maleic-acid and glutaric-acid

In this work, three polycrystalline materials containing co-crystals of theophylline with malonic, maleic, and glutaric acids were studied using (13)C, (15)N and (1)H solid-state NMR and FT-IR spectroscopy. The NMR assignments were supported by gauge including projector augmented waves (GIPAW) calculations of chemical shielding, performed using X-ray determined geometry. The experimental (13)C cross polarization/magic angle spinning (CP/MAS) NMR results and the calculated isotropic chemical shifts were in excellent agreement. A rapid and convenient method for theophylline co-crystals crystal structure analysis has been proposed for co-crystals, which are potentially new APIs.

Topics: Chemistry, Pharmaceutical; Crystallization; Crystallography, X-Ray; Dicarboxylic Acids; Glutarates; Hydrogen Bonding; Kinetics; Magnetic Resonance Spectroscopy; Maleates; Malonates; Molecular Structure; Spectroscopy, Fourier Transform Infrared; Technology, Pharmaceutical; Theophylline

The crystal form adopted by the respiratory drug theophylline was modified using a crystal engineering strategy in order to search for a solid material with improved physical stability. Cocrystals, also referred to as crystalline molecular complexes, were prepared with theophylline and one of several dicarboxylic acids. Four cocrystals of theophylline are reported, one each with oxalic, malonic, maleic and glutaric acids. Crystal structures were obtained for each cocrystal material, allowing an examination of the hydrogen bonding and crystal packing features. The cocrystal design scheme was partly based upon a series of recently reported cocrystals of the molecular analogue, caffeine, and comparisons in packing features are drawn between the two cocrystal series. The theophylline cocrystals were subjected to relative humidity challenges in order to assess their stability in relation to crystalline theophylline anhydrate and the equivalent caffeine cocrystals. None of the cocrystals in this study converted into a hydrated cocrystal upon storage at high relative humidity. Furthermore, the theophylline:oxalic acid cocrystal demonstrated superior humidity stability to theophylline anhydrate under the conditions examined, while the other cocrystals appeared to offer comparable stability to that of theophylline anhydrate. The results demonstrate the feasibility of pharmaceutical cocrystal design based upon the crystallization preferences of a molecular analogue, and furthermore show that avoidance of hydrate formation and improvement in physical stability is possible via pharmaceutical cocrystallization.

Topics: Bronchodilator Agents; Chemistry, Pharmaceutical; Crystallization; Dicarboxylic Acids; Drug Stability; Feasibility Studies; Glutarates; Hydrogen Bonding; Maleates; Malonates; Molecular Structure; Oxalic Acid; Theophylline; Water

In this work, PM(10) samples were collected in a winter and a summer in Christchurch, a New Zealand city having intensive wood and coal burning and a serious air pollution problem in winter. Oxalic, malonic, succinic, maleic, glutaric and adipic acids in the samples were analysed using ion chromatography. It was suggested that solid fuel burning had large influence on the occurrence of these low molecular weight dicarboxylic acids resulting in significantly higher wintertime concentrations of maleic acid, oxalic acid and glutaric or adipic acid. The most pronounced feature observed was that maleic acid was the second most abundant species of the detected DCAs in the winter (with a mean of 74 ngm(-3) and the highest concentration ever reported of 231 ngm(-3)). In contrast, malonic acid experienced a low abundance in both seasons. The observed seasonal patterns and molecular distribution were inconsistent with those in most other urban areas. On an average, the total detected dicarboxylic acids accounted for about 0.5% of PM(10) mass with a maximum of 1.4% in the winter. The relative importance of different sources to individual dicarboxylic acids varied with seasons and is discussed in detail.

Topics: Adipates; Air Pollutants; Cities; Coal; Dicarboxylic Acids; Environmental Monitoring; Glutarates; Maleates; Molecular Weight; New Zealand; Oxalic Acid; Particle Size; Seasons; Wood

Sodium borohydride and sodium cyanoborohydride were assessed as potential reagents for determining ligand-induced changes in accessibility to the active-site of aspartate aminotransferase. Rates of reduction of the imine formed between Lys258 and pyridoxal phosphate were determined in the presence of increasing concentrations of the dicarboxylate substrate analogues glutarate and maleate. The rate of reduction decreased to a limiting value which was about 40-fold lower than the equivalent rate in the absence of dicarboxylate. Analysis of the reaction was complicated by the increasing protonation of the imine which accompanied binding of dicarboxylates. Allowing for this increase, the true decrease in accessibility to NaBH3CN was estimated to be approximately 400-fold. Arguments are presented in support of a proposal that the ratio of closed to open conformer of the dicarboxylate-liganded enzyme is approximately 150. The effects of increasing ligand concentration on the reactivity of Cys390 were found to take place in the same range as was observed for NaBH3CN reduction. Conversely, very much higher concentrations of the dicarboxylates were required to protect against proteolysis by trypsin. It is concluded that NaBH3CN reduction and reactivity of cysteine are good determinants of the conformational status of the enzyme but that resistance to tryptic digestion is due to an additional binding mode for the dicarboxylates.

Topics: Animals; Aspartate Aminotransferases; Borohydrides; Cysteine; Glutarates; Hydrolysis; Kinetics; Ligands; Maleates; Molecular Probes; Myocardium; Oxidation-Reduction; Protein Conformation; Swine