Preparation and Solid-State Characterization of Nonstoichiometric Cocrystals of a Phosphodiesterase-IV Inhibitor and l-Tartaric Acid

Abstract

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.

Characterization and recovery of tartaric acid from wastes of wine and grape juice industries

“…Peaks in this IR region certainly arose from stretching of the C=O bond of the carboxylic acids [8]. Also, Variankaval et al found three important IR band regions for calibration of tartaric acid that were between 1500-850, 1801-1500 and 3000-2800 cm -1 [9].…”

From form to function: Crystallization of active pharmaceutical ingredients

“…Solvates and hydrates are typically excluded from this list. Such crystal forms could offer advantages in terms of bioavailability, 18,19 stability, and the ability to extend the product portfolio if sufficient advantages can be demonstrated by developing the cocrystal compared to the neutral form.…”

Small-Scale Assays for Studying Dissolution of Pharmaceutical Cocrystals for Oral Administration

“…Cocrystals can significantly increase the bioavailability of poorly soluble compounds based on limited animal bioavailability studies (11)(12)(13)(14), but it should be noted that up to now, there are no human bioavailability studies available to validate the cocrystal effect on human pharmacokinetics. Some general conclusions concerning cocrystal effects on pharmacokinetics can be revealed by an analysis performed by Shan et al (10) based on animal data from 64 cocrystals involving 21 APIs, with 80% of the studied APIs from BCS class II (10).…”