Caffeine solvates

Furthermore, supercritical CO2 does not behave as merely a mixture of liquid and gaseous CO2, but often exhibits an exceptional ability to solvate molecules in a specific way. The removal of caffeine from coffee relies on the chromatographic separation of caffeine and the other organic substances in a coffee bean supercritical fluid chromatography is a growing and exciting branch of chemistry. 

Grant and Higuchi (1990) commented on the solution behavior of solvates in their book on the solubility of organic compounds. The hydrated form will be more stable (less soluble) than the anhydrate in the general case. When the solvate is formed from a nonaqueous solvent that is miscibli in water, the free energy of solution of the solvent into the water reduces the activity of water and increases the apparent solubility of the solvate. An example is cited in which caffeine hydrate is less soluble in water than the anhydrate, but the solubility order reverses in ethanol. 

Many drags can associate with solvents to produce crystalline forms called solvates. When the solvent is water, the crystal is termed a hydrate. Thus more rapid dissolution rates are often achieved with the anhydrous form of a drag. For example, the anhydrous forms of caffeine, theophylline and glutethimide dissolve more rapidly in water than do the hydrous forms of these drags and the anhydrous form of ampicillin is about 25% more soluble in water at 37 °C than the trihydrate. 

Figure 16-3. (a) Solvation shell (top) and free-energy (bottom) functions for caffeine-C02 systems at 313K and different densities, (b) Non-spherical first shell coordination number as function of solvent density. The dashed line represents ideal behavior. From Ref [25]... 

During their preparation, drug crystals may incorporate one or more solvent molecules to form solvates. The most common solvate is water. If water molecules are already present in a crystal structure, the tendency of the crystal to attract additional water to initiate the dissolution process is reduced, and solvated (hydrated) crystals tend to dissolve more slowly than anhydrous forms. Significant differences have been reported in the dissolution rate of hydrated and anhydrous forms of ampicillin, caffeine, theophylline, glutethimide, and mercaptopurine. The clinical significance of these differences has not been examined but is likely to be slight. 

Modification of the solvent of crystallisation may result in different solvated forms. This is of particular relevance because the hydrated and anhydrous forms of a dmg can have melting points and solubilities sufficiently different to affect their pharmaceutical behaviour. For example, glutethimide exists in both an anhydrous form (m.p. 83°C, solubility 0.042% at 25°C) and a hydrated form (m.p. 68°C, solubility 0.026% at 25°C). Other anhydrous forms show similar higher solubilities than the hydrated materials and, as expected, the anhydrous forms of caffeine, theophylline, glutethimide and cholesterol show correspondingly higher dissolution rates than their hydrates. 

It can be argued that the first supercritical fluid extractions (SFE) were performed in 1879 when Flannay and Hogarth investigated the solvating capabilities of ethanol.28 However, it took roughly 100 years before supercritical fluids made any significant impact on industrial processes. The removal of caffeine from coffee beans was reported in the 1970s29 and led to... 

Hills et al. (1991) applied simultaneous supercritical fluid extraction to roasted coffee beans. This technique can be used with or without a derivatizing reagent In a dissociative mechanism, the adsorbed analyte must first desorb from a matrix active site and be dissolved in the supercritical fluid and then react to form the less polar derivative, which favors solvation in the supercritical carbon dioxide. In the associative mechanism, derivatization occurs while the analyte is adsorbed on the active site of the matrix. Reaction with the adsorbed analyte results in the desorption of the non-polar derivative into the supercritical fluid . Thus 2-hexenedioic acid (E.49) was identified for the first time as a native compound (without the use of a derivatizing agent). Benzenic and furanic compounds and caffeine were also identified. 

Capillary supercritical fluid chromatography has been demonstrated as a viable alternative for the analysis of food components which are sensitive to temperature such as flavors and fragrances. Supercritical fluids have long been recognized for their unique solvating characteristics. One of the most common uses of supercritical fluids is for the extraction of components of interest from natural materials (i.e. caffeine from coffee or oil from soybeans). Early in its development supercritical fluid chromatography (SPC) was used for the analysis of natural materials such as flavors and other food components because the technique is well suited for the analysis of compounds which thermally degrade. In this paper, the use of capillary SFC for the analysis of food components is discussed. Examples of the capillary SFC analysis of fats and flavors as well as food contaminants such as pesticides are presented. 

Recall trom basic mermodyiiainics that a j,ocess with a negative AG is spontaneous and the product—here, the solvated state—is favored relative to the unsolvated state. The authors of ffie study proposing this alternative approach derived a relationship that exhibited a reasonable correlation with measured values of LogBB. Some values obtained for AG°vv were —5.00 for ethanol (freely water soluble) and 2.08 for hexane for AG°hu the values were —0.16 and —3.45, respectively, for the same compoimds. Caffeine, a water-soluble basic drug, had calculated values of —15.27 and —9.31, respectively. The difference in the AG° values suggests that caffeine is more stable when it is solubilized in water than in a lipophilic medium. In the case of caffeine, the calculated LogBB veilue of 493 compared reasonably well with an experimental value of 40.3. 

Supercritical fluids have solvation properties similar to organic solvents, but a higher diffusivity and a lower viscosity, and these properties can be adjusted by pressure or temperature. An example is shown in Figure 3.3.53 for the system caffeine and carbon dioxide at 40 °C, which is just above the critical value of 31 °C. For elucidation, the phase diagram of CO2 is also shown. As soon as we pass the critical pressure of 73.8 bar, the solubility increases by several orders of magnitude. 

Distinctions between the solvated and nonsolvated forms of a drug substance are often easy to detect using NIR spectroscopy, making the technique a valuable part of multidisciplinary studies. The factors associated with the quantitative analysis of anhydrate/hydrate powder mixtiu es have been discussed, " and these issues illustrated in work establishing the phase boundaries in the anhydrate/hydrate system of caffeine. The interconversion between the anhydrate, monohydrate, and dihydrate forms of azithromycin have been studied, with the spectral region associated with the first overtone of water having been found to be the most useful. ... 

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