Study of β-cyclodextrin inclusion complexes with volatile molecules geraniol and α-terpineol enantiomers in solid state and in solution

Chemical Physics Letters 641 (2015) 44–50

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Study of ␤-cyclodextrin inclusion complexes with volatile molecules geraniol and ␣-terpineol enantiomers in solid state and in solution Magdalena Ceborska a,∗ , Kamila Szwed a , Monika Asztemborska a , b c,d ´ ´ Małgorzata Wszelaka-Rylik b , Ewa Kicinska , Kinga Suwinska a

Institute of Physical Chemistry, Polish Academy of Sciences, 01-224 Warsaw, Poland Faculty of Biology and Environmental Sciences, Cardinal Stefan Wyszynski University, Wóycickiego 1/3, PL-01 938 Warsaw, Poland c Faculty of Mathematics and Natural Sciences, Cardinal Stefan Wyszynski University in Warsaw, Woycickiego 1/3, 01-938 Warszawa, Poland d Institute of Chemistry, Kazan Federal University, Kremlevskaya 18, 420008 Kazan, Russia b

a r t i c l e

i n f o

Article history: Received 27 July 2015 In final form 4 October 2015 Available online 28 October 2015

a b s t r a c t Geraniol and ␣-terpineol are insoluble in water volatile compounds. ␣-Terpineol is a potentially important agent for medical applications. Formation of molecular complexes with ␤-cyclodextrin would lead to the increase of water solubility and bioavailability. ␤-Cyclodextrin forms 2:2 inclusion complexes with both enantiomers of ␣-terpineol and their precursor geraniol. Solid state complexes are thoroughly characterized by single X-ray crystallography and their stability over vast range of temperatures is proven by TG analysis. Intermolecular host–guest, host–host and guest–guest interactions give good insight into the nature of formed inclusion complexes. Stability constants of the complexes in solution are determined by HPLC. © 2015 Elsevier B.V. All rights reserved.

1. Introduction Geraniol [3,7-dimethylocta-trans-2,6-dien-1-ol] and both (+)and (−)-␣-terpineol [2-(4-methyl-1-cyclohex-3-enyl)propan-2-ol] belong to the class of terpenoids (Figure 1). Geraniol is an acyclic alcohol, which, under acidic conditions, may be converted into a cyclic ␣-terpineol [1]. ␣-Terpineols’ precursor geraniol is a monoterpenoid. It is a basic component of rose oil, palmarosa oil, and citronella oil (Java type). It also occurs in small quantities in geranium, lemon, and many other essential oils. Geraniol exhibits acaricidal properties (studied against storage food mite) [2], antimicrobial activity, which is due to its solubility in the phospholipid biolayer of cell membranes [3], it is also known for its antitumor activity against leukemia, hepatoma and melanoma cancers [4,5]. Due to its specific scent, it is also widely used in as a fragrance. Moreover, it can also be used as plant-based mosquito repellent [6]. Terpineol is a naturally occurring monoterpene alcohol that has been isolated from a variety of sources such as cajuput oil, pine oil and petitgrain oil. ␣-Terpineol exhibits

∗ Corresponding author. E-mail addresses: [email protected] (M. Ceborska), [email protected] (K. Szwed), [email protected] (M. Asztemborska), [email protected] (M. Wszelaka-Rylik), [email protected] ´ ´ (E. Kicinska), [email protected] (K. Suwinska). http://dx.doi.org/10.1016/j.cplett.2015.10.018 0009-2614/© 2015 Elsevier B.V. All rights reserved.

