Reactivity of enprostil stereoisomers in soft elastic gelatin capsules.

Enprostil (methyl 7-[(1R*,2R*,3R*)-3-hydroxy-2-[(E)-(3R*)-3-hydroxy-4-phenoxy-1-butenyl]- 5-oxocyclopentyl]-4,5-heptadienoate), a gastric acid secretion inhibitor and potent anti-ulcer drug, is formulated as a propylene carbonate solution which is filled into soft elastic gelatin capsules. The drug molecule features two unresolved asymmetric carbon atoms, and synthesis yields an equimolar mixture of four different optical isomers (two diastereomeric pairs of enantiomers). The objective of this study was to establish the degree to which enprostil does or does not degrade stereoselectively in the soft elastic gelatin capsule formulation. Accordingly, we developed an HPLC method capable of resolving enprostil diastereoisomers and applied the method to determining reaction rates of enprostil in soft elastic gelatin capsules maintained at 40 degrees C. The study included three soft elastic gelatin capsule lots: the first two contained an equimolar mixture of all four enprostil enantiomers; and the third contained an equimolar mixture of two individual diastereoisomers of known optical purity. Comparing enprostil degradation rates in the three capsule lots showed that reactivity ratios in all cases were (within the limits of experimental uncertainty) equal to unity. This observation conclusively excludes the possibility of significant enantioselectivity for enprostil degradation in the soft elastic gelatin capsule formulation. We also report kinetic equations for the general case of relating stereospecific reactivity ratios to drug product shelf life when drug concentrations are monitored with nonstereoselective analytical techniques.

HPLC analysis of thimerosal in ophthalmic solution. Comparing electrochemical with spectrophotometric detectors.

Electrochemical and spectrophotometric detectors for the reversed phase HPLC analysis of thimerosal in an ophthalmic formulation were evaluated with respect to response linearity, recovery, and lower limit of detection. The electrochemical oxidation of thimerosal at a glassy carbon electrode was characterized by both cyclic voltammetry and thin layer amperometry. The hydrodynamic half-wave potential for thimerosal (+0.6 V) was determined using a coulometric detector. The relatively low oxidation potential for thimerosal forms the basis for this highly sensitive and selective analytical technique. The amperometric lower limit of detection for thimerosal (at signal/noise = 2) was less than 400 pg. The detection limit with spectrophotometric detection at 254 nm was approximately 20 ng, a 50 fold increase.