Mechanochemical Synthesis of Aspirin Nanocrystals for Pharmaceutical Applications

Abstract

Aspirin’s oral bioavailability is about 50%, but this can be significantly improved through nanocrystal formulation and polymorphic transformation. However, achieving homogeneous nanocrystals with optimal stability and morphology remains challenging. In this study, pure aspirin was synthesized chemically, and nanocrystals were generated using both neat grinding (NG) and liquid-assisted grinding (LAG). Key parameters such as nature of liquid, liquid-to-solid ratio (η), milling frequency, milling time, and temperature were systematically optimized. Both solution crystallisation and mechanochemical milling successfully produced Form IV, which remains stable for over 60 days at ambient conditions (22–27 °C and 45–75% RH). Using water as the added liquid consistently converts aspirin Form IV to stable Form I under η = 0.07–0.15, 30Hz and 10–120 minutes milling time. With cyclohexane, Form IV transforms to Form I within 30 minutes at η = 0.1, but reverses back to Form IV after 60 minutes, increasing η kept it in Form IV for a period of over 60 days. Optimal nanocrystals were obtained by milling at 30 Hz for 30 minutes around 28 °C, with η between 0.1 and 0.2. Water proves to be most effective, as it’s hydrogen bonding disrupts the aspirin crystal lattice, and high surface tension improves shear stress transfer. This yields nanocrystals of ~150 nm, reduced the melting point by 25.1 °C, and achieved ~90% drug release within 6.5 minutes at pH 1.2 highlighting the potential of aspirin nanocrystals for enhanced bioavailability and therapeutic performance.