Crystal Engineering of Novel Pharmaceutical Cocrystal of Itraconazole with Suberic Acid

Abstract

Purpose: Cocrystallzation represents a promising formulation strategy to address the issues associated with problematic drugs, in light of its potential for fine-tuning physicochemical properties such as solubility, dissolution performance, hygroscopicity and tabletability [1, 2]. With judicious selection of a wide array of available coformers, it not only confers new cocrystals unlimited opportunities in intellectual property, but also facilitates the expansion of personalized medicines through precise tailoring of drug release profiles (e.g. immediate release and sustained release) or targeting effects based on the clinical needs of individual patients. Yet, the existence of elusive cocrystals in large quantities has hindered the progress toward effective engineering of cocrystals with desired properties. Aliphatic dicarboxylic acids with varying carbon chain lengths is a set of commonly used coformers with strong hydrogen bond accepting capability, while interestingly it has been observed cocrystallization with longer-chain acids (suberic acid, azelaic acid and sebacic acid) always failed to be achieved or exhibited low efficiency via conventional methods, albeit the structural similarity with other shorter-chain acids [3-5]. We herein speculate such phenomenon may be attributed to the thermodynamically unstable nature or the relatively high activation energy of the suspected cocrystal formations, of which the synthesis could be favored by kinetic energy driven approach. Accordingly, this study aims to employed rapid solvent evaporation method to prepare the elusive itraconazole-suberic acid cocrystal (ITZ-SUB) that was previously unobtainable using solvent-assisted milling and slow evaporation as reported in literature [3], as well as to characterize its solid-state properties. Methods: Equivalent amounts (0.425 mmol) of ITZ and SUB were dissolved in 100 mL tetrahydrofuran. The solution was sonicated until homogenous and subjected to rotary evaporation to dryness. The crystal product was oven-dried for 3 hours to remove residual solvent and grinded to fine powder prior to analysis. The solid-state properties of cocrystal formers and resulting cocrystal were investigated by various characterization techniques, including differential scanning calorimetry (DSC) for thermal properties, powder X-ray diffraction (PXRD) for crystallinity and phase purity and Fourier transform infrared (FTIR) spectroscopy for intermolecular interactions. Powder dissolution testing was subsequently conducted to evaluate the dissolution behavior. Results: Phase-pure 1:1 ITZ-SUB cocrystal was readily produced by rotary evaporation. The formation of new solid phase was confirmed by the PXRD (Figure 1), DSC (Figure 2) and FTIR results. The ITZ-SUB cocrystal possessed a lower melting temperature (135.3 °C) than both of the parent materials ITZ (167.7 °C) and SUB (141.6 °). Meanwhile, it exhibited a much higher enthalpy changes of fusion (ΔHf = 89.05 kJ/mol) than ITZ (ΔHf = 76.70 kJ/mol) and SUB (ΔHf = 49.94 kJ/mol), suggesting the constitution of a stronger crystal lattice upon cocrystallization. FTIR spectra with a dramatic reduction in phenolic O-H stretching frequency on the other hand revealed the formation of strong intermolecular hydrogen bonds. Notably, a significant enhancement in the dissolution performance was observed in the cocrystal, with a 45-fold increase in percentage drug dissolved at 60 min as compared with pure ITZ (Figure 3). Conclusion: Rapid solvent removal via rotary evaporation appears to be a versatile and robust approach for fabricating elusive cocrystals, especially for those previously misjudged as unattainable owing to the presumably unfavorable lattice energy. The resulting high degree of supersaturation created throughout the process was necessary to promote the nucleation and growth of the itraconazole-suberic acid cocrystal since it provided sufficient driving force to overcome the kinetic energy barrier. Our study revealed the newly discovered ITZ-SUB cocrystal displayed markedly superior dissolution performance over the parent drug itraconazole. The knowledge obtained can therefore advance our current understandings in effective screening and production of elusive cocrystal formulations with improved pharmaceutical properties, ultimately setting the stage for rapid advances in personalized medicine. References 1. Chow, S.F., et al., Simultaneously improving the mechanical properties, dissolution performance, and hygroscopicity of ibuprofen and flurbiprofen by cocrystallization with nicotinamide. Pharm Res, 2012. 29(7): p. 1854-65. 2. Chow, S.F., et al., Kinetic entrapment of a hidden curcumin cocrystal with phloroglucinol. Crystal Growth & Design, 2014. 14(10): p. 5079-5089. 3. Shevchenko, A., et al., Diversity in itraconazole cocrystals with aliphatic dicarboxylic acids of varying chain length. Crystal Growth & Design, 2013. 13(11): p. 4877-4884. 4. Espinosa-Lara, J.C., et al., Cocrystals of Active Pharmaceutical Ingredients—Praziquantel in Combination with Oxalic, Malonic, Succinic, Maleic, Fumaric, Glutaric, Adipic, And Pimelic Acids. Crystal Growth & Design, 2012. 13(1): p. 169-185. 5. Sarceviča, I., A. Kons, and L. Orola, Isoniazid cocrystallisation with dicarboxylic acids: vapochemical, mechanochemical and thermal methods. CrystEngComm, 2016. 18(9): p. 1625-1635.