Interaction Map Driven Cocrystallization of Ambrisentan: Structural and Biopharmaceutical Evaluation

Abstract

The present work deals with the development of cocrystal of ambrisentan (AMT) to improve its biopharmaceutical profile. Full interaction maps (FIM) of AMT were explored to find out the potential sites for hydrogen bonding and prediction of supramolecular synthons. This information was further applied to the screening of amino acids as prospective coformers for cocrystallization of AMT. Mechanochemical reactions have resulted in two cocrystals with L-aspartic acid and glycylglycine (dipeptide). The crystal structural analysis revealed that the hydrogen-bonding pattern in the developed cocrystals corroborated well with the predicted supramolecular synthons. The developed cocrystals showed a remarkable improvement in solubility, intrinsic dissolution rate, and in vivo systemic absorption as compared to the parent drug. Complementarily, Hirshfeld surface maps together with crystal features established a good structural−performance correlation of the developed cocrystals. Thus, the systematic cocrystallization driven by structural informatics tools is valuable in the development of novel solid forms with improved biopharmaceutical attributes.

Pharmaceutical cocrystals: A review of preparations, physicochemical properties and applications

“…The cocrystal of AMT with glycylglycine (GG) is constructed by the supramolecular synthon networks, the carbonyl in AMT interact with OH acid groups of GG (C O···OH acid ) as well as OH acid of another AMT molecule, leading to the bifurcated C O···HO acid interactions. The cocrystal of AMT-GG shows 2.7-fold enhancement of C max (maximum plasma concentration) and nearly 2-fold increase in the value of AUC (area under plasma concentrations–time curve) in comparison with pure AMT 158 . Baicalein is a well-known flavonoid with various pharmacological activities, such as antibacterial, anti-inflammatory, antiadipogenic, anticancer, and anti-HIV activities 154 .…”

“…The cocrystal of APG and 4,4′-bipyridine yielded 3.9-fold higher bioavailability than the parent drug 157 . Another sample, ambrisentan (AMT), is an endothelin type A receptor blocker and is approved for the treatment of pulmonary arterial hypertension 158 . The poor water solubility (0.06 mg/mL) of AMT categorizes it as a compound of BCS class II 158 .…”

“…Another sample, ambrisentan (AMT), is an endothelin type A receptor blocker and is approved for the treatment of pulmonary arterial hypertension 158 . The poor water solubility (0.06 mg/mL) of AMT categorizes it as a compound of BCS class II 158 . The cocrystal of AMT with glycylglycine (GG) is constructed by the supramolecular synthon networks, the carbonyl in AMT interact with OH acid groups of GG (C O···OH acid ) as well as OH acid of another AMT molecule, leading to the bifurcated C O···HO acid interactions.…”

“… 158 studied the factor of cocrystal structure on influencing the release profiles of piperazine ferulate salt (PRZ‒FLA), which has been used for treating kidney diseases. However, the short plasma half-life of PRZ‒FLA render it difficult to achieve therapeutic plasma levels by the oral administration 158 . A ternary cocrystal (piperazine‒ferulate‒pyrazinamide, PRZ‒FLA‒PRA) was designed to achieve the sustained release of drugs 158 .…”

“…However, the short plasma half-life of PRZ‒FLA render it difficult to achieve therapeutic plasma levels by the oral administration 158 . A ternary cocrystal (piperazine‒ferulate‒pyrazinamide, PRZ‒FLA‒PRA) was designed to achieve the sustained release of drugs 158 . In the structure of PRZ‒FLA‒PRA cocrystal, the PRZ‒FLA connected with PRA dimers by the strong hydrogen bonding interactions to form a tight network ( Fig.…”