Quality-by-Design Guided Engineering of Inhalable Co-amorphous of Itraconazole with Succinic Acid via Spray Drying

Abstract

Purpose: Itraconazole (ITZ), a synthetic triazole antifungal drug, is strongly recommended by the Infectious Diseases Society of America for the prophylaxis of Invasive pulmonary aspergillosis, and has also been investigated to effectively treat nonsmall-cell lung cancer. However, as a Class II drug in the Biopharmaceutics Classification System with extremely low aqueous solubility, ITZ requires a high oral dose to achieve an adequate concentration in the lung, causing unintended systemic toxicities. In recent studies, the ITZ cocrystal with succinic acid (SUC) have been successfully fabricated through grinding and anti-solvent crystallization, which was found to increase the dissolution rate of ITZ. 1, 2Nonetheless, the methods they used were hard to control the particle size as well as to scale up for mass production. By contrast, spray drying was shown to be a promising strategy to continuously produce inhalable co-amorphous powders with desirable particle size and morphology but without compromising the stability and hygroscopicity.3As the amorphous state of a solid is generally more water-soluble than its crystalline state, we believe that the ITZ-SUC co-amorphous could ameliorate the solubility and dissolution profile of ITZ to a much more extent. Herein, we sought to employ spray drying as a single-processing platform to engineer inhalable ITZ-SUC co-amorphous powders for pulmonary delivery. Methods: 92.28 mg of ITZ and 7.72 mg of SUC (2:1 molar ratio) were dissolved in a 100 mL mixture of Chloroform and Ethanol (1:2 v/v). Subsequently, the solution was spray-dried using Mini Spray Dryer B- 290 equipped with Dehumidifier B-296 and Inert Loop B-295 (Büchi Labortechnik, Flawil, Switzerland) with nitrogen as the drying gas. A 2-level, 2-factor factorial design was applied to investigate the effect of the solute concentration and the feed rate on the mass median aerodynamic diameter (MMAD) of the spray dried powders (Figure 2A). The solid-state properties of resulting formulations were characterized by various techniques, including differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared (FTIR) spectroscopy.The in vitroaerosol performance of spray-dried formulations was evaluated using a Next Generation Impactor (NGI). The dissolution performance was measured using the same method with our previous study.3The samples were also placed in a 60 °C oven for 1 month for stability test. Results: A phase-pure 2:1 ITZ-SUC co-amorphous was successfully prepared via spray drying. The PXRD pattern revealed its amorphous state. The DSC thermogram (Figure 1) illustrated the glass transition of the amorphous content at 44.9 °C, followed by a crystallization exotherm at 111.8 °C. Eventually, the recrystallized ITZ-SUC spray dried powders melted at 159.4 °C which is exactly the melting point of ITZ-SUC cocrystal. FTIR spectrum of the spray dried powders also showed a new broad peak at 3418 cm-1. The normal probability plot (Figure 2B) clearly indicated that the solute concentration had a significant positive effect on MMAD, while the feed rate individually has no significant effect. Based on the results of the factorial design, a spray dried formulation with the optimal aerosol performance was prepared under solute concentration of 3 mg/mL and feed rate at 1.5 mL/min. The NGI dispersion plot demonstrated that 65% of the powders deposited on stages 3-5 (Figure 3A), resulted in an MMAD of 1.51 0.02 m which is within the optimal range of 1-3m for deep lung delivery.4Compared with raw ITZ, the dissolution performance of inhalable ITZ-SUC co-amorhpous was significantly improved in terms of both the rate and the extent (Figure 3B). After 1-month incubation in a 60 °C oven, crystalline and amorphous ITZ, SUC and ITZ-SUC co-amorphous were all physically and chemically stable. Conclusion: In this study, by controlling critical parameters, especially the solute concentration and feed rate, ITZ-SUC (2:1) co-amorphous powders with particle sizes of 1.51 0.02 m were successfully prepared using spray drying. Hence, spray drying was shown to be a promising technology to develop inhalable co-amorphous formulations with desirable size distribution, morphology, dissolution profile and stability, which may potentially enhance pulmonary delivery of ITZ. Reference: 1. Remenar, J. F.;Morissette, S. L.; Peterson, M. L.; Moulton, B.; MacPhee, J. M.; Guzmán, H. R.; Almarsson, Ö., Crystal engineering of novel cocrystals of a triazole drug with 1, 4-dicarboxylic acids. J. Am. Chem. Soc. 2003,125(28), 8456-8457. 2. Karashima, M.;Sano, N.; Yamamoto, S.; Arai, Y.; Yamamoto, K.; Amano, N.; Ikeda, Y., Enhanced pulmonary absorption of poorly soluble itraconazole by micronized cocrystal dry powder formulations. Eur. J. Pharm. Biopharm. 2017,115, 65-72. 3. Weng, J.;Wong, S. N.; Xu, X.; Xuan, B.; Wang, C.; Chen, R.; Sun, C. C.; Lakerveld, R.; Kwok, P. C. L.; Chow, S. F., Cocrystal Engineering of Itraconazole with Suberic acid via Rotary Evaporation and Spray Drying. Cryst. Growth Des. 2019. 4. Yang, W.;Peters, J. I.; Williams III, R., Inhaled nanoparticles—a current review. Int. J. Pharm. 2008,356(1-2), 239-247.