Anion-switchable supramolecular gels for controlling pharmaceutical crystal growth

Abstract

The full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-pro t purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details. Gel media have been utilized for over a century for the growth of inorganic, organic and protein crystals. [1][2][3][4][5] The improved physical characteristics of the resulting crystals (better optical quality, larger size and fewer defects) are usually ascribed to the suppression of convection currents, sedimentation and nucleation afforded by the viscous gel environment. [6][7] In many instances the gel is thought to act as an inert matrix within which crystal growth occurs, however in some cases, the gel structure has been shown to influence the polymorphism, enantiomorphism and habit of crystals. 2 Occasionally gel fibres may become incorporated into the crystal, giving rise to composite materials. 8Conventional gels are formed using polymeric or clay-like materials such as gelatine, solubility were investigated to demonstrate their potential to act as crystallisation media for molecular organic compounds. Compounds 2, and 4 have been reported previously. [23][24] Novel compounds 1 and 3 were prepared by standard methods as detailed in the supplementary information. Gelators 1 -3 were chosen because they reliably form gels in a number of solvents ranging from aqueous systems to toluene. The fibrous nature of the gels is evidenced by SEM images of the dried xerogels ( Figure 1a,b). Compound 4 is a metallogelator which forms blue coloured gels with substoichiometric amounts of CuCl 2 in methanol:water. 23 Between them, these gelators can gel a range of solvents, at different temperatures (T gel ), and with a different critical gelator concentration (CGC). This class of compound has the potential to form the basis of a library of gelators which will allow the selection of gel properties and specific functionalities to match the compound and crystallisation conditions of interest. The synthetic versatility of these gelators could also in principle allow the incorporation of tailored heteronucleating functionality. While we focus upon bis(urea) compounds, the concepts outlined herein equally apply to any LMWG.Crystallisation experiments were undertaken using a range of organic compounds of both drug and non-drug species in parallel in both gel and solution media. We undertook an initial screen using candidate compounds 2-hydroxy benzyl alcohol (HBA, 5), Aspirin (ASP, 6), carbamazepine (CBZ, 7), 1-(3-methylsulfanyl-phenyl)-3-pyridin-2-yl-urea (SPU, 8) and 1,3-bis(m-nitrophenyl)urea (NPU, 9). We then carried out a detailed study on CBZwith all gelators, and a follow up study on gelator ...

Using gel morphology to control pore shape

“…The gelator was then removed by 30 washing the samples with hot methanol in a Soxhlet apparatus for up to three days. Removal of the gelator was confirmed by both chemical analysis which showed no nitrogen in the washed samples from either gelator or initiator, and by NMR spectroscopy of extracts from polymer samples immersed in DMSO-d 6 for 35 several hours which showed no signals corresponding to gelator.…”

“…The present study utilises two hexylene spaced bis-urea gelators functionalised with either alanine or phenylalanine derived end groups, namely 1 and 2 respectively (Scheme 1). 30,31 The compounds gel a variety of solvents including a 1:1 mixture of polymer precursor methyl methacrylate (MMA) and cross-linker 5 ethylene glycol dimethacrylate (EGDMA). Electron microscopy revealed that the mesoscopic morphology of the gels is different for the two compounds with xerogels of 2 showing small cylindrical fibres whilst 1 consists of two-dimensional ribbon-like structures ( Figure 1).…”

“…The soft structure of the gels can be 'fixed' in a variety of ways, for example by depositing an inorganic material on the inner or outer surface of the template, or by using LMWGs which can themselves be polymerised to give a rigid structure. 4,[9][10][11] LMWGs able to gel polymer precursors such as styrene or methyl 30 methacrylate which can subsequently be polymerised have also been used to give composite materials. 12,13 Such composites may show enhanced mechanical, 14, 15 fluorescence 13,16 or optical 17 properties compare to those of the pure polymer.…”

Supramolecular gel phase crystallization: orthogonal self-assembly under non-equilibrium conditions

“…47 A typical 50 procedure comprises warming a solution of gelator and drug substance in a compatible solvent to give a homogeneous solution and allowing the mixture to cool. The gelation and crystallization processes are orthogonal and generally time-resolved with gelation occurring over a period of minutes followed by 55 crystallization over a period of hours to days.…”

Metal ‘turn-off’, anion ‘turn-on’ gelation cascade in pyridinylmethyl ureas

“…13 In contrast, anions, particularly strong hydrogen bond acceptors such as chloride and acetate, tend to 'turn off' gelation by competitive hydrogen bonding to the urea NH groups. 19,20 Indeed reports of anion-promoted gelation are very rare. 21,22 We anticipate that changing from pyridyl ureas to simple pyridinylmethyl ureas (Scheme 1) should radically change the aggregation behaviour of the urea since the introduction of a methylene spacer between the urea and heterocycle means that the oxygen acceptor is no longer sterically hindered, hence markedly favouring urea···urea hydrogen bonding via the 2 1 (6) urea -tape motif.…”