Identification and Characterization of Interaction Product Impurities and Degradation Products of Atorvastatin Hot Melt Extrusion Formulation Using LC-HRMS/MS and ATR-IR

Abstract

Hot melt extrusion (HME) technology is widely used in pharmaceutical drug development to enhance the solubility and bioavailability of drugs. Atorvastatin (ATV) is a first-line statin for preventing cardiovascular disease, it has low oral bioavailability (14%), necessitating strategies to improve its bioavailability. This study involves identifying and characterizing interaction and degradation products formed during the HME process involving ATV and hydroxypropyl methylcellulose phthalate (HPMCP-55). It mainly focuses on identifying and characterizing unknown impurities and understanding their mechanisms. A simple, efficient, and mass spectrometry compatible high-performance liquid chromatography (HPLC) method was developed on a Welch XB C18 (4.6 × 150 mm, 3.5 μm) column using gradient elution of 10 mM ammonium acetate and acetonitrile as mobile phase. Further, attenuated total reflectance infrared spectrophotometry (ATR-IR) was also employed to investigate the interaction impurities formed between ATV and HPMCP-55 (imp-1,3) and degradation products (imp-2,4) formed during the extrusion process. LC-HRMS and ATR-IR analysis confirmed significant drug–polymer interactions during extrusion. Plausible impurity structures were elucidated via MS/MS fragmentation patterns and accurate mass. In silico toxicity prediction was performed using ProTox-II for all four impurities. The study underscores the importance of characterizing HME process impurities to understand drug stability, safety, and efficacy. This comprehensive approach facilitates thorough understanding of their potential interaction with drug candidates during the early phase of pharmaceutical development.