cyclodextrins as a excipient

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

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 9, SEPTEMBER 2012 3019

3020 LOFTSSON AND BREWSTER

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

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 9, SEPTEMBER 2012 DOI 10.1002/jps

CYCLODEXTRINS AS FUNCTIONAL EXCIPIENTS 3021

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

DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 9, SEPTEMBER 2012


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.



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



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



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.



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



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



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.



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



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



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.

REFERENCES

1. Loftsson T, Brewster ME. 1996. Pharmaceutical applicationsof cyclodextrins. 1. Drug solubilization and stabilization. JPharm Sci 85(10):10171025.

2. Rajewski RA, Stella VJ. 1996. Pharmaceutical applicationsof cyclodextrins. 2. In vivo drug delivery. J Pharm Sci85:11421168.

3. Irie T, Uekama K. 1997. Pharmaceutical applications of cy-clodextrins. III. Toxicological issues and safety evaluation. JPharm Sci 86(2):147162.

4. Dodziuk H, Ed. 2006. Cyclodextrins and their complexes.Weinheim: Wiley-VCH Verlag.

5. Bilensoy E, Ed. 2011. Cyclodextrins in pharmaceutics, cos-metics, and biomedicine. Current and future industrial appli-cations. Hoboken: Wiley.

6. Loftsson T, Brewster ME. 2010. Pharmaceutical applicationsof cyclodextrins: Basic science and product development. JPharm Pharmacol 62:16071621.

7. Stella VJ, He Q. 2008. Cyclodextrins. Tox Pathol 36:3042.8. Arima H, Motoyama K, Irie T. 2011. Recent findings on

safety profiles of cyclodextrins, cyclodextrin conjugates, andpolypseudorotaxanes. In Cyclodextrins in pharmaceutics, cos-metics, and biomedicine: Current and future industrial appli-cations; Bilensoy E, Ed. Hoboken: Wiley, pp 91122.

9. Loftsson T, Brewster ME. 2011. Pharmaceutical applicationsof cyclodextrins: Effects on drug permeation through biologicalmembranes. J Pharm Pharmacol 63:11191135.

10. Luke DR, Tomaszewski K, Damle B, Schlamm HT. 2010. Re-view of the basic and clinical pharmacology of sulfobutylether-$-cyclodextrin (SBECD). J Pharm Sci 99:32913301.

11. Hafner V, Czock D, Burhenne J, Riedel K-D, Bommer J, MikusG, Machleidt C, Weinreich T, Haefeli WE. 2010. Pharmacoki-netics of sulfobutylether-beta-cyclodextrin and voriconazole inpatients with end-stage renal failure during treatment withtwo hemodialysis systems and hemodiafiltration. AntimicrobAgents Chemother 54:25962602.

12. Peeters P, Passier P, Smeets J, Zwiers A, de Zwart M, vande Wetering-Krebbers S, van Iersel M, van Marle S, van denDobbelsteen D. 2011. Sugammadex is cleared rapidly and pri-marily unchanged via renal excretion. Biopharm Drug Disp32:159167.

13. Loftsson T, Hreinsdottir D, Masson M. 2005. Evaluation ofcyclodextrin solubilization of drugs. Int J Pharm 302:1828.

14. Coleman AW, Nicolis I, Keller N, Dalbiez JP. 1992. Aggrega-tion of cyclodextrins: An explanation of the abnormal solubilityof $-cyclodextrin. J Incl Phenom Macroc Chem 13:139143.

15. Mele A, Mendichi R, Selva A. 1998. Non-covalent asso-ciations of cyclomaltooligosaccharides (cyclodextrins) withtrans -$-carotene in water: Evidence for the formation of largeaggregates by light scattering and NMR spectroscopy. Carbo-hydrate Res 310:261267.

16. Gonzalez-Gaitano G, Rodrguez P, Isasi JR, Fuentes M, Tar-dajos G, Sanchez M. 2002. The aggregation of cyclodextrinsas studied by photon correlation spectroscopy. J Incl PhenomMacrocycl Chem 44:101105.

17. Loftsson T, Magnusdottir A, Masson M, Sigurjonsdottir JF.2002. Self-association and cyclodextrin solubilization of drugs.J Pharm Sci 91:23072316.

