(T1330-12-79) Sweet Levofloxacin Acesulfame Crystals with Improved Compaction Property and Solvates Interconversion

Purpose: Levofloxacin, an effective antibiotic for treating infections has a bitter taste, ¹ making oral administration in the form of suspensions or chewable tablets difficult. The aim of this study is to synthesize a more palatable new sweet form of levofloxacin that is suitable for developing a chewable tablet.

Methods: Levofloxacin acesulfame (Lev-Acs) was synthesized through an anion exchange reaction between levofloxacin hydrochloride (Lev-HCl) and acesulfame potassium, an artificial sweetener. 75.34g of Lev-HCl was dissolved in 600mL water, while 38.11g of Acs-K was dissolved in 200mL water. The two solutions were then combined, resulting in the formation of a Lev-Acs precipitate. Crystals suitable for single crystal X-ray diffraction (SCXD) experiments were obtained by dissolving an excess amount of Lev-Acs in methanol or water by heating, followed by cooling the solutions to RT. The crystal structures of Lev-Acs anhydrate and methanol solvate were determined by SCXD (with Mo radiation). Data was collected on a Bruker APEX-II CCD diffractometer at 130K. Crystal structures were solved using SHELXL. The phase purity of a bulk powder was evaluated by powder X-ray diffraction (PXRD). Thermal stability was assessed by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and hot stage microscopy (HSM). An excess amount of Lev-Acs anhydrate (30mg) was suspended in 5ml water at 25 and 37 ̊C and stirred for 72 hours. The suspension was filtered through a 0.45µm membrane and the amount of dissolved salt was weighted after drying a known volume of the filtered solution. Mechanical properties of the bulk powders were investigated utilizing a compaction simulator. Tabletability, compressibility, compactibility, and in-die Heckel parameter were determined.

Results: Single crystals of Lev-Acs anhydrate are rod-like (Figure 1a). The crystal structure is monoclinic with a space group C2. The unit cell parameters are: a=17.6954(9)Å, b=6.8402(4)Å, c=19.4569(9)Å, α=γ=90°, β=100.655(2)°, Z=4, and the calculated density is 1.502g/cm³. The unit cell contains one levofloxacin cation and one acesulfame anion (Figure 1b), confirming it is a mono salt. Single crystals of Lev-Acs methanol solvate are rod-like (Figure 1c). The crystal structure is monoclinic with a space group C2. The unit cell parameters are: a=17.8135(5)Å, b=6.6983(2)Å, c= 9.8978(6)Å, α=γ=90°, β=97.0500(10)°, Z=4, and the calculated density is 1.521g/cm³. The unit cell contains one methanol molecule, with no hydrogen bonds formed with adjacent molecules (Figure 1d). Thus, methanol molecules assume a space-filling role in this structure. Experimental PXRD analysis confirms that the bulk Lev-Acs anhydrate powder is phase pure, since it is consistent with the calculated PXRD pattern (Figure 1e). On heating, Lev-Acs anhydrate DSC thermogram exhibits an endotherm with an onset temperature of 250°C, followed immediately by an exothermic event (Figure 2a). HSM data reveals the release of bubbles at approximately 250°C, indicating decomposition without melting (Figure 2b). These thermal events are accompanied by as evidenced by weight loss (Figure 2a). Hence, they are attributed to thermal degradation. Although not determined, the melting point of Lev-Acs anhydrate is higher than 250°C, which surpasses that of Lev-HCl (225°C). ³ During heating, Lev-Acs methanol solvate DSC thermogram exhibits an endothermic peak at temperature between 80 to 150°C (Figure 2c). TGA analysis within the same temperature range confirms weight loss of 5.938%, which is nearly identical to the theoretical amount of methanol (5.94%) in the solvate (Figure 2c). HSM data revealed the release of bubbles at around 70 - 120°C (Figure 2d). Experimental PXRD analysis confirms the methanol solvate turn into anhydrate after heating at 90°C for 30 minutes (Figure 2d). The aqueous solubility of Lev-Acs anhydrate (3.3mg/mL at 25°C and 3.8mg/mL at 37°C) is significantly lower than Lev-HCl (210mg/mL) at 25°C. The reduced solubility limits the dissolution of levofloxacin. Moreover, the simultaneous release of acesulfame with levofloxacin is anticipated to improve the overall taste profile of Lev-Acs. Below 150MPa compaction pressure, Lev-Acs anhydrate exhibits higher tabletability (Figure 3a) and higher porosity, hence, lower BA, than Lev-HCl (Figure 3b). Analysis of compactibility profiles demonstrates the BS of Lev-Acs anhydrate is higher because of it higher TS at zero porosity (Figure 3c). Thus, the better tabletability in this pressure range is driven by higher BS of Lev-Acs.⁴ Lev-Acs also displays greater plasticity (smaller Py ⁵) (Figure 3d) than Lev-HCl, which explains why its initially higher tablet porosity became lower at higher pressures (Figure 3b).

Conclusion: Phase-pure Lev-Acs anhydrate can be obtained through an anion exchange reaction in water. The anhydrate salt form rod-like crystals with thermal stability up to 250°C. The desolvation of its methanol solvate initiates at 80°C on heating. The lower aqueous solubility of the anhydrate salt, combined with the presence of a sweetener, suggests an improved taste profile, which is important for the development of an orally palatable levofloxacin tablet. Levofloxacin acesulfame anhydrate demonstrates superior tabletability when the pressure lower than 150MPa, attributed to stronger BS. Overall, the thermal and mechanical properties of the anhydrate salt support its potential use in formulating a palatable tablet.

References: 1. Podder V, Sadiq NM. Levofloxacin. [Updated 2022 Sep 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan
2. Alayoubi A, Daihom B, Adhikari H, Mishra S, Helms R, Almoazen H. Development of a taste-masked oral suspension of clindamycin HCl using ion exchange resin Amberlite IRP 69 for use in pediatrics. Drug Dev Ind Pharm. 2016;42(10):1579-1589.
3. National Center for Biotechnology Information. PubChem Compound Summary for CID 9908810, Levofloxacin hydrochloride. Accessed July 13, 2023.
4. Sun, C. C. Materials Science Tetrahedron—A Useful Tool for Pharmaceutical Research and Development. J. Pharm. Sci. 2009, 98 (5), 1671–1687.
5. Vreeman, G.; Sun, C. C. Mean Yield Pressure from the In-Die Heckel Analysis Is a Reliable Plasticity Parameter. Int. J. Pharm. X 2021, 3, 100094.

Figure 1. a) A Lev-Acs anhydrate single crystal under an optical microscope; b) Asymmetric unit of Lev-Acs anhydrate; c) A Lev-Acs methanol solvate single crystal under an optical microscope; d) Asymmetric unit of Lev-Acs methanol solvate; e) The experimental and calculated PXRD patterns of Lev-Acs anhydrate and methanol solvate.

Figure 2. Thermal properties of Levofloxacin acesulfame anhydrate a) DSC and TGA profiles; b) HSM images at different temperatures. Thermal properties of Levofloxacin acesulfame methanol solvate c) DSC and TGA profiles; d) HSM images at different temperatures.

Figure 3. Compaction properties of Levofloxacin Acesulfame and Levofloxacin Hydrochloride, a) tabletability, b) compressibility, c) compactibility, and d) in-die Heckel profiles.