+
`
`+
`
`October 1996
`Volume 85, Number 10
`
`REVIEW ARTICLE
`
`Pharmaceutical Applications of Cyclodextrins. 1. Drug Solubilization and
`Stabilization
`
`THORSTEINN LOFTSSON*X AND MARCUS E. BREWSTER†
`Received December 29, 1995, from the *Department of Pharmacy, University of Iceland, P.O. Box 7210, IS-127 Reykjavik, Iceland, and
`†Pharmos Corporation, Two Innovation Drive, Alachua, FL 32615 .
`Final revised manuscript received March 1, 1996 .
`Accepted
`for publication March 19, 1996X.
`
`Abstract 0 Cyclodextrins are cyclic oligosaccharides which have recently
`been recognized as useful pharmaceutical excipients. The molecular
`structure of these glucose derivatives, which approximates a truncated
`cone or torus, generates a hydrophilic exterior surface and a nonpolar
`cavity interior. As such, cyclodextrins can interact with appropriately sized
`molecules to result
`in the formation of
`inclusion complexes. These
`noncovalent complexes offer a variety of physicochemical advantages
`over the unmanipulated drugs including the possibility for increased water
`solubility and solution stability. Further, chemical modification to the parent
`cyclodextrin can result in an increase in the extent of drug complexation
`and interaction.
`In this short review, the effects of substitution on various
`cyclodextrin properties and the forces involved in the drug- cyclodextrin
`complex formation are discussed. Some general observations are made
`predicting drug solubilization by cyclodextrins.
`In addition, methods which
`are useful in the optimization of complexation efficacy are reviewed. Finally,
`the stabilizing/destabilizing effects of cyclodextrins on chemically labile
`drugs are evaluated.
`
`Introduction
`Although cyclodextrins are frequently regarded as a new
`group of pharmaceutical excipients, they have been known
`for over 100 years.1 The foundations of cyclodextrin chemistry
`were laid down in the first part of this century2,3 and the first
`patent on cyclodextrins and their complexes was registered
`in 1953.4 However, until 1970 only small amounts of cyclo-
`dextrins could be produced and high production costs pre-
`vented their widespread usage in pharmaceutical formula-
`tions. Recent biotechnological advancements have resulted
`in dramatic improvements in cyclodextrin production, which
`has lowered their production costs. This has led to the
`availability of highly purified cyclodextrins and cyclodextrin
`derivatives which are well suited as pharmaceutical excipi-
`
`X Abstract published in Advance ACS Abstracts, May 1, 1996.
`
`ents. These carbohydrates are mainly used to increase the
`aqueous solubility, stability, and bioavailability of drugs, but
`they can also, for example, be used to convert liquid drugs
`into microcrystalline powders, prevent drug-drug or drug-
`additive interactions, reduce gastrointestinal or ocular irrita-
`tion, and reduce or eliminate unpleasant taste and smell.
`The following is a short review of the effects of cyclodextrins
`on the solubility and stability of drugs in aqueous solutions
`with emphasis on the more recent developments. For further
`information on cyclodextrins and their physicochemical prop-
`erties the reader is referred to several excellent books and
`reviews published in recent years.5-13
`
`Structure and Physicochemical Properties
`Cyclodextrins are cyclic (R-1,4)-linked oligosaccharides of
`R-D-glucopyranose containing a relatively hydrophobic central
`cavity and hydrophilic outer surface. Owing to lack of free
`rotation about the bonds connecting the glucopyranose units,
`the cyclodextrins are not perfectly cylindrical molecules but
`are toroidal or cone shaped. Based on this architecture, the
`primary hydroxyl groups are located on the narrow side of
`the torus while the secondary hydroxyl groups are located on
`the wider edge (Figure 1). The most common cyclodextrins
`are R-cyclodextrin, (cid:226)-cyclodextrin, and (cid:231)-cyclodextrin, which
`consist of six, seven, and eight glucopyranose units, respec-
`tively. While it is thought that, due to steric factors, cyclo-
`dextrins having fewer than six glucopyranose units cannot
`exist, cyclodextrins containing nine, ten, eleven, twelve, and
`thirteen glucopyranose units, which are designated (cid:228)-, (cid:15)-, œ-,
`Ł-, and ı-cyclodextrin, respectively, have been reported.14,15
`Of these large-ring cyclodextrins only (cid:228)-cyclodextrin has been
`well characterized.16,17 Chemical and physical properties of
`the four most common cyclodextrins are given in Table 1. The
`melting points of R-, (cid:226)-, and (cid:231)-cyclodextrin are between 240
`and 265 °C, consistent with their stable crystal
`lattice
`structure.18
`The parent cyclodextrins, in particular (cid:226)-cyclodextrin, have
`limited aqueous solubility, and their complex formation with
`
`© 1996, American Chemical Society and
`American Pharmaceutical Association
`
`S0022-3549(95)00534-X CCC: $12.00
`
`Journal of Pharmaceutical Sciences / 1017
`Vol. 85, No. 10, October 1996
`
`APOTEX EX1056
`
`Page 1
`
`

`
`+
`
`+
`
`a
`
`b
`
`Figure 1s(a) The chemical structure and (b) the toroidal shape of the (cid:226)-cyclodextrin molecule.
