Stability of low concentrations of guanine-based antivirals in sucrose or maltitol solutions
Introduction
During the formulation development of a low-strength entecavir oral solution, it was observed that entecavir degraded in the presence of sucrose, a commonly used sweetener for oral solutions. This was unexpected since entecavir exhibited satisfactory stability in aqueous solutions of pH 2–9.4. The observed degradation was of concern since a sweetener was needed to mask the bitter taste of entecavir. To understand the degradation mechanism of entecavir in the presence of sucrose, stability of two other guanine-based and structurally similar antiviral compounds, lobucavir and acyclovir (Fig. 1), was also studied in presence of sucrose. Additionally, the solution stability of these antivirals in the presence of fructose, glucose, and maltitol at different pH values and temperatures was studied. Results of the stability study and possible mechanisms of degradation of the antivirals in presence of sweeteners are reported.
Section snippets
Materials and methods
The stability of 0.2 mg/mL solutions of entecavir, lobucavir, and acyclovir was studied in 50% (w/v) sucrose, 26% (w/v) fructose, 26% (w/v) glucose, or 50% (w/v) maltitol. The stability of each drug was evaluated in 10 mM citrate buffer at pH 4, 6, and 7 for sucrose, fructose, and glucose solutions, and pH 4, 5, and 6 for maltitol solutions. The solutions were stored in glass vials with rubber stoppers and crimped with aluminum caps to prevent evaporation of the liquid. The vials were placed at 5
Results and discussion
The stability of 0.2 mg/mL entecavir, lobucavir, and acyclovir in 50% (w/v) sucrose solution was studied at different pH values and temperatures as shown in Table 2, Table 3, Table 4. All three drugs showed degradation in the presence of sucrose and the degradation trend was similar. For any given time point, as the storage temperature increased from 5 to 50 °C, drug degradation increased and the solution pH decreased slightly (Table 2, Table 3, Table 4). The lowering of pH in sucrose solutions
Conclusions
The instability of three antiviral drugs in ready-to-use solutions containing sucrose was due to hydrolysis of sucrose at pH 4 into fructose and glucose, the reducing sugars. The primary amine-containing drugs underwent nucleophilic addition with the ketone group of the acyclic form of fructose and glucose, the hydrolytic products of sucrose. Such reaction was not feasible with the alternate sweetener maltitol where the free aldehyde or ketone group is reduced to a hydroxyl group after the
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2022, Food ChemistryCitation Excerpt :The content of the sugars in raw rapeseeds from high to low was in the following order: QH > DL ≈ SC ≈ HZ > GS for sucrose, GS ≈ QH > DL > HZ ≈ SC for glucose, and GS > QH ≈ HZ for fructose. After 60 min of roasting, the sucrose content decreased significantly (p < 0.05) in all rapeseeds, likely due to its hydrolysis into glucose and fructose (Desai, Rao, Guo, Li, & Bolgar, 2007). The losses of sucrose in HZ, SC, QH, DL, and GS were 17.0%, 65.0%, 35.7%, 24.4%, and 48.1%, respectively.
One step preparation of polymeric maltitol particles, from a sugar molecule, maltitol for biomedical applications
2018, Materials Science and Engineering CCitation Excerpt :ML has been used in various sugar-free or energy-reduced foods as sweetening agent [3] to replace sucrose with low glycemic and insulinemic index [4], lower calories, and non-cariogenic properties [5]. It is a well-known modifying, emulsifier, stabilizer [6,7], sweetener, and thickener agent [8]. It has been reported that there are no genotoxic effects and it does not induce micronucleus frequency in mice bone narrow cells [9], and also ML has no risk for a human at low dosage [8,10,11].
Brønsted and Lewis acid sites of Sn-beta zeolite, in combination with the borate salt, catalyze the epimerization of glucose: A density functional theory study
2015, Journal of CatalysisCitation Excerpt :However, out of the 34 pentoses and hexoses, only 7 (d-glucose, d-galactose, d-mannose, d-fructose, d-xylose, l-arabinose, and d-ribose) are present in nature in significant amounts, and the rest are termed as “rare sugars.” These sugars, though rare, have potential applications in food and pharmaceutical industries [2–4]. To quote a few, d-tagatose is a potential drug for the treatment of Type 2 diabetes [5,6], xylitol can prevent tooth decay [7], l-ribose is used to prepare a drug having anti-hepatitis-B virus activity [8], and d-arabinose is used to prepare antitumor compounds [9,10].
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2011, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life SciencesCitation Excerpt :The phosphorylated metabolite has a half-life of 15 h [2–7]. Only a few methods were reported to estimate EV in pharmaceutical [8,9] and biological matrices [10]. Zhang et al. [10] developed a method for determination of entecavir in human plasma by LC–MS/MS, the peak shape and baseline noise is not good, and they used gradient programme for mobile phase optimization.
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Present address: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877, United States.