title: Long-term stability study of Prussian blue - a quality assessment of water content and thallium binding.
abstract: The purpose of this study is to assess the long-term stability of Prussian blue (PB) drug product (DP) and active pharmaceutical ingredient (API) under laboratory storage conditions by monitoring the loss in water content and the corresponding change of the in vitro thallium binding capacity that represents product performance. The bound water content and the in vitro thallium binding capacity of PB DPs and APIs were measured in 2003 and 2013, respectively. Water content, a critical quality attribute that directly correlates to the thallium (Tl) binding capacity was measured by thermal gravimetric analysis (TGA). The thallium binding study was conducted by testing PB in buffered solutions over the human gastrointestinal pH range with thallium concentrations ranging from 600 to 1,500 ppm. Samples were incubated at physiological temperature of 37°C in a shaking water bath to mimic gastric flux and intestinal transport. The binding equilibrium was reached at 24h. Following incubation, each sample was filtered and the free thallium was analyzed using a validated inductively coupled plasma spectroscopic method (ICP). The Langmuir isotherm was plotted to calculate maximum binding capacity (MBC). Compared with 2003, the water content of DP-1 decreased by about 14.1% (from 15.6 to 13.4 mol), and the MBC of DP-1 decreased by about 12.5% (from 714 to 625 mg/g) at pH 7.5. When low concentration of thallium (600 ppm) was used at pH 7.5, the Tl binding remained comparable for both API-1 (286 vs 276 mg/g) and DP-1 (286 vs 268 mg/g). Similarly, the Tl binding remained unchanged for both API-1 (237 vs 255 mg/g) and DP-1 (234 vs 236 mg/g) at pH 5.0. However, at pH 1.0 the binding was reduced 32.3% and 25.9% for API-1 and DP-1, respectively. Since the majority of binding takes place in the upper GI tract where pH around 5 can be expected, and therefore, the Tl binding capacity of PB should be comparable for new and aged samples. The findings that Tl binding changes with the water loss of PB and pH conditions are consistent with our previously published data. The study also represents the first quantitative assessment of the long-term stability of PB. Over last 10 years, PB DPs and APIs have lost about 20% water under ambient laboratory storage conditions which are consistent with a controlled warehouse environment. While the maximum binding capacity of PB to thallium was decreased after about 10 years of long-term storage, it is still very effective, suggesting that the shelf life of PB should be much longer than the manufacturer ascribed expiration date of 2008 under proper storage conditions.
authors.affiliation: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Testing and Research, Division of Product Quality Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993, United States.
authors.forename: Adil
authors.initials: A
authors.lastname: Mohammad
authors.affiliation: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Testing and Research, Division of Product Quality Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993, United States.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Faustino
authors.affiliation: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Testing and Research, Division of Product Quality Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993, United States.
authors.forename: Mansoor A
authors.initials: MA
authors.lastname: Khan
authors.affiliation: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Testing and Research, Division of Product Quality Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993, United States. Electronic address: Yongsheng.Yang@fda.hhs.gov.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000931:Antidotes / Q000737:chemistry*; D004355:Drug Stability; D004356:Drug Storage; D005295:Ferrocyanides / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D013793:Thallium / Q000378:metabolism*; D013997:Time Factors; D014867:Water / Q000737:chemistry*
chemical_list: D000931:Antidotes; D005295:Ferrocyanides; D014867:Water; D013793:Thallium; C000170:ferric ferrocyanide
keywords: Hydration; Particle size; Product quality; Prussian blue; Thallium binding; Water content loss