ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Kinetic study of degradation of Rosuvastatin calcium to Rosuvastatin-lactone under different solvents conditions

Raed Ghanem, Fatima Azzahra Delmani, Fakhri O. Yousef, Areej AL-Kayed, Haitham Al-Sa’doni, Khaldoun Al-Sou’od, Omar K. Almashaqbeh, Mahmoud Eqab Rabi, and Ahmad Abdo

Department of Chemistry, Al Al-Bayt University, Mafraq, Jordan

E-mail: raedag@aabu.edu.jo

Received: 18 September 2022  Accepted: 18 April 2023

Abstract:

Rosuvastatin calcium (RST) is a medication used to lower cholesterol levels by increasing the number of low-density lipoprotein receptors on the cell surface. RST undergoes different degradation processes under different conditions (Thermal, light, acidity…etc.) leading to the formation of different degradation products; 5-oxo isomer, anti-isomer, and lactone form of RST. Lactone form of RST is the major degradation product. Chromatographic techniques were used to identify and quantitatively determine the concentration of RST and its degradation products, where the aqueous aprotic solvent mixture (acetonitrile (25): water (75)) is used as an extraction medium to release RST and its degradation product RST-Lactone from the dosage form. Unfortunately, the presence of water in the extraction mixture or mobile phase could enhance the acid hydrolysis of lactone (i.e., conversion of RST-Lactone into RST) during the analysis time giving an underestimated result of the actual content of the degradation product. The type of solvent matrix used in sample extraction was found to control the direction of RST ⇌ RST-lactone equilibrium. It is found that: (a) In aprotic solvents, the forward reaction (i.e., the conversion of RST to its lactone form is the only reaction that occurs. (b) When RST extracted in the acidic aqueous mobile phase, the reverse reaction was observed, and RST-Lactone was converted into RST. (c) When organic protic solvents such as methanol was used for the extraction, both RST and RST-Lactone were stable, and no reaction was observed. Kinetics helps to distinguish and control the type of and sources of degradation impurities. The rates of both reactions were found to follow the first-order kinetics with rate constants directly related to the ageing temperature, the rate constant for the reverse reaction (RST-Lactone → RST) was 20 times greater than the forward reaction. The formation of RST-Lactone form from RST occurs via intramolecular esterification mechanisms followed by proton transfer to the solvent.

Keywords: Rosuvastatin; Statin; Rosuvastatin-lactone; Thermal stability; Kinetic study

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-023-02864-7

Chemical Papers 77 (9) 5317–5330 (2023)