The stability and solubility of progabide and its related metabolic derivatives.
The stability-pH profile of the gamma-aminobutyric acid prodrug. Progabide, was found to be bell shaped, with maximum stability occurring at pH 6 to 7 with a t1/2 of 126 min. Of its metabolic derivatives, the deamidated product PGA degraded in a similar fashion to Progabide, whereas the hydrolytic degradation product SL79.182 was, a expected, a stable compound. Progabide behaved as a typical weak base, with its solubility increasing with a decrease in pH. SL79.182 behaved as a typical phenolic weak acid, with its solubility increasing with an increase in pH. Both compounds displayed low intrinsic solubilities of 14.5 x 10(-5) M for Progabide and 33.4 x 10(-6) M for SL79.182. An increase in temperature resulted in an increase in the solubility but a decrease in the stability of Progabide. The data obtained indicate that the gastric pH and gastric emptying rate will have a profound effect on the oral bioavailability of Progabide.
Farraj
N F
NF
Department of Pharmacy, University of Nottingham, United Kingdom.
Davis
S S
SS
Parr
G D
GD
Stevens
H N
HN
D000927:Anticonvulsants / Q000493:pharmacokinetics*; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics; D012995:Solubility; D013053:Spectrophotometry; D013696:Temperature; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics
D000927:Anticonvulsants; D011355:Prodrugs; C017985:progabide; D005680:gamma-Aminobutyric Acid