Cyclodextrins as Functional Excipients: Methods to Enhance Complexation Efficiency

Cyclodextrins have gained currency as useful solubilizing excipients with an ever increasing list of beneficial properties and functionalities. Although their use in liquid dosage forms including oral and parenteral solutions is straightforward, their application to solids can be confounded by the added bulk that is contributed to the formulation. This factor has limited the use of cyclodextrin in tablets and relates systems mainly to potent drug substances. Increasing the ability of cyclodextrins to complex with drug through a manipulation of their complexation efficiency (CE) may expand the use of these materials to the increasing list of drug candidates and marketed drugs who may benefit from this technology. This brief review assesses tools and materials that have been suggested for increasing the CE for pharmaceutically useful cyclodextrins and drugs. The relative importance of impacting the drug solubility (S0) and phase-solubility isotherm slope is discussed in the context of drug ionization and salt use; the impact of polymers, charge interactions, and charge shielding; and the coincidental formation of other complex types in the media. The influence of drug form as well as supersaturation is also discussed in the context of the responsible mechanisms along with aggregation, inclusion, and noninclusion complex formation. Cyclodextrins have gained currency as useful solubilizing excipients with an ever increasing list of beneficial properties and functionalities. Although their use in liquid dosage forms including oral and parenteral solutions is straightforward, their application to solids can be confounded by the added bulk that is contributed to the formulation. This factor has limited the use of cyclodextrin in tablets and relates systems mainly to potent drug substances. Increasing the ability of cyclodextrins to complex with drug through a manipulation of their complexation efficiency (CE) may expand the use of these materials to the increasing list of drug candidates and marketed drugs who may benefit from this technology. This brief review assesses tools and materials that have been suggested for increasing the CE for pharmaceutically useful cyclodextrins and drugs. The relative importance of impacting the drug solubility (S0) and phase-solubility isotherm slope is discussed in the context of drug ionization and salt use; the impact of polymers, charge interactions, and charge shielding; and the coincidental formation of other complex types in the media. The influence of drug form as well as supersaturation is also discussed in the context of the responsible mechanisms along with aggregation, inclusion, and noninclusion complex formation. INTRODUCTIONCyclodextrins are pharmaceutical excipients that can solubilize various poorly soluble drugs through the formation of water-soluble drug–cyclodextrin complexes. Cyclodextrins are cyclic oligosaccharides containing six, seven, or eight (α-1,4)-linked D-glucopyranoside units (giving rise to α-, β-, and γ-cyclodextrin, respectively). These three so-called “parent cyclodextrins,” as well as their complexes, can have somewhat limited solubility in water, especially in the case of β-cyclodextrin. Thus, a number of water-soluble chemically modified cyclodextrin derivatives have been synthesized.1.Loftsson T. Brewster M.E. Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization.J Pharm Sci. 1996; 85: 1017-1025Abstract Full Text PDF PubMed Scopus (2013) Google Scholar, 2.Rajewski R.A. Stella V.J. Pharmaceutical applications of cyclodextrins. 2. In vivo drug delivery.J Pharm Sci. 1996; 85: 1142-1168Abstract Full Text PDF PubMed Scopus (811) Google Scholar, 3.Irie T. Uekama K. Pharmaceutical applications of cyclodextrins. III. Toxicological issues and safety evaluation.J Pharm Sci. 1997; 86: 147-162Abstract Full Text PDF PubMed Scopus (826) Google Scholar, 4.Cyclodextrins and their complexes.in: Dodziuk H. Wiley-VCH Verlag, Weinheim2006Crossref Scopus (548) Google Scholar, 5.Cyclodextrins in pharmaceutics, cosmetics, and biomedicine. Current and future industrial applications.in: Bilensoy E. Wiley, Hoboken2011Crossref Scopus (12) Google Scholar, 6.Loftsson T. Brewster M.E. Pharmaceutical applications of cyclodextrins: Basic science and product development.J Pharm Pharmacol. 