School of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Gachibowli, Central University PO, Hyderabad 500 046, India.
School of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Gachibowli, Central University PO, Hyderabad 500 046, India; CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India.
J Pharm Sci. 2018 Jun;107(6):1667-1679. doi: 10.1016/j.xphs.2018.02.014. Epub 2018 Feb 17.
The classic fixed-dose combination (FDC) of 4 tuberculosis drugs, namely rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol dihydrochloride (EDH) has the twin issues of physical stability and RIF cross-reaction in the 4-FDC. The major reason for these quality issues is the interaction between RIF and INH to yield isonicotinyl hydrazone in drug tablets. Pharmaceutical cocrystals of INH with caffeic acid (CFA) (PZA + EDH + RIF + INH-CFA cocrystal) and vanillic acid (VLA) (PZA + EDH + RIF + INH-VLA cocrystal) are able to stabilize the FDC formulation compared with the reference batch (PZA + EDH + RIF + INH). Stability studies under accelerated humidity and temperature stress conditions of 40°C and 75% relative humidity showed that the physical stability of the cocrystal formulation was superior by powder X-ray diffraction and scanning electron microscopy analysis, and chemical purity was analyzed by high-performance liquid chromatography. Changes in the composition and structure were monitored on samples drawn at 7, 15, 22, and 30 days of storage. FDC-INH-CFA cocrystal batch exhibited greater stability compared with FDC-INH-VLA cocrystal and FDC reference drug batches. The superior stability of INH-CFA cocrystal is attributed to the presence of stronger hydrogen bonds and cyclic O-H⋯O synthon in the crystal structure.
经典的 4 种结核病药物固定剂量组合（FDC），即利福平（RIF）、异烟肼（INH）、吡嗪酰胺（PZA）和盐酸乙胺丁醇（EDH），存在物理稳定性和 4-FDC 中 RIF 交叉反应这两个问题。这些质量问题的主要原因是 RIF 和 INH 之间的相互作用，导致药物片剂中生成异烟酰肼。INH 与咖啡酸（CFA）（PZA+EDH+RIF+INH-CFA 共晶）和香草酸（VLA）（PZA+EDH+RIF+INH-VLA 共晶）的药物共晶能够稳定 FDC 配方，与参比批次（PZA+EDH+RIF+INH）相比。在 40°C 和 75%相对湿度的加速湿度和温度应激条件下进行的稳定性研究表明，通过粉末 X 射线衍射和扫描电子显微镜分析，共晶配方的物理稳定性更好，通过高效液相色谱法分析化学纯度。在储存 7、15、22 和 30 天的样品上监测组成和结构的变化。与 FDC-INH-VLA 共晶和 FDC 参比药物批次相比，FDC-INH-CFA 共晶批次表现出更好的稳定性。INH-CFA 共晶的稳定性更好，是由于其晶体结构中存在更强的氢键和环状 O-H⋯O 缩合键。