`Table 1sSome Characteristics of r-, (cid:226)-, (cid:231)-, and (cid:228)-Cyclodextrina
`R
`(cid:226)
`(cid:231)
`
`(cid:228)
`
`6
`972
`4.7- 5.3
`14.5
`
`7
`1135
`6.0- 6.5
`1.85
`
`8
`1297
`7.5- 8.3
`23.2
`
`9
`1459
`10.3- 11.2
`8.19
`
`No. of glucopyranose units
`Molecular weight
`Central cavity diameter (Å)
`Water solubility at 25 (cid:176) C (g/100 mL)
`a Modified from refs 5 and 17.
`lipophilic drugs, and other compounds with limited aqueous
`solubility, frequently gives rise to B-type phase-solubility
`diagrams as defined by Higuchi.19 That is, addition of these
`unmodified cyclodextrins to aqueous drug solutions or drug
`suspensions often results in precipitation of solid drug-
`cyclodextrin complexes. The aqueous solubility of the parent
`cyclodextrins is much lower than that of comparable acyclic
`saccharides, and this could partly be due to relatively strong
`binding of the cyclodextrin molecules in the crystal state (i.e.,
`relatively high crystal lattice energy). In addition, (cid:226)- and
`(cid:228)-cyclodextrin form intramolecular hydrogen bonds between
`secondary OH groups, which detracts from hydrogen bond
`formation with surrounding water molecules, resulting in less
`negative heats of hydration.5,17 Thus, intramolecular hydro-
`gen bonding can result in relatively unfavorable enthalpies
`of solution and low aqueous solubilities. Substitution of any
`of the hydrogen bond forming hydroxyl groups, even by
`hydrophobic moieties such as methoxy and ethoxy functions,
`will result in a dramatic increase in water solubility.5 For
`example, the aqueous solubility of (cid:226)-cyclodextrin is only 1.85%
`(w/v) at room temperature but increases with increasing
`degree of methylation. The highest solubility is obtained
`when two-thirds of the hydroxyl groups (i.e., 14 of 21) are
`methylated, but then falls upon more complete alkylation.
`That is, the permethylated derivative has a solubility that is
`lower than that of, e.g., heptakis(2,6-O-dimethyl)-(cid:226)-cyclodex-
`trin but that is still considerably higher than that of unsub-
`stituted (cid:226)-cyclodextrin.7 Other common cyclodextrin deriva-
`tives are formed by other types of alkylation or hydroxy-
`alkylation of the hydroxyl groups.5,20 The main reason for the
`solubility enhancement in these derivatives is that chemical
`manipulation frequently transforms the crystalline cyclodex-
`trins into amorphous mixtures of isomeric derivatives. For
`example, (2-hydroxypropyl)-(cid:226)-cyclodextrin is obtained by treat-
`ing a base-solubilized solution of (cid:226)-cyclodextrin with propylene
`oxide, resulting in an isomeric system that has an aqueous
`solubility well in excess of 60% (w/v).21 The number of isomers
`generated based on random substitution is very large. Sta-
`tistically, for example, there are about 130 000 possible
`heptakis(2-O-(hydroxypropyl))-(cid:226)-cyclodextrin derivatives, and
`given that introduction of the 2-hydroxypropyl function also
`
`1018 / Journal of Pharmaceutical Sciences
`Vol. 85, No. 10, October 1996
`
`introduced an optically active center, the number of total
`isomers, i.e., geometrical and optical, is even much greater.
`In reality, the chemical alkylation of cyclodextrins is not
`totally random, based on relative reactivities of the hydroxy
`functions in the molecule. The secondary OH groups on the
`cyclodextrin molecule (i.e., OH-2 and OH-3 on the glucopy-
`ranose units) are somewhat more acidic than the primary OH
`group (i.e., OH-6). Thus, alkylation of OH-6, the least
`sterically crowded functionality, is favored in strong basic
`solutions while alkylation of OH-2, the most acidic of the
`hydroxyl groups but also the most hindered, is favored in a
`weak basic solution.22 Thus, some degree of regioselectivity
`is possible. Both the molar substitution, i.e., the average
`number of alkyl or hydroxyalkyl groups that have been reacted
`with one glucopyranose unit, and the location of the alkyl or
`hydroxyalkyl groups on the cyclodextrin molecule will affect
`the physicochemical properties of the derivatives including
`their ability to form drug complexes.23 However, theoretical
`studies have shown that the alkylation and hydroxyalkylation
`of the cyclodextrins should not introduce significant steric
`hindrance.24 Some of the commercially available cyclodextrins
`are listed in Table 2.
