Theophylline chemistry

The methylxanthines of interest are caffeine (1,3,7-trimethylxanthine), theophylline (1,3-dimethylxanthine), and theobromine (3,7-dimethylxanthine) and they occur in coffee, tea, mate, cocoa products, and cola beverages. This chapter is an introduction to their chemistry, isolation, and biosynthesis. While the class of methylxanthines is large and comprised of more members than these three, this chapter will essentially be limited to caffeine, theobromine, and theophylline. 

The analysis of the methylxanthines (caffeine, theobromine, and theophylline) is important in the areas of nutrition and clinical chemistry. These three compounds compose the majority of the alkaloids present in coffee, tea, cocoa, cola nuts, and guarana. 

Fig. 15. Displacement of radio-labeled analyte analog binding to MI spheres under equilibrium condition. B/B0 is the ratio of the amount of radio-labeled ligand bound in the presence of the displacing ligand (analyte), B0. Displacement of [8-3H]theophylline binding to a polymer imprinted with theophylline. Displacing ligands theophylline ( ) theobromine (+) xanthine (o) caffeine (A). Reprinted with permission from Ye L, Cormack PAG, Mosbach K (1999) Anal Commun 36 35. Copyright 1999 The Royal Society of Chemistry...

Figure 6.2. Chemical structure of 8-[3-(7-/)-galactosylcoumarin-3-carboxyamido )propyl ] theophylline (B) used in the homogeneous substrate-labeled fluorescent immunoassay for theophylline (A). (Reprinted from Ref. 3, with permission from the American Association for Clinical Chemistry.)...

Renger, B., Jehle, H., Fischer, M., and Funk, W. Validation of analytical procedures in pharmaceutical analytical chemistry HPTLC assay of theophylline in an effervescent tablet. J Planar Chrom 8 269-278 (July/Aug. 1995). 

There are many examples of second-order analyzers that are used in analytical chemistry including many hyphenated spectroscopic tools such as FTIR-TGA, IR-microscopy, as well as GC-MS, or even two-dimensional spectroscopic techniques. Another hyphenated technique that is being developed for the study of solid-state transitions in crystalline materials is dynamic vapor sorption coupled with NIR spectroscopy (DVS-NIR).26 DVS is a water sorption balance by which the weight of a sample is carefully monitored during exposure to defined temperature and humidity. It can be used to study the stability of materials, and in this case has been used to induce solid-state transitions in anhydrous theophylline. By interfacing an NIR spectrometer with a fiber-optic probe to the DVS, the transitions of the theophylline can be monitored spectroscopically. The DVS-NIR has proven to be a useful tool in the study of the solid-state transitions of theophylline. It has been used to identify a transition that exists in the conversion of the anhydrous form to the hydrate during the course of water sorption. 

Fig. 6 Influence of surface chemistry of pigments on theophylline release from pellets coated with Eudragit RS 30 D containing dibutyl phthalate as a plasticizer. (V) Titanium dioxide as fine platelets ( ) mica (x) talc (O) red iron oxide fine platelets. (From Ref. f)...

Recent developments show that dry chemistry has also been advancing in the sector of immunological detection methods. The homogeneous immunoassay technique facilitated access to the immunological detection method. The substrate-bound fluoro-immunoassay (SLFIA) serves as an example for the determination of theophylline concentration. However, the radial partition immunoassay paved the way for determining the concentration of numerous drugs and hormones. 

E220 Norton, G.E. and Mauck, J.B. (1985). Development of a Kodak Ektachem clinical chemistry slide assay for theophylline. Clin. Chem. 31, 911, Abstr. 44. 

E280 Norton, G.E, Novros, J.S. and Frickey, P.H. (1986). Analytical performance of the Kodak Ektachem clinical chemistry slides for theophylline. Clin. Chem. 32, 1058, Abstr. 42. 

E573 St. Louis, P.J., MacDonald, M., Giesbrecht, E. and Soldin, S.J. (1989). An evaluation of the Kodak Ektachem clinical chemistry slide for theophylline. Ther. Drug. Monit. II, 93-96. 

S138 Cheung, C.M. and Soldin, S.J. (1986). Clinical evaluation of a dry chemistry strip theophylline assay. Ther. Drug Monit. 8, 205-210. 

SN5 Wallinder, H., Gustafsson, L.L., Angback, K., Hoglund, P., Magnusson, A. and Arvanius, L. (1991). Assay of theophylline in vivo and in vitro evaluation of dry chemistry and immunoassay versus high-performance liquid chromatography. Ther. Drug Monit. 13, 233-239. 

ST97 Michalski, L. (1990). Evaluation and performance characteristics of the Par-amax analytical system for the determination of theophylline in a direct enzymatic method user defined chemistry. Clin. Chem. 36, 1188, Abstr. 1103. 

Fig. 11.1. Separation of some xanthine derivatives Column pBondapak C18 (300x4 rim ID), mobile phase acetonitrile - 0.01 M sodium acetate buffer (pH 4.0) (7 93), flow rate 2.0 ml/min, detection UV 254 nm. Peaks 1, 1-methyluric acid 2, 3-methyl xanthine 3, 1,3-dimethyl-uric acid 4, theobromine 5, theophylline 6, B-hydroxy-ethyltheophylline 7, phenobarbital 8, caffeine 9, 8--chlorotheophyl1ine. (reproduced with permission from ref. 56, by the courtesy of Clinical Chemistry)...

Fig. 14.8 Controlled-dispersion flow analysis manifolds for determination of (a) triglycerides and (b) theophylline, (s sample R reagent c carrier P pump T connector RC reaction coil D detector w waste). (Reproduced from [28] with permission of the Royal Society of Chemistry).

B. F. Rocks, R. A. Sherwood, and C. Riley, Controlled-Dispersion Flow Analysis in Clinical Chemistry Determination of Albumin, Triglycerides and Theophylline. Analyst, 109 (1984) 847. 

T. Kobayashi, H.Y. Wang, N. Fujii, Molecular imprinting of theophylline in acrylonitrile-acrylic acid co-polymer membrane. Chemistry Letters 10 (1995)... 

Much of the early chemistry highlighted the relationships among urea, allantoic acid, aUentoin, and the fully elaborated purines, uric acid, caffeine, theobromine, theophylline, and xanthine (Figure 13.7). 

Figures Chromatograms on MIL-53(Al)-packed column (7-cm longx4.6-mm i.d.) for RP HPLC separation using CHjCN/HjO as mobile phase at l.OmLmin b (a) ethylbenzene and toluene (b) PAHs (c) thiourea (1), phenol (2), aniline (3), benzaldehyde (4), bromobenzene (5), naphthalene (6) (d) o-benzenediol, m-benzenediol, and p-benzenediol (e) aniline, N,N-dimethylaniline, and m-nitroaniline (f) xanthine, theophylline, and caffeine. Mobile phase composition (CHjCN/HjO, v/v) (a) 7 3 (b) 10 0 (c) 6 4 (d) 1 9 (e) 9 1 (f) 5 5. UV detection at 210 run (a, c), 256 run (b), 70 run (f), and 280 nm (d, e). (Reproduced from Ref 69 with permission of The Royal Society of Chemistry. DOI 10.1039/C2AN15925B.)...

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