Wet milling induced physical and chemical instabilities of naproxen nano-crystalline suspensions

Wet-milling is the most common approach to formulate nano-crystalline suspensions. The effect of high intensity wet-milling on the physical and chemical stability of a poorly soluble drug was investigated. Naproxen (1%, w/v) was suspended in two different stabilizers (i.e. HPMC E15 and Tween 80) and stabilizer concentrations (0.2% or 0.6%, w/v) in distilled water. Wet-milling was performed at two different speeds (i.e. 3400 rpm and 2000 rpm) for four continuous hours. The milled samples were analyzed for physical and chemical instabilities. Wet-milling of naproxen-HPMC E15 at high milling intensity caused both physical and chemical instabilities as observed by particle size measurement and chemical analysis, respectively. The naproxen-Tween 80 formulations were stable regardless of milling intensity. Naproxen-HPMC E15 wet-milled samples, showed an IR peak shift suggesting strong bond formation or molecular interaction (i.e. amorphous phase). In addition, naproxen has a strong interaction with HPMC E15 as determined by MTDSC (i.e. melting point depression). The generation of amorphous phase at the naproxen-HPMC E15 crystal surface may be responsible for both aggregation and degradation during wet milling. Decarboxylated naproxen was identified as a degradation product. Milling intensity and/or selection of stabilizer/s are crucial for the stability of nano-crystalline suspensions. Published by Elsevier B. V.