Sustainable synthesis of ambrisentan – syringic acid cocrystal: employing mechanochemistry in the development of novel pharmaceutical solid form

Abstract

The present work focuses on the development of a pharmaceutical cocrystal of ambrisentan (AMT), with low aqueous solubility, which can be used to treat pulmonary arterial hypertension. In this regard, a novel cocrystal of AMT with syringic acid (SA) was prepared based on crystal engineering principles via a mechanochemical approach. The mechanistic understanding of cocrystallization has been elucidated and found that the mass transfer of the mechanochemical reaction proceeds through a eutectic intermediate phase, which is further converted into a stable cocrystal. Besides, structural features of the developed cocrystal suggest that the homomeric interactions in the drug molecule was replaced by the heteromeric interactions between SA (free hydroxyl) and AMT (pyrimidine nitrogen), forming an OH⋯N_arom supramolecular heterosynthon. The novel cocrystal reveals significant augmentation in aqueous solubility, dissolution rate and in vivo pharmacokinetic parameters as compared to the pure drug. The improvement in the oral bioavailability of AMT in the cocrystal was ascribed to the enhanced systemic absorption owing to its better solubility profile. Thus, the present study signifies the application of mechanochemistry as an efficient, greener and sustainable methodology for developing pharmaceutical cocrystals and subsequently improving the biopharmaceutical properties of a poorly soluble drug.