strong antifungal properties as shown by Zhou et al. [7]. Both enantiomers of ␣-terpineol, as well as geraniol are volatile and insoluble in water compounds. Their poor water solubility requires formulation involving solubilizing agents, one of the possibilities being molecular encapsulation with cyclodextrins to form inclusion compounds. ␤-Cyclodextrin (Figure 1) is a nontoxic macrocyclic carbohydrate compound toroid-like shaped, consisting of 7 glucopyranose units linked by 1,4-glycosidic bonds. Cyclodextrins have been used for analysis, separation including separation of enantiomers, chiral recognition as well as for physicochemical studies of inclusion phenomena of terpenoids like anethol, borneol, bornyl acetate, camphene, camphor, carvone, cineole, citral, citronellal, citronellene, eugenol, fenchone, geraniol, ␣-ionone, isomenthol, isomenthone, isopinocampheol, limonene, linalool, menthol, menthone, myrcene, neomenthol, nerol, ␣phellandrene, perillaldehyde, pinenes, pulegone, terpinen-4-ol, terpineols, terpinolene, tricyclic diterpenoid acids, etc. by a number of researchers [8–29]. ␤-Cyclodextrin may also be used to encapsulate active pharmaceutical ingredients (API) and thus it can be used in the process of drug design. Nevertheless, due to the crystallization problems, there are only a few examples of crystalline complexes of cyclodextrins with APIs [30–32]. The possibility of formation of inclusion compounds by geraniol and ␣-teerpineol with ␤-cyclodextrin was first suggested by Araujo et al. [33] and Mazzobre et al. [34]. To gain insight in the

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Figure 1. Molecular formulas with atom numbering: (a) ␤-cyclodextrin (numbers in parentheses refer to the second symmetry independent molecule, hydrogen atoms were omitted for clarity), (b) geraniol, (c) (+)-␣-terpineol and (d) (−)-␣-terpineol. For the geraniol and terpineol molecules the letters A and B after the atom number were used to distinguish the two symmetry independent molecules.

possibility of complex formation and the mode of inclusion of geraniol and (+)- and (−)-␣-terpineol into ␤-cyclodextrin cavity we present the molecular structures of their inclusion complexes determined using X-ray crystallography. At the same time, the complex formation in solution was proved by high performance liquid chromatography (HPLC), establishing for all three complexes the same 1:1 (2:2) inclusion stoichiometry as in the solid state. Moreover, the TG analysis was performed in order to determine the quantity of water present in the crystals as well as to establish the guest release from the molecular complex.

2. Experimental

2.2. Synthesis of the complexes 2.2.1. ˇ-Cyclodextrin/geraniol Crystals of ␤-cyclodextrin/geraniol were obtained by the slow diffusion of geraniol vapour into the 0.01 M solution of ␤cyclodextrin. Monocrystals appropriate for X-ray measurement were obtained after 2 weeks. 2.2.2. ˇ-Cyclodextrin/(+)- and (−)-˛-terpineol To the 0.01 M solution of ␤-cyclodextrin (10 mL) the solution of (+)- or (−)-␣-terpineol (15.4 mg, 0.01 mM) in methanol (0.5 mL) was added and the obtained solution was left at RT. Monocrystals appropriate for X-ray measurement were obtained after one week.

2.1. Materials 2.3. X-ray crystallography ␤-Cyclodextrins was purchased from Cyclolab and used as received. Geraniol, (+)-␣-terpineol and (−)-␣-terpineol were obtained from Fluka. Distilled water was used for aqueous solutions.

2.3.1. Data collectiom and refinement The X-ray data were collected at 100(1)K on a SuperNova Agi´˚ lent diffractometer using CuK˛ radiation (radiation,  = 1.54184 A).

