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Optimizing the Dissolution and Diffusion Characteristics of Ganciclovir through Salt Formation
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DOI：10.1021/acs.cgd.5c01509.png)
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Abstract
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Ganciclovir (GCV) is a guanine nucleoside analogue with potent activity against cytomegalovirus used in managing severe infections in immunocompromised patients. It is a biopharmaceutical classification system (BCS) class III medication, exhibiting high aqueous solubility but limited membrane permeability, which restricts its absorption in the intestinal membrane. This investigation aimed to identify biologically compatible salts of GCV to enhance its diffusion characteristics through salt formation with aliphatic dicarboxylic acids, namely, oxalic acid (OXA) and maleic acid (MLE). The synthesized organic salts were subjected to solid-state characterization, including powder X-ray diffraction (PXRD), differential scanning calorimetry, and thermogravimetric analysis, as well as Fourier-transform infrared spectroscopy. Rietveld refinement of the PXRD data provided detailed crystal structures, confirming proton transfer from the carboxylic acid groups of the coformers to the N3 atom of the imidazole ring within the guanine moiety of the drug. The GCV–MLE salt was obtained as an anhydrous form, whereas GCV–OXA crystallized as a sesquihydrated salt. Stability studies based on ground-state optimization energies indicated that GCV–OXA possessed superior stability compared with both GCV–MLE and the native drug. Consistently, both salt forms demonstrated notable physicochemical stability for more than one month under controlled conditions of 35 ± 5 °C and 75 ± 5% relative humidities. Evaluation of the solubility and diffusion of the salts, along with the marketed forms of GCV and GCV sodium salt in phosphate buffer (pH 6.8) revealed marked improvements, with aqueous solubility increasing by up to 2-fold and permeation flux enhanced by as much as 5-fold relative to the parent drug. These enhancements are ascribed to the ionic interactions between GCV and the respective salt former. Furthermore, the improved diffusion profiles of the GCV salts showed a positive correlation with their augmented solubility, elevated distribution coefficients, pronounced concentration gradients, and increased polarity conferred by the selected salt coformers.
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