• Rades, Thomas
• Grohganz, Holger
• Kasten, Georgia
• Dengale, Swapnil
• Lobo, Lonita
• Löbmann, Korbinian

Abstract

<p>Liquid-assisted grinding (LAG) and dry ball milling (DBM) have recently been used to obtain different physical forms of drug-amino acid salts with promising dissolution and physical stability properties. In this work, crystalline and co-amorphous naproxen-arginine mixtures were prepared using LAG and DBM, respectively, and compared with regard to their in vitro and in vivo performance. X-ray powder diffraction and Fourier-transformed infrared spectroscopy showed that LAG led to the formation of a crystalline salt, while DBM led to a co-amorphous salt. These results agreed with the differential scanning calorimetry profiles: a melting point of 230 °C was determined for the crystalline salt, while the co-amorphous formulation showed a single glass transition temperature at approx. 92 °C. Both solid state forms of the salt showed increased intrinsic dissolution rates (14.8 and 74.1-fold, respectively) and also higher solubility (25.3 and 29.8-fold, respectively) compared to the pure crystalline drug in vitro. Subsequently, the co-amorphous salt revealed an improved bioavailability in a pharmacokinetic study, showing a 1.5-fold increase in AUC_0-t and a 2.15-fold increase in c_max compared to the pure crystalline drug. In contrast, even though showing a better in vitro performance, the crystalline salt interestingly did not show an increase in bioavailability in comparison to pure crystalline naproxen.</p>

Topics

• amorphous
• glass
• glass
• liquid-assisted grinding
• milling
• glass transition temperature
• differential scanning calorimetry
• ball milling
• ball milling
• infrared spectroscopy
• calorimetry profile