Caffeine complexation

Donbrow, M., Touitou, E., and Ben Shalom, H. 1976. Stability of salicylamide-caffeine complex at different temperatures and its thermodynamic paramefleiUharm. Pharmac28 766-769. 

Higuchi, T. Pitman, I.H. Caffeine complexes with low water solubility synthesis and dissolution rates of 1 1 and 1 2 caffeine-gentisic acid complexes. J. Pharm. Sci. 1973, 62, 55-58. 

Kolarovic L, Traitler H. 1982. Determination of polycyclic aromatic hydrocarbons in vegetable oils by caffeine complexation and glass capillary gas chromatography. J Chromatogr 237 263-272. 

T. S. C. Wang, Analytical Chemistry of Bilirubins New Methods, Caffeine Complexation, Stability, and Biosynthesis of Conjugates. Diss. Abstr. Int. 

In a similar study,an olive oil impregnated Millipore membrane was employed to determine the transport kinetics of several drugs between two aqueous compartments buffered at pH 1.2 and 7.4. Apparent first-order rate constants obtained for the drugs alone can be correlated with reported in vivo absorption rate constants. Each of the drugs is known to complex with caffeine, and in each case caffeine significantly reduces the rate of transport. Furthermore, calculated m vitro rate constants agree well with reported in vivo rote constants for the drug-caffeine complexes. 

Martin R, Lilley T H, Bailey N A, Falshaw C P, Haslam E, Magnolato D, Begley M J 1986 Polyphenol-caffeine complexation. J Chem Soc Chem Commun 105-106... 

Destmction of the aluminum complex with ammonia then permits hydrocarbon extraction of the alkaloid. The alkaloid is subsequently both isolated and used as its tartrate salt. This nonnarcotic dmg, for which tolerance may develop, is frequently used orally with caffeine (16) for treatment of migraine it acts to constrict cerebral blood vessels, thus reducing blood flow to the brain. 

Ai,A/-bis(hydroxymethyl) formamide [6921-98-8] (21), which in solution is in equiUbrium with the monomethylol derivative [13052-19-2] and formaldehyde. With ben2aldehyde in the presence of pyridine, formamide condenses to yield ben2yhdene bisformamide [14328-12-2]. Similar reactions occur with ketones, which, however, requite more drastic reaction conditions. Formamide is a valuable reagent in the synthesis of heterocycHc compounds. Synthetic routes to various types of compounds like imida2oles, oxa2oles, pyrimidines, tria2ines, xanthines, and even complex purine alkaloids, eg, theophylline [58-55-9] theobromine [83-67-0], and caffeine [58-08-2], have been devised (22). 

The principal CGA isomers identified in green coffee include three caffeoylquinic acid isomers, 3-CQA [327-97-9], 4-CQA [905-99-7], and 5-CQA [906-33-2], three dicaffeoylquinic acid isomers, 3,4-diCQA [14534-61-3], 3,5-diCQA [2450-53-5], and 4,5-diCQA [57378-72-0], and three feruloylquinic acid isomers, 3-FQA [1899-29-2], 4-FQA, and 5-FQA [40242-06-6]. The total CGA level is somewhat higher in robustas compared to arabicas. The 5-CQA is the predominant isomer both in arabicas, ie, 4—5% dry basis (db), and in robustas, 5—6% db, and is known to form in vitro and possibly in vivo complexes with caffeine [58-08-2]. Greater compositional differences between robustas and arabicas are found in the minor CGA isomers, eg, 3,4-diCQA, 5-FQA,... 

Beryllium, calcium, boron, and aluminum act in a similar manner. Malonic acid is made from monochloroacetic acid by reaction with potassium cyanide followed by hydrolysis. The acid and the intermediate cyanoacetic acid are used for the synthesis of polymethine dyes, synthetic caffeine, and for the manufacture of diethyl malonate, which is used in the synthesis of barbiturates. Most metals dissolve in aqueous potassium cyanide solutions in the presence of oxygen to form complex cyanides (see Coordination compounds). 

Caffeine and nicotine have more complex reinforcing effects on dopamine. Caffeine, a methylxanthine compound, appears to exert its central ac-... 

MDMA and MDE also produced locomotor patterns that differed significantly from other stimulants. Previous studies in rats have demonstrated that amphetamine-induced hyperactivity involves complex patterns of widely distributed locomotion with frequent directional changes (Geyer et al. 1986 Geyer et al. 1987). In contrast, similar levels of behavioral activation produced by scopolamine or apomorphine are associated with relatively smooth locomotor paths, in which the same movement patterns are frequently repeated. Other stimulants, such as caffeine or nicotine, increase the amount of locomotor activity without significantly altering its pattern (Geyer... 

