期刊
JOURNAL OF PHARMACEUTICAL SCIENCES
卷 107, 期 6, 页码 1667-1679出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.xphs.2018.02.014
关键词
tuberculosis; fixed dose combination; isonicotinyl hydrazone; isoniazid; pyrazinamide; rifampicin; ethambutol dihydrochloride
资金
- JC Bose Fellowship [SR/S2/JCB-06/2009]
- CSIR [02/0223/15/EMR-II]
- SERB [EMR/2015/002075]
- UGC
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 degrees 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 center dot center dot center dot O synthon in the crystal structure. (c) 2018 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.
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