Coamorphous drug systems: enhanced physical stability and dissolution rate of indomethacin and naproxen

TY - JOUR

T1 - Coamorphous drug systems: enhanced physical stability and dissolution rate of indomethacin and naproxen

AU - Löbmann, Korbinian

AU - Laitinen, Riikka

AU - Grohganz, Holger

AU - Gordon, Keith C.

AU - Strachan, Clare

AU - Rades, Thomas

PY - 2011/10/3

Y1 - 2011/10/3

N2 - One of the challenges in drug development today is that many new drug candidates are poorly water-soluble, and one of the approaches to overcome this problem is to transfer a crystalline drug into its amorphous form, thus increasing dissolution rate and apparent solubility of the compound. In this study, a coamorphous drug/drug combination between the two nonsteroidal anti-inflammatory drugs, naproxen and γ-indomethacin, was prepared and investigated. At molar ratios of 2:1, 1:1 and 1:2, the drugs were quench cooled in order to obtain a coamorphous binary phase. Physical stability was examined at 277.15 and 298.15 K under dry conditions (phosphorus pentoxide) and analyzed with X-ray powder diffraction (XRPD). Intrinsic dissolution testing was carried out to identify dissolution advantages of the coamorphous form over its crystalline counterparts or amorphous indomethacin. Fourier transform infrared spectroscopy (FTIR) was used for analyses at the molecular level to detect potential molecular interactions. Differential scanning calorimetry (DSC) thermograms were employed to assess the glass transition temperatures (T g), and the results were compared with predicted T gs from the Gordon-Taylor equation. Results showed that naproxen could be made amorphous in combination with indomethacin while this was not possible with naproxen alone. Peak shifts in the FTIR spectra indicated molecular interactions between both drugs, and it is suggested that the two drugs formed a heterodimer. Therefore, samples at the 1:2 and 2:1 ratios showed recrystallization of the excess drug upon storage whereas the 1:1 ratio samples remained amorphous. Intrinsic dissolution testing showed increased dissolution rate of both drugs in the coamorphous form as well as a synchronized release for the 1:1 coamorphous blend. All T gs displayed negative deviations from the Gordon-Taylor equation with the 1:1 ratio showing the largest deviation. In a novel approach of predicting the glass transition temperature, the 1:1 drug ratio was inserted as an individual component in the Gordon-Taylor equation with the excess drug representing the second compound. This approach resulted in a good fit to the experimentally determined T gs.

AB - One of the challenges in drug development today is that many new drug candidates are poorly water-soluble, and one of the approaches to overcome this problem is to transfer a crystalline drug into its amorphous form, thus increasing dissolution rate and apparent solubility of the compound. In this study, a coamorphous drug/drug combination between the two nonsteroidal anti-inflammatory drugs, naproxen and γ-indomethacin, was prepared and investigated. At molar ratios of 2:1, 1:1 and 1:2, the drugs were quench cooled in order to obtain a coamorphous binary phase. Physical stability was examined at 277.15 and 298.15 K under dry conditions (phosphorus pentoxide) and analyzed with X-ray powder diffraction (XRPD). Intrinsic dissolution testing was carried out to identify dissolution advantages of the coamorphous form over its crystalline counterparts or amorphous indomethacin. Fourier transform infrared spectroscopy (FTIR) was used for analyses at the molecular level to detect potential molecular interactions. Differential scanning calorimetry (DSC) thermograms were employed to assess the glass transition temperatures (T g), and the results were compared with predicted T gs from the Gordon-Taylor equation. Results showed that naproxen could be made amorphous in combination with indomethacin while this was not possible with naproxen alone. Peak shifts in the FTIR spectra indicated molecular interactions between both drugs, and it is suggested that the two drugs formed a heterodimer. Therefore, samples at the 1:2 and 2:1 ratios showed recrystallization of the excess drug upon storage whereas the 1:1 ratio samples remained amorphous. Intrinsic dissolution testing showed increased dissolution rate of both drugs in the coamorphous form as well as a synchronized release for the 1:1 coamorphous blend. All T gs displayed negative deviations from the Gordon-Taylor equation with the 1:1 ratio showing the largest deviation. In a novel approach of predicting the glass transition temperature, the 1:1 drug ratio was inserted as an individual component in the Gordon-Taylor equation with the excess drug representing the second compound. This approach resulted in a good fit to the experimentally determined T gs.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1021/mp2002973

DO - 10.1021/mp2002973

M3 - Journal article

C2 - 21815614

SN - 1543-8384

VL - 8

SP - 1919

EP - 1928

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

IS - 5

ER -