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The data were processed with CrysAlisPro [35]. The structures were solved by direct methods and refined using SHELXL-2013 [36,37]. All hydrogen atoms were added to the model in calculated positions and refined as ‘riding’ atoms with Uiso = 1.2 Ueq of the parent atom (Uiso = 1.5 Ueq for CH3 and OH groups). Hydrogen atoms of water molecules were not included into the structural model due to high uncertainty of their positions and disorder. 2.3.2. Crystal data for ˇ-cyclodextrin/geraniol C42 H70 O35 ·C10 H18 O·10.5H2 O, M = 1487.33, colorless plate, 0.22 × 0.18 × 0.05 mm3 , triclinic, space group P1 (No. 1), V = 3614.4(4) A˚ 3 , Z = 2, Dc = 1.339 g/cm3 , F000 = 1544, T = 99.9(2)K, 2 max = 143.3◦ , 24 940 reflections collected, 16 713 unique (Rint = 0.055). Final GooF = 1.133, R = 0.089, wR = 0.238, R indices based on 15 204 reflections with I > 2(I) (refinement on F2 ), 1856 parameters, 42 restraints. Lp and absorption corrections applied,  = 1.044 mm−1 . Absolute structure parameter x = 0.6(2) [38]. The Flack parameter x refines to 0.6(2), and the absolute structure cannot be determined reliably on the basis of diffraction data. Nevertheless, as the cyclodextrin molecule is enantiomerically pure and its absolute configuration is known, it was used as the reference for the structural model. CCDC 972427. 2.3.3. Crystal data for ˇ-cyclodextrin/(–)-˛-terpineol C42 H70 O35 C10 H18 O 9.5H2 O, M = 1469.32, colorless block, 0.11 × 0.08 × 0.05 mm, monoclinic, space group P21 (No. 4), V = 6659.0(3) A˚ 3 , Z = 4, Dc = 1.455 g/cm3 , F0 0 0 = 3126, T = 100(2)K, 2 max = 142.5◦ , 24 682 reflections collected, 18 351 unique (Rint = 0.030). Final GooF = 1.38, R = 0.112, wR = 0.304, R indices based on 15 519 reflections with I > 2(I) (refinement on F2 ), 1814 parameters, 52 restraints. Lp and absorption corrections applied,  = 1.116 mm−1 . Absolute structure parameter x = 0.03(9) [38]. CCDC 972428. 2.3.4. Crystal data for ˇ-cyclodextrin/(+)-˛-terpineol C42 H70 O35 C10 H18 O 9H2 O, M = 1460.32, colorless plate, 0.23 × 0.18 × 0.08 mm, monoclinic, space group P21 (No. 4), V = 6657.5(1) A˚ 3 , Z = 4, Dc = 1.430 g/cm3 , F0 0 0 = 3042, T =v100(2)K, 2 max = 142.8◦ , 26 604 reflections collected, 18 193 unique (Rint = 0.014). Final GooF = 1.04, R = 0.061, wR = 0.174, R indices based on 17 570 reflections with I > 2(I) (refinement on F2 ), 1902 parameters, 30 restraints. Lp and absorption corrections applied,  = 1.106 mm−1 . Absolute structure parameter x = 0.11(4) [38]. CCDC DC 972429. 2.4. Calculations of intermolecular interactions and crystal energies An opix [39] computer program package was used for the calculation of intermolecular interactions and crystal energies. The functional form for the i–j atom–atom potential in the opix code is: Eij (kJ/mole) = A exp(−BRij ) − CRij−6 + 1389.36qi qj /Rij

(2)

with R in angstroms and q in electrons. The A, B and C parameters set used describe the Williams potentials [40]. 2.5. HPLC apparatus and conditions Chromatographic experiments were performed using a Waters 515 HPLC pump, a Rheodyne injector with 5 ␮l loop, a column thermostat Jetsream II Plus, and Waters 2414 refractive index detector. The column used was: Symmetry C18, 3.5 ␮m, 4.6 mm × 75 mm (Waters, USA). The mobile phase was water-ethanol solution (80:20, v:v) with appropriate amounts of ␤-cyclodextrin. Flow rate

