Elsevier

Fluid Phase Equilibria

Volume 289, Issue 1, 25 February 2010, Pages 20-31
Fluid Phase Equilibria

Experimental solid–liquid phase equilibria of {cholesterol + binary solvent mixture: 1-Alcohol (C4–C10) + cyclohexane}

https://doi.org/10.1016/j.fluid.2009.10.009Get rights and content

Abstract

Solid–liquid phase diagrams (SLE) have been determined for {cholesterol + 1-alcohol (1-heptanol, 1-octanol, 1-nonanol, 1-decanol}, or binary solvent mixture {1-alcohol (1-butanol, 1-pentanol, 1-hexanol, 1-heptanol, 1-octanol, 1-nonanol, 1-decanol) + cyclohexane} using a dynamic method at ambient pressure. Simple eutectic systems with complete miscibility in the liquid phase were observed. The solubility increases with an increase in the number of carbon atoms in the 1-alcohol chain length. The temperature of the eutectic points shifts to the lower cholesterol mole fractions as the alkyl chain length of the 1-alcohol decreases. The higher cross-intermolecular interaction was observed for the longer length of an alcohol, especially with 1-decanol. The solubility data in 1-alcohols were compared with values calculated by means of the Wilson, UNIQUAC and UNIQUAC ASM equations utilizing parameters derived from the SLE results. The existence of a solid–solid first order phase transition in cholesterol has been taken into consideration in calculations. The average root–mean–square deviation for the correlation of the solubility data in alcohols and cyclohexane has been on the level of σT = 2.8 K. Solid–liquid equilibria, for the ternary systems (cholesterol + binary solvent) have been discussed as a function of the mole fraction of a second named component in the solute-free mixed solvent (xC0). The experimental results have shown the influence of the solvent or binary solvent mixture on the temperature of the solid–solid phase transition (Ttr). The addition of cyclohexane to the binary solvent mixture causes in general an increasing the solid–solid phase transition temperature of the cholesterol. The synergistic effect of solubility was observed in binary solvent mixtures with maximum at xC0=0.60.8. Isotherms reveal decreasing effect of the enhanced solubility with an increase in temperature. SLE curves for two ternary systems were correlated with the Wilson model as an example.

Introduction

This paper is a continuation of our systematic study on the interactions between unlike molecules in systems of polar compounds, such as acetyl-substituted naphthols, or benzoyl-substituted naphthols with 1-alcohols [1], [2] amines with 1-alcohols [3], [4], [5], [6], nitriles with 1-alcohols [7] and pharmaceuticals with 1-alcohols [8]. Substance such as acetyl-substituted naphthols, or benzoyl-substituted naphthols can form pairs of isostructural aromatic compounds such as 2-acetyl-1-naphthol (1-hydroxy-2-acetonaphthone), (2AN) and 1-acetyl-2-naphthol (2-hydroxy-1-acetonaphthone), (1AN), or similarly 2-benzoyl-1-naphthol (1-hydroxy-2-benzonaphthone), (1BN), and 1-benzoyl-2-naphthol (2-hydroxy-1-benzonaphthone, (2BN), capable of forming stable or non-stable intramolecular hydrogen bonds in polar solvents [1], [2]. The results presented in the past indicated the role played by the intra- and inter-molecular hydrogen bonding in the dissolution process [[1], [2] and the literature cited in].

On the other side, the binary mixtures of (nitrile + 1-alcohol) show weaker cross interactions than the binary mixtures of (amine + 1-alkanol), especially for the short chain alcohols, or amines (see Refs. [3], [4], [5], [6], [7] and the literature cited in). Heats of mixing data and the values of the excess molar volumes in binary systems were proved by the solubility data.

Pharmaceuticals are more soluble in ethanol, or in 1-octanol; it depends on the polar end groups of the substance [8]. Solubility of the drugs as atropine, pentoxifylline, flurbiprofen and meclofenamic acid sodium salt in alcohols decreases with the increase in the length of alcohol carbon chain, what is a typical behaviour for most of the organic substances. Contrary, ibuprofen reveals very low solubility in ethanol and better solubility in 1-octanol. This is unquestionably the influence of the polar specific groups of the drug molecule on its phase behaviour in different solvents [8]. During solubility measurements of drugs, it was noticed that a soluble compound may transform to a more-stable polymorph [9], [10].

Cholesterol (5-cholesten-3β-ol) is a globular organic compound, steroid, with four cyclic rings, one double bond and one hydroxyl end group. The solubility of cholesterol has long attracted the attention of experimentalists. The solubility of cholesterol in 1-alcohols from methanol to 1-undecanol and their binary mixtures at four temperatures was already measured, indicating the influence of strong solvation of cholesterol by an alcohol [11]. It was shown that the solubility of cholesterol in 1-alcohols increases from ethanol to 1-undecanol with exception of 1-octanol and 1-nonanol, for which the observed solubility was as that for 1-hexanol [11]. The solubility of cholesterol in three alcohols (1-butanol, 1-pentanol, 1-hexanol) was also earlier measured by us [12]. The strong interaction between cholesterol and alcohols can result on the solid–solid transition temperature and even on the enthalpy of melting [11]. Such effects were observed earlier for the corticosteroids [13]. The solubility of cholesterol was measured in fats and oils [14], [15] various organic solvents [11], [15], [16], [17] and water [15], [18]. It was observed earlier, that some alcohols [16] and various macromolecules or cyclodextrins [18] can enhance the aqueous solubility of cholesterol.

