title: Wet milling induced physical and chemical instabilities of naproxen nano-crystalline suspensions.
abstract: 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. 3,400 rpm and 2,000 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.
authors.affiliation: University of Connecticut, School of Pharmacy, Storrs, CT 06269, USA.
authors.forename: Sumit
authors.initials: S
authors.lastname: Kumar
authors.affiliation: University of Connecticut, School of Pharmacy, Storrs, CT 06269, USA. Electronic address: d.burgess@uconn.edu.
authors.forename: Diane J
authors.initials: DJ
authors.lastname: Burgess
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry; D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D004339:Drug Compounding; D004355:Drug Stability; D065347:Hypromellose Derivatives / Q000737:chemistry*; D053758:Nanoparticles / Q000737:chemistry*; D009288:Naproxen / Q000737:chemistry*; D010316:Particle Size; D011136:Polysorbates / Q000737:chemistry*; D033362:Powder Diffraction; D017550:Spectroscopy, Fourier Transform Infrared; D014961:X-Ray Diffraction
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011136:Polysorbates; D065347:Hypromellose Derivatives; D009288:Naproxen
keywords: Instability; Nano-crystalline suspension; Nano-milling; Solid-state transformation; Wet milling