Formulation of Liquid Propofol as a Cocrystalline Solid

Abstract

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.

High-Z′ structures of organic molecules: their diversity and organizing principles

“…In addition to THIOUR05 there is an intermediate phase for the sequence XOJYEC/01/02 (McKellar et al, 2014), with Z 0 changing from 2 to 6 and back to 2 as the temperature is lowered. Structure superpositions suggest that the Z 0 = 7 structure of o-chloranil (Rosokha et al, 2006) might be an intermediate phase, but there is no experimental evidence to support that conjecture.…”

Pharmaceutical cocrystals: A review of preparations, physicochemical properties and applications

“…For manufacturers, solid drug forms provide a convenient way to purify, identify, transport, and store drugs. For patients, solid forms are more convenient to carry and administer than liquid forms 87 . However, some drugs exist in a liquid state at room temperature due to their low melting points.…”

“…McKellar et al. 87 adopted cocrystal approach to obtain a novel solid form of propofol using isonicotinamide as the coformer ( Fig. 10 ).…”

Identifying and characterizing translationally modulated molecular crystal structures

“…In nine pairs the transition changes both the volume and the symmetry. In almost all cases, the higher-Z 0 structure was determined at a lower temperature than the lower-Z 0 structure but there are three well documented exceptions to that generalization [JAWQIH01/JAWQIH03 (Hao et al, 2005;Siegler et al, 2008), VIVSAV04/VIVSAV01 (Ś lepokura, 2016), and XOJYEC02/ XOJYEC01 (McKellar et al, 2014)]. More information about relationships between specific supercells and their basic cells is given in the supporting information.…”