Optimizacija metode za ugotavljanje vsebnosti nečistote L v kalcijevem rosuvastatinatu

Planina Medin, Luka (author), Pajk, Stane (mentor), Časar, Zdenko (co-mentor)

Rosuvastatin spada v skupino statinov, zdravil za zdravljenje hiperlipidemije. Fiziološke ravni lipidov v krvi so pomemben dejavnik pri preprečevanju kardiovaskularnih bolezni. Statini so inhibitorji HMG-CoA reduktaze, encima v jetrih, ki sodeluje pri tvorbi holesterola. Rosuvastatin so patentirali v devetdesetih letih, odobrili za prodajo v ZDA leta 2003, od leta 2016 pa je na voljo tudi kot generično zdravilo. Veliko statinov, predvsem rosuvastatin, spada med najbolje prodajana zdravila na svetu. Strukturno je rosuvastatin zelo podoben ostalim sinteznim statinom, z izjemo sulfonamidne skupine, ki je prisotna le v rosuvastatinu. Cilj te magistrske naloge je bil optimizacija metode za ugotavljanje vsebnosti nečistote L v kalcijevem rosuvastatinatu. V začetnih fazah smo metodo skušali optimizirati z uporabo različnih kolon, nadaljevali smo s spremembo osnovnih kromatografskih pogojev (delež mobilnih faz, temperatura kolone, pretok). Ko tudi s spremembo kromatografskih pogojev nismo dobili želenih rezultatov, smo se lotili korenitejših sprememb: sprememba topila, sprememba sestave mobilne faze, zamenjava UPLC, ki ima binarno črpalko, za sistem UHPLC, ki ima kvartarno črpalko. Ko smo odkrili ustrezno metodo, ki je imela zadostno resolucijo in občutljivost, smo jo delno validirali. Preverili smo najpomembnejše validacijske parametre; mejo vrednotenja, linearnost, natančnost, točnost, faktor odzivnosti in stabilnost vzorcev. Z validacijo smo potrdili, da je nova metoda ustrezna za rutinsko uporabo.

• Language: Slovenian
• Keywords: rosuvastatin, statini, tekočinska kromatografija, nečistota L, optimizacija, validacija
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2019
• PID: 20.500.12556/RUL-107517
• Publication date in RUL: 24.04.2019

Secondary language

• Language: English
• Title: Optimization of a method for determination of the impurity L in rosuvastatin calcium

Abstract

Rosuvastatin belongs to a group of medicines called statins. They are prescribed to treat hyperlipidemia. Physiological levels of lipids in blood are an important aspect in prevention of cardiovascular diseases. Statins are HMG-CoA reductase inhibitors, liver enzyme taking part in cholesterol production. Rosuvastatin was patented in the nineties and approved for sale in the United States in 2003. Since 2016 rosuvastatin is available as a generic drug. Statins and especially rosuvastatin, are one of the most successful and profitable drugs worldwide. Structurally rosuvastatin is very similar to other synthetic statins with the exception of a sulfonamide functional group, present only in rosuvastatin. The goal of this thesis was optimization of a method for determination of the impurity L in rosuvastatin calcium. In the early stages we tried to optimize the method by using a variety of columns. Then we tried changing basic chromatographic conditions (mobile phase proportion, column temperature, flow). When also these changes did not yield satisfactory results, we opted for more radical modifications: solvent substitution, mobile phase composition, transition from UPLC (with binary pump) to UHPLC system (with quarternary pump). When we obtained a suitable method with satisfactory resolution and sensitivity we performed its partial validation. We investigated basic validation parameters; limit of quantification, linearity, precision, accuracy, response factor and sample stability. Validation confirmed that the new method is suitable for routine use.

• Keywords: rosuvastatin, statins, liquid chromatography, impurity L, optimization, validation