To employ crystal engineering for the design and synthesis of a series of novel salts/cocrystals incorporating phenolic acids, aiming to modulate the solubility of gefitinib (GEF), a multifunctional antineoplastic drug, five distinct solid forms of GEF salts/cocrystals were successfully obtained for the first time, including two salts (3-hydroxybenzoic acid, 3-HBA, and ferulic acid, FA), one cocrystal (4-hydroxybenzoic acid, 4-HBA), and two salt cocrystals (3,5-dinitrobenzoic acid, 35DNB, and salicylic acid, SA). Characterization of the new forms was conducted using single crystal and powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, and Fourier transform infrared spectroscopy. ΔpK_a analyses and C–O bond length analyses were applied to differentiate between the salts and cocrystals of GEF with various phenolic acids. The solubility and stability of the solid samples were also assessed, revealing significant enhancements in solubility and superior stability under specific temperature, humidity, and light conditions for the new salts/cocrystals. These findings suggest that the newly synthesized salts/cocrystals GEF–SA, GEF–3-HBA, and GEF–4-HBA hold promise as potential candidates for improving the aqueous solubility of GEF.

中文翻译：

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吉非替尼盐/酚酸共晶体是一种有前景的提高溶解度的固态方法

为了利用晶体工程设计和合成一系列含有酚酸的新型盐/共晶，旨在调节多功能抗肿瘤药物吉非替尼（GEF）的溶解度，成功获得了五种不同固体形式的GEF盐/共晶首次，包括两种盐（3-羟基苯甲酸，3-HBA和阿魏酸，FA），一种共晶（4-羟基苯甲酸，4-HBA）和两种盐共晶（3,5-二硝基苯甲酸，35DNB）和水杨酸，SA）。使用单晶和粉末 X 射线衍射、差示扫描量热法、热重分析和傅里叶变换红外光谱对新形式进行了表征。应用Δp Ka_分析和 C-O 键长分析来区分 GEF 与各种酚酸的盐和共晶。还评估了固体样品的溶解度和稳定性，结果表明新盐/共晶在特定温度、湿度和光照条件下溶解度显着增强且稳定性优异。这些发现表明，新合成的盐/共晶体 GEF-SA、GEF-3-HBA 和 GEF-4-HBA 有希望成为改善 GEF 水溶性的潜在候选物。