A Twist in Cocrystals of Salts: Changes in Packing and Chloride Coordination Lead to Opposite Trends in the Biopharmaceutical Performance of Fluoroquinolone Hydrochloride Cocrystals
A Twist in Cocrystals of Salts: Changes in Packing and Chloride Coordination Lead to Opposite Trends in the Biopharmaceutical Performance of Fluoroquinolone Hydrochloride Cocrystals
复制标题
DOI：
10.1021/cg500345a
复制
发表时间：
2014-06-01
影响因子：
3.8
通讯作者：
Senosiain, Juan P.
中科院分区：
文献类型：
--
作者：
Martinez-Alejo, Juan M.;Dominguez-Chavez, Jorge G.;Senosiain, Juan P.
氟喹诺酮类药物是广泛使用的抗生素，通常作为盐酸盐处方，因为中性形式由于其两性离子性质而表现出低溶解度。以环丙沙星盐酸盐（CiHCl）或（S，S）-莫西沙星盐酸盐（MoHCl）与4-羟基苯甲酸（4HBA）为共晶成体，以盐/共晶化学计量比为1:1得到了CiHCl-4HBA和MoHCl-4HBA两种共晶固体。通过x射线粉末衍射分析鉴定了共晶相，并用红外光谱、热重分析-差示扫描量热法和单晶x射线衍射分析对其进行了表征。新的固相可以通过不同的方法形成，即溶液介导相变、溶剂滴磨、溶剂蒸发结晶和反应结晶。考察了其相稳定性、热力学溶解度和溶解速率等药学相关性质。当悬浮在酸性水溶液中时，所有的共晶相保持稳定，并且在加速温度/相对湿度下暴露30天不发生转变。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的热稳定性、溶解度和溶解速率方面表现出相反的趋势。加热后，CiHCl- 4hba共晶在分解前先释放共晶，与CiHCl中心点1.34H(2)O相比，其溶解度和溶解速率较低。与母体莫西沙星盐相比，mohl - 4hba共晶在单相转变过程中熔融，溶解度和溶解速率均有所提高。本文所研究的共晶的相似组成和氟喹诺酮类化合物的结构相似，可以对固态的超分子结构和物理化学性质进行详细的面对面比较。4HBA在晶格中的掺入引起了离子组分（氯离子和氟喹啉离子）分子间相互作用的数量、类型和强度的变化，这可能与溶解度和溶解速率性质有关。虽然共晶cihl - 4hba保留了初始盐酸盐的超分子组装的基本特征，并与共晶前体形成了一个整体的三维氢键网络，但mohl - 4hba表现出单一的二维组装。4HBA分子与氯离子之间通过O-H中心，Cl中心，Cl中心，H- o氢键形成线性链，取代了通常的带电辅助N+-> H中心，Cl-中心，Cl-中心相互作用。
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 analysis-differential 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 center dot 1.34H(2)O. 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 center dot center dot center dot Cl-center dot center dot center dot H-O hydrogen bonds in place of the usual charged-assisted N+-> H center dot center dot center dot Cl- interactions.