Anal. Chem. W Q P , 64, 1632-1634
1892
TECHNICAL NOTES
Solubility Behavior of @-CyciodextrinIn WaterKosolvent Mixtures Alexis K. Chatjigakis, Cecile Donz6, and Anthony W. Coleman* CNRS, UPR 180, Laboratoire de Physique, Centre Pharmaceutique, UniuersitB de Paris-Sud, Chatenay-Malabry, F92290, France
Philippe Cardot Laboratoire de Chimie Analytique et de Electrochimie Organiques, Centre Pharmaceutique, UniuersitB de Paris-Sud, Chatenay-Malabry, F92290, France
INTRODUCTION b-cyclodextrin, the most readily available of the cyclodextrins, shows an anomalously low aqueous solubility (1.85 gD00 mL). This property is a limiting factor in the investigation of the properties of inclusion compounds formed by this cyclic oligosaccharide. Various methods have been used to increase the solubility, including the addition of urea,l metal salts,2,3 ethanol: and 2-propanol,5 and most recently, Stewart has described the effects of several other common solvents.6 The use of cosolvents in the formation of cyclodextrin inclusion compounds has received considerable attention7p8 and in particular Warnerg has shown that fluorescence lifetimes in pyrenel y-cyclodextrin complexes are dependent on the nature of the alcohol used as cosolvent. In this paper we report the solubility of 8-cyclodextrin in a series of water/cosolvent mixtures for compositions between 0 and 100% mole fraction cosolvent. The solubility variations may best be explained in terms of changes in the intrinsic solvent properties.
EXPERIMENTAL SECTION Materials. 8-Cyclodextrin was a gift from Roquette. Dimethyl sulfoxide (dmso) was spectrophotometric grade from Merck. Acetonitrile (CHaCN) and tetrahydrofuran (tho were HPLC grade obtained from Labosi. Methanol and 2-propanol were analytical grade supplied by Merck. Absolute ethanol was from Prolabo. These solventswere used as supplied. Water was purified by double distillation in glass. Procedure. The water/cosolvent mixtures were prepared volume to volume, and 50 mL of the mixture was placed in a stoppered conical flask. To this mixture was added 1 g of 4cyclodextrinand the resultant solution stirred in a thermostated bath for 72 h. Stirring was carried out on a 15-post magnetic stirrer, using identically sized stirrer bars (25 mm) for each solution and with no change in stirrer speed. After 72 h, we consider that maximum dissolution should have occurred. Solutions for which complete dissolution of the 8-CD had not occurred were filtered, and the concentration of 8-CD in the (1) Pharr, D. Y.;Fu, Z. S.; Smith, T. K.; Hinze, W. L. Anal. Chem. 1989,61, 275-279. (2) Buvari, A.; Barcza, I. J.Inclusion Phenom. Mol. Recognit. Chem. 1989, 7, 379. (3) Coleman, A. W.; Nicolis, I. J. Supramol. Chem., in press. (4) Zukowski, J.; Sybilska, D.; Jurczak, J. Anal. Chem. 1985,57,22152219.
( 5 ) Donz6, C.; Chatjigakis, A.; Coleman, A. W. J.Inclusion Phenom. Mol. Recognit. Chem., in press. (6) Taghvaei, M.; Stewart, G. H. Anal. Chem. 1991, 63, 1902-1904. (7) Kano, K.; Takenoshita, I.; Ogawa, T. Chem.Lett. 1980,1035-1038. (8)Kano, K.; Takenoshita, I.; Ogawa, T. Chem. Lett. 1982,321-324. (9) Nelson, G.; Patonay, G.; Warner, I. M. Anal. Chem. 1988,60,274279.
