in K1:1 . The result is in all cases an increase
in the CE.
Salt Formation
Salt formation of acidic and basic drugs is the most
common method of increasing aqueous solubility during drug development.35 The solubility of the salt is
governed by the solubility product constant of the
salt, the solubility of the unionized drug, and the pKa
value. The counterion can originate from the drug
salt or it can be adventitiously present in the aqueous
solution as, for example, a buffer salt. As a free base,
carvedilol (pKa 7.8) has aqueous solubility of less than
1 :g/mL (pH > 9) but its solubility increases to about
0.1 mg/mL (pH < 5) upon protonization.36 The counterion present in an aqueous carvedilol solution will
also have a significant effect on the solubility. The
carvedilol solubility at pH values below 4 is five times
greater in aqueous acetic acid solution than in aqueous phosphoric acid solution (Fig. 3). This difference
in aqueous solubility affects the cyclodextrin solubilization of the drug. Thus, the CE of HP$CD is only
0.05 in the aqueous phosphoric acid solution but 1.62
in the acetic acid solution. Other examples of CE enhancement as a function of salt selection are shown in
Table 5. In general, but not in every instance, the most
soluble salt possesses the highest CE. It has been suggested that in some cases the counterions participate
directly in complex formation; that is, that in some
cases, a ternary drugcyclodextrinsalt complex is being formed.39,37,40,41 Some organic acids, especially

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LOFTSSON AND BREWSTER

Table 4. The Effect of Drug Ionization on the Complexation Efficiency (CE) and on the Value of the DrugCyclodextrin K1:1
Stability Constant at Room Temperature
Effect of pH on CE

Drug

Ionizeda

K1:1 (M1 )

pKa

Cyclodextrin

pH

CE

pH

CE

Flavopiridol Base
(Alvocidib)

5.7

HP$CD

8.4

0.03

4.3

0.22

445

124

30

Naproxen

Acid

4.2

HP$CD

2.0

0.3

7.0

0.9

5160

665

31,32

Naringenin

Acid

6.7

HP$CD

4.0

0.3

8.0

1.3

833

44

33

Phenytoin

Acid

8.06

HP$CD

2.7

0.08

7.6

0.15

HP$CD
SBE$CD

7.4
7.4

0.1
0.1

11.0
11.0

14
14

Structure

Unionizeda

Unionized Ionized References

See Fig. 2

1215
1267

352
476

34
34

The drug is either partly or fully unionized/ionized at the given pH.

hydroxy acids such as citric and tartaric acid, are

known to increase the aqueous solubility of the poorly
soluble $-cyclodextrin possibly through modification of intramolecular and intermolecular hydrogenbonding system of $-cyclodextrin.42 However, the
solubility enhancement can also be related to the tendency of cyclodextrins and their complexes to selfassemble in aqueous solutions to form nano-sized
aggregates.2125

formation, and the salicylate ion is too large to enter

the cyclodextrin cavity coincidently with hydrocortisone to form a ternary complex. More likely explanation is that these ions participate in the formation
of water-soluble drugcyclodextrin aggregate that are
too small to scatter light in aqueous solutions. Formation of such ternary complexes is sometime observed
as an increase in the K1:1 value. Hydroxyaromatic
acids are also well known complexing agents capable
of participating in ternary complexes.44

Salts and Neutral Drugs

Addition of small amount of sodium acetate to
aqueous media containing hydrocortisone and $cyclodextrin results in an over threefold enhancement in hydrocortisone solubility (Fig. 4) and
likewise sodium salicylate enhances $-cyclodextrin
solubilization of hydrocortisone and vice versa
(Fig. 5). Such increases in solubilization through
complexation of a neutral drug (hydrocortisone) and
neutral $-cyclodextrin cannot be explained by salt
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 9, SEPTEMBER 2012

Water-Soluble Polymers
Water-soluble polymers are known to enhance the CE
of cyclodextrins.4547 Both the polymers and cyclodextrins can form water-soluble complexes with poorly
soluble, lipophilic drugs but when used in combination, a synergistic solubilization effect is observed,
that is, the apparent drug solubility is greater than
the sum of polymer and cyclodextrin solubilization
DOI 10.1002/jps

CYCLODEXTRINS AS FUNCTIONAL EXCIPIENTS

Table 5.

