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Cyclodextrins as Functional Excipients: Methodsto Enhance
Complexation Efficiency
THORSTEINN LOFTSSON,1 MARCUS E. BREWSTER2
1Faculty of Pharmaceutical Sciences, University of Iceland,
IS-107 Reykjavik, Iceland
2Pharmaceutical 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 everincreasing list of beneficial
properties and functionalities. Although their use in liquid
dosageforms including oral and parenteral solutions is
straightforward, their application to solidscan be confounded by
the added bulk that is contributed to the formulation. This factor
haslimited 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
theircomplexation efficiency (CE) may expand the use of these
materials to the increasing list of drugcandidates andmarketed
drugs whomay benefit from this technology. This brief review
assessestools and materials that have been suggested for increasing
the CE for pharmaceutically usefulcyclodextrins and drugs. The
relative importance of impacting the drug solubility (S0)
andphase-solubility isotherm slope is discussed in the context of
drug ionization and salt use; theimpact of polymers, charge
interactions, and charge shielding; and the coincidental formation
ofother complex types in the media. The influence of drug form as
well as supersaturation is alsodiscussed in the context of the
responsible mechanisms along with aggregation, inclusion,
andnoninclusion complex formation. 2012 Wiley Periodicals, Inc. and
the American PharmacistsAssociation J Pharm Sci 101:30193032,
2012Keywords: cyclodextrin; complex; solubilization; complexation
efficiency; dissolution;solubility; preformulation; inclusion
compounds
INTRODUCTION
Cyclodextrins are pharmaceutical excipients thatcan solubilize
various poorly soluble drugs throughthe formation of water-soluble
drugcyclodextrincomplexes. Cyclodextrins are cyclic
oligosaccharidescontaining six, seven, or eight ("-1,4)-linked
D-glucopyranoside units (giving rise to "-, $-, and (-cyclodextrin,
respectively). These three so-called par-ent cyclodextrins, as well
as their complexes, canhave somewhat limited solubility in water,
espe-cially in the case of $-cyclodextrin. Thus, a num-ber of
water-soluble chemically modified cyclodextrinderivatives have been
synthesized.16 Cyclodextrinsand cyclodextrin derivatives of
pharmaceutical in-terest are depicted in Table 1. Cyclodextrins
gener-ally have a rather favorable toxicological profile, es-
Correspondence to: Thorsteinn Loftsson (Telephone:
+354-525-4464; Fax: +354-525-4071; E-mail: [email protected])Journal
of Pharmaceutical Sciences, Vol. 101, 30193032 (2012) 2012 Wiley
Periodicals, Inc. and the American Pharmacists Association
pecially in comparison to other pharmaceutical ex-cipients, such
as surfactants, water-soluble polymers,and organic solvents.3,7,8
Because of their generationby bacterial digestion of starch; their
hydrophilicity(log Koctanol/water), which is in most cases less
than7; their high molecular weight (MW); and the largenumber of
hydrogen donors and acceptors, the oralbioavailability of
cyclodextrins is very low mean-ing that they act as true drug
carriers. Toxicologi-cal studies have shown that orally
administered cy-clodextrins are practically nontoxic because of
theirlow absorption into the systemic blood circulation.8,9
Even when given via parenteral administration, hy-drophilic
cyclodextrins are primarily eliminated un-changed from the body via
renal excretion with a totalplasma clearance that is close to
glomerular filtrationrates.7,1012 In patients with normal kidney
function,about 90% of the cyclodextrin will be excreted within6h
and about 99% within 12h after intravenous ad-ministration.
Cyclodextrins are listed in a number ofpharmacopoeias and are
accepted as pharmaceutical
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Table 1. Some Cyclodextrins That Can be Found in Commercial
Pharmaceutical Products69
Cyclodextrin MSa Synonyms MW (Da)Oral Bioavailability
in Rats (%)Solubility in Water at Room
Temperature (mg/mL)Current Usage inMarketed Products
"-Cyclodextrin Alfadex 973 1 145 Oral and
parenteralformulations.
$-Cyclodextrin Betadex 1135 0.6 18.5 Oral, buccal, and
topicalformulations.
2-Hydroxypropyl-$-cyclodextrin
0.65 Hydroxypropylbetadex 1400 3 >600 Oral, parenteral,
rectal,and ophthalmicformulations.
Sulfobutylether$-cyclodextrinsodium salt
0.9 2163 1.6 >500 Parenteral formulations.
Methylated$-cyclodextrin
1.8 1312 12 >600 Ophthalmic and nasalformulations.
(-Cyclodextrin Gammadex 1297 0.02 232 Parenteral
formulation.2-Hydroxypropyl-
(-cyclodextrin0.6 1576 600 Parenteral and ophthalmic
formulations.
aThe 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 regula-tory agencies.
For example, monographs for the par-ent "-, $-, and (-cyclodextrin
can be found in theUnited States Pharmacopoeia (USP)/National
For-mulary and all three are included in the US Foodand Drug
Administration (FDA) generally recog-nized as safe list.
