Effect of carbonate salts on the kinetics of acid-catalyzed dimerization of adefovir dipivoxil.
OBJECTIVE
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.
Yuan
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LC
Department of Formulation and Process Development, Gilead Sciences, Inc., Foster City, California 94404-1146, USA. lungchi.yuan@praecis.com
Dahl
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TC
Oliyai
R
R
D000143:Acids / Q000493:pharmacokinetics*; D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D002254:Carbonates / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical; D019281:Dimerization; D063065:Organophosphonates
D000143:Acids; D000998:Antiviral Agents; D002254:Carbonates; D063065:Organophosphonates; D000225:Adenine; C106812:adefovir dipivoxil