`
`Cyclodextrin Complexes
`The central cavity of the cyclodextrin molecule is lined with
`skeletal carbons and ethereal oxygens of the glucose residues.
`It is therefore lipophilic. The polarity of the cavity has been
`estimated to be similar to that of aqueous ethanolic solution.5
`It provides a lipophilic microenvironment into which suitably
`sized drug molecules may enter and be included. No covalent
`bonds are formed or broken during drug-cyclodextrin complex
`formation, and in aqueous solutions, the complexes are readily
`dissociated. Free drug molecules are in equilibrium with the
`molecules bound within the cyclodextrin cavity. Measure-
`ments of stability or equilibrium constants (Kc) or the dis-
`sociation constants (Kd) of the drug-cyclodextrin complexes
`are important since this is an index of changes in physico-
`chemical properties of a compound upon inclusion. Most
`methods for determining the K values are based on titrating
`changes in the physicochemical properties of the guest
`molecule, i.e., the drug molecule, with the cyclodextrin and
`then analyzing the concentration dependencies. Additive
`properties that can be titrated in this way to provide informa-
`tion on the K values include25 aqueous solubility,19,26-28
`chemical reactivity,10,29,30 molar absorptivity and other optical
`properties (CD, ORD),31-34 phase solubility measurements,35
`NMR chemical shifts,23,36 pH-metric methods,37 calorimetric
`titration,38 freezing point depression,39 and LC chromato-
`
`Page 2
`
`

`
`+
`
`+
`
`Table 2sSome Currently Available Cyclodextrins Obtained by
`Substitution of the OH Groups Located on the Edge of the Cyclodextrin
`Ringa
`
`R
`
`Methyl
`
`Butyl
`
`2-Hydroxypropyl
`
`Acetyl
`
`Succinyl
`
`Glucosyl
`Maltosyl
`
`Carboxymethyl ether
`
`Phosphate ester
`
`Simple polymers
`Carboxymethyl
`
`Cyclodextrin Derivatives
`
`(cid:226)
`
`Alkylated:
`
`Methyl
`Ethyl
`Butyl
`
`Hydroxylalkylated:
`Hydroxyethyl
`2-Hydroxypropyl
`2-Hydroxybutyl
`Esterified:
`
`Acetyl
`Propionyl
`Butyryl
`Succinyl
`Benzoyl
`Palmityl
`Toluenesulfonyl
`Esterified and Alkylated:
`Acetyl methyl
`Acetyl butyl
`Branched:
`Glucosyl
`Maltosyl
`
`Ionic:
`Carboxymethyl ether
`Carboxymethyl ethyl
`Phosphate ester
`3-Trimethylammonium-2-
`hydroxypropyl ether
`Sulfobutyl ether
`Polymerized:
`Simple polymers
`Carboxymethyl
`
`(cid:231)
`
`Methyl
`
`Butyl
`Pentyl
`
`Hydroxyethyl
`2-Hydroxypropyl
`
`Acetyl
`
`Succinyl
`
`Glucosyl
`Maltosyl
`
`Carboxymethyl ether
`
`Phosphate ester
`
`Simple polymers
`Carboxymethyl
`
`the
`a Since both the number of substitutes and their location will affect
`physicochemical properties of the cyclodextrin molecules, such as their aqueous
`solubility and complexing abilities, each derivative listed should be regarded as a
`group of closely related cyclodextrin derivatives.
`
`graphic retention times.40 While it is possible to use both
`guest or host changes to generate equilibrium constants, guest
`properties are usually most easily assessed. Connors has
`evaluated the population characteristics of cyclodextrin com-
`plex stabilities in aqueous solution.41
`The thermodynamic parameters, i.e., the standard free
`energy change (¢G), the standard enthalpy change (¢H), and
`the standard entropy change (¢S), can be obtained from the
`temperature dependence of the stability constant of the
`cyclodextrin complex.42 The thermodynamic parameters for
`several series of drugs and other compounds have been
`determined and analyzed.43-45 The thermodynamic param-
`eters of several other drugs are listed in Table 3. The complex
`formation is almost always associated with a relatively large
`negative ¢H and a ¢S that can be either positive or negative.