2-Hydroxypropyl-$-cyclodextrin iscompendial in the USP and European
Pharmacopoeiaand both 2-hydroxypropyl-$-cyclodextrin and
sul-fobutylether $-cyclodextrin are cited in the FDAs listof
pharmaceutical ingredients. Furthermore, thesecyclodextrins have
gained similar status in both Eu-rope and Japan. Currently,
cyclodextrins can be foundin over 35 commercially available drug
products, in-cluding tablets, parenteral solutions, eye drops,
oint-ments, and suppositories.6
A major obstacle to pharmaceutical exploitationof cyclodextrins
is their formulation bulk. In soliddosage forms, cyclodextrin can
only be used as sol-ubility enhancers for potent drugs and drugs
withmedium potency and only if these drugs have rela-tively high
complexation efficiency (CE) (Table 2). TheCE of a poorly soluble
lipophilic drug can range from
zero, when no complexation is observed, to infinity,when every
cyclodextrin molecule present in solutionforms a complex with the
drug. Importantly, the valueof the CE in aqueous media is rarely
greater than 1.5with an average value of about 0.3, indicating that
onaverage only about one out of every four cyclodextrinmolecules
present in a given complexation mediumis in a complex with a drug
molecule.13 The formula-tion bulk of low potency drugs and drugs
displayinglow CE will often be too large for a single dose
tablet(Table 3). Frequently, an increase in the drugcy-clodextrin
complexmolar ratio will lead to an increasein drug bioavailability.
Optimum drug bioavailabil-ity is frequently obtained with a minimum
amountof cyclodextrin, that is, by including material suffi-cient
to produce desired effect but avoiding excessamounts of
cyclodextrin. Thus, enhancement of theCE is of importance to
pharmaceutical formulators.Here, methods that can be applied to
enhance the CEare reviewed. Although the examples used relate
tocyclodextrin containing media, many of these samemethods can be
applied to other complexing agentsand other types of
solubilizers.
Table 2. The Relationship Between Drug Potency, Complexation
Efficiency (CE), and Formulation Bulk, that is the Weight of
aDrugCyclodextrin (DCD) Complex Containing the Drug Dose, Assuming
Drug Molecular Weight of 400Da and That of theCyclodextrin to be
1400Da
The Weight of a Dry Complex Containing the Drug Dose
Drug DoseCE = with DCDMolar Ratio of 1:1
High CE with DCDMolar Ratio of 1:2
Medium CE with DCDMolar Ratio of 1:4a
High potency drug (5mg) 23mg 35mg 70mgMedium potency drug (50mg)
230mg 350mg 700mgLow potency drug (500mg) 2300mg 3500mg 7000mg
aThe 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 areforming drug complex assuming 1:1 DCD
complex formation.13
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Table 3. The Relationship Between the Drug Dose, Complexation
Efficiency (CE), and the Dosage Bulk upon Complexation
with2-Hydroxypropyl-$-Cyclodextrin (MW 1400Da)
Drug MW (Da)Common OralDose (mg) S0 (mg/mL) Slope K1:1 (M1)a
CEb
DCD MolarRatioc
Dosage Bulk(mg)
Acetazolamide 222.2 250 0.64 0.197 85 0.246 1:5 8200Alprazolam
308.8 0.25 0.07 0.055 250 0.058 1:18 20Digoxin 780.9 0.05 0.99
0.303 6800 0.435 1:3 0.3Econazole 381.7 150 0.37 0.145 180 0.170
1:7 3200Flunitrazepam 313.3 1 0.00 0.110 1100 0.010 1:100
450Miconazole 416.1 1000 0.09 0.080 260 0.087 1:12 42,000Naproxen
230.3 500 0.12 0.282 780 0.393 1:4 13, 000Sulfamethoxazole 253.3
800 0.39 0.359 360 0.561 1:3 14,000Triazolam 343.2 0.25 0.03 0.017
200 0.017 1:60 60
aAccording to Eq. 9.bAccording to Eq. 12.cAccording 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.
CYCLODEXTRIN COMPLEXES AND AQUEOUSSOLUBILITY
In aqueous solutions, cyclodextrins form inclusioncomplexes with
poorly water-soluble drugs by takingup a lipophilic moiety of the
drug molecule into thesomewhat hydrophobic central cavity of the
cyclodex-trin (Fig. 1). In dilute solutions, such inclusion
com-plexes are dominating or even the only form of drugcyclodextrin
superstructure. However, cyclodextrinsare also known to form
noninclusion drugcyclodex-trin complexes.1421 As the cyclodextrin
concentrationincreases, the cyclodextrin molecules and their
com-plexes self-assemble to form aggregates that oftenrange in size
between 20 and 100nm in diameter.2126
The aggregation and the size of the aggregates in-creases with
increasing cyclodextrin concentration.Excipients that solubilize
and stabilize aggregates,such as small ionized molecules (e.g.,
salts of organicacids and bases) and water-soluble polymers (e.g.,
cel-lulose derivatives) can improve the magnitude of theCE. To
explain themechanisms underlying this effect,we first need to
review briefly the phase-solubility the-ory of Higuchi and
Connors,27 understanding that thetheory is based on the formation
of soluble complexes,be the inclusion, noninclusion, or a
combination of thetwo. Furthermore, the relationship is not
indicative
Figure 1. Schematic drawing of a drugcyclodextrin com-plex
formation and self-assemble of complexes to form com-plex
aggregate.
of what form the complexes are, that is, individualcomplexes or
complex aggregates; only that they arewater soluble.
