New Cocrystals of Hydrochlorothiazide: Optimizing Solubility and Membrane Diffusivity
New Cocrystals of Hydrochlorothiazide: Optimizing Solubility and Membrane Diffusivity
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DOI：
10.1021/acs.cgd.6b01540
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发表时间：
2017-01-01
影响因子：
3.8
通讯作者：
Desiraju, Gautam R.
中科院分区：
文献类型：
--
作者：
Gopi, Shanmukha Prasad;Banik, Manas;Desiraju, Gautam R.
氢氯噻嗪（HCT）是一种溶解度和渗透性较差的利尿药。使用机械化学研磨（液体辅助和纯研磨），通过与哌嗪 (PPZ)、四甲基吡嗪 (TMPZ)、吡啶酰胺 (PCM)、异烟肼 (INZ)、丙二酰胺 (MAM) 和异烟酸 (INIC) 共结晶，改变了 HCT 的物理化学性质。通过单晶 X 射线衍射 (SCXRD)、粉末 X 射线衍射、傅里叶变换红外光谱和差示扫描量热法对获得的固体进行表征，并进行溶解度和膜渗透性研究。 SCXRD 显示纯 HCT 的稳定多晶型物中发现的 N-H...O 磺酰胺联体合成子已被共晶中的药物共形成体杂合成子所取代。与母体活性药物成分相比，HCT-PPZ 和 HCT-PCM 共晶在溶解度和膜渗透性/扩散方面表现出改善。溶解度和扩散速率的提高归因于新固体形式中药物-共形成体的相互作用。检查结构-性质关系以评估新固体形式的溶解度和扩散速率。以前用常规方法无法制备的INIC共晶是通过长时间研磨6天获得的。
Hydrochlorothiazide (HCT) is a diuretic drug with poor solubility and permeability. Physicochemical properties of HCT have been modified by cocrystallization with piperazine (PPZ), tetramethylpyrazine (TMPZ), picolinamide (PCM), isoniazid (INZ), malonamide (MAM), and isonicotinic acid (INIC) using mechanochemical grinding (liquid assisted and neat). The solids obtained were characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction, Fourier transform infrared spectroscopy, and differential scanning calorimetry and subjected to solubility and membrane permeability studies. SCXRD showed that the N-H...O sulfonamide catemer synthons found in the stable polymorph of pure HCT have been replaced by drug-coformer heterosynthons in the cocrystals. HCT-PPZ and HCT-PCM cocrystals showed improvement in solubility and membrane permeability/diffusion compared to the parent active pharmaceutical ingredient. The improved solubility and diffusion rates are due to the drug-coformer interactions in the new solid forms. A structure-property relationship is examined to evaluate the solubility and diffusion rates of the new solid forms. The cocrystal with INIC, which could not be prepared previously by conventional methods, was obtained by prolonged grinding for 6 days.