`Also, complex formation is largely independent of the chemical
`properties of the guest (i.e., drug) molecules. The association
`of binding constants with substrate polarizability suggests
`that van der Waals forces are important in complex forma-
`tion.50 Hydrophobic interactions are associated with a slightly
`positive ¢H and a large positive ¢S; therefore, classical
`hydrophobic interactions are entropy driven, suggesting that
`they are not involved with cyclodextrin complexation since,
`as indicated, these are enthalpically driven processes. Fur-
`thermore, for a series of guests there tends to be a linear
`relationship between enthalpy and entropy, with increasing
`
`7
`7
`
`7
`7
`2
`4
`5
`6
`2
`3
`4
`6
`5
`8
`9
`1
`
`(cid:226)-CD
`
`Diazepam (pKa 3.3)
`
`(cid:226)-CD
`
`Hydrochlorothiazide
`(pKa 8.8 and 10.4)
`
`Hydrocortisone
`Phenytoin, un-ionized
`Phenytoin, ionized
`Naproxen
`Adenine arabinoside
`Adenosine
`Ibuprofen (pKa 5.2)
`
`(cid:226)-CD
`(cid:226)-CD
`(cid:226)-CD
`(cid:226)-CD
`
`Table 3sStandard Enthalpy Change (¢H) and Standard Entropy Change
`(¢S) for Several Drug- Cyclodextrin Complexes
`pH ¢H(kJ/mol) ¢S(J/(mol K)) Ref
`Cyclodextrina
`Drug
`- 32
`- 70
`HP-R-CD
`49
`- 38
`- 67
`(cid:226)-CD
`46
`- 21
`- 21
`46
`- 13
`31
`18
`- 28
`- 64
`32
`- 21
`- 53
`32
`- 29
`47
`15
`- 32
`47
`4
`- 29
`47
`3
`- 17
`47
`34
`- 0.2
`47
`70
`- 3.3
`47
`69
`- 17
`47
`22
`- 18
`47
`19
`- 40
`47
`62
`- 39
`47
`59
`- 42
`47
`70
`- 68
`- 166
`HP-(cid:226)-CD
`48
`Acetylsalicylic acid
`- 18
`- 26
`HP-(cid:226)-CD
`49
`Acetazolamide
`- 71
`- 151
`17(cid:226)-Estradiol
`HP-(cid:226)-CD
`49
`- 20
`- 6
`HP-(cid:226)-CD
`49
`Hydrocortisone
`- 55
`- 127
`HP-(cid:226)-CD
`48
`1
`Methyl acetylsalicylate
`- 63
`- 144
`HP-(cid:226)-CD
`48
`1
`Methyl salicylate
`- 57
`- 134
`M/DM-(cid:226)-CD
`48
`1
`Acetylsalicylic acid
`- 20
`- 28
`M/DM-(cid:226)-CD Methyl acetylsalicylate
`48
`1
`- 28
`- 56
`HP-(cid:231)-CD
`48
`1
`Acetylsalicylic acid
`- 75
`- 194
`HP-(cid:231)-CD
`48
`1
`Methyl acetylsalicylate
`- 73
`- 176
`HP-(cid:231)-CD
`48
`1
`Methyl salicylate
`a HP-R-CD:
`(2-hydroxypropyl)-R-cyclodextrin . (cid:226)-CD: (cid:226)-cyclodextrin. HP-(cid:226)-
`(2-hydroxypropyl)-(cid:226)-cyclodextrin. M/DM-(cid:226)-CD: mixture of maltosyl- and
`CD:
`dimaltosyl-(cid:226)-cyclodextrin (3:7). HP-(cid:231)-CD:
`(2-hydroxypropyl)-(cid:231)-cyclodextrin.
`enthalpy related to less negative entropy values.43-45,48 This
`effect, termed compensation, is often correlated with water
`acting as a driving force in complex formation. The main
`driving force for complex formation could, therefore, be the
`release of enthalpy-rich water from the cyclodextrin cavity.47
`The water molecules located inside the cavity cannot satisfy
`their hydrogen-bonding potentials; therefore, they are of
`higher enthalpy.51 The energy of the system is lowered when
`these enthalpy-rich water molecules are replaced by suitable
`guest molecules which are less polar than water. Other
`mechanisms that are thought to be involved with complex
`formation have been identified in the case of R-cyclodextrin.
`In this instance, release of ring strain is thought to be involved
`with the driving force for compound-cyclodextrin interaction.
`Hydrated R-cyclodextrin is associated with an internal hy-
`drogen bond to an included water molecule which perturbs
`the cyclic structure of the macrocycle. Elimination of the
`included water and the associated hydrogen bond is related
`to a significant release of steric strain decreasing the system
`enthalpy.52
`In addition, “nonclassical hydrophobic effects”
`have been invoked to explain complexation. These nonclas-
`sical hydrophobic effects are a composite force in which the
`classic hydrophobic effects (characterized by large positive ¢S)
`and van der Waals effects (characterized by negative ¢H and
`negative ¢S) are operating in the same system. Using
`adamantanecarboxylates as probes, R-, (cid:226)-, and (cid:231)-cyclodextrins
`were examined.53 In the case of R-cyclodextrin, experimental
`data indicated small changes in ¢H and ¢S consistent with
`little interaction between the bulky probe and the small cavity.
