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首页> 外文期刊>Crystal growth & design >A Twist in Cocrystals of Salts: Changes in Packing and Chloride Coordination Lead to Opposite Trends in the Biopharmaceutical Performance of Fluoroquinolone Hydrochloride Cocrystals
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A Twist in Cocrystals of Salts: Changes in Packing and Chloride Coordination Lead to Opposite Trends in the Biopharmaceutical Performance of Fluoroquinolone Hydrochloride Cocrystals

机译：盐共晶体的扭曲：堆积和氯化物配位的变化导致氟喹诺酮盐酸盐共晶体生物制药性能的相反趋势

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Fluoroquinolones are extensively used antibiotics that are generally prescribed as hydrochloride salts because the neutral forms display low solubility due to their zwitterionic character. Starting from the hydrochloride salts of ciprofloxacin(CiHCl) or (S,S)-moxifloxacin (MoHCl) and 4-hydroxybenzoic acid (4HBA) as a cocrystal former, two cocrystalline solids, CiHCl~?4HBA and MoHCl~?4HBA, were obtained in a salt/ coformer stoichiometric ratio of 1:1. The cocrystalline phases were identified by X-ray powder diffraction analysis and further characterized by IR spectroscopy, thermogravimetric analysisdifferential scanning calorimetry, and single crystal X-ray diffraction analysis. The novel solid phases could be formed using different methodologies, namely, solution-mediated phase transformation, solvent drop grinding, crystallization by solvent evaporation, and reaction crystallization. Pharmaceutically relevant properties such as phase stability, thermodynamic solubility, and dissolution rate were examined. All cocrystalline phases remained stable when suspended in acidic aqueous solutions and did not transform upon accelerated temperature/relative humidity exposition for 30 days. Interestingly, opposite trends in the thermal stability, solubility, and dissolution rate of the cocrystals were exhibited by the different fluoroquinolones in comparison to the parent starting salts. Upon heating, the CiHCl~?4HBA cocrystal releases first the coformer before decomposing and displayed a lower solubility and dissolution rate in comparison to CiHCl·1.34H_2O. By contrast, the MoHCl~?4HBA cocrystal melts in a single-phase transition process and showed enhanced solubility and dissolution rate when compared to the parent moxifloxacin salt. The similar composition of the cocrystals and the structural resemblance of the fluoroquinolones examined herein allowed for a detailed vis-a?-vis comparison between the supramolecular structures in the solid-state and the physicochemical properties. The incorporation of 4HBA in the crystal lattice caused changes in the number, type, and strength of the intermolecular interactions between the ionic components (chloride and fluoroquinolinium cations), which could be related to the solubility and dissolution rate properties. While the cocrystal CiHCl~?4HBA retained essential features of the supramolecular assembly found also for the starting hydrochloride and gave an overall three-dimensional hydrogen bonded network with the cocrystal former, MoHCl~?4HBA showed a singular two-dimensional assembly, with linear chains formed between the 4HBA molecules and chloride ions through O?H···Cl~?···H?O hydrogen bonds in place of the usual chargedassisted N~+?H···Cl~? interactions.
机译：氟喹诺酮类药物是广泛使用的抗生素，通常被指定为盐酸盐，因为中性形式由于其两性离子特性而显示出低溶解性。从环丙沙星（CiHCl）或（S，S）-莫西沙星（MoHCl）和4-羟基苯甲酸（4HBA）的盐酸盐作为共结晶剂，得到两种共结晶固体，CiHCl〜？4HBA和MoHCl〜？4HBA盐/辅料化学计量比为1：1。共晶相通过X射线粉末衍射分析鉴定，并进一步通过IR光谱，热重分析，差示扫描量热法和单晶X射线衍射分析表征。可以使用不同的方法来形成新的固相，即溶液介导的相变，溶剂滴磨，通过溶剂蒸发的结晶以及反应结晶。检查了药物相关的性质，例如相稳定性，热力学溶解度和溶解速率。当悬浮在酸性水溶液中时，所有共晶相保持稳定，并且在加速的温度/相对湿度下暴露30天未发生转变。有趣的是，与母体起始盐相比，不同的氟喹诺酮类化合物在共晶体的热稳定性，溶解度和溶解速率方面显示出相反的趋势。加热后，CiHCl〜？4HBA共晶体先分解释放出共形成剂，然后分解，与CiHCl·1.34H_2O相比，溶解度和溶解速率更低。相比之下，与母体莫西沙星盐相比，MoHCl〜4HBA共晶体在单相转变过程中熔融并显示出增加的溶解度和溶解速率。共结晶的相似组成和本文检验的氟喹诺酮类化合物的结构相似性允许在固态和物理化学性质之间的超分子结构之间进行详细的目视比较。在晶格中掺入4HBA会导致离子组分（氯化物和氟喹啉鎓阳离子）之间的分子间相互作用的数量，类型和强度发生变化，这可能与溶解度和溶解速率特性有关。共结晶CiHCl〜？4HBA保留了对于起始盐酸盐也发现的超分子组装的基本特征，并与共结晶形成剂形成了一个整体的三维氢键网络，而MoHCl〜？4HBA显示了一个具有线性链的奇异二维组装通过O？H···Cl〜？···H2O氢键形成4HBA分子与氯离子之间的取代基，取代了通常的带电辅助的N〜+？H···Cl〜？互动。

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