Effects of Counterions (Salts) on the Cyclodextrin Solubilization at Room Temperature

Drug

pKa

Counterion

Econazole (base)

6.6

None
Nitrate
Citrate
Gluconate
Lactate
Maleate
Tartrate
None
Hydrochloride
Citrate
Tartrate
None
Arginine

Manidipine (base)

5.4, 8.2

Naproxen (acid)

4.2

Aqueous media
Dilute phosphoric acid

pH
3.7

CE
0.05

Dilute acetic acid

3.7

1.62

Solubility (mg/mL)a

Cyclodextrin

K1:1 (M1 )

CE

References

0.005
0.48
3.50
2.70
3.35
1.70
0.95
0.001
0.33
0.48
0.64
0.03
2.20

"CD

"CD
"CD
"CD
"CD
"CD
$CD

$CD
$CD
HP$CD
HP$CD

2630

130
169
103
448
429
20,000

500
450
665

0.04

1.1
0.5
0.9
1.9
1.0
0.03

0.3
0.4
0.9
>5

37

38

31,32,39

D:CD molar ratio

1:23
1:2

Figure 3. A pH-solubility profile of carvedilol in dilute

aqueous hydrochloride (HCl), phosphoric acid (H3 PO4 ), and
acetic acid (CH3 COOH) solutions at 25 C. The table shows
the complexation efficiency (CE) and the carvedilolHP$CD
molar ratio (D:HP$CD) in aqueous HP$CD solution saturated with carvedilol. The figure and table are based on
data from Ref. 36.

when assessed individually. The maximum CE is typically obtained at relatively low polymer concentrations or between 0.1% and 1% (w/v).45,48 The effect of
water-soluble polymers on cyclodextrin solubilization
of drugs has been reviewed.47 Some more recent examples are shown in Table 6. Table 6 shows that the
enhancement of CE is due to an increase in the apparent stability constant of the complex (K1:1 ). Watersoluble polymers are known to form water-soluble
complexes with poorly soluble drugs.5558 However,
only free drug molecules, that is, molecules not bound
to polymers, are able to form complex with cyclodextrins. In aqueous polymer solutions saturated with a
given drug, the concentration of free drug is equal to
the solubility of the drug in the pure aqueous media.

DOI 10.1002/jps

3025

Figure 4. The phase solubility of hydrocortisone in aqueous $-CD solutions or suspensions at room temperature
(22 C23 C). Pure water () and aqueous 1% (w/v) sodium
acetate solution (). The figure is based on data from Ref. 43.

Figure 5. The phase solubility of hydrocortisone in

aqueous sodium acetate solutions at room temperature
(22 C23 C). Pure water () and aqueous 4% (w/v) $-CD
suspension (). The figure is based on data from Ref. 43.

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LOFTSSON AND BREWSTER

Table 6.

Effects of Water-Soluble Polymers on the Cyclodextrin Solubilization at Room Temperature

Drug

pKa

pH

Acetazolamide

7.2

Water

HP$CD

Carbamazepine

7.0

Water

HP$CD

Celecoxib

9.7

Water

HP$CD

Water

(CD

Daidzein

7.5

Water

HP$CD

Famotidine

6.8

Water

$CD

Irbesartan

4.7

Water

$CD

Naproxen

4.2

1.1

Dexamethasone

Water

$CD
$CD
$CD
$CD
$CD
$CD
$CD
$CD
$CD
HP$CD
HP$CD
HP$CD
HP$CD
HP$CD
HP$CD
HP$CD
HP$CD
HP$CD
HP$CD

5.7

Water

HP$CD

4.0

6.5

1.1

4.0

6.5

Pregnenolone

Sulfamethoxazole

Polymer

K1:1 (M1 )

