EFFECTS OF THERMAL ENERGY, MECHANICAL ENERGY AND SOLVENT ON POLYMORPHIC TRANSFORMATION OF LEVOFLOXACIN HEMIHYDRATE

• Main Author: Alicia Wulung, Dea
• Format: Theses
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/78934
• Institution: Institut Teknologi Bandung

The quality of pharmaceutical dosage forms is determined by the quality of the active pharmaceutical ingredient (API). The quality of API itself is determined by its raw material source and solid state. Solid state can undergo phase transformation during manufacturing process. Levofloxacin is an optical S-isomer of ofloxacin which is widely used in the world as an antibacterial agent. Levofloxacin can be assigned to Biopharmaceutics Rlassification System (BCS) class I and included in list of products requiring bioequivalence study. Levofloxacin can exist in form of hemihydrate and monohydrate. In pharmaceutical dosage forms levofloxacin hemihydrate form is used because of its stability. Thermal energy, mechanical energy and solvent are involved in tablet manufacturing process and all might induce polymorphic transformation of levofloxacin hemihydrate. The aim of this study was to study the physicochemical characterization of two different sources of levofloxacin hemihydrates and the effects of thermal energy, mechanic energy and solvent to each batch of levofloxacin hemihydrate. Levofloxacin hemihydrates were characterized by infrared spectroscopy, differential scanning calorimetry (DSC), and powder XRay diffraction (PXRD) method. Besides water content, crystal habit, powder flow properties, elastic modulus, particle size distribution, solubility, and dissolution testing were also performed. To understand the effect of thermal energy levofloxacin hemihydrate was heated in 60, 110 and 180 oc. On the other side, to understand the effect of mechanic energy compression at 4,9; 14, 7, dan 19,6 kN and grinding for 180 minutes were performed. The effect of solvent was studied by recrystallization in water, ethanol 50% and ethanol 95%. Solvent drop grinding (SDG) technique was performed to understand the effects of those three combinations of energy. Polymorphic transformation of levofloxacin hemihydrate after treatment was characterized by DSC and PXRD method and water content, crystal habit and dissolution testing There was a difference in physicochemical characteristic between two different sources of levofloxacin hemihydrate. Both material of levofloxacin hemihydrate were relatively stable at 600C and 1 IOOC. But, polymorphic transfonnation of levofloxacin anhydrate to polymorph y and colour change occurred at temperature 1800C. Levofloxacin anhydrate was not formed after heating because during cooling after heating levofloxacin anhydrate absorbed moisture from environment and formed levofloxacin hemihydrate. Grinding induced particle size reduction and decreased crystallinity. In contrast, compression force increased crystallinity. There was no water content change in levofloxaci1T after grinding. On the surface and fracture of levofloxacin hemihydrate tablet plastic deformation was observed, but no sintering phenomenon. Both API sources showed different polymorphic transformation rates. There was no hydrate transformation during recrystallization of levofloxacin hemihydrate in ethanol 95%. However levofloxacin monohydrate was formed after recrystallization in water and ethanol 50%. There was crystal habit change after recrystallization, from plate shape to needle shape. SDG caused a decrease in crystallinity and polymorphic transformation of levofloxacin anhydrate to polymorph u. Polymorphic transformation in SDG was faster than grinding. Dissolution rate was not affected by polymorphic transformation due to API source, grinding, solvent, and SDG, but only affected by compression force. The higher the compression force, the slower the dissolution rate. Although dissolution rate was not affected, API source, thermal energy, grinding, solvent and SDG could affect polymorphic transformation which could also affect the stability and in vivo condition of levofloxacin hemihydrate. Hence, API source, thermal energy, mechanical energy, and solvent during tablet manufacturing of levofloxacin hemihydrate must be controlled. Keywords: levofloxacin hemihydrates, energy, thermal, nychanic, solvent, polymorphic transformation