(T1430-03-19) Levofloxacin, a Complex Fluoroquinolone Drug and Its Organic Solvent-Free Journey to Amorphization

Purpose: The purpose of this research was to investigate whether a stable and crystalline form of levofloxacin hemihydrate (LVXh), a fluoroquinolone drug, could undergo amorphization via ball milling (BMing) and/or spray drying (SDing), without the use of organic solvents. According to literature, LVXh has never been ball milled (BMed) or spray dried (SDed) before, but LVX can exist in several hydrated and anhydrous/dehydrated forms, suggesting complex solid-state transformations upon pharmaceutical processing. Emphasis is placed on efficacy of BMing, since this process is regarded as sustainable and many mechanochemical reactions can be assisted by BMing. Thus, the above processes were utilized for comparative purposes to achieve amorphous LVX.

Methods: Ball milling was performed using a Retsch mixer mill MM400 and Retsch planetary ball mill PM 100 (Germany), while spray drying from water was performed using a Büchi B-290 mini spray dryer (Switzerland). The samples were characterized by powder X-ray diffraction (PXRD), dynamic vapor sorption (DVS), differential Scanning Calorimetry (DSC) and Fourier Transform Infrared Spectroscopy.

Results: LVXh was BMed between 0.5-4 hours using different mills and parameters. Both mills demonstrated a reduction in peak intensity and the broadening of Bragg peaks when the processed powders were analyzed via PXRD (Figure 1). This indicated crystallite size reduction and the formation of crystallite lattice microstrains.¹PXRD of samples obtained by MM400 displayed slightly more reduced peak intensities in comparison to diffractograms of systems made by PM100. Unfortunately, the complete conversion to the amorphous phase was not achieved. However, DSC and DVS detected partial amorphization, confirming the presence of the amorphous phase in the BMed samples. This was demonstrated by the appearance of a new exotherm between 85-100 ̊C for milled samples via DSC (Figure 2). For DVS, this was depicted by the weight loss at around 70% RH and crystallization back to LVXh (Figure 3). Additionally, changes to BMed LVXh were prominent via DSC as new and shifted endothermic peaks were detected at 214-240 ̊C compared to LVXh raw (221-240 ̊C). Lastly, LVXh was SDed and confirmed the possibility to fully amorphise the sample as demonstrated by Mesallati et al using ciprofloxacin, another fluoroquinolone with a similar structure to LVXh.² The glass transition of the SDed sample was determined at around 80 ̊C and the exotherm of crystallization appeared at 100 ̊C. Lastly, absorption of -OH in -COOH shifted from 3257 cm^-1 for LVXh to 3450 cm^-1 for LVXam. Subtle changes in this area were depicted for BMed LVXh.

Conclusion: To conclude, complete amorphisation of LVXh was not achieved via BMing process. Conversely, complete amorphisation was achieved via SDing. The findings indicate that the outcomes of achieving amorphization are process and mechanism dependent. Nevertheless, the use of BMing may still be a promising approach for the amorphization of complex fluoroquinolone drugs like LVXh. However, they may require the use of additional excipients to facilitate successful conversion of the drug to the amorphous phase. In conclusion, more work should be done to investigate the amorphisation of fluoroquinolone drugs via mechanochemistry with the use of excipients to facilitate potential conversion of drug.

References: 1. OLIVEIRA, P. M., WILLART, J.-F., SIEPMANN, J., SIEPMANN, F. & DESCAMPS, M. 2018. Using Milling To Explore Physical States: The Amorphous and Polymorphic Forms of Dexamethasone. Crystal Growth Design, 18, 1748-1757.
2. MESALLATI, H., MUGHEIRBI, N. A. & TAJBER, L. 2016. Two Faces of Ciprofloxacin: Investigation of Proton Transfer in Solid State Transformations.

Acknowledgements: This research is funded by a Science Foundation Ireland grant co-funded under the European Regional Development Fund (SFI/12/RC/2275_P2).

Figure 1. PXRD analysis of LVXh following ball milling for 0-4 hours using (a) MM400 and 25 mL ZrO2 jar with one 1.2 cm ball at 25 Hz (1/s) and (b) PM100 and 50 mL stainless steel jar with three 1.5 cm balls at 400 rpm.

Figure 2. DSC analysis of LVXh following ball milling for 0-4 hours using (a) MM400 and 25 mL ZrO2 jar with one 1.2 cm ball at 25 Hz and (b) PM100 and 50 mL stainless steel jar with three 1.5 cm balls at 400 rpm.

Figure 3. DVS isotherms of: (a) LVXh BMed for 4 hours at 400 rpm using PM100 and (b) of LVXam SDed in water.