`In the case of (cid:226)-cyclodextrin, a deep and snug-fitting complex
`was formed leading to a large negative ¢H and a near zero
`¢S. Finally, complexation with (cid:231)-cyclodextrin demonstrated
`near zero ¢H values and large positive ¢S values consistent
`with a classical hydrophobic interaction. Evidently, the cavity
`size of (cid:231)-cyclodextrin was too large to provide for a significant
`
`Journal of Pharmaceutical Sciences / 1019
`Vol. 85, No. 10, October 1996
`
`Page 3
`
`

`
`+
`
`+
`
`Table 4sEffect of Poly(vinylpyrrolidone) Concentration on the Value of
`the Apparent Stability Constant (Kc) of Some
`Drug-
`(2-Hydroxypropyl)-(cid:226)-cyclodextrin (1:1) Complexes at Room
`Temperature (20- 23 (cid:176) C)a
`
`PVP (% w/v)
`
`Acetazolamide
`
`0.00
`0.10
`0.25
`0.50
`
`86.2
`95.4
`97.0
`96.2
`
`Kc (M-1)
`Hydrocortisone
`
`1010
`1450
`c
`1190
`
`17(cid:226)-Estradiol
`
`52900
`58800
`78200
`80400
`
`a From ref 49. b Poly(vinylpyrrolidone). c Not determined.
`
`contribution by van der Waals-type interactions. These
`various explanations show that there is no simple construct
`to describe the driving force for complexation. Although
`release of enthalpy-rich water molecules from the cyclodextrin
`cavity is probably an important driving force for drug-
`cyclodextrin complex formation, other forces may be impor-
`tant. These forces include van der Waals interactions,34,54
`hydrogen bonding,55,56 hydrophobic interactions,34,57 release
`of ring strain in the cyclodextrin molecule,56 and changes in
`solvent-surface tensions.58
`Methods of preparing drug-cyclodextrin complexes have
`been reviewed.25
`In the solution phase, the procedure is
`generally as follows: an excess amount of the drug is added
`to an aqueous cyclodextrin solution, and the suspension is
`agitated for up to 1 week at the desired temperature. The
`suspension is then filtered or centrifuged to form a clear drug-
`cyclodextrin complex solution. For preparation of solid for-
`mulations of the drug-cyclodextrin complex, the water is
`removed from the aqueous drug-cyclodextrin complex solu-
`tion by evaporation or sublimation. It is sometimes possible
`to shorten this process by formation of supersaturated solu-
`tions through sonication followed by precipitation at the
`desired temperature. In some cases, the efficiency of com-
`plexation is not very high, and therefore, relatively large
`amounts of cyclodextrins must be used to complex small
`amounts of drug. To add to this difficulty, vehicle additives,
`osmolality modifiers, and pH adjustments commonly used in
`drug formulations, such as sodium chloride, buffer salts,
`surfactants, preservatives, and organic solvents, very often
`reduce the efficiency. For example, in aqueous solutions,
`ethanol and propylene glycol at low concentrations have been
`shown to reduce the cyclodextrin complexation of testosterone
`and ibuprofen by acting as competing guest molecules while
`at higher concentrations they can reduce complexation through
`a manipulation of solvent dielectric constant.48,59 Likewise,
`non-ionic surfactants have been shown to reduce cyclodextrin
`complexation of diazepam60 and preservatives to reduce the
`cyclodextrin complexation of various steroids.61 On the other
`hand, additives such as ethanol can promote complex forma-
`tion in the solid or semisolid state.62 Un-ionized drugs usually
`form a more stable cyclodextrin complex than their ionic
`counterparts; thus, the complexation efficiency of basic drugs
`can be enhanced by addition of ammonia to the aqueous
`complexation media.
`For example, solubilization of pancratistatin with (hydroxy-
`propyl)-cyclodextrins was optimized upon addition of am-
`monium hydroxide.63 Freeze-drying of the solutions removed
`ammonia, resulting in ammonia-free solid complex prepara-
`tions which dissolved rapidly to form clear supersaturated
`pancratistatin solutions. The resulting solutions were stable
`for a few hours, time sufficient for potential use in parenteral
`preparations. Finally, enhanced complexation can be obtained
`by formation of ternary complexes (or cocomplexes) between
`a drug molecule, a cyclodextrin molecule, and a third compo-
`nent. For instance, addition of a small amount of various
`
`1020 / Journal of Pharmaceutical Sciences
`Vol. 85, No. 10, October 1996
`
`water-soluble polymers to an aqueous complexation medium,
`followed by heating of the medium in an autoclave, can
`significantly increase the apparent stability constant of the
`drug-cyclodextrin complex (Table 4).49,64,65 A somewhat
`similar effect has been obtained through formation of drug-
`hydroxy acid-cyclodextrin ternary complexes or salts with
`basic drugs.66-68
`
`Drug Solubilization
`
`The most common pharmaceutical application of cyclodex-
`trins is to enhance drug solubility in aqueous solutions. Some
`of the reports generated on this topic have been reviewed,5-9
`and additional data is available from the individual cyclodex-
`trin manufacturers. The solubilizing effects of various cyclo-
`dextrins on three different drugs are listed in Table 5.
