A zwitterionic salt–cocrystal: in vitro insights from niraparib tosylate, an anti-cancer drug

Abstract

Niraparib is an anti-cancer drug marketed as a tosylate monohydrate salt (brand name ZEJULA). Although it was approved by USFDA and the European Union in 2017, niraparib tosylate is known to exist in only three solid forms till today. Amongst the three, the monohydrate is a stable form and the other two (anhydrous and non-stoichiometric hydrate) forms are quite unstable. Despite niraparib's potential value as a cancer treatment drug, there are currently very limited or no scientific reports on its solid form landscape. In this regard, this molecule has been chosen as a potential candidate for our research to find alternative solid forms that suite the early entry opportunity in the US or other generic markets. In this study, we initially investigated the reasons for the unstable nature of niraparib tosylate polymorphs other than its monohydrate. Further, we successfully synthesized a novel multicomponent solid form of niraparib tosylate with L-proline (NIR·TOS·PRO). Interestingly, the new multi-component solid is a “zwitterionic salt–cocrystal”. To the best of our knowledge, this is the first case study reporting a zwitterionic salt–cocrystal. Preliminarily, the salt–cocrystal was characterized using powder X-ray diffraction and differential scanning calorimetry. Further, we carried out the structural elucidation for niraparib tosylate monohydrate as well as the new salt–cocrystal using single-crystal X-ray diffraction. The new salt–cocrystal was subjected to powder dissolution studies at pH 1.2, pH 4.5, and pH 6.8 to compare with the marketed form, “niraparib tosylate monohydrate (NIR·TOS·H₂O)”. Six-month stability studies were also performed according to the ICH guidelines. The solubility of NIR·TOS·PRO is found to be the same as that of the marketed form, which is an advantage in meeting the criteria of bioequivalence with RLD (reference listed drug), essentially to obtain the regulatory approval for US or other generic markets.