fitrate was determined by optical rotation measurements. For solutions in which complete dissolution had occurred a further 2 g of 8-CD was added and the above cycle repeated until solid 8-CD remained, at which point the saturation concentration was measured. For water/dmso mixtures containing more than 40% mole fraction dmso, 5-g portions of 8-cyclodextrin were added to 50 mL of the appropriatesolvent mixture until no further dissolution occurred. Solutions at the last unsaturated value were then prepared, and 500-mg portions of 8-cyclodextrinwere added to obtain a more accurate solubility. Experimentswere performed in a thermostated bath at 22 O C (exceptfor water/dmso mixtures, 25 "C).To obtain the temperature/dependencecurves for water/ 2-propanolmixtures, the solubilitieswere measured at 21,25,30, and 35 OC. Optical rotation measurements were carried out for known concentrationsof 8-cyclodextrinin the solvent mixtures. In all cases a linear relationship was obtained between concentration and optical rotation. Comparison with the specific rotation of 163grad dm2/gfor8-cyclodextrin in pure water showed the optical rotation to be solvent invariant.
RESULTS AND DISCUSSION The solubilities of 8-cyclodextrin in aqueous mixtures of dimethyl sulfoxide, methanol, ethanol, tetrahydrofuran, and acetonitrile are presented in Table I, as a function of percent volume/volume. For water/2-propanol mixtures the temperature-dependent solubilities are given in Table 11. Whilst percent volume/volume is a convenient laboratory measure, the use of percent mole fraction allows a better understanding of the results and facilitates comparison with data concerning other physical properties. The solubilities as a function of percent mole fraction are presented in graphical form in Figures 1 (dmso); 2a (methanol), 2b (ethanol), 3 (tetrahydrofuran), 4 (acetonitrile),and 5 (2-propanol) as a function of temperature. The solubility of 8-CD in water a t 25 O C has been determined to be 1.8 g/100 mL in close agreement with the literature value of 1.85 g/100 mL.1° Stewart has previously reported6 that the solubility of 8CD in water/dmso mixtures, containing less than 10% mole fraction dmso, remains essentially constant. We have measured the solubility in the region above 10% dmso mole fraction. Below 30% dmso the solubility remains constant (2 g/100 mL). Between 30% and 40% dmso the solubility rapidly increases to 77 g/100 mL. In the region 40-86 % the solubility is constant and then decreases to 50 g/100 mL for 100% dmso. The lH NMR spectra of 8-cyclodextrin in DzO (10) Duchbne, D. Cyclodextrim and their industrial wes;Editions de
Sant& Paris, 1987; Chapter 10. 0 1992 Amerlcan Chemical Society
ANALYTICAL CHEMISTRY, VOL. 84, NO. 14,JULY 15, 1992
Table I. Solubility (g/lOO mL) of 8-Cyclodextrin in Aqueous Solutions of Organic Solvents 5% cosolvent MeOH EtOH dmso CH&N 0 10 20 30
40 50 60 65.7 70 72.4 80 81.5 90
1.60 1.00 0.71 0.50 0.40 0.34 0.26
1.60 1.82 2.01 2.20 1.80 1.30 0.80
0.10
0.29
1.8 2.0 2.1 2.2 2.7 6.3 16.0 47.0
1.60 3.11 3.70 2.60 1.80 0.88 0.30
thf 1.60 2.10 2.20 1.88 1.30 0.90 0.50
0.10
0.20
0.05
0.19
0.00
0.05
0.00
0.00
1699
76.5 0.05
0.10
0.00
0.05
0.00
0.00
96 100
75.0 74.5 73.0 50.0
Table 11. Solubility (g/lOO mL) of 8-Cyclodextrin in Aqueous Solutions of 2-Propanol at Various Temperatures % 2-PrOH
0 5 10 15 20 25 30 40 50 60 70 80 90 100
T=21°C 1.60 3.41 4.80 6.00 7.00 7.00 6.90 3.60 2.32 1.10 0.40 0.10 0.02 0.00
T=25OC 1.80 4.30 6.03 7.40 8.10 8.70 8.30 6.10 3.01 1.40 0.50 0.20 0.10 0.00
T=30°C 2.30 5.61 8.30 10.70 11.40 11.90 11.60 8.00 3.99 1.60 0.50 0.20 0.10 0.00
I
T=35OC 2.50 6.30 9.21 11.60 13.30 14.20 13.50 9.20 4.90 1.82 0.60 0.20 0.10 0.00
I
-.,
0 0
10
20
30
40
50
60
1
c, 70
80
90
100
YMOLEFRAcTI)NffW
90
Figure 3. Solublllty (el100 mL) of 0-cyclodextrln vs mole fraction of thf in water/thf mlxtures.