18. Loftsson T, Masson M, Brewster ME. 2004. Self-associationof cyclodextrins and cyclodextrin complexes. J Pharm Sci93:10911099.

19. Bonini M, Rossi S, Karlsson G, Almgren M, Lo Nostro P,Baglioni P. 2006. Self-assembly of $-cyclodextrin in water. Part1: Cryo-TEM and dynamic and static light scattering. Lang-muir 22:14781484.

20. He W, Fu P, Shen XH, Gao HC. 2008. Cyclodextrin-based aggregates and characterization by microscopy. Micron39:495516.

21. Messner M, Kurkov SV, Jansook P, Loftsson T. 2010. Self-assembled cyclodextrin aggregates and nanoparticles. Int JPharm 387:199208.

22. Jansook P, Kurkov SV, Loftsson T. 2010. Cyclodextrins assolubilizers: Formation of complex aggregates. J Pharm Sci99:719729.

23. Messner M, Kurkov SV, Brewster ME, Jansook P, LoftssonT. 2011. Self-assembly of cyclodextrin complexes: Aggrega-tion of hydrocortisone/cyclodextrin complexes. Int J Pharm407:174183.

24. Messner M, Kurkov SV, Flavia`-Piera R, Brewster ME, Lofts-son T. 2011. Self-assembly of cyclodextrin complexes: The ef-fect of the guest molecule. Int J Pharm 408:235247.

25. Messner M, Kurkov SV, Palazon MM, Fernandez BA, Brew-ster ME, Loftsson T. 2011. Self-assembly of cyclodextrin com-plexes: Effect of temperature, agitation andmedia compositionon aggregation. Int J Pharm 419:322328.

26. Rao JP, Geckeler KE. 2011. Cyclodextrin supramacro-molecules: Unexpected formation in aqueous phase under am-bient conditions. Macromol Rapid Commun 32:426430.

27. Higuchi T, Connors KA. 1965. Phase-solubility techniques.Adv Anal Chem Instrum 4:117212.

28. Schwartz PA, CTR, Cooper JE. 1977. Solubility and ionizationcharacteristics of phenytoin. J Pharm Sci 66:994997.

29. Trissel LA, Ed. 2011. Handbook on injectable drugs. 16th ed.Bethesda: American Society of Health-System Pharmacists.



30. Li P, Tabibi E, Yalkowsky SH. 1998. Combined effect of com-plexation and pH on solubilization. J PharmSci 87:15351537.

31. Zia V, Rajewski RA, Stella VJ. 2001. Effect of cyclodex-trin charge on complexation of neutral and charged sub-strates: Comparison of (SBE)7M-$-CD toHP-$-CD. PharmRes18:667673.

32. Loftsson T, Masson M, Sigurjonsdottir JF. 1999. Methodsto enhance the complexation efficiency of cyclodextrins. STPPharma Sci 9:237242.

33. Tommasini S, Calabro` ML, Raneri D, Ficarra P, Ficarra R.2004. Combined effect of pH and polysorbates with cyclodex-trins on solubilization of naringenin. J Pharm Biom Anal36:327333.

34. Savolainen J, Jarvinen K, Matilainen L, Jarvinen T.1998. Improved dissolution and bioavailability of pheny-toin by sulfobutylether-$-cyclodextrin (SBE)7m-$-CD) andhydroxypropyl-$-cyclodextrin (HP-$-CD) complexation. Int JPharm 165:6978.

35. Serajuddin ATM. 2007. Salt formation to improve drug solu-bility. Adv Drug Deliv Rev 59:603616.

36. Loftsson T, Vogensen SB, Desbos C, Jansook P. 2008.Carvedilol: Solubilization and cyclodextrin complexation. Atechnical note. AAPS PharmSciTech 9:425430.

37. Mura P, Faucci MT, Manderioli A, Bramanti G. 2001. Mul-ticomponent systems of econazole with hydroxyacids and cy-clodextrins. J Incl Phenom Macroc Chem 39:131138.