2010; 62: 1607-1621Crossref PubMed Scopus (618) Google Scholar Cyclodextrins and cyclodextrin derivatives of pharmaceutical interest are depicted in Table 1. Cyclodextrins generally have a rather favorable toxicological profile, especially in comparison to other pharmaceutical excipients, such as surfactants, water-soluble polymers, and organic solvents.3.Irie T. Uekama K. Pharmaceutical applications of cyclodextrins. III. Toxicological issues and safety evaluation.J Pharm Sci. 1997; 86: 147-162Abstract Full Text PDF PubMed Scopus (826) Google Scholar,7.Stella V.J. He Q. Cyclodextrins.Tox Pathol. 2008; 36: 30-42Crossref PubMed Scopus (540) Google Scholar,8.Arima H. Motoyama K. Irie T. Recent findings on safety profiles of cyclodextrins, cyclodextrin conjugates, and polypseudorotaxanes.in: Bilensoy E. Cyclodextrins in pharmaceutics, cosmetics, and biomedicine: Current and future industrial applications. Wiley, Hoboken2011: 91-122Crossref Scopus (39) Google Scholar Because of their generation by bacterial digestion of starch; their hydrophilicity (log Koctanol/water), which is in most cases less than −7; their high molecular weight (MW); and the large number of hydrogen donors and acceptors, the oral bioavailability of cyclodextrins is very low meaning that they act as true drug carriers. Toxicological studies have shown that orally administered cyclodextrins are practically nontoxic because of their low absorption into the systemic blood circulation.8.Arima H. Motoyama K. Irie T. Recent findings on safety profiles of cyclodextrins, cyclodextrin conjugates, and polypseudorotaxanes.in: Bilensoy E. Cyclodextrins in pharmaceutics, cosmetics, and biomedicine: Current and future industrial applications. Wiley, Hoboken2011: 91-122Crossref Scopus (39) Google Scholar,9.Loftsson T. Brewster M.E. Pharmaceutical applications of cyclodextrins: Effects on drug permeation through biological membranes.J Pharm Pharmacol. 2011; 63: 1119-1135Crossref PubMed Scopus (202) Google Scholar Even when given via parenteral administration, hydrophilic cyclodextrins are primarily eliminated unchanged from the body via renal excretion with a total plasma clearance that is close to glomerular filtration rates.7.Stella V.J. He Q. Cyclodextrins.Tox Pathol. 2008; 36: 30-42Crossref PubMed Scopus (540) Google Scholar,10.Luke D.R. Tomaszewski K. Damle B. Schlamm H.T. Review of the basic and clinical pharmacology of sulfobutylether-β-cyclodextrin (SBECD).J Pharm Sci. 2010; 99: 3291-3301Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, 11.Hafner V. Czock D. Burhenne J. Riedel K.-.D. Bommer J. Mikus G. Machleidt C. Weinreich T. Haefeli W.E. Pharmacokinetics of sulfobutylether-beta-cyclodextrin and voriconazole in patients with end-stage renal failure during treatment with two hemodialysis systems and hemodiafiltration.Antimicrob Agents Chemother. 2010; 54: 2596-2602Crossref PubMed Scopus (70) Google Scholar, 12.Peeters P. Passier P. Smeets J. Zwiers A. de Zwart M. van de Wetering-Krebbers S. van Iersel M. van Marle S. van den Dobbelsteen D. Sugammadex is cleared rapidly and primarily unchanged via renal excretion.Biopharm Drug Disp. 2011; 32: 159-167Crossref PubMed Scopus (35) Google Scholar In patients with normal kidney function, about 90% of the cyclodextrin will be excreted within 6 h and about 99% within 12 h after intravenous administration. Cyclodextrins are listed in a number of pharmacopoeias and are accepted as pharmaceutical excipients and food additives by various regulatory agencies. For example, monographs for the parent α-, β-, and γ-cyclodextrin can be found in the United States Pharmacopoeia (USP)/National Formulary and all three are included in the US Food and Drug Administration (FDA) “generally recognized as safe” list. 2-Hydroxypropyl-β-cyclodextrin is compendial in the USP and European Pharmacopoeia and both 2-hydroxypropyl-β-cyclodextrin and sulfobutylether β-cyclodextrin are cited in the FDA's list of pharmaceutical ingredients. Furthermore, these cyclodextrins have gained similar status in both Europe and Japan. Currently, cyclodextrins can be found in over 35 commercially available drug products, including tablets, parenteral solutions, eye drops, ointments, and suppositories.6.Loftsson T. Brewster M.E. Pharmaceutical applications of cyclodextrins: Basic science and product development.J Pharm Pharmacol. 