Enhanced Solubility, Dissolution, and Permeability of Abacavir by Salt and Cocrystal Formation
Xu Ji, Di Wu, Chang Li, Jiulong Li, Qin Sun, Dewu Chang, Qiuxiang Yin, Lina Zhou, Chuang Xie, Junbo Gong, Wei Chen
Abstract
Abacavir (ABC) is a carbocyclic 2′-deoxyguanosine nucleoside reverse transcriptase inhibitor specifically prescribed for the treatment of HIV infection. However, as a BCS class III drug, the poor permeability seriously limits its absorption in the body. This study attempts to improve the permeability of ABC through the crystal engineering method of salt/cocrystal formation. Herein, four multicomponent crystals of ABC with dicarboxylic acids were prepared: namely, the salt ABC-oxalic acid (ABC-OXA) and the cocrystals ABC-glutaric acid (ABC-GLA), ABC-suberic acid (ABC-SUA), and ABC-azelaic acid (ABC-AZA). The salt/cocrystals were characterized by single-crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and Fourier transform infrared (FT-IR) spectroscopy. In comparison with ABC, the synthesized salt/cocrystals showed significant improvement in the aqueous solubility, dissolution rate, and permeability. In addition, a correlation of permeability revealed that the permeability of abacavir and its salt and cocrystals was mainly determined by the concentration gradient in the donor chamber and influenced by multiple factors, including the partition coefficient (lipophilicity). This study is another successful example of improving the solubility and permeability of drugs through crystal engineering of salt and cocrystal formation.