`Although prediction of compound solubilization by cyclodex-
`trins continues to be highly empirical, various historical
`observations permit several general statements. First, the
`lower the aqueous solubility of the pure drug, the greater the
`relative solubility enhancement obtained through cyclodextrin
`complexation. Drugs that possess aqueous solubility in the
`micromole/liter range generally demonstrate much greater
`enhancement than drugs possessing solubility in the micro-
`mole/liter range or higher. In Table 5, the enhancement factor,
`i.e., the solubility in the aqueous cyclodextrin solution divided
`by the solubility in pure water, for paclitaxel, for example, is
`much larger than the enhancement factors for hydrocortisone
`and pancratistatin. A similar observation was made when
`the solubilizing effect of (2-hydroxypropyl)-(cid:226)-cyclodextrin on
`53 different drugs was investigated.9 Second, cyclodextrin
`derivatives of lower molar substitution are better solubilizers
`than the same type of derivatives of higher molar substitution.
`In Table 5, both randomly methylated (cid:226)- and (cid:231)-cyclodextrins
`with molar substitution 0.6 provide for better solubilization
`than the same type of randomly methylated cyclodextrins with
`molar substitution 1.8. With the exception of R-cyclodextrin,
`permethylated derivatives (of (cid:226)- and (cid:231)-cyclodextrin) possess
`a lower complexing potential (lower Kc value) than the parent
`cyclodextrins.23 Of the commercially available materials, the
`methylated cyclodextrins with relatively low molar substitu-
`tion appear to be the most powerful solubilizers. The chain
`length of the alkyl group, on the other hand, appears to be of
`less importance.24,70 Third, charged cyclodextrins can be
`powerful solubilizers, but their solubilizing effect appears to
`depend on the relative proximity of the charge to the cyclo-
`dextrin cavity. The farther away the charge is located, the
`better the complexing abilities. For example, (2-hydroxy-3-
`(trimethylammonio)propyl)-(cid:226)- and -(cid:231)-cyclodextrin possess ex-
`cellent solubilizing effects while (cid:226)-cyclodextrin sulfate has a
`relatively low complexation potential (Table 5). Sulfobutyl
`ether (cid:226)-cyclodextrin, where the anion has been moved away
`from the cavity by a butyl ether spacer group, is an excellent
`solubilizer.71 (Carboxymethyl)-(cid:226)-cyclodextrin is another in-
`teresting anionic cyclodextrin derivative.72 Compared to
`neutral cyclodextrins, enhanced complexation is frequently
`observed when the drug and cyclodextrin molecules have
`opposite charge but decreased complexation is observed if they
`carry same type of charge. For example,
`(2-hydroxy-3-
`(trimethylammonio)propyl)-(cid:226)-cyclodextrin is an excellent solu-
`bilizer for many acidic drugs capable of forming anions.