2010; 62: 1607-1621Crossref PubMed Scopus (618) Google ScholarTable 1Some Cyclodextrins That Can be Found in Commercial Pharmaceutical Products6.Loftsson T. Brewster M.E. Pharmaceutical applications of cyclodextrins: Basic science and product development.J Pharm Pharmacol. 2010; 62: 1607-1621Crossref PubMed Scopus (618) Google Scholar, 7.Stella V.J. He Q. Cyclodextrins.Tox Pathol. 2008; 36: 30-42Crossref PubMed Scopus (540) Google Scholar, 8.Arima H. Motoyama K. Irie T. Recent findings on safety profiles of cyclodextrins, cyclodextrin conjugates, and polypseudorotaxanes.in: Bilensoy E. Cyclodextrins in pharmaceutics, cosmetics, and biomedicine: Current and future industrial applications. Wiley, Hoboken2011: 91-122Crossref Scopus (39) Google Scholar, 9.Loftsson T. Brewster M.E. Pharmaceutical applications of cyclodextrins: Effects on drug permeation through biological membranes.J Pharm Pharmacol. 2011; 63: 1119-1135Crossref PubMed Scopus (202) Google ScholarCyclodextrinMSaThe molar degree of substitution (MS) is defined as the average number of substituents that have reacted with one glucopyranose repeat unit.SynonymsMW (Da)Oral Bioavailability in Rats (%)Solubility in Water at Room Temperature (mg/mL)Current Usage in Marketed Productsα-CyclodextrinAlfadex9731145Oral and parenteral formulations.β-CyclodextrinBetadex11350.618.5Oral, buccal, and topical formulations.2-Hydroxypropyl-β-cyclodextrin0.65Hydroxypropylbetadex14003>600Oral, parenteral, rectal, and ophthalmic formulations.Sulfobutylether β-cyclodextrin sodium salt0.921631.6>500Parenteral formulations.Methylated β-cyclodextrin1.81312≤12>600Ophthalmic and nasal formulations.γ-CyclodextrinGammadex12970.02232Parenteral formulation.2-Hydroxypropyl-γ-cyclodextrin0.61576<0.1>600Parenteral and ophthalmic formulations.a The molar degree of substitution (MS) is defined as the average number of substituents that have reacted with one glucopyranose repeat unit. Open table in a new tab A major obstacle to pharmaceutical exploitation of cyclodextrins is their formulation bulk. In solid dosage forms, cyclodextrin can only be used as solubility enhancers for potent drugs and drugs with medium potency and only if these drugs have relatively high complexation efficiency (CE) (Table 2). The CE of a poorly soluble lipophilic drug can range from zero, when no complexation is observed, to infinity, when every cyclodextrin molecule present in solution forms a complex with the drug. Importantly, the value of the CE in aqueous media is rarely greater than 1.5 with an average value of about 0.3, indicating that on average only about one out of every four cyclodextrin molecules present in a given complexation medium is in a complex with a drug molecule.13.Loftsson T. Hreinsdóttir D. Másson M. Evaluation of cyclodextrin solubilization of drugs.Int J Pharm. 2005; 302: 18-28Crossref PubMed Scopus (507) Google Scholar The formulation bulk of low potency drugs and drugs displaying low CE will often be too large for a single dose tablet (Table 3). Frequently, an increase in the drug–cyclodextrin complex molar ratio will lead to an increase in drug bioavailability. Optimum drug bioavailability is frequently obtained with a minimum amount of cyclodextrin, that is, by including material sufficient to produce desired effect but avoiding excess amounts of cyclodextrin. Thus, enhancement of the CE is of importance to pharmaceutical formulators. Here, methods that can be applied to enhance the CE are reviewed. Although the examples used relate to cyclodextrin containing media, many of