(M1130-09-52) Inclusion Complexes of Posaconazole with Hydroxypropyl- and Sulfobutylether-β-Cyclodextrins for Intravenous Injections: Formulation and Stability Studies

Purpose: Posaconazole, a crucial antifungal drug in the triazole group, effectively treats invasive fungal infections, particularly in immunocompromised individuals, targeting Candida, Aspergillus, and zygomycetes. However, its clinical utility is hindered by challenges such as lipophilicity, poor aqueous solubility, and pH-dependent solubility favoring acidic environments. These factors lead to inconsistent oral bioavailability, necessitating intravenous (IV) formulations for reliable drug delivery in severe infections or patients unable to take oral medications. Cyclodextrins (CDs) are cyclic oligosaccharides frequently used to enhance poorly water-soluble drugs' solubility and stability by forming inclusion complexes with hydrophobic drugs. Hydroxypropyl-β-cyclodextrin (HPβCD) and sulfobutylether-β-cyclodextrin (SBEβCD) are utilized in FDA-approved IV injection products. However, the FDA-approved IV formulation of posaconazole specifically employs SBEβCD, which has shown clinical effectiveness. Exploring the use of HPβCD as an alternative to SBEβCD in posaconazole formulations offers numerous potential advantages, including improved solubility, potentially reduced toxicity, enhanced stability, and greater versatility in formulation development. These benefits could lead to better patient outcomes, particularly in IV formulations requiring rapid and reliable drug delivery. This study aimed to compare the inclusion complexes of posaconazole with HPβCD and SBEβCD in terms of liquid and solid-states characterizations and compare the formulation and stability of posaconazole IV injections with HPβCD and SBEβCD, providing valuable insights into the feasibility and advantages of using HPβCD in posaconazole formulations, potentially paving the way for safer and more effective antifungal therapies.

Methods: This study involved the preparation of HP- and SBE-βCD inclusion complexes of posaconazole specifically designed for intravenous administration. The phase solubility study was conducted to compare the inclusion complexes with and without pH adjustment for their saturation solubility, stability rate constant, complexation efficiency, and change in Gibbs free energy. Solid-state characterizations of the inclusion complexes were determined using Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC), comparing posaconazole, HPβCD, SBEβCD, physical mixture, and freeze-dried complex of posaconazole and βCDs. An 18 mg/mL posaconazole IV injection batch with HPβCD was aseptically prepared by dissolving posaconazole in a pH 2.6 adjusted solution containing 40% HPβCD and edetate disodium. This preparation was compared to an FDA-approved posaconazole IV injection composition that uses SBEβCD. Both injection formulations have then been compared for their visual appearance, pH, osmolality, and percentage of drug recovery. The HPLC method for posaconazole IV injection has been developed and validated to determine the limit of detection (LOD), the limit of quantitation (LOQ), linearity, system suitability, accuracy, repeatability, and benchtop stability. The stability study was conducted by storing the sterile injection glass vials at three distinct storage temperatures: 40°C, room temperature, and 4°C. Subsequently, the samples were analyzed for their level of clarity, pH, osmolality, and percentage of drug recovery at various intervals over a period of three months.

Results: The phase solubility study showed that HPβCD at pH 2.6 demonstrated the highest solubilizing capacity for posaconazole, as shown in Figure 1A. Solid-state characterizations in Figures 1B – 1C showed that posaconazole remains mostly crystalline in physical mixtures with βCDs, while freeze-dried samples indicated reduced intensity and shifted endothermic peaks in DSC and changes in FTIR spectra, resulting in increased amorphization and potential interactions (inclusion complex), potentially improving posaconazole’s solubility and stability. HPLC method for Posaconazole IV injection was developed and validated, showing linearity (R² = 0.9998), precision (0.64% relative standard deviation), repeatability, and stability indication. The validation data in Figure 2 supports the method's reliability for analyzing posaconazole. Both IV injections showed clear and transparent solutions with a pH of 2.6. SBEβCD-contained IV injection exhibited a very hypertonic solution injection, with an osmolality value of over 1700 mOsm/kg, 3.5-fold higher than HPβCD-contained IV injection. The stability data at the accelerated (40°C), RT, and 4°C storage conditions for 3 months showed that both IV injections remained clear with acceptable pH (2.6 - 3.0), as shown in Figure 3A. Drug assay values remained greater than 90%, as shown in Fig. 3B, indicating stable formulations.

Conclusion: Posaconazole IV injection utilizing HPβCD has been successfully formulated with desirable quality attributes, with improved solubility and osmolality/ tonicity compared to SBEβCD-contained IV injection. A stability-indicating HPLC method for posaconazole in IV injections has been established. The 3 months stability data showed satisfactory stability of the posaconazole in the injection formulations.

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Acknowledgements: This research was supported by funding from Ashland Inc.

Phase solubility study and solid-state characterizations of posaconazole with HP-/ SBE-β-Cyclodextrins inclusion complexes

Development and validation of HPLC-UV method development and specifications of posaconazole IV injections

Stability data of posaconazole IV injections