CE

References

0.25% (w/v) HPMC

0.25% (w/v) NaCMC
0.25% (w/v) PVP

0.25% (w/v) HPMC

0.25% (w/v) NaCMC
0.25% (w/v) PVP

0.5% (w/v) PVP

0.5% (w/v) HPMC
0.5% (w/v) PEG 4000

0.25% (w/v) HPMC

0.25% (w/v) NaCMC
0.25% (w/v) HDMBr

1% (w/w) HPMC
1% (w/w) PVP

0.75% (w/v) HPMC

1% (w/v) PEG 4000

1% (w/v) PVP

0.1% (w/v) NaCMC

0.1% (w/v) PVP

0.1% (w/v) NaCMC

0.1% (w/v) PVP

0.1% (w/v) NaCMC

0.1% (w/v) PVP

0.1% (w/v) NaCMC

0.1% (w/v) PVP

0.1% (w/v) NaCMC

0.1% (w/v) PVP

0.1% (w/v) NaCMC

0.1% (w/v) PVP

0.25% (w/v) HPMC

0.25% (w/v) NaCMC
0.25% (w/v) PVP

0.25% (w/v) HPMC

0.25% (w/v) NaCMC
0.25% (w/v) PVP

85
120
72
95
630
760
650
650
635
909
819
728
1210
2620
3330
3830
1410
1490
1750
650
19,000
130
159
201
3270
3930
4110
1890
2290
2350
210
230
260
4890
6340
7030
2610
3620
4130
230
322
368
1200
2800
1000
2200
360
220
400
780

0.25
0.36
0.21
0.27
0.68
0.83
0.71
0.70
0.006
0.008
0.007
0.006
0.26
0.86
0.76
0.97
0.015
0.016
0.019
1.7
50
0.06
0.07
0.09
0.15
0.18
0.19
0.18
0.22
0.23
1.2
1.3
1.5
0.22
0.29
0.32
0.26
0.35
0.40
1.3
1.8
2.1
0.12
0.29
0.11
0.23
0.56
0.34
0.62
1.2

13

Cyclodextrin

13

49

50

51

52
53

54

13

13

$CD, $-cyclodextrin; HP$CD, 2-hydroxypropyl-$-cyclodextrin; (CD, (-cyclodextrin; PVP, polyvinylpyrrolidone; HPMC, hydroxypropyl methylcellulose;
PEG, polyethylene glycol; NaCMC, carboxymethylcellulose sodium salt; HDMBr, hexadimethrine bromide.

Thus, the concentration of available drug molecules

should not be affected by the polymers and S0 in Eq.
12 would be expected to be constant. The observed
increase in CE is due to an increase in the K1:1 value
(Table 6).
It is known that water-soluble polymers, as well
as surfactants, are able to stabilize self-assembled
nanostructures.59 Polymers stabilize and enhance the
solubilizing effects of micelles, and polymers are used
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 9, SEPTEMBER 2012

to stabilize particulated pharmaceutical systems of

various types.6062 Water-soluble polymers are also
known to enhance aqueous solubility of cyclodextrins and cyclodextrin complexes.63 Furthermore, cyclodextrins have been reported to solubilize poorly
soluble compounds through formation of aggregates
or micellar-like structures2125 and the solubilizing
effect of some cyclodextrin complexes exceeds that
of the corresponding pure cyclodextrin.43,64 These
DOI 10.1002/jps

CYCLODEXTRINS AS FUNCTIONAL EXCIPIENTS

observations together with the fact that the enhancement in CE is due to an increase in the apparent stability constant of the complex suggest that the polymers enhance the stability of the cyclodextrin complex
aggregates and perhaps the ability of the aggregates
to solubilize poorly soluble drugs through micellartype solubilization.21
Cosolvents
Organic cosolvents increase aqueous solubility of nonpolar drugs by reducing the hydrogen bond density in
the aqueous mixture and thereby reducing the ability of water to squeeze out nonpolar drugs.65 Cosolvents such as ethanol can enhance the apparent
S0 and this will, like in the case of drug ionization,
lead to enhanced CE. On the contrary and as in the
case of drug ionization, addition of organic solvents
to the aqueous complexation media will decrease the
value of K1:1 . In case of ionization, the decrease is due
to decreased lipophilicity of the drug or drug moiety
entering the somewhat lipophilic cyclodextrin cavity.
In case of organic cosolvents, the apparent K1:1 decreases due to decreased polarity of the aqueous complexation media. The polarity of the cavity has been
estimated to be similar to that of an aqueous ethanolic solution.66 The dielectric constant () of the parent
$-cyclodextrin cavity has been determined to be 48
or about equal to that of 55% (v/v) ethanol in water at 25 C.67 The tendency of the drug molecule to
enter the cyclodextrin cavity decreases with decreasing polarity (decreasing ) of the complexation media.
Cosolvent molecules may participate in the complexation through formation of drugcyclodextrincosolvent ternary complexes or hamper complexation by
competing with the drug for a space in the cavity.
Thus, cosolvents can both increase and decrease cyclodextrin solubilization of drugs and their effect is
concentration dependent.6871
Table 7 shows the effect of ethanol concentration
on the cyclodextrin solubilization of fluasterone in
ethanolwater mixtures. The value of the apparent
stability constant (K1:1 ) of the fluasteroneHP$CD
complex decreases with increasing ethanol concentration but Figure 6 shows that although the fluasterone
solubility in aqueous HP$CD solution decreases with
increasing ethanol concentration at low ethanol concentrations, it increases at ethanol concentrations
above about 40% (v/v). This initial decrease and then
increase is due to changes in the CE (CE = S0
K1:1 , Eq. 12). At low ethanol concentrations, the value
of K1:1 decreases faster than the apparent solubility
(S0 ) increases, but at higher ethanol concentrations,
S0 increases faster than K1:1 change. The result is an
U-shaped solubility curve with a minimum at about
25% (v/v) ethanol solution. Table 7 and Figure 6 emphasize the fact that in aqueous solutions, CE is a
DOI 10.1002/jps

