EFFECT OF COMPLEXATION OF FUROSEMIDE POLYMORPHS ON STABILITY IN SOLID STATE

CLAUDIA GARNERO; MARCELA LONGHI

Rosdario

Congreso; 2° Reunión Internacional de Ciencias Farmacéuticas; 2012

Introduction It is well-established that pharmaceutical solids can exist in several polymorphic forms having very different physical and mechanical properties that lead to a strong impact on the activity of the drug molecules. Furosemide (FUR) is widely applied as a strong loop diuretic, but seven polymorphic forms are known: four true polymorphs (I, II, III, IV), two solvates (IV-DMS and V-dioxane) and one amorphous form [1-3]. In addition, FUR, further undergoes photochemical degradation. This study focuses on investigating the effect of complexation with B-cyclodextrin (B-CD) and maltodextrin (MD) on the solid state stability of two polymorphs of FUR (I and II). Materials and methods In order to investigate the influence of binary complexes on the photochemical degradation processes of FUR polymorphs under accelerated storage conditions, each FUR polymorph and the systems FUR I:B-CD, FUR II:B-CD, FUR I:MD and FUR II:MD were stored in glass vials at 40ºC and 75% relative humidity (RH) and exposed to daylight into a stability chamber. The solid samples obtained by kneading, spray-drying, freeze-drying and physical mixture were accurately weighed before storage and at pre-determined intervals were withdrawn. The drug content was measured to evaluate the chemical stability of the samples, for which the solids were dissolved and analyzed applying an HPLC stability indicating method. All chemicals used were of analytical grade and the solvents were HPLC grade. Analyses were performed using an Agilent 1100 series system. The method was validated according to ICH guideline. Results and discussion The results revealed that exist significant differences in the stability of both FUR polymorphs and their systems with B-CD and MD in the solid state. It is interesting to note that FUR II was more stable than FUR I. In addition, the free polymorphs showed greater degradation than the complex forms. Particularly, the complexation with B-CD had a higher stabilizing effect on FUR polymorphs with respect to the system with MD. Additionally, it was observed the influence of the preparation method on the stability of the different systems. The increase of drug stability suggests the presence of interactions between each FUR polymorph and the ligands (B-CD and MD) in the systems obtained by kneading, spray-drying and freeze-drying, confirming the formation of supramolecular complexes with a protective effect. Finally, the recovery in the physical mixtures was lower than in the supramolecular complexes, demonstrating absence of interaction in these solid systems. However, their profiles reflected differences between the polymorphic forms. Conclusions Our results demonstrate the stability differences between the polymorphs I and II of FUR. Additionally, we can confirm the capability of B-CD and MD to interact with each FUR polymorph, generating binary complexes that retarded the photodegradation in the solid state. Acknowledgments We thank Ferromet S.A. (agent of Roquette in Argentina) for their donation of B-cyclodextrin. References 1.Doherty C, York P. Int. J. Pharm. 47 (1988) 141-155. 2.Matsuda Y, Tatsumi E. Int. J. Pharm. 60 (1990) 11-26. 3.Latosinska J N, Latosinska M, Medycki W, Osuchowicz J. Chem. Phy. Lett. 430 (2006) 127–132.