Nitazoxanide Cocrystals in Combination with Succinic, Glutaric, and 2,5-Dihydroxybenzoic Acid

Combination of nitazoxanide (NTZ)
with a total of 32 cocrystal
formers gave cocrystals with succinic acid (NTZ-SUC, 2:1) and glutaric
acid (NTZ-GLU, 1:1). Additionally, 2,5-dihydroxybenzoic acid provided
a cocrystal solvate with acetonitrile (NTZ-25DHBA-CH3CN,
1:1:1). All solid phases were characterized by X-ray powder diffraction
analysis, IR spectroscopy, thermogravimetric analysis, differential
scanning calorimetry, and single-crystal X-ray diffraction analysis.
Single-crystal X-ray crystallography revealed that NTZ and the carboxylic
acid cocrystal formers were linked in all three cocrystals through
the same supramolecular heterodimeric synthon, C­(N)­NH···HOOC.
Despite having different stoichiometries, the crystal structures of
NTZ-SUC and NTZ-GLU showed similarities in the supramolecular organization,
both containing two-dimensional layers formed by NTZ molecules, which
were further interconnected by single (NTZ-SUC) and homodimeric entities
(NTZ-GLU) of the cocrystal former. Basic physical stability tests
showed that cocrystals NTZ-SUC and NTZ-GLU are stable at least for
one month under standardized temperature/relative humidity stress
conditions but decompose within 1 h into the corresponding physical
phase mixtures, when exposed to aqueous solutions simulating physiological
gastrointestinal conditions. Measurement of the dissolution rates
gave small increases of the intrinsic dissolution rate constants when
compared with NTZ. Pressure stability tests showed that the cocrystals
support higher pressures (at least up to 60 kg/cm2) than
NTZ.

将硝唑尼特（nitazoxanide, NTZ）与共计32种共晶形成物进行组合，成功制备得到与琥珀酸（NTZ-SUC，摩尔比2:1）及戊二酸（NTZ-GLU，摩尔比1:1）的共晶。此外，2,5-二羟基苯甲酸可与乙腈形成共晶溶剂化物（NTZ-25DHBA-CH₃CN，摩尔比1:1:1）。所有固相产物均通过X射线粉末衍射（X-ray powder diffraction）分析、红外（IR）光谱、热重分析（thermogravimetric analysis）、差示扫描量热法（differential scanning calorimetry）以及单晶X射线衍射分析完成表征。单晶X射线晶体学研究揭示，在三种共晶中，NTZ与羧酸类共晶形成物均通过同一超分子异二聚体合成子C(N)NH···HOOC实现连接。尽管二者化学计量比存在差异，但NTZ-SUC与NTZ-GLU的晶体结构在超分子组装模式上具有相似性：两者均包含由NTZ分子构成的二维层状结构，该层状结构进一步分别通过共晶形成物的单实体（NTZ-SUC）与同二聚体实体（NTZ-GLU）实现相互交联。基础物理稳定性测试结果显示，NTZ-SUC与NTZ-GLU在标准化温度/相对湿度胁迫条件下至少可稳定保存一个月；但当暴露于模拟生理胃肠道环境的水溶液中时，两种共晶会在1小时内分解为对应的物相混合物。溶出速率测试表明，与原始NTZ相比，两种共晶的固有溶出速率常数仅小幅提升。压力稳定性测试则证实，相较于NTZ，两种共晶可承受更高压力（至少可达60 kg/cm²）。