3027

Table 7. The Effect of Ethanol on the

2-Hydroxypropyl-$-Cyclodextrin (HP$CD) Complexation of
Fluasterone at 25 C,

CE = S0 K1: 1
Ethanol Conc. (%, v/v)

K1:1 (M1 )

0.0
0.2
1.0
6.3
12.5
18.8
25.6
37.6
50.1
62.7
75.2

79
78
78
76
73
70
67
62
55
49
43

180,000
200,000
180,000
61,000
18,000
7500
3000
660
110
34
7

CE
0.028
0.031
0.028
0.022
0.015
0.015
0.014
0.019
0.015
0.025
0.030

a The dielectric constant () of the ethanolwater mixtures was

calculated as the weighted average of that for pure water ( = 78.5) and
pure ethanol ( = 24.3) at 25 C.
K1:1 is the apparent stability constant of the fluasteroneHP$CD 1:1
complex in the aqueous ethanol solution and CE is the complexation
efficiency. The values were determined from experimental data presented
in Refs. 69 and 70.

better indicator of the cyclodextrin solubilization of

poorly soluble drug than K1:1 .
ChargeCharge Interaction
Because of chargecharge attraction, the negatively
charged sulfobutyl ether $-cyclodextrin frequently interacts somewhat stronger with positively charged
drug molecules than, for example, the uncharged
HP$CD.31,72,73 Example of such enhanced solubilization due to chargecharge interaction is the solubilization of ziprasidone. The free base has very low
aqueous solubility (about 0.3 :g/mL), but it is possible
to obtain about 3000-fold solubility enhancement
through formation of the ziprasidone mesylate (solubility 0.9 mg free base per 1 mL), but still the

Figure 6. The effect of ethanol on the 2-hydroxypropyl-$cyclodextrin (HP$CD) solubilization of fluasterone at 25 C.

The figure is based on data presented in Refs. 69 and 70.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 9, SEPTEMBER 2012

3028

LOFTSSON AND BREWSTER

Table 8. The Effect of Counterion (Salt Form) and ChargeCharge Interaction on K1:1 and CE of the
2-Hydroxypropyl-$-Cyclodextrin (HP$CD) and Sulfobutyl Ether $-Cyclodextrin Sodium Salt (SBE$CD) Complexes of
Ziprasidone at Ambient Temperature
HP$CD
Counterion
Free base
Hydrochloride
Aspartate
Tartrate
Esylate
Mesylate

Solubility in Water (mg/mL)a

0.0003
0.08
0.2
0.2
0.5
0.9

K1:1

(M1 )

2800
1500
20
240
130
60

SBE$CD
CE
0.002
0.02
0.009
0.1
0.1
0.2

K1:1

(M1 )

6700
4700
30
1200
280
570

CE
0.005
0.06
0.1
0.5
0.3
1.2

a The solubility values represent free base (mg) dissolved in 1 mL of pure water. The pKa of the protonated ziprasidone is 6.5.
The values were estimated from experimental data presented in Refs.74 and 75.

