Polymorphs, cocrystal and hydrate of nilutamide

Abstract

Nilutamide (Nil), commercialized under the trade names Nilandron and Anandron, is a nonsteroidal antiandrogen drug used in prostate cancer treatment. The attempts to cocrystallize nilutamide with adenine (Adn) and orotic acid monohydrate (OMH) resulted in the formation of four novel solid forms of the drug, namely the [Nil + Adn] (1 : 1) cocrystal, two new polymorphs of Nil (forms IV and V), and the Nil hydrate ([Nil·H₂O] (2 : 0.57)). The crystal structures of the solid forms were elucidated by single-crystal X-ray diffraction. New nilutamide polymorphic forms IV and V were found to contain multiple symmetry-independent molecules in the asymmetric unit whose Z′ = 3 (form IV) and Z′ = 2 (form V), while the three previously reported forms (form I, form II, form III) had Z′ = 1. Despite several attempts, the bulk phase-pure materials of form IV, form V, and [Nil·H₂O] (2 : 0.57) could not be attained due to the concomitant crystallization of the solid forms and the poor reproducibility of the crystallization trials. Hence, only limited characterization studies were performed on these phases. In this work, structural elucidation, Hirshfeld, and conformational analysis were explored to understand the similarities and dissimilarities in the crystal packing environment for all the crystal structures. Thermal analysis reveals the phase transformation of [Nil·H₂O] (2 : 0.57) to form II. Crystal structure analysis paved the way to understand the prominence of various intermolecular interactions along with the amide dimer and catemer formation. For the [Nil + Adn] (1 : 1) cocrystal, the thermodynamic solubility was evaluated using eutectic concentrations of the components and found to be higher than that of the parent Nil. The effect of hydroxypropyl methylcellulose on the dissolution behavior of the cocrystal was explored.