was 1 mL/min. Measurements were performed at the temperature 25 ◦ C. 2.6. Termogravimetric analysis Thermal analysis was performed using Du Pont Thermal Analyst System 2100, TGA 951; thermal program: heat from room temperature at 5 ◦ C/min; the sample was dried on air for 30 minutes; purge gas: argon; sample pan: platinum. 3. Results and discussion 3.1. Crystal and molecular structures In solid state geraniol as well as both enantiomers of ␣-terpineol form with ␤-cyclodextrin inclusion complexes of stoichiometry 2:2 (host:guest). Two cyclodextrin molecules are arranged in molecular capsules by formation of head-to-head dimers stabilized by intermolecular O–H· · ·O hydrogen bonds between secondary hydroxyl groups of the two host molecules forming the capsule. Two symmetrically independent guest molecules occupy the internal space in the capsules. All guest molecules within the cavities are oriented head-to-head. In all structures no specific guest–guest directional interactions neither between guest molecules in the same capsule nor between the guest molecules from the adjacent (top and bottom) capsules were detected. The cyclodextrin molecules are involved in a number of O–H· · ·O and C–H· · ·O hydrogen bonds to the adjacent cyclodextrin molecules as well as to water molecules present in large quantities in all the three crystals and located between the capsules (see the packing diagrams below). Part of the water molecules is disordered over several positions. 3.1.1. ˇ-Cyclodextrin/geraniol In the molecular complex the two geraniol molecules are in their extended conformation (Figure 2a) which makes them too long for the cyclodextrin cavity. The inclusion of geraniol in ␤-cyclodextrin is shown in Figure 2b and c. The aliphatic ends of geraniol molecules are slightly penetrating the second cyclodextrin’s cavity of the same capsule and the hydroxylic ends of geraniol extend beyond the molecular capsule (primary hydroxylic rim) as shown in Figure 2b. Geraniol molecules do not interact with the host capsule by any specific directional interactions. Moreover, there are no interactions between geraniol molecules included within the dimolecular capsule. The only host–guest interactions present are O H· · ·O hydrogen bonds between the hydroxyl groups of geraniol which are pointing out of the cavity at both ‘ends’ of the complex to the cyclodextrins forming adjacent capsules. All the host–host and host–guest interactions are listed in Table 1 (see ESI). The ␤-cyclodextrin/geraniol capsules stack along the c crystallographic axis and form channels ‘filled’ with geraniol molecules. The capsules axes are inclined to the axis of stacking by approx. 11◦ (see Figure 2e). The ␤-cyclodextrin/geraniol crystals contain quite large amount of water molecules (10.5 molecules per one dimeric complex). Water molecules are surely involved in O H· · ·O hydrogen bonds to ␤-cyclodextrin molecules and to themselves, but these interactions were not located due to the ambiguity of positions of water hydrogens. Some of the water molecules are disordered over two positions and the occupancy factors of 0.5 were applied. Water molecules are located in the space between the columns of stacked complexes and these regions may be described as narrow channels running along c crystallographic axis (Figure 2d). 3.1.2. ˇ-Cyclodextrin/(+)-˛-terpineol The (−)-␣-terpineol molecule is considerably shorter compared to the geraniol molecule and the two guest molecules are better

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Figure 2. (a) Conformation of the geraniol molecule as found in the ␤-cyclodextrin/geraniol complex in solid state, (b) ␤-cyclodextrin/geraniol (2:2) dimer formation: side view, (c) ␤-cyclodextrin/geraniol (2:2) dimer formation: top view, (d) packing diagram for ␤-cyclodextrin/geraniol structure – view along the c crystallographic axis, and (e) packing diagram for ␤-cyclodextrin/geraniol structure dimers stacking.

Table 1 Calculated energies (kJ/mol) of intermolecular interactions [18]. Interaction ␤-Cyclodextrin/geraniol Molecule A Host–guest Molecule B Host–host Guest–guest ␤-cyclodextrin/(−)-␣-terpineol Molecule A Host–guest Molecule B Host–host Guest–guest ␤-cyclodextrin/(+)-␣-terpineol Guest pair AD Molecule A Host–guest Molecule B Host–host Guest–guest Guest pair BC Molecule A Host–guest Molecule B Host–host

