Nanosuspension and Microenvironmental pH Modification to Enhance Atorvastatin Dissolution in Fixed-Dose Combination Ezetimibe/Atorvastatin Tablets

A Fixed-dose combination (FDC) therapy of ezetimibe (EZT) and atorvastatin (ATV) is increasingly prescribed for high-risk hyperlipidemic patients with cardiovascular disease. However, the pharmaceutical production of FDC EZT/ATV tablets often results in poor ATV dissolution under acidic conditions, failing to meet regulatory requirements. This study aimed to improve ATV dissolution in acidic media through nanosuspension (NS) technology and microenvironmental pH modification. The experimental stages included preparation and characterization of ATV-NS, optimization of FDC EZT/ATV-nanocrystal tablets with pH modifiers, and evaluation of dissolution similarity (f2) against the innovator product Atozet®. ATV-NS was prepared via sonication and high-pressure homogenization using different stabilizers. Poloxamer 188-stabilized ATV-NS demonstrated optimal stability (particle size: 466.6 ± 8.9 nm; polydispersity index: 0.12 ± 0.10; zeta potential: −44.20 ± 0.06 mV) and significantly enhanced solubility (p < 0.05) compared with pure ATV. FDC EZT/ATV-nanocrystal tablets incorporating pH modifiers achieved f2 values for ATV of 52.36, 51.31, and 51.09 in NaCl/HCl pH 1.2, acetate buffer pH 4.5, and phosphate buffer pH 6.8, respectively. In contrast, EZT exhibited f2 values of 18.18, 16.72, and 14.66 (acceptable range: 50–100). Although complete profile similarity was not obtained for EZT, ATV dissolution in acidic media improved significantly (p < 0.05), supporting the feasibility of developing a bioequivalent generic FDC EZT/ATV tablet.