Untitled

Abstract

The pH dependence of the interconversion kinetics, equilibrium, and solubilities of the lactone and hydroxyacid forms of the HMG-CoA reductase inhibitor, CI-981 ([R-(R*,R*)]-2-(4-fluorophenyl)- beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl ]- 1H-pyrrole-1-hepatonic acid), are important considerations when choosing and developing one of the forms of these compounds. Over a pH range of 2.1 to 6.0 and at 30 degrees C, the apparent solubility of the sodium salt of CI-981 (i.e., the hydroxyacid form) increases about 60-fold, from 20.4 micrograms/mL to 1.23 mg/mL, and the profile yields a pKa for the terminal carboxyl group of 4.46. In contrast, over a pH range of 2.3 to 7.7 and also at 30 degrees C, the apparent solubility of the lactone form of CI-981 varies little, and the mean solubility is 1.34 (+/- 0.53) micrograms/mL. The kinetics of interconversion and the equilibrium between the hydroxyacid and the lactone forms have been studied as a function of pH, buffer concentration, and temperature at a fixed ionic strength (0.5 M) using a stability-indicating HPLC assay. The acid-catalyzed reaction is reversible, whereas the base-catalyzed reaction can be treated as an irreversible reaction. More specifically, at pH < 6, an equilibrium favoring the hydroxyacid form is established, whereas at pH > 6, the equilibrium reaction is no longer detectable and greatly favors the hydroxyacid form.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitation of the acid and lactone forms of atorvastatin and its biotransformation products in human serum by high-performance liquid chromatography with electrospray tandem mass spectrometry

“…The stabilization of the lactone compounds by lowering the pH to 6.0 was in line with the published work on the effect of pH on the rate and equilibrium for the interconversion between the acid and lactone forms of atorvastatin (CI-981) in buffer solutions. 10 We did not find a significant difference in the degree of hydrolysis or lactonization when the serum was adjusted to pH 4-6. It was for the same reason of minimizing the interconversion that the reconstitution solution pH was adjusted to 5.0.…”

Efficacy and cytotoxicity in cell culture of novel α-hydroxytropolone inhibitors of hepatitis B virus ribonuclease H

“…It also demonstrated comparable activity against HBV replication as #107. In vivo lactonization has previously been suggested to occur for some of the cholesterol-lowering drugs, statins, either through intestinal non-enzymatic reactions due to the low pH, or by an intracellular enzymatic mechanism mediated by uridine diphosphate (UDP)-glucuronosyltransferases (Kearney et al, 1993; Prueksaritanont et al, 2002). It is unknown if the same mechanisms are involved in possible lactonization of compound #107.…”

Quantitative determination of pravastatin and R-416, its main metabolite in human plasma, by liquid chromatography–tandem mass spectrometry

“…The pH of this mixture was adjusted to 6.0 with 0.1 M phosphate solution (pH 4.0). It is important to keep the pH of the sample in a range of 3-6 in order to minimize the interconversion of the acid and lactone forms of pravastatin and R-416 [6,10]. The mixture was mixed briefly using a vortex mixer and applied to a Bond Elut ® C 8 (200 mg/3 mL) cartridge, which had been preconditioned by washing successively twice with each 3 mL of acetonitrile and with each 3 mL of distilled water.…”