solubility is much too low for a parenteral formulation. Table 8 shows the effects of various counterions
on the stability constants of ziprasidonecyclodextrin
complexes and the CE. Increasing the water solubility of ziprasidone through salt formation decreases
the value of the apparent stability constant and, in
general, the most water-soluble salts have the smallest stability constant. However, the increased solubility results in enhanced CE. Chargecharge attraction
enhanced the CE even further and, thus, the aqueous solubility ziprasidone mesylate in aqueous 40%
(w/v) sulfobutyl ether $-cyclodextrin sodium salt corresponds to 44 mg of the freebase per 1 mL of the
unbuffered complexation medium (pH 3.9).74
Multiple Complexes
Drugs and/or cyclodextrins are sometimes able to
form simultaneously two or more types of complexes.
For example, quinolones can both form metalion coordination complexes and monomolecular inclusiontype cyclodextrin complexes.7678 Both types of complexes are able to enhance the aqueous solubility of
quinolones. However, when used in combination, a
synergistic solubilizing effect is observed.79 Apparently, the metal complex increases S0 , resulting in
enhanced CE. Interaction of aliphatic polyalcohols
with metalions is generally insignificant in acidic
and neutral solutions but coordination complexes can
be significant under basic conditions where the OH
groups are ionized. Cyclodextrins (pKa > 12) are also
known to form metalion coordination complexes under basic conditions through deprotonation of the OH
groups.80
As mentioned previously, hydroxy acids, and other
low MW organic acids, increase the aqueous solubility of the poorly soluble $-cyclodextrin.42 Most probably, this enhancement is related to the tendency
of $-cyclodextrin, and other natural cyclodextrins,
to self-assemble to form nanoparticles in aqueous
solution19,21,81,82 and the ability of these acids to solubilize and stabilize these aggregates. Likewise, watersoluble polymers are able to enhance aqueous solubility of $-cyclodextrin and its complexes, most probably
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 9, SEPTEMBER 2012

through stabilization of cyclodextrin aggregates.63,83

These polymer (drugcyclodextrin complexes) complexes are molecular complexes. Other types of multiple complexes are also known such as those of
quinolones where quinolonemetal ion complexes
form complexes with cyclodextrin and these double complexes form complexes with water-soluble
polymer.79 Formation of such multiple complexes frequently results in better drug solubilization than can
be obtained by any solubilization method used singly.

PREPARATION OF SOLID
DRUGCYCLODEXTRIN COMPLEXES
The most common methods for preparation of solid
drugcyclodextrin complexes on laboratory scale are
lyophilization or spray drying of aqueous drug
cyclodextrin complex solutions. Poorly soluble complexes can an also be prepared by the coprecipitation
method or the neutralization method where changes
in medium pH is used to decrease the aqueous solubility of a drugcyclodextrin complex.84 Other methods
can be used for production of solid drugcyclodextrin
complexes on industrial scale.85 These include, especially for $-cyclodextrin, the slurry method, where the
cyclodextrin and the poorly soluble drug are mixed
thoroughly in an aqueous slurry, the kneading method
(also called the paste method), where cyclodextrin and
drug are kneaded in presence of small amount of water to form paste that is then dried, and the grinding method, where solid drugcyclodextrin complexes
are prepared from a dry mixture of the two components. The previously described methods can be used
to enhance the CE when solid drugcyclodextrin complexes are being prepared, at least as long as some water is present during the preparation. However, other
methods that, for example, temporarily increase S0
during preparation of the solid complexes have also
been applied.
Heating
Heating of an aqueous drug suspension, in an autoclave or in an ultrasonic bath, during laboratory-scale
DOI 10.1002/jps

CYCLODEXTRINS AS FUNCTIONAL EXCIPIENTS

3029

preparation of solid drugcyclodextrin complexes accelerates the drug dissolution and frequently results in formation of a supersaturated drug solution
upon cooling to room temperature.86 Heating during
the preparation of solid drugcyclodextrin complexes
by the slurry and kneading methods will also promote complex formation and enhance the CE. The
heating will not only increase the drug solubility
(increase S0 ) but also the solubility of poorly soluble
cyclodextrins such as that of the natural "-, $-, and
(-cyclodextrins, both of which will improve the complexation and shorten the time needed for the solid
complex preparation.87

words, the triclosan$-cyclodextrin complex is thermodynamically unstable. When the complex is dissolved, the energy of the system will be lowered by
expelling triclosan molecules from the complex, formation of supersaturated triclosan solution, and
eventually reaching equilibrium solubility (Fig. 7).
Similar observations were made when cyclodextrin
complexes of basic drugs were prepared in aqueous
acetic acid solutions. However, acetic acid has much
lower vapor pressure (16 Torr at 25 C) and, thus, it is
more difficult to remove the acid from the dry complexes than ammonia.90

