TY - JOUR

T1 - In vitro and in vivo comparison between crystalline and co-amorphous salts of naproxen-arginine

AU - Kasten, Georgia

AU - Lobo, Lonita

AU - Dengale, Swapnil

AU - Grohganz, Holger

AU - Rades, Thomas

AU - Löbmann, Korbinian

PY - 2018/11/1

Y1 - 2018/11/1

N2 - 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 AUC0-t and a 2.15-fold increase in cmax 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.

AB - 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 AUC0-t and a 2.15-fold increase in cmax 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.

KW - Amino acid

KW - Co-amorphous formulations

KW - Dissolution

KW - In vivo

KW - Oral bioavailability study

KW - Salts

U2 - 10.1016/j.ejpb.2018.09.024

DO - 10.1016/j.ejpb.2018.09.024

M3 - Journal article

C2 - 30266670

AN - SCOPUS:85054074902

VL - 132

SP - 192

EP - 199

JO - European Journal of Pharmaceutics and Biopharmaceutics

JF - European Journal of Pharmaceutics and Biopharmaceutics

SN - 0939-6411

ER -