Mixtures of solvents can reveal the special solubility effects as positive [1], [2], [19] or negative synergistic effects [20]. The occurrence of synergistic effects can be predicted on the basis of Hildebrand–Scatchard theory [21]; however, for polar solutes and polar solvents the solubility parameters describing appropriate interactions must be considered according to Barton [22]. It was found by us that solutes with stable intramolecular hydrogen bonds, such as 1AN, 1BN, and 2-nitro-5-methylphenol, forming stable associates in the solution (such as alkanoic acids and non-polar compounds such as naphthalene) showed the synergistic effects in binary solvents exhibiting GE > 0 as (alcohols + n-hydrocarbons, or cyclohydrocarbons), or (alcohols + halohydrocarbons) or (methylene iodide + cyclohexane) [[1], [2], [19] and literature cited in]. The maximum solubility corresponds to that composition of a binary solvent system, which shows maximum positive deviations from ideality (i.e. azeotrope point, solid compound (AxBy) at low temperatures).

One can expect that cholesterol, capable of forming hydrogen bonded associates even in the polar solution, might exhibit the synergistic effect of solubility in the (1-alcohol + cyclohexane) binary solvent mixture.

Cyclohexane is often used in the measurements of solubility of drugs or polar substances as an inert solvent. Ethanol is a typical media used for delivering of drugs or steroids to the human body and 1-octanol is a model compound of human cell and skin-membrane.

Recently, the solubility of cholesterol was studied in binary solvent mixture (n-hexane + ethanol) and the increased solubility in the binary solvent mixture was observed [23].

Earlier we measured the solubility of cholesterol in three alcohols [12] and in cyclohexane [17]; in the present work we extended our thermodynamic study to new mixtures. Solid–liquid phase equilibria (SLE) were measured for {cholesterol + 1-alcohol (1-heptanol, 1-octanol, 1-nonanol, 1-decanol}, or binary solvent mixture {1-alcohol (1-butanol, 1-pentanol, 1-hexanol, 1-heptanol, 1-octanol, 1-nonanol, 1-decanol) + cyclohexane} using a dynamic method at ambient pressure. The binary solvent mixture was chosen following our earlier studies, where the use of mixed solvents has shown the phenomenon of enhanced solubility in comparison with pure solvents (synergistic effect).

Section snippets

Experimental

The origin of the chemicals and their mass fraction purities were as follows: cholesterol (CAS Registry no. 57-88-5, SIGMA, USA, standard for chromatography, 99+%) was used without further purification; 1-alcohols (Aldrich Chemical Co., 99+) were fractionally distilled over different drying reagents to a mass fraction purity better than 99.8%, determined by GLC. Liquids were stored over freshly activated molecular sieves of type 4 Å (Union Carbide). Analysis, using the Karl-Fischer technique,

Results and discussion

Experimental solid–liquid phase equilibrium temperatures of {cholesterol (1) + 1-alcohol (2)} mixtures and those of {cholesterol (1) + (1-alcohol + cyclohexane) (2)} are given in Table 2.

The existence of solid–solid phase transition, Ttr for cholesterol was observed at different temperatures for different solvents. It was proved earlier that the phase transition temperature and the enthalpy of fusion of cholesterol may depend on the crystallization conditions [11], [24], [25]. For the cholesterol

Solid–liquid phase equilibrium correlation

The equation frequently applied to the solid–liquid equilibrium data calculations is:lnx1=ΔfusH1R1T1Tfus,1+ΔtrH1R1T1Ttr,1ΔfusCp,1RlnTTfus,1+Tfus,1T1+lnγ1where x1, 1, fusH1, fusCp,1, Tfus,1, T, ΔtrH1 and Ttr,1 are mole fraction, activity coefficient, enthalpy of fusion, difference in solute heat capacity between the liquid and solid phase at melting temperature, melting temperature, equilibrium temperature, enthalpy of the solid–solid phase transition and transition temperature,

Conclusion

The data presented in this paper indicate that the solubilities of cholesterol in 1-alcohols, or in binary solvent systems were controlled by different interactions. The competition between hydrogen bonded 1-alcohols molecules, hydrogen bonded cholesterol molecules and the interaction of unlike molecules is an important factor determining the phase behaviour. The phenomenon of the solid–solid phase transition of cholesterol in all systems has been observed at different temperatures. However,

Acknowledgments

We gratefully acknowledge Ms. J. Rolińska for some solubility measurements. Funding for this research was provided by the Ministry of Science and Higher Education in years 2007-2010 (Grant No 1206/GDR/2007/03).

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