these same methods can be applied to other complexing agents and other types of solubilizers.Table 2The Relationship Between Drug Potency, Complexation Efficiency (CE), and Formulation Bulk, that is the Weight of a Drug–Cyclodextrin (D–CD) Complex Containing the Drug Dose, Assuming Drug Molecular Weight of 400 Da and That of the Cyclodextrin to be 1400 DaThe Weight of a Dry Complex Containing the Drug DoseDrug DoseCE = ∞ with D–CD Molar Ratio of 1:1High CE with D–CD Molar Ratio of 1:2Medium CE with D–CD Molar Ratio of 1:4aThe average CE of 28 different drugs was determined to be 0.3, indicating that on the average only one out of every four cyclodextrin molecules are forming drug complex assuming 1:1 D–CD complex formation.13High potency drug (5 mg)23 mg35 mg70 mgMedium potency drug (50 mg)230 mg350 mg700 mgLow potency drug (500 mg)2300 mg3500 mg7000 mga The average CE of 28 different drugs was determined to be 0.3, indicating that on the average only one out of every four cyclodextrin molecules are forming drug complex assuming 1:1 D–CD complex formation.13.Loftsson T. Hreinsdóttir D. Másson M. Evaluation of cyclodextrin solubilization of drugs.Int J Pharm. 2005; 302: 18-28Crossref PubMed Scopus (507) Google Scholar Open table in a new tab Table 3The Relationship Between the Drug Dose, Complexation Efficiency (CE), and the Dosage Bulk upon Complexation with 2-Hydroxypropyl-β-Cyclodextrin (MW 1400 Da)DrugMW (Da)Common Oral Dose (mg)S 0 (mg/mL)SlopeK 1:1 (M−1)aAccording to Eq. 9.CEbAccording to Eq. 12.D–CD Molar RatiocAccording to Eq. 13.Dosage Bulk (mg)Acetazolamide222.22500.640.197850.2461:58200Alprazolam308.80.250.070.0552500.0581:1820Digoxin780.90.050.990.30368000.4351:30.3Econazole381.71500.370.1451800.1701:73200Flunitrazepam313.310.000.11011000.0101:100450Miconazole416.110000.090.0802600.0871:1242,000Naproxen230.35000.120.2827800.3931:413,000Sulfamethoxazole253.38000.390.3593600.5611:314,000Triazolam343.20.250.030.0172000.0171:6060The dosage bulk is the weight of drug–cyclodextrin complex containing the drug dose. The table is based on data from 13.Loftsson T. Hreinsdóttir D. Másson M. Evaluation of cyclodextrin solubilization of drugs.Int J Pharm. 2005; 302: 18-28Crossref PubMed Scopus (507) Google Scholar.a According to Eq. 9.b According to Eq. 12.c According to Eq. 13. Open table in a new tab CYCLODEXTRIN COMPLEXES AND AQUEOUS SOLUBILITYIn aqueous solutions, cyclodextrins form inclusion complexes with poorly water-soluble drugs by taking up a lipophilic moiety of the drug molecule into the somewhat hydrophobic central cavity of the cyclodextrin (Fig. 1). In dilute solutions, such inclusion complexes are dominating or even the only form of drug–cyclodextrin superstructure. However, cyclodextrins are also known to form noninclusion drug–cyclodextrin complexes.14.Coleman A.W. Nicolis I. Keller N. Dalbiez J.P. Aggregation of cyclodextrins: An explanation of the abnormal solubility of β-cyclodextrin.J Incl Phenom Macroc Chem. 1992; 13: 139-143Crossref Scopus (242) Google Scholar, 15.Mele A. 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Lo Nostro P. Baglioni P. Self-assembly of β-cyclodextrin in water. Part 1: Cryo-TEM and dynamic and static light scattering.Langmuir. 2006; 22: 1478-1484Crossref PubMed Scopus (240) Google Scholar, 20.He W. Fu P. Shen X.H. Gao H.C. Cyclodextrin-based aggregates and characterization by microscopy.Micron. 2008; 39: 495-516Crossref PubMed Scopus (205) Google Scholar, 21.Messner M. Kurkov S.V. Jansook P. Loftsson T. Self-assembled cyclodextrin aggregates and nanoparticles.Int J Pharm. 2010; 387: 199-208Crossref PubMed Scopus (255) Google Scholar As the cyclodextrin concentration increases, the cyclodextrin molecules and their complexes self-assemble to form aggregates that often range in size between 20 and 100 nm in diameter.21.Messner M. Kurkov S.V. Jansook P. Loftsson T. Self-assembled cyclodextrin aggregates and nanoparticles.Int J Pharm. 