Untitled

Abstract

In aqueous solutions, dalvastatin (1) undergoes epimerization as well as hydrolysis. The transformation of the drug was studied as a function of pH at 25 degrees C in aqueous solutions containing 20% acetonitrile. At all pH values, first-order plots for the conversion are biphasic, indicating rapid equilibration of 1 with its epimer (2) and slower hydrolysis of 1 to the corresponding beta-hydroxy acid (3). Apparent first-order rate constants for the biexponential equation are given as a function of pH. The alkyl-oxygen cleavage of the lactone ring results in the epimerization of 1 to 2, whereas the acyl-oxygen cleavage results in the hydrolysis of 1 to 3. The epimerization is an SN1 reaction reaching an equilibrium of [1]eq/[2]eq = 1.27. The epimerization rate is increased with an increase in the water content of the solvent. The hydrolysis of 1 to 3 is acid and base catalyzed. The hydrolysis is reversible in acidic media and irreversible in neutral and basic media. At pH values greater than 9, the hydrolysis reaction proceeds more rapidly than the epimerization.

Impact assessment of metabolite instability in the development and validation of LC–MS/MS bioanalytical assays for measurement of rosuvastatin in human plasma and urine samples

“…The enzymatic conversion from the hydroxy acid form to the lactone form is mediated by uridine 5 0diphospho-glucuronosyltransferases. The acid-base-mediated interconversions greatly favors the hydroxy acid form when pH > 6, and can be reversed when the pH is lower such as at pH 2; therefore, it is important to keep the ex vivo sample pH between 4 and 5 to maintain the interconversion at equilibrium (Jemal & Xia, 2000;Kearney et al, 1993;Won, 1994). While the conversion from rosuvastatin lactone to rosuvastatin in clinical samples can be controlled by acidifying the plasma samples (Cooper et al, 2003), the implementation of sample pre-treatment procedures during sample collection at the clinical site is often difficult to carry out, especially in late phase clinical trials.…”

“…The extent of the conversion is dependent upon the pH, solvent composition and temperature (Kaufman, 1990;Kearney et al, 1993;Won, 1994;Yang & Hwang, 2006). Rosuvastatin is a synthetic statin.…”

A review of current trends and advances in modern bio-analytical methods: Chromatography and sample preparation

“…Minimizing interconversion will depend on conditions during the bio-analytical procedure, pH being one of the most important factors, together with temperature. Other reasons for sample instability could be epimerization [120,121] or E to Z isomerisation reactions [122,123], influenced again by pH or light exposure.…”

LC-MS Development Strategies for Quantitative Bioanalysis

“…One of the challenges faced in plasma sample collection, storage, and extraction is the instability of drugs, *Address correspondence to this author at Bristol-Myers Squibb, Bioanalytical and Discovery Analytical Sciences, Route 206 and Province Line Road, Princeton, NJ 08543, USA; Tel: 609-252-3572; Fax: 609-252-7825; E-mail: mohammed.jemal@bms.com metabolites and prodrugs in biological samples. Compound stability in plasma may be affected by enzymes and/or pH of the biological samples, anticoagulants, storage temperature and freeze-thaw cycles [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. While the degradation of a drug during sample collection and storage causes underestimation of the drug concentration, the degradation of the metabolite or prodrug may cause over-estimation of the drug concentration.…”

“…Epimerization is another potential cause for sample instability [21,22]. A sample that contains a thiol drug and its disulfide metabolite may also cause an analytical challenge due to the potential for the conversion of the thiol to the disulfide or vice versa [23].…”