E6-exp

Ecoul

Etot

−105.3 −100.2 −28.1 −30.0

−7.7 −5.7 −0.1 0.8

−113.0 −105.9 −28.2 −29.2

−107.4 −104.7 −21.8 −23.7

−1.8 −2.0 −0.1 1.0

−109.2 −106.7 −21.9 −24.7

−107.2 −107.6 −25.0 −24.2

−3.3 −6.3 1.3 −0.2

−110.5 −113.9 −23.7 −24.4

−108.4 −109.7 −24.1

−3.3 −3.6 0.1

−111.7 −113.3 −24.0

hidden in the capsule. The methyl substituent at the cyclohexene ring of (−)-␣-terpineol molecules is slightly penetrating the second cyclodextrin’s cavity of the same capsule but, contrary to the ␤-cyclodextrin/geraniol complex, the hydroxylic ends of (−)␣-terpineol do not extend beyond the molecular capsule as shown in Figure 3a. Contrary to the complex with geraniol, the (−)-␣terpineol molecules interact with their own host capsule with two C H· · ·O hydrogen bonds and one O–H· · ·O hydrogen bond to the primary hydroxyl group of the adjacent complex. There are no specific interactions between the two guest molecules included within the host capsule. All the host–host and host–guest interactions are listed in Table 2 (see ESI). The ␤-cyclodextrin/(−)-␣-terpineol capsules stack along the a crystallographic axis and form

channels ‘filled’ with (−)-␣-terpineol molecules. The capsules axes are inclined to the axis of stacking by approx. 5◦ (see Figure 3d). The crystal of ␤-cyclodextrin/(−)-␣-terpineol contains, similarly to the one with geraniol, quite large amount of water molecules (9.5 molecules per one dimeric complex). The water molecules are surely involved in O H· · ·O hydrogen bonds to the ␤-cyclodextrin molecules and to themselves, but these interactions were not located due to the ambiguity of the water hydrogens positions. A disorder of water molecules over two positions was observed and for these molecules the occupancy factors of 0.5 were applied. The water molecules are located in the space between the columns of stacked complexes and these regions may be described as narrow channels running along the a crystallographic axis (Figure 3c). 3.1.3. ˇ-Cyclodextrin/(+)-˛-terpineol The inclusion of (+)-␣-terpineol in ␤-cyclodextrin is shown in Figure 4. The ␣-cyclodextrin/(+)-␣-terpineol crystal structure is isostructural to the ␤-cyclodextrin/(−)-␣-terpineol one. Nevertheless, there is one considerable difference – in the present structure both guest molecules present in the capsule are disordered over two positions with the site occupancy factor equal to 0.5. If one of the (+)-␣-terpineol molecules in the capsule is in the orientation A, the second one must be in the orientation D, and analogously, if one is in the orientation B, the second one must be in the orientation C (pairs AD and BC). Like in the ␤-cyclodextrin/(−)-␣-terpineol complex, the methyl substituent at the cyclohexene ring of (+)-␣-terpineol molecules are slightly penetrating the second cyclodextrin’s cavity of the same capsule and do not extend beyond the molecular capsule (Figure 4a). In the orientation AD guest molecules interact with the own host capsule with three C–H· · ·O hydrogen bonds and two O–H· · ·O hydrogen bonds to the primary hydroxyl groups of the cyclodextrin of the adjacent capsule. In the orientation BC

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Figure 3. (a) ␤-Cyclodextrin/(−)-␣-terpineol (2:2) dimer formation – side view, (b) ␤-Cyclodextrin/(−)-␣-terpineol (2:2) dimer formation – top view, (c) packing diagram for ␤-cyclodextrin/(−)-␣-terpineol structure – view along a crystallographic axis, and (d) packing diagram for ␤-cyclodextrin/(−)-␣-terpineol structure – dimers stacking.

Table 2 Stability constants for complexes formed by geraniol and (+)- and (−)-terpineol with ␤-cyclodextrin.