2010; 387: 199-208Crossref PubMed Scopus (255) Google Scholar, 22.Jansook P. Kurkov S.V. Loftsson T. Cyclodextrins as solubilizers: Formation of complex aggregates.J Pharm Sci. 2010; 99: 719-729Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar, 23.Messner M. Kurkov S.V. Brewster M.E. Jansook P. Loftsson T. Self-assembly of cyclodextrin complexes: Aggregation of hydrocortisone/cyclodextrin complexes.Int J Pharm. 2011; 407: 174-183Crossref PubMed Scopus (65) Google Scholar, 24.Messner M. Kurkov S.V. Flavià-Piera R. Brewster M.E. Loftsson T. Self-assembly of cyclodextrin complexes: The effect of the guest molecule.Int J Pharm. 2011; 408: 235-247Crossref PubMed Scopus (63) Google Scholar, 25.Messner M. Kurkov S.V. Palazón M.M. Fernández B.Á. Brewster M.E. Loftsson T. Self-assembly of cyclodextrin complexes: Effect of temperature, agitation and media composition on aggregation.Int J Pharm. 2011; 419: 322-328Crossref PubMed Scopus (37) Google Scholar, 26.Rao J.P. Geckeler K.E. Cyclodextrin supramacromolecules: Unexpected formation in aqueous phase under ambient conditions.Macromol Rapid Commun. 2011; 32: 426-430Crossref PubMed Scopus (16) Google Scholar The aggregation and the size of the aggregates increases with increasing cyclodextrin concentration. Excipients that solubilize and stabilize aggregates, such as small ionized molecules (e.g., salts of organic acids and bases) and water-soluble polymers (e.g., cellulose derivatives) can improve the magnitude of the CE. To explain the mechanisms underlying this effect, we first need to review briefly the phase-solubility theory of Higuchi and Connors,27.Higuchi T. Connors K.A. Phase-solubility techniques.Adv Anal Chem Instrum. 1965; 4: 117-212Google Scholar understanding that the theory is based on the formation of soluble complexes, be the inclusion, noninclusion, or a combination of the two. Furthermore, the relationship is not indicative of what form the complexes are, that is, individual complexes or complex aggregates; only that they are water soluble.The Phase-Solubility TheoryIf m drug molecules (D) associate with n cyclodextrin molecules (CD) to form a complex (DmCDn), the following equilibrium is suggested18.Loftsson T. Másson M. Brewster M.E. Self-association of cyclodextrins and cyclodextrin complexes.J Pharm Sci. 2004; 93: 1091-1099Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar,27.Higuchi T. Connors K.A. Phase-solubility techniques.Adv Anal Chem Instrum. 1965; 4: 117-212Google Scholar:m⋅D+n×CD⇄Km:nDmCDn(1) where Km:n is the stability constant (also known as binding constant, formation constant, or association constant) of the substrate–ligand (or guest–host) complex. The stability constant can be written as follows:Km:n=[DmCDn][D]m×[CD]n(2) where the brackets denote molar concentrations. In general, higher order complexes are formed in a stepwise fashion where a 1:1 complex is formed in the first step, 1:2 (or 2:1) complex in the next step, and so on:D+CD⇄D/CD(3) D/CD+CD⇄D/CD2(4) Consequently, the stability constants can be written as follows:K1:1=[D/CD][D]×[CD](5) K1:2=[D/CD2][D/CD]×[CD](6) If the intrinsic drug solubility, that is, the drug solubility in the aqueous complexation media when no cyclodextrin is present, is given as S0 and a formed complex is represented by D/CD, then[D]=S0(7) [D]T=S0+[D/CD](8) where [D]T represents the total drug solubility, assuming 1:1 D–CD complex formation according to (3), (5). A plot of [D]T versus [CD]T for the formation of 1:1 D–CD complex should give a straight line with the y-intercept representing S0 and the slope defined as follows:K1:1=SlopeS0(1−Slope)(9) If one drug molecule (n = 1) forms a complex with two cyclodextrin molecules (m = 2), then the following equations apply:[D]T=S0+[D/CD]+[D/CD2](10) [D]T=S0+K1:1×S0×[CD]+K1:1×K1:2×S0×[CD]2(11) indicating that a plot of [D]T versus [CD]T (assuming that [CD] ≫ ([D/CD] + 2 × [D/CD2]) or [CD] ≈ [CD]T) fitted to the quadratic relationship will allow for the estimation of K1:1 and K1:2.Dissolved drug molecules can form water-soluble dimers, trimers, and higher order aggregates as well as be associated with other excipients present in the aqueous complexation media. Frequently, only individual drug molecules can form complexes with dissolved cyclodextrin molecules. Dimers, trimers, and water-soluble oligomers are often unable to form cyclodextrin complexes.13.Loftsson T. Hreinsdóttir D. Másson M. Evaluation of cyclodextrin solubilization of drugs.Int J Pharm. 