No abstract

Solid-state NMR (1H/13C CPMAS) was utilized to identify structural differences in amylose tris(3,5-dimethylphenylcarbamate) chiral stationary phase (Chiralpak AD), as a function of mobile-phase composition. Dry Chiralpak AD stationary phase displayed an amorphous CPMAS NMR spectrum. However, CPMAS spectra of Chiralpak AD flushed with organic mobile phases clearly displayed evidence of solvent complexes. Chiralpak AD flushed with nonpolar hexane exhibited solvent complexes with minimal structural perturbation. For Chiralpak AD flushed with hexane containing alcohol modifiers, however, solvent incorporation caused significant difference in conformation distribution as evidenced by increased resolution of 13C peaks in the CPMAS spectrum of the stationary phase. 2-Propanol modifier displayed more efficient displacement of incorporated hexane while forming relatively more distinct/ordered solvent complexes with Chiralpak AD in comparison to ethanol modifier. Reversed elution order and unusual retention behavior on Chiralpak AD as a function of mobile-phase modifier was reported earlier. These chromatographic behaviors are believed to be due to different alterations of the steric environment of the chiral cavities in the CSP by the different mobile-phase modifiers. In addition, on the basis of the chemical shift of C-1 carbon on the amylose backbone, it is possible that Chiralpak AD's structure is a helix with a number of fold less than six.

No abstract

We report the first case of a pharmaceutical cocrystal formed between an inorganic acid and an active pharmaceutical ingredient (API), which enabled us to develop a stable crystalline and bioavailable solid dosage form for pharmaceutical development where otherwise only unstable amorphous free form or salts could have been used.

Evidence for a series of nonstoichiometric, isostructural, cocrystalline complexes of L-883555, a phosphodiesterase-IV inhibitor, and L-tartaric acid with stoichiometries ranging from 0.3:1 to 0.9:1 is reported here. The free base form of this compound had insufficient bioavailability and, hence, could not be developed as a candidate for safety assessment studies. Several L-tartaric acid complexes were produced during an attempted salt-formation process, with the objective of increasing the bioavailability. It was found that the amount of L-tartaric acid incorporated in the cocrystalline complexes could be controlled by adjusting the acid: base ratio in the reaction mixture without accompanying proton transfer between acid and base. Spectroscopic techniques were employed to locate the site of intermolecular interaction between the acid and base as the N-oxide group in the base and the carboxylic acid of L-tartaric acid. Thermal and spectroscopic analysis of the degradation behavior for the various complexes showed the existence of at least two types of binding between the acid and base in those complexes with stoichiometries >0.5:1. The canonical hemitartrate complex was found to be more thermally stable than the other complexes, with acid:base stoichiometries lesser than or greater than 0.5:1 and was found to have much higher bioavailability than the free base in rhesus monkeys. This work shows the potential of designing suitable cocrystalline complexes driven by favorable interactions between an acid and base in cases where conventional proton transfer does not occur to form a true salt, offering a route toward increased bioavailability in poorly absorbed compounds.