The Phase-Solubility Theory
If m drug molecules (D) associate with n cyclodex-trin molecules
(CD) to form a complex (DmCDn), thefollowing equilibrium is
suggested18,27:
m D + n CDKm:n DmCDn (1)
where Km:n is the stability constant (also known asbinding
constant, formation constant, or associationconstant) of the
substrateligand (or guesthost) com-plex. The stability constant can
be written as follows:
Km:n =[DmCDn
]
[D]m [CD]n (2)
where the brackets denote molar concentrations. Ingeneral,
higher order complexes are formed in a step-wise fashion where a
1:1 complex is formed in the firststep, 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 writtenas
follows:
K1:1 =[D/CD
]
[D] [CD] (5)
K1:2 =[D/CD2
]
[D/CD
] [CD] (6)
If the intrinsic drug solubility, that is, the drug sol-ubility
in the aqueous complexation media when no
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cyclodextrin is present, is given as S0 and a formedcomplex is
represented by D/CD, then
[D] = S0 (7)
[D]T = S0 + [D/CD] (8)
where [D]T represents the total drug solubility, as-suming 1:1
DCD complex formation according toEqs. 3 and 5. A plot of [D]T
versus [CD]T for the forma-tion of 1:1 DCD complex should give a
straight linewith the y-intercept representing S0 and the
slopedefined as follows:
K1:1 = SlopeS0 (1 Slope) (9)
If one drug molecule (n = 1) forms a complex withtwo
cyclodextrinmolecules (m= 2), then the followingequations
apply:
[D]T = S0 + [D/CD] + [D/CD2] (10)
[D]T = S0 +K1:1 S0 [CD] +K1:1 K1:2 S0 [CD]2 (11)
indicating that a plot of [D]T versus [CD]T (assumingthat [CD]
([D/CD] + 2 [D/CD2]) or [CD] [CD]T)fitted to the quadratic
relationship will allow for theestimation of K1:1 and K1:2.
Dissolved drug molecules can form water-solubledimers, trimers,
and higher order aggregates as wellas be associated with other
excipients present in theaqueous complexation media. Frequently,
only indi-vidual drug molecules can form complexes with dis-solved
cyclodextrin molecules. Dimers, trimers, andwater-soluble oligomers
are often unable to form cy-clodextrin complexes.13 Under such
conditions, the y-intercept will not be equal to S0 and this can
causeconsiderable error in the value of K. A more accuratemethod
for determination of the solubilizing effect ofcyclodextrins is to
determine their CE, that is, theconcentration ratio between
cyclodextrin in a complexand free cyclodextrin. CE is calculated
from the slopeof the phase-solubility diagrams, is independent
ofboth S0 and the intercept, and is more reliable whenthe
influences of various pharmaceutical excipientson the
solubilization are being investigated. For 1:1DCD complexes, the CE
is calculated as follows:
CE =[D/CDn
]
[CD
] = S0 K1:1 = Slope(1 Slope) (12)
And the drugcyclodextrin molar ratio in a particularcomplexation
media saturated with the drug can becalculated from the CE:
D :CDmolar ratio = 1 : (CE + 1)CE
(13)
Equation 13 shows that CE of 1.0 gives D:CD mo-lar ratio of 1:2
and CE of 5.0 gives molar ratio of 4:5.Examples of CE in pure
aqueous solutions at roomtemperature are shown in Table 3. Table 3
shows thatthe value of K1:1 for the acetazolamideHP$CD com-plex in
pure water at room temperature is 85M1,indicating that about 90% of
the HP$CD moleculeswill be in a complex in an unsaturated aqueous
solu-tion containing equimolar amounts of acetazolamide(MW 222.2Da)
and HP$CD (MW 1400 Da). How-ever, in 20% (w/v) HP$CD aqueous
solution (i.e.,0.14M) saturated with the drug ([D] = constant= S0 =
0.003M), only about 20% of the HP$CDmolecules, or one out of every
five HP$CD molecules,will be complexed with acetazolamide. This
solu-tion can be lyophilized to produce a solid powder
ofacetazolamideHP$CD complex. Tablets of acetazo-lamide commonly
contain 250 mg of the drug thatcorresponds to 8200 mg of the
acetazolamideHP$CDcomplex powder. Even if the CE can be enhanced
toproduce a acetazolamideHP$CD (1:1) dry complexpowder, the
formulation bulk of this medium to lowpotency drug would be very
high (i.e., 1250mg).
ENHANCING THE CE
The CE is the product of the apparent solubility ofthe poorly
soluble drug in the complexation media(assumed to be S0 in Eq. 12)
and the apparent stabil-ity constant of the complex (K1:1),
assuming formationof 1:1 drugcyclodextrin complex. Thus, according
toEq. 12, the CE can be increased by either increasingthe value of
S0 or the value of K1:1, or both valuessimultaneously. In many
cases, the true magnitudesof S0 and K1:1 remain constant while
their apparentvalues increase. For example, the intrinsic
solubil-ity of an acid is the solubility of its unionized form(HA),
but the apparent solubility at a given pH isthe total solubility,
that is, of both the unionized andionized species ([HA]T = [HA] +
[A]). Likewise, theapparent solubility of a metastable amorphous
drugis much higher than the equilibrium solubility of
itscrystalline form. Thus, itraconazole is converted to
itsamorphous form to enhance its cyclodextrin solubi-lization in
parenteral and oral solutions.6 Cocrystalsand polymorphic forms can
also result in enhancedapparent solubility and better cyclodextrin
solubiliza-tion of poorly soluble drugs. As cyclodextrins and
cy-clodextrin complexes are able to self-assemble andsolubilize
drugs in micellar-like fashion, pharmaceu-tical excipients that
stabilize and solubilize nanopar-ticles and micelles, such as
polymers and low MWorganic acids, are also able to enhance the CE.
Fre-quently, such enhancement is associated with appar-ent increase
in the value of K1:1.
