A New Thermodynamically Favored Flubendazole/Maleic Acid Binary Crystal Form: Structure, Energetics, and in Silico PBPK Model-Based Investigation

Abstract

The use of flubendazole (FBZ) in the treatment of lymphatic filariasis and onchocerciasis (two high incidence neglected tropical diseases) has been hampered by its poor aqueous solubility. A material consisting of binary flubendazole/maleic acid crystals (FBZ/MA), showing considerably improved solubility and dissolution rate relative to flubendazole alone, has been prepared in this work through solvent assisted mechanical grinding. The identification of FBZ/MA as a binary crystalline compound with salt character (proton transfer from MA to FBZ) relied on the combined results of powder X-ray diffraction, Raman spectroscopy, attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), thermogravimetry (TG), and differential scanning calorimetry (DSC). Isothermal solution microcalorimetry studies further suggested that the direct formation of FBZ/MA from its precursors in the solid state is thermodynamically favored. A comparison of the in silico pharmacokinetic performance of the FBZ/MA with that of pure FBZ based on a rat fasted physiology model indicated that the absorption rate, mean plasma peak concentration, and absorption extension of FBZ/MA were ∼2.6 times, ∼1.4 times, and 60% larger, respectively, than those of FBZ. The results here obtained therefore suggest that the new FBZ/MA salt has a considerable potential for the development of stable and affordable pharmaceutical formulations with improved dissolution and pharmacokinetic properties. Finally, powder X-ray diffraction studies also led to the first determination of the crystal structure of FBZ.

Novel pharmaceutical salts of albendazole

“…[18][19][20] Similarly, a flubendazole salt with maleic acid was published recently. 21 Even though there are related drugs listed in Scheme 1a from literature reports, the crystal structures of albendazole salts are new observations in present study.…”

First and Second Dissociation Enthalpies in Bi-Component Crystals Consisting of Maleic Acid and L-Phenylalanine

“…In the case of MA:Phe and MA:Phe 2 , reactions (2) and (3) can be written in a compact form as: MA:Phe b (cr) → MA(cr I) + b Phe(cr I) where cr I refers to the form I maleic acid or L-phenylalanine precursors used in this work, with b = 1 for reaction (2) and b = 2 for reaction (3). The standard molar enthalpy of reaction (4), , at 298.15 K, for MA:Phe and MA:Phe 2 was obtained from [ 27 , 31 ]: where , , and represent the standard molar enthalpies of the following processes, at 298.15 K, determined by solution calorimetry: MA:Pheb(cr) + n H 2 O(l) → [MA + bPhe + n H 2 O](aq) MA(cr I) + n H 2 O(l) → [MA + n H 2 O](aq) …”

“…However, in contrast with the large body of available structural information [ 28 ], studies where the thermodynamic stability of multi-component crystals has been quantitatively assessed in terms of enthalpy or Gibbs energy changes are scarce. Representative examples include systems such as the already mentioned hydroquinone:quinhydrone [ 29 ] and, more recently, celecoxib:nicotinamide [ 30 ], flubendazole:maleic acid [ 31 ], fumaric acid:glycine [ 27 ], maleic acid:glycine [ 27 ], sulfamethazine:salicylic acid [ 32 , 33 ], itraconazole:4-aminobenzoic acid [ 34 ], and itraconazole:4-hydroxybenzamide [ 34 ].…”

Prediction of solubility of two-component molecular crystals

“…If we analyze the studies on experimental determination of the formation enthalpies of co-crystals/salts, the average value that can be obtained is 10 kJ mol −1 . [13][14][15][16][17][18][19][20] Based on this, the sum of the melting enthalpies of the individual components (if we consider the stoichiometry of the co-crystal to be 1 : 1), taking into account (minus) 10 kJ mol −1 , can be used as the reference value of the co-crystal/salt melting enthalpies (for calculations). A few Fig.…”