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.

The enantioseparation process is of great interest to the pharmaceutical industry since more than 50% of the pharmaceutically active ingredients are known to be chiral and one enantiomer is usually preferred over the racemic mixture. Crystallization is widely used as the final step to reject the enantiomeric impurity from a mixture. Yet, a fundamental guidance on developing a purification procedure for systems forming racemic compounds (which account for more than 90% of all chiral systems) is not available. In this work, it is shown that the enantiomeric excess (ee) of the eutectic point is the key information needed to assess the feasibility of a crystallization process and to predict the purity and the yield of the product. In a dilute solution, the eutectic ee is determined solely by a eutectic constant (K eu), a new parameter introduced in this paper. K eu is defined as the ratio of the activity of the major enantiomer to that of the minor enantiomer. A eutectic constant equation was derived from the basics of thermodynamics, and for the first time, it was shown that the K eu is independent of solvent if no solvates are formed but varies with temperature. With an understanding of how the eutectic ee changes with solvent and temperature, the time and material required in developing a crystallization procedure for ee enhancement can be dramatically reduced. This theory was supported by experimental data, and its application was demonstrated on a system of pharmaceutical interest.

The relative gas‐phase basicities of eight reference compounds (α‐methylstyrene, isopropyl ether, n‐pentyl ether, 2,4‐dimethyl‐3‐pentanone, methyl benzoate, n‐butyl ether, methyl trimethylacetate, and methyl cyclopropanecarboxylate) are redetermined by FT/ICR MS and are now self‐consistent to less than 0.8 kJ/mol.

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A thermally induced irreversible conformational transition of amylose tris(3,5-dimethylphenylcarbamate) (i.e., Chiralpak AD) chiral stationary phase (CSP) in the enantioseparation of dihydropyrimidinone (DHP) acid racemate was studied for the first time by quasi-equilibrated liquid chromatography with cyclic van't Hoff and step temperature programs and solid-state ((13)C CPMAS and (19)F MAS) NMR using ethanol and trifluoroacetic acid (TFA)-modified n-hexane as the mobile phase. The conformational transition was controlled by a single kinetically driven process, as evidenced by the chromatographic studies. Solid-state NMR was used to study the effect of the temperature on the conformational change of the solvated phase (with or without the DHP acid enantiomers and TFA) and provided some viable structural information about the CSP and the enantiomers.

Molecular dynamics simulation techniques are used to analyze damage production in Ge by the thermal spike process and to compare the results to those obtained for Si. As simulation results are sensitive to the choice of the inter-atomic potential, several potentials are compared in terms of material properties relevant for damage generation, and the most suitable potentials for this kind of analysis are identified. A simplified simulation scheme is used to characterize, in a controlled way, the damage generation through the local melting of regions in which energy is deposited. Our results show the outstanding role of thermal spikes in Ge, since the lower melting temperature and thermal conductivity of Ge make this process much more efficient in terms of damage generation than in Si. The study is extended to the modeling of full implant cascades, in which both collision events and thermal spikes coexist. Our simulations reveal the existence of bigger damaged or amorphous regions in Ge than in Si, which may be formed by the melting and successive quenching induced by thermal spikes. In the particular case of heavy ion implantation, defect structures in Ge are not only bigger, but they also present a larger net content in vacancies than in Si, which may act as precursors for the growth of voids and the subsequent formation of honeycomb-like structures.

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