通过制备三种塞来昔布低共熔混合物以提高其水溶性和可压片性

doi:10.5246/jcps.2026.07.045

摘要/Abstract

摘要：

塞来昔布(Cel)属于生物药剂学分类系统(BCS)II类药物，其水溶性极差，且粉末力学性能不佳，难以满足片剂制剂开发的要求。本研究分别制备了塞来昔布与对氨基苯甲酸(Paba)、吡啶甲酰胺(Pca)及异烟酰胺(Isa)的三种低共熔混合物(EM)，以改善塞来昔布的上述性能，并采用差示扫描量热法(DSC)、粉末X射线衍射法(PXRD)和傅里叶变换红外光谱法(FTIR)对其进行表征。本研究对这些低共熔混合物开展了二元相图分析及体外特性研究，涵盖平衡溶解度、溶出度和可压片性分析。结果表明，制备塞来昔布低共熔混合物可显著改善其药剂学性能：塞来昔布-异烟酰胺低共熔混合物的平衡溶解度为原料药的1.7倍；塞来昔布-对氨基苯甲酸低共熔混合物的最大溶出度约为原料药的2倍。此外，三种低共熔混合物的抗张强度均高于片剂成型所需的1.7 MPa临界抗张强度，可用于直接压片工艺。

关键词: 塞来昔布, 低共熔混合物, 可压片性, 溶解度

Abstract:

Celecoxib (Cel), categorized as a Biopharmaceutics Classification System (BCS) Class II compound, exhibits extremely limited aqueous solubility together with inadequate powder mechanical performance, thereby posing substantial challenges for conventional tablet formulation. To address these limitations, three eutectic mixtures (EMs) of Cel were systematically developed using p-aminobenzoic acid (Paba), pyridinecarboxamid (Pca), and isonicotinamide (Isa) as coformers. The resulting systems were thoroughly characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier-transform infrared spectroscopy (FTIR). A comprehensive physicochemical evaluation was subsequently conducted, including the construction of binary phase diagrams as well as in vitro assessments encompassing equilibrium solubility, dissolution behavior, and tabletability profiling. The formation of eutectic systems markedly enhanced the pharmaceutical performance of Cel across multiple dimensions. Notably, the equilibrium solubility of the Cel-Isa eutectic increased to approximately 1.7-fold relative to pristine Cel, while the Cel-Paba system exhibited a nearly twofold enhancement in maximum dissolution. In addition, all eutectic formulations demonstrated tensile strengths exceeding the critical threshold of 1.7 MPa required for robust tablet formation, indicating substantially improved compactibility. Collectively, these findings highlighted that all three EMs possessed suitable mechanical integrity for direct compression, thereby offering a promising and practical strategy for improving both the biopharmaceutical and manufacturability attributes of Cel.

Key words: Celecoxib, Eutectic mixture, Tabletability, Solubility

Supporting:

银翎, 刘晶晶, 张东, 余先萍, 孙黄辉, 邓月义. 通过制备三种塞来昔布低共熔混合物以提高其水溶性和可压片性[J]. 中国药学(英文版), 2026, 35(7): 630-642.

Ling Yin, Jingjing Liu, Dong Zhang, Xianping Yu, Huanghui Sun, Yueyi Deng. Improving the solubility and tabletability of Celecoxib by preparing its three eutectic mixtures[J]. Journal of Chinese Pharmaceutical Sciences, 2026, 35(7): 630-642.

图/表 7

Figure 1. Structures of Cel, Paba, Pca, Isa.

Figure 2. DSC curves and binary phase diagram. (a) DSC curves of Cel, Paba, alone, and different proportions of Cel-Paba mixtures; (b) DSC curves of Cel, Pca, alone, and different proportions of Cel-Pca mixtures; (c) DSC curves of Cel, Isa, alone, and different proportions of Cel-Isa mixtures; (d) Binary phase diagram of Cel-Paba EM; (e) Binary phase diagram of Cel-Pca EM; (f) Binary phase diagram of Cel-Isa EM.

Figure 3. X-ray diffractograms of Cel, Paba, Pca, Isa, and EM.

Figure 4. The FTIR spectra of Cel with Paba, Pca, Isa, and their EMs.

Figure 5. Equilibrium solubility of EMs prepared from Cel with Paba, Pca, and Isa.

Figure 6. Dissolution curves of EMs. (a) Dissolution curves of Cel, Cel-Paba-PM, and Cel-Paba-EM; (b) Dissolution curves of Cel, Cel-Pca-PM, and Cel-Pca-EM; (c) Dissolution curves of Cel, Cel-Isa-PM, and Cel-Isa-EM.

Figure 7. Tensile strength curves of EMs prepared from Cel, Paba, Pca, and Isa.

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