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首页> 外文期刊>Crystal growth & design >Preparation and solid-state characterization of nonstoichiometric cocrystals off a phosphodiesterase-IV inhibitor annul L-tartaric acid
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Preparation and solid-state characterization of nonstoichiometric cocrystals off a phosphodiesterase-IV inhibitor annul L-tartaric acid

机译：磷酸二酯酶-IV抑制剂环戊二酸-酒石酸的非化学计量共晶体的制备和固态表征

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摘要

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 hemiartrate 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.
机译：此处报道了L-883555，磷酸二酯酶IV抑制剂和L-酒石酸的一系列非化学计量，同构，共晶复合物的证据，化学计量比范围为0.3：1至0.9：1。该化合物的游离碱形式的生物利用度不足，因此无法开发为安全性评估研究的候选者。在尝试成盐的过程中产生了几种L-酒石酸络合物，目的是提高生物利用度。已经发现，可以通过调节反应混合物中酸：碱的比例来控制掺入共结晶配合物中的L-酒石酸的量，而不会伴随酸和碱之间的质子转移。使用光谱技术来定位酸和碱之间的分子间相互作用的位点，该碱为L​​-酒石酸的碱中的N-氧化物基团。对各种配合物的降解行为的热分析和光谱分析表明，在那些化学计量比> 0.5：1的配合物中，酸和碱之间至少存在两种​​结合类型。发现标准的半酒石酸酯复合物比其他复合物更热稳定，酸：碱的化学计量比小于或大于0.5：1，并且发现其生物利用度比猕猴中的游离碱高得多。这项工作表明在不发生常规质子转移形成真正的盐的情况下，设计一种合适的共晶配合物的潜力，该配合物由酸与碱之间的良好相互作用驱动，从而为吸收不良的化合物提供了提高生物利用度的途径。

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