Some New Soluble Forms of Theophylline

Holbert, James M.; Grote, I.W.; LeMAISTRE, J. W.

doi:10.1002/jps.3030381008

Cited by 2 publications

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“…Theophylline (1,3-dimethyl-7H-purine-2,6-dione, or 1,3-dimethylxanthine, Figure ) is used in treatment of respiratory diseases such as acute asthma, although its use is hindered by low solubility and conversion between anhydrous and hydrated forms. The solubility and physical stability at elevated relative humidity are often improved by the addition of acid or base “guest” compounds ,– to form a complex (salt or co-crystal), and theophylline is therefore an ideal compound for investigating properties relating to its complexes.…”

Section: Introductionmentioning

confidence: 99%

Identification of Protonation State by XPS, Solid-State NMR, and DFT: Characterization of the Nature of a New Theophylline Complex by Experimental and Computational Methods

et al. 2010

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Recent studies suggested that X-ray photoelectron spectroscopy (XPS) sensitively determines the protonation state of nitrogen functional groups in the solid state, providing a means for distinguishing between co-crystals and salts of organic compounds. Here we describe how a new theophylline complex with 5-sulfosalicylic acid dihydrate was established as a salt by XPS prior to assignment with conventional methods. The presence of a C=NH(+) (N9) N1s peak in XPS allows assignment as a salt, while this peak is clearly absent for a theophylline co-crystal. The large low frequency shift for N9 observed by (15)N solid-state nuclear magnetic resonance spectroscopy (ssNMR) and corresponding density functional theory (DFT) calculations confirm that protonation has occurred. The crystal structure and further analytical studies confirm the conclusions reached with XPS and ssNMR. This study demonstrates XPS as an alternative technique for determining whether proton transfer has occurred in acid-base complexes.

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Section: Introductionmentioning

confidence: 99%

Identification of Protonation State by XPS, Solid-State NMR, and DFT: Characterization of the Nature of a New Theophylline Complex by Experimental and Computational Methods

et al. 2010

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“…15,[21][22][23][24] Theophylline (1,3-dimethyl-7H-purine-2,6-dione, or 1,3-dimethylxanthine, Figure 1) is used in treatment of acute asthma, tremor therapy, and as a diuretic, although it is limited 7,25 by its low solubility and conversion between anhydrous and monohydrate forms. The low water solubility of theophylline can be improved by the addition of acid or base "guest" molecules [26][27][28][29][30] to form a complex (salt or co-crystal), as theophylline is amphoteric. Formation of co-crystals and salts has also been studied in order to improve the stability of anhydrous theophylline on exposure to elevated relative humidity (RH), 7,21 as interconversion between the anhydrous and monohydrate forms are known to occur as a function of RH.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Proton Transfer in Co-Crystals by X-ray Photoelectron Spectroscopy (XPS)

Stevens

Byard

Schroeder

2010

Crystal Growth & Design

113

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Characterization at the molecular level establishes X-ray photoelectron spectroscopy (XPS) as a useful technique for determining the extent of proton transfer in molecular crystals by studying theophylline-citric acid co-crystals alongside solid-state nuclear magnetic resonance (ssNMR) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). A complex has been formed by milling theophylline with either anhydrous or monohydrate citric acid and established as a 1:1 co-crystal by a combination of both conventional and novel analytical methods. The absence of peaks from the starting materials in the X-ray diffraction powder pattern indicates that the product was formed quantitatively, with elemental analysis and XPS revealing a 1:1 stoichiometry. Thermogravimetric analysis demonstrated the complex was anhydrous, with differential scanning calorimetry showing a melting temperature different from that of the starting materials. The absence of a CNH+ N1s peak in XPS and the small magnitude of 15N ssNMR and ATR-FTIR shifts relative to anhydrous theophylline revealed that proton transfer, and hence salt formation, had not occurred. The combination of analytical techniques allows the complex to be assigned as a 1:1 co-crystal without the need for a single crystal structure.

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Some New Soluble Forms of Theophylline

Cited by 2 publications

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Identification of Protonation State by XPS, Solid-State NMR, and DFT: Characterization of the Nature of a New Theophylline Complex by Experimental and Computational Methods

Identification of Protonation State by XPS, Solid-State NMR, and DFT: Characterization of the Nature of a New Theophylline Complex by Experimental and Computational Methods

Characterization of Proton Transfer in Co-Crystals by X-ray Photoelectron Spectroscopy (XPS)

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