Pharmaceutical salts of ethionamide with GRAS counter ion donors to enhance the solubility
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- 作者：Sunil Kumar Nechipadappu ; Darshak R. Trivedi
- 关键词：API ; active pharmaceutical ingredient ; ETH ; ethionamide ; CNB ; 2-chloro-4-nitrobenzoic acid ; 2 ; 6HBA ; 2 ; 6-dihydroxybenzoic acid ; 2 ; 3HBA ; 2 ; 3-dihydroxybenzoic acid ; DNB ; 2 ; 4-dinitrobenzoic acid ; SCXRD ; single crystal x-ray diffraction ; PXRD ; powder X-ray diffraction ; FT-IR ; Fourier transform infrared ; DSC ; differential scanning calorimetry ; NMR ; nuclear magnetic resonance ; RH ; relative humidity
- 刊名：European Journal of Pharmaceutical Sciences
- 出版年：2017
- 出版时间：1 January 2017
- 年：2017
- 卷：96
- 期：Complete
- 页码：578-589
- 全文大小：2275 K
- 卷排序：96
文摘
Pharmaceutical salts of BCS class II second line anti-tuberculosis drug ethionamide (ETH) with various counter ions namely, 2-chloro-4-nitrobenzoic acid (CNB), 2,6-dihydroxybenzoic acid (2,6HBA), 2,3-dihydroxybenzoic acid (2,3HBA) and 2,4-dinitrobenzoic acid (DNB) were synthesized by crystal engineering approach. All the synthesized salts were characterized by various spectroscopic (NMR, FT-IR,), thermal (DSC & TGA) and PXRD techniques. The crystal structure of the synthesized salts was determined by single-crystal X-ray diffraction techniques. All the reported salts, except ETH-2,3HBA exhibited charge assisted acid pyridine heterosynthon. In ETH-2,3HBA hydoxyl pyridine heterosynthon is observed. In ETH-CNB salt, both ionic and neutral acid pyridine heterosynthon were observed in the asymmetric unit. ETH-DNB salt consists of both partial and complete proton transfer from DNB to ETH in the asymmetric unit. All the synthesized salts were found to be non-hygroscopic at accelerated humid condition (~ 75% RH). Solubility experiment has been performed in purified water and in 0.1 N HCl (pH = 1) solution and found that the solubility of ETH-CNB salt was about eight-fold higher soluble than ETH in purified water. The solubility of synthesized salts follows the order of ETH < ETH-2,3HBA < ETH-2,6HBA < ETH-CNB in purified water.