2005; 302: 18-28Crossref PubMed Scopus (507) Google Scholar Under such conditions, the y-intercept will not be equal to S0 and this can cause considerable error in the value of K. A more accurate method for determination of the solubilizing effect of cyclodextrins is to determine their CE, that is, the concentration ratio between cyclodextrin in a complex and free cyclodextrin. CE is calculated from the slope of the phase-solubility diagrams, is independent of both S0 and the intercept, and is more reliable when the influences of various pharmaceutical excipients on the solubilization are being investigated. For 1:1 D–CD complexes, the CE is calculated as follows:CE=[D/CDn][CD]=S0×K1:1=Slope(1−Slope)(12) And the drug–cyclodextrin molar ratio in a particular complexation media saturated with the drug can be calculated from the CE:D:CDmolarratio=1:(CE+1)CE(13) Equation 13 shows that CE of 1.0 gives D:CD molar ratio of 1:2 and CE of 5.0 gives molar ratio of 4:5. Examples of CE in pure aqueous solutions at room temperature are shown in Table 3. Table 3 shows that the value of K1:1 for the acetazolamide–HPβCD complex in pure water at room temperature is 85 M−1, indicating that about 90% of the HPβCD molecules will be in a complex in an unsaturated aqueous solution containing equimolar amounts of acetazolamide (MW 222.2 Da) and HPβCD (MW 1400 Da). However, in 20% (w/v) HPβCD aqueous solution (i.e., 0.14 M) saturated with the drug ([D] = constant = S0 = 0.003 M), only about 20% of the HPβCD molecules, or one out of every five HPβCD molecules, will be complexed with acetazolamide. This solution can be lyophilized to produce a solid powder of acetazolamide–HPβCD complex. Tablets of acetazolamide commonly contain 250 mg of the drug that corresponds to 8200 mg of the acetazolamide–HPβCD complex powder. Even if the CE can be enhanced to produce a acetazolamide–HPβCD (1:1) dry complex powder, the formulation bulk of this medium to low potency drug would be very high (i.e., 1250 mg).ENHANCING THE CEThe CE is the product of the apparent solubility of the poorly soluble drug in the complexation media (assumed to be S0 in Eq. 12) and the apparent stability constant of the complex (K1:1), assuming formation of 1:1 drug–cyclodextrin complex. Thus, according to Eq. 12, the CE can be increased by either increasing the value of S0 or the value of K1:1, or both values simultaneously. In many cases, the true magnitudes of S0 and K1:1 remain constant while their apparent values increase. For example, the intrinsic solubility of an acid is the solubility of its unionized form (HA), but the apparent solubility at a given pH is the total solubility, that is, of both the unionized and ionized species ([HA]T = [HA] + [A−]). Likewise, the apparent solubility of a metastable amorphous drug is much higher than the equilibrium solubility of its crystalline form. Thus, itraconazole is converted to its amorphous form to enhance its cyclodextrin solubilization in parenteral and oral solutions.6.Loftsson T. Brewster M.E. Pharmaceutical applications of cyclodextrins: Basic science and product development.J Pharm Pharmacol. 2010; 62: 1607-1621Crossref PubMed Scopus (618) Google Scholar Cocrystals and polymorphic forms can also result in enhanced apparent solubility and better cyclodextrin solubilization of poorly soluble drugs. As cyclodextrins and cyclodextrin complexes are able to self-assemble and solubilize drugs in micellar-like fashion, pharmaceutical excipients that stabilize and solubilize nanoparticles and micelles, such as polymers and low MW organic acids, are also able to enhance the CE. Frequently, such enhancement is associated with apparent increase in the value of K1:1.Drug IonizationNormally, the more lipophilic unionized form of a given drug molecule has a greater affinity for the somewhat hydrophobic cyclodextrin cavity than the