38. Csabai K, Vikmon M, Szejtli J, Redenti E, Poli G, VenturaP. 1998. Complexation of manidipine with cyclodextrins andtheir derivatives. J Incl Phenom Macroc Chem 31:169178.

39. Mura P, Maestrelli F, Cirri M. 2003. Ternary systems ofnaproxen with hydroxypropyl-$-cyclodextrin and amino acids.Int J Pharm 260:293302.

40. Redenti E, Szente L, Szejtli J. 2000. Drug/cyclodextrin/hydroxy acid multicomponent systems. Properties and phar-maceutical applications. J Pharm Sci 89:18.

41. Redenti E, Szente L, Szejtli J. 2001. Cyclodextrin complexesof salts of acidic drugs. Thermodynamic properties, struc-tural features, and pharmaceutical applications. J Pharm Sci90:979986.

42. Fenyvesi E, Vikmon M, Szeman J, Redenti E, Delcanale M,Ventura P, Szejtli J. 1999. Interaction of hydoxy acids with$-cyclodextrin. J Incl Phenom Macroc Chem 33:339344.

43. Loftsson T, Matthasson K, Masson M. 2003. The effects oforganic salts on the cyclodextrin solubilization of drugs. Int JPharm 262:101107.

44. Riley CM, Rytting JH, Kral MA, Eds. 1991. Takeru Higuchi, amemorial tribute. Volume 3Equilibria and thermodynamics.Lawrence: Allen Press.

45. Loftsson T, Fridriksdottir H, Sigurdardottir AM, Ueda H.1994. The effect of water-soluble polymers on drugcyclodex-trin complexation. Int J Pharm 110:169177.

46. Loftsson T. 1998. Increasing the cyclodextrin complexationof drugs and drug biovailability through addition of water-soluble polymers. Pharmazie 53:733740.

47. Loftsson T, Masson M. 2004. The effects of water-soluble poly-mers on cyclodextrins and cyclodextrin solubilization of drugs.J Drug Del Sci Tech 14:3543.

48. Loftsson T, Sigurardottir AM. 1994. The effect ofpolyvinylpyrrolidone and hydroxypropyl methylcellulose onHP$CD complexation of hydrocortisone and its permeabil-ity through hairless mouse skin. Eur J Pharm Sci 2:297301.

49. Chowdary KPR, Srinivas SV. 2006. Influence of hydrophilicpolymers on celecoxib complexation with hydroxypropyl $-cyclodextrin. AAPS PharmSciTech 7(3):79.

50. Jansook P, Moya-Ortega MD, Loftsson T. 2010. Effect of self-aggregation of (-cyclodextrin on drug solubilization. J InclPhenom Macrocycl Chem 68:229236.

51. Borghetti GS, Pinto AP, Lula IS, Sinisterra RD, Teixeira HF,Bassani VL. 2011. Daidzein/cyclodextrin/hydrophilic polymerternary systems. Drug Dev Ind Pharm 37:886893.

52. Patel AR, Vavia PR. 2008. Preparation and evaluation of tastemasked famotidine formulation using drug/$-cyclodextrin/polymer ternary complexation approach. AAPS PharmSciTech9:544550.

53. Hirlekar RS, Sonawane SN, Kadam VJ. 2009. Studies on theeffect of water-soluble polymers on drugcyclodextrin complexsolubility. AAPS PharmSciTech 10:858863.

54. Cirri M, Maestrelli F, Corti G, Furlanetto S, Mura P. 2006.Simultaneous effect of cyclodextrin complexation, pH, andhydrophilic polymers on naproxen solubilization. J PharmBiomed Anal 42:126131.

55. Higuchi T, Kuramoto R. 1954. Possible complex forma-tion between macromolecules and certain pharmaceuticalsI: Polyvinylpyrrolidone with sulfathiazole, procain hydrochlo-ride, sodium salicylate, benzyl penicillin, chloeamphenicol,mandelic acid, caffeine, theophylline, and cortisone. J AmPharm Assoc 43:393397.

56. Guttman D, Higuchi T. 1956. Possible complex formation be-tween macromolecules and certain pharmaceuticals X: The in-teraction of some phenolic compounds with polyethylene gly-cols, polypropylene glycols, and polyvinylpyrrolidone. J AmPharm Assoc 45:659664.