4
I
/ o
io
20
1
30
40 50 BO 70 X M O L E ~ D N f f ~
eo
ao
100
Flgure 1. Solubility (g/lOOmL) of fi-cyclodextrln vs mole fraction of dmso in water/dmso mixtures.
and in dmso-de differ considerably.ll For solutions of 0-CD in D20/dmso-d6 mixtures containing less than 20% mole fraction of dmso-ds, the obtained 'H NMR spectra are essentially identical to those observed for j3-CD dissolved in pure D20. In mixtures where the mole fraction of dmso-de is greater than 40% ,the spectra are essentially identical to those observed for 8-CD in pure dmso-de. The dramatic modification of solubility occurs at a composition of approximately 2 D2O:l dmso-de and is apparently related to the bulk solvent properties. The curves of viscosity12and of excess (11)Wife, R. L.;Reed, D. E.; Leworthy, D. P.; Barnett, D. M.; Regan, P. D.; Volger, H. C. Proceedings of the First International Symposium on Cyclodextrim; Akadlmiai Kiado: Budapeet, 1982;Chapter 4. (12)Cowie, J. M. G.; Toporowski, P. M. Can. J. Chem. 1961,39,22402243.
0
10
20
40 50 60 70 K MXE FRACTKNOF ACETONITRILE
30
BO
90
100
Figure 4. Solublllty (g/ 100 mL) of &cyciodextrln vs mole fractlon of CH3CN in water/CH&N mixtures.
free energy13 of water/dmso mixtures also show dramatic changes centered on the 2 H2O:l dmso composition. It is notable that up to 86% mole fraction the solubility curve takes the exact form of the excess partial molar volume curve of water/dmso mixture13.l~ The curve for methanol (Figure 2a) shows a decrease to effectively zero solubility in 100% methanol. Stewart has previously measured solubilities in the region where the mole fraction of methanol was less than 15%. The solubility (13)Kenttamaa, J.;Lindberg, J. J. J.SuomenKemistelehti 196O,B33, 98-100. (14)Kenttamaa, J.;Lindberg, J. J. J. Suomen Kemistilehti 1960,B33, 32-35.
ANALYTICAL CHEMISTRY, VOL. 64, NO. 14, JULY 15, 1992
1834 18 16 14
-
0
I
10
20
30
%
40
~
50
F
W
EO
~
C
70
+
-
80
90
100
~
Flgurr 5. Sdublllty (g/100 mL) of &cyclodextrln vs mole fraction of CROH in w a t e r / W H mixtures as a function of temperature: (+) T = 21 OC; (0)T = 25 OC; ( 0 ) T = 30 OC; T = 35 OC.
m
.