ionized form and, thus, the unionized form has a higher K1:1 value. However, ionization of a poorly water-soluble drug will increase the S0 value and if the increase in S0 is greater than the decrease in K1:1, then an increase in the CE will be observed (see Eq. 12). For example, phenytoin is a poorly soluble drug with a pKa value of 8.06 in pure water at room temperature.28.Schwartz P.A. TR C. Cooper J.E. Solubility and ionization characteristics of phenytoin.J Pharm Sci. 1977; 66: 994-997Abstract Full Text PDF PubMed Scopus (77) Google Scholar Unionized phenytoin has CE of 0.08, indicating that in aqueous solutions only one out of every 15 cyclodextrin molecules forms a complex with phenytoin (Fig. 2). Thus, cyclodextrin solubilization of phenytoin in aqueous formulations was not practical and the only way to prepare a parenteral phenytoin solution was to use mixture of water and organic solvents and at the same time increase the pH to values above 10.29.Handbook on injectable drugs.in: Trissel L.A. 16th ed. American Society of Health-System Pharmacists, Bethesda2011Google Scholar Increasing the pH from acidic to 7.55 results in partial (about 24%) ionization of the drug and consequently increases the S0. This, in turn, increases the CE from 0.08 to 0.15 with one out of every eight cyclodextrin molecules forming a complex with the drug. Increasing the pH further to 11 results in almost complete (over 99%) ionization of the drug and increase in the CE to 14, meaning that almost every cyclodextrin molecule in the solution forms a complex with the drug. The ionized forms of all four drugs shown in Table 4 have lower K1:1 value than the corresponding unionized forms. The ionization increases the S0 value but decreases the K1:1, but the increase in S0 is more than sufficient to compensate for the decrease in K1:1. The result is in all cases an increase in the CE.Figure 2A pH-solubility profile in pure water and a phase-solubility profile for phenytoin in aqueous buffer solutions containing 0%–6% (w/v) 2-hydroxypropyl-β-cyclodextrin (HPβCD) at 25°C. The figures and table are based on data from 28.Schwartz P.A. TR C. Cooper J.E. Solubility and ionization characteristics of phenytoin.J Pharm Sci. 1977; 66: 994-997Abstract Full Text PDF PubMed Scopus (77) Google Scholar and unpublished results.View Large Image Figure ViewerDownload (PPT)Table 4The Effect of Drug Ionization on the Complexation Efficiency (CE) and on the Value of the Drug–Cyclodextrin K1:1 Stability Constant at Room TemperatureDrugStructurepKaCyclodextrinEffect of pH on CEK1:1 (M−1)ReferencesUnionizedaThe drug is either partly or fully unionized/ionized at the given pH.IonizedpHCEpHCEUnionizedIonizedFlavopiridol (Alvocidib)Base5.7HPßCD8.40.034.30.2244512430.Li P. Tabibi E. Yalkowsky S.H. Combined effect of complexation and pH on solubilization.J Pharm Sci. 1998; 87: 1535-1537Abstract Full Text PDF PubMed Scopus (76) Google ScholarNaproxenAcid4.2HPßCD2.00.37.00.9516065531.Zia V. Rajewski R.A. Stella V.J. Effect of cyclodextrin charge on complexation of neutral and charged substrates: Comparison of (SBE)7M-β-CD to HP-β-CD.Pharm Res. 2001; 18: 667-673Crossref PubMed Scopus (125) Google Scholar, 32.Loftsson T. Másson M. Sigurjónsdóttir J.F. Methods to enhance the complexation efficiency of cyclodextrins.STP Pharma Sci. 1999; 9: 237-242Google ScholarNaringeninAcid6.7HPßCD4.00.38.01.38334433.Tommasini S. Calabrò M.L. Raneri D. Ficarra P. Ficarra R. Combined effect of pH and polysorbates with cyclodextrins on solubilization of naringenin.J Pharm Biom Anal. 2004; 36: 327-333Crossref PubMed Scopus (43) Google ScholarPhenytoinAcid8.06HPßCD2.70.087.60.15See Fig. 2HPßCD7.40.111.014121535234.Savolainen J. Järvinen K. Matilainen L. Järvinen T. Improved dissolution and bioavailability of phenytoin by sulfobutylether-β-cyclodextrin (SBE)7m-β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) complexation.Int J Pharm. 1998; 165: 69-78Crossref Scopus (44) Google ScholarSBEßCD7.40.111.014126747634.Savolainen J. Järvinen K. Matilainen L. Järvinen T. Improved dissolution and bioavailability of pheny