`Another finding is that while many ionizable drugs are able
`to form cyclodextrin complexes, the stability constant of the
`complex is much larger for the un-ionized than for the ionized
`form. For example, both the un-ionized and the cationic (i.e.,
`the protonated) form of chlorpromazine give rise to 1:1
`complexes with (cid:226)-cyclodextrin but the stability constant for
`the un-ionized form is 4 times larger than for the cationic
`
`Page 4
`
`

`
`+
`
`+
`
`Table 5sSolubility of Drugs in Different Cyclodextrin Solutions at Room Temperature
`
`Drug
`
`Cyclodextrina
`
`Concnb (% w/v)
`
`Solubility (mM)
`
`Enhancementc Factor
`
`Ref
`
`Hydrocortisone (MW 362)
`
`Paclitaxel (Taxol, MW 854)d
`
`Pancratistatin (MW 325)
`
`None
`Glucosyl-R-CD
`Maltosyl-R-CD
`HP-(cid:226)-CD MS 0.6
`HE-(cid:226)-CD
`RM-(cid:226)-CD MS 0.6
`RM-(cid:226)-CD MS 1.8
`HTMAP-(cid:226)-CD MS 0.5
`CM-(cid:226)-CD MS 0.6
`Glucosyl-(cid:226)-CD
`Maltosyl-(cid:226)-CD
`RM-(cid:231)-CD MS 0.6
`RM-(cid:231)-CD MS 1.8
`None
`(cid:226)-CD
`Dimaltosyl-(cid:226)-CD
`HE-(cid:226)-CD
`HP-(cid:226)-CD
`DM-(cid:226)-CD
`(cid:231)-CD
`HP-(cid:231)-CD
`None
`HTMAP-(cid:226)-CD MS 1.4
`S-(cid:226)-CD Na-salt MS 2.3
`CM-(cid:226)-CD Na-salt MS 0.6
`HP-(cid:226)-CD MS 0.5
`Maltosyl-(cid:226)-CD MS 0.14
`DM-(cid:226)-CD MS 2.0
`HE-(cid:226)-CD
`(cid:231)-CD
`HTMAP-(cid:231)-CD MS 0.3
`HP-(cid:231)-CD MS 0.7
`TM-(cid:231)-CD MS 3.0
`
`10
`10
`10
`10
`10
`10
`10
`10
`10
`10
`10
`10
`
`1.5
`50
`50
`50
`50
`15
`50
`
`10
`10
`10
`10
`10
`10
`10
`10
`10
`10
`10
`
`0.993
`7.45
`11.3
`33.7
`48.3
`72.2
`50.8
`30.3
`44.6
`46.9
`28.7
`58.8
`38.6
`4 · 10-4
`0.005
`0.115
`0.914
`0.856
`39.6
`0.020
`0.080
`0.16
`0.86
`0.28
`0.83
`1.0
`0.95
`1.2
`0.83
`0.80
`0.49
`0.83
`0.49
`
`7.50
`11.4
`33.9
`48.6
`72.7
`51.2
`30.1
`44.9
`47.2
`28.9
`55.2
`38.9
`
`13
`288
`2285
`2140
`99.000
`50
`200
`
`5.4
`1.8
`5.2
`6.3
`5.9
`7.5
`5.2
`5.0
`3.1
`5.2
`3.1
`
`49
`49
`49
`49
`49
`27
`27
`27
`27
`49
`49
`27
`27
`69
`69
`69
`69
`69
`69
`69
`69
`63
`63
`63
`63
`63
`63
`63
`63
`63
`63
`63
`63
`
`randomly methylated (cid:226)-cyclodextrin.
`(hydroxyethyl)-(cid:226)-cyclodextrin. RM-(cid:226)-CD:
`(2-hydroxypropyl)-(cid:226)-cyclodextrin. HE-(cid:226)-CD:
`a(cid:226)-CD: (cid:226)-cyclodextrin. HP-(cid:226)-CD:
`HTMAP-(cid:226)-CD: (2-hydroxy-3-(trimethylammonio)propyl)-(cid:226)-cyclodextrin. CM-(cid:226)-CD: (carboxymethyl)-(cid:226)-cyclodextrin. Glucosyl-(cid:226)-CD: glucosyl-(cid:226)-cyclodextrin. Maltosyl-
`(cid:226)-CD: maltosyl-(cid:226)-cyclodextrin. DM-(cid:226)-CD: 2,6-O-dimethyl-(cid:226)-cyclodextrin. S-(cid:226)-CD: (cid:226)-cyclodextrin sulfate. (cid:231)-CD: (cid:231)-cyclodextrin. RM-(cid:231)-CD:
`randomly methylated
`(cid:231)-cyclodextrin. HP-(cid:231)-CD: (2-hydroxypropyl)-(cid:231)-cyclodextrin. HTMAP-(cid:231)-CD: (2-hydroxy-3-(trimethylammonio)propyl)-(cid:231)-cyclodextrin. TM-(cid:231)-CD:
`trimethyl (cid:231)-cyclodextrin.
`MS: molar substitution (i.e., the average number of OH groups on each glucose repeat unit that have been substituted). Na salt: sodium salt. b Concentration of the
`aqueous cyclodextrin solution. c The solubility in the aqueous cyclodextrin solution divided by the solubility in water. d pH 7.4
`
`form.37 The Kc for the phenytoin-(cid:226)-cyclodextrin complex is
`over 3 times larger for the un-ionized form than for the anionic
`form.46 However, it is frequently possible to enhance cyclo-
`dextrin solubilization of ionizable drugs by appropriate pH
`adjustments. Thus, the solubilizing effects of both (2-hydrox-
`ypropyl)-(cid:226)-cyclodextrin and dimethyl-(cid:226)-cyclodextrin on dihy-
`droergotamine mesylate have been found to increase with
`decreasing pH (i.e., formation of the cationic form). Both the
`saturation solubility and the slopes of the phase-solubility
`diagrams increase with decreasing pH.73 Similar results have
`been reported for the complexation of phenytoin with (cid:226)-cy-
`clodextrin46 and for the complexation of indomethacin,74
`prazepam, acetazolamide, and sulfamethoxazole75 with (2-
`hydroxypropyl)-(cid:226)-cyclodextrin.
