Formulation of Liquid Propofol as a Cocrystalline Solid

This work details a crystal engineering strategy to obtain a novel solid form of the liquid drug molecule propofol using isonicotinamide as a cocrystal former. Knowledge of intermolecular hydrogen bonded supramolecular synthons has been exploited to select a potential cocrystal former based on the likely growth unit formed. The structure of the cocrystal, solved using single-crystal X-ray diffraction, is reported, confirming the molecular packing and key intermolecular interactions adopted in the novel solid form. The potential to enhance a drug’s properties is demonstrated by an increased melting point compared to the native drug form, such that the liquid drug becomes a stable solid at room temperature. Unusually, the propofol/isonicotinamide complex has three structurally similar, temperature-dependent polymorphs, and the crystal structure of each form is reported herein.本研究详述了一种晶体工程策略：以异烟酰胺（isonicotinamide）作为共晶形成剂，将液态药物分子丙泊酚（propofol）制备为新型固体形态。研究团队基于对分子间氢键超分子合成子（intermolecular hydrogen bonded supramolecular synthons）的认知，依据预期形成的生长基元筛选出了潜在共晶形成剂。本研究报道了通过单晶X射线衍射（single-crystal X-ray diffraction）解析得到的共晶晶体结构，证实了该新型固体形态中的分子堆积方式与关键分子间相互作用。相较于原料药原晶型，该共晶的熔点显著提升，可使原本为液态的丙泊酚在室温下成为稳定固体，从而证实了其改善药物属性的潜力。值得注意的是，丙泊酚/异烟酰胺复合物存在三种结构相似且具有温度依赖性的多晶型，本文报道了每种晶型的晶体结构。