Patel Himanshu, Stalcup Apryll, Dansereau Richard, Sakr Adel
College of Pharmacy, University of Cincinnati, 3223 Eden Ave., Cincinnati, OH 45219, USA.
Int J Pharm. 2003 Oct 2;264(1-2):35-43. doi: 10.1016/s0378-5173(03)00387-9.
Levothyroxine tablets, 50 microg, have been marketed for many decades but have had numerous recalls due to degradation and failure to meet potency. These experiments were devised to study the effects of various excipients on the stability of levothyroxine sodium pentahydrate in aqueous slurries and in formulated tablets. The active alone was found to be stable in the solid state for 6 months at 40 degrees C/75% RH whether stored in open or closed containers, and was found to be non-hygroscopic under normal processing conditions (>30% RH). In aqueous slurries with an excipient, the stability of the active improved as the pH of the slurry was increased from pH 3 to 11. Tablets manufactured with lactose anhydrous, starch, or microcrystalline cellulose failed to meet USP assay requirements at 3 months at 40 degrees C/75% RH. Tablets manufactured with dibasic calcium phosphate or mannitol met USP assay requirements at 3, but not 6 months when stored at 40 degrees C/75% RH. Tablets manufactured with dibasic calcium phosphate and a basic pH modifier, such as sodium carbonate, sodium bicarbonate, or magnesium oxide, met the USP assay requirements at both 3 and 6 months. Thus, the use of basic pH modifiers is a potential technique for improving the stability of levothyroxine sodium pentahydrate tablets.
50微克的左甲状腺素片已上市数十年，但因降解和效价不达标而多次被召回。设计这些实验是为了研究各种辅料对五水合左甲状腺素钠在水性浆料和制成片剂中的稳定性的影响。单独的活性成分在40℃/75%相对湿度下，无论储存在开放或密闭容器中，在固态下6个月都是稳定的，并且在正常加工条件下（>30%相对湿度）被发现是非吸湿的。在含有辅料的水性浆料中，随着浆料pH值从pH 3增加到11，活性成分的稳定性提高。用无水乳糖、淀粉或微晶纤维素制成的片剂在40℃/75%相对湿度下3个月时未能达到美国药典的含量测定要求。用磷酸氢钙或甘露醇制成的片剂在40℃/75%相对湿度下储存3个月时符合美国药典含量测定要求，但6个月时不符合。用磷酸氢钙和碱性pH调节剂（如碳酸钠、碳酸氢钠或氧化镁）制成的片剂在3个月和6个月时均符合美国药典含量测定要求。因此，使用碱性pH调节剂是提高五水合左甲状腺素钠片稳定性的一种潜在技术。