K

−1

[M

]

(+)-␣-Terpineol

(−)-␣-Terpineol

Geraniol

413 ± 10

399 ± 8

334 ± 9

guest molecules do not interact with the own host capsule with any specific directional interactions and there is only one O–H· · ·O hydrogen bond to the primary hydroxyl groups of the cyclodextrin of the adjacent capsule. For the pair AD of (+)-␣-terpineol molecules within the host cavity there are two specific interactions between the guest H atoms ˚ and and double bonds ␲-electrons (H7A3· · ·␲(C2D C3D) [3.15 A] ˚ For the pair BC of (+)-␣-terpineol H7D3· · ·␲(C2A C3A) [3.14 A]). molecules within the host cavity there are no specific interactions between the guest molecules included within the host cavity. Also, there are no short contacts present between hydrogen atoms belonging to guest molecules in neighboring capsules. All the host–host and host–guest interactions are listed in Table 3 (see ESI). Packing diagram for ␤-cyclodextrin/(+)-␣-terpineol structure is very similar to that found for ␤-cyclodextrin/(−)-␣-terpineol. Complex capsules stack along the a crystallographic axis and form channels ‘filled’ with (+)-␣-terpineol molecules. The capsules axes are inclined to the axis of stacking by approx. 5◦ (see Figure 4f). The crystal of ␤-cyclodextrin/(+)-␣-terpineol contains, similarly to these with geraniol and (−)-␣-terpineol, quite large amount of water molecules (9 molecules per one dimeric complex). Water molecules are surely involved in O–H· · ·O hydrogen bonds to ␤-cyclodextrin molecules and to themselves, but these interactions were not located due to the ambiguity of water hydrogens positions. Disorder of water molecules over two positions was

observed and for these molecules the occupancy factors of 0.5 were applied. Water molecules are located in the space between the columns of stacked complexes and these regions may be described as narrow channels running along a crystallographic axis (Figure 4e).

3.2. Intermolecular interactions and crystal energies Each of individual ␤-cyclodextrin/guest complexes is slightly different while looking at the host–guest interactions. The differences between the host–guest, host–host and guest–guest interactions within molecular capsule by means of interaction energy components E6-exp and Ecoul , for the three complexes are shown in Table 1. Calculated total interaction energies for ␤-cyclodextrin/geraniol and ␤-cyclodextrin/(+)- and (−)-␣-terpineol complexes in solid state are very similar and do not indicate the molecular recognition of these molecules by ␤-cyclodextrin. 3.3. Determination of stability constants by HPLC Reversed phase high performance liquid chromatography with the mobile phase modified with ␤-cyclodextrin was applied for determination of stability constants of complexes formed between ␤-cyclodextrin and terpenoids: geraniol, (+)- and (−)-terpineol with assumptions that: (1) adsorption of ␤-cyclodextrin at the surface of the stationary phase is very small, (2) adsorption of its complex with solute on the stationary phase can be neglected, (3) the solute molecule is adsorbed at the surface of the stationary phase and complexed by ␤-cyclodextrin in the bulk mobile phase, (4) the complexes of 1:1 stoichiometry are formed.

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Figure 4. (a) ␤-Cyclodextrin/(+)-␣-terpineol (2:2) dimer formation guest molecules at occupancy AD – side view, (b) same – top view, (c) ␤-cyclodextrin/(+)-␣-terpineol (2:2) dimer formation guest molecules at occupancy BC – side view, (d) same – top view, and (e) packing diagram for ␤-cyclodextrin/(+)-␣-terpineol structure – view along the a crystallographic axis (e) packing diagram for ␤-cyclodextrin/(+)-␣-terpineol structure dimers stacking (disorder of guest molecules is visible).

The retention behavior in a reversed-phase chromatographic system containing natural ␤-cyclodextrin as a mobile phase additive can be described by the following equation [41,42]. 1 1 K[CD] = + k kR kR

Table 3 Water lost from crystals of complexes formed by geraniol and (+)- and (−)-␣terpineol with ␤-cyclodextrin. Compound

