(T0930-03-20) Dissolution Profile Control of Novel Ketoconazole Complexes Using Different Coformers

Purpose: Improving the solubility of poorly water-soluble drugs is a key challenge in the development of oral products. One promising approach involves inducing and utilizing supersaturation through formulation strategies, known as supersaturated formulations. Various formulations can generate supersaturation, including amorphous solids, crystalline salts, crystalline solvates, and cocrystals.^1,2 However, once the drug concentration reaches the thermodynamically unstable supersaturation region, the supersaturated state cannot be maintained and the drug concentration decreases to the equilibrium solubility of a crystal form.³ To utilize supersaturation as a strategy to improve the dissolution profile of poorly water-soluble drugs, both the generating and maintenance of a metastable supersaturated state are essential. Supersaturable crystalline forms such as cocrystals have been studied to obtain immediate drug release from their forms with water-soluble coformers^4,5. However, the researches to obtain cocrystals that exhibit a dissolution profile that generates and maintains a metastable supersaturated state in supersaturation remain insufficient. Therefore, we investigated whether drug release could be controlled by forming complexes with hydrophobic coformers. In this study, we investigated methodologies for improving solubility through complexes exhibiting profiles that maintain a metastable supersaturated state, using ketoconazole (KTZ), a poorly water-soluble compound classified as Biopharmaceutics Classification System (BCS) class II, as a model compound.

Methods: For the synthesis of the KTZ complexes, a certain equivalent of KTZ and coformers, terephthalic acid (TPA), 2-hydroxyterephthalic acid (2HTPA) and 2,5-dihydroxyterephthalic acid (2,5DHTPA), were suspended in methanol. The suspension was stirred for approximately 72 h at room temperature. Each suspension was filtered, and the complexes were dried at 40°C under a reduced pressure. The resulting complexes were each passed through a 100 μm sieve. The Powder X-Ray Diffraction (PXRD patterns of the complexes were unique and different from those of KTZ and coformers. The in vitro dissolution profiles of the KTZ and coformers from the complex and pure KTZ were assessed using a simple small-scale dissolution vessel filled with Fasted State Simulated Intestinal Fluid (FaSSIF) stirred at 200 rpm by a magnetic stirrer at 37°C. Each complex and KTZ were added to FaSSIF (8 mL). The applied amount was set to 2 mg as KTZ, which was 1/100 of the clinical dose (200 mg). All in vitro samples were analyzed with a HPLC system equipped with a variable wavelength ultraviolet detector. The column (YMC-UltraHT Hydrosphere C18, 50 mm × 2.0 mm I.D., YMC, Japan) was used with a mobile phase consisting of 0.1% (v/v) phosphate in water (solvent A) and acetonitrile (solvent B) with a gradient at 40°C. All the treated samples were injected at a volume of 3 μL into the HPLC system.

Results: The dissolution profiles of KTZ from complexes and pure KTZ showed that the solubility of KTZ in all complexes was higher than that of pure KTZ. However, the dissolution profiles were different for each complex. In KTZ-TPA, the maximum dissolved concentration of KTZ was about 70 μg/mL, maintained for 15 min, after which the dissolved concentration decreased with time. For both KTZ-2HTPA and KTZ-2,5DHTPA, the maximum dissolved concentration of KTZ was approximately 200 μg/mL. However, the dissolved concentration was maintained for 30 min in KTZ-2HTPA, while it was maintained for only 15 min in KTZ-2,5DHTPA, after which it rapidly decreased to the equilibrium solubility of pure KTZ. Based on the dissolved concentration of coformer, which reflects the dissolution of the complexes, the profile of the dissolved amount (% of dissolution) of each complex was also evaluated. The dissolution profiles of complexes were different among complexes. Half of the KTZ-TPA dissolved within 10 min; however, as observed in the TPA profile, the remaining solid of the complex continued to dissolve gradually over time. KTZ-2HTPA dissolved linearly with time and more than 1 h was required to dissolve 40%. The dissolution rate of KTZ-2,5DHTPA was the fastest among the three complexes studied. At the first measurement point (5 min), 100 % of KTZ-2,5DHTPA was dissolved, indicating that nearly all of the KTZ was released.

Conclusion: In this study, all KTZ complexes showed higher solubility than pure KTZ. These results suggest that complexation with coformers is an effective approach to improve the solubility of poorly water-soluble compounds. Furthermore, we evaluated the in vitro dissolution properties of the complexes in relation to coformers behavior. The results indicated that excessive dissolution of the complex is undesirable for compounds prone to rapid recrystallization. This study demonstrated that the dissolution profiles of the KTZ complexes could be controlled by using different coformers, which may help develop optimal formulations that maximize oral absorption of poorly water-soluble drugs.

References: １ Hisada, N.; Takano, R.; Tanaka, N. et al. Characterizing the dissolution profiles of supersaturable salts, cocrystals, and solvates to enhance in vivo oral absorption. Eur. J. Pharm. Biopharm. 2016, 103, 192-199.
2 Smith, A. J.; N.; Kavuru, P.; Wojtas, L. et al. Cocrystals of Quercetin with Improved Solubility and Oral Bioavailability. Mol. Pharmaceutics 2011, 8, 1867–1876
3 Brouwers, J.; Brewster, M. E.; Augustijns, P. Supersaturating Drug Delivery Systems: The Answer to Solubility-Limited Oral Bioavailability? J. Pharm. Sci. 2009, 98, 2549−2572.
4 Remenar, J.F.; Morissette, S.L.; Peterson, M.L. et al. Crystal Engineering of Novel Cocrystals of a Triazole Drug with 1,4-Dicarboxylic Acids. J. Am. Chem. Soc. 2003, 125, 8456-7.
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Acknowledgements: Authors Shoko Takeyama, Yumi Tsuruta and Yoshimine Fujii are employees of Daiichi Sankyo Co., Ltd. Setsunan University had received a research grant from Daiichi Sankyo Co., Ltd.