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Figure 2. A pH-solubility profile in pure water and a
phase-solubility profile for phenytoin inaqueous buffer solutions
containing 0%6% (w/v) 2-hydroxypropyl-$-cyclodextrin (HP$CD) at25C.
The figures and table are based on data from Ref. 28 and
unpublished results.
Drug Ionization
Normally, the more lipophilic unionized form of agiven drug
molecule has a greater affinity for thesomewhat hydrophobic
cyclodextrin cavity than theionized form and, thus, the unionized
form has ahigher K1:1 value. However, ionization of a
poorlywater-soluble drug will increase the S0 value andif the
increase in S0 is greater than the decrease inK1:1, then an
increase in the CE will be observed (seeEq. 12). For example,
phenytoin is a poorly solubledrug with a pKa value of 8.06 in pure
water at roomtemperature.28 Unionized phenytoin has CE of
0.08,indicating that in aqueous solutions only one out ofevery 15
cyclodextrin molecules forms a complex withphenytoin (Fig. 2).
Thus, cyclodextrin solubilization ofphenytoin in aqueous
formulations was not practicaland the only way to prepare a
parenteral phenytoinsolution was to use mixture of water and
organic sol-vents and at the same time increase the pH to
valuesabove 10.29 Increasing the pH from acidic to 7.55 re-sults in
partial (about 24%) ionization of the drugand consequently
increases the S0. This, in turn, in-creases the CE from 0.08 to
0.15 with one out of everyeight cyclodextrin molecules forming a
complex withthe drug. Increasing the pH further to 11 results
inalmost complete (over 99%) ionization of the drug andincrease in
the CE to 14, meaning that almost everycyclodextrin molecule in the
solution forms a complexwith the drug. The ionized forms of all
four drugsshown in Table 4 have lower K1:1 value than the
cor-responding unionized forms. The ionization increasesthe S0
value but decreases the K1:1, but the increase
in S0 is more than sufficient to compensate for thedecrease in
K1:1. The result is in all cases an increasein the CE.
Salt Formation
Salt formation of acidic and basic drugs is the mostcommon
method of increasing aqueous solubility dur-ing drug development.35
The solubility of the salt isgoverned by the solubility product
constant of thesalt, the solubility of the unionized drug, and the
pKavalue. The counterion can originate from the drugsalt or it can
be adventitiously present in the aqueoussolution as, for example, a
buffer salt. As a free base,carvedilol (pKa 7.8) has aqueous
solubility of less than1:g/mL (pH > 9) but its solubility
increases to about0.1mg/mL (pH < 5) upon protonization.36 The
coun-terion present in an aqueous carvedilol solution willalso have
a significant effect on the solubility. Thecarvedilol solubility at
pH values below 4 is five timesgreater in aqueous acetic acid
solution than in aque-ous phosphoric acid solution (Fig. 3). This
differencein aqueous solubility affects the cyclodextrin
solubi-lization of the drug. Thus, the CE of HP$CD is only0.05 in
the aqueous phosphoric acid solution but 1.62in the acetic acid
solution. Other examples of CE en-hancement as a function of salt
selection are shown inTable 5. In general, but not in every
instance, themostsoluble salt possesses the highest CE. It has been
sug-gested that in some cases the counterions participatedirectly
in complex formation; that is, that in somecases, a ternary
drugcyclodextrinsalt complex is be-ing formed.39,37,40,41 Some
organic acids, especially
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Table 4. The Effect of Drug Ionization on the Complexation
Efficiency (CE) and on the Value of the DrugCyclodextrin
K1:1Stability Constant at Room Temperature
Effect of pH on CE
Unionizeda Ionizeda K1:1 (M1)
Drug Structure pKa Cyclodextrin pH CE pH CE Unionized Ionized
ReferencesFlavopiridol(Alvocidib)
Base 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 See Fig. 2
HP$CD 7.4 0.1 11.0 14 1215 352 34SBE$CD 7.4 0.1 11.0 14 1267 476
34
aThe drug is either partly or fully unionized/ionized at the
given pH.
hydroxy acids such as citric and tartaric acid, areknown to
increase the aqueous solubility of the poorlysoluble $-cyclodextrin
possibly through modifica-tion of intramolecular and intermolecular
hydrogen-bonding system of $-cyclodextrin.42 However, thesolubility
enhancement can also be related to the ten-dency of cyclodextrins
and their complexes to self-assemble in aqueous solutions to form
nano-sizedaggregates.2125
Salts and Neutral Drugs
Addition of small amount of sodium acetate toaqueous media
containing hydrocortisone and $-cyclodextrin results in an over
threefold enhance-ment in hydrocortisone solubility (Fig. 4)
andlikewise sodium salicylate enhances $-cyclodextrinsolubilization
of hydrocortisone and vice versa(Fig. 5). Such increases in
solubilization throughcomplexation of a neutral drug
(hydrocortisone) andneutral $-cyclodextrin cannot be explained by
salt
formation, and the salicylate ion is too large to enterthe
cyclodextrin cavity coincidently with hydrocorti-sone to form a
ternary complex. More likely expla-nation is that these ions
participate in the formationof water-soluble drugcyclodextrin
aggregate that aretoo small to scatter light in aqueous solutions.
