Temozolomide–Hesperetin Drug–Drug Cocrystal with Optimized Performance in Stability, Dissolution, and Tabletability

Abstract

A new 1:1 drug–drug cocrystal of temozolomide and hesperetin was successfully prepared by liquid-assisted grinding, slurry conversion crystallization, and evaporation crystallization. The obtained cocrystal was comprehensively characterized by single-crystal and powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis, as well as by Fourier transform infrared and nuclear magnetic resonance spectroscopy. The two drug molecules in the cocrystal are connected via O–H···O hydrogen bonds between the carbonyl oxygen of temozolomide and the phenolic hydroxyl group of hesperetin. The drug–drug cocrystal enhances the hydroscopic stability of hesperetin and the physicochemical stability of temozolomide. In addition, the cocrystal optimizes the dissolution behavior of temozolomide and hesperetin at pH 1.2 and pH 6.8 in comparison to the pristine drugs. Further, a compressibility assessment was also conducted, and the cocrystal exhibits a superior tabletability in comparison with temozolomide. Therefore, the drug–drug cocrystal has the potential to be developed as an efficient oral formulation of a drug combination which will overcome the weaknesses of each parent drug.

Crystal Structure, Solubility, and Pharmacokinetic Study on a Hesperetin Cocrystal with Piperine as Coformer

“…The cocrystals' structure including supramolecular synthons, crystal-packing details, and the location of hydrogen bonds in the supramolecular synthons can be obtained by vSCXRD analysis [23]. The crystallographic data and refinement details are depicted in Table 1.…”

“…However, the clinical development of HES is limited because of poor water solubility. Numerous HES cocrystals with picolinic acid (PICO), nicotinamide (NICO), caffeine (CAFF), and temozolomide (TMZ-HSP) have been reported, the first three cocrystals in aqueous buffer showed maximum concentration of HES to be nearly four to five times higher than the pure substance, and for TMZ-HSP, the maximum solubility of HES was significantly increased by 17.8 (at pH 1.2) and 26.3 (at pH 6.8) times [23,24]. The increase in solubility of the above HES cocrystals is due to the water-soluble coforms.…”

Compatibility of Drotaverine Hydrochloride with Ibuprofen and Ketoprofen Nonsteroidal Anti-Inflammatory Drugs Mixtures

“…An optimal formulation of this kind can be achieved by forming cocrystals or eutectic mixtures [ 1 , 2 ]. Pharmaceutical cocrystals may potentiate the physicochemical and mechanical properties of the substances [ 3 ], bioavailability [ 4 ], solubility [ 4 , 5 ] or stability [ 3 , 6 ] as well as in vivo activity [ 1 ], while a eutectic mixture behaves like a single pure substance having a melting temperature lower than that of the components which is correlated with increased bioavailability [ 7 ]. Usually, cocrystals are composed of an API and another substance whose role is to potentiate its properties called coformer, and are obtained by different techniques: (i) traditional, solvent evaporation, solvent reduced technique, or mechanochemical processing-solid state grinding, and (ii) advanced: microwave-assisted synthesis or supercritical fluid technology [ 2 , 8 ].…”

Cocrystallization of Febuxostat with Pyridine Coformers: Crystal Structural and Physicochemical Properties Analysis

“…Over the past decades, drug cocrystals and salts screening has been an important tool for optimizing the drug-forming properties [1][2][3][4][5][6][7][8]. Due to the diversity of cocrystal formers (CCFs), researchers can design drug cocrystal and salt forms in a targeted manner to optimize their solubility, mechanical properties, hygroscopicity, stability, and bioavailability [9][10][11][12][13][14]. However, due to the low success rate of the screening process, it remains a challenge to rationally assemble the structure of API molecules through hydrogen bonding to obtain the desired properties in drug crystal engineering.…”

“…e ΔpKa values between FEB and coformers are given in Table S1. For acid-base complex whose ΔpKa >3, the probability of salt formation will be high, and when 0 <ΔpKa <3, it is difficult to predict whether proton transfer will occur [14,25,26]. Whether the final product is a cocrystal or a salt will be disclosed by crystallographic data.…”