Preparation of Metastable Complexes

CYCLODEXTRIN AND SUPERSATURATION

The CE of poorly soluble acidic and basic drugs

can be temporarily increased through ionization of
the drug (i.e., increasing S0 ) in aqueous medium
by addition of a volatile base or a volatile acid,
respectively.8890 After the complex formation, the
base or acid is removed during the drying process,
resulting in formation of unionized drugcyclodextrin complex. The complex thus formed is metastable
and rapidly dissociates upon dissolution in aqueous media, frequently forming supersaturated drug
solutions. Figure 7 shows the dissolution profiles
for metastable triclosan$-cyclodextrin complex, conventional triclosan$-cyclodextrin complex, and pure
triclosan.90 Triclosan is a weak acid (pKa 7.9) and
ammonia is a volatile base (vapor pressure 7400 Torr
at 25 C). When the triclosan$-cyclodextrin complex
was prepared in aqueous ammonia solutions, ionization of triclosan increased its solubility and, consequently the CE. The ammonia was then removed
during lyophilization of the complexation medium
producing $-cyclodextrin complexes of the unionized
triclosan, which has much lower CE than the ionized
form. However, the unionized triclosan is unable to
leave the complex while it is in a solid state. In other

As was suggested in the sections above, cyclodextrins

can contribute to dosage form design and efficacy not
only through mechanisms associated with inclusion
and noninclusion interactions but also in their ability to influence the tendency of the dissolving drug to
supersaturate as well as to stabilize the formed supersaturated solution.9193 To that end, cyclodextrin can
play a significant role in the spring and parachute
design approach inherent in the creation of supersaturating drug delivery systems.91 In this conceptual
framework, a drug is converted to a higher energy
or more rapidly dissolving form such that it generates drug concentrations in excess of its thermodynamic solubility. The formed metastable supersaturated system then needs to be stabilized using excipients that inhibit drug nucleation or crystal growth.
This physically stabilized system should provide for
an increased drug level for a long enough period so
that significant drug absorption can take place. Formulation springs may include water-miscible organic
solvents, lipids, salts and cocrystals, polymorphs, the
amorphous phase, or a solid amorphous dispersion.91
Cyclodextrin can encourage spring behavior as suggested above as well as through their ability to act
as useful matrix elements into which the amorphous
form might be dispersed. This has been exploited by
the use of solvent- (i.e., spray drying) and melt-based
(i.e., melt extrusion) processing approaches.94 System components, which may act as precipitation inhibitors, include cellulosic and other polymers, surfactants, and cyclodextrins. The ability of cyclodextrins
to act as parachutes, that is to limit nucleation rate
or crystal growth, is well advanced in the literature,
although the exact mechanism has yet to be defined
in detail.88,92,9597 In any case, cyclodextrins, distinct
from their ability to complex drugs, have shown to
stabilize formed supersaturated solution and as such
to improve the oral bioavailability for poorly watersoluble drugs.92 Cyclodextrins, thus, offer the useful
and potentially synergistic property of acting as both
the glassy carrier in an amorphous solid dispersion
as well as the formulation component that sustain

Figure 7. Dissolution profile of metastabile triclosan

$CD complex (), conventional complex (), and pure triclosan () at ambient temperature. The dissolution medium
was 0.01 M aqueous pH 4.5 acetate buffer solution. Based
on Ref. 90.
DOI 10.1002/jps

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 9, SEPTEMBER 2012

3030

LOFTSSON AND BREWSTER

supersaturation once formed from the dissolving

dosage form.

CONCLUSIONS
Cyclodextrins are important functional excipients
that are used in over 40 marketed products in various global regions. The continuing exploitation of
these materials is evidenced by not only new products
using these materials for traditional reasons, that is
solubility or bioavailability modification, but also new
cyclodextrins with highly specialized actions such as
R
product (Merck, New
sugammadex in the Bridion
Jersey), which acts to remove neuromuscular blockers such as rocuronium or vecuronium, resulting in
a termination of their action. Expanding the use of
cyclodextrins in oral dosage forms will require mechanisms to limit their amounts as otherwise formulation bulk becomes limiting. Techniques that may be
interesting in this regard include those that impact
both apparent drug solubility as well as the efficiency
by which the drug interacts with the cyclodextrin
molecule. The use of drug salts, polymers, and cosolvents may be useful to varying degrees in this regard.
In addition, processing approaches that may make cyclodextrins function better solubilizers should be considered and include the use of heat during processing
as well as volatile bases, acids, and processing solvents. Finally, considering overarching formulation
concepts such as supersaturation may further help
in the optimal use and placement of cyclodextrin in
solid oral dosage forms.

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