Forma-tion of such ternary complexes is sometime observedas an
increase in the K1:1 value. Hydroxyaromaticacids are also well
known complexing agents capableof participating in ternary
complexes.44
Water-Soluble Polymers
Water-soluble polymers are known to enhance the CEof
cyclodextrins.4547 Both the polymers and cyclodex-trins can form
water-soluble complexes with poorlysoluble, lipophilic drugs but
when used in combina-tion, a synergistic solubilization effect is
observed,that is, the apparent drug solubility is greater thanthe
sum of polymer and cyclodextrin solubilization
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Table 5. Effects of Counterions (Salts) on the Cyclodextrin
Solubilization at Room Temperature
Drug pKa Counterion Solubility (mg/mL)a Cyclodextrin K1:1 (M1)
CE References
Econazole (base) 6.6 None 0.005 "CD 2630 0.04 37Nitrate 0.48
Citrate 3.50 "CD 130 1.1Gluconate 2.70 "CD 169 0.5Lactate 3.35 "CD
103 0.9Maleate 1.70 "CD 448 1.9Tartrate 0.95 "CD 429 1.0
Manidipine (base) 5.4, 8.2 None 0.001 $CD 20,000 0.03
38Hydrochloride 0.33 Citrate 0.48 $CD 500 0.3Tartrate 0.64 $CD 450
0.4
Naproxen (acid) 4.2 None 0.03 HP$CD 665 0.9 31,32,39Arginine
2.20 HP$CD >5
Aqueous media
pH
CE
D:CD molar ratio
Dilute phosphoric acid 3.7 0.05 1:23
Dilute acetic acid 3.7 1.62 1:2
Figure 3. A pH-solubility profile of carvedilol in diluteaqueous
hydrochloride (HCl), phosphoric acid (H3PO4), andacetic acid
(CH3COOH) solutions at 25C. The table showsthe complexation
efficiency (CE) and the carvedilolHP$CDmolar ratio (D:HP$CD) in
aqueous HP$CD solution satu-rated with carvedilol. The figure and
table are based ondata from Ref. 36.
when assessed individually. The maximum CE is typ-ically
obtained at relatively low polymer concentra-tions or between 0.1%
and 1% (w/v).45,48 The effect ofwater-soluble polymers on
cyclodextrin solubilizationof drugs has been reviewed.47 Some more
recent ex-amples are shown in Table 6. Table 6 shows that
theenhancement of CE is due to an increase in the ap-parent
stability constant of the complex (K1:1). Water-soluble polymers
are known to form water-solublecomplexes with poorly soluble
drugs.5558 However,only free drug molecules, that is, molecules not
boundto polymers, are able to form complex with cyclodex-trins. In
aqueous polymer solutions saturated with agiven drug, the
concentration of free drug is equal tothe solubility of the drug in
the pure aqueous media.
Figure 4. The phase solubility of hydrocortisone in aque-ous
$-CD solutions or suspensions at room temperature(22C23C). Pure
water () and aqueous 1% (w/v) sodiumacetate solution (). The figure
is based on data from Ref. 43.
Figure 5. The phase solubility of hydrocortisone inaqueous
sodium acetate solutions at room temperature(22C23C). Pure water ()
and aqueous 4% (w/v) $-CDsuspension (). The figure is based on data
from Ref. 43.
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Table 6. Effects of Water-Soluble Polymers on the Cyclodextrin
Solubilization at Room Temperature
Drug pKa pH Cyclodextrin Polymer K1:1 (M1) CE References
Acetazolamide 7.2 Water HP$CD 85 0.25 130.25% (w/v) HPMC 120
0.360.25% (w/v) NaCMC 72 0.210.25% (w/v) PVP 95 0.27
Carbamazepine 7.0 Water HP$CD 630 0.68 130.25% (w/v) HPMC 760
0.830.25% (w/v) NaCMC 650 0.710.25% (w/v) PVP 650 0.70
Celecoxib 9.7 Water HP$CD 635 0.006 490.5% (w/v) PVP 909
0.0080.5% (w/v) HPMC 819 0.0070.5% (w/v) PEG 4000 728 0.006
Dexamethasone Water (CD 1210 0.26 50
0.25% (w/v) HPMC 2620 0.860.25% (w/v) NaCMC 3330 0.760.25% (w/v)
HDMBr 3830 0.97
Daidzein 7.5 Water HP$CD 1410 0.015 511% (w/w) HPMC 1490 0.0161%
(w/w) PVP 1750 0.019
Famotidine 6.8 Water $CD 650 1.7 520.75% (w/v) HPMC 19,000
50
Irbesartan 4.7 Water $CD 130 0.06 531% (w/v) PEG 4000 159 0.071%
(w/v) PVP 201 0.09
Naproxen 4.2 1.1 $CD 3270 0.15 54$CD 0.1% (w/v) NaCMC 3930
0.18$CD 0.1% (w/v) PVP 4110 0.19
4.0 $CD 1890 0.18$CD 0.1% (w/v) NaCMC 2290 0.22$CD 0.1% (w/v)
PVP 2350 0.23
6.5 $CD 210 1.2$CD 0.1% (w/v) NaCMC 230 1.3$CD 0.1% (w/v) PVP
260 1.5
1.1 HP$CD 4890 0.22HP$CD 0.1% (w/v) NaCMC 6340 0.29HP$CD 0.1%
(w/v) PVP 7030 0.32
4.0 HP$CD 2610 0.26HP$CD 0.1% (w/v) NaCMC 3620 0.35HP$CD 0.1%
(w/v) PVP 4130 0.40
6.5 HP$CD 230 1.3HP$CD 0.1% (w/v) NaCMC 322 1.8HP$CD 0.1% (w/v)
PVP 368 2.1
Pregnenolone Water HP$CD 1200 0.12 130.25% (w/v) HPMC 2800
0.290.25% (w/v) NaCMC 1000 0.110.25% (w/v) PVP 2200 0.23
Sulfamethoxazole 5.7 Water HP$CD 360 0.56 130.25% (w/v) HPMC 220
0.340.25% (w/v) NaCMC 400 0.620.25% (w/v) PVP 780 1.2
$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 moleculesshould not be
affected by the polymers and S0 in Eq.12 would be expected to be
constant. The observedincrease in CE is due to an increase in the
K1:1 value(Table 6).
