title: A new stressed test to predict the foreign matter formation of minodronic acid in solution.
abstract: A formulation containing 0.5 mg/ml minodronic acid, 40 mM citrate, pH 4.5, and sodium chloride, stored in regular flint glass ampoules, was stable without particulate increase under high temperature conditions, such as 40 degrees C for 6 months, or 50 or 60 degrees C for 3 months. However, when stored at 25 degrees C, there was an increase in >or=2 microm particles at the 5-month timepoint. This demonstrated that long-term stability cannot simply be predicted by the evaluation of samples just stored at higher temperatures. Therefore, a new stressed test was designed which is useful in the rapid selection of formulations that are stable and without particulate increase. Since the particulate matter is apparently a complex of minodronic acid and aluminum ions leaching from ampoules, samples were placed at 80 degrees C for up to 4 weeks to accelerate aluminum leaching. Although no particulate increase was observed directly after storage at 80 degrees C, 4 freeze-thaw cycles following the storage caused a drastic particulate increase. The evaluation of samples subjected to the freeze-thaw cycles indicated that the following formulation modifications have inhibitory effects on particulate generation: (1). addition of meglumine, diethanolamine, mannitol, or glycerol to the formulation; (2). increase of citric acid concentration; (3). decrease of minodronic acid concentration. These modifications also worked well for samples stored at 25 degrees C for 6 months, and particulate increase did not occur. This method is a powerful tool for predicting the stability of minodronic acid in solution.
authors.affiliation: Institute for Drug Development and Research, Yamanouchi Pharmaceutical Co, Ltd 180 Ozumi Yaizu-shi, Shizuoka-ken, 425-0072 Japan. nakamurk@yamanouchi.co.jp
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Nakamura
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Yokohama
authors.forename: Masataka
authors.initials: M
authors.lastname: Katsuma
authors.forename: Toyohiro
authors.initials: T
authors.lastname: Sawada
authors.forename: Takashi
authors.initials: T
authors.lastname: Sonobe
mesh_terms: D004164:Diphosphonates / Q000737:chemistry*; D004340:Drug Contamination / Q000517:prevention & control*; D004355:Drug Stability; D004356:Drug Storage / Q000379:methods; D005544:Forecasting; D007093:Imidazoles / Q000737:chemistry*; D019999:Pharmaceutical Solutions / Q000737:chemistry*; D013314:Stress, Mechanical; D013678:Technology, Pharmaceutical / Q000379:methods*
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D019999:Pharmaceutical Solutions; C087958:YM 529