`As mentioned before, it is also possible to enhance com-
`plexation and, thus, the solubilizing effect of cyclodextrins by
`addition of polymers or hydroxy acids to the cyclodextrin
`solutions. It has been shown that polymers, such as water-
`soluble cellulose derivatives and other rheological agents, can
`form complexes with cyclodextrins and that such complexes
`possess physicochemical properties different from those of
`individual cyclodextrin molecules.49,76 In aqueous solutions
`water-soluble polymers increase the solubilizing effect of
`cyclodextrins on various hydrophobic drugs by increasing the
`apparent stability constants of the drug-cyclodextrin com-
`plexes. For example, the solubilizing effect of 10% (w/v) (2-
`hydroxypropyl)-(cid:226)-cyclodextrin solution on a series of drugs and
`other compounds was increased from 12 to 129% when 0.25%
`
`(w/v) poly(vinylpyrrolidone) was added to the aqueous cyclo-
`dextrin solution.49 Water-soluble polymers are also capable
`of increasing aqueous solubilities of the parent cyclodextrins
`without decreasing their complexing abilities, thus making
`them more feasible as pharmaceutical excipients. Likewise,
`addition of hydroxy acids, such as citric, malic, or tartaric acid,
`can enhance the solubilizing effect of cyclodextrins through
`formation of super complexes or salts.67
`It is frequently
`possible to obtain even larger solubilization enhancement by
`applying several methods simultaneously. For instance,
`prazepam is a benzodiazepine with a pKa of about 3.
`(2-
`Hydroxypropyl)-(cid:226)-cyclodextrin has a solubilizing effect on both
`the un-ionized and the ionized form of the drug, and as
`expected, hydroxypropyl methylcellulose has a synergistic
`effect on the solubilization. However, the synergistic effect
`was more pronounced for the ionized form (Figure 2).75
`Finally, pharmaceutical formulations should contain as small
`an amount of cyclodextrin as possible since excess cyclodextrin
`can reduce, e.g., drug bioavailability and preservative efficacy.
`Drug solubility should be determined in the final formulation
`and under normal production conditions to determine if too
`much, or too little, cyclodextrin is being used.
`
`Effect on Drug Stability
`The effects of cyclodextrins on the chemical stability of
`drugs is another useful property of these excipients and has
`been extensively examined in the literature.10 Cyclodextrin
`
`Journal of Pharmaceutical Sciences / 1021
`Vol. 85, No. 10, October 1996
`
`Page 5
`
`

`
`+
`
`+
`
`observed first-order rate constant (kobs) is the weight average
`of the two rate constants:
`
`d[D]t
`dt
`
`) -kobs[D]t
`
`and
`
`kobs ) koff + kc(1 - ff)
`
`where ff is the fraction of free drug in solution, or
`
`ff )
`
`1
`1 + Kc[CD]
`
`A Lineweaver-Burk type of equation25 can be obtained by
`further manipulations of the above equations:
`
`1
`ko - kobs
`
`)
`
`1
`Kc(ko - kc)
`
`1
`[CD]
`
`+ 1
`ko - kc
`
`A plot of 1/(ko - kobs) versus 1/[CD] will give rise to a straight
`line (i.e. if the assumption of a 1:1 complex is correct) with a
`y-intercept equal to 1/(ko - kc) and a slope equal to 1/Kc(ko -
`kc), from which the values of kc and Kc can be derived. At low
`concentration most drug-cyclodextrin complexes are of 1:1
`stoichiometry. Even complexes which are of higher order
`stoichiometry at high cyclodextrin and/or drug concentration
`form 1:1 complexes at lower concentration. The stoichiometry
`(i.e., the guest:host molar ratio) will, however, affect the
`stabilizing/destabilizing effect of the complexation.77-80 Thus,
`at relatively high concentrations the antiallergic drug, tra-
`nilast, forms a 2:1 (guest:host) complex with (cid:231)-cyclodextrin
`which accelerates the drug degradation (dimerization) by
`approximately 5500-fold. With increasing (cid:231)-cyclodextrin con-
`centrations, 1:1 and 1:2 complexes are formed resulting in a
`decreased rate of dimerization.77 The rate of dimerization
`was, for example, 19 300 times slower within the 1:2 complex
`than outside it. Similar observations were made when the
`degradation rate of some pilocarpine prodrugs was studied
`in aqueous (2-hydroxypropyl)-(cid:226)-cyclodextrin solutions.80 As
`mentioned before, the enthalpy of the system decreases during
`complex formation, resulting in increased complexation (i.e.,
`increased Kc value) when the temperature is lowered. T