It is known that water-soluble polymers, as wellas surfactants,
are able to stabilize self-assemblednanostructures.59 Polymers
stabilize and enhance thesolubilizing effects of micelles, and
polymers are used
to stabilize particulated pharmaceutical systems ofvarious
types.6062 Water-soluble polymers are alsoknown to enhance aqueous
solubility of cyclodex-trins and cyclodextrin complexes.63
Furthermore, cy-clodextrins have been reported to solubilize
poorlysoluble compounds through formation of aggregatesor
micellar-like structures2125 and the solubilizingeffect of some
cyclodextrin complexes exceeds thatof the corresponding pure
cyclodextrin.43,64 These
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CYCLODEXTRINS AS FUNCTIONAL EXCIPIENTS 3027
observations together with the fact that the enhance-ment in CE
is due to an increase in the apparent sta-bility constant of the
complex suggest that the poly-mers enhance the stability of the
cyclodextrin complexaggregates and perhaps the ability of the
aggregatesto solubilize poorly soluble drugs through micellar-type
solubilization.21
Cosolvents
Organic cosolvents increase aqueous solubility of non-polar
drugs by reducing the hydrogen bond density inthe aqueous mixture
and thereby reducing the abil-ity of water to squeeze out nonpolar
drugs.65 Co-solvents such as ethanol can enhance the apparentS0 and
this will, like in the case of drug ionization,lead to enhanced CE.
On the contrary and as in thecase of drug ionization, addition of
organic solventsto the aqueous complexation media will decrease
thevalue of K1:1. In case of ionization, the decrease is dueto
decreased lipophilicity of the drug or drug moietyentering the
somewhat lipophilic cyclodextrin cavity.In case of organic
cosolvents, the apparent K1:1 de-creases due to decreased polarity
of the aqueous com-plexation media. The polarity of the cavity has
beenestimated to be similar to that of an aqueous ethano-lic
solution.66 The dielectric constant () of the parent$-cyclodextrin
cavity has been determined to be 48or about equal to that of 55%
(v/v) ethanol in wa-ter at 25C.67 The tendency of the drug molecule
toenter the cyclodextrin cavity decreases with decreas-ing polarity
(decreasing ) of the complexation media.Cosolvent molecules may
participate in the complex-ation through formation of
drugcyclodextrincosol-vent ternary complexes or hamper complexation
bycompeting with the drug for a space in the cavity.Thus,
cosolvents can both increase and decrease cy-clodextrin
solubilization of drugs and their effect isconcentration
dependent.6871
Table 7 shows the effect of ethanol concentrationon the
cyclodextrin solubilization of fluasterone inethanolwater mixtures.
The value of the apparentstability constant (K1:1) of the
fluasteroneHP$CDcomplex decreases with increasing ethanol
concentra-tion but Figure 6 shows that although the
fluasteronesolubility in aqueous HP$CD solution decreases
withincreasing ethanol concentration at low ethanol
con-centrations, it increases at ethanol concentrationsabove about
40% (v/v). This initial decrease and thenincrease is due to changes
in the CE (CE = S0 K1:1, Eq. 12). At low ethanol concentrations,
the valueof 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 anU-shaped solubility curve with a
minimum at about25% (v/v) ethanol solution. Table 7 and Figure 6
em-phasize the fact that in aqueous solutions, CE is a
Table 7. The Effect of Ethanol on
the2-Hydroxypropyl-$-Cyclodextrin (HP$CD) Complexation
ofFluasterone at 25C,
CE = S0 K1: 1Ethanol Conc. (%, v/v) a K1:1 (M1) CE
0.0 79 180,000 0.0280.2 78 200,000 0.0311.0 78 180,000 0.0286.3
76 61,000 0.022
12.5 73 18,000 0.01518.8 70 7500 0.01525.6 67 3000 0.01437.6 62
660 0.01950.1 55 110 0.01562.7 49 34 0.02575.2 43 7 0.030
aThe dielectric constant () of the ethanolwater mixtures
wascalculated as the weighted average of that for pure water ( =
78.5) andpure ethanol ( = 24.3) at 25C.
K1:1 is the apparent stability constant of the fluasteroneHP$CD
1:1complex in the aqueous ethanol solution and CE is the
complexationefficiency. The values were determined from
experimental data presentedin Refs. 69 and 70.
better indicator of the cyclodextrin solubilization ofpoorly
soluble drug than K1:1.
ChargeCharge Interaction
Because of chargecharge attraction, the negativelycharged
sulfobutyl ether $-cyclodextrin frequently in-teracts somewhat
stronger with positively chargeddrug molecules than, for example,
the unchargedHP$CD.31,72,73 Example of such enhanced
solubiliza-tion due to chargecharge interaction is the
solubi-lization of ziprasidone. The free base has very lowaqueous
solubility (about 0.3:g/mL), but it is possibleto obtain about
3000-fold solubility enhancementthrough formation of the
ziprasidone mesylate (sol-ubility 0.9mg free base per 1mL), but
still the
Figure 6. The effect of ethanol on the
2-hydroxypropyl-$-cyclodextrin (HP$CD) solubilization of
fluasterone at 25C.The figure is based on data presented in Refs.