Chlorogenic acid forms a 1 1 complex with caffeine, which can be crystallized from aqueous alcohol and yields very little free caffeine on extraction with chloroform. Other compounds with which caffeine will complex in this way include isoeugenol, coumarin, indole-acetic acid, and anthocyanidin. The basis for this selection was the requirement for a substituted aromatic ring and a conjugated double bond in forming such a complex. This kind of complex does modify the physiological effects of caffeine.14 Complex formation will also increase the apparent aqueous solubility of caffeine in the presence of alkali benzoates, cinnamates, citrates, and salicylates.9... 

Where the complexing agent is phenolic, the pH must be such that the phenol is undissociated usually such complexes form at a pH below 6. Free caffeine concentrations are increased above pH 6.14... 

The methylxanthines vary in their ability to form certain metal complexes. For example, theophylline will complex with both copper and silver whereas caffeine will not.16 The interpretation of this is that the metal ion forms a pentacyclic complex involving the phenolic 0 at C-6 and N at 7.18... 

Tea is second only to water in worldwide consumption. Annual production of about 1.8 million T of dry leaf provides world per capita consumption of 40 L of beverage (Table l).1 The scientific interest in tea is due in part to the unusual chemical composition of its leaf and the complex series of reactions that occur when these components are converted to those found in commercial dry tea. Many of the reaction products interact with caffeine, modifying flavor and contributing to the technical problems of tea processing, as will be shown later. 

The known changes in polyphenolic material have already been noted. Fermentation also results in slight loss of extractable caffeine. Decreases of 5 to 7% have been observed.31 Higher-than-normal fermentation times and temperatures accelerate this effect. The fate of caffeine made unavailable during fermentation is not definitely known. It has been demonstrated that caffeine interacts with polyphenols,80-81 so it is likely that the alkaloid becomes complexed with the most insoluble thearubigen fractions that do not become part of the beverage.31... 

Instant tea produced as described above will dissolve completely in hot water but not in cold water, as the caffeine-polyphenol complexes are insoluble under those conditions. Since virtually all instant tea manufacture in the U.S. is for iced tea preparation, process modification is required. This initial extract may be cooled to 5 to 10°C and the cold water insoluble material or cream be allowed to precipitate. Under these conditions, 20 to 35% of the extract solids may be separated by centrifugation. The supernatant solids will reconstitute in cold water after concentration and drying.105 It is also possible to process the cream to make a portion of it compatible with the product and thereby retain the caffeine and some polyphenolic components that are present in this fraction.106 Commercial use of the enzyme Tannase, which removes gallic acid from gallated tea polyphenols107 and reduces cream formation108 can be used to reduce cream losses and manufacture instant teas retaining more of the natural polyphenol content. 

Caffeine contained in tea beverage is absorbed at about the same rate as caffeine in coffee, cola drinks, or in pure water. Data to support this conclusion was obtained in a human feeding experiment.109 The theory that complexation of caffeine with the polyphenolic material in tea retards absorption110-111 is not borne out. 

One of the most significant differences between Arabica and Robusta coffees is in the caffeine content. Robusta coffees contain almost twice the caffeine found in Arabica coffees. There are some other differences recognized thus far Robustas contain almost no sucrose and only very small amounts of the kaurane and furokaurane-type diterpenes they contain higher proportions of phenols, complex carbohydrates (both soluble and hydrolyzable), volatile fatty acids on roasting, and sulfur compounds, all in comparison with Arabicas. References to these distinctions can be found in Chapter 6 of this book. 

Even this brief survey suggests the complexity of attempting to determine the efficacy of caffeine as an ergogenic aid for endurance activity in view of so many serious potential limitations to the research. With this in mind, the next section reviews some of the more significant research findings. 

In addition to gender, task difficulty or complexity appears to be a substantial factor in arousal. Information processing tasks, particularly complex ones, have been shown to increase arousal levels in otherwise unstimulated subjects.60 The more complex the task, the higher the arousal level and the greater the chance that a given caffeine dosage would contribute to overstimulation. The additive nature of arousal sources — in this case caffeine and complexity — means that arousal is high when caffeine is present and complexity or difficulty level is substantial. The result is that caffeine impairs performance on complex tasks,50 51 particularly in female subjects. 

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