TY - JOUR

T1 - Biorelevant characterisation of amorphous furosemide salt exhibits conversion to a furosemide hydrate during dissolution

AU - Nielsen, Line Hagner

AU - Gordon, Sarah

AU - Pajander, Jari Pekka

AU - Østergaard, Jesper

AU - Rades, Thomas

AU - Müllertz, Anette

N1 - Special Section: Formulating Better Medicines for Children

PY - 2013/11/30

Y1 - 2013/11/30

N2 - Biorelevant dissolution behaviour of the amorphous sodium salt and amorphous acid forms of furosemide was evaluated, together with investigations of the solid state changes during in vitro dissolution in medium simulating the conditions in the small intestine. UV imaging of the two amorphous forms, as well as of crystalline furosemide salt and acid showed a higher rate of dissolution of the salt forms in comparison with the two acid forms. The measured dissolution rates of the four furosemide forms from the UV imaging system and from eluted effluent samples were consistent with dissolution rates obtained from micro dissolution experiments. Partial least squares-discriminant analysis of Raman spectra of the amorphous acid form during flow through dissolution showed that the amorphous acid exhibited a fast conversion to the crystalline acid. Flow through dissolution coupled with Raman spectroscopy showed a conversion of the amorphous furosemide salt to a more stable polymorph. It was found by thermogravimetric analysis and hot stage microscopy that the salt forms of furosemide converted to a trihydrate during dissolution. It can be concluded that during biorelevant dissolution, the amorphous and crystalline furosemide salt converted to a trihydrate, whereas the amorphous acid exhibited fast conversion to the crystalline acid.

AB - Biorelevant dissolution behaviour of the amorphous sodium salt and amorphous acid forms of furosemide was evaluated, together with investigations of the solid state changes during in vitro dissolution in medium simulating the conditions in the small intestine. UV imaging of the two amorphous forms, as well as of crystalline furosemide salt and acid showed a higher rate of dissolution of the salt forms in comparison with the two acid forms. The measured dissolution rates of the four furosemide forms from the UV imaging system and from eluted effluent samples were consistent with dissolution rates obtained from micro dissolution experiments. Partial least squares-discriminant analysis of Raman spectra of the amorphous acid form during flow through dissolution showed that the amorphous acid exhibited a fast conversion to the crystalline acid. Flow through dissolution coupled with Raman spectroscopy showed a conversion of the amorphous furosemide salt to a more stable polymorph. It was found by thermogravimetric analysis and hot stage microscopy that the salt forms of furosemide converted to a trihydrate during dissolution. It can be concluded that during biorelevant dissolution, the amorphous and crystalline furosemide salt converted to a trihydrate, whereas the amorphous acid exhibited fast conversion to the crystalline acid.

U2 - 10.1016/j.ijpharm.2013.08.029

DO - 10.1016/j.ijpharm.2013.08.029

M3 - Journal article

C2 - 24050989

VL - 457

SP - 14

EP - 24

JO - International Journal of Pharmaceutics

JF - International Journal of Pharmaceutics

SN - 0378-5173

IS - 1

ER -