69 and 70.
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3028 LOFTSSON AND BREWSTER
Table 8. The Effect of Counterion (Salt Form) and ChargeCharge
Interaction on K1:1 and CE of the2-Hydroxypropyl-$-Cyclodextrin
(HP$CD) and Sulfobutyl Ether $-Cyclodextrin Sodium Salt (SBE$CD)
Complexes ofZiprasidone at Ambient Temperature
HP$CD SBE$CD
Counterion Solubility in Water (mg/mL)a K1:1 (M1) CE K1:1 (M1)
CE
Free base 0.0003 2800 0.002 6700 0.005Hydrochloride 0.08 1500
0.02 4700 0.06Aspartate 0.2 20 0.009 30 0.1Tartrate 0.2 240 0.1
1200 0.5Esylate 0.5 130 0.1 280 0.3Mesylate 0.9 60 0.2 570 1.2
aThe solubility values represent free base (mg) dissolved in 1mL
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 formula-tion. Table
8 shows the effects of various counterionson the stability
constants of ziprasidonecyclodextrincomplexes and the CE.
Increasing the water solubil-ity of ziprasidone through salt
formation decreasesthe value of the apparent stability constant
and, ingeneral, the most water-soluble salts have the small-est
stability constant. However, the increased solubil-ity results in
enhanced CE. Chargecharge attractionenhanced the CE even further
and, thus, the aque-ous solubility ziprasidone mesylate in aqueous
40%(w/v) sulfobutyl ether $-cyclodextrin sodium salt cor-responds
to 44 mg of the freebase per 1mL of theunbuffered complexation
medium (pH 3.9).74
Multiple Complexes
Drugs and/or cyclodextrins are sometimes able toform
simultaneously two or more types of complexes.For example,
quinolones can both form metalion co-ordination complexes and
monomolecular inclusion-type cyclodextrin complexes.7678 Both types
of com-plexes are able to enhance the aqueous solubility
ofquinolones. However, when used in combination, asynergistic
solubilizing effect is observed.79 Appar-ently, the metal complex
increases S0, resulting inenhanced CE. Interaction of aliphatic
polyalcoholswith metalions is generally insignificant in acidicand
neutral solutions but coordination complexes canbe significant
under basic conditions where the OHgroups are ionized.
Cyclodextrins (pKa > 12) are alsoknown to form metalion
coordination complexes un-der basic conditions through
deprotonation of the OHgroups.80
As mentioned previously, hydroxy acids, and otherlow MW organic
acids, increase the aqueous solubil-ity of the poorly soluble
$-cyclodextrin.42 Most prob-ably, this enhancement is related to
the tendencyof $-cyclodextrin, and other natural cyclodextrins,to
self-assemble to form nanoparticles in aqueoussolution19,21,81,82
and the ability of these acids to solu-bilize and stabilize these
aggregates. Likewise, water-soluble polymers are able to enhance
aqueous solubil-ity of $-cyclodextrin and its complexes, most
probably
through stabilization of cyclodextrin aggregates.63,83
These polymer (drugcyclodextrin complexes) com-plexes are
molecular complexes. Other types of mul-tiple complexes are also
known such as those ofquinolones where quinolonemetal ion
complexesform complexes with cyclodextrin and these dou-ble
complexes form complexes with water-solublepolymer.79 Formation of
such multiple complexes fre-quently results in better drug
solubilization than canbe obtained by any solubilization method
used singly.
PREPARATION OF SOLIDDRUGCYCLODEXTRIN COMPLEXES
The most common methods for preparation of soliddrugcyclodextrin
complexes on laboratory scale arelyophilization or spray drying of
aqueous drugcyclodextrin complex solutions. Poorly soluble
com-plexes can an also be prepared by the coprecipitationmethod or
the neutralization method where changesinmedium pH is used to
decrease the aqueous solubil-ity of a drugcyclodextrin complex.84
Other methodscan be used for production of solid
drugcyclodextrincomplexes on industrial scale.85 These include,
espe-cially for $-cyclodextrin, the slurry method, where
thecyclodextrin and the poorly soluble drug are mixedthoroughly in
an aqueous slurry, the kneadingmethod(also called the pastemethod),
where cyclodextrin anddrug are kneaded in presence of small amount
of wa-ter to form paste that is then dried, and the grind-ing
method, where solid drugcyclodextrin complexesare prepared from a
dry mixture of the two compo-nents. The previously described
methods can be usedto enhance the CE when solid drugcyclodextrin
com-plexes are being prepared, at least as long as somewa-ter is
present during the preparation. However, othermethods that, for
example, temporarily increase S0during preparation of the solid
complexes have alsobeen applied.
Heating
Heating of an aqueous drug suspension, in an auto-clave or in an
ultrasonic bath, during laboratory-scale
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preparation of solid drugcyclodextrin complexes ac-celerates the
drug dissolution and frequently re-sults in formation of a
supersaturated drug solutionupon cooling to room temperature.86
Heating duringthe preparation of solid drugcyclodextrin complexesby
the slurry and kneading methods will also pro-mote complex
formation and enhance the CE. Theheating will not only increase the
drug solubility(increase S0) but also the solubility of poorly
solublecyclodextrins such as that of the natural "-, $-,
and(-cyclodextrins, both of which will improve the com-plexation
and shorten the time needed for the solidcomplex preparation.87
Preparation of Metastable Complexes
The CE of poorly soluble acidic and basic drugscan be
temporarily increased through ionization ofthe drug (i.e.,
increasing S0) in aqueous mediumby addition of a volatile base or a
volatile acid,respectively.8890 After the complex formation,
thebase or acid is removed during the drying process,resulting in
formation of unionized drugcyclodex-trin complex. The complex thus
formed is metastableand rapidly dissociates upon dissolution in
aque-ous media, frequently forming supersaturated drugsolutions.