57. Racz I. 1989. Drug formulations. Budapest: John Wiley andSons.

58. Loftsson T, Fridriksdottir H, Gudmundsdottir TK. 1996. Theeffect of water-soluble polymers on aqueous solubility of drugs.Int J Pharm 127:293296.

59. Fendler JH. 1996. Self-assembled nanostructured materials.Chem Mater 8:16161624.

60. Attwood D, Florence AT. 1983. Surfactant systems. Theirchemistry, pharmacy and biology. London: ChapmannandHall.

61. Malmsten M. 2002. Surfactants and polymers in drug deliv-ery. New York: Marcel Dekker.

62. 2006. Remington: The science and practice of pharmacy. 21sted.Philadelphia: Lippincott Williams & Wilkins.

63. Loftsson T, fri-Driksdottir H. 1998. The effect of water-solublepolymers on the aqueous solubility and complexing abilities of$-cyclodextrin. Int J Pharm 163:115121.

64. Kurkov SV, Ukhatskaya EV, Loftsson T. 2011. Drug/cyclodextrin: Beyond inclusion complexation. J Incl PhenomMacrocycl Chem 69:297301.

65. Yalkowsky SH. 1999. Solubility and solubilization in aqueousmedia. Washington D.C.: American Chemical Society.

66. Fromming KH, Szejtli J. 1994. Cyclodextrins in pharmacy.Dordrecht: Kluwer Academic Publishers.

67. Street KW, Acree WE. 1988. Estimation of the effectivedielectric-constant of cyclodextrin cavities based on the flu-orescence properties of pyrene-3-carboxaldehyde. Appl Spec-trosc 42:13151318.

68. Connors KA. 1997. The stability of cyclodextrin complexes insolution. Chem Rev 97:13251357.

69. Li P, Zhao L, Yalkowsky SH. 1999. Combined effect of cosolventand cyclodextrin on solubilization of nonpolar drugs. J PharmSci 88:11071111.

70. He Y, Li P, Yalkowsky SH. 2003. Solubilization of fluas-terone in cosolvent/cyclodextrin combinations. Int J Pharm264:2534.

71. Viernstein H, Weiss-Greiler P, Wolschann P. 2003. Solubilityenhancement of low soluble biologically active compoundsTemperature and cosolvent dependent inclusion complexation.Int J Pharm 256:8594.

72. Okimoto K, Rajewski RA, Uekama K, Jona JA, Stella VJ.1996. The interaction of charged and uncharged drugs withneutral (HP-$-CD) and anionically charged (SBE7-$-CD) $-cyclodextrins. Pharm Res 13(2):256264.



73. Miyajima M, Ozeki T, Stella VJ. 2004. Binding constants foraromatic amino acids and their derivatives with sulfobutylether $-cyclodextrin determined using capillary electrophore-sis. J Drug Del Sci Tech 14:383387.

74. Kim Y, Oksanen DA, Massefski W, Blake JF, Duffy EM,Chrunyk B. 1998. Inclusion of ziprasidone mesylate with $-cyclodextrin sulfobutyl ether. J Pharm Sci 87:15601567.

75. Kim Y, Johnson KC, Shanker RM. 2001. Inclusion complexesof arylheterocyclic salts. US Patent Appl No.09/147,239, PfizerInc.

76. Ross DL, Riley CM. 1992. Physicochemical properties of thefluoroquinolone antimicrobials: III. Complexation of lome-floxacin with various metal ions and the effect of metal ioncomplexation on aqueous solubility. Int J Pharm 87:203213.

77. Ross DL, Riley CM. 1993. Physicochemical properties of thefluoroquinolone antimicrobials: V. Effect of fluoroquinolonestructure and pH on the complexation of various fluoro-quinolones with magnesium and calcium ions. Int J Pharm93:121129.

78. Orfanou F, Michaleas S, Benaki D, Galanopoulou O, Voul-gari A, Antoniadou-Vyza E. 2009. Photostabilization of ox-olinic acid in hydroxypropyl-$-cyclodextrins: Implications forthe effect of molecular self-assembly phenomena. J Incl Phe-nom Macroc Chem 64:289297.

