Levofloxacin in nanostructured lipid carriers: Preformulation and critical process parameters for a highly incorporated formulation

The first step of a successful nanoformulation development is preformulation studies, in which the best excipients, drug-excipient compatibility and interactions can be identified. During the formulation, the critical process parameters and their impact must be studied to establish the stable system with a high drug entrapment efficiency (EE).

This work followed these steps to develop nanostructured lipid carriers (NLCs) to deliver the antibiotic levofloxacin (LV). The preformulation studies covered drug solubility in excipients and thorough characterization using thermal analysis, X-ray diffraction and spectroscopy. A design of experiment based on the process parameters identified nanoparticles with < 200 nm in size, polydispersity <= 0.3, zeta potential −21 to −24 mV, high EE formulations (>71 %) and an acceptable level of LV degradation products (0.37–1.13 %).

To the best of our knowledge, this is the first time that a drug degradation is reported and studied in work on nanostructured lipids. LV impurities following the NLC production were detected, mainly levofloxacin N-oxide, a degradation product that has no antimicrobial activity and could interfere with LV quantification in spectrophotometric experiments. Also, the achievement of the highest EE in lipid nanoparticles than those described in the literature to date and the apparent protective action of NLC of entrapped-LV against degradation are important findings.

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Materials

Levofloxacin hemihydrate (LV, (2S)-7-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)-10-oxo-4-oxa-1-azatricyclo [7.3.1.0^5,13]trideca-5(13),6,8,11-tetraene-11-carboxylic acid hemihydrate) was purchased from FluoroChem (UK) and also generously donated by Sanofi-Medley Farmacêutica Ltda from Brazil. Levofloxacin N-oxide standard was purchased from Eurobram (Germany). Oleic acid was purchased from Dinâmica Química Contemporânea Ltda (Brazil). Super Refined™ polysorbate-80, Super Refined™ oleic acid, beeswax and Crodamol™ CP (cetyl palmitate) were donated by Croda (UK). Precirol® ATO 5, Compritol® 888 ATO, Geleol™ mono and diglycerides, Gelucire® 50/13 (stearoyl polyoxylglycerides) and Biogapress Vegetal BM 297 ATO (glyceryl dipalmitostearate) were donated by Gattefossé (France), while Tego® care 450 (polyglyceryl-3 methylglucose distearate) was donated by Evonik. Dynasan® 116 (glyceryl tripalmitate) and Dynasan® 118 (glyceryl tristearate) were provided by IOI Oleochemical (Germany). Stearic acid and phosphate buffered saline (PBS) sachets were purchased from Sigma-Aldrich (Germany) (one sachet dissolved in 1000 mL of deionized water yields 0.01 M phosphate buffer, KCl 0.0027 M and NaCl 0.137 M sodium chloride, pH 7.4, at 25 °C). Potassium bromide (KBr) of infrared grade was obtained from Sigma-Aldrich (Ireland). All other chemicals and solvents were of analytical grade.

Viviane Lucia Beraldo-Araújo, Ana Flávia Siqueira Vicente, Marcelo van Vliet Lima, Anita Umerska, Eliana B. Souto, Lidia Tajber, Laura Oliveira-Nascimento, Levofloxacin in nanostructured lipid carriers: Preformulation and critical process parameters for a highly incorporated formulation, International Journal of Pharmaceutics, Volume 626, 2022, 122193, ISSN 0378-5173,
https://doi.org/10.1016/j.ijpharm.2022.122193.