decreases rapidly from 1.6 to 0.5 g/100 mL at 15% We found that the rate of decrease slows between 20% and 30%. For measurements of the excess partial molar volume of MeOHI water mixtures, a maximum value is observed a t 22% methan01.l~ The values for ethanol are given at 22 "C-a value intermediate between the previously reported values of 10 and 37 OC.16 The curve obtained (Figure 2b) shows an increase in solubility to a maximum value (2.2 g/100 mL) at a 10% mole fraction. This point corresponds to the maximum reported for the excess partial molar volume of a watedethan01 mixture.15 A similar curve is observed for tetrahydrofuran (Figure 3) with a maximum observed solubility of 2.2 g/100 mL at a 5 % mole fraction. Again, in this system, the mole fraction corresponding to the maximum solubility is identical to that giving a maximum for the excess partial molar volume of the solvent mixture.17 For acetonitrile (Figure 4), a maximum solubility of 3.7 g/100 mL a t 8% mole fraction is observed. The maximum solubility observed does not coincide with the maximum observed excesspartial molar volume or any other bulk solvent property. Acetonitrile differs in its mode of interaction with water and unlike the other solvents studied does not form clathrate systems with water.18 In the case of 2-propanol, we have previously shown5that at 25 OC the maximum solubility of 8-CD is 8.7 g/100 mL at (15) Franks,F. Water,A Comprehensive Treatise;Plenum Press: New
York-London, 1973; Vol. 2., Chapter 5. (16) Schlenk, H.; Sand, D. M. J. Am. Chem. SOC.1961,83,2312-2320. (17) Morcom, K. W.; Smith, R. W. Trans.Faraday SOC.1970,66,10731080.
(18) Franke, F. Water,A Comprehensive Treatise;Plenum Press: New York-London, 1973; Vol. 2, Chapter 9.
an 8% mole fraction, once more corresponding to the mole fraction giving a maximum excess partial molar ~0lume.19 The solubility curves at 21, 25,30, and 35 OC are presented in Figure 5 with the maximum solubilities being 7,8.7,11.9, and 14.2 g/lOO mL, respectively. The mole fraction of 2propanol a t which the maximum solubility occurs is constant at 8%. At all temperatures the solubility rapidly decreases at mole fractions above 8% and above 25% mole fraction it is always below the basal (100% water) value of 2 g/100 mL. In conclusion we have shown that for a number of solvents, dimethyl sulfoxide, acetonitrile, ethanol, 2-propanol, and tetrahydrofuran, the solubility of 8-cyclodextrin may be increased in cosolvent/water mixtures. For alcohols and thf the percent mole fraction of the cosolvent leading to the maximum value of solubility may be related to bulk properties of the aqueous mixture and in particular to the excess partial molar volumes. The magnitude of the increase in solubility also parallels the observed increase in excess partial molar volume. It is interesting to note that Warnere found fluorescence lifetimes of pyrene in water/alcohol mixtures in the presence of cyclodextrin to increase in the order methanol, ethanol, propanol, the order observed for increased solubilization. In the case of dmso two plateau regions of nearconstant solubility are observed and NMR measurements suggest that for mixtures that have compositions in these zones the cyclodextrin molecules observe,an essentially onesolvent system. This may arise from the formation of a strong 2:l HzO/dmso complex, as demonstrated by infrared spectroscopy,mresulting in the excesswater or dmso present being an essentially pure solvent. Acetonitrile is different from other solvents studied in that it forms neither clathrates in liquid water nor strong water/cosolvent complexes. It would appear to belong to a class of cosolvents in which a different relation exists between bulk solvent properties and 8-cyclodextrin solubility. We propose that the enhanced solubility of 8-cyclodextrin is related not to a cosolvent-host interaction but is best explained in terms of variation in the structure and properties of the solvent mixture. If this is the case, solubilitydata should be predictable for a wide range of solvent mixtures on the basis of measurements of the bulk solvent properties and of an understanding of the cosolvent water interactions, which will allow the solvents to be classed in their interactions with water. RECEIVED for review December 30, 1991. Accepted April 16, 1992. (19) Roux, G.; Roberta, D.; Perron, G.; Desnoyers, J. E. J. SoZution Chem. 1980,9,9,629-647. (20) Safford,G. J.;Schaffer, P. C.;Leung,P. S.;Doebbler,G. F.; Brady, G. W.; Lyden, E. F. X. J. Chem. Phys. 1969,50, 2140.