79. Yamakawa T, Nishimura S. 2003. Liquid formulation of anovel non-fluorinated topical quinolone, T-3912, utilizing thesynergic solubilizing effect of the combined use of magne-sium ions and hydroxypropyl-$-cyclodextrin. J Control Release86:101113.

80. Norkus E. 2009. Metal ion complexes with native cyclodex-trins. An overview. J Incl Phenom Macroc Chem 65:237248.

81. Wu A, Shen X, He Y. 2006. Investigation of (-cyclodextrin nan-otube induced by N,N-diphenylbenzidine molecule. J ColloidsInterface Sci 297:525533.

82. Wu A, Shen X, He Y. 2006. Micrometer-sized rodlike structureformed by the secondary assembly of cyclodextrin nanotube. JColloids Interface Sci 302:8794.

83. Loftsson T, Fridiriksdottir H, Masson M. 1996. Solubilizationof $-cyclodextrin. Pharm Res 13(Suppl.):222.

84. Loftsson T. 1999. Pharmaceutical applications of $-cyclodextrin. Pharm Technol 23(12):4050.

85. Hedges AR. 1998. Industrial applications of cyclodextrins.Chem Rev 98:20352044.

86. Loftsson T, Hreinsdottir D. 2006. Determination of aqueoussolubility by heating and equilibration: A technical note. AAPSPharmSciTech 7(1)(1):www.aapspharmscitech.org.

87. Szejtli J. 1988. Cyclodextrin technology. Dordrecht: KluwerAcademic Publisher.

88. Torres-Labandeira JJ, Davignon P, Pitha J. 1991. Oversat-urated solutions of drug in hydroxypropyl cyclodextrins: Par-enteral preparation of pancratistatin. J PharmSci 80:384386.

89. Pitha J, Hoshino T, Torres-Labandeira J, Irie T. 1992. Prepa-ration of drughydroxypropyl cyclodextrin complexes by amethod using ethanol or aqueous ammonium hydroxide ascosolubilizers. Int J Pharm 80:253258.

90. Loftsson T, Sigur-Dsson HH, Masson M, Schipper N. 2004.Preparation of solid drug/cyclodextrin complexes of acidic andbasic drugs. Pharmazie 59:2529.

91. Brouwers J, Brewster ME, Augustijns P. 2009. Supersaturat-ing drug delivery systems: The answer to solubility-limitedoral bioavailability? J Pharm Sci 98:25492572.

92. Brewster ME, Vandecruys R, Peeters J, Neeskens P,Verreck G, Loftsson T. 2008. Comparative interactionof 2-hydroxypropyl-$-cyclodextrin and sulfobutylether-$-cyclodextrin with itraconazole: Phase-solubility behavior andstabilization of supersaturated drug solutions. Eur J PharmSci 34:94103.

93. Brewster ME, Vandecruys R, Verreck G, Peeters J. 2008. Su-persaturating drug delivery systems: Effect of hydrophiliccyclodextrins and other excipients on the formation andstabilization of supersaturated drug solutions. Pharmazie63:217220.

94. Rambali B, Verreck G, Baert L, Massart DL. 2003. Itracona-zole formulation studies of the melt-extrusion process withmixture design. Drug Dev Ind Pharm 29:641652.

95. Xiang T, Anderson B. 2002. Stable supersaturatedaqueous solutions of Silatecan 7-t-butyldimethylsilyl-10-hydroxycamptothecin via chemical conversion in the pres-ence of a chemically modified-$-cyclodextrin. Pharm Res19:12151222.

96. UekamaK, Ikegami K,Wang Z, Horiuchi Y, HirayamaF. 1992.Inhibitory effect of 2-hydroxypropyl-$-cyclodextrin on crystal-growth of nifedipine during storageSuperior dissolution andoral bioavailability compared with polyvinylpyrrolidone K-30.J Pharm Pharmacol 44:7378.

97. Iervolino M, Raghavan SL, Hadgraft J. 2000. Membrane pen-etration enhancement of ibuprofen using supersaturation. IntJ Pharm 198:229238.


cyclodextrins as a excipient

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use of cyclodextrin

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pharmaceutical excipients