Sample mass mg

Temperature range ◦ C

Weight change %

␤Cyclodextrin/ geraniol

2.70

20–55

8.11

␤Cyclodextrin/(−)␣-terpineol ␤Cyclodextrin/(+)␣-terpineol

4.52

55–100 25–100

3.32 8.87

6.68

25–100

8.00

(1)

where k is the observed retention factor of investigated analyte, kR is the retention factor of analyte obtained in the mobile phase without ␤-cyclodextrin and K is the stability constant of the complex of 1:1 stoichiometry formed between cyclodextrin and analyte. The reverse of the retention factor is linearly related to the concentration of ␤-cyclodextrin. The slope provides directly a value for K. Figure 5 presents the relation of the reversal of retention factor (1/k) of geraniol, (+)- and (−)-␣-terpineol against ␤-cyclodextrin concentration. As predicted by Eq. (1), the linear relationship of 1/k versus ␤-cyclodextrin concentration indicates a 1:1 stoichiometry of the complexes formed between the three studied terpenoids and ␤-cyclodextrin. The separation of enantiomers of ␣-terpineols is not observed. Table 2 presents the stability constants of studied complexes determined from Eq. (1). The stability constants of (+)- and

(−)-terpineol with ␤-cyclodextrin are the same in the range of experimental error. ␤-cyclodextrin forms less stable complex with acyclic geraniol compared to monocyclic terpineols. The discrepancy between calculated interaction energies in solid state and experimentally determined stability constants may be explained by possible contribution of solvent in complex formation in solution, which was not considered in the calculations.

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Acknowledgements This research was partly financed by the European Union within the European Regional Development Fund (POIG.01.01.0214-102/09).

Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.cplett.2015.10.018. References

Figure 5. Relation between the reversal of retention factors 1/k for geraniol 䊏, (+)␣-terpineol  and (−)-␣-terpineol 䊉 versus ␤-cyclodextrin concentration.

3.4. Thermogravimetric analysis The mobility of water molecules was studied by TG analysis. The results are given in Table 3 (for TGA plots see ESI). The amount of water derived from TG analysis is in agreement with the crystal data (water content calculated from crystal structure model is 12.7, 11.5 and 11.1% for geraniol, (–)-␣-terpineol and (−)-␣-terpineol containing crystals, respectively). The higher values obtained from X-ray crystal structure analysis may be explained by the disorder of some of the water molecules and the difficulties in applying correct s.o.f. values which were arbitrary assigned as 1 or 0.5. It is also possible that small amount of water is released above 100 ◦ C. It is worth to notice that the water molecules in ␤cyclodextrin/geraniol crystals show different behavior compared to these bound in the ␤-cyclodextrin/(−)-␣-terpineol and ␤cyclodextrin/(+)-␣-terpineol crystals. In ␤-cyclodextrin/geraniol crystals water is released in two distinct peaks while in ␤cyclodextrin/(−)-␣-terpineol and ␤-cyclodextrin/(+)-␣-terpineol crystals only one peak is observed at the same temperature range (Table). This means, that part (approximately 2–3) water molecules present in the asymmetric unit are bound more tightly in the crystal lattice compared to the rest. Nevertheless, the detailed inspection of water molecules in view of the possible hydrogen bond formation as well as the number, length and type (water–cyclodextrin and water–water) of O· · ·O distances did not allow to identify which water molecules in the structural model are differently bonded and are responsible for this effect. Further heating up to 250 ◦ C shows, for all the three compounds, a total weight loss of 15% which is associated with slow guest release or guest and residual water release (see above). The content of water and guest molecules in crystals calculated from structural model is 23.2, 22.1 and 21.6% for geraniol, (−)-␣-terpineol and (−)␣-terpineol containing crystals, respectively. This means, that in 250 ◦ C the guest molecules are still included in the host dimers and it indicates quite high thermal stability of the inclusion complex. 4. Conclusions ␤-Cyclodextrin is a suitable molecular container for both ␣terpineol enantiomers and their precursor geraniol. Unfortunately, the stability constants do not differ for the two enantiomers of ␣terpineol which means that ␤-cyclodextrin cannot be successfully used as a chiral agent to separate these enantiomers. Calculated host-guest interactions are in agreement with the experimental data. It was shown that inclusion complexes of geraniol and terpineol enantiomers are stable over vast range of temperatures.

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