Enhanced Solubility, Dissolution, and Permeability of Abacavir by Salt and Cocrystal Formation

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.

Extending the Range of Nitrofurantoin Solid Forms: Effect of Molecular and Crystal Structure on Formation Thermodynamics and Physicochemical Properties

“…In addition to solubility, coformer lipophilicity (or partition coefficient, log P ) is another crucial factor governing the membrane permeability of cocrystals. − NFT has a log P value of −0.7, which indicates the hydrophilic nature of the drug. It was therefore expected that the 2AmBZA and 2OHBZA coformers with higher log P values (0.5 and 1.4, respectively) in comparison to those of iNA (log P = −0.3) and PicAm (log P = 0), would improve the NFT diffusion behavior.…”

Crystalline salts of a diuretic drug torasemide with improved solubility and dissolution properties

“…The higher solubility and dissolution rates of the torasemide salts over those of the polymorphs may be attributed to ionic hydrogen bonds between the drug and coformer, strength and efficiency of the crystal packing, greater solute-solvent interactions (solvation/hydration energy) and influence of the coformer's solubility. 38,39,[77][78][79] The enhanced dissolution of crystalline salts could lead to higher bioavailability and shorter t max (time to reach maximum drug concentration) values. Suitable formulations may be optimized for crystalline salts for further enhancement in drug properties for applications in the development of faster dissolving tablets of torasemide 33,34 for quicker onset of diuretic action.…”

Synthesis of Ternary Cocrystals, Salts, and Hydrates of Acefylline with Enhanced Dissolution and High Permeability

“…Perlovich 53 built a database of cocrystals and the individual APIs and coformers based on their melting points and fusion enthalpy along with prediction of solubility based on the solubility of the individual components. Crystal engineering and heterosynthon-based strategies to improve solubility, 54−56 solubility and permeability, 57,58 and stability 59 in multicomponent cocrystals 60 continue to be reported for important API categories. 61 Acefylline (ACF) is one such API having poor aqueous solubility (1 mg/mL) and relatively low membrane permeability (log P −0.8 to −1.1) in the BCS class IV category, and its piperazine salt has a higher solubility of 14.7 mg/mL.…”

“…Perlovich built a database of cocrystals and the individual APIs and coformers based on their melting points and fusion enthalpy along with prediction of solubility based on the solubility of the individual components. Crystal engineering and heterosynthon-based strategies to improve solubility, − solubility and permeability, , and stability in multicomponent cocrystals continue to be reported for important API categories …”