Figure 7 shows the dissolution profilesfor metastable
triclosan$-cyclodextrin complex, con-ventional
triclosan$-cyclodextrin complex, and puretriclosan.90 Triclosan is
a weak acid (pKa 7.9) andammonia is a volatile base (vapor pressure
7400 Torrat 25C). When the triclosan$-cyclodextrin complexwas
prepared in aqueous ammonia solutions, ioniza-tion of triclosan
increased its solubility and, conse-quently the CE. The ammonia was
then removedduring lyophilization of the complexation
mediumproducing $-cyclodextrin complexes of the unionizedtriclosan,
which has much lower CE than the ionizedform. However, the
unionized triclosan is unable toleave the complex while it is in a
solid state. In other
Figure 7. Dissolution profile of metastabile triclosan$CD
complex (), conventional complex (), and pure tri-closan () at
ambient temperature. The dissolutionmediumwas 0.01M aqueous pH 4.5
acetate buffer solution. Basedon Ref. 90.
words, the triclosan$-cyclodextrin complex is ther-modynamically
unstable. When the complex is dis-solved, the energy of the system
will be lowered byexpelling triclosan molecules from the complex,
for-mation of supersaturated triclosan solution, andeventually
reaching equilibrium solubility (Fig. 7).Similar observations were
made when cyclodextrincomplexes of basic drugs were prepared in
aqueousacetic acid solutions. However, acetic acid has muchlower
vapor pressure (16Torr at 25C) and, thus, it ismore difficult to
remove the acid from the dry com-plexes than ammonia.90
CYCLODEXTRIN AND SUPERSATURATION
As was suggested in the sections above, cyclodextrinscan
contribute to dosage form design and efficacy notonly through
mechanisms associated with inclusionand noninclusion interactions
but also in their abil-ity to influence the tendency of the
dissolving drug tosupersaturate as well as to stabilize the formed
super-saturated solution.9193 To that end, cyclodextrin canplay a
significant role in the spring and parachutedesign approach
inherent in the creation of supersat-urating drug delivery
systems.91 In this conceptualframework, a drug is converted to a
higher energyor more rapidly dissolving form such that it
gener-ates drug concentrations in excess of its thermody-namic
solubility. The formed metastable supersatu-rated system then needs
to be stabilized using excip-ients that inhibit drug nucleation or
crystal growth.This physically stabilized system should provide
foran increased drug level for a long enough period sothat
significant drug absorption can take place. For-mulation springs
may include water-miscible organicsolvents, lipids, salts and
cocrystals, polymorphs, theamorphous phase, or a solid amorphous
dispersion.91
Cyclodextrin can encourage spring behavior as sug-gested above
as well as through their ability to actas useful matrix elements
into which the amorphousform might be dispersed. This has been
exploited bythe use of solvent- (i.e., spray drying) and
melt-based(i.e., melt extrusion) processing approaches.94 Sys-tem
components, which may act as precipitation in-hibitors, include
cellulosic and other polymers, surfac-tants, and cyclodextrins. The
ability of cyclodextrinsto act as parachutes, that is to limit
nucleation rateor crystal growth, is well advanced in the
literature,although the exact mechanism has yet to be definedin
detail.88,92,9597 In any case, cyclodextrins, distinctfrom their
ability to complex drugs, have shown tostabilize formed
supersaturated solution and as suchto improve the oral
bioavailability for poorly water-soluble drugs.92 Cyclodextrins,
thus, offer the usefuland potentially synergistic property of
acting as boththe glassy carrier in an amorphous solid dispersionas
well as the formulation component that sustain
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3030 LOFTSSON AND BREWSTER
supersaturation once formed from the dissolvingdosage form.
CONCLUSIONS
Cyclodextrins are important functional excipientsthat are used
in over 40 marketed products in var-ious global regions. The
continuing exploitation ofthese materials is evidenced by not only
new productsusing these materials for traditional reasons, that
issolubility or bioavailability modification, but also
newcyclodextrins with highly specialized actions such assugammadex
in the Bridion R product (Merck, NewJersey), which acts to remove
neuromuscular block-ers such as rocuronium or vecuronium, resulting
ina termination of their action. Expanding the use ofcyclodextrins
in oral dosage forms will require mech-anisms to limit their
amounts as otherwise formula-tion bulk becomes limiting. Techniques
that may beinteresting in this regard include those that impactboth
apparent drug solubility as well as the efficiencyby which the drug
interacts with the cyclodextrinmolecule. The use of drug salts,
polymers, and cosol-vents may be useful to varying degrees in this
regard.In addition, processing approaches that maymake
cy-clodextrins function better solubilizers should be con-sidered
and include the use of heat during processingas well as volatile
bases, acids, and processing sol-vents. Finally, considering
overarching formulationconcepts such as supersaturation may further
helpin the optimal use and placement of cyclodextrin insolid oral
dosage forms.
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JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 9, SEPTEMBER
2012 DOI 10.1002/jps