title: Stability of low concentrations of guanine-based antivirals in sucrose or maltitol solutions.
abstract: Three guanine-based antiviral drugs, entecavir, lobucavir, and acyclovir showed degradation in presence of sucrose in ready-to-use solutions held at 50 degrees C, with more degradation at pH 4 than at pH 6 or 7. LC/MS analysis of the solutions showed isomeric adducts of the drugs and reducing sugars. Sucrose, a disaccharide and a non-reducing sugar, was the source of monosaccharides, the reducing sugars. Sucrose showed pH-dependent hydrolysis at 50 degrees C into two monosaccharides, fructose and glucose, with more sucrose hydrolyzing at pH 4 than pH 6 or 7. Additionally, the three drugs showed pH-dependent degradation at 50 degrees C in fructose and glucose solutions with the following rank order: pH 7>pH 6>pH 4. This indicated that the increased degradation of the drugs in sucrose solutions at pH 4 was mainly due to more hydrolysis of sucrose into fructose and glucose compared to pH 6 or 7, and subsequent reactions of the fructose and glucose with the drugs. Based on structures of the major degradants, it is proposed that the main cause of the degradation was nucleophilic addition of the primary amine group of the drugs to the carbonyl group of the fructose and glucose. This reaction was facilitated as the solution pH increased from 4 to 7. All the drugs showed satisfactory stability regardless of the storage temperature or solution pH in maltitol, an alternate sweetener. The free aldehyde or ketone group in maltitol precursors is reduced to a hydroxyl group after the hydrogenation process making maltitol less susceptible to nucleophilic addition.
authors.affiliation: Pharmaceutical Research Institute, Bristol-Myers Squibb Company, New Brunswick, NJ 08903-0191, United States. divyakant.desai@bms.com
authors.forename: D
authors.initials: D
authors.lastname: Desai
authors.forename: V
authors.initials: V
authors.lastname: Rao
authors.forename: H
authors.initials: H
authors.lastname: Guo
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Bolgar
mesh_terms: D000212:Acyclovir / Q000737:chemistry; D000998:Antiviral Agents / Q000737:chemistry*; D004355:Drug Stability; D005632:Fructose / Q000737:chemistry; D005947:Glucose / Q000737:chemistry; D006147:Guanine / Q000031:analogs & derivatives / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008320:Maltose / Q000031:analogs & derivatives* / Q000737:chemistry; D019999:Pharmaceutical Solutions; D012996:Solutions; D013395:Sucrose / Q000737:chemistry*; D013402:Sugar Alcohols / Q000737:chemistry*; D013696:Temperature
chemical_list: D000998:Antiviral Agents; D019999:Pharmaceutical Solutions; D012996:Solutions; D013402:Sugar Alcohols; D005632:Fructose; D013395:Sucrose; C413685:entecavir; D006147:Guanine; D008320:Maltose; C063638:lobucavir; C010745:maltitol; D005947:Glucose; D000212:Acyclovir