Development of stabilized tenofovir disoproxil tablet: degradation profile, stabilization, and bioequivalence in beagle dogs

Abstract

The purpose of this study was to develop a hydrolysis-resistant optimized oral formulation of tenofovir disoproxil (TD) using a stabilizer. To develop a stabilized TD tablet bioequivalent to the commercial TD fumarate (TDF, Viread) tablet, TD free base was prepared and its degradation profile and stability were investigated. The TD tablet showed antiviral activity, but its absorption was limited in the intestinal tract because of premature degradation. The drug subjected to severe conditions for the stress test was catalyzed under neutral, basic, oxidative, and thermolytic conditions, whereas it was comparatively stable under acidic, photolytic, and humid states. The compatibility study showed that sodium bisulfite (SB) stabilized TD by preventing its degradation in aqueous and 3% peroxide solutions compared with the unstabilized TD. According to the stability analysis and degradation profile, four TD tablet formulations were prepared. The selected TD tablets were composed of non-hygroscopic excipients (lipophilic-fumed silica, anhydrous lactose, and microcrystalline cellulose [MCC]), SB, croscarmellose sodium (CCS), and hydrogenated castor oil (HCO), and were manufactured using a dry granulation method because of their hydrolytic properties. The stabilized TD tablet showed similar dissolution properties as the TDF (Viread) reference tablet in pH 1.2, 4.0, and 6.8 and water. Moreover, the lower degradation rate of the tablet in simulated gastrointestinal fluid demonstrated that its intestinal absorption might have improved owing to prevention of its enzymatic hydrolysis and the pH effect. Finally, the formulated TD tablet was bioequivalent to the TDF (Viread) reference tablet in beagle dogs.

QbD Consideration for Developing a Double-Layered Tablet into a Single-Layered Tablet with Telmisartan and Amlodipine

“…The dissolution test [27] was carried out according to the 'telmisartan and amlodipine tablets' dissolution test of U.S. Pharmacopeia (USP), with 900 mL of pH 7.5 ± 0.1 phosphate buffer (6.8 g of monobasic potassium phosphate dissolved in 1 L of water) as the dissolution medium at 37 ± 0.5 • C for telmisartan and 500 mL of 0.01 N hydrochloric acid for amlodipine besylate. The speed of the paddle was set to 75 rpm.…”

“…The content and impurity level of telmisartan and amlodipine were analyzed using a high-performance liquid chromatography (HPLC) system [27] equipped with a UV/Vis detector (Agilent 1200 series, Santa Clara, CA, USA) and a separation module, according to the 'telmisartan and amlodipine tablets' of U.S. Pharmacopeia (USP). The assay of telmisartan and amlodipine content was performed using a Luna C18 column (4.6 × 250 mm, 5 µm; Phenomenex Inc., Torrance, CA, USA) as a stationary phase.…”

Enhanced Degradation of Sulfamethoxazole (SMX) in Toilet Wastewater by Photo-Fenton Reactive Membrane Filtration

“…In pathway A, the SMX forms monohydroxylated sulfamethoxazole by direct attack of HO• on the aromatic moiety of SMX and/or hydrolysis of unstable radical cation SMX• + formed by interaction with SO4 − [42]. Subsequently, the sulfonamide bond is cleaved by reactive oxygen species to produce monohydroxylated sulfanilic acid and 3-amino-5-methyl-isoxazole [43,44]. In pathway B, cleavage of the S-N bond, which leads to the hydrolyzation of SMX into C6H8NO2S and C5H7N2O, respectively.…”