Mohammad A, Yang Y, Khan M A, Faustino P J
Food and Drug Administration, Center for Drug Evaluation and Research, Division of Product Quality Research , Silver Spring, MD , USA.
Clin Toxicol (Phila). 2015 Feb;53(2):102-7. doi: 10.3109/15563650.2014.998337. Epub 2015 Jan 22.
Prussian blue, ferric hexacyanoferrate is approved for (oral) treatment of internal contamination with radioisotopes of cesium or thallium. Cyanide makes up 35-40% of Prussian blue's molecular composition; thus, cyanide may be released during transit through the digestive tract under physiological pH conditions.
The purpose of this study is to assess the long-term stability of Prussian blue drug products and active pharmaceutical ingredients and its impact on cyanide release. The study involves the determination and comparison of the loss in water content and cyanide released from Prussian blue under pH conditions that bracket human physiological exposure.
Test samples of active pharmaceutical ingredient and drug product were stored for 10 years at ambient temperatures that mimic warehouse storage conditions. Water loss from Prussian blue was measured using thermogravimetric analysis. An in vitro physiological pH model that brackets gastric exposure and gastrointestinal transit was utilized for cyanide release. Prussian blue was incubated in situ at pH: 1.0, 5.0, and 7.0 @ 37°C for 1-24 h. Cyanide was measured using a validated colorimetric method by UV-Vis spectroscopy.
Although the water content (quality attribute) of Prussian blue active pharmaceutical ingredient and drug product decreased by about 10.5% and 13.8%, respectively, since 2003, the cyanide release remained comparable. At pH of 7.0 for 24 h cyanide released from active pharmaceutical ingredient-1 was 21.33 ± 1.76 μg/g in 2004, and 28.45 ± 3.15 μg/g in 2013; cyanide released from drug product-1 was 21.89 ± 0.56 μg/g in 2004, and 27.31 ± 5.78 μg/g in 2013. At gastric pH of 1.0 and upper gastrointestinal pH of 5.0, the data for active pharmaceutical ingredients and drug products were also comparable in 2013. The cyanide release is still pH-dependent and follows the same trend as observed in 2003 with minimum release at pH of 5.0 and maximal release at pH of 1.0. In summary, this is the long-term stability study of Prussian blue which correlates cyanide release to water loss. Cyanide released from Prussian blue was maximum at pH of 1.0 (47.47 μg/g) and minimum at pH of 5.0-7.0 (20.01 μg/g).
Based on maximal dose, maximal residence time in stomach and intestine, the maximal cyanide released from Prussian blue is about 1.31 mg, which is far below the minimal lethal dose of cyanide of 50 mg, and therefore does not present a safety concern following long-term storage.
普鲁士蓝，即六氰合铁酸铁，被批准用于（口服）治疗铯或铊放射性同位素的体内污染。氰化物占普鲁士蓝分子组成的35 - 40%；因此，在生理pH条件下，氰化物可能在通过消化道的过程中释放出来。
本研究的目的是评估普鲁士蓝药品和活性药物成分的长期稳定性及其对氰化物释放的影响。该研究涉及测定和比较在模拟人体生理暴露的pH条件下，普鲁士蓝的水分损失和释放的氰化物。
活性药物成分和药品的测试样品在模拟仓库储存条件的环境温度下储存10年。使用热重分析法测量普鲁士蓝的水分损失。利用一个模拟胃部暴露和胃肠道转运的体外生理pH模型来测定氰化物的释放。将普鲁士蓝在pH值为1.0、5.0和7.0，温度为37°C的条件下原位孵育1 - 24小时。使用经过验证的比色法通过紫外 - 可见光谱法测量氰化物。
自2003年以来，尽管普鲁士蓝活性药物成分和药品的水分含量（质量属性）分别下降了约10.5%和13.8%，但氰化物的释放量仍相当。在pH值为7.0孵育24小时的情况下，活性药物成分 - 1在2004年释放的氰化物为21.33 ± 1.76 μg/g，在2013年为28.45 ± 3.15 μg/g；药品 - 1在2004年释放的氰化物为21.89 ± 0.56 μg/g，在2013年为27.31 ± 5.78 μg/g。在胃部pH值为1.0和上消化道pH值为5.0时，2013年活性药物成分和药品的数据也具有可比性。氰化物的释放仍然依赖于pH值，并且与2003年观察到的趋势相同，即在pH值为5.0时释放量最小，在pH值为1.0时释放量最大。总之，这是一项将氰化物释放与水分损失相关联的普鲁士蓝长期稳定性研究。普鲁士蓝在pH值为1.0时释放的氰化物最多（47.47 μg/g），在pH值为5.0 - 7.0时最少（20.01 μg/g）。
基于最大剂量、在胃和肠道中的最长停留时间计算，普鲁士蓝释放的最大氰化物量约为1.31 mg，远低于氰化物的最小致死剂量50 mg，因此长期储存后不存在安全问题。
