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

The present work focused on the development of pharmaceutical cocrystal of ambrisentan (AMT) with low aqueous solubility 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 using a mechanochemical approach. The mechanistic understanding of cocrystallization has been elucidated and found that the mass transfer of mechanochemical reaction proceeds through a eutectic intermediate phase which is further converted into stable cocrystal. Besides, structural features of developed cocrystal suggest that the homomeric interaction in the drug molecule replaced by the heteromeric interaction between SA (free hydroxyl) and AMT (pyrimidine nitrogen) forming OH∙∙∙Narom supramolecular heterosynthon. Novel cocrystal reveals significant augmentation in aqueous solubility, dissolution rate and in-vivo pharmacokinetic parameters as compared to the pure drug. Improvement in the oral bioavailability of AMT in cocrystal was ascribed to the enhanced systemic absorption owing to its better solubility profile. Thus, the present work signifies the application of mechanochemistry as an efficient, greener and sustainable methodology to developing pharmaceutical cocrystal and subsequently improving the biopharmaceutical properties of the poorly soluble drug. Keywords: Biopharmaceutical properties; crystal engineering; cocrystallization; mechanochemical synthesis; Green Chemistry