Effect of carbonate salts on the kinetics of acid-catalyzed dimerization of adefovir dipivoxil.

PURPOSE: The chemical stability and product(s) distribution of adefovir dipivoxil (ADV) was examined in the presence of soluble and insoluble carbonate salts. METHODS: Chemical stability of ADV in the solid state at 60 degrees C/30% RH was examined. Stability was also examined in the presence of excess formaldehyde vapor at 23 degrees C/53% RH. ADV and its degradation product(s) were determined by reverse phase HPLC. RESULTS: Addition of aqueous soluble carbonate salts, such as sodium carbonate, compromised the stability of ADV in solid state. However, aqueous insoluble carbonates, such as calcium carbonate and magnesium carbonate, enhanced the stability of ADV as compared to the control formulation. Pivalic acid, a degradation product of ADV, was shown to accelerate the degradation rate of ADV in solid state. The de-stabilizing effect of this acid on ADV stability was diminished in the presence of magnesium carbonate. Pivalic acid also increased the rate at which ADV dimers were formed in the presence of formaldehyde vapor. Addition of insoluble carbonates reduced the rate of formaldehyde-catalyzed dimerization of ADV. CONCLUSIONS: Addition of insoluble carbonate salts decreased the rate of degradation of ADV by minimizing the extent of formaldehyde-catalyzed dimerization in solid state.

Biexponential decomposition of a neuraminidase inhibitor prodrug (GS-4104) in aqueous solution.

PURPOSE: To examine the degradation kinetics and identify the degradation products of a neuraminidase inhibitor prodrug. GS-4104. METHODS: Degradation was studied as a function of pH and temperature using a stability-indicating RP-HPLC assay. Degradation products were isolated by RP-HPLC and identified by NMR. Specific rate constants were calculated based on a scheme defined by products(s) analysis. RESULTS: Three distinct degradation products were observed in the pH region studied (pH 2-8): isomer I, GS-4071, and isomer II. Isomer I resulted from the N, N-migration of the acetyl group. Gs-4071 was formed by the hydrolysis of the ethyl ester. Both GS-4071 and isomer I degraded further to isomer II by N, N-acyl migration and ester hydrolysis, respectively. The N, N-acyl migration reaction was characterized using two dimensional heteronuclear multiple bond correlation (HMBC) NMR. The decomposition kinetics of GS-4104 follow a biexponential decay at pH 2-7. The degradation kinetics of Gs-4104 at pH 4.0, 70 degree C were independent of the initial GS-4104 concentration. CONCLUSIONS: The degradation profile indicates that development of solution or solid dosage from of GS-4104 with adequate shelf-life stability at room temperature is feasible.

Mechanisms to control drug release from pellets coated with a silicone elastomer aqueous dispersion.

The mass transport of two different compounds through polydimethylsiloxane (PDMS)-silica films was investigated to demonstrate qualitatively how this coating system can alter the release of various compounds. Various ratios of PDMS elastomer and silica were used to coat monodisperse particle-sized pellets layered with an ionizable compound (tartrazine) and a nonionized compound (acetaminophen). The 2:1 PDMS-silica composition containing the polyethylene glycol (PEG) 8000 pore former allowed mainly pore transport through void spaces in the PDMS films. Both compounds rapidly diffused through the film as a result of the solubilization and subsequent removal of the PEG 8000 from the film matrix. As the PDMS-silica ratios in the films changed from a 1:1 to a 2:1 to a 4:1 (all without polyethylene glycol 8000) coating formulation, the differences in release rate between acetaminophen and tartrazine changed. The lower ratio of PDMS-silica allowed much faster tartrazine diffusion compared to acetaminophen. As the ratio increased from 1:1 to 2:1, the two compounds were released at similar rates. When the ratio reached 4:1, acetaminophen was released significantly faster than tartrazine. Explanations for these differences and the mechanisms controlling the drug release are discussed in the text. In some circumstances, osmolality and pH affected drug release from dosage forms coated with this polymer system. This study demonstrated that utilization of this polymer system offers a useful tool for the formulation scientist to modify release rates of ionic and nonionic drug substances.